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A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia
Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 1002–1008
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Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia Huafang Li a, Qing Rui b,⁎, Xiaoping Ning c, Haiyan Xu c, Niufan Gu a a b c
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China Xian Janssen Pharmaceutical Limited, Beijing, PR China Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA
a r t i c l e
i n f o
Article history: Received 4 November 2010 Received in revised form 3 February 2011 Accepted 3 February 2011 Available online 18 February 2011 Keywords: Long-acting injectable Paliperidone palmitate PANSS Risperidone Schizophrenia
a b s t r a c t This open-label, rater-blinded, parallel-group study was designed to evaluate noninferiority of paliperidone palmitate (PP), a once-monthly injectable atypical antipsychotic, to once-biweekly risperidone long-acting injectable (RIS-LAI) in adult Chinese patients with acute schizophrenia. Eligible Chinese adults (N = 452) with schizophrenia were randomized (1:1) to either PP (N = 229; deltoid injections on day 1 [150 mg eq.] and day 8 [100 mg eq.]; then once-monthly deltoid or gluteal injections, flexibly dosed [50, 100, or 150 mg eq.]), or RIS-LAI (N = 223; once-biweekly gluteal injections, flexibly dosed [25, 37.5 or 50 mg]). RIS-LAI-treated patients received oral risperidone supplementation (1-6 mg/day) at initiation and with RIS-LAI dose increases. Mean (SD) Positive and Negative Syndrome Scale (PANSS) total score at baseline was 83.2 (12.44). Mean (SD) change from baseline to endpoint in PANSS total scores (primary efficacy measure) was: − 23.6 (16.28) for PP group and − 26.9 (15.43) for RIS-LAI group. PP was noninferior to RIS-LAI (least squares mean difference [95% CI]: − 2.3 [− 5.20; 0.63]; predetermined non-inferiority margin: − 5.5). Mean (SD) change from baseline to endpoint in Clinical Global Impression-Severity scale score was: − 1.5 (1.24; PP group), − 1.7 (1.16; RIS-LAI group) and in Personal and Social Performance Scale scores was: 16.8 (14.76; PP group), 18.6 (13.92; RIS-LAI group). The incidence of treatment-emergent adverse events (TEAEs) was similar between the two groups (73% [PP]; 75% [RIS-LAI]). The most common TEAEs were akathisia, tremor, and insomnia. The study demonstrated the noninferiority of PP (50–150 mg eq., flexibly dosed, without oral paliperidone supplementation) to risperidone-LAI (25–50 mg, flexibly dosed, with oral risperidone supplementation) for the treatment of acute schizophrenia in adult Chinese patients. PP injections were generally tolerable, and no new safety signals were detected in this population. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Schizophrenia is a chronic psychiatric disorder associated with substantially reduced quality of life and significant impairment in psychosocial functioning. Noncompliance and high discontinuation rates are common problems in management of schizophrenia and
Abbreviations: AIMS, Abnormal Involuntary Movement Scale; ANCOVA, analysis of covariance; BARS, Barnes Akathisia Rating Scale; BMI, body mass index; CGI-S, Clinical Global Impression-Severity; CI, confidence interval; CRF, case report form; DSM-IV, Diagnostic and Statistical Manual, 4th edition; ECG, electrocardiogram; EPS, extrapyramidal symptoms; i.m., intramuscular; ITT, intent-to-treat; LAI, long-acting-injectable; LOCF, last-observation-carried-forward; LSM, least square means; PANSS, Positive and Negative Syndrome Scale; PP, paliperidone palmitate; PSP, Personal and Social Performance; RIS-LAI, risperidone-LAI; S.D., Standard deviation; SAS, Simpson and Angus Rating Scale; TEAE, treatment-emergent adverse event; QTcB, Bazett's correction; QTcF, Fridericia's correction; U.S.A., United States of America. ⁎ Corresponding author at: Therapeutic Area Head, CNS, Medical Affairs, Xian Janssen Pharmaceutical Limited, 14F, Tower 3, China Central Place, 77 Jian Guo Road, Chaoyang District, Beijing, 100025, PR China. Tel.: +86 10 5821 8307; fax: +86 10 5821 8703. E-mail address: [email protected] (Q. Rui). 0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2011.02.001
related disorders (Keith et al., 2004). Long-acting injectable (LAI) formulations of antipsychotics increase compliance by means of sustained drug delivery and regular treatment monitoring, and consequently may improve the long-term management of schizophrenia (Nasrallah, 2007). Risperidone-LAI (RIS-LAI) was the first LAI formulation of an atypical antipsychotic (Rainer, 2008). It is approved in the United States (Risperdal® CONSTA® prescribing information, 2010) and China as a biweekly injection for the treatment of schizophrenia. Recently developed, paliperidone palmitate (PP) is the first oncemonthly LAI atypical antipsychotic available in the US (Citrome, 2010) and is approved (US) for the acute and maintenance treatment in schizophrenia in adults (INVEGA® SUSTENNA™ prescribing information, 2010). This open-label, randomized, rater-blinded, active-controlled, parallel-group, 13-week study evaluated the noninferiority of PP intramuscular (i.m.) injections without oral paliperidone supplementation to RIS-LAI with oral risperidone supplementation in adult Chinese patients with acute schizophrenia. The safety and tolerability of PP in the treatment of schizophrenia were also assessed.
H. Li et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 1002–1008
2. Methods 2.1. Patients Men and women, aged 18 years or older, diagnosed with schizophrenia (Diagnostic and Statistical Manual, 4th edition [DSM-IV] criteria) for at least one year before screening, having acute symptoms of disease with Positive and Negative Syndrome Scale (PANSS) total score (Kay et al., 1987) between 60 and 120 (inclusive) at screening and baseline and with body mass index (BMI) of 17.0 kg/m2 or greater were enrolled. Major exclusion criteria included: a primary, active DSM-IV diagnosis on Axis I other than schizophrenia; decrease of at least 25% in the PANSS total score between screening and baseline; active substance dependence (DSM-IV criteria) within 3 months preceding screening; presence or history of any significant or unstable systemic disease; significant risk of suicidal or violent behavior and history of treatment resistance towards two different antipsychotic treatments. Those patients who used typical injectable antipsychotic within 1 injection interval before screening, clozapine within 3 months before baseline, RIS-LAI within 6 weeks before screening, PP within 10 months before baseline, or received electroconvulsive therapy within 60 days before screening were excluded. Mood stabilizers, antiparkinsonian medications, beta-blockers, over-the-counter prescriptions or herbal agents with psychoactive properties were not allowed during the study. Women who were pregnant, planning to become pregnant or were nursing, were also excluded. The Independent Ethics Committee or Institutional Review Board at each study site approved the protocol. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, consistent Good Clinical Practices, and applicable regulatory requirements. All participants signed an informed consent to participate in the study. 2.2. Study drugs Paliperidone palmitate (INVEGA® SUSTENNA™) was supplied as a 50, 100, or 150 mg eq. injectable, unrefrigerated suspension. As doses of PP can be expressed both in terms of milligram equivalents (mg eq.) of the pharmacologically active fraction, i.e., paliperidone, and in milligrams of PP, the doses expressed as 50, 100 and 150 mg eq. equate to 78, 156 and 234 mg of PP, respectively. RIS-LAI (Risperdal® CONSTA®) was supplied as risperidone depot microspheres in strengths of 25, 37.5, and 50 mg. It required refrigeration and reconstitution. Oral risperidone tablets were supplied in 1-mg dose strength, packaged in child-resistant blister packs. 2.3. Study design, randomization and blinding The study was conducted from January 2008 to January 2009 at 10 centers in China. The study consisted of screening phase of up to 7 days for washout of disallowed psychotropic medications and for oral tolerability testing (patients without documented tolerability to oral risperidone or paliperidone ER or RIS-LAI or PP were administered paliperidone ER 6 mg/day for 4 to 6 days), and an open-label phase of 13 weeks. Eligible patients were randomly assigned (1:1) to either of two treatment groups: flexibly dosed PP without any oral supplementation, or RIS-LAI with oral risperidone supplementation. Randomization was based on a computer-generated randomization schedule balanced by using permuted blocks of treatments. 2.4. Drug administration During the open-label phase, PP group patients received i.m. (deltoid) injections of 150 mg eq. PP on day 1 and 100 mg eq. PP on day 8, and subsequent once-monthly i.m. (deltoid or gluteal) injections of 50 or 100 mg eq. PP on days 36 and 50, 100, or 150 mg
1003
eq. PP on day 64. In the RIS-LAI group, i.m. (gluteal) injections of RISLAI 25 mg were administered on day 8 and i.m. (gluteal) injections of 25, 37.5, or 50 mg were given every 2 weeks thereafter (day 22: 25 mg; days 36 and 50: 25 or 37.5 mg; days 64 and 78: 25, 37.5 or 50 mg). For both treatment groups, the investigator could increase or decrease the dose of study medication on days 36 and 64 depending upon the tolerability and efficacy. RIS-LAI group patients received oral risperidone 2 mg/day at baseline and flexible doses, 1–6 mg/day for the first 28 days and for up to 3 weeks of treatment with each dose increase (Fig. 1). Deltoid injections (PP only) were administered using a 1.5-inch needle for patients weighing ≥90 kg, and a 1-inch needle for patients weighing b90 kg. Gluteal injections were administered using a 1.5-inch needle for PP and a 2-inch needle for RIS-LAI. Antiparkinsonian medications that were allowed in case of emergence or worsening of extrapyramidal symptoms (EPS) included trihexyphenidyl, benztropine, biperidin, or antihistamines with anticholinergic properties. Benzodiazepines (at the permitted maximum daily doses) were allowed except within 6 h of any efficacy or safety assessment. Beta-blockers; treatment of insomnia (zolpidem, zaleplon, zopiclone or eszopiclone); and use of topical anesthetic creams were allowed. Antidepressants (except nonselective/irreversible monoamine oxidase inhibitors) were allowed if they had been used at a stable dose for at least 30 days before screening. Ongoing individual psychotherapy was allowed to continue during the study. 2.5. Efficacy assessments The primary efficacy variable was the change in the PANSS total score from baseline to the last postrandomization assessment. Secondary efficacy variables included the changes from baseline to endpoint in the Clinical Global Impression-Severity (CGI-S) scale score (Guy, 1976a), Personal and Social Performance (PSP) scale score (Morosini et al., 2000), PANSS subscale scores, PANSS Marder factor scores (Marder et al., 1997), and the responder rate (percentage of patients with a 30% or more reduction in PANSS total score). The PANSS and CGIS were evaluated at baseline, during weeks 1, 5, and 9, and at the end of the study or early withdrawal. PSP scores were obtained at baseline and at the end of the study or early withdrawal. All efficacy assessments were administered and evaluated by independent, blinded, and trained raters at each site to reduce potential bias during the data collection and evaluation of clinical endpoints. 2.6. Safety assessments Safety was evaluated by an assessment of treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital sign measurements, physical examination findings, electrocardiograms, EPS rating scales (Simpson and Angus Rating Scale [SAS], (Simpson and Angus, 1970), Barnes Akathisia Rating Scale [BARS], (Barnes, 1989) and Abnormal Involuntary Movement Scale [AIMS], (Guy, 1976b)), investigator's evaluation of the injection site (redness, pain, swelling, and induration), and patient's evaluation of the injection site pain as measured by a Visual Analog Scale (0 [no pain]–100 [maximal pain]). 2.7. Data analysis 2.7.1. Analysis sets Per-protocol analysis set (primary population for the efficacy analyses) included all randomized patients who received at least 2 injections of the study medications and for whom the time between any 2 injections did not exceed 35 days for PP or 21 days for RIS-LAI, had both a baseline and at least one postbaseline assessment for the primary efficacy variables, had minimum 5 weeks exposure to the study medications, and did not have major protocol deviations. The intent-to-treat (ITT) analysis set included all randomized patients who received at least one dose of study medications and had at least
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Screening/washout/oral tolerability test (≤ 7 days)
Randomized (n=452)
Paliperidone palmitate (n=229)
Risperidone-LAI* (n=223)
Withdrawn (n=64) Adverse events (n=4) Pregnancy (n=2) Protocol deviation (n=3) Lack of efficacy (n=22) Lost to follow up (n=9) Withdrew consent (n=16) Other reasons (n=8)
Withdrawn (n=38) Adverse events (n=5) Pregnancy (n=0) Protocol deviation (n=1) Lack of efficacy (n=9) Lost to follow up (n=14) Withdrew consent (n=5) Other reasons (n=4)
Day 1: 150 mg eq. (deltoid) Day 8: 100 mg eq. (deltoid) Day 36: 50 or 100mg eq. (deltoid or gluteal) Day 64: 50, 100 or 150mg eq. (deltoid or gluteal)
Completed (n=165; 72.1%)
Day 8: 25mg Day 22: 25mg Day 36: 25, 37.5 mg Day 50: same as day 36 Day 64: 25, 37.5 or 50mg Day 78: same as day 64 Oral risperidone supplement: Day 1: 2 mg/day Day 2 to 28: 1-6 mg/day (flexible dose) Day 36-57: 1-2 mg/day for 21 days if increase in RIS-LAI dose was necessary. Day 64-85: 1-2 mg/day for 21 days if increase in RIS-LAI dose was necessary.
