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0300-7995 doi:10.1185/03007995.2014.898630
2014, 1–11
Article ST-0339.R1/898630 All rights reserved: reproduction in whole or part not permitted
Original article Clinical effectiveness and resource utilization of paliperidone ER for schizophrenia: Pharmacoepidemiologic International Longitudinal Antipsychotic Registry (PILAR)
A. Schreiner L. Hargarter Janssen EMEA, Neuss, Germany
K. Hitschfield Praxis Dr Hitschfeld Facharzt fu¨r Psychiatrie und Psychotherapie, Hamburg, Germany
J.I. Lee Seoul National Hospital, Seoul, Korea
I. Lenskaya Republic Centre of Psychiatry, Almaty City, Kazakhstan
A.H. Sulaiman Department of Psychological Medicine, University of Malaya, Kuala Lumpur, Malaysia
J. Diels Janssen EMEA Market Access, Beerse, Belgium
on behalf of the PILAR study group Address for correspondence: A. Schreiner, Department of Medical and Scientific Affairs, Janssen Europe, Middle East and Africa, Johnson & Johnson Platz 1, 41470 Neuss, Germany. Tel.: +49 1735131062; [email protected] Keywords: Effectiveness – Oral antipsychotics – Paliperidone ER – Schizophrenia Accepted: 24 February 2014; published online: 19 March 2014 Citation: Curr Med Res Opin 2014; 1–11
Abstract Objective: To document prescribing patterns in clinical practice and assess long-term outcomes related to initiation of paliperidone ER and other oral antipsychotics among patients with schizophrenia in a naturalistic setting. Research design and methods: An international, non-interventional, naturalistic study of adult patients (18 years) with schizophrenia. Patients were assigned to the relevant treatment group (paliperidone ER or ‘all other oral antipsychotics’) after switching to, or initiating, oral antipsychotic treatment. Retrospective 12 month data collection was followed by 12 month prospective data collection, with 3-monthly assessments. The primary endpoint was time to all-cause discontinuation of new medication. Secondary endpoints included Clinical Global Impression–Severity (CGI-S) score, Clinical Global Impression–Schizophrenia (CGI-SCH) score, Personal and Social Performance (PSP) score, health-related quality of life (HR-QoL) and quality of sleep, evaluation of healthcare resource utilization and patient’s treatment satisfaction. Results: A total of 4051 patients were included in the intent-to-treat (ITT) analysis set. All-cause study discontinuation rates were comparable between the paliperidone ER group (16.8%) and the ‘all other oral antipsychotics’ group (15.5%). There was no difference in the time to discontinuation of newly initiated antipsychotic treatments between paliperidone ER and ‘all other oral antipsychotics’ groups. Paliperidone ER was associated with greater improvements from baseline to endpoint in both the PSP scale score (þ14.2 vs þ13.1, p ¼ 0.041) and the physical component of quality of life (SF-12 Physical scores; þ3.9 vs þ2.9, p ¼ 0.003) compared to ‘all other oral antipsychotics’. Improvements in mean CGI-S score, CGI-SCH score, HR-QoL, quality of sleep and daytime drowsiness, as well as patients’ treatment satisfaction were comparable between treatment groups. The incidence of adverse events was comparable between groups. Conclusions: This study provides valuable data on the prescribing habits and treatment outcomes associated with use of paliperidone ER in everyday clinical practice, and supports previous findings of the favorable functional improvement and treatment satisfaction associated with paliperidone ER. Clinical trial registration: NCT00696813; R076477SCH4015 (Register of German Association of Research-based Pharmaceutical Companies [VFA] http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb).
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Introduction Schizophrenia is a chronic, severe disorder1 with a significant social and economic impact not only on patients, but on their families, friends, and the wider community2,3. It is characterized by a variety of clinical manifestations including positive, negative and affective symptoms, cognitive impairment and reduced social and occupational functioning4. The relatively early age of onset, progression and chronicity of the disease and its impact on patient functioning imposes a high economic burden on society, which means it can account for between 1.5% and 3% of total healthcare costs5. Of these costs, hospitalization for schizophrenia is a large contributor to the burden on healthcare systems, whereas the cost of pharmacotherapy makes a relatively small contribution5. Treatment goals in schizophrenia include controlling both positive and negative symptoms, preventing the recurrence of psychotic episodes, improving the patient’s functioning and quality of life, which can involve improving both physical and mental health, and facilitating social and vocational reintegration6. Pharmacological therapy is used in the treatment of the majority of patients with schizophrenia. While second-generation antipsychotics (SGAs) offer some particular advantages over firstgeneration antipsychotics (FGAs), there is room for further advances in treatment effectiveness from new treatment options, as has been indicated in studies such as the CATIE7 and CUtLASS8 trials. Once daily, oral paliperidone extended-release (ER) has been approved for the treatment of schizophrenia by the European Medicines Agency and the US Food and Drug Administration9,10. The majority of trials of paliperidone ER conducted thus far have been randomized, controlled, short in duration (6 weeks)11–13, and have studied the effects of fixed doses in selected, largely homogeneous groups of patients. The beneficial effect of paliperidone ER on symptoms (as demonstrated by decreases in Positive and Negative Syndrome Scale [PANSS] total scores and Clinical Global Impression–Severity [CGI-S] scale scores), on patient functioning (as demonstrated by significant improvements in Personal and Social Performance [PSP] scale scores)11–13, and on relapse prevention14 has been established. Onset of efficacy was observed as early as Day 4 of treatment15. A recent single-arm study in adults hospitalized with an acute exacerbation of schizophrenia showed that flexibly dosed paliperidone ER (3–12 mg/day for 6 weeks) was associated with a clinically meaningful treatment response16. Early onset of effect was also confirmed, with significant improvement from baseline observed as early as Day 2. There remains a need to understand prescribing patterns relating to the use of paliperidone ER and other oral antipsychotics in a naturalistic setting, and how these practices relate to healthcare costs and resource 2
Clinical effectiveness of paliperidone ER Schreiner et al.
utilization. The Pharmacoepidemiologic International Longitudinal Antipsychotic Registry (PILAR) was an observational study intended to document prescribing patterns prospectively in daily clinical practice and to assess long-term outcomes related to initiation of oral antipsychotic treatment in a naturalistic setting.
Methods Objectives The overall study objective was to document prescribing patterns in daily clinical practice and assess long-term treatment outcomes related to initiation of treatment with oral antipsychotics in a naturalistic setting. An additional objective of the study was to collect data retrospectively, which allowed the evaluation of treatment outcomes before and after treatment initiation with paliperidone ER or other oral antipsychotics.
Study population Patients meeting selection criteria were men and women 18 years of age with an established diagnosis of schizophrenia, who had recently been switched (2 weeks prior to enrolment) to, or started on, paliperidone ER or another oral FGA or SGA. Participants were able to provide written informed consent and to fill out self-administered questionnaires. Treatment decisions were made by the treating physician prior to, and independently of, the study, following routine clinical practice and local prescribing information. Patients with established treatment-resistant schizophrenia, who had not responded to an adequate treatment trial with more than two SGAs and/or clozapine, or those with a history of neuroleptic malignant syndrome, were not eligible for documentation in this study. There were no restrictions regarding inpatient or outpatient populations.
Study design The PILAR study was an international, non-interventional, naturalistic study on the use of paliperidone ER and other newly or recently initiated oral antipsychotic treatments, documenting 44000 patients from Canada, Europe and Asia between 2007 and 2011. The study consisted of two components: one conducted locally in Germany (R076477SCH4015, Register of German Association of Research-based Pharmaceutical Companies (VFA) http://www.vfa.de/de/arzneimittelforschung/datenbanken-zu-arzneimitteln/nisdb), and an international component conducted in 12 countries across Canada, Europe and Asia (NCT00696813). Data from these studies were collected in a single database www.cmrojournal.com ! 2014 Informa UK Ltd
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and this article presents key findings from the pooled results. Patients were enrolled and assigned to the relevant treatment group after switching to, or initiating, a new oral antipsychotic treatment. The study design then consisted of two parts: (1) retrospective data collection using a 12 month chart review covering the period up to and including the day before baseline, and (2) 12 months of prospective data collection, for which patients were scheduled for 3-monthly assessments (including both clinician-administered evaluations and patient self-reported assessments). Patients were considered to have completed the study if all assessments within the 12 month prospective data collection period had been documented. Discontinuation of an antipsychotic medication during this period did not imply withdrawal from the study (dropout was defined as a patient whose documentation ended before all the 12 month prospective data had been collected). Physicians were advised that all treatments and dose adjustments should be based on approved local labels, and that management decisions should be made at the physician’s discretion, using clinical judgment and routine practice. No study drug was provided: patients received medication according to their usual care.
Data collection Electronic data capture was used and the majority of the data transcribed by the study investigators from the source documents onto the electronic case report form (CRF) and then transmitted in a secure manner to the sponsor.
Study endpoints/assessments The primary effectiveness endpoint was time to all-cause discontinuation of new medication in the paliperidone ER group compared with the ‘all other oral antipsychotics’ group. The following parameters were also assessed: time to first post-baseline hospitalization, overall severity of symptoms and clinical deterioration of psychiatric condition (as measured by Clinical Global Impression– Schizophrenia [CGI-SCH] and Severity [CGI-S] scale scores), personal and social functioning (as measured by PSP scale scores), health-related quality of life and quality of sleep (using a quality of life questionnaire, the Short Form-12 item health survey [SF-12], and quality of sleep visual analogue scales [VAS]), evaluation of healthcare resource utilization, and patient’s treatment satisfaction (determined using a categorical question at baseline and endpoint). Additional patient characteristics documented at baseline included psychiatric history and diagnosis, the reason ! 2014 Informa UK Ltd www.cmrojournal.com
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for switching to the new antipsychotic, the patient’s current antipsychotic and any other concomitant medication or substance abuse. The retrospective chart review and prospective followups collected data on antipsychotic medication history, adverse and serious adverse drug reactions (ADRs and SADRs), and history of healthcare resource utilization (hospitalizations, emergency room and outpatient visits). In addition, throughout the prospective period the following were also documented: antipsychotic treatment, concomitant medications, substance abuse, psychiatric symptoms, level of functioning and adverse and serious adverse events (AEs and SAEs).
