Scholarly article on topic 'Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia'

Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia Academic research paper on "Clinical medicine"

CC BY-NC-ND
0
0
Share paper
Academic journal
Schizophrenia Research
OECD Field of science
Keywords
{Schizophrenia / "Paliperidone palmitate" / "Long-acting injectable and oral antipsychotics" / "Randomized controlled trial" / "Recently diagnosed" / "Relapse prevention"}

Abstract of research paper on Clinical medicine, author of scientific article — Andreas Schreiner, Kaire Aadamsoo, A. Carlo Altamura, Manuel Franco, Philip Gorwood, et al.

Abstract Objective Relapse and acute exacerbation are common in schizophrenia and may impact treatment response and outcome. Evidence is conflicting in respect to superiority of long-acting injectable antipsychotic therapies versus oral antipsychotics in relapse prevention. This randomized controlled study assessed the efficacy of paliperidone palmitate versus oral antipsychotics for relapse prevention. Method Eligible patients with a recent diagnosis of schizophrenia (within 1–5years) were randomized 1:1 to paliperidone palmitate (n=376) or oral antipsychotic monotherapy (n=388) and entered a 2-week initial acute oral treatment phase. Patients who met predefined response criteria were eligible to enter the 24-month rater-blinded core treatment phase. Patients were evaluated for relapse, symptoms, functioning, quality of life, treatment satisfaction, and tolerability. Results In the core treatment phase, time to relapse was significantly longer in the paliperidone palmitate (n=352) compared with the oral antipsychotics arm (n=363): 85% of patients were relapse-free at 469 versus 249days (P =0.019). Significantly fewer patients receiving paliperidone palmitate met the relapse criteria (52 [14.8%] versus 76 [20.9%, oral antipsychotics]; P =0.032), representing a 29.4% relative risk reduction. For paliperidone palmitate, a significantly greater improvement in Positive and Negative Syndrome Scale total score on Day 8 (P =0.021) and a trend at endpoint (P =0.075) were observed. Functioning improvements were comparable between treatment arms. No new safety signals were identified. Conclusion The observed time to relapse superiority of paliperidone palmitate over oral antipsychotics provides further evidence for the value of long-acting injectable antipsychotic therapies in the treatment of schizophrenia, including during the early stages of illness.

Academic research paper on topic "Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia"

ELSEVIER

Contents lists available at ScienceDirect

Schizophrenia Research

journal homepage: www.elsevier.com/locate/schres

Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia

Andreas Schreiner a'*, Kaire Aadamsoo b, A. Carlo Altamurac, Manuel Franco d, Philip Gorwood e, Nikolaj G. Neznanovf, Juan Schronen g, Alp Ucok h, Mathias Zink ', Adam Janikj, Pierre Cherubin k, Marjolein Lahaye Ludger Hargarter a

a Medical Affairs, Janssen CilagEMEA, Neuss, Germany b North Estonia Medical Centre Foundation, Tallinn, Estonia

c Department of Psychiatry, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy

d Psychiatric Department, Zamora Hospital, Zamora, Spain

e Hôpital Sainte-Anne, Paris Descartes University (INSERM U894), France

f St Petersburg V.M. Bekhterev Psychoneurological Research Institute, St Petersburg, Russia

g Welgemoed Medical Centre, Cape Town, South Africa

h Istanbul Medical Faculty, Istanbul, Turkey

i Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany j Global Clinical Operations, Janssen-Cilag, Warsaw, Poland k Medical Affairs, Janssen CilagEMEA, Issy-les-Moulineaux, France l Biostatistics, Janssen Cilag Benelux, Tilburg, The Netherlands

ARTICLE INFO ABSTRACT

Objective: Relapse and acute exacerbation are common in schizophrenia and may impact treatment response and outcome. Evidence is conflicting in respect to superiority of long-acting injectable antipsychotic therapies versus oral antipsychotics in relapse prevention. This randomized controlled study assessed the efficacy of paliperidone palmitate versus oral antipsychotics for relapse prevention.

Method: Eligible patients with a recent diagnosis of schizophrenia (within 1-5 years) were randomized 1:1 to paliperidone palmitate (n = 376) or oral antipsychotic monotherapy (n = 388) and entered a 2-week initial acute oral treatment phase. Patients who met predefined response criteria were eligible to enter the 24-month rater-blinded core treatment phase. Patients were evaluated for relapse, symptoms, functioning, quality of life, treatment satisfaction, and tolerability.

Results: In the core treatment phase, time to relapse was significantly longer in the paliperidone palmitate (n = 352) compared with the oral antipsychotics arm (n = 363): 85% of patients were relapse-free at 469 versus 249 days (P = 0.019). Significantly fewer patients receiving paliperidone palmitate met the relapse criteria (52 [14.8%] versus 76 [20.9%, oral antipsychotics]; P = 0.032), representing a 29.4% relative risk reduction. For paliperidone palmitate, a significantly greater improvement in Positive and Negative Syndrome Scale total score on Day 8 (P = 0.021) and a trend at endpoint (P = 0.075) were observed. Functioning improvements were comparable between treatment arms. No new safety signals were identified.

Conclusion: The observed time to relapse superiority of paliperidone palmitate over oral antipsychotics provides further evidence for the value of long-acting injectable antipsychotic therapies in the treatment of schizophrenia, including during the early stages of illness.