Completed (n=185; 83%)
Fig. 1. Patient disposition. LAI: long-acting-injectable.
one efficacy measurement during the open-label phase. The safety analysis set included all patients who received at least one dose of study medication. 2.7.2. Statistical analysis Efficacy variables were analyzed using the last-observationcarried-forward (LOCF) approach in the per-protocol analysis set. The primary efficacy variable was analyzed using an analysis of covariance (ANCOVA) model with treatment as factor and baseline PANSS total score as the covariate. Noninferiority of PP without oral paliperidone supplementation to RIS-LAI with oral risperidone supplementation was to be concluded if the lower limit of the 2sided 95% confidence interval (CI) for the difference in mean change in PANSS total score (from baseline to endpoint) between RIS-LAI and PP exceeded −5.5. A sensitivity analysis was performed using mixed model repeated measures method with observed case data and an unstructured variance–covariance matrix with time, treatment, and time-by-treatment interaction as factors and baseline PANSS total score as a covariate. An exploratory analysis was also performed to assess a possible interaction between treatment and baseline BMI group for the primary efficacy variable. The changes from baseline to endpoint for CGI-S, PSP, PANSS subscale scores, and PANSS Marder factor scores were analyzed similarly as for the primary efficacy
variable. A Cochran–Mantel–Haenszel test was used to analyze the percentages of PANSS responders. Safety results were assessed using descriptive statistics and frequency distributions in the safety analysis set. 2.7.3. Sample size determination Assuming a true difference of 0 between RIS-LAI and PP, a standard deviation of 19 for the change in PANSS total score, and a one-sided significance level of 0.025, 189 patients per treatment group were required to demonstrate with 80% power that PP is no worse than RISLAI by 5.5 points in the change in PANSS total score. Assuming 90% of randomly assigned patients would be evaluated for the per-protocol analysis, 210 patients per treatment group were to be randomized to each treatment group. 3. Results 3.1. Patient disposition and baseline characteristics Out of 452 randomized patients, 350 (77.4%) patients completed the study and 102 (22.6%) were withdrawn (Fig. 1). The safety analysis set included 452 patients and per-protocol analysis set included 413 patients. Major protocol deviations were reported in
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8 patients in the all randomized patient analysis set (PP group [n = 1]: efficacy assessment deviation and RIS-LAI group [n = 7]: efficacy assessment deviation, error in study drug administration, selection criteria not met, treatment deviation) and 2 patients in the ITT analysis set (both from RIS-LAI group): treatment deviation in 1 patient and error in study drug administration in both patients. Demographic and baseline characteristics were comparable across treatment groups (Table 1). More women (60.0%) were enrolled in the study. Patients' ages ranged from 18 to 64 years. Approximately 5% of the patients had BMI ≥ 30 kg/m2. The mean age at diagnosis of schizophrenia was 26 years. At baseline, the mean (SD) PANSS total score was 83.2 (12.44). In the per-protocol analysis set, the mean (SD) of mean doses administered to individual patients throughout the study was 115.8 (9.07) mg eq. for PP and 29.8 (4.67) mg for RIS-LAI; the median (range) of the same was 112.5 (87.5; 137.5) mg eq. for PP and 29.2 (25.0; 37.5) mg for RIS-LAI. The mean (SD) daily dose of supplemental oral risperidone dispensed to RIS-LAI group patients was 2.5 (0.98) mg from day 1 through day 28, 1.8 (0.52) mg from day 36 through day 57, and 1.7 (0.47) mg from day 64 through day 85. The median (range) daily dose of supplemental oral risperidone dispensed to RIS-LAI group patients was: 2 (1; 6) mg from day 1 through day 28; 2 (1; 4) mg from day 36 through day 57; and 2 (1; 2) mg from day 64 through day 85.
and PP groups was greater than the protocol prespecified noninferiority margin of −5.5 at endpoint (Table 2). Results of repeated measure mixed effect model corroborated the finding that PP was noninferior to RIS-LAI (difference in LSM [95% CI] on day 92: −2.5 [− 5.34, 0.42]). Noninferiority of PP to RIS-LAI, based on same ANCOVA analysis and noninferiority margin as above, was observed as early as day 8 (the first assessment) and demonstrated at every subsequent time point assessed. PP was not demonstrated to be noninferior to RIS-LAI in the ITT analysis set as the difference in LSM for the change in PANSS total score between the groups was −4.0 with a 95% CI of (− 7.13, − 0.89) and the lower limit of the 95% CI (−7.13) was lower than −5.5 at endpoint. Results of the exploratory analysis for the primary efficacy variable indicated less improvement in PANSS total score with increased BMI in the PP group; no such trend was observed in the RIS-LAI group. However, there was no evidence for a significant treatment-by-baseline BMI category interaction at 10% level. Similar improvements were seen in both treatment groups for CGI-S, PSP (Table 2) and the PANSS subscale scores and Marder factor scores (Table 3). At endpoint, 70.7% patients from the PP group and 78.4% patients from the RIS-LAI group responded (improvement in PANSS score by ≥30%) to treatment (point estimate [95% CI] of the relative risk of PP vs. RIS-LAI: 0.9 [0.81, 1.01]).
3.2. Efficacy findings
3.3. Safety findings
PP was demonstrated to be noninferior to RIS-LAI as the lower limit of the 95% CI (−5.20, 0.63) for the difference in least square means (LSM) for the change in PANSS total score, between RIS-LAI
The overall rates of TEAEs were similar in the PP (73.4%) and RISLAI (74.9%) groups. Overall, the most common TEAEs were akathisia, tremor, and insomnia (Fig. 2). Discontinuation due to TEAEs occurred in 8 (3.5%) patients in the PP group and 9 (4%) in the RIS-LAI group. The most frequent (n ≥ 2) reasons for discontinuation were irritability and psychiatric symptoms. Suicide-related adverse events were reported in 3 patients in the RIS-LAI group and none in the PP group. One patient from the RIS-LAI group died (completed suicide) during the study. The patient had no history of suicide attempt or ideation. No deaths were reported in the PP group. Somnolence was reported as a neurologic adverse event in 11 (4.8%) patients in the PP group and 6 (2.7%) patients in RIS-LAI group. Fewer patients experienced serious TEAEs in the PP group (n = 3, 1.3%) than in the RIS-LAI group (n = 8, 3.6%). One patient in the PP group (schizophrenia) and 3 patients in the RIS-LAI group
Table 1 Demographic and baseline characteristics (safety analysis set). Paliperidone Risperidone LAI palmitate (N = 223) (N = 229) Age (years), mean (SD) Sex, n (%) Men Women Racea, n (%) Han Muslim Weight (kg), mean (SD) Body mass index (kg/m2), mean (SD) Category, n (%) Normal b 25 Overweight 25–b30 Obese ≥ 30 Schizophrenia type, n (%) Disorganized Catatonic Paranoid Residual Undifferentiated Baseline total PANSS, mean (SD) Prior psychotropic therapyb, n (%) Total number of patients with prior psychotropic therapy Anti-EPS Antidepressants Atypical antipsychotics Benzodiazepines Beta blockers Non-benzodiazepines hypnotics and anxiolytics Stimulants Typical antipsychotics
32.0 (10.75)
31.5 (11.03)
87 (38.0) 142 (62.0)
94 (42.2) 129 (57.8)
228 (99.6) 1 (0.4) 62.9 (12.24) 23.1 (3.83)
222 (100.0) 0 62.3 (12.27) 23.1 (3.96)
167 (72.9) 50 (21.8) 12 (5.2)
159 (71.3) 52 (23.3) 12 (5.4)
7 (3.1) 0 (0) 153 (66.8) 3 (1.3) 66 (28.8) 82.5 (12.2)
9 (4.0) 1 (0.4) 148 (66.4) 0 65 (29.1) 83.9 (12.66)
66 (28.9) 20 (8.8) 2 (0.9) 29 (12.7) 24 (10.5) 3 (1.3) 4 (1.8) 0 15 (6.6)
57 (26.1) 23 (10.6) 0 25 (11.5) 19 (8.7) 1 (0.5) 2 (0.9) 1 (0.5) 11 (5.0)
LAI = Long-acting-injectable; PANSS = Positive and Negative Syndrome Scale. a Risperidone LAI: N = 222. b Intent-to-analysis set (N=228 for paliperidone palmitate, N=218 for risperidone LAI).
