Schizophrenia Research 145 (2013) 1017109
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`Contents lists available at SciVerse ScienceDirect
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`Schizophrenia Research
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`ELSEV l
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`ER
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`journal homepage: www.elsevier.com/locate/schres
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`Efficacy and safety of lurasidone 80 mg/day and 160 mg/day in the treatment ofA
`schizophrenia: A randomized, double—blind, placebo— and active—controlled trial“
`
`Antony Loebel a'b, Josephine Cucchiaro a"), Kaushik Sarma a"), Lei Xu 3'1), Chuanchieh Hsu a"), Amir H. Kalali 5,
`Andrei Pikalov a'b, Steven G. Potkin d’*
`a Sunovion Pharmaceuticals Inc, Marlborough, MA, USA
`b Surroviun Pharmaceuticals Inc, Fort Lee, NJ, USA
`C Quintiles Inc, and the University of California, San Diego, San Diego, CA, [IS/l
`d Department of Psychiatry and Human Behavior, University of California at Irvine, Irvine, CA, USA
`
`ARTICLE INFO
`
`ABSTRACT
`
`Keywords:
`Lurasidone
`Quetiapine XR
`Schizophrenia
`Antipsychotic agents
`Drug therapy
`Clinical trial
`
`Article history:
`Received 23 October 2012
`Received in revised form 9 January 2013
`Accepted 11 January 2013
`Available online 13 February 2013
`
`Objective: This study was designed to evaluate the short—term efficacy and safety of once—daily lurasidone
`(80 mg/day and 160 mg/day) in the treatment of an acute exacerbation of schizophrenia.
`Methods: Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation
`of psychotic symptoms, were randomly assigned to 6 weeks of fixededose, doublerblind treatment with
`lurasidone 80 mg (n:125), lurasidone 160 mg (n:121), quetiapine XR 600 mg (QXReGOO mg; n:119;
`active control included to test for assay sensitivity), or placebo (n : 121 ), all dosed once daily in the evening,
`Efficacy was evaluated using a mixedemodel repeatedemeasures analysis of the change from Baseline
`to Week 6 in Positive and Negative Syndrome Scale (PANSS) total score (the primary efficacy measure)
`and Clinical Global Impressions severity (CGIAS) score (the key secondary efficacy measure).
`Results: Treatment with both doses of lurasidone or with QXRrGOO mg was associated with significantly
`greater improvement at Week 6 on PANSS total score, PANSS positive and negative subscale scores, and
`CGI—S score compared with placebo. The endpoint responder rate (220% improvement in PANSS total
`score) was higher in subjects treated with lurasidone 80mg (65%; p<0.001), lurasidone 160 mg (79%;
`p<0.001), and QXR—BOO mg (79%; p<0.001) compared with placebo (41%). The proportion of patients
`experiencing 27% weight gain was 4% for each lurasidone group, 15% for the QXR—GOO mg group, and 3%
`for the placebo group. Endpoint changes in levels of cholesterol, triglycerides, and low—density lipoprotein
`(LDL) cholesterol were comparable for both lurasidone groups and placebo, while the QXR—GOO mg group
`showed a significant median increase compared with the placebo group in levels of cholesterol (p<0.001),
`LDL cholesterol (p<0.01), and triglycerides (p<0.05).
`Conclusions: Lurasidone 80 mg and 160 mg closes administered once—daily in the evening, were safe and
`effective treatments for subjects with acute schizophrenia, with increased response rates observed at the
`higher dose. Dose—related adverse effects were limited, and both doses were generally well—tolerated.
`
`© 2013 EISEVICI' B,V. Open access under CC BY-NC-NDliceuse
`
`1. Introduction
`
`Lurasidone hydrochloride (HCl) is a novel benzisothiazol deriva
`tive that has recently been approved by the FDA for the treatment of
`schizophrenia. Lurasidone has potent binding affinity for D2, 57HT2A
`and 5HT7 receptors (antagonist effect), moderate affinity for SHTlA
`
`*5 Previous presentations: Portions ofthis manuscript have been previously presented
`at the annual meeting of the American College of Neuroplrarnracology. Miami Beach. FL.
`Dec 5—9, 2010: and the 163m annual meeting of the American Psychiatric Association,
`Honolulu, HI, May 14—18, 2011.
`* Corresponding author at: Department of Psychiatry and Human Behavior, University
`of California, Irvine, 5251 Califomia Avenue, Suite 240, Irvine, CA 9261 7, USA. Tel.: + 1 949
`824 8040: fax: +1 949 824 3324.
`E—mail address: sgpotldn®uci.edu (5.6. Potkin).
`
`0920—9964 (E) 2013 EISEVier B.V. Open access under CC BY-NC-ND license.
`http://dx.doi.org/T0.10]6/j.schres.2013.0‘l.009
`
`(partial agonist effect) and agc receptors (antagonist effect), and no
`appreciable affinity for H1 and M1 receptors (lshibashi et al., 2010).