Statistical analyses Approximately 787 patients (528 in the paliperidone ER arm and 259 in the ‘all other oral antipsychotics’ treatment arm) were needed to detect, with 80% power and a significance at alpha ¼ 0.05, a between-group difference in all-cause discontinuation of 10%. Repeated measures (assessments by time interval) were analyzed as follows: observed cases, endpoint analysis, mixed model (Repeated Measures Mixed Model [RMMM]). Analyses were adjusted for baseline differences in patient demographics, and all statistical tests were performed at the 5% significance level (two-tailed tests). Kaplan–Meier plots and a log-rank test were used to evaluate time to treatment discontinuation. A Cox proportional hazard model with covariate adjustment was also performed to adjust for differences between groups at baseline in age and gender, body mass index (BMI), reason for initiation of antipsychotic treatment, number of psychiatric hospitalizations in the retrospective period, substance abuse at baseline, and baseline values for CGI, PSP and SF-12. Kaplan–Meier plots, a log-rank test and Cox regression were used to evaluate time to first post-baseline hospitalization. For patients who were in hospital at baseline, time to hospitalization was defined as the number of days between discharge of the ongoing hospitalization and the first post-baseline admission (patients without hospitalization were censored at the last follow-up date). Frequency of hospitalization by type (full or partial) and reason (psychiatric, social or other) was analyzed by negative binomial regression. Changes in CGI-S, CGI-SCH, PSP and SF-12 scores, quality of life, sleep VAS, clinical status, patient characteristics and treatment satisfaction were compared between groups using an analysis of covariance (ANCOVA) mixed model with covariate adjustment. Clinical deterioration rates and responder rates on CGI-S and PSP scales were evaluated by means of logistic regression with adjustment for possible covariates. Clinical effectiveness of paliperidone ER Schreiner et al.
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A post hoc comparison was also conducted with the aim of comparing the impact of monotherapy versus polytherapy on long-term patient outcomes. Patients receiving polytherapy have previously been considered to have suboptimal outcomes17 and the effectiveness of paliperidone ER in this group of patients was of particular interest. The study protocol was reviewed by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) and the study was conducted in line with good clinical practice. Each patient or legally acceptable representative gave written informed consent for participation according to local requirements and for treatment data to be entered into the electronic case report form (eCRF) for the study. Recording of patients’ personal data was limited to those data necessary to investigate the efficacy, safety, quality and utility of the medications studied, and data were processed with adequate precautions to ensure
confidentiality and compliance with applicable data protection laws and regulations.
Results Study population Documentation was initiated for 4142 patients (Figure 1). Sixty-two patients were excluded from the analysis because they were not newly treated with paliperidone ER or another oral antipsychotic. Twenty-nine patients documented in the ‘all other oral antipsychotics’ group were excluded from the intent to treat (ITT) analysis set due to violation of protocol (initiation on an antipsychotic treatment excluded by the protocol such as clozapine or risperidone long-acting injectable [RLAI]). Unless otherwise specified, data presented in this article represent the ITT analysis set.
Documentation initiated n=4142 Screening failures n=62 Enrolled n=4080 Protocol violations n=29 ITT population n=4051
Safety population n=4080
Paliperidone ER n=2865 All other antipsychotics n=1186
Paliperidone ER n=2865 All other antipsychotics n=1215
Completed 12 months n=3386 (83.6%)
Discontinuers n=665 (16.4%)
Paliperidone ER n=2384 (83.2%) All other antipsychotics n=1002 (84.5%)
Paliperidone ER n=481 (16.8%) All other antipsychotics n=184 (15.5%) Lost fo follow-up n=350 (8.6%) Paliperidone ER n=239 (8.3%) All other antipsychotics n=111 (9.4%) Withdrawal of consent n=116 (2.9%) Paliperidone ER n=92 (3.2%) All other antipsychotics n=24 (2.0%) Non-adherence n=39 (1.0%) Paliperidone ER n=28 (1.0%) All other antipsychotics n=11 (0.9%) Death n=20 (0.5%) Paliperidone ER n=18 (0.6%) All other antipsychotics n=2 (0.2%) Other n=140 (3.5%)
ITT, intent to treat; ER, extended dose
Paliperidone ER n=104 (3.6%) All other antipsychotics n=36 (3.0%)
Figure 1. Study design and population (ITT).
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Table 1. Study population: baseline characteristics (ITT analysis set). Paliperidone ER
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Variable Age at baseline (years) Age at diagnosis (years) Years since diagnosis BMI (kg/m2) Weight (kg) Height (cm) CGI-S CGI-SCH1: Positive symptoms CGI-SCH2: Negative symptoms CGI-SCH3: Depressive symptoms CGI-SCH4: Cognitive symptoms PSP SF-12: Mental subscale SF-12: Physical subscale VAS: Quality of sleep VAS: Daytime drowsiness Treatment satisfaction Hospital stays (year before) Hospital days (year before)
All other oral antipsychotics
t-test
n
Mean
Median
SD
n
Mean
Median
SD
p Value
2865 2576 2576 2860 2860 2862 2862 2862 2862 2860 2861 2856 2784 2784 2850 2850 2788 2865 2865
39.28 29.13 9.84 26.32 76.25 169.89 4.23 3.64 3.59 2.77 3.08 53.38 36.46 44.10 57.90 41.49 3.58 0.42 16.23
38 27 7 26 75 170 4 4 4 3 3 55 36 44 61 42 3 0 0
12.49 10.23 9.27 5.16 17.25 9.92 1.07 1.46 1.30 1.31 1.31 16.16 11.39 8.86 27.75 27.50 1.31 0.75 43.36
1186 1031 1031 1185 1185 1186 1185 1184 1183 1184 1184 1183 1145 1145 1180 1180 1124 1186 1186
40.59 30.38 9.68 26.62 76.95 169.75 4.34 3.71 3.73 2.97 3.22 52.71 35.07 43.78 55.32 42.45 3.45 0.45 18.48
40 28 7 26 75 169 4 4 4 3 3 55 34 44 57 43 3 0 0
12.92 11.09 9.29 5.53 17.76 9.77 1.02 1.46 1.26 1.26 1.33 15.66 11.18 9.09 28.55 27.15 1.31 0.75 47.86
0.0025 0.0013 0.6245 0.1010 0.2416 0.6873 0.0026 0.1838 0.0020 0.0015 0.0039 0.2242 0.0005 0.3172 0.0078 0.3117 0.0048 0.2614 0.1444
BMI, body mass index; CGI-S, Clinical Global Impression–Severity; CGI-SCH: Clinical Global Impression–Schizophrenia; PSP: Personal and Social Performance Scale; SF-12: Short Form-12 item health survey; VAS: Visual Analogue Scale.
Table 2. Mean modal dose of antipsychotic treatment during the entire treatment course. Antipsychotic treatment
Amisulpride Aripiprazole Olanzapine Paliperidone ER Quetiapine Risperidone Ziprasidone
Patients
Modal dose (mg/day)
Licensed dose range (mg/day)
n*
%
Mean
SD
Range
102 187 167 2864 238 267 119
3 5 4 71 6 7 3
537.5 15.1 13.5 7.2 434.4 4.2 109.2
342.2 7.6 6.7 2.9 291 2.60 57.5
30–1600 3–45 3–40 3–27 25–1600 1–12 20–240
400–120018 10–3019 5–2020 3–129 150–75021 2–1622 40–16023
ER, extended release; SD, standard deviation. *ITT analysis set, the population of patients receiving other oral antipsychotics (n ¼ 107) was too heterogeneous for inclusion in this analysis.
Baseline characteristics of the ITT population are provided in Table 1. The mean (SD) age of patients in the ITT analysis set was 39.7 (12.6) years and 53.8% of patients were male. Baseline characteristics were comparable between the paliperidone ER group and the ‘all other oral antipsychotics’ group on most parameters; however, statistically significant differences (p50.05) were noted between the two treatment groups for some baseline characteristics (Table 1). The majority of the patients were outpatients; 18.4% of patients were hospitalized at baseline (17.6% in the paliperidone ER group and 20.2% in the ‘all other oral antipsychotics’ group). Of the 4051 patients included in the ITT analysis set for analysis of effectiveness, 3386 (83.6%) were considered completers, while documentation was discontinued prematurely for 665 (16.4%; Figure 1). All-cause study discontinuation (dropout) rates were comparable between the paliperidone ER group (16.8%) and the ‘all other ! 2014 Informa UK Ltd www.cmrojournal.com
oral antipsychotics’ group (15.5%). The most common reason for study discontinuation was ‘lost to follow-up’ (8.6% of all patients; Figure 1).
Dosing The mean modal dose of all antipsychotics was above the minimum licensed dose9,18–23 (Table 2). However, modal dose range data indicated doses above the maximum approved dose were prescribed for individual patients during the course of the study, for all oral antipsychotics with the exception of risperidone (Table 2). The mean daily dose of paliperidone ER at baseline was 6.0 (2.3) mg. The range of daily doses of paliperidone ER at baseline was 3–24 mg (approved dose range 3–12 mg/ day). The mean modal daily dose of paliperidone ER during the entire treatment course was 7.2 (2.9) mg Clinical effectiveness of paliperidone ER Schreiner et al.
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(range of modal daily doses of paliperidone ER during the entire course of treatment: 3–27 mg/day; Table 2).
polytherapy (defined as being treated with 41 antipsychotic at Day 28 after baseline) showed a greater betweengroup difference in time to discontinuation than in the total study cohort: the proportion of patients still receiving their newly initiated antipsychotic treatment after 12 months in the polytherapy subgroup was 74.1% for the paliperidone ER group and 68.8% for the ‘all other oral antipsychotics’ group (HR ¼ 0.83, 95% CI 0.65–1.05, p ¼ 0.12). When study dropouts were included in the definition of treatment discontinuation, the proportion of patients treated with polytherapy still receiving treatment after 12 months was 67.9% and 60.5% for the paliperidone ER and the ‘all other oral antipsychotics’ group, respectively (HR ¼ 0.78, 95% CI 0.63–0.96, p ¼ 0.017; Figure 2). The HR adjusted for baseline covariates was 0.79 (95% CI 0.63–1.00, p ¼ 0.05).
