Larry Alphs 1*, Cynthia A Bossie 1, Jennifer K Sliwa 1, Yi-Wen Ma 2 and Norris Turner 1. Abstract

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1 PRIMARY RESEARCH Open Access Onset of efficcy with cute long-cting injectble pliperidone plmitte tretment in mrkedly to severely ill ptients with schizophreni: post hoc nlysis of rndomized, double-blind clinicl tril Lrry Alphs 1*, Cynthi A Bossie 1, Jennifer K Sliw 1, Yi-Wen M 2 nd Norris Turner 1 Abstrct Bckground: This post hoc nlysis (tril registrtion: CliniclTrils.gov NCT ) ssessed onset of efficcy nd tolerbility of cute tretment with once-monthly pliperidone plmitte (PP), long-cting typicl ntipsychotic initited by dy 1 nd dy 8 injections, in mrkedly to severely ill schizophreni popultion. Methods: Subjects entering the 13-week, double-blind tril were rndomized to PP (39, 156, or 234 mg [25, 100, nd 150 mg eq of pliperidone, respectively]) or plcebo. This subgroup nlysis included those with bseline Clinicl Globl Impressions-Severity (CGI-S) score indicting mrked to severe illness. PP subjects received 234-mg dy 1 injection (deltoid), followed by their ssigned dose on dy 8 nd monthly therefter (deltoid or glutel). Thus, dt for PP groups were pooled for dys 4 nd 8. Mesures included Positive nd Negtive Syndrome Scle (PANSS), CGI-S, Personl nd Socil Performnce (PSP), nd dverse events (AEs). Anlysis of covrince (ANCOVA) nd lst-observtion-crried-forwrd (LOCF) methodologies, without multiplicity djustments, were used to ssess chnges in continuous mesures. Onset of efficcy ws defined s the first time point tretment group showed significnt PANSS improvement (ssessed dys 4, 8, 22, 36, 64, nd 92) versus plcebo, which ws mintined through end point. Results: A totl of 312 subjects met inclusion criterion for this subgroup nlysis. After the dy 1 injection, men PANSS totl scores improved significntly with PP (ll received 234 mg) versus plcebo t dy 4 (P = 0.012) nd dy 8 (P = 0.007). After the dy 8 injection, significnt PANSS improvement persisted t ll subsequent time points in the 234-mg group versus plcebo (P < 0.05). PANSS improvements were greter from dy 36 through end point in the 156-mg group (P < 0.05) nd only t end point in the 39-mg group (P < 0.05). CGI-S nd PSP scores improved significntly in the 234-mg nd 156-mg PP groups versus plcebo t end point (P < 0.05 for both, respectively); improvement in the 39-mg group ws not significnt. The most common AEs for PP-treted subjects ( 10%, ny tretment group) were hedche, insomni, schizophreni excerbtion, injection site pin, nd gittion. Conclusions: In this mrkedly to severely ill popultion, cute tretment with 234 mg PP improved psychotic symptoms compred with plcebo by dy 4. After subsequent injections, observed improvements re suggestive of dose-dependent effect. No unexpected tolerbility findings were noted. * Correspondence: llphs@its.jnj.com 1 Ortho-McNeil Jnssen Scientific Affirs, LLC, Titusville, NJ, USA Full list of uthor informtion is vilble t the end of the rticle 2011 Alphs et l; licensee BioMed Centrl Ltd. This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution License ( which permits unrestricted use, distribution, nd reproduction in ny medium, provided the originl work is properly cited.