`The efficacy of lurasidone, in onceedaily closes ranging from 40
`to 120 mg, in the treatment of acute exacerbations of schizophrenia
`has been demonstrated in previous doublerblind, placeboecontrolled
`studies (Nakamura et al., 2009: Citrome, 2011: Meltzer et al., 2011:
`Ogasa et al., 2013). Since lurasidone doses above 120 mg/d have not
`been previously studied in any placebo—controlled clinical trial, it is
`unclear whether closes above 120 mg/d have utility in the treatment
`of schizophrenia.
`Empirically establishing the full therapeutic dosing range for new
`antipsychotic agents has proven to be challenging. Examination of
`atypical antipsychotic dosing patterns over time suggests that dose
`ranges ultimatelyjudged to be optimal in the “real world" may differ
`from initial recommendations based on the results of registration
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`102
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`A. Loebel etaL/ Schizophrenia Research 145 (2013) 1017109
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`trials (Citrome et al., 2005: Cutler et al., 2008: Kinon et al., 2008:
`Citrome et al., 2009). Although the specific reasons for such gradual
`evolution in dosage patterns are not clear, clinical trials may include
`subjects with somewhat less diagnostic heterogeneity, comorbidity
`and illness severity than patients encountered in clinical practice
`settings (Seeman. 2001). In addition. since D2 receptor occupancy
`rates show a significant degree of inter—individual variability at a
`given dose (Kapur et al., 2000; Mamo et al., 2004; Catafau et al.,
`2009). higher daily doses may be required in some patients to ensure
`that adequate steady—state plasma and CNS concentrations are reached.
`From a practical standpoint, dose escalation is one of the most fre—
`quently used treatment strategies for patients with more severe illness
`and those who do not respond to initial treatment at lower therapeutic
`doses (Kinon et al., 2004; Schwartz and Stahl. 2011).
`This is the first placeborcontrolled trial to evaluate the efficacy and
`safety of treatment with lurasidone 160 mg/d, a dose above the previ—
`ously established therapeutic range. The study utilized a fixed—dose
`design that included a lurasidone 80 mg arm (to permit assessment
`of dose—response effects) and a quetiapine XR arm (QXR—600 mg),
`to establish assay sensitivity.
`
`2. Methods
`
`This was a multiregional. prospective. parallelrgroup study in which
`subjects with a primary diagnosis of schizophrenia, who had been re—
`cently hospitalized for an acute exacerbation of psychotic symptoms,
`were randomly assigned to receive 6 weeks of doublerblind treatment
`with once—daily evening doses of lurasidone (80 mg, 160 mg). QXR
`(600 mg), or placebo. The study was conducted between October 21,
`2008, and June 2, 2010, enrolling a total of 486 subjects at 24 centers
`in the United States (n: 151 subjects), 10 centers in Russia (n : 87),
`10 centers in India (n=98), 9 centers in Ukraine (n: 75), 6 centers
`in Romania (n=49), and 4 centers in Colombia (n=26). Subjects
`who successfully completed this 6—week trial were eligible for enroll—
`ment in a 12—month double—blind extension study.
`All subjects who entered the trial reviewed and provided informed
`consent. The study protocol was approved by an independent ethics
`committee associated with each study center. The study was conducted
`in accordance with 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 safety and clinical outcome data at regular intervals
`during the study.
`
`2.1. Entry criteria
`
`Hospitalized male and female subjects 18775 years of age. inclusive,
`who met DSM—IV—TR criteria for a primary diagnosis of schizophrenia as
`determined by clinical interview using the Mini International Neuro—
`psychiatric Interview Plus (Sheehan et al., 1998) were enrolled. Subjects
`were also required to have an illness duration greater than 1 year with
`the current acute exacerbation of psychotic symptoms no longer than
`2 months and. at the Screening and Baseline visits, to have a Clinical
`Global Impression, Severity (CGI—S) score 24 (moderate 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 disorganization, hallucinations,
`unusual thought content, and suspiciousness.
`
`2.2. Study medication
`
`All study medication was identically overencapsulated to preserve
`the double—blind. After completing a Screening period (:14 days)
`during which they were tapered off psychotropic medication, sub—
`jects completed a 3— to 7—day placebo washout period. At Baseline
`(day 0), subjects were randomly assigned (in a 1:1:1:1 ratio) via an
`
`interactive voice response system to one of four treatment arms:
`lurasidone, 80 mg/day; lurasidone, 160 mg/day; QXR, 600 mg/day;
`or placebo. Study medication was administered in the evening with
`a meal or within 30 min after eating. Subjects assigned to lurasidone
`80 mg/day started treatment at their target dose. Subjects assigned to
`lurasidone 160 mg/day started treatment at a dose of 120 mg/day for
`2 days before being increased to their target dose. Subjects assigned
`to QXR 600 mg/day were started at a dose of 300 mg/day for 2 days
`before being increased to their target dose (consistent with manufac—
`turer recommendations). The QXR dosage of600 mg/day was selected
`because it has been established as an effective dose in the middle
`of the approved dosing range for the treatment of patients with
`schizophrenia (Seroquel XR USPI), and because there does not appear
`to be a significant efficacy advantage when using the highest approved
`800 mg dose (Kahn et al., 2007: Lindenmayer et al., 2011 : Zhornitsky
`et al., 2011).