© 2015 Janssen Pharmaceutica NV. Published by Elsevier B.V. This is an open access article under the CC BY-NC-

ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

CrossMark

Article history:

Received 24 February 2015

Received in revised form 10 August 2015

Accepted 11 August 2015

Available online 1 October 2015

Keywords: Schizophrenia Paliperidone palmitate

Long-acting injectable and oral antipsychotics Randomized controlled trial Recently diagnosed Relapse prevention

1. Introduction

Despite the availability of effective treatment for schizophrenia, relapse and acute exacerbations are common (Emsley et al., 2013a). Response to treatment after relapse is variable; some patients display

* Corresponding author. E-mail address: aschrein@its.jnj.com (A. Schreiner).

emergent refractoriness following relapse even when the interval between onset of first relapse symptoms and initiation of treatment is brief (Emsley et al., 2013b).

Evidence regarding the superiority of long-acting injectable antipsychotic therapies (LATs) over oral antipsychotics in terms of relapse prevention is conflicting (Leucht et al., 2011; Kishimoto et al., 2013; Kishimoto et al., 2014), with long-term comparisons scarce (Kane et al., 2010; Rosenheck et al., 2011). Hence, naturalistic and

http: //dx.doi.org/10.1016/j.schres.2015.08.015

0920-9964/© 2015 Janssen Pharmaceutica NV. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

appropriately designed studies are needed to compare these treatment options (Kirson et al., 2013; Alphs et al., 2014), particularly in recently diagnosed patients with schizophrenia. The Prevention of Relapse with Oral Antipsychotics versus Injectable Paliperidone Palmitate (PROSIPAL) study was a randomized controlled, open-label, rater-blinded study that assessed the efficacy of paliperidone palmitate (PP) (Janssen-Cilag International NV, 2015), an atypical LAT, compared with oral antipsychotic monotherapy, in recently diagnosed patients with schizophrenia.

2. Methods

2.1. Study design

This multicenter, randomized, prospective, active-controlled, open-label, rater-blinded, international 24-month study in recently diagnosed (within 1-5 years) patients with schizophrenia (NCT01081769) was conducted in 141 centers across 26 countries (Appendix); it comprised a 2-week initial acute oral treatment phase and a 24-month core treatment phase.

Patients expected by the investigator to benefit from switching to one of the study medications were eligible to enter the initial acute oral treatment phase; patients were eligible for the core treatment phase if they then met all predefined response criteria:

• A score of <4 for at least four of the following Positive and Negative Syndrome Scale (PANSS) items: P1 (delusions), P2 (conceptual disorganization), P3 (hallucinatory behavior), P6 (suspiciousness/persecu-tion), P7 (hostility), and G8 (uncooperativeness) and

• Clinical Global Impression-Severity (CGI-S) score < 4, and

• No intolerable side effects of study medication.

Patients were maintained on PP or on the same oral antipsychotic (aripiprazole, quetiapine, olanzapine, paliperidone extended-release [ER], risperidone, or haloperidol as clinically indicated by the investigator) until the end of the core treatment phase, or until relapse or withdrawal from study.

The protocol was reviewed and approved by the Independent Ethics Committee/Institutional Review Board in each participating country. The study was conducted in accordance with the Declaration of Helsinki (2008) and Good Clinical Practice (International Conference on Harmonisation). Eligible patients were informed of the risks and benefits of the trial and were required to provide written informed consent for participation during an initial screening visit (Visit 1 [Day — 14]). Standard medical and psychiatric assessments were completed to confirm the patients' clinical history and current symptomatology.

2.2. Subjects

2.2.1. Key inclusion criteria

Patients experiencing an acute episode of schizophrenia with a PANSS total score of 70-120 at screening were eligible for this study if aged 18-65 years, with a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth edition) criteria made 1-5 years previously and a history of >2 relapses requiring psychiatric hospitalization in the preceding 24 months; this may have included the current acute episode.

2.2.2. Key exclusion criteria

Patients were not eligible if they were antipsychotic-naive, considered by the investigator to be treatment-resistant or unsuitable for treatment with an atypical oral antipsychotic or oral haloperidol mono-therapy, or had received clozapine within the previous 3 months. Other exclusion criteria included use of LATs within three injection cycles before screening, starting a psychotherapy program within 2 months

preceding baseline, a history or current symptoms of tardive dyskinesia or a history of neuroleptic malignant syndrome, or involuntary hospitalization.

2.3. Treatment

2.3.1. initial 2-week acute oral treatment phase

After screening, patients were randomized (1:1) to either PP or oral antipsychotic treatment and immediately entered the 2-week initial acute oral treatment phase. Patients randomized to PP had their previous oral antipsychotic replaced with oral paliperidone ER (dose range: 3-12 mg once daily). Patients randomized to oral antipsychotics had their previous oral antipsychotic (Supplementary Table 1) replaced with an oral antipsychotic different to the one they were using when they relapsed, as clinically indicated by the investigator. In both treatment arms, previous oral antipsychotics were tapered off over a maximum of 7 days.

A maximum of five, from a possible six, different oral antipsychotics (haloperidol plus four out of five oral atypical antipsychotics) were available to each study site; investigators could choose to prescribe any to the first randomized patient at their site. Subsequent patients were each prescribed a different oral antipsychotic at the investigator's discretion, to ensure equal distribution of medications. If >4 patients were allocated to the oral antipsychotic arm at a single site, all treatments were again made available to that site such that for the fifth patient the investigator was again able to choose from five oral antipsychotics. Oral antipsychotics were dispensed for self-administration and at each visit; patients were reminded to take their medication. The investigator or designated study personnel maintained a log of all drugs dispensed and returned (pill counts) at each visit; no routine blood level tests were conducted. Drug supplies for each patient were inventoried and accounted for throughout the study.