2 Pge 2 of 10 Bckground Rpid symptom control in ptients with schizophreni represents n immedite tretment gol, prticulrly for those who re mrkedly or severely ill, becuse cute symptoms re ssocited with emotionl distress, disruptions to the ptient s life, nd the risk of dngerous behviors [1]. Knowing when to expect response with given ntipsychotic is n importnt clinicl considertion in mnging these ptients. Current dt suggest tht, lthough it my tke severl weeks to chieve full therpeutic effect with n ntipsychotic, most of the improvement in psychotic symptoms is often seen within 2 weeks, with n onset of ction within the first few dys [2-4]. It hs lso been reported tht erly ntipsychotic response my be indictive of subsequent response in ptients with schizophreni [5]. Achieving n dequte response cn be hindered by non-dherence to the tretment regimen, significnt problem in mnging ptients with schizophreni [6-8]. Non-dherence within the first dys of tretment, which hs been reported in nerly one-qurter of ptients [9], cn impede the onset of efficcy. The use of long-cting injectble ntipsychotics obvites the need to tke dily mediction nd my help to improve dherence [1,10]. Reports indicte tht long-cting injectble ntipsychotics differ with respect to their onset of ction. Although it is difficult to compre onset dt cross studies for the vrious gents becuse of the vstly different study designs nd popultions, there re reports tht suggest efficcy cn occur s erly s within the first few dys of tretment [11-14]. Pliperidone plmitte is the plmitte ester of pliperidone [15]. This typicl ntipsychotic is NnoCrystl ( suspension of pliperidone plmitte in n queous formultion, which is given once monthly by injection (deltoid or glutel) fter recommended initition regimen of 234 mg on dy 1 nd 156 mg on dy 8 (both dministered in the deltoid) [15,16]. This formultion ws designed to rpidly ttin therpeutic blood levels [15]. Severl controlled clinicl studies hve confirmed tht pliperidone plmitte is effective in controlling symptoms [17-19] nd delys time to relpse in ptients with schizophreni [20] without the use of orl ntipsychotic supplementtion. This post hoc nlysis evluted the onset of efficcy of cute tretment with pliperidone plmitte nd dose effect in mrkedly to severely ill subjects with schizophreni over 13 weeks of tretment. Tolerbility mesures lso were evluted. Methods This ws post hoc nlysis of 13-week, rndomized, double-blind, plcebo-controlled, multicenter study of three pliperidone plmitte fixed doses in subjects with schizophreni (CliniclTrils.gov: NCT ; study ID: CRO12550). Methods for the overll study hve previously been reported in detil [19]. The overll study ws conducted in ccordnce with the ethicl principles tht hve their origin in the Declrtion of Helsinki nd tht re consistent with good clinicl prctice nd pplicble regultory requirements. The originl study protocol ws reviewed nd pproved by n independent ethics committee or n institutionl review bord t ech study site, nd ll subjects provided written informed consent before entering the study. Subjects Subjects who were t lest 18 yers of ge were eligible for study enrollment if they hd dignosis of schizophreni per the Dignostic nd Sttisticl Mnul of Mentl Disorders, 4th edition (DSM-IV) [21],estblishedtlest 1 yer before screening, nd if they hd Positive nd Negtive Syndrome Scle (PANSS) [22] totl score of t lest 70 t screening nd between 60 nd 120, inclusive, t bseline [19]. The criterion for inclusion in this subgroup nlysis ws Clinicl Globl Impressions-Severity (CGI- S) [23] score 5 t bseline (mrkedly to severely ill). Study mediction In this report, dosing of pliperidone plmitte is expressed s milligrms. Pliperidone plmitte dosing lso my be expressed s milligrm equivlents (mg eq) of pliperidone. Pliperidone plmitte doses of 39, 78, 117, 156, nd 234 mg re equivlent to 25, 50, 75, 100, nd 150 mg eq of pliperidone, respectively [15]. Study design nd rndomiztion Thereweretwostudyperiods:screeningperiodofup to 7 dys for wshout of disllowed psychotropic medictions nd 13-week double-blind, fixed-dose tretment period. Subjects were rndomly ssigned (on 1:1:1:1 bsis) to fixed