Table 2 Change in efficacy variables from baseline to endpoint (LOCF) (per-protocol analysis set).
PANSS total scorea, mean (SD) Baseline Change from baseline Difference of LSM (95% CI) CGI-S scorea, mean (SD) Baseline Change from baseline Difference of LSM (95% CI) PSP scoreb, mean (SD) Baseline Change from baseline Difference of LSM (95% CI)
Paliperidone palmitate (N = 205)
Risperidone LAI (N = 208)
82.1 (11.95) − 23.6 (16.28)
84.4 (12.69) − 26.9 (15.43) − 2.3 (− 5.20;0.63) N = 207 5.0 (0.81) − 1.7 (1.16) − 0.1 (− 0.33;0.10) N = 190 45.3 (11.29) 18.6 (13.92) 0.5 (− 2.14; 3.12)
N = 204 4.9 (0.82) − 1.5 (1.24) N = 184 47.8 (12.42) 16.8 (14.76)
LOCF = last observation carried forward; LAI = Long-acting-injectable; PANSS = Positive and Negative Syndrome Scale; CGI-S = Clinical Global Impression-Severity; PSP = Personal and Social Performance Scale; LSM = Least square means; CI = Confidence interval. a Negative change in score indicates improvement. b Positive change in score indicates improvement.
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Table 3 Change from baseline to endpoint (LOCF) in PANSS subscale scores and Marder factor scores (per-protocol analysis set). Paliperidone palmitate (N = 205) PANSS subscales mean (SD) Positive subscale Baseline Change from baseline Difference of LSM (95% CI) Negative subscale Baseline Change from baseline Difference of LSM (95% CI) General psychopathology Baseline Change from baseline Difference of LSM(95% CI) PANSS Marder factors mean (SD) Positive symptoms Baseline Change from baseline Difference of LSM (95% CI) Negative symptoms Baseline Change from baseline Difference of LSM (95% CI) Disorganized thoughts Baseline Change from baseline Difference of LSM (95% CI) Uncontrolled hostility/excitement Baseline Change from baseline Difference of LSM (95% CI) Anxiety/depression Baseline Change from baseline Difference of LSM (95% CI)
Risperidone LAI (N = 208)
20.6 (5.59) − 7.7 (6.26)
20.7 (4.86) − 9.0 (5.83) − 1.2 (− 2.14; − 0.21)
21.3 (6.46) − 5.2 (5.85)
22.2 (6.98) − 5.6 (5.68) − 0.0 (− 0.95; 0.93)
40.2 (6.57) − 9.5 (9.27)
41.4 (6.76) − 12.3 (8.04) − 0.9 (− 2.30; 0.55)
26.7 (6.08) − 9.1 (7.28)
27.3 (5.91) − 10.9 (7.07) − 1.4 (− 2.61; − 0.24)
22.2 (6.87) − 5.3 (6.39)
23.0 (7.45) − 5.6 (5.96) 0.0 (− 0.96; 1.05)
16.2 (4.52) − 4.2 (4.00)
16.8 (4.76) − 4.6 (4.26) − 0.1 (− 0.77; 0.54)
8.9 (3.85) − 3.1 (3.71)
8.8 (3.80) − 3.4 (3.67) − 0.4 (− 0.86; 0.07)
8.1 (3.02) − 1.9 (3.02)
8.5 (3.10) − 2.3 (3.16) − 0.1 (− 0.54; − 0.34)
Negative change in score indicates improvement. LAI = Long-acting-injectable; PANSS = Positive and Negative Syndrome Scale; LSM = Least square means; CI = Confidence interval.
(nausea and vomiting, convulsion, and benzhexol overdose) experienced serious adverse events. The most common (N10%) EPS-related events were akathisia (PP: n = 30 [13.1%]; RIS-LAI: n = 44 [19.7%]) and tremor (PP: n = 24 [10.5%]; RIS-LAI: n = 40 [17.9%]). The percentage of patients who required use of anti-EPS medication in the open-label period was lower in the PP group (31.4%) than in the RIS-LAI group (46.2%).
Insomnia
Overall, the incidence of potentially prolactin-related adverse events was similar between the PP group (n= 19 [8.3%]) and the RIS-LAI group (n= 20 [9.0%]). These events included increase in serum prolactin (PP: n = 17 [7.4%]; RIS-LAI: n = 12[5.4%]); galactorrhea (only in PP: n = 1 [0.4%]); hyperprolactinemia (PP: n = 1 [0.4%]; RIS-LAI: n = 5 [2.2%]); amenorrhea (only in RIS-LAI: n = 3 [2.3%]); and amenorrhea–galactorrhea syndrome (only in RIS-LAI: n = 1 [0.8%]). At baseline, the mean prolactin levels in men and women were above the upper limit of normal range (ULN) in both groups; overall, fewer patients in the PP group than RIS-LAI group had prolactin levels above the ULN (Table 4). The mean changes in prolactin levels from baseline to endpoint were significantly larger in women than in men for both PP (37.7 ng/mL [women] vs 9.8 ng/mL [men]) and RIS-LAI (31.1 ng/mL [women] vs 8.2 ng/mL [men]) groups. Treatment-emergent glucose-related adverse events (blood glucose increased) were reported in one (0.4%) patient in PP group and 2 (0.9%) patients in RIS-LAI group. At endpoint, the mean (SD) increases in body weight (PP: 1.5 [3.10] kg; RIS-LAI: 1.5 [3.24] kg); percentage of patients showing increase in weight ≥ 7% (PP: n = 32 [15.5%]; RIS-LAI: n = 35 [17.3%]) and percentage of patients showing decrease in weight ≥ 7% (PP: n = 2 [1.0%]; RIS-LAI: n = 3 [3.0%]) were similar between the two groups. There were no serious cardiac-related adverse events reported during this study. The incidence of treatment-emergent tachycardia were similar between the 2 treatment groups (4 [b2%] patients in each group). None of the patients had treatment-emergent orthostatic hypotension based on vital sign measurements (defined as a decrease in systolic [N20 mmHg] or diastolic [N10 mmHg] blood pressure after standing for at least 2 min and an increase in pulse rate N15 bpm when compared with supine measurements), although one TEAE of mild orthostatic hypotension was reported in one PP-treated patient on day 64 (day PP was administered). None of the patients showed clinically noteworthy changes in QTc intervals from baseline to endpoint. There were no reports of ventricular tachycardia, ventricular fibrillation, torsades de pointes; hyperthermia; anaphylactic reaction; pancreatitis-related adverse events; neuroleptic malignant syndrome; potential rhabdomyolosis-related event; or potential syndrome of inappropriate antidiuretic hormone secretion-related events. There were no clinically relevant changes in vital signs or clinical or hematological laboratory values during the study except that one patient in the PP group showed abnormally high alanine aminotransferase level at endpoint (at screening: 15 U/L; at endpoint: 341 U/L; normal range: 0-55 U/L) and one patient in RIS-LAI group showed abnormally high total bilirubin at endpoint (at screening: 17.8 μmol/L; at endpoint: 134 μmol/L; normal range: 0–20.5 μmol/L). Overall, local injection site tolerability was good. Most injection site-related adverse events were mild and included injection site induration (PP vs. RIS-LAI: 0.9% vs. 0%), injection site pain (2.6% vs. 0.4%), and injection site swelling (1.7% vs. 0%). The investigator
Akathisia Table 4 Treatment-emergent abnormal prolactin levels (safety analysis set).
Tremor Upper respiratory tract infection Constipation Blood prolactin increased Restlessness
Baseline prolactin levels
Postbaseline prolactin levels
≤ 1 × ULN ≤ 2 × ULN ≤ 2 × ULN
N 1 × ULN N 2 × ULN N 5 × ULN
Bradykinesia Musculoskeletal stiffness Paliperidone Palmitate (N=229) Risperidone LAI (N=223)
Anxiety 0
2
4
6
8
10 12 14 16 18 20 22
Percent Fig. 2. Treatment-emergent adverse events experienced by at least 5% of patients in any treatment group (safety analysis set). LAI: long-acting-injectable.
Paliperidone palmitate
Risperidone LAI
Men (N = 76)a, n (%)
Women (N = 120)a, n (%)
Men (N = 80)a, n (%)
Women (N = 103)a, n (%)
17 (22) 21 (28) 7 (9)
30 (25) 43 (36) 25 (21)
24 (30) 25 (31) 6 (8)
30 (29) 41 (40) 28 (27)
ULN: upper limit of normal range. a Number of patients with prolactin levels measured at both baseline and postbaseline. Different local laboratories used different reference ranges for prolactin levels. The highest upper limit of normal range used in this study was 25 ng/mL for men and 35 ng/mL for women.