Clinical effectiveness
Time to discontinuation of initiated treatment There was no difference in the time to discontinuation of newly initiated antipsychotic treatments between the paliperidone ER group and the ‘all other oral antipsychotics’ group. The proportion of patients still on treatment after 12 month follow-up was 73.9% in the paliperidone ER group and 73.2% in the ‘all other oral antipsychotics’ group (p ¼ 0.948). When study dropouts were included in the definition of treatment discontinuations, the proportion of patients still receiving treatment after 12 months was 66.6% and 63.8% in the paliperidone ER group and the ‘all other oral antipsychotics’ group, respectively (HR ¼ 0.92, 95% CI 0.82–1.03, p ¼ 0.145). Post hoc analyses of the primary endpoint in the subgroup of patients (28%; 1140/4051) receiving drug
Time to hospitalization There was no significant difference in the time to hospitalization between the paliperidone ER group and the ‘all other oral antipsychotics’ group. Overall, 27% of patients were hospitalized during the year following treatment initiation. The proportion of patients without hospitalization 12 months after initiation of treatment was 85.0% in the paliperidone ER group and 83.2% in the ‘all other oral
100
Paliperidone ER All other
86.7%
90
79.5% Patients still on initial treatment (%)
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Treatment outcomes were documented prospectively for time to treatment discontinuation, time to first postbaseline hospitalization, overall severity of symptoms, personal and social performance as well as health related quality of life and quality of sleep.
80
71.5% 67.9%
81.7% 70
p=0.017
70.9%
60
64.5% 60.5%
50 40 30 20 10 0 0
90
160
270
360
583 211
436 160
Days since baseline N patients at risk: n= 813 n= 327
705 267
646 232
Kaplan–Meier curve indicating 95% confidence intervals, intent-to-treat analysis set; patients treated with polytherapy (dropout=event)
Figure 2. Time to discontinuation of initial treatment: subgroup of patients treated with polytherapy (dropout ¼ event).
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94.2%
100
Paliperidone ER All other 84.5%
88.9% 90 Patients still on initial treatment (%)
91.9%
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80.6%
80 82.9% 78.3%
70
75.2% p=0.049
60 50 40 30 20 10 0 0
90
160
270
360
622 235
451 176
Days since baseline N patients at risk: n= 813 n= 327
742 295
682 256
Kaplan–Meier curve indicating 95% confidence intervals, intent-to-treat analysis set; patients treated with polytherapy
Figure 3. Time to hospitalization: patients treated with polytherapy.
antipsychotics’ group (p ¼ 0.14). Post hoc analysis on the time to first hospitalization amongst patients receiving polytherapy revealed a larger between-group difference between paliperidone ER and the ‘all other oral antipsychotics’ group than in the total patient cohort: 80.6% of patients were without hospitalization after 12 months for the paliperidone ER group, compared with 75.2% for the ‘all other oral antipsychotics’ group (HR ¼ 0.76, 95% CI 0.58–1.00, p ¼ 0.049; Figure 3). The adjusted HR, based on the multivariate Cox model, adjusting for baseline covariates was 0.75 (95% CI 0.54–1.03, p ¼ 0.07). The greatest difference in time to first hospitalization was between patients newly initiated on paliperidone ER (n ¼ 2309 [80.6%] without hospitalization at 12 months), and those newly initiated on risperidone (n ¼ 183 [68.5%] without hospitalization at 12 months; adjusted HR ¼ 0.55, 95% CI 0.32–0.94, p ¼ 0.03) and quetiapine (n ¼ 157 [65.8%] without hospitalization at 12 months; adjusted HR ¼ 0.52, 95% CI 0.31–0.88, p ¼ 0.016). Pre- versus post-baseline analysis showed that there was a numerically greater decrease in the proportion of patients hospitalized in the paliperidone ER group (30% of patients hospitalized pre-baseline; 25% hospitalized post-baseline) than in the ‘all other antipsychotics’ group (32% of patients hospitalized pre-baseline; 29% hospitalized postbaseline). However, this difference did not reach statistical significance. ! 2014 Informa UK Ltd www.cmrojournal.com
Other outcome measures Additional outcome measures for patients treated with paliperidone ER and ‘all other oral antipsychotics’ are presented in Table 3. Improvements in overall severity of symptoms (mean CGI-S and CGI-SCH scores), healthrelated quality of life (SF-12 Mental), quality of sleep and daytime drowsiness (VAS scores), as well as patients’ treatment satisfaction were comparable between the paliperidone ER group and the ‘all other oral antipsychotics’ group. Results that reached statistical significance were a greater improvement over time in patients in the paliperidone ER group than in the ‘all other oral antipsychotics’ group in patient functioning, based on change in PSP scale score (þ14.2 vs þ13.1, p ¼ 0.041) and the physical component of quality of life (SF-12 Physical scores; þ3.9 vs þ2.9, p ¼ 0.003), based on a mixed model. Although the protocol was not designed to detect differences with individual antipsychotics, it was apparent that the improvement in CGI-S score over time was significantly more pronounced for paliperidone ER (mean CGI-S score reduced from 4.2 to 3.2) than for quetiapine (mean CGI-S score reduced from 4.2 at baseline to 3.5 at 12 months; p50.0001 [both unadjusted and adjusted]), and significantly less pronounced than for olanzapine (mean CGI-S score reduced from 4.5 at baseline to 3.2 at 12 months; p50.026 [unadjusted] and p ¼ 0.024 Clinical effectiveness of paliperidone ER Schreiner et al.
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Table 3. Mean changes of additional outcomes.
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Outcome measure
Paliperidone ER
All other oral antipsychotics
Baseline
Month 12
Change
Baseline
Month 12
Change
All individual antipsychotics: range
CGI-S (mean score) CGI-SCH (mean score) Positive symptoms Negative symptoms Depressive symptoms Cognitive symptoms PSP (mean score)
4.2
3.2
1.0
4.3
3.3
1.0
0.7–1.3
3.6 3.6 2.8 3.1 53.3
2.4 2.7 2.0 2.3 67.5
1.2 0.9 0.8 0.8 þ14.2 p ¼ 0.041*
3.7 3.7 3.0 3.2 52.8
2.5 2.9 2.1 2.5 65.9
1.2 0.8 0.9 0.7 þ13.1
1.0–1.5 0.8–1.0 0.8–1.0 0.7–0.8 þ8.5–þ16.0
SF-12 (mean score) SF-12 Physical
44.0
47.9
43.9
46.8
þ2.9
þ1.9–þ3.9
36.5
43.8
þ3.9 p ¼ 0.003* þ7.3
35.0
42.5
þ7.5
þ6.5–þ9.9
58.0 41.5 3.6
75.2 25.1 5.0
þ17.2 16.4 þ1.4
55.3 42.5 3.4
73.2 27.0 5.0
þ17.9 15.5 þ1.6
þ9.3–þ25.3 10.7–17.8 þ1.2–þ1.8
65.8 83.9 26.3
54.0 67.9 26.8
11.8 16.0 þ0.5
66.9 84.0 26.6
58.3 69.5 27.3
8.6 14.5 þ0.7
5.2–14.7 2.1–16.7 þ0.2–þ1.7
37.1 7.9
36.2 5.0
0.9 2.9
33.6 7.9
33.0 5.7
0.6 2.2
3.1–þ3.4 1.0–4.3
SF-12 Mental Visual analogue scale (mean score) Quality of sleep Daytime drowsiness Treatment satisfaction (mean score) Healthcare resource utilization (% of patients) Concomitant medications Outpatients visits Patient characteristics (mean BMI [kg/m2]) Substance abuse (% of patients) Tobacco Alcohol, cannabis and other
BMI, body mass index; CGI-S, Clinical Global Impression–Severity; CGI-SCH, Clinical Global Impression–Schizophrenia; PSP, Personal and Social Performance Scale; SF-12, Short Form 12 item health survey. With the exception of mean change in BMI, all changes in score presented in Table 3 represent an improvement in clinical status/patient condition. *Improvement in mean score over time significantly different at the 5% level (mixed model) when paliperidone ER group compared to the ‘all other oral antipsychotics’ group.
[adjusted]). Improvement in CGI-SCH positive symptoms score over time was also significantly less for quetiapine (mean score reduced from 3.5 at baseline to 2.5 with quetiapine at 12 months) compared with paliperidone ER (3.6 reducing to 2.4 at 12 months; p50.005); a similar result was also observed for CGI-SCH negative symptoms (reduced from 3.7 to 2.9 with quetiapine vs 3.6 to 2.7 with paliperidone ER; p ¼ 0.016). All results were based on a RMMM approach. There was a similar change in BMI for the paliperidone ER group and the ‘all other oral antipsychotics’ group. However, when comparing the subgroup of patients newly initiated on olanzapine, the mean increase in BMI was significantly higher (mean increase of 1.7 kg/m2) than with paliperidone ER (0.5 kg/m2; p50.0001). The decrease in the number of patients with substance abuse over time was similar in the paliperidone ER group and the ‘all other oral antipsychotics’ group (Table 3).
proportion of patients receiving antipsychotic monotherapy at Day 28 after baseline was comparable between treatment groups (71.6% of patients in the paliperidone ER group and 72.4% of patients in the ‘all other oral antipsychotics’ group). The majority of patients treated with polytherapy (multiple antipsychotics at Day 28 after baseline; 1140/4051) were receiving the newly initiated antipsychotic in addition to another, either newly initiated, or pre-existing oral FGA or SGA. There was a decrease in the proportion of patients taking any concomitant medications from baseline to Month 12 and a similar trend from baseline to Month 12 in the percentage of patients with outpatient visits. There was also a trend for a decrease in both groups in the proportion of patients taking anticholinergics and benzodiazepines/sedatives/anxiolytics (Table 3).
Safety Healthcare resource utilization Overall, 71.9% (2911/4051) of patients were receiving oral antipsychotic monotherapy at Day 28 after baseline. The 8
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The incidence of adverse drug reactions (ADRs) and AEs was comparable between the paliperidone ER and the ‘all other oral antipsychotics’ group in the retrospective data collection as well as in the prospective phase of the study. www.cmrojournal.com ! 2014 Informa UK Ltd
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Table 4. Frequency and system class of ADRs/AEs.
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Patients experiencing 1 event ADRs during the retrospective period Serious ADRs AEs during the prospective period Serious AEs
Paliperidone ER (% of patients)
All other oral antipsychotics (% of patients)
27.7 1.1 37.1 13.1
29.1 2.0 36.5 14.0
Most common adverse events reported during the prospective period (2% in any treatment group) Schizophrenia 7.8 4.5 Weight increase 3.7 4.4 Psychotic disorder 3.5 4.3 EPS 2.3 1.6 Insomnia 2.2 2.2 Fatigue 1.4 2.1 ADR, adverse drug reaction; AE, adverse event; ER, extended release; EPS, extrapyramidal symptom.