doses of pliperidone plmitte (39, 156, or 234 mg) or plcebo. On dy 1 of the study, ll subjects received deltoid injection of pliperidone plmitte 234 mg or mtching plcebo. Subjects were required to remin on their previous ntipsychotic mediction until the dy before the first injection of pliperidone plmitte or plcebo. On dy 8 nd monthly therefter on dys 36 nd 64, subjects received their ssigned tretment per the rndomiztion schedule, injected inthedeltoidorglutel muscle t the investigtor s discretion. Orl ntipsychotic supplementtion ws not permitted. Inptient hospitliztion Subjects could be voluntrily hospitlized during the screening period t the investigtor s discretion. Subjects were required to be hospitlized from the dy of the

3 Pge 3 of 10 first injection on dy 1 until t lest fter the second injection of the study drug on dy 8. Study ssessments The primry efficcy mesure ws the chnge in the PANSS [22] totl score from bseline to ech time point (dys 4, 8, 22, 36, 64, nd 92) nd end point. Onset of efficcy ws defined s the first time point t which given tretment group showed significnt PANSS improvement over plcebo nd mintined significnt improvement until end point. Other mesures were chnges in CGI-S [23] nd Personl nd Socil Performnce (PSP) [24] scores from bseline to end point. Sfety ssessments included the recording nd monitoring of tretment-emergent dverse events (AEs) nd lbortory tests. Additionlly, subjects were ssessed for movement disorders with the Simpson- Angus Scle (SAS) [25], Brnes Akthisi Rting Scle (BARS) [26], nd Abnorml Involuntry Movement Scle (AIMS) [27]. Anlysis set In this post hoc nlysis, ll efficcy nd sfety nlyses were performed on the intent-to-tret (ITT) nlysis set, which included ll rndomized subjects who received t lest one dose of double-blind study mediction nd hd both bseline nd t lest one post-bseline efficcy ssessment. Sttisticl nlysis Anlyses compred the three pliperidone plmitte groups (note tht per the study design the pliperidone plmitte groups were pooled for dys 4 nd 8) with the plcebo group t bseline t ech time point (including end point), using the ITT nlysis set. Men (SD), medin, minimum, nd mximum were used for summry of continuous vribles; percentge nd frequency were used for ctegoricl vribles. Between-tretment-group differences in continuous vribles were evluted using n nlysis of covrince (ANCOVA) model, with tretment nd country s fctors nd bseline score s covrite. Chnges from bseline re presented s lestsqures (LS) mens nd stndrd errors (SEs). Chnge from bseline in PANSS totl score ws further evluted for ll subjects using mixed model with time, country, tretment, nd tretment-by-time interction s fctors nd bseline vlue s covrite. An unstructured vrince-covrince mtrix ws employed for this nlysis. Between-tretment-group differences in benzodizepine use nd response rtes were evluted using the Cochrn-Mntel-Henszel test, controlling for country. LS men chnges from bseline to end point nd their 95% confidence intervls for effect sizes of tretment versus plcebo were clculted using Cohen s d methodology, nd between-group differences were evluted using the ANCOVA model described bove. All sttisticl tests were two sided, nd no djustments were mde for multiplicity. Lst-observtion-crried-forwrd (LOCF) methodology ws used. Results Bseline demogrphic nd clinicl chrcteristics Of the 652 subjects in the originl study, 312 (47.9%) hd mrked to severe bseline illness s defined by the CGI-S scle. Among these subjects, 88.1% hd CGI-S rtings of mrked illness nd 11.9% hd severe illness. Bseline demogrphic nd clinicl chrcteristics ppered similr between the three pliperidone plmitte groups nd the plcebo group (Tble 1). With the exception of the PANSS totl score nd bseline CGI-S score, bseline demogrphics nd clinicl chrcteristics were similr to those of the overll study popultion. The men (SD) PANSS totl score t bseline ws 87.1 (11.2) for the overll popultion versus 94.7 (8.9) for the mrkedly to severely ill popultion. Subject disposition Completion rtes were 38.6% of the plcebo group nd 48.6%, 50.0%, nd 50.6% of the 39-mg, 156-mg, nd 234-mg pliperidone plmitte groups, respectively (Tble 1). The