`Subjects were eligible for hospital discharge after completing
`21 days ofdoublerblind treatment ifthey met specific clinical stability
`criteria.
`
`2.3. Assessments
`
`The screening evaluation consisted of the Mini International Neu—
`ropsychiatric Interview Plus (Sheehan et al., 1998), medical and psy
`chiatric histories, a physical examination, measurement of vital signs,
`ECG, and laboratory tests. Efficacy was assessed using the PANSS
`total and subscale scores (Kay et al., 1987; Marder et al., 1997). the
`CGI—S (Guy. 1976), the Montgomery—Asberg Depression Rating Scale
`(MADRS: Montgomery and Asberg. 1979), the Negative Symptom
`Assessment Scale (NSA716; Axelrod et al., 1993), an interviewer admin
`istered version of the Quality of Well—being Scale (QWB—SA; Kaplan
`et al., 1998): and the single—item, subject—rated Medication Satisfaction
`Questionnaire (MSQ; Vernon et al., 2010). The subjectrrated, 8ritem
`Epworth Sleepiness Scale was administered at Baseline, and Weeks 3
`and 6 to evaluate the level of daytime sleepiness.
`Safety evaluations included vital signs, weight. body mass index,
`waist circumference.
`laboratory tests (including lipids, glucose,
`glycosylated hemoglobin [HbA1c], insulin, and prolactin, C—reactive
`protein). 12—lead ECG, and subject—reported adverse events. Extrapy—
`ramidal symptoms were assessed with the Simpson—Angus Rating
`Scale (Simpson and Angus, 1970), the Barnes Rating Scale for Drug
`Induced Akathisia (Barnes. 1989), and the Abnormal Involuntary
`Movement Scale (Guy, 1976).
`The present study also included an assessment of the effects of
`treatment on cognitive function using a computerized cognitive bat—
`tery (CogState: Pietrzak et al., 2009). Cognitive assessment findings
`from this study will be reported elsewhere (Harvey et al., 2011).
`
`2.4. Statistical methods
`
`The study was powered at 97.5% to detect an 8—point difference
`with a pooled standard deviation of 19 between lurasidone and place—
`bo in Week 6 changerfromrbaseline in PANSS total scores and reject
`the null hypothesis of no difference from placebo in at least one
`lurasidone dose at an ot—level of 0.05 based on a 2—sided test.
`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 CGI—S score at Week 6. Both measures were
`evaluated by a mixed—model repeated—measures (MMRM) analysis with
`an unstructured covariance matrix, as used in a previously reported clini—
`cal trial (Meltzer et al., 2011). The p—values for the comparison of each
`lurasidone group with the placebo group at Week 6 on changes fi‘om
`Baseline in PANSS total score and in CGI—S score were adjusted for multi—
`ple comparisons using the Hommel—based tree—gatekeeping procedure.
`The QXR—6OO mg treatment group was compared with placebo using
`the same mixed—model repeated measures model, without adjustment
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`A. Loebel eta]. ,/ Schizophrenia Research 145 (2013) 1017109
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`103
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`for multiplicity for the comparison with placebo. A prespecified secondary
`analysis was also conducted for change in PANSS total score and CGl—S
`score at Week 6 LOCF endpoint, using an analysis of covariance
`(ANCOVA) model, with effects for Baseline score, pooled center. and
`treatment.
`The PANSS responder rates (defined a priori as 220% improve—
`ment in PANSS total score) were evaluated with logistic regression
`using responder outcome as the dependent variable, treatment as a
`categorical factor, and Baseline PANSS total score as a covariate,
`The PANSS subscores and symptom factor scores were evaluated
`using MMRM and a supportive ANCOVA. MADRS, N SA—1 6, and QWB—SA
`were evaluated using ANCOVA. There was no adjustment for multiplicity
`for these parameters.
`Significance testing of safety parameters was performed based on
`a nonparametric rank ANCOVA with Baseline value as a covariate, not
`adjusted for multiple comparisons.
`
`3. Results
`
`A total of 668 subjects were screened and entered the washout
`period, of whom 488 were randomly assigned to 6 weeks of double
`blind treatment (Fig. 1). Baseline demographic and clinical character—
`istics were comparable among the four treatment groups and similar
`to previously reported from other trials (Table 1). Greater than 70% of
`subjects completed study treatment in the lurasidone 80 mg (71.2%)
`and 160 mg groups (76.9%), and the QXR—600 mg group (80.8%),
`while a lower proportion ofsubjects in the placebo group completed
`treatment (60.7%; Fig. 1).