2.3.2.24-month core treatment phase

Patients randomized to PP received intramuscular PP 150 mg eq. on Day 1 (deltoid), 100 mg eq. on Day 8 (deltoid), 75 mg eq. on Day 38 (deltoid or gluteal), and once monthly thereafter with flexible dosing 25-150 mg eq. (deltoid or gluteal). Patients randomized to the oral antipsychotic arm continued on the same drug that they had been prescribed in the initial acute oral treatment phase, at the dose defined by the investigator. Dose adjustments were permissible throughout the study within the locally-approved dose range. Assessments were performed on Day 1, Day 8, and then monthly for the first 4 months, at 6 months and quarterly thereafter until Month 24. Adverse events and concomitant medications were recorded continuously. Upon relapse, treatment with study medication was terminated; an alternative antipsychotic could be started at the investigator's discretion.

2.4. Efficacy assessments

The primary efficacy outcome was time to relapse per criteria described by Csernansky et al. (2002) (Appendix). Secondary outcomes included the proportion of patients with relapse at endpoint, PANSS total and subscale scores, Marder factor scores (Marder et al., 1997), percentage of treatment responders (>30% decrease in PANSS total score from baseline to last observation carried forward endpoint [LOCF, 24 months or at early discontinuation]), CGI-S and Clinical Global Impression-Change (CGI-C) (Guy, 1972), Personal and Social Performance (PSP) scale (Morosini et al., 2000), Short Form (36) Health Survey (SF-36) (Ware and Sherbourne, 1992, Ware and Gandek, 1994), European Quality of Life-5 Dimensions (EQ-5D) (EuroQol Group, 1990), Subjective Well-Being under Neuroleptics Scale (SWN-S) (Naber, 1995), patient treatment satisfaction (Treatment Satisfaction Questionnaire for Medication; TSQM) (Atkinson et al., 2004), and physician's treatment satisfaction (7-point categorical scale).

2.5. Safety and tolerability

Safety and tolerability assessments included treatment-emergent adverse events (TEAEs), extrapyramidal symptoms (using the Abnormal Involuntary Movement Scale [AIMS], Barnes Akathisia Rating Scale [BARS], and Simpson Angus Rating Scale [SAS]), and changes in body weight and body mass index. No protocol-based laboratory tests were obligatory.

2.6. Data analysis.

The whole intent-to-treat (ITT) population included all randomized patients who received > 1 dose of study medication during the 2-week initial acute oral treatment phase. The core ITT population comprised patients who responded to the 2-week initial acute oral treatment phase and received > 1 dose of study medication in the 24-month core treatment phase. Efficacy and safety analyses were performed on core ITT patients who had at least one post-baseline (Day 1 of the 24-month core treatment phase [Visit 2, responder assessment]) efficacy or safety measurement, respectively, in the 24-month core treatment phase.

The sample size was calculated based on the primary efficacy variable 'time to a relapse event', assuming that the proportion of patients experiencing a relapse event during the core treatment phase would be 20% in patients receiving PP and 30% in those receiving oral antipsychotics. In total, 296 patients per treatment arm and 143 events were required to detect this difference, with a power of 80% and two-tailed significance level of 5%. Assuming that 3% of subjects would not be included in the survival analysis, 306 subjects per treatment group (1:1 randomization ratio) were required in the 24-month core treatment phase.

Descriptive statistics were computed for efficacy and safety assessments when appropriate. All statistical analyses were two-tailed; conclusions were based on 5% significance. Two-sided 95% confidence

intervals were computed where applicable. Time to relapse was analyzed using standard methods including Kaplan-Meier product-limit survival curve estimates for the 85th percentile, representing the lowest percentile for which estimates for both treatment arms were available, log-rank tests, and proportional hazard regression models. For secondary efficacy assessments, change from baseline at each visit and at LOCF endpoint were analyzed using the Wilcoxon signed-rank test; differences between treatment groups were analyzed using the Wilcoxon two-sample test. Categorical variables, e.g. response rates, were evaluated using Fisher's exact test. Unless otherwise stated, all efficacy assessments reported at endpoint refer to LOCF endpoint.

3. Results

3.1. Baseline demographics and patient disposition

Overall, 775 patients provided informed consent; of these, 769 were randomized and entered the 2-week initial acute oral treatment phase (Fig. 1). No significant differences were observed between the two arms for any baseline demographic (Table 1).

Overall, 91.5% of patients randomized to PP received the drug as specified per protocol; mean average dose from the fourth injection inclusive (i.e. during the flexible dosing period onwards) was 101.7 ± 29.3 mg eq. Mean modal daily doses of the oral antipsychotics are described in Table 2.

3.2. Efficacy outcomes

Time to relapse (primary outcome) was significantly longer in patients receiving PP compared with those receiving oral antipsychotics (P = 0.019; hazard ratio 1.5; 95% confidence interval 1.1,2.2). The 85th percentile for time to relapse was 469 days for PP versus 249 days for oral antipsychotics. Significantly fewer patients receiving PP met the

Fig. 1. Flow and outcomes of the study population.

*Of the study completers, 62.5% (PP) and 55.9% (oral APs) of patients completed their Month 24 visit. AP = antipsychotic, ITT = intent-to-treat, PP = paliperidone palmitate.

Table 1

Patient demographics and baseline characteristics in the core ITT population.