most common resons for tretment discontinution were lck of efficcy in the plcebo (28.9%), pliperidone plmitte 39-mg (22.2%), nd pliperidone plmitte 156-mg (19.4%) groups nd withdrwl of consent in the pliperidone plmitte 234-mg group (24.7%). Benzodizepine use Proportions of subjects who used benzodizepines during the study were 63.9% in the plcebo group nd 69.4%, 66.7%, nd 64.7% in the pliperidone plmitte 39-mg, 156-mg, nd 234-mg groups, respectively. No significnt differences were observed between the tretment groups versus plcebo in benzodizepine use. Efficcy After the dy 1 injection, LS men PANSS totl scores improved significntly with pliperidone plmitte (ll received 234 mg) versus plcebo t dy 4 (P = 0.012) nd dy 8 (P = 0.007) (Figure 1). After the dy 8 injection of the ssigned dose, significnt PANSS improvement ws seen t ll subsequent time points in the 234-mg group versus plcebo (P < 0.05). PANSS improvement versus plcebo ws greter from dy 36 through end point in the 156-mg group (P < 0.05) nd only t end point in the 39-mg group (P < 0.05) (Tble 2). LS men (SE) CGI-S nd PSP scores improved significntly by dy 36 (-1.4 [0.2] nd 14.4 [1.9], respectively)

4 Pge 4 of 10 Tble 1 Bseline demogrphic nd clinicl chrcteristics Bseline demogrphics/ptient chrcteristics Plcebo, n=83 Pliperidone plmitte 234/39 mg, n = /156 mg, n = /234 mg, n = 85 Age in yers, men (SD) 40.3 (11.2) 40.1 (10.2) 38.4 (10.6) 39.0 (11.0) Sex, n (%) Mle 56 (67.5) 50 (69.4) 47 (65.3) 60 (70.6) Femle 27 (32.5) 22 (30.6) 25 (34.7) 25 (29.4) Rce, n (%) Cucsin 39 (47.0) 40 (55.6) 35 (48.6) 40 (47.1) Africn Americn 36 (43.4) 24 (33.3) 26 (36.1) 35 (41.2) Asin 8 (9.6) 5 (6.9) 10 (13.9) 6 (7.1) Other 0 (0) 3 (4.2) 1 (1.4) 4 (4.7) Age t dignosis in yers, men (SD) 24.9 (8.1) 24.2 (6.8) 25.8 (8.7) 24.3 (8.0) Bseline PANSS totl score, men (SD) 92.6 (9.2) 95.8 (8.9) 94.5 (7.9) 96.0 (9.2) Bseline CGI-S score, n (%) Mrked (= 5) 73 (88.0) 60 (83.3) 68 (94.4) 74 (87.1) Severe ( 6) 10 (12.1) 12 (16.7) 4 (5.6) 11 (12.9) Prior hospitliztion for psychosis, n (%) None 5 (6.0) 5 (6.9) 6 (8.3) 7 (8.2) 1 19 (22.9) 10 (13.9) 9 (12.5) 11 (12.9) 2 16 (19.3) 13 (18.1) 18 (25.0) 17 (20.0) 3 9 (10.8) 12 (16.7) 13 (18.1) 12 (14.1) 4 34 (41.0) 32 (44.4) 26 (36.1) 38 (44.7) Disposition Completed, n (%) 32 (38.6) 35 (48.6) 36 (50.0) 43 (50.6) Discontinued, n (%) 51 (61.5) 37 (51.4) 36 (50.0) 42 (49.4) Resons for discontinution Lck of efficcy 24 (28.9) 16 (22.2) 14 (19.4) 14 (16.5) Withdrew consent 14 (16.9) 10 (13.9) 11 (15.3) 21 (24.7) Adverse event 7 (8.4) 6 (8.3) 7 (9.7) 5 (5.9) Lost to follow-up 4 (4.8) 5 (6.9) 3 (4.2) 1 (1.2) Other 2 (2.4) 0 (0) 1 (1.4) 1 (1.2) Ech pliperidone plmitte subject received 234 mg of pliperidone plmitte on dy 1 nd then their ssigned dose dy 8 nd monthly therefter. CGI-S = Clinicl Globl Impression-Severity scle; PANSS = Positive nd Negtive Syndrome Scle. in the 234-mg pliperidone plmitte group (P <0.05) versus plcebo. LS men (SE) CGI-S scores were improved significntly t dy 36 nd t end point, nd LS men (SE) PSP scores improved significntly t end point for the 156-mg pliperidone plmitte group versus plcebo (P < 0.05). Improvement in CGI-S nd PSP scores in the 39-mg group did not rech significnce t ny time point. Corresponding effect sizes for pliperidone plmitte versus plcebo t end point for the PANSS (Figure 2), CGI-S (Figure 3), nd PSP (Figure 4) showed similr results. Results were similr using the mixed-model repeted mesures nlysis of the PANSS totl score (overll LS men (SE) tretment difference versus plcebo: 39-mg tretment group -4.0 (1.9), P = 0.034; 156-mg tretment group, -6.5 (1.9), P < 0.001; 234-mg tretment group, -6.4 (1.8), P < 0.001). The percentge of subjects who chieved response t end point ws 15.7% in the plcebo group nd 36.1% (P = versus plcebo), 34.7% (P = 0.026), nd 41.2% (P < 0.001) for the 39-mg, 156- mg, nd 234-mg pliperidone plmitte groups, respectively. Sfety Reported AEs, discontinutions due to AEs, nd extrpyrmidl symptom (EPS)-relted AEs re shown in Tble 3. The most common AEs in pliperidone plmitte-treted subjects ( 10% in ny tretment group) were hedche, insomni, schizophreni excerbtion, injection site pin, nd gittion.