The incidence of AEs and most common AEs reported during the prospective data collection period are presented in Table 4. During the retrospective period the most common ADRs experienced by patients in both groups were increase in weight (5.2%), schizophrenia (3.3%) and extrapyramidal symptoms (3.0%). During the study there were numerically more deaths in the paliperidone ER group (n ¼ 18 [0.6%]) than in the ‘all other oral antipsychotics’ group (n ¼ 2 [0.2%]). For the paliperidone ER group, the majority of deaths were considered not related (11/18) or doubtfully related (5/18) to study treatment. The causes of death for the two patients in the ‘all other antipsychotics’ group were considered to be not related to any of the individual antipsychotics. The cause of death was considered by the investigator as possibly related to paliperidone ER in two patients: one patient died from cardiac failure and one patient committed suicide. While the death due to cardiac failure was considered possibly related to the prescribed medication by the treating physician, this patient had discontinued paliperidone ER approximately 7 months before death.
Discussion This observational study was designed to document prescribing patterns in daily clinical practice and to assess long-term treatment outcomes related to initiation of treatment with oral antipsychotics. Important data on the effectiveness and long-term treatment outcomes related to initiation of treatment with paliperidone ER and other oral antipsychotics in a naturalistic setting were gathered. Effectiveness endpoint data, along with the finding that fewer than one third of patients (28%) required antipsychotic polytherapy in both groups, indicate that the effectiveness of paliperidone ER was comparable to that of the ! 2014 Informa UK Ltd www.cmrojournal.com
‘all other oral antipsychotics’ group. The ‘all other oral antipsychotics’ group consisted of patients receiving highly heterogeneous medications including FGAs, and comparison of paliperidone ER with other individual SGAs was therefore relevant. These comparisons demonstrated important significant differences compared with other specific SGAs in relation to outcomes such as hospitalization, clinical symptoms (based on CGI-S, CGISCH), body weight and BMI. Data from this naturalistic study demonstrate that patients receiving paliperidone ER had significantly greater improvements in PSP scale scores than those receiving other SGAs. This finding is in line with randomized controlled pivotal trials that have demonstrated significant and clinically relevant improvement of patients’ personal and social performance following treatment with paliperidone ER11–13. It is also consistent with previous findings that treatment with paliperidone ER can result in significantly better personal and social functioning than treatment with oral risperidone24. The discontinuation rates and safety analyses documented in this study indicate that the tolerability of paliperidone ER in general was comparable to that of ‘all other oral antipsychotics’. However, as mentioned above, this grouped comparison of all oral antipsychotics other than paliperidone may mask significant differences between individual antipsychotics. The safety data in this study are in line with the tolerability profile of paliperidone ER documented in previous randomized placebo-controlled trials11–13. Paliperidone ER was found to have an advantage over olanzapine in maintaining BMI and body weight. This finding has also been documented in a recent head-to-head trial of paliperidone ER compared with oral olanzapine25. Evidence from meta-analyses indicates that some SGAs may be associated with increased risk of weight gain and metabolic changes in comparison with FGAs. The benefits of paliperidone ER Clinical effectiveness of paliperidone ER Schreiner et al.
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when compared with other widely used SGAs such as olanzapine is therefore clinically relevant, in particular since a substantial proportion of patients with schizophrenia are overweight or obese and often have numerous additional cardiovascular risk factors (such as smoking, lack of exercise and poor diet)26. Physical quality of life scores were also significantly more improved with paliperidone ER vs other SGAs in this study. There is currently much focus on improving physical health in individuals with mental health problems27, and these findings regarding physical quality of life and BMI are therefore particularly salient. The tolerability profile of paliperidone ER may, in part, reflect the drug’s distinct pharmacodynamic and pharmacokinetic characteristics15. Post hoc analyses of a subgroup of patients receiving polytherapy revealed that time to treatment discontinuation and time to first hospitalization were significantly longer for patients initiated on paliperidone ER, compared with the ‘all other oral antipsychotics’ group. This finding suggests that treatment with paliperidone ER may be particularly beneficial in a subgroup of patients whose outcomes have previously been thought to be suboptimal17,28. The favorable effects of paliperidone ER in patients concomitantly treated with other antipsychotic medications may in part relate to the drug’s limited hepatic metabolism9 and low propensity to cause hepatic drug–drug interactions15. Around 50% of patients with schizophrenia are reported to be prescribed more than one concomitant antipsychotic therapy29,30; the improved outcomes with paliperidone ER within this subgroup are therefore relevant for clinical practice. In this current registry study, we report a decrease in healthcare resource utilization from baseline to endpoint for patients receiving either paliperidone ER or ‘all other antipsychotics’, as demonstrated by the proportion of patients taking any concomitant medications, as well as a decrease in the percentage of patients with outpatient visits, using anticholinergics and benzodiazepines/sedatives/anxiolytics from baseline to Month 12. These data provide important information that will inform the design of future cost-effectiveness analyses based on rigorous comparative assessments. Gaining a clearer understanding of the impact of individual treatments on healthcare resource utilization in patients with schizophrenia has the potential to reduce overall healthcare costs directly31 and to reduce societal or indirect costs by reducing the care time required by carers and by providing patients opportunities to return to employment. This study is limited by the inherent difficulties associated with data collected within a naturalistic setting. As with any non-randomized, non-interventional observational study, there may be treatment assignment bias and baseline differences between the treatment groups – as evidenced by a number of significant differences in baseline characteristics between the paliperidone ER group and 10
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the ‘all other oral antipsychotics group’. Consequently, despite the use of statistical multivariate modeling approaches to adjust for these differences, direct comparisons of outcomes from the treatment groups may still be difficult to interpret since baseline differences may influence the results.
Conclusions The data captured in the PILAR registry provide valuable information on the prescribing habits and treatment outcomes associated with use of oral antipsychotics in a naturalistic setting. Furthermore, the findings expand on the evidence obtained from randomized controlled clinical trials with paliperidone ER and support previous positive findings of the functional improvement and treatment satisfaction associated with paliperidone ER32. The differences between paliperidone ER and individual oral antipsychotics highlight the heterogeneous nature of SGAs in terms of effectiveness and adverse effects, and indicate that treatment needs to be individualized to each patient33. The data captured in this registry also provide important information that will inform the design of future studies and cost-effectiveness analyses involving more rigorous comparative assessments.
Transparency Declaration of funding This study was funded by Janssen Pharmaceutical Companies of Johnson & Johnson in Europe, Middle East & Africa (EMEA). All authors contributed to interpretation of the results, developed the draft of the manuscript, participated in subsequent revisions and read and approved the final manuscript. Declaration of financial/other relationships A.S. has disclosed that he is a full-time employee of Janssen-Cilag Medical & Scientific Affairs Europe, Middle East & Africa and a shareholder of Johnson & Johnson. K.H. and J.I.L. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. I.L. has disclosed that she has acted as a presenter on behalf of Janssen Cilag. A.H.S. has disclosed that he has received grants from and participated in research with Pfizer, Lundbeck, Janssen Cilag and Otsuka, acted as a presenter on behalf for: AstraZeneca, Eli Lilly, Lundbeck, Janssen Cilag, Sanofi Aventis and Servier as well as attended advisory board meetings for Pfizer and Otsuka. L.H. has disclosed that he is a full-time employee of Janssen-Cilag Medical & Scientific Affairs Europe, Middle East & Africa. J.D. has disclosed that he is a full-time employee of Janssen-Cilag Market Access Europe, Middle East & Africa. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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Acknowledgments Medical writing assistance with the preparation of this manuscript was provided by ApotheCom ScopeMedical and funded by Janssen EMEA. The authors thank all the PILAR investigators and nurses, patients and their families for their participation in the registry. They also thank Angelika Mehnert for her contribution to the discussion and interpretation of the statistical analysis results.