Paliperidone palmitate Oral APs Total

Characteristic (n = 352) (n = 363) (N = 715)

Mean age, years (SD) 32.6 (10.7) 32.6 (10.1) 32.6 (10.4)

Sex, n (%)

Male 213 (60.5) 201 (55.4) 414 (57.9)

Female 139 (39.5) 162 (44.6) 301 (42.1)

Mean weight, kg (SD)* 74.8 (15.4) 75.7 (14.8) 75.3 (15.1)

Mean BMI, kg/m2 (SD)* 25.5 (4.7) 25.8 (4.4) 25.7 (4.6)

Psychiatric history

Paranoid subtype, n (%) 308 (87.5) 308 (84.8) 616 (86.2)

Mean age at diagnosis, years (SD) 30.1 (10.6) 30.1 (10.1) 30.1 (10.4)

Mean age at start of first AP treatment, years (SD)* 29.1 (10.5) 29.2 (10.0) 29.1 (10.2)

Mean time from diagnosis to study entry, years (SD) 3.0 (1.7) 2.9 (1.5) 2.9 (1.6)

Mean time from start of first AP treatment to study entry, years (SD)* 4.0 (3.0) 3.8 (2.4) 3.9 (2.7)

Ever been hospitalized, n (%)* 328 (93.2) 332 (91.7) 660 (92.4)

Previous hospitalizations, mean (SD)T 3.1 (2.1) 3.1 (2.2) 3.1 (2.2)

Currently hospitalized, n (%)' 106 (32.3) 108 (32.5) 214 (32.4)

Suicide attempts since diagnosis, n (%)

1 12 (3.4) 18 (5.0) 30 (4.2)

>2 10 (2.8) 9 (2.5) 19 (2.7)

Baseline PANSS total score, mean (SD)§ 82.5 (12.0) 81.5 (11.7) -

Baseline CGI-S, mean (SD)§ 3.9 (0.4) 3.8 (0.4) -

Baseline PSP total score, mean (SD)' 55.3 (11.3) 55.3 (11.1) -

Previous antipsychotic medications used by >5% patients1, n (%)

Haloperidol 43 (12.2) 42 (11.6) 85 (11.9)

Olanzapine 36 (10.2) 21 (5.8) 57 (8.0)

Risperidone 62 (17.6) 64(17.6) 126 (17.6)

Trifluoperazine 13 (3.7) 25 (6.9) 38 (5.3)

Comorbidities in > 10% of patients, n (%)

Cardiovascular 37 (10.5) 38 (10.5) 75 (10.5)

Eyes, ears, nose and throat 36 (10.2) 44(12.1) 80 (11.2)

Gastrointestinal 43 (12.2) 47 (12.9) 90 (12.6)

Neurologic 33 (9.4) 38 (10.5) 71 (9.9)

Psychiatric 35 (9.9) 44(12.1) 79 (11.0)

AP = antipsychotic, BMI = body mass index, CGI-S = Clinical Global Impression-Severity, ITT = intent-to-treat, n = number of patients, PANSS = Positive and Negative Syndrome Scale, PSP = Personal and Social Performance, SD = standard deviation. * n = 352 (PP), n = 362 (oral APs). T n = 325 (PP), n = 331 (oral APs). J n = 328 (pp), n = 332 (oral APs). § n = 350 (PP), n = 360 (oral APs), Day 1 visit. ' n = 346 (PP), n = 355 (oral APs), Day 1 visit. 1 Prior to the initial acute phase of treatment.

relapse criteria (52 [14.8%] versus 76 [20.9%, oral antipsychotics]; P = 0.032), representing a 29.4% relative risk reduction (Fig. 2).

Secondary outcomes are described in Supplementary Table 2. A statistically significantly greater improvement in PANSS total score was observed on Day 8 (mean change -4.8 versus — 3.7 [oral antipsychotics]; P = 0.021); a trend in favor of PP was observed at endpoint (mean change —16.6 versus —14.1 [oral antipsychotics]; P = 0.075) (Supplementary Fig. 1). At endpoint, a >30% improvement in PANSS total score was observed in 75.6% (PP) versus 69.4% (oral antipsychotics) of patients (P = 0.079). Both treatment arms showed comparable significant

improvements at every time point for PANSS total score. Significantly greater improvements were observed in favor of PP for the PANSS General Psychopathology subscale score at Day 8 (P = 0.018) and endpoint (P = 0.045), and for the Marder factors 'disorganized thoughts' (Day 8, P = 0.042) and 'uncontrolled hostility/excitement' (Day 8, P = 0.033, endpoint, P = 0.008).

At endpoint, 65.4% of patients receiving PP and 65.0% receiving oral antipsychotics were rated mildly or less severely ill, compared with 14.0% and 16.1%, respectively, at baseline (CGI-S total score). Changes in CGI-S from baseline to endpoint were statistically significant within

Table 2

Dosing (daily dose in mg) and drug exposure information for the core ITT oral APs group.

Aripiprazole Haloperidol Olanzapine Paliperidone ER Quetiapine Risperidone

(n = 81) (n = 34) (n = 49) (n = 77) (n = 65) (n = 57)

First dose (acute phase), n 81 34 49 77 65 57

Mean (SD) 14.4 (5.8) 7.1 (5.2) 9.5 (4.2) 6.6 (2.4) 284.6 (174.3) 3.7 (1.6)

Range 5, 30 1,20 5, 20 3,12 100, 800 2, 8

Baseline dose, n 81 34 49 76 64 57

Mean (SD) 17.9 (7.0) 8.3 (5.1) 12.0 (4.7) 7.7 (2.5) 453.1 (184.3) 4.2 (1.4)

Range 10, 30 2, 20 5, 20 3,12 100, 800 2, 6

Modal dose, n 81 34 49 77 65 57

Mean (SD) 19.1 (7.7) 8.2 (4.6) 12.9 (5.2) 7.5 (2.7) 489.2 (188.0) 4.3 (1.6)

Range 10, 30 2,15 5, 25 3,15 100, 800 2, 8

Last dose,n 81 34 49 77 65 57

Mean (SD) 19.6 (7.7) 7.4 (4.3) 13.3 (5.3) 7.8 (3.1) 501.5 (204.3) 4.3 (1.5)

Range 10, 30 2,15 5, 25 3,15 100, 900 2, 8

AP = antipsychotic, ER = extended release, ITT = intent-to-treat, SD = standard deviation.