5 Pge 5 of 10 0 Dy 4 Dy 8 Dy 22 Dy 36 Dy 64 End point LS Men (SE) Chnge From Bseline , b Plcebo Pliperidone Plmitte: 234/39 mg Pliperidone Plmitte: 234/156 mg Pliperidone Plmitte: 234/234 mg 25, b, b, c b c P < 0.05, 234-mg pliperidone plmitte versus plcebo. P < 0.05, 156-mg pliperidone plmitte versus plcebo. P < 0.05, 39-mg pliperidone plmitte versus plcebo. Figure 1 Lest-squres (LS) men Positive nd Negtive Syndrome Scle (PANSS) totl score chnge from bseline for the pliperidone plmitte dose groups versus plcebo group (lst-observtion-crried-forwrd [LOCF] nlysis). All pliperidone plmittetreted subjects received pliperidone plmitte 234 mg on dy 1 nd then received their ssigned tretment on dys 8, 36, nd 64. SE = stndrd error. Men SAS, BARS, nd AIMS scores were low ( 1) in ll groups t bseline nd end point. No significnt differences for pliperidone plmitte groups versus plcebo were observed in the men chnge from bseline to end point score for these movement disorder rting scles. The LS men (SE) weight chnge (kg) from bseline to end point ws 0.4 (0.7) in the plcebo group versus 0.7 (0.6) in the pliperidone plmitte 39-mg group (P = 0.652), 0.8 (0.7) in the 156-mg group (P = 0.513), nd 1.1 (0.7) in the 234-mg group (P = 0.269). No significnt between-group differences were observed for the chnge from bseline to end point in triglyceride, high-density lipoprotein, or low-density lipoprotein levels for pliperidone plmitte versus plcebo. Smll but significnt differences were observed in LS men (SE) chnge from bseline to end point in plsm glucose levels (mmol/l) between plcebo (-0.31 [0.17]) nd the 39-mg (0.05 [0.16]; P = 0.033) nd 156-mg (0.02 [0.16]; P = 0.049) pliperidone plmitte dose groups; the difference between the plcebo group nd the 234-mg pliperidone plmitte group ws not significnt (-0.13 [0.2]; P = 0.253). Prolctin levels incresed significntly with pliperidone plmitte versus plcebo in mles nd femles in ll dose groups (P 0.001, Tble 4). In the mrkedly to severely ill popultion, one subject in the pliperidone plmitte 39-mg group hd n AE potentilly relted to prolctin (ejcultion disorder).

