A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia

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Abstract

This 13-week double-blind study was designed to assess noninferiority of the recently approved (in the U.S.) injectable atypical antipsychotic paliperidone palmitate (PP) versus risperidone long-acting injectable (RIS-LAI) in adult patients with schizophrenia. Patients (N = 1220) were randomized (1:1) to either a) PP: deltoid injections on day 1 (150 mg eq.), day 8 (100 mg eq.), and once-monthly flexible dosing as deltoid or gluteal injections on day 36 (50 mg eq. or 100 mg eq.) and day 64 (50 mg eq. or 100 mg eq. or 150 mg eq.) or b) RIS-LAI: gluteal injections days 8 and 22 (25 mg), days 36, 50 (25 or 37.5 mg) and days 64, 78 (25, 37.5 or 50 mg). RIS-LAI-treated patients received oral supplementation with RIS 1–6 mg/day (days 1 to 28), and PP-treated patients received oral placebo. The safety analysis set (n = 1214) included 58% men, 78% white, with mean (SD) baseline PANSS total score: PP, 84.1 (12.09); and RIS-LAI, 83.6 (11.28). Mean (SD) change from baseline to endpoint in PANSS total score decreased similarly in both groups; PP (−18.6 [15.45]) and RIS-LAI (−17.9 [14.24]). PP treatment was noninferior to RIS-LAI (point estimate [95% CI]: 0.4 [−1.62;2.38], per-protocol analysis set [primary analysis]). The tolerability and safety of PP was generally similar to RIS-LAI with no new safety or tolerability findings.

Research highlights

►Paliperidone palmitate was demonstrated to be noninferior to risperidone long-acting injectable in treatment of schizophrenia using the approved initiation dose strategy. ►Paliperidone palmitate was generally safe and tolerable. ►Pharmacokinetic results were similar between both treatments.

Introduction

The intramuscular (i.m.) long-acting injectable (LAI) formulations of antipsychotic medications were developed to enhance treatment adherence and improve the long-term management of schizophrenia (Keith et al., 2004, Nasrallah, 2007). Due to their sustained delivery, LAIs help reduce relapse secondary to non-adherence and provide clinical stability necessary for psychosocial interventions (Kane et al., 2003, Nasrallah, 2007). Despite frequent non-adherence to oral medications and subsequent relapse, LAIs are not commonly used. The rates vary across countries but only 30% or fewer patients are prescribed an LAI (Patel et al., 2009, Barnes et al., 2009). Suboptimal knowledge of the antipsychotic LAIs is possibly associated with the underutilization of these formulations in many countries, highlighting the role of stigma and the need for more research (Kane and Garcia-Ribera, 2009, Patel et al., 2009).

Risperidone-LAI (RIS-LAI) was the first atypical antipsychotic available as an injectable formulation. The recommended dosage for patients with schizophrenia is 25 to 50 mg every 2 weeks (RISPERDAL® CONSTA® Prescribing Information), with oral supplementation for first 3 weeks of treatment. Paliperidone palmitate (PP) is the palmitate ester of paliperidone (9-hydroxy-risperidone), the active metabolite of risperidone. PP is a once-monthly atypical antipsychotic LAI approved in the US for the acute and maintenance treatment of schizophrenia in adults and is formulated to provide sustained plasma concentrations of paliperidone, the pharmacologically active fraction (Invega® Sustenna™ Prescribing Information). The deltoid initiation regimen for PP allows rapid attainment of therapeutic concentrations (Samtani et al., 2009), precluding any need for oral supplementation. PP at doses of 25–150 mg eq. demonstrated efficacy and was generally safe and tolerable in previous double-blind, placebo-controlled studies in adult patients with schizophrenia (Hough et al., 2009, Pandina et al., 2010, Gopal et al., 2010).