`
`3. 1 . Eflicacy
`
`Using a mixed—model repeated—measures analysis, LS mean change
`(SE) from Baseline to Week 6 in PANSS total score was found to be
`significantly greater for the lurasidone 80 mg (—22.2 [1.8]; adjusted
`p<0,001) and 160 mg (—26.5 [1.8]: adjusted p<0,001) groups com—
`pared with the placebo group (— 10.3 [1.8]) (Table 2). The LS mean
`change (SE) from Baseline to Week 6 in PANSS total score was also
`significantly greater for the QXR—600 mg group vs. placebo (—27.8
`[1.8], p<0.001), thus confirming the assay sensitivity of the study.
`LS mean change from Baseline in the PANSS total score was similar
`for lurasidone 160 mgvs, QXR—600 mg ( 7265 vs, 7278: unadjusted
`p=0.62; Bonferroni corrected p2 1.00), however. this change was
`
`Table 1
`Baseline characteristics of subjects randomized to treatment with lurasidone, quetiapine
`XR or placebo — safety population.
`
`Characteristic
`Treatment group
`Lurasidone
`Lurasidone Queu'apine
`Placebo
`80 mg/d
`160 mg/d
`XR 600 mg/d
`(N = 121)
`
`(N=125)
`(N=121)
`(N=119)
`n
`%
`N
`%
`n
`%
`n
`%
`
`Male
`96
`77
`82
`68
`77
`65
`77
`64
`Race
`56
`68
`58
`69
`52
`63
`60
`75
`White
`21
`25
`1G
`19
`24
`29
`18
`22
`Black
`20
`24
`22
`26
`21
`25
`19
`24
`Asian
`3
`4
`4
`5
`3
`4
`3
`4
`Other
`8
`10
`8
`10
`7
`8
`8
`10
`Ethnicity, Hispanic/Latino
`48
`58
`46
`55
`52
`63
`51
`Prior hospitalizations: 24 64
`
`
`SD Mean SD MeanMean SD Mean SD
`Age, years
`36.2
`10.9 37.9
`11.3
`37.4
`10.4 37.4
`10.8
`Age at onset of illness,
`24.6
`8.3
`25.7
`7.8 24.5
`8.6 25.5
`8.6
`years
`Duration of illness, years
`Duration of current
`episode. days
`10.2
`10.2 96.6
`11.8 97.7
`9.7 97.5
`97.7
`PANSS total score a
`0.5
`0.6
`4.9
`0.6
`4.9
`0.5
`5.0
`5.0
`CGl-severity a
`
`
`
`
`
`7.8 12.3 8.1 11.311.27.611.6MADRS total score a 6.7
`
`
`
`
`11.1
`31.3
`
`11.8
`9.2
`12.9 31.7
`
`12.4
`8.8
`12.7 31.5
`
`11.3
`10.4
`13.6 32.6
`
`9.3
`14.3
`
`a Data for these parameters are based on the intent—to—treat population.
`
`greater with QXR—600 mg compared with lurasidone 80 mg (—27.8
`vs. — 22,2: unadjusted for multiple comparisons, p = 0,028: Bonferroni
`corrected, p = 0.056).
`Statistically significant separation from placebo (—2.4 [05]) on
`the PANSS total score was observed by Day 4 in the lurasidone
`80 mg (—4.1 [0.5]: p=0.014) and 160 mg (—4.8 [0.5]: p<0.001)
`groups, and in the QXR—600 mg group (— 4.0 [0.5]; p : 0.028). Signif—
`icant separation from placebo was also observed at each subsequent
`assessment week for each of the three study treatments (Fig. 2).
`For the key secondary efficacy measure, the CGl—S, the LS mean
`change score from Baseline to Week 6 was significantly greater for
`both lurasidone treatment groups, and for QXR—600 mg. compared
`with the placebo group (Table 2).