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assessments of the injection site showed that induration, swelling, and redness were observed in b12% of patients in both groups and were generally mild. The patients' assessment of injection pain showed that in both groups, the highest mean Visual Analog Scale scores occurred on day 1 of injections and the average intensity of injection pain generally decreased over time in both groups. The average intensity of injection site pain did not change significantly over time. 4. Discussion PP and RIS-LAI groups showed similar improvement in the primary efficacy variable in this 13-week, open-label study. In the per-protocol analysis set, which was the population assessed for the primary analysis, the results indicated that PP (50–150 mg eq., without oral paliperidone supplementation) was noninferior to RIS-LAI (25– 50 mg, with oral risperidone supplementation) in treating adult Chinese patients with acute schizophrenia. Both treatment groups also showed similar improvements in all secondary efficacy variables, further supporting the comparable efficacy of PP and RIS-LAI in these patients. The efficacy findings for PP were also consistent with previous PP studies in adult patients with schizophrenia (Gopal et al., 2010; Kramer et al., 2010; Nasrallah, 2007; Pandina et al., 2010). A 13 week double-dummy, double-blind study, which used a similar dosing initiation regimen of 150 mg eq. PP on day 1 and 100 mg eq. on day 8, in adult patients with acute schizophrenia, studied across 14 countries, also demonstrated noninferiority of PP with RIS-LAI (Pandina et al., 2011). This dosing initiation regimen has been approved in the US (INVEGA® SUSTENNA™ prescribing information, 2010). The present 13-week open-label study using the approved dosing initiation regimen, confirmed the noninferiority of PP to RIS-LAI, although in a different ethnic group from the previous 13-week study (Pandina et al., 2011). In previous studies, heterogeneity of treatment effect related to baseline BMI (Fleischhacker et al., 2008; Gopal et al., 2010; Nasrallah, 2007) was observed and patients with higher BMI showed a slower initial rise in plasma concentrations of paliperidone compared with patients with normal BMI, indicating that the pharmacokinetics of PP is largely influenced by BMI. However, no significant treatment-bybaseline BMI category interactions were observed in this study. Deltoid injections during dosing initiation and a longer (1.5 in.) needle length used in this study have been shown to improve the initial rise in plasma concentrations of PP (Samtani et al., 2009). Additionally, the mean baseline BMI of this patient population (23.1 kg/m2) was approximately 20% less than that of in previous studies (27–29 kg/m2) (Fleischhacker et al., 2008; Gopal et al., 2010; Nasrallah, 2007). The incidences of EPS-related events reported during this study were higher compared with previous studies (Pandina et al., 2010, 2011). The use of anti-EPS medication was also increased from baseline to endpoint. Based on the clinical experience, Chinese patients may be more likely to experience EPS when treated with PP or RIS-LAI due to smaller body weights which might result into relatively higher drug exposures compared with that of western population. Additionally, unlike the other studies, the investigators were required to enter information on EPS-related adverse events on a separate CRF page, which could have led to bias in reporting and may in part have contributed to the higher reported incidence of these events. The percentage of patients requiring anti-EPS medications during openlabel period was lower in the PP group than in the RIS-LAI group. Treatment-emergent glucose-related adverse event were reported in b1% patients in both treatment groups. Increases in body weight were similar between groups. Cardio-metabolic events associated with use of atypical antipsychotics are of significant clinical concern (Mathews and Muzina, 2007). It is noteworthy that low incidences of weight gain and glucose-related events were reported in this study. The results corroborated the findings from other studies with PP and
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RIS-LAI (Hough et al., 2009; Kane et al., 2003; Keks et al., 2007; Pandina et al., 2010). Consistent with the known pharmacology of paliperidone (Citrome, 2010; Janicak and Winans, 2007), increases in prolactin levels were observed in both treatment groups and the incidences of potentially prolactin-related adverse events were similar (b10%) between groups. However, the incidence rate of potentially prolactinrelated clinical symptoms, galactorrhea, amenorrhea, and amenorrhea–galactorrhea syndrome was small (b5%) indicating that the clinical relevance of documented hyperprolactinemia was low. The safety profiles of PP and RIS-LAI groups were comparable during this 13-week study. The safety and tolerability results were consistent with previous clinical studies of PP (Nasrallah, 2007; Pandina et al., 2011). Overall, local injection site tolerability was good for PP and RIS-LAI groups. The mild injection-site pain was similar across groups. An open-label design of this study may have led to some bias in patients who were treated with a known efficacious drug, RIS-LAI (with oral supplementation of risperidone), and may have resulted in the higher dropout rate in the PP group wherein patients received an investigational drug and had a longer interval of injections (every 4 weeks vs. 2 weeks), compared with the RIS-LAI group. Consistent with this, twice as many patients discontinued due to lack of efficacy and three times as many withdrew consent in the PP-compared with the RIS-LAI group. While most of the secondary efficacy variables supported the outcome of the primary finding, which demonstrated the comparability of PP to RIS-LAI, a small difference was noted for the improvements seen in the positive subscale score and positive Marder factor score, favoring RIS-LAI. However, this small difference was not considered to be clinically significant. Noninferiority of PP to RIS-LAI was demonstrated in the per-protocol analysis set but not in the ITT analysis set. The per-protocol analysis set was more clinically relevant as these patients were required to have a minimum 5 weeks of exposure to the open-label phase treatment. The ITT set did not require patients to meet this criterion. The difference in results for two analysis sets could be related to the higher dropout rate in the PP group. The ITT analysis set included patients, who discontinued early during the study and had high PANSS total scores at the time of discontinuation, which could have resulted in the high mean PANSS total score at the endpoint, and the lower limit of the 95% CI of the difference in LSM not exceeding −5.5 (LOCF approach). Also, the sample size was based on optimistic assumptions about population heterogeneity as the study was to be conducted in an ethnically homogenous (single country) population, in which BMI was not anticipated to be a significant issue. Hence the width of the CIs for the primary endpoint may have been greater than anticipated. There are several distinctions between PP and RIS-LAI. PP does not require oral paliperidone supplementation, uses a small-gauge needle, and is administered once-monthly rather than biweekly. These differences may aid in patient compliance. The PP formulation does not require refrigeration, which provides convenience to clinical practitioners. 5. Conclusion This open-label, rater-blinded study demonstrated noninferiority of PP (50–150 mg eq., flexibly dosed, without oral paliperidone supplementation) to RIS-LAI (25–50 mg, flexibly dosed, with oral risperidone supplementation) for the treatment of acute schizophrenia in adult Chinese patients. PP injections were generally tolerable, and no new safety signals were detected in this population. Study support Funded by Xian-Janssen Pharmaceutical Limited, Beijing, PR China. The sponsor provided a formal review of the manuscript.
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Registration This study is registered at ClinicalTrials.gov (NCT00604279). Disclosures Drs. Li and Gu were investigators for this study. They were advisors for Wyeth Limited and AstraZeneca International. Dr. Ning was an employee of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. at the time of study. Dr. Rui is an employee of Xian Janssen Pharmaceutical Limited, Beijing, PR China, a Johnson & Johnson company. Dr. Xu is an employee of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., New Jersey, USA. All authors met ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data and made the final decision about where to publish these data and approved submission to the journal. Previous presentations Data from this study were presented at the 27th International College of Neuropsychopharmacology Congress, Hong Kong, 6–10 June 2010 and the World Psychiatric Association International Congress, Beijing, China, Sept. 1–5, 2010. Acknowledgments Dr. Sarika Shirke (SIRO Clinpharm Pvt. Ltd.) provided writing assistance and Dr. Wendy P. Battisti (Johnson & Johnson Pharmaceutical Research & Development, L.L.C) provided additional writing assistance and editorial support for this manuscript. The authors thank the study participants, without whom this study would not have been accomplished, as well as the following investigators for their participation in this study: Drs. Gu, N; Zang, H; Wang, C; Xie, S; Tan, Q; Li, K; Zheng, H; Xu, Y; Wang, X and Shi, J. References Barnes T. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672–6. Citrome L. Paliperidone palmitate — review of the efficacy, safety and cost of a new secondgeneration depot antipsychotic medication. Int J Clin Pract 2010;64:216–39. Fleischhacker W, Gopal S, Samtani M, Quiroz J, Pandina G, Vermeulen A, et al. Optimization of the dosing strategy for the long-acting injectable antipsychotic paliperidone palmitate: results of two randomized double-blind studies and population pharmacokinetic simulations. Paper presented at: the annual meeting of American College of Neuropsychopharmacology; December 7–11; Scottsdale, Arizona 2008; 2008. Gopal S, Hough D, Xu H, Lull J, Gassmann-Mayer C, Remmerie B, et al. Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophre-
nia: a randomized, double-blind, placebo-controlled, dose–response study. Int Clin Psychopharmacol 2010;25:247–56. Guy. CGI-S. Clinical Global Impression Severity, Early Clinical Drug Evaluation Unit (ECDEU), Assessment manual for psychopharmacology, Rev. Ed. Rockville, Maryland: National Institute of Mental Health; 1976a. Guy W. AIMS. Abnormal Involuntary Movement Scale.Early Clinical Drug Evaluation Unit (ECDEU) Assessment for psychopharmacology. Rockville, Maryland: National Institute of Mental Health; 1976b. Hough D, Lindenmayer J, Gopal S, Melkote R, Lim P, Herben V, et al. Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:1022–31. INVEGA® SUSTENNA™ prescribing information. [updated March 2010; cited 2010 April 20]; Available from:http://www.invegasustenna.com/invegasustenna/ shared/pi/invegasustenna.pdf. Janicak P, Winans E. Paliperidone ER: a review of the clinical trial data. Neuropsychiatr Dis Treat 2007;3:869–83. Kane J, Eerdekens M, Lindenmayer J, Keith S, Lesem M, Karcher K. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry 2003;160:1125–32. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261–76. Keith SJ, Pani L, Nick B, Emsley R, San L, Turner M, et al. Practical application of pharmacotherapy with long-acting risperidone for patients with schizophrenia. Psychiatr Serv 2004;55:997-1005. Keks N, Ingham M, Khan A, Karcher K. Long-acting injectable risperidone v. olanzapine tablets for schizophrenia or schizoaffective disorder. Br J Psychiatry 2007;191: 131–9. Kramer M, Litman R, Hough D, Lane R, Lim P, Liu Y, et al. Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study. Int J Neuropsychopharmacol 2010;13:635–47. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997;58:538–46. Mathews M, Muzina D. Atypical antipsychotics: new drugs, new challenges. Cleve Clin J Med 2007;74:597–606. Morosini P, Magliano L, Brambilla L, Ugolini S, Pioli R. 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 2000;101:323–9. Nasrallah HA. The case for long-acting antipsychotic agents in the post-CATIE era. Acta Psychiatr Scand 2007;115:260–7. Pandina G, Lindenmayer J, Lull J, Lim P, Gopal S, Herben V, et al. A randomized, placebocontrolled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol 2010;30:235–44. Pandina G, Lane R, Gopal S, Gassmann-Mayer C, Hough D, Remmerie B, et al. A doubleblind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2011;35: 218–26. Rainer MK. Risperidone long-acting injection: a review of its long term safety and efficacy. Neuropsychiatr Dis Treat 2008;4:919–27. Risperdal® CONSTA® prescribing information. [updated Sept 2009; cited 2010 April 20]; Available from:http://www.risperdalconsta.com/risperdalconsta/shared/pi/ risperdalconsta.pdf#zoom=100. Samtani MN, Vermeulen A, Stuyckens K. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic. Clin Pharmacokinet 2009;48: 585–600. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212:11–9.