Fig. 2. Kaplan-Meier plot of time to relapse*.

•Relapse was defined by any of the following: psychiatric hospitalization; an increase in the level of psychiatric care (e.g. significant crisis intervention needed to avert hospitalization, clinically notable increases in the frequency or intensity of patient contact required to maintain outpatient status) and an increase of 25% from BL in the Positive and Negative Syndrome Scale total score (or an increase of 10 points if the BL score was <40); deliberate self-injury; suicidal or homicidal ideation that was clinically significant in the investigator's judgment; violent behavior resulting in clinically significant injury to another person or property damage; substantial clinical deterioration, defined as a change score of 6 (much worse) or 7 (very much worse) on the CGI-C scale; the required dose of AP exceeds the maximum approved dose. AP = antipsychotic, BL = baseline, CGI-C = Clinical Global Impression-Change, PP = paliperidone palmitate.

each group; they did not reach statistical significance between groups (P = 0.4837 [Supplementary Fig. 2]).

PSP total score improved significantly from baseline to endpoint in both groups (mean change 9.8 [PP] versus 8.7 [oral antipsychotics]; both P< 0.0001 within groups); these improvements were not significant between groups (P = 0.2831 [Supplementary Fig. 3]). Significant improvements in SF-36, EQ-5D, and SWN-S scores were observed in both treatment arms (Supplementary Table 2). No significant differences were observed between groups except for a significantly greater improvement in EQ-5D index score in favor of oral antipsychotics at Month 12 (P =0.017).

In the PP arm, TSQM significantly improved across all domains (P < 0.05) except the 'side effects' subscale score. Significantly greater improvements in the TSQM 'convenience' subscale score were observed in favor of PP (Month 24 [P < 0.01], Month 12, and endpoint [P < 0.0001]). There were no significant differences in patients' treatment satisfaction in favor of oral antipsychotics (Supplementary Table 2) except for mean improvement from baseline in the 'effectiveness' subscale score at Month 24 (P < 0.05). Greater improvements in physician's treatment satisfaction were observed for PP versus oral antipsychotics in scores for 'safety' (Month 12, P < 0.01), 'mode of administration' (Months 12, 24, endpoint, P < 0.0001), and 'overall satisfaction' (Months 12, 24, endpoint, P< 0.05).

3.3. Safety and tolerability

The most common TEAE reported was increase in body weight (Table 3); the proportion of patients reporting a >7% increase is shown in Table 4. No new safety signals were observed in either study arm.

In the safety ITT population (n = 715), > 1 serious TEAEs were reported in 11.6% (PP) and 12.7% (oral antipsychotics) of patients. Fourteen (4.0%) and 11 (3.0%) patients withdrew from the study due to a TEAE in the PP and oral antipsychotics arms, respectively. Two deaths occurred: one of cardiac arrest (PP), considered unrelated to study drug; and one of sudden death (oral olanzapine), considered doubtfully related to study drug (Appendix).

The proportion of patients with a TEAE of hyperprolactinemia and/or at least one potentially prolactin-related TEAE was similar between treatment arms (6.3% [PP] versus 5.0% [oral antipsychotics])

(Supplementary Table 3). There were no statistically significant differences between treatment arms in changes from baseline to endpoint for extrapyramidal symptom rating scales (Table 3).

4. Discussion

This study aimed to provide robust evidence as to the role of LATs in the early stages of schizophrenia. Time to relapse was significantly longer for patients receiving PP compared with those receiving oral antipsychotics. The observed reduction in relative risk of relapse is comparable with recent clinical studies and meta-analyses (Leucht et al., 2011; Grimaldi-Bensouda et al., 2012). A recent study of injectable aripiprazole failed to demonstrate an advantage on relapse rates over the oral formulation (Fleischhacker et al., 2014). However, patients were only followed for 38 weeks; an advantage may have become apparent in the longer term, as observed in the present study. The relapse rate reported herein for patients receiving PP is comparable with that found in one of the few long-term studies of LATs in early illness, where 8% of patients with recent-onset psychosis who showed a clinical response to long-acting injectable risperidone (LAI-R) relapsed over 2 years (Emsley et al., 2008). Another study (Rosenheck et al., 2011) found similar times to hospitalization between unstable patients with schizophrenia receiving oral antipsychotics and those receiving LAI-R. However, several factors may have contributed to this outcome, including the smaller sample size compared with that originally planned, biweekly frequency of study visits, and the chronicity and illness severity of included patients.

In the present study, the greater observed improvement in symptom control at Day 8, and a trend toward better symptom control at endpoint in patients receiving PP compared with oral antipsychotics, is consistent with a 2-year, active-controlled study of patients with schizophrenia or related disorders, in which patients randomized to LAI-R had a significantly greater improvement in symptom control compared with those receiving oral quetiapine (Gaebel et al., 2010). Similarly, a more robust reduction in psychotic symptoms was observed in patients receiving LAI-R than in oral second generation antipsychotics (Buckley et al., 2015). However, there was no advantage in time to relapse; the authors noted that frequent clinical contact may have reduced relapse in both groups and the power to detect between-group differences. Nevertheless, the absence of significant differences

Table 3

Safety outcomes in the core ITT population for safety.