`A pairwise comparison of improvement at Week 6 (using MMRM)
`found trend level differences in favor of the 160 mg dose compared
`
`Screened
`N=665
`
`_
`-
`Screen fllmus‘ “—180
`
`Llp io an day drug-tree screening perlod
`3-7 day single-blind. placebo washout
`Randomized 5‘ Baseline
`
`N=4BB
`
`Lnrasidone 30 mg
`Lurasidone IEll mg
`Queliapine XR sna mg
`
`
`N-125
`N-1 21
`N-120
`
`S—weeli Dfl treatment
`(eligibleror discharge from hospital after a weeks)
`
`S-week DB treatment
`$week DB treatment
`S-week 03 treatment
`[eligible for discharge lrorn hospital arteraweeks)
`(eligible for discharge tram hospital after aweeks)
`[eligible for niscnarge from nosprtat alter 3 weeks)
`
`
` Discontinued during DEI , N223 (23.1%) Discontinued during DB.N=23119.2%)
`
`Discontinued during DB . N343 (39.3%)
`Discontinued during DB . N=36 [23.8%]
`Insufficient response. N=26 (23 0%)
`insufficient response. N=16 (12 8%)
`lrfiufficiert response, N=12 (9 9%)
`Insufficient response. («i=0 (5 0%)
`
`Adverse events, N=S (4r %)
`Adverse events. N=S (4 0%)
`Adverse evenls, N=4 (3.3%;
`Adverse events N=4 (3.3%)
`Lost lo follow-up. N=0 (0%)
`Leslie iollow-up. N=1 (-3.6%)
`Losltofollow-up, N=1 (0.8%)
`Lost to follow-up, N=O (0%)
`Withdraw consent, N=12 :9 6%:
`Withdraw consent, N=14 (l1 5%)
`Wltndrew consent, N=§I (7 4%:
`Withdraw consent, N=13 (105%)
`
`other. N=2 (1.7%)
`Other. N=1 (0.8%)
`Other. N=2 (1.6%)
`Other. N=U (0%)
`
`Completed Study. “=93 (76.9%) Completed Study . N=97 ‘3".B%)
`
`Completed Sludy‘ N=B9 01.2%)
`
`Completed Study . N=74 30.7%)
`
`Fig. 1. Flow diagram and subjecL dispusiLiun.
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`A. Loebel etaL/ Schizophrenia Research 145 (2013) 1017109
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`Table 2
`Change from baseline to week 6 on efficacy measures for patients with schizophrenia in a randomized, double—blind, placebo— and quetiapine XR—controlled study of lurasidone —
`intent—to—treat population.
`
`Measure 3
`Treatment group
`Lurasidone 80 mg/(l
`Lurasidone 160 mg/d
`Quetiapine XR 600 mg/d
`Placebo (N =120)
`
`(N=125)
`(N=121)
`(N=116)
`Estimate
`SE
`Estimate
`SE
`Estimate
`SE
`Estimate
`SE
`
`PANss"
`1.8
`710.3
`1.8
`727.8M
`1.8
`7265”“
`1.8
`7222*”
`Total score change
`0.6
`— 3.9
`0.6
`— 9.7‘”
`0.6
`— 92*“
`0.6
`— 17*“
`Positive subscale score change
`0.5
`— 2.2
`0.4
`— 5.4“”
`0.4
`— 55*”
`0.4
`— 5.1 ***
`Negative subscale score change
`0.9
`— 5.0
`0.8
`—12.9***
`0.8
`712.3”:
`0.8
`7100*”
`General psychopathology subscale score change
`0.1
`7 0.9
`0.1
`7 1.7***
`0.1
`71.7‘”
`0.1
`71.5‘”
`CGl—chcrity score change b
`0.8
`— 3.4
`0.8
`— 8.6W
`0.8
`— 89*”
`0.8
`— 78*”
`NSA716 total score change C
`0.5
`— 1.0
`0.5
`— 4.3 M
`0.5
`744*“
`0.5
`740*“
`MADRS total score change C
`0.02
`+ 0.63
`0.02
`—— 0.71m
`0.02
`—— 0.71 m
`0.02
`—— 067*
`Quality of well—being (SA) ‘”
`
`
`0.2
`-l— 0.7
`0.2
`—— 1.8““
`0.2
`716*”
`0.1
`715*”
`Medication satisfaction questionnaire ‘
`
`*l‘<0.05: ‘*l‘<0.01: *“l‘<0.001.
`“ Endpoint change scores are shown for all measures except the QWB7SA PANSS: positive and negative symptom scale: CGI: clinical global impression scale: MADRS:
`Montgomery—Asberg Depression Rating Scale; NSA—16: Negative Symptom Assessment Scale.
`b p—values, comparing drug to placebo. are based on a repeated measures linear regression model of the change from Baseline score, with fixed effects for pooled center, visit as a
`categorical variable, Baseline score, treatment and treatment by visit interaction, assuming an unstructured covariance matrix.
`‘ p—values are based on an ANCOVA at Week 6 LOCF endpornt with treatment and pooled center as fixed factors and Baseline value as a covariate.
`
`with the 80 mg dose of lurasidone on the PANSS total score (p = 0.085)
`and the CGl—S score (p : 0.057). For LOCF—endpoint change in the
`PANSS total score, the Cohen's d effect size was 058 for lurasidone
`80 mg compared to 0.83 for lurasidone 160 mg; and for the C615
`score, the Cohen's cl effect size was 0.54 for lurasidone 80 mg compared
`to 0,8] for lurasidone 160 mg. The ANCOVA 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.
`Treatment with both doses of lurasidone and QXR—SOO mg were
`associated with significantly greater Week 6 improvement, compared
`with placebo, in the PAN SS positive and negative subscores (Table 2).