Both PP and RIS-LAI are effective and tolerated in the treatment of schizophrenia (Hough et al., 2009, Hough et al., 2010, Kane et al., 2003, Keks et al., 2007, Kramer et al., 2010, Pandina et al., 2010). In an earlier study (Fleischhacker et al., 2009) that compared efficacy of these two LAIs, adequate plasma levels of paliperidone were not achieved for PP as a result of an inadequate initiation dosing regimen with PP (initiated as gluteal injections of 50 mg eq. on days 1 and 8). Hence, PP did not demonstrate noninferiority to RIS-LAI in that study.

A direct comparison between PP and an already approved LAI atypical antipsychotic provides valuable comparative information on efficacy, safety, and tolerability of the agents in the treatment of schizophrenia. The present 13-week study was also conducted to address European Medicines Agency guidelines to demonstrate noninferiority of new injectable antipsychotics to approved formulations. The study included a modified dosing initiation regimen and was designed to demonstrate that PP (without oral supplementation) initiated as deltoid injections (day 1 [150 mg eq.], day 8 [100 mg eq.]) and subsequent flexible dosing (50, 100, or 150 mg eq.) once-monthly was not less efficacious than RIS-LAI (25, 37.5, or 50 mg) administered every 2 weeks with oral supplementation. The safety and tolerability of PP in the treatment of schizophrenia was also assessed.

Section snippets

Patients

Consenting men and women (18 years or older) with an established Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia for at least one year before screening, a Positive and Negative Syndrome Scale [PANSS] total score at screening between 60 and 120 (inclusive), and with a body mass index  17.0 kg/m2 and < 40 kg/m2, were enrolled.

Main exclusion criteria included a history of: primary active DSM-IV Axis I diagnosis other than schizophrenia, decrease

Patient characteristics and disposition

In total, 1220 patients were randomly assigned to 1 of the 2 treatment groups of which 927 (76%) patients completed the study, (456 [75%]) flexibly dosed PP and (471 [77%]) flexibly dosed RIS-LAI, Fig. 1). The analysis sets were: safety analysis set (n = 1214), ITT analysis set (n = 913), per-protocol set (n = 765), and PK analysis set (n = 950).

In general, the demographic and baseline characteristics were similar among the treatment groups in the safety analysis set (Table 2) and consistent across all

Discussion

The primary as well as secondary efficacy findings of this study revealed that PP and RIS-LAI treatment over a 13-week period resulted in similar improvements in patients with acute schizophrenia. Notably, in contrast to an earlier noninferiority study of PP and RIS-LAI (Fleischhacker et al., 2009), treatment in the current study was initiated with a high dose of 150 mg eq. PP in the deltoid muscle to optimize early and effective plasma concentrations of PP. Consequently, the efficacy of PP in

Conclusions

In the current study, noninferiority of PP (50, 100, or 150 mg eq.; i.e. 78, 156, or 234 mg) without oral supplementation to RIS-LAI (25, 37.5, 50 mg) with oral risperidone was established in treatment of schizophrenia using the approved (US) initiation dose strategy for PP. Pharmacokinetic results were also similar between both treatments. PP was generally safe and tolerable in these patients.

Conflict of interest statement

This study was sponsored by Johnson & Johnson Pharmaceutical Research and Development, L.L.C. Dr. George Simpson was an investigator on this study and he has received research funding from Astra-Zeneca, Roche, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Drs. Pandina, Gopal, Hough, and Gassmann-Mayer, and Ms. Lane are employees of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Mr. Remmerie, Chem. Eng., is an employee of Johnson & Johnson Pharmaceutical

Author disclosure

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. The sponsor provided a formal review of the manuscript.

Role of funding source

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. funded this study and was responsible for study design and data collection, analysis and its interpretation. The sponsor also was responsible for deciding to publish the data. Many of the authors are employees of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., as noted.

Acknowledgments

Dr. Madhavi Patil (SIRO Clinpharm Pvt. Ltd.) provided writing assistance and Dr. Wendy P. Battisti (Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) provided additional editorial support for this manuscript. We thank Drs. Pilar Lim and Joseph Palumbo for their thoughtful contributions to data interpretation and review of the manuscript.

We thank the following investigators for their participation in this study:

Austria: Geretsegger Christian, MD Schoenbeck, Georg, MD; Bulgaria:

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