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p n p
A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia Huafang Li a, Qing Rui b,⁎, Xiaoping Ning c, Haiyan Xu c, Niufan Gu a a b c
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China Xian Janssen Pharmaceutical Limited, Beijing, PR China Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA
a r t i c l e
i n f o
Article history: Received 4 November 2010 Received in revised form 3 February 2011 Accepted 3 February 2011 Available online 18 February 2011 Keywords: Long-acting injectable Paliperidone palmitate PANSS Risperidone Schizophrenia
a b s t r a c t This open-label, rater-blinded, parallel-group study was designed to evaluate noninferiority of paliperidone palmitate (PP), a once-monthly injectable atypical antipsychotic, to once-biweekly risperidone long-acting injectable (RIS-LAI) in adult Chinese patients with acute schizophrenia. Eligible Chinese adults (N = 452) with schizophrenia were randomized (1:1) to either PP (N = 229; deltoid injections on day 1 [150 mg eq.] and day 8 [100 mg eq.]; then once-monthly deltoid or gluteal injections, flexibly dosed [50, 100, or 150 mg eq.]), or RIS-LAI (N = 223; once-biweekly gluteal injections, flexibly dosed [25, 37.5 or 50 mg]). RIS-LAI-treated patients received oral risperidone supplementation (1-6 mg/day) at initiation and with RIS-LAI dose increases. Mean (SD) Positive and Negative Syndrome Scale (PANSS) total score at baseline was 83.2 (12.44). Mean (SD) change from baseline to endpoint in PANSS total scores (primary efficacy measure) was: − 23.6 (16.28) for PP group and − 26.9 (15.43) for RIS-LAI group. PP was noninferior to RIS-LAI (least squares mean difference [95% CI]: − 2.3 [− 5.20; 0.63]; predetermined non-inferiority margin: − 5.5). Mean (SD) change from baseline to endpoint in Clinical Global Impression-Severity scale score was: − 1.5 (1.24; PP group), − 1.7 (1.16; RIS-LAI group) and in Personal and Social Performance Scale scores was: 16.8 (14.76; PP group), 18.6 (13.92; RIS-LAI group). The incidence of treatment-emergent adverse events (TEAEs) was similar between the two groups (73% [PP]; 75% [RIS-LAI]). The most common TEAEs were akathisia, tremor, and insomnia. The study demonstrated the noninferiority of PP (50–150 mg eq., flexibly dosed, without oral paliperidone supplementation) to risperidone-LAI (25–50 mg, flexibly dosed, with oral risperidone supplementation) for the treatment of acute schizophrenia in adult Chinese patients. PP injections were generally tolerable, and no new safety signals were detected in this population. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Schizophrenia is a chronic psychiatric disorder associated with substantially reduced quality of life and significant impairment in psychosocial functioning. Noncompliance and high discontinuation rates are common problems in management of schizophrenia and
Abbreviations: AIMS, Abnormal Involuntary Movement Scale; ANCOVA, analysis of covariance; BARS, Barnes Akathisia Rating Scale; BMI, body mass index; CGI-S, Clinical Global Impression-Severity; CI, confidence interval; CRF, case report form; DSM-IV, Diagnostic and Statistical Manual, 4th edition; ECG, electrocardiogram; EPS, extrapyramidal symptoms; i.m., intramuscular; ITT, intent-to-treat; LAI, long-acting-injectable; LOCF, last-observation-carried-forward; LSM, least square means; PANSS, Positive and Negative Syndrome Scale; PP, paliperidone palmitate; PSP, Personal and Social Performance; RIS-LAI, risperidone-LAI; S.D., Standard deviation; SAS, Simpson and Angus Rating Scale; TEAE, treatment-emergent adverse event; QTcB, Bazett's correction; QTcF, Fridericia's correction; U.S.A., United States of America. ⁎ Corresponding author at: Therapeutic Area Head, CNS, Medical Affairs, Xian Janssen Pharmaceutical Limited, 14F, Tower 3, China Central Place, 77 Jian Guo Road, Chaoyang District, Beijing, 100025, PR China. Tel.: +86 10 5821 8307; fax: +86 10 5821 8703. E-mail address: [email protected] (Q. Rui). 0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2011.02.001
related disorders (Keith et al., 2004). Long-acting injectable (LAI) formulations of antipsychotics increase compliance by means of sustained drug delivery and regular treatment monitoring, and consequently may improve the long-term management of schizophrenia (Nasrallah, 2007). Risperidone-LAI (RIS-LAI) was the first LAI formulation of an atypical antipsychotic (Rainer, 2008). It is approved in the United States (Risperdal® CONSTA® prescribing information, 2010) and China as a biweekly injection for the treatment of schizophrenia. Recently developed, paliperidone palmitate (PP) is the first oncemonthly LAI atypical antipsychotic available in the US (Citrome, 2010) and is approved (US) for the acute and maintenance treatment in schizophrenia in adults (INVEGA® SUSTENNA™ prescribing information, 2010). This open-label, randomized, rater-blinded, active-controlled, parallel-group, 13-week study evaluated the noninferiority of PP intramuscular (i.m.) injections without oral paliperidone supplementation to RIS-LAI with oral risperidone supplementation in adult Chinese patients with acute schizophrenia. The safety and tolerability of PP in the treatment of schizophrenia were also assessed.
H. Li et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 1002–1008
2. Methods 2.1. Patients Men and women, aged 18 years or older, diagnosed with schizophrenia (Diagnostic and Statistical Manual, 4th edition [DSM-IV] criteria) for at least one year before screening, having acute symptoms of disease with Positive and Negative Syndrome Scale (PANSS) total score (Kay et al., 1987) between 60 and 120 (inclusive) at screening and baseline and with body mass index (BMI) of 17.0 kg/m2 or greater were enrolled. Major exclusion criteria included: a primary, active DSM-IV diagnosis on Axis I other than schizophrenia; decrease of at least 25% in the PANSS total score between screening and baseline; active substance dependence (DSM-IV criteria) within 3 months preceding screening; presence or history of any significant or unstable systemic disease; significant risk of suicidal or violent behavior and history of treatment resistance towards two different antipsychotic treatments. Those patients who used typical injectable antipsychotic within 1 injection interval before screening, clozapine within 3 months before baseline, RIS-LAI within 6 weeks before screening, PP within 10 months before baseline, or received electroconvulsive therapy within 60 days before screening were excluded. Mood stabilizers, antiparkinsonian medications, beta-blockers, over-the-counter prescriptions or herbal agents with psychoactive properties were not allowed during the study. Women who were pregnant, planning to become pregnant or were nursing, were also excluded. The Independent Ethics Committee or Institutional Review Board at each study site approved the protocol. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, consistent Good Clinical Practices, and applicable regulatory requirements. All participants signed an informed consent to participate in the study. 2.2. Study drugs Paliperidone palmitate (INVEGA® SUSTENNA™) was supplied as a 50, 100, or 150 mg eq. injectable, unrefrigerated suspension. As doses of PP can be expressed both in terms of milligram equivalents (mg eq.) of the pharmacologically active fraction, i.e., paliperidone, and in milligrams of PP, the doses expressed as 50, 100 and 150 mg eq. equate to 78, 156 and 234 mg of PP, respectively. RIS-LAI (Risperdal® CONSTA®) was supplied as risperidone depot microspheres in strengths of 25, 37.5, and 50 mg. It required refrigeration and reconstitution. Oral risperidone tablets were supplied in 1-mg dose strength, packaged in child-resistant blister packs. 2.3. Study design, randomization and blinding The study was conducted from January 2008 to January 2009 at 10 centers in China. The study consisted of screening phase of up to 7 days for washout of disallowed psychotropic medications and for oral tolerability testing (patients without documented tolerability to oral risperidone or paliperidone ER or RIS-LAI or PP were administered paliperidone ER 6 mg/day for 4 to 6 days), and an open-label phase of 13 weeks. Eligible patients were randomly assigned (1:1) to either of two treatment groups: flexibly dosed PP without any oral supplementation, or RIS-LAI with oral risperidone supplementation. Randomization was based on a computer-generated randomization schedule balanced by using permuted blocks of treatments. 2.4. Drug administration During the open-label phase, PP group patients received i.m. (deltoid) injections of 150 mg eq. PP on day 1 and 100 mg eq. PP on day 8, and subsequent once-monthly i.m. (deltoid or gluteal) injections of 50 or 100 mg eq. PP on days 36 and 50, 100, or 150 mg
1003
eq. PP on day 64. In the RIS-LAI group, i.m. (gluteal) injections of RISLAI 25 mg were administered on day 8 and i.m. (gluteal) injections of 25, 37.5, or 50 mg were given every 2 weeks thereafter (day 22: 25 mg; days 36 and 50: 25 or 37.5 mg; days 64 and 78: 25, 37.5 or 50 mg). For both treatment groups, the investigator could increase or decrease the dose of study medication on days 36 and 64 depending upon the tolerability and efficacy. RIS-LAI group patients received oral risperidone 2 mg/day at baseline and flexible doses, 1–6 mg/day for the first 28 days and for up to 3 weeks of treatment with each dose increase (Fig. 1). Deltoid injections (PP only) were administered using a 1.5-inch needle for patients weighing ≥90 kg, and a 1-inch needle for patients weighing b90 kg. Gluteal injections were administered using a 1.5-inch needle for PP and a 2-inch needle for RIS-LAI. Antiparkinsonian medications that were allowed in case of emergence or worsening of extrapyramidal symptoms (EPS) included trihexyphenidyl, benztropine, biperidin, or antihistamines with anticholinergic properties. Benzodiazepines (at the permitted maximum daily doses) were allowed except within 6 h of any efficacy or safety assessment. Beta-blockers; treatment of insomnia (zolpidem, zaleplon, zopiclone or eszopiclone); and use of topical anesthetic creams were allowed. Antidepressants (except nonselective/irreversible monoamine oxidase inhibitors) were allowed if they had been used at a stable dose for at least 30 days before screening. Ongoing individual psychotherapy was allowed to continue during the study. 2.5. Efficacy assessments The primary efficacy variable was the change in the PANSS total score from baseline to the last postrandomization assessment. Secondary efficacy variables included the changes from baseline to endpoint in the Clinical Global Impression-Severity (CGI-S) scale score (Guy, 1976a), Personal and Social Performance (PSP) scale score (Morosini et al., 2000), PANSS subscale scores, PANSS Marder factor scores (Marder et al., 1997), and the responder rate (percentage of patients with a 30% or more reduction in PANSS total score). The PANSS and CGIS were evaluated at baseline, during weeks 1, 5, and 9, and at the end of the study or early withdrawal. PSP scores were obtained at baseline and at the end of the study or early withdrawal. All efficacy assessments were administered and evaluated by independent, blinded, and trained raters at each site to reduce potential bias during the data collection and evaluation of clinical endpoints. 2.6. Safety assessments Safety was evaluated by an assessment of treatment-emergent adverse events (TEAEs), clinical laboratory tests, vital sign measurements, physical examination findings, electrocardiograms, EPS rating scales (Simpson and Angus Rating Scale [SAS], (Simpson and Angus, 1970), Barnes Akathisia Rating Scale [BARS], (Barnes, 1989) and Abnormal Involuntary Movement Scale [AIMS], (Guy, 1976b)), investigator's evaluation of the injection site (redness, pain, swelling, and induration), and patient's evaluation of the injection site pain as measured by a Visual Analog Scale (0 [no pain]–100 [maximal pain]). 2.7. Data analysis 2.7.1. Analysis sets Per-protocol analysis set (primary population for the efficacy analyses) included all randomized patients who received at least 2 injections of the study medications and for whom the time between any 2 injections did not exceed 35 days for PP or 21 days for RIS-LAI, had both a baseline and at least one postbaseline assessment for the primary efficacy variables, had minimum 5 weeks exposure to the study medications, and did not have major protocol deviations. The intent-to-treat (ITT) analysis set included all randomized patients who received at least one dose of study medications and had at least
1004
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Screening/washout/oral tolerability test (≤ 7 days)
Randomized (n=452)
Paliperidone palmitate (n=229)
Risperidone-LAI* (n=223)
Withdrawn (n=64) Adverse events (n=4) Pregnancy (n=2) Protocol deviation (n=3) Lack of efficacy (n=22) Lost to follow up (n=9) Withdrew consent (n=16) Other reasons (n=8)
Withdrawn (n=38) Adverse events (n=5) Pregnancy (n=0) Protocol deviation (n=1) Lack of efficacy (n=9) Lost to follow up (n=14) Withdrew consent (n=5) Other reasons (n=4)
Day 1: 150 mg eq. (deltoid) Day 8: 100 mg eq. (deltoid) Day 36: 50 or 100mg eq. (deltoid or gluteal) Day 64: 50, 100 or 150mg eq. (deltoid or gluteal)
Completed (n=165; 72.1%)
Day 8: 25mg Day 22: 25mg Day 36: 25, 37.5 mg Day 50: same as day 36 Day 64: 25, 37.5 or 50mg Day 78: same as day 64 Oral risperidone supplement: Day 1: 2 mg/day Day 2 to 28: 1-6 mg/day (flexible dose) Day 36-57: 1-2 mg/day for 21 days if increase in RIS-LAI dose was necessary. Day 64-85: 1-2 mg/day for 21 days if increase in RIS-LAI dose was necessary.