`Week 6 improvement in the NSA—16 scale was also significant for
`both doses of lurasidone and for QXR—SOO mg (Table 2) compared
`with placebo.
`The proportion ofresponders (220% improvement in PANSS total
`score from Baseline to LOCF—endpoint) was higher in subjects treated
`with lurasidone 80 mg (65%; p<0.001) and lurasidone 160 mg (79%:
`p<0.001) compared with subjects treated with placebo (41 %). The
`proportion of responders was also higher for QXR—6OO mg (79% vs.
`
`placebo, 41%; p<0.001). The responder rate was significantly higher
`for the 160 mg dose of lurasidone compared with the 80 mg dose
`(p=0.018), with an NNT of8 (95%—Cl, 5, 39).
`Treatment with both doses of lurasidone and QXR7600 mg were
`associated with significantly greater Week 6 improvement in depres—
`sive symptoms assessed using the MADRS compared with the placebo
`group (Table 2); and significantly greater improvement in both the
`quality of well—being self—assessment (QWB—SA) scale, and the medi—
`cation satisfaction questionnaire compared with the placebo group
`(MSQ; Table 2).
`
`3.2. Safety
`
`3.2.]. Body weight, body mass index (BMI), and waist circumference
`Treatment with lurasidone 80 mg was associated with a small
`but significant increase in weight and BMI when compared with pla—
`cebo, while changes in weight, BMI, and waist circumference were
`similar for the lurasidone 160 mg and placebo groups (Table 3),
`Clinically significant (27%) increase in weight was reported by a
`
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`Wk3
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`
`Wkfi
`
`
`
`
`
`LSmeanchangefrombaseline
`
`'3
`
`-3D
`
`+ Lurnsiduna an my ("=125]
`-fi- Lurasidone ISO mg (n=121)
`+ Quetiapine XR ano mg [ml 16)
`+ Placebo ("=12D]
`
`
`
`Fig. 2. Change from baseline in PANSS total score — mixed model repeated measurements analysis (MMRM. Intent—to—treat population). Is means and p—values were computed
`based on a repeated measures linear regression model of the change from Baseline score, with fixed effects for pooled center, visit as a categorical variable, baseline score, treatment
`and treatment by visit interaction. assuming an unstructured covariance matrix. Comparisons with placebo: a Day 4: p=0.014 for lurasrdone 80 mg: p<0.001 for lurasrdone
`160 mg: p=0.028 for quetiapine XK b Week 1: p<0.001 for lurasidone 80 mg and 160 mg. and for quetiapine XR. C Week 2: p<0.001 for lurasidone 80 mg and 160 mg. and
`for quetiapine XR d Week 3: p<0.001 for lurasidone 80 mg and 160 mg, and for quetiapine XK ‘3 Week 4: p<0.001 for lurasidone 80 mg and 160 mg, and for quetiapine XR.
`fWeek 5: p<0.001 for lurasidone 80 mg and 160 mg, and for quetiapine XR. g Week 6: p<0.001 for lurasidone 80 mg and 160 mg, and for quetiapine XR.
`
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`
`Table 3
`Effect of 6 weeks of treatment with lurasidone, quetiapine XR, or placebo on weight. body mass index, waist circumference, and laboratory test results (week 6 LOCF—endpoint
`analysis, safety population).a
`
`Measure
`Treatment group
`
`Lur’asidone 80 rug/d
`Lurasidone 160 rug/d
`Quetiapine XR 600 mg/d
`Placebo
`n
`Value
`n
`Value
`n
`Value
`n
`Value
`
`
`
`
`
`
`125
`116
`
`116
`
`125
`116
`
`125
`115
`125
`111
`125
`111
`125
`111
`125
`111
`125
`111
`
`125
`109
`120
`106
`125
`111
`
`76.1 (17.3)
`——0.6 (2.6)*
`
`5 (4.3)
`
`25.7 (4.95)
`——0.2 (0.85)‘
`
`
`
`88.3 (13.2)
`——0.9 (3.0)
`180.0
`—4.0
`107.0
`—3.0
`43.0
`0.0*
`106.0
`+2.0
`92.0
`—1.0
`
`5.4 (0.4)
`+0.1 (0.4)
`8.8
`—0.4
`7.5
`+0.8
`
`Weight, kg, mean (SD)
`Base me
`Ciange
`2 7% increase in weight. n (%)
`Wee(6
`Body mass index, kg/mz, mean (SD)
`Base inc
`Ciange
`Waist circumference, cm, mean (SD)
`Base ine
`Ciange
`Total c iolcstcrol. mg/dL median
`Base me
`Ciange
`LDL cholesterol. mg/dL, median
`Base ine
`C1ange
`HDL cholesterol. mg/dL median
`Base me
`C range
`Triglycerides (mg/d1.)
`Base ine
`Ciangc
`Glucose. mg/dL. median
`Base ine
`Ciange
`l-[bA1c mean % (SD)
`Base ine
`Ciange
`Insulin, mU/L, median
`Base ine
`Ciange
`Pro acti n, ng/mla median
`Base inc
`Ciange
`* p< 0.05; *= p<0.01; *** p< 0.001.
