Comparison of Relapse Prevention with 3 Different Paliperidone Formulations in Patients with Schizophrenia Continuing versus Discontinuing Active Antipsychotic Treatment: A Post-Hoc Analysis of 3 Similarly Designed Randomized Studies

Maju Mathews, Srihari Gopal, Arun Singh, Isaac Nuamah, Katalin Pungor, Wilson Tan, Bernardo Soares, Edward Kim, Adam J Savitz, Maju Mathews, Srihari Gopal, Arun Singh, Isaac Nuamah, Katalin Pungor, Wilson Tan, Bernardo Soares, Edward Kim, Adam J Savitz

Abstract

Background: Sudden discontinuation from antipsychotic treatment is a common occurrence in patients with schizophrenia. Lower rates of relapse could be expected for patients discontinuing treatment from longer-acting formulations vs their shorter-acting equivalents.

Objective: To compare relapse rates and time-to-relapse between the active (analogous to adherent patients) and placebo (analogous to non-adherent patients in the real-world) arms of three different formulations of paliperidone (oral paliperidone extended release [paliperidone ER], paliperidone palmitate once monthly [PP1M], and paliperidone palmitate three monthly [PP3M] long-acting injectables).

Methods: Data from three similarly designed, randomized relapse prevention studies in adult patients with schizophrenia were analyzed.

Results: In total, 922 patients were included (active treatment: 473, placebo: 449). Lowest percentage of patients experienced relapse with PP3M <PP1M <paliperidone and ER, in both the active treatment (PP3M, 9% <PP1M, 18% <paliperidone ER, 22%) and placebo (PP3M, 29% <PP1M, 48% <paliperidone ER, 52%) groups. The post-discontinuation median-time-to-relapse was significantly longer with PP3M (395 days [274 days to "not-reached"])> PP1M (172 days [134-222 days])> paliperidone ER (58 days [42-114 days]) and was "not-estimable" in the active treatment group due to low relapse rates. Hazard ratios (HR) of the three paliperidone formulations relative to their respective placebos were PP3M ([HR: 3.81; 95% CI: 2.08, 6.99; P< 0.0001]> PP1M [HR: 3.60; 95% CI: 2.45, 5.28; P<0.0001]> paliperidone ER [HR: 2.83; 95% CI: 1.73, 4.63; P<0.001]).

Conclusion: The lower percentage of relapse during active treatment and longer time to relapse after discontinuing active treatment with longer-duration antipsychotic formulations suggests the benefit of longer-acting over shorter-acting formulations, especially in patients susceptible to poor adherence.Clinical trial registration: paliperidone ER (NCT00086320), PP1M (NCT00111189), and PP3M (NCT01529515).

Keywords: oral paliperidone extended release; paliperidone palmitate once monthly; paliperidone palmitate three monthly; relapse prevention; schizophrenia.

Conflict of interest statement

SG, MM, AS, AJS and IN are employees of Janssen Research & Development, LLC, United States. AJS, SG, KP, EK and MM hold stocks of Johnson & Johnson. KP is an employee of Janssen-Cilag GmbH, Neuss, Germany, WT is an employee of Janssen Pharmaceutical Companies of Johnson and Johnson, Singapore and BS is an employee of Jan-Cilag UK and EK is an employee of Janssen Scientific Affairs, LLC, Titusville, New Jersey, United States. The authors report no other conflicts of interest in this work.

© 2020 Mathews et al.

Figures

Figure 1
Figure 1
Flowchart of overall study design, highlighting major similarities and differences. aOne patient in each treatment group was randomized but was in the transition/maintenance phase when the study was stopped and did not receive any double-blind injections. Abbreviations: ER, extended release; LAI, long-acting injectable; PP1M, paliperidone palmitate once monthly LAI; PP3M, paliperidone palmitate three monthly LAI.
Figure 2
Figure 2
Kaplan-Meier plots of three paliperidone formulations vs placebo. (A) Paliperidone ER. (B) PP1M. (C) PP3M. Abbreviations: ER, extended release; LAI, long-acting injectable; PP1M, paliperidone palmitate once monthly LAI; PP3M, paliperidone palmitate three monthly LAI;
Figure 3
Figure 3
Forest plot of the hazard ratios from paliperidone ER and paliperidone palmitate studies with placebo. Abbreviations: CI, confidence interval; ER, extended release; LAI, long-acting injectable.
Figure 4
Figure 4
Positive and Negative Syndrome Scale (PANSS) total scores over time for three different formulations of Paliperidone. (A) Paliperidone ER. (B) PP1M. (C) PP3M. Abbreviations: ER, extended release; LAI, long-acting injectable; PP1M, paliperidone palmitate once monthly LAI; PP3M, paliperidone palmitate three monthly ; RI/ST, run-in and stabilization phases

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