Completed (n=185; 83%)
Fig. 1. Patient disposition. LAI: long-acting-injectable.
one efficacy measurement during the open-label phase. The safety analysis set included all patients who received at least one dose of study medication. 2.7.2. Statistical analysis Efficacy variables were analyzed using the last-observationcarried-forward (LOCF) approach in the per-protocol analysis set. The primary efficacy variable was analyzed using an analysis of covariance (ANCOVA) model with treatment as factor and baseline PANSS total score as the covariate. Noninferiority of PP without oral paliperidone supplementation to RIS-LAI with oral risperidone supplementation was to be concluded if the lower limit of the 2sided 95% confidence interval (CI) for the difference in mean change in PANSS total score (from baseline to endpoint) between RIS-LAI and PP exceeded −5.5. A sensitivity analysis was performed using mixed model repeated measures method with observed case data and an unstructured variance–covariance matrix with time, treatment, and time-by-treatment interaction as factors and baseline PANSS total score as a covariate. An exploratory analysis was also performed to assess a possible interaction between treatment and baseline BMI group for the primary efficacy variable. The changes from baseline to endpoint for CGI-S, PSP, PANSS subscale scores, and PANSS Marder factor scores were analyzed similarly as for the primary efficacy
variable. A Cochran–Mantel–Haenszel test was used to analyze the percentages of PANSS responders. Safety results were assessed using descriptive statistics and frequency distributions in the safety analysis set. 2.7.3. Sample size determination Assuming a true difference of 0 between RIS-LAI and PP, a standard deviation of 19 for the change in PANSS total score, and a one-sided significance level of 0.025, 189 patients per treatment group were required to demonstrate with 80% power that PP is no worse than RISLAI by 5.5 points in the change in PANSS total score. Assuming 90% of randomly assigned patients would be evaluated for the per-protocol analysis, 210 patients per treatment group were to be randomized to each treatment group. 3. Results 3.1. Patient disposition and baseline characteristics Out of 452 randomized patients, 350 (77.4%) patients completed the study and 102 (22.6%) were withdrawn (Fig. 1). The safety analysis set included 452 patients and per-protocol analysis set included 413 patients. Major protocol deviations were reported in
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8 patients in the all randomized patient analysis set (PP group [n = 1]: efficacy assessment deviation and RIS-LAI group [n = 7]: efficacy assessment deviation, error in study drug administration, selection criteria not met, treatment deviation) and 2 patients in the ITT analysis set (both from RIS-LAI group): treatment deviation in 1 patient and error in study drug administration in both patients. Demographic and baseline characteristics were comparable across treatment groups (Table 1). More women (60.0%) were enrolled in the study. Patients' ages ranged from 18 to 64 years. Approximately 5% of the patients had BMI ≥ 30 kg/m2. The mean age at diagnosis of schizophrenia was 26 years. At baseline, the mean (SD) PANSS total score was 83.2 (12.44). In the per-protocol analysis set, the mean (SD) of mean doses administered to individual patients throughout the study was 115.8 (9.07) mg eq. for PP and 29.8 (4.67) mg for RIS-LAI; the median (range) of the same was 112.5 (87.5; 137.5) mg eq. for PP and 29.2 (25.0; 37.5) mg for RIS-LAI. The mean (SD) daily dose of supplemental oral risperidone dispensed to RIS-LAI group patients was 2.5 (0.98) mg from day 1 through day 28, 1.8 (0.52) mg from day 36 through day 57, and 1.7 (0.47) mg from day 64 through day 85. The median (range) daily dose of supplemental oral risperidone dispensed to RIS-LAI group patients was: 2 (1; 6) mg from day 1 through day 28; 2 (1; 4) mg from day 36 through day 57; and 2 (1; 2) mg from day 64 through day 85.
and PP groups was greater than the protocol prespecified noninferiority margin of −5.5 at endpoint (Table 2). Results of repeated measure mixed effect model corroborated the finding that PP was noninferior to RIS-LAI (difference in LSM [95% CI] on day 92: −2.5 [− 5.34, 0.42]). Noninferiority of PP to RIS-LAI, based on same ANCOVA analysis and noninferiority margin as above, was observed as early as day 8 (the first assessment) and demonstrated at every subsequent time point assessed. PP was not demonstrated to be noninferior to RIS-LAI in the ITT analysis set as the difference in LSM for the change in PANSS total score between the groups was −4.0 with a 95% CI of (− 7.13, − 0.89) and the lower limit of the 95% CI (−7.13) was lower than −5.5 at endpoint. Results of the exploratory analysis for the primary efficacy variable indicated less improvement in PANSS total score with increased BMI in the PP group; no such trend was observed in the RIS-LAI group. However, there was no evidence for a significant treatment-by-baseline BMI category interaction at 10% level. Similar improvements were seen in both treatment groups for CGI-S, PSP (Table 2) and the PANSS subscale scores and Marder factor scores (Table 3). At endpoint, 70.7% patients from the PP group and 78.4% patients from the RIS-LAI group responded (improvement in PANSS score by ≥30%) to treatment (point estimate [95% CI] of the relative risk of PP vs. RIS-LAI: 0.9 [0.81, 1.01]).
3.2. Efficacy findings
3.3. Safety findings
PP was demonstrated to be noninferior to RIS-LAI as the lower limit of the 95% CI (−5.20, 0.63) for the difference in least square means (LSM) for the change in PANSS total score, between RIS-LAI
The overall rates of TEAEs were similar in the PP (73.4%) and RISLAI (74.9%) groups. Overall, the most common TEAEs were akathisia, tremor, and insomnia (Fig. 2). Discontinuation due to TEAEs occurred in 8 (3.5%) patients in the PP group and 9 (4%) in the RIS-LAI group. The most frequent (n ≥ 2) reasons for discontinuation were irritability and psychiatric symptoms. Suicide-related adverse events were reported in 3 patients in the RIS-LAI group and none in the PP group. One patient from the RIS-LAI group died (completed suicide) during the study. The patient had no history of suicide attempt or ideation. No deaths were reported in the PP group. Somnolence was reported as a neurologic adverse event in 11 (4.8%) patients in the PP group and 6 (2.7%) patients in RIS-LAI group. Fewer patients experienced serious TEAEs in the PP group (n = 3, 1.3%) than in the RIS-LAI group (n = 8, 3.6%). One patient in the PP group (schizophrenia) and 3 patients in the RIS-LAI group
Table 1 Demographic and baseline characteristics (safety analysis set). Paliperidone Risperidone LAI palmitate (N = 223) (N = 229) Age (years), mean (SD) Sex, n (%) Men Women Racea, n (%) Han Muslim Weight (kg), mean (SD) Body mass index (kg/m2), mean (SD) Category, n (%) Normal b 25 Overweight 25–b30 Obese ≥ 30 Schizophrenia type, n (%) Disorganized Catatonic Paranoid Residual Undifferentiated Baseline total PANSS, mean (SD) Prior psychotropic therapyb, n (%) Total number of patients with prior psychotropic therapy Anti-EPS Antidepressants Atypical antipsychotics Benzodiazepines Beta blockers Non-benzodiazepines hypnotics and anxiolytics Stimulants Typical antipsychotics
32.0 (10.75)
31.5 (11.03)
87 (38.0) 142 (62.0)
94 (42.2) 129 (57.8)
228 (99.6) 1 (0.4) 62.9 (12.24) 23.1 (3.83)
222 (100.0) 0 62.3 (12.27) 23.1 (3.96)
167 (72.9) 50 (21.8) 12 (5.2)
159 (71.3) 52 (23.3) 12 (5.4)
7 (3.1) 0 (0) 153 (66.8) 3 (1.3) 66 (28.8) 82.5 (12.2)
9 (4.0) 1 (0.4) 148 (66.4) 0 65 (29.1) 83.9 (12.66)
66 (28.9) 20 (8.8) 2 (0.9) 29 (12.7) 24 (10.5) 3 (1.3) 4 (1.8) 0 15 (6.6)
57 (26.1) 23 (10.6) 0 25 (11.5) 19 (8.7) 1 (0.5) 2 (0.9) 1 (0.5) 11 (5.0)
LAI = Long-acting-injectable; PANSS = Positive and Negative Syndrome Scale. a Risperidone LAI: N = 222. b Intent-to-analysis set (N=228 for paliperidone palmitate, N=218 for risperidone LAI).