6 Pge 6 of 10 Tble 2 Efficcy ssessments from bseline to end point (LOCF nlysis) Plcebo, n = 83 Pliperidone plmitte Efficcy mesure 234/39 mg, n = /156 mg, n = /234 mg, n = 85 PANSS totl score Bseline, men (SD) 92.6 (9.2) 95.8 (8.9) 94.5 (7.9) 96.0 (9.2) LS men (SE) chnge from bseline -9.8 (2.8) (2.7) (2.8) (2.8) P vlue for LS men (vs plcebo) <0.001 CGI-S score Bseline, men (SD) 5.1 (0.3) 5.2 (0.4) 5.1 (0.2) 5.1 (0.3) LS men (SE) chnge from bseline -0.9 (0.2) -1.1 (0.2) -1.3 (0.2) -1.5 (0.2) P vlue for LS men (vs plcebo) PSP score Bseline, men (SD) 42.9 (10.1) 41.3 (10.4) 44.7 (11.5) 41.0 (10.1) LS men (SE) chnge from bseline 10.3 (2.2) 11.5 (2.1) 15.1 (2.2) 17.7 (2.2) P vlue for LS men (vs plcebo) Ech pliperidone plmitte subject received 234 mg of pliperidone plmitte on dy 1 nd then their ssigned dose dy 8 nd monthly therefter. CGI-S = Clinicl Globl Impression-Severity scle; LOCF = lst-observtion-crried-forwrd; LS = lest-squres; PANSS = Positive nd Negtive Syndrome Scle; PSP = Personl nd Socil Performnce. Discussion This subgroup nlysis of ptients with moderte to severe schizophreni showed tht cute tretment with long-cting pliperidone plmitte, compred with plcebo, improved symptoms s erly s dy 4 (the first post-bseline time point), with improvement continuing t dy 8. Thus, these findings support rpid symptom control fter dy 1 deltoid injection of pliperidone plmitte 234 mg in these ptients. The demonstrted onset of response within week of inititing tretment with long-cting pliperidone plmitte is consistent with tht documented with number of other 234/234 mg 0.64 (95% CI: 0.33, 0.95) 0.55 (95% CI: 0.33, 0.77) 234/156 mg 0.53 (95% CI: 0.21, 0.85) 0.49 (95% CI: 0.27, 0.71) 234/39 mg 0.33 (95% CI: 0.01, 0.66) b 0.28 (95% CI: 0.06, 0.50) b Effect Size Mrkedly to Severely Ill Overll Popultion P 0.001, versus plcebo. b P < 0.05, versus plcebo. Figure 2 Effect size for chnge from bseline to end point on Positive nd Negtive Syndrome Scle (PANSS) totl score for mrkedly to severely ill subjects nd overll study popultion. CI = confidence intervl.

7 Pge 7 of /234 mg 0.57 (95% CI: 0.27, 0.88) 0.50 (95% CI: 0.29, 0.72) 234/156 mg 0.37 (95% CI: 0.05, 0.69) b 0.35 (95% CI: 0.13, 0.57) b 234/39 mg 0.14 (95% CI: 0.18, 0.47) 0.14 (95% CI: 0.08, 0.37) Effect Size Mrkedly to Severely Ill Overll Popultion P 0.001, versus plcebo. b P < 0.05, versus plcebo. Figure 3 Effect size for chnge from bseline to end point on Clinicl Globl Impressions-Severity (CGI-S) score for mrkedly to severely ill subjects nd overll study popultion. CI = confidence intervl. ntipsychotics, including orl gents [2,3,11,13,28-30]. Of note, orl ntipsychotic supplementtion ws not permitted in this pliperidone plmitte tril. Thus, improvement cnnot be ttributed to dditive effects with other drugs. After the injections of pliperidone plmitte 234, 156, or 39 mg t dy 8 nd monthly therefter, dt t the subsequent time points suggested dose-dependent response in this more severely ill subpopultion. This conclusion is supported by improvements in symptomtology (PANSS totl scores) t ech time point, s well s with mesures of clinicl sttus (CGI-S) nd functioning (PSP) t end point. The 234-mg group showed the most robust effect in this subgroup by ll mesures (Figures 1, 2, 3, nd 4), lthough the 156-mg group showed substntil nd sttisticlly significnt improvement by these mesures (except for non-significnt improvement versus plcebo on PANSS totl chnge on dy 22). In contrst, the 39-mg group did not show significnt improvement compred with plcebo except t end point on PANSS totl score. Further, the CGI-S nd PSP improvements t this lowest dose never reched sttisticl significnce compred with plcebo. It is relevnt to note here tht the pliperidone plmitte initition regimen used in this study differed somewht from the recommended regimen of deltoid injections with 234 mg on dy 1 nd 156 mg on dy 8 [16]. Thus, the dy 