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References 1. S´witaj P, Anczewska M, Chrostek A, et al. Disability and schizophrenia: a systematic review of experienced psychosocial difficulties. BMC Psychiatry 2012;12:193 2. Bellack AS, Green MF, Cook JA, et al. Assessment of community functioning in people with schizophrenia and other severe mental illnesses: a white paper based on an NIMH-sponsored workshop. Schizophr Bull 2007;33:805-22 3. Knapp M. Costs of schizophrenia. Psychiatry 2005;4:33-5 4. Maguire GA. Comprehensive understanding of schizophrenia and its treatment. Am J Health Syst Pharm 2002;59(Suppl 5):S4-11 5. Knapp M. Schizophrenia costs and treatment cost-effectiveness. Acta Psychiatr Scand Suppl 2000;407:15-18 6. NICE Schizophrenia Guidelines CG178, February 2014. Available at: http:// www.nice.org.uk/nicemedia/live/14382/66534/66534.pdf [Last accessed 18 February 2014] 7. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:120923 8. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006;63:1079-87 9. Paliperidone ER SmPC. Janssen. August 2013. Available at: http:// www.medicines.org.uk/EMC/medicine/19828/SPC/INVEGAþ1.5þmg% 2cþ3þmg%2cþ6þmg%2cþ9þmg%2cþ12þmgþprolongedreleaseþtablets/ [Last accessed 17 February 2014] 10. Lautenschlager M, Heinz A. Paliperidone-ER: first atypical antipsychotic with oral extended release formulation. Expert Rev Neurother 2008;8:193-200 11. Davidson M, Emsley R, Kramer M, et al. Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study. Schizophr Res 2007;93:117-30 12. Kane J, Canas F, Kramer M, et al. Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial. Schizophr Res 2007;90:147-61 13. Marder SR, Kramer M, Ford L, et al. Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebocontrolled study. Biol Psychiatry 2007;62:1363-70 14. Kramer M, Simpson G, Maciulis V, et al. Paliperidone extended-release tablets for prevention of symptom recurrence in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 2007;27:6-14 15. Wang SM, Han C, Lee SJ, et al. Paliperidone: a review of clinical trial data and clinical implications. Clin Drug Investig 2012;32:497-512 16. Schmauss M, Jukic´ V, Siracusano A, et al. Flexible dosing with paliperidone ER in the treatment of patients with acutely exacerbated
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schizophrenia: results from a single-arm, open-label study. Curr Med Res Opin 2012;28:1395-404 Centorrino F, Goren JL, Hennen J, et al. Multiple versus single antipsychotic agents for hospitalized psychiatric patients: case–control study of risks versus benefits. Am J Psychiatry. 2004;161:700-6 Amisulpride SmPC. May 2013. Sanofi-Aventis. Available at: http:// www.medicines.org.uk/EMC/medicine/26091/SPC/Amisulprideþ100mgþ Tablets/ [Last accessed 17 February 2014] Aripiprazole SmPC. November 2013. Otsuka. Available at: http://www.medicines.org.uk/EMC/medicine/18494/SPC/AbilifyþTablets%2cþ OrodispersibleþTablets%2cþOralþSolutionþ(Otsukaþ%26þBristolMyersþSquibb)/[Last accessed 17 February 2014] Olanzapine SmPC. October 2012. Accord. Available at: http://www.medicines.org.uk/EMC/medicine/25892/SPC/Olanzapineþ20þmgþFilmcoatedþTablets/ [Last accessed 17 February 2014] Quetiapine SmPC. February 2013. Actavis. Available at: http://www.medicines.org.uk/emc/medicine/26237/SPC/Quetiapineþ25mgþfilm-coatedþ tablets/ [Last accessed 17 February 2014] Risperidone SmPC. October 2013. Janssen-Cilag. Available at: http:// www.medicines.org.uk/EMC/medicine/24905/SPC/Risperidoneþ4þmgþ Tablets/ [Last accessed 17 February 2014] Ziprasidone SmPC. July 2013. Pfizer. Available at: http://www.medicines.ie/ medicine/6166/SPC/GEODONþCapsulesþ20mg,þ40mg,þ60mg,þ80mg/ [Last accessed 17 February 2014] Wang Y, Li WS, Gu DK, et al. [Efficacy of paliperidone extended-release tablets in the improvement of social functions in schizophrenics: a randomized and controlled study]. Zhonghua Yi Xue Za Zhi 2010;90:2030-5 Schreiner A, Niehaus D, Shuriquie NA, et al. Metabolic effects of paliperidone extended release versus oral olanzapine in patients with schizophrenia: a prospective, randomized, controlled trial. J Clin Psychopharmacol 2012; 32:449-57 De Hert M, Correll CU, Bobes J, et al. Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry 2011;10:52-77 Jones S, Howard L, Thornicroft G. ‘Diagnostic overshadowing’: worse physical health care for people with mental illness. Acta Psychiatr Scand 2008;118:169-71 Joukamaa M, Helio¨vaara M, Knekt P, et al. Schizophrenia, neuroleptic medication and mortality. Br J Psychiatry 2006;188:122-7 Suokas JT, Suvisaari JM, Haukka J, et al. Description of long-term polypharmacy among schizophrenia outpatients. Soc Psychiatry Psychiatr Epidemiol 2013;48:631-8 Roh D, Chang JG, Kim CH, et al. Antipsychotic polypharmacy and high-dose prescription in schizophrenia: a 5-year comparison. Aust N Z J Psychiatry 2014;48:52-60 Sun SX, Liu GG, Christensen DB, et al. Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States. Curr Med Res Opin 2007;23: 2305-12 Canuso CM, Grinspan A, Kalali A, et al. Medication satisfaction in schizophrenia: a blinded-initiation study of paliperidone extended release in patients suboptimally responsive to risperidone. Int Clin Psychopharmacol 2010;25:155-64 Horacek J, Bubenikova-Valesova V, Kopecek M, et al. Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 2006;20:389-409
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0300-7995 doi:10.1185/03007995.2014.898630
2014, 1–11
Article ST-0339.R1/898630 All rights reserved: reproduction in whole or part not permitted
Original article Clinical effectiveness and resource utilization of paliperidone ER for schizophrenia: Pharmacoepidemiologic International Longitudinal Antipsychotic Registry (PILAR)
A. Schreiner L. Hargarter Janssen EMEA, Neuss, Germany
K. Hitschfield Praxis Dr Hitschfeld Facharzt fu¨r Psychiatrie und Psychotherapie, Hamburg, Germany
J.I. Lee Seoul National Hospital, Seoul, Korea
I. Lenskaya Republic Centre of Psychiatry, Almaty City, Kazakhstan
A.H. Sulaiman Department of Psychological Medicine, University of Malaya, Kuala Lumpur, Malaysia
J. Diels Janssen EMEA Market Access, Beerse, Belgium
on behalf of the PILAR study group Address for correspondence: A. Schreiner, Department of Medical and Scientific Affairs, Janssen Europe, Middle East and Africa, Johnson & Johnson Platz 1, 41470 Neuss, Germany. Tel.: +49 1735131062; [email protected] Keywords: Effectiveness – Oral antipsychotics – Paliperidone ER – Schizophrenia Accepted: 24 February 2014; published online: 19 March 2014 Citation: Curr Med Res Opin 2014; 1–11
Abstract Objective: To document prescribing patterns in clinical practice and assess long-term outcomes related to initiation of paliperidone ER and other oral antipsychotics among patients with schizophrenia in a naturalistic setting. Research design and methods: An international, non-interventional, naturalistic study of adult patients (18 years) with schizophrenia. Patients were assigned to the relevant treatment group (paliperidone ER or ‘all other oral antipsychotics’) after switching to, or initiating, oral antipsychotic treatment. Retrospective 12 month data collection was followed by 12 month prospective data collection, with 3-monthly assessments. The primary endpoint was time to all-cause discontinuation of new medication. Secondary endpoints included Clinical Global Impression–Severity (CGI-S) score, Clinical Global Impression–Schizophrenia (CGI-SCH) score, Personal and Social Performance (PSP) score, health-related quality of life (HR-QoL) and quality of sleep, evaluation of healthcare resource utilization and patient’s treatment satisfaction. Results: A total of 4051 patients were included in the intent-to-treat (ITT) analysis set. All-cause study discontinuation rates were comparable between the paliperidone ER group (16.8%) and the ‘all other oral antipsychotics’ group (15.5%). There was no difference in the time to discontinuation of newly initiated antipsychotic treatments between paliperidone ER and ‘all other oral antipsychotics’ groups. Paliperidone ER was associated with greater improvements from baseline to endpoint in both the PSP scale score (þ14.2 vs þ13.1, p ¼ 0.041) and the physical component of quality of life (SF-12 Physical scores; þ3.9 vs þ2.9, p ¼ 0.003) compared to ‘all other oral antipsychotics’. Improvements in mean CGI-S score, CGI-SCH score, HR-QoL, quality of sleep and daytime drowsiness, as well as patients’ treatment satisfaction were comparable between treatment groups. The incidence of adverse events was comparable between groups. Conclusions: This study provides valuable data on the prescribing habits and treatment outcomes associated with use of paliperidone ER in everyday clinical practice, and supports previous findings of the favorable functional improvement and treatment satisfaction associated with paliperidone ER. Clinical trial registration: NCT00696813; R076477SCH4015 (Register of German Association of Research-based Pharmaceutical Companies [VFA] http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb).
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Introduction Schizophrenia is a chronic, severe disorder1 with a significant social and economic impact not only on patients, but on their families, friends, and the wider community2,3. It is characterized by a variety of clinical manifestations including positive, negative and affective symptoms, cognitive impairment and reduced social and occupational functioning4. The relatively early age of onset, progression and chronicity of the disease and its impact on patient functioning imposes a high economic burden on society, which means it can account for between 1.5% and 3% of total healthcare costs5. Of these costs, hospitalization for schizophrenia is a large contributor to the burden on healthcare systems, whereas the cost of pharmacotherapy makes a relatively small contribution5. Treatment goals in schizophrenia include controlling both positive and negative symptoms, preventing the recurrence of psychotic episodes, improving the patient’s functioning and quality of life, which can involve improving both physical and mental health, and facilitating social and vocational reintegration6. Pharmacological therapy is used in the treatment of the majority of patients with schizophrenia. While second-generation antipsychotics (SGAs) offer some particular advantages over firstgeneration antipsychotics (FGAs), there is room for further advances in treatment effectiveness from new treatment options, as has been indicated in studies such as the CATIE7 and CUtLASS8 trials. Once daily, oral paliperidone extended-release (ER) has been approved for the treatment of schizophrenia by the European Medicines Agency and the US Food and Drug Administration9,10. The majority of trials of paliperidone ER conducted thus far have been randomized, controlled, short in duration (6 weeks)11–13, and have studied the effects of fixed doses in selected, largely homogeneous groups of patients. The beneficial effect of paliperidone ER on symptoms (as demonstrated by decreases in Positive and Negative Syndrome Scale [PANSS] total scores and Clinical Global Impression–Severity [CGI-S] scale scores), on patient functioning (as demonstrated by significant improvements in Personal and Social Performance [PSP] scale scores)11–13, and on relapse prevention14 has been established. Onset of efficacy was observed as early as Day 4 of treatment15. A recent single-arm study in adults hospitalized with an acute exacerbation of schizophrenia showed that flexibly dosed paliperidone ER (3–12 mg/day for 6 weeks) was associated with a clinically meaningful treatment response16. Early onset of effect was also confirmed, with significant improvement from baseline observed as early as Day 2. There remains a need to understand prescribing patterns relating to the use of paliperidone ER and other oral antipsychotics in a naturalistic setting, and how these practices relate to healthcare costs and resource 2
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utilization. The Pharmacoepidemiologic International Longitudinal Antipsychotic Registry (PILAR) was an observational study intended to document prescribing patterns prospectively in daily clinical practice and to assess long-term outcomes related to initiation of oral antipsychotic treatment in a naturalistic setting.
Methods Objectives The overall study objective was to document prescribing patterns in daily clinical practice and assess long-term treatment outcomes related to initiation of treatment with oral antipsychotics in a naturalistic setting. An additional objective of the study was to collect data retrospectively, which allowed the evaluation of treatment outcomes before and after treatment initiation with paliperidone ER or other oral antipsychotics.
Study population Patients meeting selection criteria were men and women 18 years of age with an established diagnosis of schizophrenia, who had recently been switched (2 weeks prior to enrolment) to, or started on, paliperidone ER or another oral FGA or SGA. Participants were able to provide written informed consent and to fill out self-administered questionnaires. Treatment decisions were made by the treating physician prior to, and independently of, the study, following routine clinical practice and local prescribing information. Patients with established treatment-resistant schizophrenia, who had not responded to an adequate treatment trial with more than two SGAs and/or clozapine, or those with a history of neuroleptic malignant syndrome, were not eligible for documentation in this study. There were no restrictions regarding inpatient or outpatient populations.