Table 2 Change in efficacy variables from baseline to endpoint (LOCF) (per-protocol analysis set).
PANSS total scorea, mean (SD) Baseline Change from baseline Difference of LSM (95% CI) CGI-S scorea, mean (SD) Baseline Change from baseline Difference of LSM (95% CI) PSP scoreb, mean (SD) Baseline Change from baseline Difference of LSM (95% CI)
Paliperidone palmitate (N = 205)
Risperidone LAI (N = 208)
82.1 (11.95) − 23.6 (16.28)
84.4 (12.69) − 26.9 (15.43) − 2.3 (− 5.20;0.63) N = 207 5.0 (0.81) − 1.7 (1.16) − 0.1 (− 0.33;0.10) N = 190 45.3 (11.29) 18.6 (13.92) 0.5 (− 2.14; 3.12)
N = 204 4.9 (0.82) − 1.5 (1.24) N = 184 47.8 (12.42) 16.8 (14.76)
LOCF = last observation carried forward; LAI = Long-acting-injectable; PANSS = Positive and Negative Syndrome Scale; CGI-S = Clinical Global Impression-Severity; PSP = Personal and Social Performance Scale; LSM = Least square means; CI = Confidence interval. a Negative change in score indicates improvement. b Positive change in score indicates improvement.
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Table 3 Change from baseline to endpoint (LOCF) in PANSS subscale scores and Marder factor scores (per-protocol analysis set). Paliperidone palmitate (N = 205) PANSS subscales mean (SD) Positive subscale Baseline Change from baseline Difference of LSM (95% CI) Negative subscale Baseline Change from baseline Difference of LSM (95% CI) General psychopathology Baseline Change from baseline Difference of LSM(95% CI) PANSS Marder factors mean (SD) Positive symptoms Baseline Change from baseline Difference of LSM (95% CI) Negative symptoms Baseline Change from baseline Difference of LSM (95% CI) Disorganized thoughts Baseline Change from baseline Difference of LSM (95% CI) Uncontrolled hostility/excitement Baseline Change from baseline Difference of LSM (95% CI) Anxiety/depression Baseline Change from baseline Difference of LSM (95% CI)
Risperidone LAI (N = 208)
20.6 (5.59) − 7.7 (6.26)
20.7 (4.86) − 9.0 (5.83) − 1.2 (− 2.14; − 0.21)
21.3 (6.46) − 5.2 (5.85)
22.2 (6.98) − 5.6 (5.68) − 0.0 (− 0.95; 0.93)
40.2 (6.57) − 9.5 (9.27)
41.4 (6.76) − 12.3 (8.04) − 0.9 (− 2.30; 0.55)
26.7 (6.08) − 9.1 (7.28)
27.3 (5.91) − 10.9 (7.07) − 1.4 (− 2.61; − 0.24)
22.2 (6.87) − 5.3 (6.39)
23.0 (7.45) − 5.6 (5.96) 0.0 (− 0.96; 1.05)
16.2 (4.52) − 4.2 (4.00)
16.8 (4.76) − 4.6 (4.26) − 0.1 (− 0.77; 0.54)
8.9 (3.85) − 3.1 (3.71)
8.8 (3.80) − 3.4 (3.67) − 0.4 (− 0.86; 0.07)
8.1 (3.02) − 1.9 (3.02)
8.5 (3.10) − 2.3 (3.16) − 0.1 (− 0.54; − 0.34)
Negative change in score indicates improvement. LAI = Long-acting-injectable; PANSS = Positive and Negative Syndrome Scale; LSM = Least square means; CI = Confidence interval.
(nausea and vomiting, convulsion, and benzhexol overdose) experienced serious adverse events. The most common (N10%) EPS-related events were akathisia (PP: n = 30 [13.1%]; RIS-LAI: n = 44 [19.7%]) and tremor (PP: n = 24 [10.5%]; RIS-LAI: n = 40 [17.9%]). The percentage of patients who required use of anti-EPS medication in the open-label period was lower in the PP group (31.4%) than in the RIS-LAI group (46.2%).
Insomnia
Overall, the incidence of potentially prolactin-related adverse events was similar between the PP group (n= 19 [8.3%]) and the RIS-LAI group (n= 20 [9.0%]). These events included increase in serum prolactin (PP: n = 17 [7.4%]; RIS-LAI: n = 12[5.4%]); galactorrhea (only in PP: n = 1 [0.4%]); hyperprolactinemia (PP: n = 1 [0.4%]; RIS-LAI: n = 5 [2.2%]); amenorrhea (only in RIS-LAI: n = 3 [2.3%]); and amenorrhea–galactorrhea syndrome (only in RIS-LAI: n = 1 [0.8%]). At baseline, the mean prolactin levels in men and women were above the upper limit of normal range (ULN) in both groups; overall, fewer patients in the PP group than RIS-LAI group had prolactin levels above the ULN (Table 4). The mean changes in prolactin levels from baseline to endpoint were significantly larger in women than in men for both PP (37.7 ng/mL [women] vs 9.8 ng/mL [men]) and RIS-LAI (31.1 ng/mL [women] vs 8.2 ng/mL [men]) groups. Treatment-emergent glucose-related adverse events (blood glucose increased) were reported in one (0.4%) patient in PP group and 2 (0.9%) patients in RIS-LAI group. At endpoint, the mean (SD) increases in body weight (PP: 1.5 [3.10] kg; RIS-LAI: 1.5 [3.24] kg); percentage of patients showing increase in weight ≥ 7% (PP: n = 32 [15.5%]; RIS-LAI: n = 35 [17.3%]) and percentage of patients showing decrease in weight ≥ 7% (PP: n = 2 [1.0%]; RIS-LAI: n = 3 [3.0%]) were similar between the two groups. There were no serious cardiac-related adverse events reported during this study. The incidence of treatment-emergent tachycardia were similar between the 2 treatment groups (4 [b2%] patients in each group). None of the patients had treatment-emergent orthostatic hypotension based on vital sign measurements (defined as a decrease in systolic [N20 mmHg] or diastolic [N10 mmHg] blood pressure after standing for at least 2 min and an increase in pulse rate N15 bpm when compared with supine measurements), although one TEAE of mild orthostatic hypotension was reported in one PP-treated patient on day 64 (day PP was administered). None of the patients showed clinically noteworthy changes in QTc intervals from baseline to endpoint. There were no reports of ventricular tachycardia, ventricular fibrillation, torsades de pointes; hyperthermia; anaphylactic reaction; pancreatitis-related adverse events; neuroleptic malignant syndrome; potential rhabdomyolosis-related event; or potential syndrome of inappropriate antidiuretic hormone secretion-related events. There were no clinically relevant changes in vital signs or clinical or hematological laboratory values during the study except that one patient in the PP group showed abnormally high alanine aminotransferase level at endpoint (at screening: 15 U/L; at endpoint: 341 U/L; normal range: 0-55 U/L) and one patient in RIS-LAI group showed abnormally high total bilirubin at endpoint (at screening: 17.8 μmol/L; at endpoint: 134 μmol/L; normal range: 0–20.5 μmol/L). Overall, local injection site tolerability was good. Most injection site-related adverse events were mild and included injection site induration (PP vs. RIS-LAI: 0.9% vs. 0%), injection site pain (2.6% vs. 0.4%), and injection site swelling (1.7% vs. 0%). The investigator
Akathisia Table 4 Treatment-emergent abnormal prolactin levels (safety analysis set).
Tremor Upper respiratory tract infection Constipation Blood prolactin increased Restlessness
Baseline prolactin levels
Postbaseline prolactin levels
≤ 1 × ULN ≤ 2 × ULN ≤ 2 × ULN
N 1 × ULN N 2 × ULN N 5 × ULN
Bradykinesia Musculoskeletal stiffness Paliperidone Palmitate (N=229) Risperidone LAI (N=223)
Anxiety 0
2
4
6
8
10 12 14 16 18 20 22
Percent Fig. 2. Treatment-emergent adverse events experienced by at least 5% of patients in any treatment group (safety analysis set). LAI: long-acting-injectable.
Paliperidone palmitate
Risperidone LAI
Men (N = 76)a, n (%)
Women (N = 120)a, n (%)
Men (N = 80)a, n (%)
Women (N = 103)a, n (%)
17 (22) 21 (28) 7 (9)
30 (25) 43 (36) 25 (21)
24 (30) 25 (31) 6 (8)
30 (29) 41 (40) 28 (27)
ULN: upper limit of normal range. a Number of patients with prolactin levels measured at both baseline and postbaseline. Different local laboratories used different reference ranges for prolactin levels. The highest upper limit of normal range used in this study was 25 ng/mL for men and 35 ng/mL for women.