8 injections in the glutel muscle (versus deltoid), with 39 mg (lower thn the recommended dy 8 dose of 156 mg), my hve resulted in prticulrly low pliperidone plmitte blood levels [15] nd my hve contributed to some of the observed results. Nevertheless, it is not unresonble to find tht higher doses my be needed in mny modertely to severely ill ptients nd they should be considered when mnging such ptients. The dose-dependent trend in improvements observed in this subgroup ws similr to tht observed in the overll study popultion, lthough it ppered to be consistently more robust in this mrkedly to severely ill subgroup. This trend ws observed for improvements in the PANSS, CGI-S, nd PSP scores (Figures 2, 3, nd 4), s well s in discontinution rtes for lck of efficcy. This finding my be expected with n efficcious tretment in ptients who re prticulrly ill or symptomtic nd thus hve more room for improvement (tht is,

8 Pge 8 of /234 mg 0.56 (95% CI: 0.87, 0.25) 0.47 (95% CI: 0.69, 0.25) 234/156 mg 0.36 (95% CI: 0.69, 0.04) b 0.33 (95% CI: 0.55, 0.11) b 234/39 mg 0.09 (95% CI: 0.42, 0.24) 0.08 (95% CI: 0.30, 0.15) Mrkedly to Severely Ill Overll Popultion P 0.001, versus plcebo. b P < 0.05, versus plcebo. Figure 4 Effect size for chnge from bseline to end point on Personl nd Socil Performnce (PSP) score for mrkedly to severely ill subjects nd overll study popultion. CI = confidence intervl. Tble 3 Tretment-emergent dverse events (AEs) Adverse events, n (%) Plcebo, n = 83 Pliperidone plmitte 234/39 mg, n = /156 mg, n = /234 mg, n = 85 Ptients with 1 AE 57 (68.7) 49 (68.1) 53 (73.6) 55 (64.7) Discontinution due to AEs 7 (8.4) 6 (8.3) 7 (9.7) 5 (5.9) Most common AEs* Insomni 13 (15.7) 8 (11.1) 5 (6.9) 10 (11.8) Hedche 7 (8.4) 11 (15.3) 9 (12.5) 6 (7.1) Schizophreni excerbtion 8 (9.6) 6 (8.3) 10 (13.9) 4 (4.7) Injection site pin 5 (6.0) 10 (13.9) 2 (2.8) 7 (8.2) Anxiety 6 (7.2) 3 (4.2) 5 (6.9) 7 (8.2) Agittion 8 (9.6) 8 (11.1) 2 (2.8) 2 (2.4) Akthisi 5 (6.0) 1 (1.4) 5 (6.9) 5 (5.9) Psychotic disorder 6 (7.2) 3 (4.2) 4 (5.6) 2 (2.4) Dizziness 1 (1.2) 1 (1.4) 5 (6.9) 3 (3.5) Upper respirtory trct infection 1 (1.2) 0 1 (1.4) 5 (5.9) Constiption 3 (3.6) 2 (2.8) 4 (5.6) 0 Ptients with 1 EPS-relted AE 7 (8.4) 5 (6.9) 9 (12.5) 10 (11.8) Ech pliperidone plmitte subject received 234 mg of pliperidone plmitte on dy 1 nd then their ssigned dose dy 8 nd monthly therefter. *Defined s 5% in ny one group. EPS = extrpyrmidl symptom.

9 Pge 9 of 10 Tble 4 Lest-squres (LS) men (SE) chnge from bseline in prolctin levels (ng/ml) t end point Vrible Plcebo, n = 83 Pliperidone plmitte 234/39 mg, n = /156 mg, n = /234 mg, n = 85 Mles n Bseline, men (SD) 31.7 (21.1) 28.7 (21.2) 30.2 (25.2) 28.4 (19.0) LS men (SE) chnge from bseline (4.1) 1.3 (3.9) 0.6 (4.1) 2.6 (3.9) P vlue for LS men (vs plcebo) <0.001 <0.001 <0.001 Femles n Bseline, men (SD) 81.8 (50.9) 76.2 (53.0) 85.7 (56.3) 80.0 (67.8) LS men (SE) chnge from bseline (17.1) 17.8 (16.3) 17.8 (16.8) 42.9 (17.9) P vlue for LS men (vs plcebo) <0.001 <0.001 Ech pliperidone plmitte subject received 234 mg of pliperidone plmitte on dy 1 nd then their ssigned dose dy 8 nd monthly therefter. regression to the men phenomenon). Of note, lthough the mrkedly to severely ill subjects in this report were symptomtic subgroup, on verge they were not resistnt one. Tolerbility findings in this subgroup did not suggest tht AEs were generlly more common with the highest dose of 234 mg. However, dt were consistent with dose-dependent trend for nxiety nd upper respirtory trct infection. Also, EPS-relted AE rtes werethelowestt39mgndcomprblet156mg nd 234 mg. In the mrkedly to severely ill subgroup, there ws trend for dose-dependent increse in weight, with men increse of 1.1 (0.7) kg in the highest dose group t end point (P = vs plcebo). The incidence of EPS-relted AEs nd chnges in weight were similr to those of the overll study popultion [16]. Consistent