Paliperidone palmitate (n = 352) Oral APs (n = 363)

Proportion of patients reporting >1 TEAE, n (%) 251 (71.3) 225 (62.0)

Number of TEAEs rated as possibly, probably or 448 (50.3) 294 (43.8)

very likely related to study drug, n (%)

TEAEs occurring in >5% of patients, n (%)

Injection-site pain 24 (6.8) 0 (0.0)

Nasopharyngitis 25(7.1) 18 (5.0)

Increase in weight 56 (15.9) 63 (17.4)

Headache 39 (11.1) 31 (8.5)

Tremor 18 (5.1) 8 (2.2)

Anxiety 20 (5.7) 16 (4.4)

Insomnia 34 (9.7) 29 (8.0)

Schizophrenia 29 (8.2) 35 (9.6)

Suicidal ideation 16 (4.5) 20 (5.5)

Patients reporting a potentially 21 (6.0) 15(4.1)

prolactin-related TEAE without a TEAE of

hyperprolactinemia or blood prolactin

increased reported, n (%)

Frequency of reported 2 (0.6) 4(1.1)

hyperprolactinemia/blood prolactin

increased without any other potentially

prolactin-related TEAE, n (%)

Potentially prolactin-related TEAEs occurring

in > 1% of

patients, n (%)

Amenorrhea 11 (3.1) 7 (1.9)

Galactorrhea 6 (1.7) 1 (0.3)

Glucose-related TEAEs, n (%)

Diabetes mellitus inadequate control 0 (0.0) 1 (0.3)

EPS-related TEAEs occurring in > 1% of

patients, n (%)

Akathisia 15 (4.3) 14(3.9)

Dyskinesia 5(1.4) 2 (0.6)

Muscle rigidity 8 (2.3) 4(1.1)

Parkinsonism 3(1.1) 4(1.1)

Restlessness 4(1.1) 1 (0.3)

Tremor 18 (5.1) 8 (2.2)

AIMS total score, Mean (SD)

Baseline 0.4 (1.3) 0.4 (1.4)

Endpoint LOCF 0.3 (0.9) 0.3 (1.4)

Change from baseline to endpoint LOCF -0.1 (1.2) - 0.1 (1.4)

Pvalue* 0.1183 0.2025

Pvalued 0.8800

BARS total score, Mean (SD)

Baseline 0.4 (0.9) 0.4 (1.0)

Endpoint LOCF 0.3 (1.0) 0.2 (0.8)

Change from baseline to endpoint LOCF -0.1 (1.2) - 0.2 (1.0)

Pvalue* 0.1772 0.0003

Pvalued 0.6615

SAS Global score, Mean (SD)

Baseline 0.1 (0.2) 0.2 (0.3)

Endpoint LOCF 0.1 (0.2) 0.1 (0.2)

Change from baseline to endpoint LOCF -0.1 (0.2) - 0.1 (0.2)

P value* <0.0001 0.0001

Pvalued 0.1525

Patient weight, kg, Mean (SD)

Baseline 74.8 (15.2) 76.1 (14.8)

Endpoint LOCF 77.1 (15.6) 78.0 (14.8)

Change from baseline to endpoint LOCF 2.3 (5.9) 1.9 (6.2)

Pvalue* <0.0001 <0.0001

Pvalued 0.2648

BMI, kg/m2, Mean (SD)

Baseline 25.5 (4.7) 25.9 (4.4)

Endpoint LOCF 26.3 (4.8) 26.6 (4.4)

Change from baseline to endpoint LOCF 0.8 (2.0) 0.7 (2.1)

P value* <0.0001 <0.0001

Pvalued 0.2748

AIMS = Abnormal Involuntary Movement Scale, AP = antipsychotic, BARS = Barnes Akathisia Rating Scale, BMI = body mass index, EPS = extrapyramidal symptoms, ITT = intent-to-treat, LOCF = last observation carried forward, n = number of patients, SAS = Simpson Angus Scale, SD = standard deviation, TEAE = treatment-emergent adverse event. * P value for within-group difference measured by Wilcoxon signed-rank test. T P value for between-group difference measured by Wilcoxon two-sample test.

between groups in other objective symptom measurements, despite the more frequent occurrence of relapse of patients in the oral treatment arm, may reflect the now-recognized view that transition to relapse can be abrupt with few/no early warning signs (Emsley et al., 2013a).

Due to the comprehensive examination of prolactin changes associated with paliperidone ERand PP in their development programs, measurement of prolactin plasma levels was not required in this study. The proportion of patients receiving PP reporting a potentially prolactin-related TEAE in this study was similar to that reported in the development program (107/3173; 3.4%) (Einarson et al., 2012).

Strengths of this study include the active comparator arm, 2-year duration, randomized controlled, rater-blinded design, treatment choice of oral AP for the investigator, high completion rates (77.3% in the PP group and 73.3% in the oral AP group), flexible dosing according to the label, and a more naturalistic study population compared with the pivotal studies (inclusion/exclusion criteria).