`Comparisons of the lurasidone and quetiapine XR groups vs. placebo at LOCF End Joint are based on a rank ANCOVA analysis. Significance testing was not performed for waist
`circumference, HhA1c, and insulin.
`“ I-le1c = glycated hemoglobin: LDL = low—density lipoprotcin: HDL = high-density lipoprotein.
`
`74.4 (17.2)
`——0.6 (3.1)
`
`5 (4.4)
`
`
`
`25.6 (4.85)
`——0.2 (1.0)
`
`87.0 (14.25)
`——1.3 (3.8)
`188.0
`—7.5
`112.0
`—4.0
`43.0
`0.0
`110.0
`+9.0
`90.0
`0.0
`
`5.5 (0.45)
`0.01 (0.28)
`9.0
`——0.5
`8.6
`——3.0***
`
`
`
`119
`111
`
`111
`
`119
`111
`
`119
`111
`119
`107
`119
`107
`119
`107
`119
`106
`119
`107
`
`119
`104
`116
`104
`119
`107
`
`72.1 (17.0)
`——2.1 (3.3)***
`
`17 (15.3)
`
`
`
`25.5 (5.2)
`——0.7 (1.1)***
`
`87.35 (14.5)
`——1.8(5.2)
`186.0
`—— 6.0M
`111.0
`"4.0“
`42.0
`00*
`115.0
`+8.0‘
`91.0
`+3.0
`
`5.5 {0.5)
`0.03 (0.31)
`8.7
`+0.4
`8.7
`—0.3
`
`121
`115
`
`115
`
`12
`115
`
`12
`115
`12
`11
`12
`11
`12
`11
`12
`11
`12
`110
`
`
`
`12
`108
`118
`109
`121
`111
`
`75.85 (16.3)
`——0.1 (2.5)
`
`3 (2.6)
`
`
`
`26.1 (4.8)
`——0.0 (0.8)
`
`88.4 (13.0)
`——0.2 (3.0)
`184.0
`—7.0
`111.0
`—3.0
`42.0
`—3.0
`102.0
`+9.0
`93.0
`0.0
`
`5.5 {0.4)
`0.01 (0.30)
`9.0
`—0.3
`10.1
`—0.8
`
`21
`13
`
`13
`
`2
`13
`
`2
`10
`2
`11
`
`14
`2
`11
`2
`11
`2
`12
`
`
`
`12
`1
`2
`11
`2
`11
`
`
`
`similar proportion of subjects in both the lurasidone 80 mg (11 : 5; 4%)
`and 160 mg (n: 5; 4%) groups, and the placebo group (n = 3: 3%). In
`contrast, there was a significant mean increase in the QXRrBOO mg
`group compared with the placebo group in both weight and BMI
`(Table 3), with 17 subjects (15%) having a clinically significant weight
`gain.
`
`3.2.2. Metabolic parameters
`Changes in lipid levels were comparable for both lurasidone dosage
`groups and the placebo group, while the QXR—GOO mg group showed
`a significant median increase compared with the placebo group in
`levels of cholesterol. LDL, and triglycerides (p<0.05. LOCFrendpoint:
`Table 3). Changes in glucose and insulin were also comparable for
`both lurasidone groups. and the QXR—EOO mg and placebo groups
`(Table 3). There were no clinically relevant changes in HbAlc values
`for any treatment group. and no endpoint differences for the lurasidone
`and QXR—GOO mg treatment groups compared with placebo,
`Categorical shifts from normal to high (abnormal) values for lipid
`and glucose parameters were as follows: total cholesterol (lurasidone
`80 mg, 7.2%: lurasidone 160 mg, 5.3%: QXR—SOO mg, 15.9%: placebo,
`6.3%), LDL cholesterol (lurasidone 80 mg, 7.2%; lurasidone 160 mg.
`6.1%; QXR—BOO mg, 15.0%: placebo, 4.5%), triglycerides (lurasidone
`80 mg, 2.7%: lurasidone 160 mg, 5.3%: QXR—SOO mg 10.4%: placebo,
`6.3%). glucose (lurasidone 80 mg. 15.3%; lurasidone 160 mg. 18.8%:
`QXR—BOO mg, 26.2%; placebo 18.2%; Supplementary Table 1).
`
`3.2.3. Prolactin and other laboratory values
`Median changes in prolactin levels at Week 6 (LOCF) were compa—
`rable for the lurasidone 80 mg, QXRrSOO mg and placebo groups, but
`were significantly higher for the lurasidone 160 mg group compared
`with placebo (Table 3), Additional gender—specific information on
`the effect of study treatment on prolactin is summarized in Supplee
`mentary Table 1. No other clinically relevant differences were noted
`for any other laboratory values when comparing either lurasidone
`treatment group to the placebo group.