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assessments of the injection site showed that induration, swelling, and redness were observed in b12% of patients in both groups and were generally mild. The patients' assessment of injection pain showed that in both groups, the highest mean Visual Analog Scale scores occurred on day 1 of injections and the average intensity of injection pain generally decreased over time in both groups. The average intensity of injection site pain did not change significantly over time. 4. Discussion PP and RIS-LAI groups showed similar improvement in the primary efficacy variable in this 13-week, open-label study. In the per-protocol analysis set, which was the population assessed for the primary analysis, the results indicated that PP (50–150 mg eq., without oral paliperidone supplementation) was noninferior to RIS-LAI (25– 50 mg, with oral risperidone supplementation) in treating adult Chinese patients with acute schizophrenia. Both treatment groups also showed similar improvements in all secondary efficacy variables, further supporting the comparable efficacy of PP and RIS-LAI in these patients. The efficacy findings for PP were also consistent with previous PP studies in adult patients with schizophrenia (Gopal et al., 2010; Kramer et al., 2010; Nasrallah, 2007; Pandina et al., 2010). A 13 week double-dummy, double-blind study, which used a similar dosing initiation regimen of 150 mg eq. PP on day 1 and 100 mg eq. on day 8, in adult patients with acute schizophrenia, studied across 14 countries, also demonstrated noninferiority of PP with RIS-LAI (Pandina et al., 2011). This dosing initiation regimen has been approved in the US (INVEGA® SUSTENNA™ prescribing information, 2010). The present 13-week open-label study using the approved dosing initiation regimen, confirmed the noninferiority of PP to RIS-LAI, although in a different ethnic group from the previous 13-week study (Pandina et al., 2011). In previous studies, heterogeneity of treatment effect related to baseline BMI (Fleischhacker et al., 2008; Gopal et al., 2010; Nasrallah, 2007) was observed and patients with higher BMI showed a slower initial rise in plasma concentrations of paliperidone compared with patients with normal BMI, indicating that the pharmacokinetics of PP is largely influenced by BMI. However, no significant treatment-bybaseline BMI category interactions were observed in this study. Deltoid injections during dosing initiation and a longer (1.5 in.) needle length used in this study have been shown to improve the initial rise in plasma concentrations of PP (Samtani et al., 2009). Additionally, the mean baseline BMI of this patient population (23.1 kg/m2) was approximately 20% less than that of in previous studies (27–29 kg/m2) (Fleischhacker et al., 2008; Gopal et al., 2010; Nasrallah, 2007). The incidences of EPS-related events reported during this study were higher compared with previous studies (Pandina et al., 2010, 2011). The use of anti-EPS medication was also increased from baseline to endpoint. Based on the clinical experience, Chinese patients may be more likely to experience EPS when treated with PP or RIS-LAI due to smaller body weights which might result into relatively higher drug exposures compared with that of western population. Additionally, unlike the other studies, the investigators were required to enter information on EPS-related adverse events on a separate CRF page, which could have led to bias in reporting and may in part have contributed to the higher reported incidence of these events. The percentage of patients requiring anti-EPS medications during openlabel period was lower in the PP group than in the RIS-LAI group. Treatment-emergent glucose-related adverse event were reported in b1% patients in both treatment groups. Increases in body weight were similar between groups. Cardio-metabolic events associated with use of atypical antipsychotics are of significant clinical concern (Mathews and Muzina, 2007). It is noteworthy that low incidences of weight gain and glucose-related events were reported in this study. The results corroborated the findings from other studies with PP and
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RIS-LAI (Hough et al., 2009; Kane et al., 2003; Keks et al., 2007; Pandina et al., 2010). Consistent with the known pharmacology of paliperidone (Citrome, 2010; Janicak and Winans, 2007), increases in prolactin levels were observed in both treatment groups and the incidences of potentially prolactin-related adverse events were similar (b10%) between groups. However, the incidence rate of potentially prolactinrelated clinical symptoms, galactorrhea, amenorrhea, and amenorrhea–galactorrhea syndrome was small (b5%) indicating that the clinical relevance of documented hyperprolactinemia was low. The safety profiles of PP and RIS-LAI groups were comparable during this 13-week study. The safety and tolerability results were consistent with previous clinical studies of PP (Nasrallah, 2007; Pandina et al., 2011). Overall, local injection site tolerability was good for PP and RIS-LAI groups. The mild injection-site pain was similar across groups. An open-label design of this study may have led to some bias in patients who were treated with a known efficacious drug, RIS-LAI (with oral supplementation of risperidone), and may have resulted in the higher dropout rate in the PP group wherein patients received an investigational drug and had a longer interval of injections (every 4 weeks vs. 2 weeks), compared with the RIS-LAI group. Consistent with this, twice as many patients discontinued due to lack of efficacy and three times as many withdrew consent in the PP-compared with the RIS-LAI group. While most of the secondary efficacy variables supported the outcome of the primary finding, which demonstrated the comparability of PP to RIS-LAI, a small difference was noted for the improvements seen in the positive subscale score and positive Marder factor score, favoring RIS-LAI. However, this small difference was not considered to be clinically significant. Noninferiority of PP to RIS-LAI was demonstrated in the per-protocol analysis set but not in the ITT analysis set. The per-protocol analysis set was more clinically relevant as these patients were required to have a minimum 5 weeks of exposure to the open-label phase treatment. The ITT set did not require patients to meet this criterion. The difference in results for two analysis sets could be related to the higher dropout rate in the PP group. The ITT analysis set included patients, who discontinued early during the study and had high PANSS total scores at the time of discontinuation, which could have resulted in the high mean PANSS total score at the endpoint, and the lower limit of the 95% CI of the difference in LSM not exceeding −5.5 (LOCF approach). Also, the sample size was based on optimistic assumptions about population heterogeneity as the study was to be conducted in an ethnically homogenous (single country) population, in which BMI was not anticipated to be a significant issue. Hence the width of the CIs for the primary endpoint may have been greater than anticipated. There are several distinctions between PP and RIS-LAI. PP does not require oral paliperidone supplementation, uses a small-gauge needle, and is administered once-monthly rather than biweekly. These differences may aid in patient compliance. The PP formulation does not require refrigeration, which provides convenience to clinical practitioners. 5. Conclusion This open-label, rater-blinded study demonstrated noninferiority of PP (50–150 mg eq., flexibly dosed, without oral paliperidone supplementation) to RIS-LAI (25–50 mg, flexibly dosed, with oral risperidone supplementation) for the treatment of acute schizophrenia in adult Chinese patients. PP injections were generally tolerable, and no new safety signals were detected in this population. Study support Funded by Xian-Janssen Pharmaceutical Limited, Beijing, PR China. The sponsor provided a formal review of the manuscript.
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Registration This study is registered at ClinicalTrials.gov (NCT00604279). Disclosures Drs. Li and Gu were investigators for this study. They were advisors for Wyeth Limited and AstraZeneca International. Dr. Ning was an employee of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. at the time of study. Dr. Rui is an employee of Xian Janssen Pharmaceutical Limited, Beijing, PR China, a Johnson & Johnson company. Dr. Xu is an employee of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., New Jersey, USA. All authors met ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data and made the final decision about where to publish these data and approved submission to the journal. Previous presentations Data from this study were presented at the 27th International College of Neuropsychopharmacology Congress, Hong Kong, 6–10 June 2010 and the World Psychiatric Association International Congress, Beijing, China, Sept. 1–5, 2010. Acknowledgments Dr. Sarika Shirke (SIRO Clinpharm Pvt. Ltd.) provided writing assistance and Dr. Wendy P. Battisti (Johnson & Johnson Pharmaceutical Research & Development, L.L.C) provided additional writing assistance and editorial support for this manuscript. The authors thank the study participants, without whom this study would not have been accomplished, as well as the following investigators for their participation in this study: Drs. Gu, N; Zang, H; Wang, C; Xie, S; Tan, Q; Li, K; Zheng, H; Xu, Y; Wang, X and Shi, J. References Barnes T. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672–6. Citrome L. Paliperidone palmitate — review of the efficacy, safety and cost of a new secondgeneration depot antipsychotic medication. Int J Clin Pract 2010;64:216–39. Fleischhacker W, Gopal S, Samtani M, Quiroz J, Pandina G, Vermeulen A, et al. Optimization of the dosing strategy for the long-acting injectable antipsychotic paliperidone palmitate: results of two randomized double-blind studies and population pharmacokinetic simulations. Paper presented at: the annual meeting of American College of Neuropsychopharmacology; December 7–11; Scottsdale, Arizona 2008; 2008. Gopal S, Hough D, Xu H, Lull J, Gassmann-Mayer C, Remmerie B, et al. Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophre-
nia: a randomized, double-blind, placebo-controlled, dose–response study. Int Clin Psychopharmacol 2010;25:247–56. Guy. CGI-S. Clinical Global Impression Severity, Early Clinical Drug Evaluation Unit (ECDEU), Assessment manual for psychopharmacology, Rev. Ed. Rockville, Maryland: National Institute of Mental Health; 1976a. Guy W. AIMS. Abnormal Involuntary Movement Scale.Early Clinical Drug Evaluation Unit (ECDEU) Assessment for psychopharmacology. Rockville, Maryland: National Institute of Mental Health; 1976b. Hough D, Lindenmayer J, Gopal S, Melkote R, Lim P, Herben V, et al. Safety and tolerability of deltoid and gluteal injections of paliperidone palmitate in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:1022–31. INVEGA® SUSTENNA™ prescribing information. [updated March 2010; cited 2010 April 20]; Available from:http://www.invegasustenna.com/invegasustenna/ shared/pi/invegasustenna.pdf. Janicak P, Winans E. Paliperidone ER: a review of the clinical trial data. Neuropsychiatr Dis Treat 2007;3:869–83. Kane J, Eerdekens M, Lindenmayer J, Keith S, Lesem M, Karcher K. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry 2003;160:1125–32. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261–76. Keith SJ, Pani L, Nick B, Emsley R, San L, Turner M, et al. Practical application of pharmacotherapy with long-acting risperidone for patients with schizophrenia. Psychiatr Serv 2004;55:997-1005. Keks N, Ingham M, Khan A, Karcher K. Long-acting injectable risperidone v. olanzapine tablets for schizophrenia or schizoaffective disorder. Br J Psychiatry 2007;191: 131–9. Kramer M, Litman R, Hough D, Lane R, Lim P, Liu Y, et al. Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study. Int J Neuropsychopharmacol 2010;13:635–47. Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997;58:538–46. Mathews M, Muzina D. Atypical antipsychotics: new drugs, new challenges. Cleve Clin J Med 2007;74:597–606. Morosini P, Magliano L, Brambilla L, Ugolini S, Pioli R. 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 2000;101:323–9. Nasrallah HA. The case for long-acting antipsychotic agents in the post-CATIE era. Acta Psychiatr Scand 2007;115:260–7. Pandina G, Lindenmayer J, Lull J, Lim P, Gopal S, Herben V, et al. A randomized, placebocontrolled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol 2010;30:235–44. Pandina G, Lane R, Gopal S, Gassmann-Mayer C, Hough D, Remmerie B, et al. A doubleblind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2011;35: 218–26. Rainer MK. Risperidone long-acting injection: a review of its long term safety and efficacy. Neuropsychiatr Dis Treat 2008;4:919–27. Risperdal® CONSTA® prescribing information. [updated Sept 2009; cited 2010 April 20]; Available from:http://www.risperdalconsta.com/risperdalconsta/shared/pi/ risperdalconsta.pdf#zoom=100. Samtani MN, Vermeulen A, Stuyckens K. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic. Clin Pharmacokinet 2009;48: 585–600. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212:11–9.