Protocol-required activities may have enhanced patient adherence in the oral treatment arm due to the number of assessments and treatment delivery controlled directly by the prescriber, including pill-count. In particular, the discontinuation rate for patients randomized to oral antipsychotics in this study (26.7%) was lower than that observed in other studies of patients with early schizophrenia (Kahn et al., 2008; McEvoy et al., 2007). Moreover, patients for whom LATs are typically used (i.e. those who are partially or non-adherent with oral antipsy-chotics) may be under-represented, leading to under-estimation of the value of LATs in non-adherent patients. Nevertheless, it may be possible that some patients were not adherent to treatment e.g. discarding medication prior to the pill count. Other limitations include the non-blinding of medication (consequent to the required complexity of the study design), potential bias favoring the oral arm (patients in the PP arm had to switch treatments whereas those in the oral arm remained on their current medication), any potential selection bias between LATs and oral psychotics somehow inherent in the clinician's choice, and lack of control of other non-pharmacological treatment variables between sites. In this study, in the oral treatment arm the six most frequently prescribed oral antipsychotics were offered; in order to maintain a balance between oral treatments, investigators were not always able to choose among all six oral APs for individual patients. Overall, pragmatic open-label studies are considered valuable because they add clinically relevant information on treatment effectiveness, complementing the evidence provided by RCTs (Kirson et al., 2013).

Despite their potential advantages, most treatment guidelines advise limiting the use of LATs to multiple-episode or non-adherent patients, with controversy in relation to their role in early schizophrenia (Kim et al., 2012). Nevertheless, less equivocal recommendations advocating their use in early illness are emerging, not least during the critical period of the first 2-5 years following diagnosis, when important decisions in social and vocational role functioning are made (Malla et al., 2013; Altamuraetal., 2012). The superiority of PP over oral antipsychot-ic monotherapy in time to relapse in recently diagnosed patients observed in this study may help to bring greater clarity to the role of LATs, as well as to dispel some of the reticence by psychiatrists toward their use in the treatment of patients with schizophrenia, including the early stages of illness. Further research in patients early in the course of their illness is recommended.

Role of the funding source

The study sponsor was involved in the conception and design of the study, and in the collection, analysis and interpretation of data.

Authors' contributions

Andreas Schreiner, Ludger Hargarter, and Marjolein Lahaye were involved in study design. Ludger Hargarter was the responsible medical officer of the sponsor and was involved in study conduct. Pierre Cherubin and Adam Janik were involved in study management. Kaire Aadamsoo, A Carlo Altamura, Philip Gorwood, Manuel Franco, Nikolaj G. Neznanov, Alp Ucolk Juan Schronen and Mathias Zink were involved in data collection.

Proportion of patients with >7% increase in body weight (from BL to LOCF endpoint) by antipsychotic treatment.

Haloperidol Quetiapine Paliperidone ER Paliperidone palmitate Aripiprazole Risperidone Olanzapine

(n = 34) (n = 65) (n = 76) (n = 350) (n = 81) (n = 56) (n = 48)

n(%) 4(11.8) 10 (15.4) 15 (19.7) 72 (20.6) 19 (23.5) 15 (26.8) 18 (37.5)

95% CI of proportion 4.7,26.6 8.6,26.1 12.3,30.0 16.7,25.1 15.6,33.8 17.0,39.6 25.2,51.6

Percentages calculated relative to n values from each treatment group.

BL = baseline, CI = confidence interval, ER = extended release, LOCF = last observation carried forward.

All authors were involved in the data interpretation, manuscript development and review. All authors have approved the final draft of the manuscript for publication.

Conflicts of interest

Andreas Schreiner is a full-time employee of Janssen Cilag and a shareholder ofJohn-son & Johnson. Ludger Hargarter, Adam Janik and Pierre Cherubin are full-time employees of Janssen Cilag. Marjolein Lahaye is a part-time employee of Janssen Cilag. Manuel Franco has been involved in clinical trials for Johnson & Johnson, Roche, Lilly, Pfizer, Lupin, Otsuka and AstraZeneca. Philip Gorwood has received research grants from Eli Lilly and Servier, and fees for presentations at congresses or participation in scientific boards from AstraZeneca, Biocodex, Bristol-Myers-Squibb, Janssen, Lilly, Lundbeck, Naurex, Otsuka, Roche, Sanofi Pasteur MSD and Servier. Mathias Zink has received unrestricted scientific grants of Servier and the German Research Foundation (DFG); speaker and travel grants were provided from Astra Zeneca, Lilly, Pfizer Pharma GmbH, Bristol Myers Squibb Pharmaceuticals, Otsuka, Servier, Lundbeck and Trommsdorff. Juan Schronen has attended an advisory board for Janssen. A Carlo Altamura has served as a consultant or participated in advisory boards for Roche, Lundbeck, AstraZeneca, Bristol Myers Squibb, Janssen Cilag, Sanofi, Eli Lilly, Pfizer, Otsuka and Takeda. Alp Ucok has received honoraria from Abdi Ibrahim, Otsuka, AstraZeneca and Janssen. Kaire Aadamsoo and Nikolaj G Neznanov have no conflict of interest to declare.

Acknowledgments

This study was sponsored by Janssen-Cilag International NV. Medical writing support was provided by apothecom scopemedical ltd., sponsored by Janssen Pharmaceutica NV. The authors wish to thank all of the investigational sites for their participation in this study.

Appendix A. Supplementary data

Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.schres.2015.08.015.

References

Alphs, L., Schooler, N., Lauriello, J., 2014. How study designs influence comparative effectiveness outcomes: the case of oral versus long-acting injectable antipsychotic treatments for schizophrenia. Schizophr. Res. 156 (2-3), 228-232. Altamura, A.C., Aguglia, E., Bassi, M., et al., 2012. Rethinking the role of long-acting atypical antipsychotics in the community setting. Int. Clin. Psychopharmacol. 27 (6), 336-349. Atkinson, M.J., Sinha, A., Hass, S.L., et al., 2004. Validation of a general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic disease. Health Qual. Life Outcomes 2,12. Buckley, P.F., Schooler, N.R., Goff, D.C., et al., 2015. Comparison of SGA oral medications and a long-acting injectable SGA: the PROACTIVE study. Schizophr. Bull. 41 (2), 449-459.