`
`3.24. Physical examination and vital signs
`Orthostatic hypotension (systolic) occurred in 3 of 246 subjects
`(1.2%) in the combined lurasidone treatment groups. and in 4 of 17
`subjects (3.4%) in the QXR—BOO mg group: orthostatic tachycardia
`occurred in 7 of 246 subjects (2.8%) in the combined lurasidone treat—
`ment groups, and in 11 of 117 subjects (9.4%) in the QXR—SOO mg
`group. There were no other clinically significant treatment—emergent
`changes in either of the lurasidone groups, or the QXR—600 mg group.
`compared with the placebo group, in physical examination findings
`or vital signs,
`
`3.2.5. ECG
`Treatment with lurasidone was not associated with any treatment—
`emergent ECG abnormalities compared with placebo. The mean LOCF—
`endpoint increase in the Bazett—corrected QT interval (QTCB) and
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`
`the Fridericiaecorrected QT interval (QTcF). was 1.9 ms and 3.1 ms,
`respectively, in the lurasidone 80 mg group, 3.9 ms and 2.8 ms in
`the lurasidone 160 mg group, 10.4 ms and 3.0 ms in the quetiapine
`XR group. and 7.6 ms and 6.1 ms in the placebo group. There was
`no difference between the lurasidone 80 mg and 160 mg groups
`and the placebo group in the proportion of subjects with an in—
`crease from Baseline of 2301115 or 260 ms in QTc interval. either
`Ql‘cB or Ql‘cl-L No subject in any treatment group had a Ql‘c interval
`>500 ms.
`
`3.2.6. Extrapyramidal symptoms and akathisia
`The incidence of extrapyramidal—related adverse events was
`11.2% in the lurasidone 80 mg group. 13.2% in the lurasidone
`160 mg group, 5.9% in the QXR—SOO mg group, and 0.8% in the place—
`bo group (Supplementary Table 2). Parkinsonism was the most fre—
`quently reported EPSerelated event, reported by 5.6% of subjects
`in the lurasidone 80 mg group, 6.6% of subjects in the lurasidone
`160 mg group, 3.4% of subjects in the QXR—600 mg group, and no
`subjects in the placebo group. The incidence of akathisia was 8.0%
`in the lurasidone 80 mg group, 7.4% in the lurasidone 160 mg group,
`1.7% in the QXReBOO mg group, and 0.8% in the placebo group
`(Table 4). The effect of study treatment on movement disorder signs
`or symptoms, as measured by change in SAS, BAS, and AIMS scores,
`was generally absent to mild in subjects treated with lurasidone.
`
`There were relatively small LS mean (z: SE) changes at Week 6
`(LOCF) in the BAS total score and SAS mean scores, respectively, in
`
`
`subjects treated with lurasidone 80 mg (70.1 :: 0.1: 70.01::001)
`
`
`
`and 160 mg (+0.1 :01: 0.002001). QXR—600 mg (—0.2 ::0.1:
`
`
`
`— 0.05 :: 0.01), and placebo (
`0.1 __ 0.1:
`0.03 __ 0.01). Fewer than
`5% of lurasidoneetreated subjects showed a categorical shift at Week
`6 (LOCF) from absent/mild to moderate—to—severe symptoms in any
`BAS item. There were minimal—to—no changes from Baseline in the
`AIMS total score for any treatment group.
`The proportion of subjects receiving an as—needed anticholiner—
`gic medication was 16% in the lurasidone 80 mg group, 17% in the
`lurasidone 160 mg group, 9% in the QXR—600 mg group, and 0.8% in
`the placebo group.
`Discontinuations due to extrapyramidal adverse events occurred
`in 0.8% of subjects in the lurasidone 80 mg group, 0.8% in the
`lurasidone 160 mg group, 0.8% in the QXR—SOO mg group, and no sub—
`jects in the placebo group. Discontinuations due to akathisia occurred
`in 1.6% of subjects in the lurasidone 80 mg group, 0.8% in the lurasidone
`160 mg group, and in no subjects in the QXR—GOO mg and placebo
`groups.
`
`3.2.7. Epworth Sleepiness Scale (ESS)
`At Baseline, the LS mean (:: SE) ESS total scores were similar for
`
`
`the lurasidone 80 mg (6.1 :: 0.4) and 160 mg (6.3 :: 04) groups, the
`
`
`QXR7600 mg group (6.1 :: 0.4 , and the placebo group (6.4:: 0.4),
`indicating a slight chance of dozing or sleeping during daytime hours.
`At Week 6 (LOCF), treatment with lurasidone 80 mg and 160 mg, re—
`spectively was associated with a similar decrease (i.e., improvement)
`
`in LS mean (z: SE) ESS total scores compared to placebo (—1.1 :: 0.3
`
`and
`0.7 __ 0.3 vs.
`0.9 __ 0.3: p > 0.50 for both comparis