Study design The PILAR study was an international, non-interventional, naturalistic study on the use of paliperidone ER and other newly or recently initiated oral antipsychotic treatments, documenting 44000 patients from Canada, Europe and Asia between 2007 and 2011. The study consisted of two components: one conducted locally in Germany (R076477SCH4015, Register of German Association of Research-based Pharmaceutical Companies (VFA) http://www.vfa.de/de/arzneimittelforschung/datenbanken-zu-arzneimitteln/nisdb), and an international component conducted in 12 countries across Canada, Europe and Asia (NCT00696813). Data from these studies were collected in a single database www.cmrojournal.com ! 2014 Informa UK Ltd
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and this article presents key findings from the pooled results. Patients were enrolled and assigned to the relevant treatment group after switching to, or initiating, a new oral antipsychotic treatment. The study design then consisted of two parts: (1) retrospective data collection using a 12 month chart review covering the period up to and including the day before baseline, and (2) 12 months of prospective data collection, for which patients were scheduled for 3-monthly assessments (including both clinician-administered evaluations and patient self-reported assessments). Patients were considered to have completed the study if all assessments within the 12 month prospective data collection period had been documented. Discontinuation of an antipsychotic medication during this period did not imply withdrawal from the study (dropout was defined as a patient whose documentation ended before all the 12 month prospective data had been collected). Physicians were advised that all treatments and dose adjustments should be based on approved local labels, and that management decisions should be made at the physician’s discretion, using clinical judgment and routine practice. No study drug was provided: patients received medication according to their usual care.
Data collection Electronic data capture was used and the majority of the data transcribed by the study investigators from the source documents onto the electronic case report form (CRF) and then transmitted in a secure manner to the sponsor.
Study endpoints/assessments The primary effectiveness endpoint was time to all-cause discontinuation of new medication in the paliperidone ER group compared with the ‘all other oral antipsychotics’ group. The following parameters were also assessed: time to first post-baseline hospitalization, overall severity of symptoms and clinical deterioration of psychiatric condition (as measured by Clinical Global Impression– Schizophrenia [CGI-SCH] and Severity [CGI-S] scale scores), personal and social functioning (as measured by PSP scale scores), health-related quality of life and quality of sleep (using a quality of life questionnaire, the Short Form-12 item health survey [SF-12], and quality of sleep visual analogue scales [VAS]), evaluation of healthcare resource utilization, and patient’s treatment satisfaction (determined using a categorical question at baseline and endpoint). Additional patient characteristics documented at baseline included psychiatric history and diagnosis, the reason ! 2014 Informa UK Ltd www.cmrojournal.com
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for switching to the new antipsychotic, the patient’s current antipsychotic and any other concomitant medication or substance abuse. The retrospective chart review and prospective followups collected data on antipsychotic medication history, adverse and serious adverse drug reactions (ADRs and SADRs), and history of healthcare resource utilization (hospitalizations, emergency room and outpatient visits). In addition, throughout the prospective period the following were also documented: antipsychotic treatment, concomitant medications, substance abuse, psychiatric symptoms, level of functioning and adverse and serious adverse events (AEs and SAEs).
Statistical analyses Approximately 787 patients (528 in the paliperidone ER arm and 259 in the ‘all other oral antipsychotics’ treatment arm) were needed to detect, with 80% power and a significance at alpha ¼ 0.05, a between-group difference in all-cause discontinuation of 10%. Repeated measures (assessments by time interval) were analyzed as follows: observed cases, endpoint analysis, mixed model (Repeated Measures Mixed Model [RMMM]). Analyses were adjusted for baseline differences in patient demographics, and all statistical tests were performed at the 5% significance level (two-tailed tests). Kaplan–Meier plots and a log-rank test were used to evaluate time to treatment discontinuation. A Cox proportional hazard model with covariate adjustment was also performed to adjust for differences between groups at baseline in age and gender, body mass index (BMI), reason for initiation of antipsychotic treatment, number of psychiatric hospitalizations in the retrospective period, substance abuse at baseline, and baseline values for CGI, PSP and SF-12. Kaplan–Meier plots, a log-rank test and Cox regression were used to evaluate time to first post-baseline hospitalization. For patients who were in hospital at baseline, time to hospitalization was defined as the number of days between discharge of the ongoing hospitalization and the first post-baseline admission (patients without hospitalization were censored at the last follow-up date). Frequency of hospitalization by type (full or partial) and reason (psychiatric, social or other) was analyzed by negative binomial regression. Changes in CGI-S, CGI-SCH, PSP and SF-12 scores, quality of life, sleep VAS, clinical status, patient characteristics and treatment satisfaction were compared between groups using an analysis of covariance (ANCOVA) mixed model with covariate adjustment. Clinical deterioration rates and responder rates on CGI-S and PSP scales were evaluated by means of logistic regression with adjustment for possible covariates. Clinical effectiveness of paliperidone ER Schreiner et al.
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A post hoc comparison was also conducted with the aim of comparing the impact of monotherapy versus polytherapy on long-term patient outcomes. Patients receiving polytherapy have previously been considered to have suboptimal outcomes17 and the effectiveness of paliperidone ER in this group of patients was of particular interest. The study protocol was reviewed by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) and the study was conducted in line with good clinical practice. Each patient or legally acceptable representative gave written informed consent for participation according to local requirements and for treatment data to be entered into the electronic case report form (eCRF) for the study. Recording of patients’ personal data was limited to those data necessary to investigate the efficacy, safety, quality and utility of the medications studied, and data were processed with adequate precautions to ensure
confidentiality and compliance with applicable data protection laws and regulations.
Results Study population Documentation was initiated for 4142 patients (Figure 1). Sixty-two patients were excluded from the analysis because they were not newly treated with paliperidone ER or another oral antipsychotic. Twenty-nine patients documented in the ‘all other oral antipsychotics’ group were excluded from the intent to treat (ITT) analysis set due to violation of protocol (initiation on an antipsychotic treatment excluded by the protocol such as clozapine or risperidone long-acting injectable [RLAI]). Unless otherwise specified, data presented in this article represent the ITT analysis set.
Documentation initiated n=4142 Screening failures n=62 Enrolled n=4080 Protocol violations n=29 ITT population n=4051
Safety population n=4080
Paliperidone ER n=2865 All other antipsychotics n=1186
Paliperidone ER n=2865 All other antipsychotics n=1215
Completed 12 months n=3386 (83.6%)
Discontinuers n=665 (16.4%)
Paliperidone ER n=2384 (83.2%) All other antipsychotics n=1002 (84.5%)
Paliperidone ER n=481 (16.8%) All other antipsychotics n=184 (15.5%) Lost fo follow-up n=350 (8.6%) Paliperidone ER n=239 (8.3%) All other antipsychotics n=111 (9.4%) Withdrawal of consent n=116 (2.9%) Paliperidone ER n=92 (3.2%) All other antipsychotics n=24 (2.0%) Non-adherence n=39 (1.0%) Paliperidone ER n=28 (1.0%) All other antipsychotics n=11 (0.9%) Death n=20 (0.5%) Paliperidone ER n=18 (0.6%) All other antipsychotics n=2 (0.2%) Other n=140 (3.5%)
ITT, intent to treat; ER, extended dose
Paliperidone ER n=104 (3.6%) All other antipsychotics n=36 (3.0%)
Figure 1. Study design and population (ITT).
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Table 1. Study population: baseline characteristics (ITT analysis set). Paliperidone ER
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Variable Age at baseline (years) Age at diagnosis (years) Years since diagnosis BMI (kg/m2) Weight (kg) Height (cm) CGI-S CGI-SCH1: Positive symptoms CGI-SCH2: Negative symptoms CGI-SCH3: Depressive symptoms CGI-SCH4: Cognitive symptoms PSP SF-12: Mental subscale SF-12: Physical subscale VAS: Quality of sleep VAS: Daytime drowsiness Treatment satisfaction Hospital stays (year before) Hospital days (year before)
All other oral antipsychotics
t-test
n
Mean
Median
SD
n
Mean
Median
SD
p Value
2865 2576 2576 2860 2860 2862 2862 2862 2862 2860 2861 2856 2784 2784 2850 2850 2788 2865 2865
39.28 29.13 9.84 26.32 76.25 169.89 4.23 3.64 3.59 2.77 3.08 53.38 36.46 44.10 57.90 41.49 3.58 0.42 16.23
38 27 7 26 75 170 4 4 4 3 3 55 36 44 61 42 3 0 0
12.49 10.23 9.27 5.16 17.25 9.92 1.07 1.46 1.30 1.31 1.31 16.16 11.39 8.86 27.75 27.50 1.31 0.75 43.36
1186 1031 1031 1185 1185 1186 1185 1184 1183 1184 1184 1183 1145 1145 1180 1180 1124 1186 1186
40.59 30.38 9.68 26.62 76.95 169.75 4.34 3.71 3.73 2.97 3.22 52.71 35.07 43.78 55.32 42.45 3.45 0.45 18.48
40 28 7 26 75 169 4 4 4 3 3 55 34 44 57 43 3 0 0
12.92 11.09 9.29 5.53 17.76 9.77 1.02 1.46 1.26 1.26 1.33 15.66 11.18 9.09 28.55 27.15 1.31 0.75 47.86
0.0025 0.0013 0.6245 0.1010 0.2416 0.6873 0.0026 0.1838 0.0020 0.0015 0.0039 0.2242 0.0005 0.3172 0.0078 0.3117 0.0048 0.2614 0.1444
BMI, body mass index; CGI-S, Clinical Global Impression–Severity; CGI-SCH: Clinical Global Impression–Schizophrenia; PSP: Personal and Social Performance Scale; SF-12: Short Form-12 item health survey; VAS: Visual Analogue Scale.
Table 2. Mean modal dose of antipsychotic treatment during the entire treatment course. Antipsychotic treatment
Amisulpride Aripiprazole Olanzapine Paliperidone ER Quetiapine Risperidone Ziprasidone
Patients
Modal dose (mg/day)
Licensed dose range (mg/day)
n*
%
Mean
SD
Range
102 187 167 2864 238 267 119
3 5 4 71 6 7 3
537.5 15.1 13.5 7.2 434.4 4.2 109.2
342.2 7.6 6.7 2.9 291 2.60 57.5
30–1600 3–45 3–40 3–27 25–1600 1–12 20–240
400–120018 10–3019 5–2020 3–129 150–75021 2–1622 40–16023
ER, extended release; SD, standard deviation. *ITT analysis set, the population of patients receiving other oral antipsychotics (n ¼ 107) was too heterogeneous for inclusion in this analysis.