with the known phrmcology of pliperidone, men prolctin levels incresed from bseline to end point in the mrkedly to severely ill popultion, with greter increse observed in women. The incidence of AEs potentilly relted to prolctin in this subpopultion ws low ( 1%) nd similr to tht observed in the overll study popultion [19] nd in other clinicl trils of pliperidone plmitte [17,18,31]. Thus, no unexpected tolerbility findings were noted in this subgroup nlysis overll. This post hoc nlysis ws performed with dt from tril tht ws not specificlly designed to study mrkedly to severely ill subjects. In the originl tril, study inclusion criteri for symptomtology required only tht subjects hve PANSS scores of t lest 70 t screening nd 60 to 120 t bseline. Nonetheless, 48% of subjects met our subgroup criterion for t lest mrked illness t entry, providing sufficient smple for study. However, dt were not vilble to demonstrte how long subjects were t this level of illness severity. Also, most of the subjects in this nlysis were rted s mrkedly ill, nd s such, these dt my not generlize to those with more severe illness. Of note, within this subgroup of mrkedly to severely ill subjects, 49% to 62% of ech tretment group discontinued before completion of the 13-week study period. The rtes in the overll popultion were 46% to 57%, respectively [19]. Although such premture discontinution rtes re not unexpected in trils of schizophreni, this must be considered when interpreting results. Conclusions In this post hoc nlysis of 13-week study, cute tretment with pliperidone plmitte initited t 234 mg, without orl ntipsychotic supplementtion, improved symptoms (s determined by PANSS score) compred with plcebo by dy 4 in mrkedly to severely ill ptients with schizophreni. After the subsequent dy 8 nd monthly injections of 39, 156, or 234 mg, improvements in symptomtology, clinicl sttus, nd functioning exhibited dose-dependent trend, with the lest robust effect t 39 mg, significnt improvements t 156 mg, nd the most robust effect t 234 mg. No unexpected tolerbility findings were noted. These findings suggest tht cute tretment with pliperidone plmitte is n effective nd tolerted tretment option for mrkedly to severely ill ptients with schizophreni nd provide dosing dt tht cn help guide clinicins when mnging these ptients. Acknowledgements This reserch nd mnuscript were funded by Ortho-McNeil Jnssen Scientific Affirs, LLC, Titusville, NJ, USA. The uthors wish to thnk J Thoms Hskins, PhD (employee of Johnson & Johnson Phrmceuticl Reserch nd Development, LLC), for his involvement in the erly stges of dt nlysis nd dissemintion. The uthors lso wish to thnk Mtthew Grzywcz, PhD, Mrguerite York, PhD, nd ApotheCom for providing writing, editoril, nd technicl ssistnce. This work ws previously presented t the 163rd Annul Meeting of the Americn Psychitric Assocition, My 22-26, 2010, New Orlens, Louisin, USA, nd t the Collegium Interntionle Neuro-

10 Pge 10 of 10 Psychophrmcologicum Biennil Interntionl Congress, June 6-10, 2010, Hong Kong, Chin. Author detils 1 Ortho-McNeil Jnssen Scientific Affirs, LLC, Titusville, NJ, USA. 2 Johnson & Johnson Phrmceuticl Reserch nd Development, LLC, Titusville, NJ, USA. Authors contributions LA, CAB, JKS, nd NT prticipted in the design of this subnlysis. Y-WM performed the sttisticl nlyses. All uthors (LA, CAB, JKS, Y-WM, nd NT) were involved in developing the drfts of the mnuscript, prticipted in its subsequent revisions, nd red nd pproved the finl mnuscript. Competing interests LA, CAB, JKS, nd NT re employees of Ortho-McNeil Jnssen Scientific Affirs, LLC, nd Johnson & Johnson stockholders. Y-WM is n employee of Johnson & Johnson Phrmceuticl Reserch nd Development, LLC, nd Johnson & Johnson stockholder. Received: 21 December 2010 Accepted: 11 April 2011 Published: 11 April 2011 References 1. 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