Csernansky, J.G., Mahmoud, R., Brenner, R., et al., 2002. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N. Engl. J.Med. 346 (1), 16-22. Einarson, T.R., Hemels, M.E., Nuamah, I., Gopal, S., Coppola, D., Hough, D., 2012. An analysis of potentially prolactin-related adverse events and abnormal prolactin values in randomized clinical trials with paliperidone palmitate. Ann. Pharmacother. 46 (10), 1322-1330.

Emsley, R., Chiliza, B., Asmal, L., Harvey, B.H., 2013a. The nature of relapse in schizophrenia. BMC Psychiatry 13, 50. Emsley, R., Chiliza, B., Asmal, L., 2013b. The evidence for illness progression after relapse

in schizophrenia. Schizophr. Res. 148 (1-3), 117-121. Emsley, R., Medori, R., Koen, L., Oosthuizen, P.P., Niehaus, D.J., Rabinowitz, J., 2008. Long-acting injectable risperidone in the treatment of subjects with recent-onset psychosis: a preliminary study. J. Clin. Psychopharmacol. 28 (2), 210-213.

EuroQol Group, 1990. EuroQol — a new facility for the measurement of health-related quality of life. Health Policy 16 (3), 199-208.

Fleischhacker, W.W., Sanchez, R., Perry, P.P., et al., 2014. Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomized, non-inferiority study. Br. J. Psychiatry 205 (2), 135-144.

Gaebel, W., Schreiner, A., Bergmans, P., et al., 2010. Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: results of a long-term, open-label, randomized clinical trial. Neuropsychopharmacology 35 (12), 2367-2377.

Grimaldi-Bensouda, L., Rouillon, F., Astruc, B., et al., 2012. Does long-acting injectable risperidone make a difference to the real-life treatment of schizophrenia? Results of the Cohort for the General study of Schizophrenia (CGS). Schizophr. Res. 134 (2-3), 187-194.

Guy, W., 1972. ECDEU Assessment Manual for Psychopharmacology — Revised. (ed). US Department of Health and Human Services, Rockville, MD DHHS publication no. ADM 91-338.

Janssen-Cilag International, N.V., 2015. Xeplion SmPC, http://www.ema.europa.eu/docs/en_ GB/document_library/EPAR_-_Product_Information/human/002105/WC500103317. pdf Accessed 8 September 2015.

Kahn, R.S., Fleischhacker, W.W., Boter, H., et al., 2008. Effectiveness ofantipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet 371 (9618), 1085-1097.

Kane, J.M., Detke, H.C., Naber, D., et al., 2010. Olanzapine long-acting injection: a 24-week, randomized, double-blind trial of maintenance treatment in patients with schizophrenia. Am. J. Psychiatry 167 (2), 181-189.

Kim, B., Lee, S.H., Yang, Y.K., Park, J.I., Chung, Y.C., 2012. Long-acting injectable antipsy-chotics for first-episode schizophrenia: the pros and cons. Schizophr. Res. Treatment 2012, 560836.

Kirson, N.Y., Weiden, P.J., Yermakov, S., et al., 2013. Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: synthesizing results across different research designs. J. Clin. Psychiatry 74 (6), 568-575.

Kishimoto, T., Nitta, M., Borenstein, M., Kane, J.M., Correll, C.U., 2013. Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies. J. Clin. Psychiatry 74 (10), 957-965.

Kishimoto, T., Robenzadeh, A., Leucht, C., et al., 2014. Long-acting injectable vs oral anti-psychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr. Bull. 40 (1), 192-213.

Leucht, C., Heres, S., Kane, J.M., Kissling, W., Davis, J.M., Leucht, S., 2011. Oral versus depot antipsychotic drugs for schizophrenia — a critical systematic review and meta-analysis of randomised long-term trials. Schizophr. Res. 127 (1-3), 83-92.

Malla, A., Tibbo, P., Chue, P., et al., 2013. Long-acting injectable antipsychotics: recommendations for clinicians. Can. J. Psychiatry 58 (5 suppl 1), 30S-35S.

Marder, S.R., Davis, J.M., Chouinard, G., 1997. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J. Clin. Psychiatry 58 (12), 538-546.

McEvoy, J.P., Lieberman, J.A., Perkins, D.O., et al., 2007. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am. J. Psychiatry 164 (7), 1050-1060.

Morosini, P., Magliano, L., Brambilla, L., Ugolini, S., Piolo, R., 2000. Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr. Scand. 101 (4), 323-329.

Naber, D., 1995. A self-rating to measure subjective effects of neuroleptic drugs, relationships to objective psychopathology, quality of life, compliance and other clinical variables. Int. Clin. Psychopharmacol. 10 (suppl 3), 133-138.

Rosenheck, R.A., Krystal, J.H., Lew, R., et al., 2011. Long-acting risperidone and oral anti-psychotics in unstable schizophrenia. N. Engl. J. Med. 364 (9), 842-851.

Ware Jr., J.E., Sherbourne, C.D., 1992. The MOS 36-item Short-Form Health Survey (SF-36). I. Conceptual framework and item selection. Med. Care 30 (6), 473-483.

Ware Jr., J.E., Gandek B., the IQOLA Project Group, 1994. The SF-36® Health Survey: development and use in mental health research and the IQOLA Project. Int. J. Mental Health 23 ( 2), 49-73.