Baseline characteristics of the ITT population are provided in Table 1. The mean (SD) age of patients in the ITT analysis set was 39.7 (12.6) years and 53.8% of patients were male. Baseline characteristics were comparable between the paliperidone ER group and the ‘all other oral antipsychotics’ group on most parameters; however, statistically significant differences (p50.05) were noted between the two treatment groups for some baseline characteristics (Table 1). The majority of the patients were outpatients; 18.4% of patients were hospitalized at baseline (17.6% in the paliperidone ER group and 20.2% in the ‘all other oral antipsychotics’ group). Of the 4051 patients included in the ITT analysis set for analysis of effectiveness, 3386 (83.6%) were considered completers, while documentation was discontinued prematurely for 665 (16.4%; Figure 1). All-cause study discontinuation (dropout) rates were comparable between the paliperidone ER group (16.8%) and the ‘all other ! 2014 Informa UK Ltd www.cmrojournal.com
oral antipsychotics’ group (15.5%). The most common reason for study discontinuation was ‘lost to follow-up’ (8.6% of all patients; Figure 1).
Dosing The mean modal dose of all antipsychotics was above the minimum licensed dose9,18–23 (Table 2). However, modal dose range data indicated doses above the maximum approved dose were prescribed for individual patients during the course of the study, for all oral antipsychotics with the exception of risperidone (Table 2). The mean daily dose of paliperidone ER at baseline was 6.0 (2.3) mg. The range of daily doses of paliperidone ER at baseline was 3–24 mg (approved dose range 3–12 mg/ day). The mean modal daily dose of paliperidone ER during the entire treatment course was 7.2 (2.9) mg Clinical effectiveness of paliperidone ER Schreiner et al.
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(range of modal daily doses of paliperidone ER during the entire course of treatment: 3–27 mg/day; Table 2).
polytherapy (defined as being treated with 41 antipsychotic at Day 28 after baseline) showed a greater betweengroup difference in time to discontinuation than in the total study cohort: the proportion of patients still receiving their newly initiated antipsychotic treatment after 12 months in the polytherapy subgroup was 74.1% for the paliperidone ER group and 68.8% for the ‘all other oral antipsychotics’ group (HR ¼ 0.83, 95% CI 0.65–1.05, p ¼ 0.12). When study dropouts were included in the definition of treatment discontinuation, the proportion of patients treated with polytherapy still receiving treatment after 12 months was 67.9% and 60.5% for the paliperidone ER and the ‘all other oral antipsychotics’ group, respectively (HR ¼ 0.78, 95% CI 0.63–0.96, p ¼ 0.017; Figure 2). The HR adjusted for baseline covariates was 0.79 (95% CI 0.63–1.00, p ¼ 0.05).
Clinical effectiveness
Time to discontinuation of initiated treatment There was no difference in the time to discontinuation of newly initiated antipsychotic treatments between the paliperidone ER group and the ‘all other oral antipsychotics’ group. The proportion of patients still on treatment after 12 month follow-up was 73.9% in the paliperidone ER group and 73.2% in the ‘all other oral antipsychotics’ group (p ¼ 0.948). When study dropouts were included in the definition of treatment discontinuations, the proportion of patients still receiving treatment after 12 months was 66.6% and 63.8% in the paliperidone ER group and the ‘all other oral antipsychotics’ group, respectively (HR ¼ 0.92, 95% CI 0.82–1.03, p ¼ 0.145). Post hoc analyses of the primary endpoint in the subgroup of patients (28%; 1140/4051) receiving drug
Time to hospitalization There was no significant difference in the time to hospitalization between the paliperidone ER group and the ‘all other oral antipsychotics’ group. Overall, 27% of patients were hospitalized during the year following treatment initiation. The proportion of patients without hospitalization 12 months after initiation of treatment was 85.0% in the paliperidone ER group and 83.2% in the ‘all other oral
100
Paliperidone ER All other
86.7%
90
79.5% Patients still on initial treatment (%)
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Treatment outcomes were documented prospectively for time to treatment discontinuation, time to first postbaseline hospitalization, overall severity of symptoms, personal and social performance as well as health related quality of life and quality of sleep.
80
71.5% 67.9%
81.7% 70
p=0.017
70.9%
60
64.5% 60.5%
50 40 30 20 10 0 0
90
160
270
360
583 211
436 160
Days since baseline N patients at risk: n= 813 n= 327
705 267
646 232
Kaplan–Meier curve indicating 95% confidence intervals, intent-to-treat analysis set; patients treated with polytherapy (dropout=event)
Figure 2. Time to discontinuation of initial treatment: subgroup of patients treated with polytherapy (dropout ¼ event).
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94.2%
100
Paliperidone ER All other 84.5%
88.9% 90 Patients still on initial treatment (%)
91.9%
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2014
80.6%
80 82.9% 78.3%
70
75.2% p=0.049
60 50 40 30 20 10 0 0
90
160
270
360
622 235
451 176
Days since baseline N patients at risk: n= 813 n= 327
742 295
682 256
Kaplan–Meier curve indicating 95% confidence intervals, intent-to-treat analysis set; patients treated with polytherapy
Figure 3. Time to hospitalization: patients treated with polytherapy.
antipsychotics’ group (p ¼ 0.14). Post hoc analysis on the time to first hospitalization amongst patients receiving polytherapy revealed a larger between-group difference between paliperidone ER and the ‘all other oral antipsychotics’ group than in the total patient cohort: 80.6% of patients were without hospitalization after 12 months for the paliperidone ER group, compared with 75.2% for the ‘all other oral antipsychotics’ group (HR ¼ 0.76, 95% CI 0.58–1.00, p ¼ 0.049; Figure 3). The adjusted HR, based on the multivariate Cox model, adjusting for baseline covariates was 0.75 (95% CI 0.54–1.03, p ¼ 0.07). The greatest difference in time to first hospitalization was between patients newly initiated on paliperidone ER (n ¼ 2309 [80.6%] without hospitalization at 12 months), and those newly initiated on risperidone (n ¼ 183 [68.5%] without hospitalization at 12 months; adjusted HR ¼ 0.55, 95% CI 0.32–0.94, p ¼ 0.03) and quetiapine (n ¼ 157 [65.8%] without hospitalization at 12 months; adjusted HR ¼ 0.52, 95% CI 0.31–0.88, p ¼ 0.016). Pre- versus post-baseline analysis showed that there was a numerically greater decrease in the proportion of patients hospitalized in the paliperidone ER group (30% of patients hospitalized pre-baseline; 25% hospitalized post-baseline) than in the ‘all other antipsychotics’ group (32% of patients hospitalized pre-baseline; 29% hospitalized postbaseline). However, this difference did not reach statistical significance. ! 2014 Informa UK Ltd www.cmrojournal.com
Other outcome measures Additional outcome measures for patients treated with paliperidone ER and ‘all other oral antipsychotics’ are presented in Table 3. Improvements in overall severity of symptoms (mean CGI-S and CGI-SCH scores), healthrelated quality of life (SF-12 Mental), quality of sleep and daytime drowsiness (VAS scores), as well as patients’ treatment satisfaction were comparable between the paliperidone ER group and the ‘all other oral antipsychotics’ group. Results that reached statistical significance were a greater improvement over time in patients in the paliperidone ER group than in the ‘all other oral antipsychotics’ group in patient functioning, based on change in PSP scale score (þ14.2 vs þ13.1, p ¼ 0.041) and the physical component of quality of life (SF-12 Physical scores; þ3.9 vs þ2.9, p ¼ 0.003), based on a mixed model. Although the protocol was not designed to detect differences with individual antipsychotics, it was apparent that the improvement in CGI-S score over time was significantly more pronounced for paliperidone ER (mean CGI-S score reduced from 4.2 to 3.2) than for quetiapine (mean CGI-S score reduced from 4.2 at baseline to 3.5 at 12 months; p50.0001 [both unadjusted and adjusted]), and significantly less pronounced than for olanzapine (mean CGI-S score reduced from 4.5 at baseline to 3.2 at 12 months; p50.026 [unadjusted] and p ¼ 0.024 Clinical effectiveness of paliperidone ER Schreiner et al.
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Table 3. Mean changes of additional outcomes.
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Outcome measure
Paliperidone ER
All other oral antipsychotics
Baseline
Month 12
Change
Baseline
Month 12
Change
All individual antipsychotics: range
CGI-S (mean score) CGI-SCH (mean score) Positive symptoms Negative symptoms Depressive symptoms Cognitive symptoms PSP (mean score)
4.2
3.2
1.0
4.3
3.3
1.0
0.7–1.3
3.6 3.6 2.8 3.1 53.3
2.4 2.7 2.0 2.3 67.5
1.2 0.9 0.8 0.8 þ14.2 p ¼ 0.041*
3.7 3.7 3.0 3.2 52.8
2.5 2.9 2.1 2.5 65.9
1.2 0.8 0.9 0.7 þ13.1
1.0–1.5 0.8–1.0 0.8–1.0 0.7–0.8 þ8.5–þ16.0
SF-12 (mean score) SF-12 Physical
44.0
47.9
43.9
46.8
þ2.9
þ1.9–þ3.9
36.5
43.8
þ3.9 p ¼ 0.003* þ7.3
35.0
42.5
þ7.5
þ6.5–þ9.9
58.0 41.5 3.6
75.2 25.1 5.0
þ17.2 16.4 þ1.4
55.3 42.5 3.4
73.2 27.0 5.0
þ17.9 15.5 þ1.6
þ9.3–þ25.3 10.7–17.8 þ1.2–þ1.8
65.8 83.9 26.3
54.0 67.9 26.8
11.8 16.0 þ0.5
66.9 84.0 26.6
58.3 69.5 27.3
8.6 14.5 þ0.7
5.2–14.7 2.1–16.7 þ0.2–þ1.7
37.1 7.9
36.2 5.0
0.9 2.9
33.6 7.9
33.0 5.7
0.6 2.2
3.1–þ3.4 1.0–4.3
SF-12 Mental Visual analogue scale (mean score) Quality of sleep Daytime drowsiness Treatment satisfaction (mean score) Healthcare resource utilization (% of patients) Concomitant medications Outpatients visits Patient characteristics (mean BMI [kg/m2]) Substance abuse (% of patients) Tobacco Alcohol, cannabis and other
BMI, body mass index; CGI-S, Clinical Global Impression–Severity; CGI-SCH, Clinical Global Impression–Schizophrenia; PSP, Personal and Social Performance Scale; SF-12, Short Form 12 item health survey. With the exception of mean change in BMI, all changes in score presented in Table 3 represent an improvement in clinical status/patient condition. *Improvement in mean score over time significantly different at the 5% level (mixed model) when paliperidone ER group compared to the ‘all other oral antipsychotics’ group.
[adjusted]). Improvement in CGI-SCH positive symptoms score over time was also significantly less for quetiapine (mean score reduced from 3.5 at baseline to 2.5 with quetiapine at 12 months) compared with paliperidone ER (3.6 reducing to 2.4 at 12 months; p50.005); a similar result was also observed for CGI-SCH negative symptoms (reduced from 3.7 to 2.9 with quetiapine vs 3.6 to 2.7 with paliperidone ER; p ¼ 0.016). All results were based on a RMMM approach. There was a similar change in BMI for the paliperidone ER group and the ‘all other oral antipsychotics’ group. However, when comparing the subgroup of patients newly initiated on olanzapine, the mean increase in BMI was significantly higher (mean increase of 1.7 kg/m2) than with paliperidone ER (0.5 kg/m2; p50.0001). The decrease in the number of patients with substance abuse over time was similar in the paliperidone ER group and the ‘all other oral antipsychotics’ group (Table 3).
proportion of patients receiving antipsychotic monotherapy at Day 28 after baseline was comparable between treatment groups (71.6% of patients in the paliperidone ER group and 72.4% of patients in the ‘all other oral antipsychotics’ group). The majority of patients treated with polytherapy (multiple antipsychotics at Day 28 after baseline; 1140/4051) were receiving the newly initiated antipsychotic in addition to another, either newly initiated, or pre-existing oral FGA or SGA. There was a decrease in the proportion of patients taking any concomitant medications from baseline to Month 12 and a similar trend from baseline to Month 12 in the percentage of patients with outpatient visits. There was also a trend for a decrease in both groups in the proportion of patients taking anticholinergics and benzodiazepines/sedatives/anxiolytics (Table 3).
Safety Healthcare resource utilization Overall, 71.9% (2911/4051) of patients were receiving oral antipsychotic monotherapy at Day 28 after baseline. The 8
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The incidence of adverse drug reactions (ADRs) and AEs was comparable between the paliperidone ER and the ‘all other oral antipsychotics’ group in the retrospective data collection as well as in the prospective phase of the study. www.cmrojournal.com ! 2014 Informa UK Ltd
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Table 4. Frequency and system class of ADRs/AEs.
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Patients experiencing 1 event ADRs during the retrospective period Serious ADRs AEs during the prospective period Serious AEs
Paliperidone ER (% of patients)
All other oral antipsychotics (% of patients)
27.7 1.1 37.1 13.1
29.1 2.0 36.5 14.0
Most common adverse events reported during the prospective period (2% in any treatment group) Schizophrenia 7.8 4.5 Weight increase 3.7 4.4 Psychotic disorder 3.5 4.3 EPS 2.3 1.6 Insomnia 2.2 2.2 Fatigue 1.4 2.1 ADR, adverse drug reaction; AE, adverse event; ER, extended release; EPS, extrapyramidal symptom.
The incidence of AEs and most common AEs reported during the prospective data collection period are presented in Table 4. During the retrospective period the most common ADRs experienced by patients in both groups were increase in weight (5.2%), schizophrenia (3.3%) and extrapyramidal symptoms (3.0%). During the study there were numerically more deaths in the paliperidone ER group (n ¼ 18 [0.6%]) than in the ‘all other oral antipsychotics’ group (n ¼ 2 [0.2%]). For the paliperidone ER group, the majority of deaths were considered not related (11/18) or doubtfully related (5/18) to study treatment. The causes of death for the two patients in the ‘all other antipsychotics’ group were considered to be not related to any of the individual antipsychotics. The cause of death was considered by the investigator as possibly related to paliperidone ER in two patients: one patient died from cardiac failure and one patient committed suicide. While the death due to cardiac failure was considered possibly related to the prescribed medication by the treating physician, this patient had discontinued paliperidone ER approximately 7 months before death.
Discussion This observational study was designed to document prescribing patterns in daily clinical practice and to assess long-term treatment outcomes related to initiation of treatment with oral antipsychotics. Important data on the effectiveness and long-term treatment outcomes related to initiation of treatment with paliperidone ER and other oral antipsychotics in a naturalistic setting were gathered. Effectiveness endpoint data, along with the finding that fewer than one third of patients (28%) required antipsychotic polytherapy in both groups, indicate that the effectiveness of paliperidone ER was comparable to that of the ! 2014 Informa UK Ltd www.cmrojournal.com
‘all other oral antipsychotics’ group. The ‘all other oral antipsychotics’ group consisted of patients receiving highly heterogeneous medications including FGAs, and comparison of paliperidone ER with other individual SGAs was therefore relevant. These comparisons demonstrated important significant differences compared with other specific SGAs in relation to outcomes such as hospitalization, clinical symptoms (based on CGI-S, CGISCH), body weight and BMI. Data from this naturalistic study demonstrate that patients receiving paliperidone ER had significantly greater improvements in PSP scale scores than those receiving other SGAs. This finding is in line with randomized controlled pivotal trials that have demonstrated significant and clinically relevant improvement of patients’ personal and social performance following treatment with paliperidone ER11–13. It is also consistent with previous findings that treatment with paliperidone ER can result in significantly better personal and social functioning than treatment with oral risperidone24. The discontinuation rates and safety analyses documented in this study indicate that the tolerability of paliperidone ER in general was comparable to that of ‘all other oral antipsychotics’. However, as mentioned above, this grouped comparison of all oral antipsychotics other than paliperidone may mask significant differences between individual antipsychotics. The safety data in this study are in line with the tolerability profile of paliperidone ER documented in previous randomized placebo-controlled trials11–13. Paliperidone ER was found to have an advantage over olanzapine in maintaining BMI and body weight. This finding has also been documented in a recent head-to-head trial of paliperidone ER compared with oral olanzapine25. Evidence from meta-analyses indicates that some SGAs may be associated with increased risk of weight gain and metabolic changes in comparison with FGAs. The benefits of paliperidone ER Clinical effectiveness of paliperidone ER Schreiner et al.
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when compared with other widely used SGAs such as olanzapine is therefore clinically relevant, in particular since a substantial proportion of patients with schizophrenia are overweight or obese and often have numerous additional cardiovascular risk factors (such as smoking, lack of exercise and poor diet)26. Physical quality of life scores were also significantly more improved with paliperidone ER vs other SGAs in this study. There is currently much focus on improving physical health in individuals with mental health problems27, and these findings regarding physical quality of life and BMI are therefore particularly salient. The tolerability profile of paliperidone ER may, in part, reflect the drug’s distinct pharmacodynamic and pharmacokinetic characteristics15. Post hoc analyses of a subgroup of patients receiving polytherapy revealed that time to treatment discontinuation and time to first hospitalization were significantly longer for patients initiated on paliperidone ER, compared with the ‘all other oral antipsychotics’ group. This finding suggests that treatment with paliperidone ER may be particularly beneficial in a subgroup of patients whose outcomes have previously been thought to be suboptimal17,28. The favorable effects of paliperidone ER in patients concomitantly treated with other antipsychotic medications may in part relate to the drug’s limited hepatic metabolism9 and low propensity to cause hepatic drug–drug interactions15. Around 50% of patients with schizophrenia are reported to be prescribed more than one concomitant antipsychotic therapy29,30; the improved outcomes with paliperidone ER within this subgroup are therefore relevant for clinical practice. In this current registry study, we report a decrease in healthcare resource utilization from baseline to endpoint for patients receiving either paliperidone ER or ‘all other antipsychotics’, as demonstrated by the proportion of patients taking any concomitant medications, as well as a decrease in the percentage of patients with outpatient visits, using anticholinergics and benzodiazepines/sedatives/anxiolytics from baseline to Month 12. These data provide important information that will inform the design of future cost-effectiveness analyses based on rigorous comparative assessments. Gaining a clearer understanding of the impact of individual treatments on healthcare resource utilization in patients with schizophrenia has the potential to reduce overall healthcare costs directly31 and to reduce societal or indirect costs by reducing the care time required by carers and by providing patients opportunities to return to employment. This study is limited by the inherent difficulties associated with data collected within a naturalistic setting. As with any non-randomized, non-interventional observational study, there may be treatment assignment bias and baseline differences between the treatment groups – as evidenced by a number of significant differences in baseline characteristics between the paliperidone ER group and 10
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the ‘all other oral antipsychotics group’. Consequently, despite the use of statistical multivariate modeling approaches to adjust for these differences, direct comparisons of outcomes from the treatment groups may still be difficult to interpret since baseline differences may influence the results.
Conclusions The data captured in the PILAR registry provide valuable information on the prescribing habits and treatment outcomes associated with use of oral antipsychotics in a naturalistic setting. Furthermore, the findings expand on the evidence obtained from randomized controlled clinical trials with paliperidone ER and support previous positive findings of the functional improvement and treatment satisfaction associated with paliperidone ER32. The differences between paliperidone ER and individual oral antipsychotics highlight the heterogeneous nature of SGAs in terms of effectiveness and adverse effects, and indicate that treatment needs to be individualized to each patient33. The data captured in this registry also provide important information that will inform the design of future studies and cost-effectiveness analyses involving more rigorous comparative assessments.
Transparency Declaration of funding This study was funded by Janssen Pharmaceutical Companies of Johnson & Johnson in Europe, Middle East & Africa (EMEA). All authors contributed to interpretation of the results, developed the draft of the manuscript, participated in subsequent revisions and read and approved the final manuscript. Declaration of financial/other relationships A.S. has disclosed that he is a full-time employee of Janssen-Cilag Medical & Scientific Affairs Europe, Middle East & Africa and a shareholder of Johnson & Johnson. K.H. and J.I.L. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. I.L. has disclosed that she has acted as a presenter on behalf of Janssen Cilag. A.H.S. has disclosed that he has received grants from and participated in research with Pfizer, Lundbeck, Janssen Cilag and Otsuka, acted as a presenter on behalf for: AstraZeneca, Eli Lilly, Lundbeck, Janssen Cilag, Sanofi Aventis and Servier as well as attended advisory board meetings for Pfizer and Otsuka. L.H. has disclosed that he is a full-time employee of Janssen-Cilag Medical & Scientific Affairs Europe, Middle East & Africa. J.D. has disclosed that he is a full-time employee of Janssen-Cilag Market Access Europe, Middle East & Africa. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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Acknowledgments Medical writing assistance with the preparation of this manuscript was provided by ApotheCom ScopeMedical and funded by Janssen EMEA. The authors thank all the PILAR investigators and nurses, patients and their families for their participation in the registry. They also thank Angelika Mehnert for her contribution to the discussion and interpretation of the statistical analysis results.
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Clinical effectiveness of paliperidone ER Schreiner et al.
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