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Long-acting injectable paliperidone palmitate versus oral paliperidone extended release: a comparative analysis from two placebo-controlled relapse prevention studies.

Markowitz M, Fu DJ, Levitan B, Gopal S, Turkoz I, Alphs L - Ann Gen Psychiatry (2013)

Bottom Line: This analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia.The safety profile of PP was similar to that of paliperidone ER.Future studies are needed to confirm these findings.

View Article: PubMed Central - HTML - PubMed

Affiliation: Janssen Scientific Affairs, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, USA. mmarkowi@its.jnj.com.

ABSTRACT

Background: Increasing availability and use of long-acting injectable antipsychotics have generated a need to compare these formulations with their oral equivalents; however, a paucity of relevant data is available.

Methods: This post hoc comparison of the long-term efficacy, safety and tolerability of maintenance treatment with paliperidone palmitate (PP) versus oral paliperidone extended release (ER) used data from two similarly designed, randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention trials. Assessments included measures of time to relapse, symptom changes/functioning and treatment-emergent adverse events (TEAEs). Time to relapse between treatment groups was evaluated using a Cox proportional hazards model. Between-group differences for continuous variables for change scores during the DB phase were assessed using analysis of co-variance models. Categorical variables were evaluated using Chi-square and Fisher's exact tests. No adjustment was made for multiplicity.

Results: Approximately 45% of enrolled subjects in both trials were stabilised and randomised to the DB relapse prevention phase. Risk of relapse was higher in subjects treated with paliperidone ER than in those treated with PP [paliperidone ER/PP hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.46-4.35; p < 0.001]. Similarly, risk of relapse after withdrawal of paliperidone ER treatment (placebo group of the paliperidone ER study) was higher than after withdrawal of PP (paliperidone ER placebo/PP placebo HR, 2.25; 95% CI, 1.59-3.18; p < 0.001). Stabilised schizophrenic subjects treated with PP maintained functioning demonstrated by the same proportions of subjects with mild to no difficulties in functioning at DB baseline and end point [Personal and Social Performance (PSP) scale total score >70, both approximately 58.5%; p = 1.000] compared with a 10.9% decrease for paliperidone ER (58.5% vs 47.6%, respectively; p = 0.048). The least squares mean change for Positive and Negative Syndrome Scale (PANSS) total score at DB end point in these previously stabilised subjects was 3.5 points in favour of PP (6.0 vs 2.5; p = 0.025). The rates of TEAEs and AEs of interest appeared similar.

Conclusions: This analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia. The safety profile of PP was similar to that of paliperidone ER. Future studies are needed to confirm these findings.

No MeSH data available.


Related in: MedlinePlus

Designs of the two studies used in the analysis. A Paliperidone extended release (ER) vs placebo study. B Paliperidone palmitate (PP) vs placebo study. aSubjects remained in the double-blind phase until they experienced a relapse, until they withdrew from the study or until the study was completed. The double-blind phase was followed by an open-label extension in each study. Based on significant efficacy, both studies were terminated early. At the time the studies were stopped, a total of 91 subjects in the paliperidone ER study and a total of 76 subjects in the PP study were in the stabilisation phase and were considered as completing the entire study per protocol. Subjects (n = 25) in the PP study who did not meet the more stringent stabilisation criteria employed in the paliperidone ER study were excluded to standardise the study criteria. bSeven dropouts [1 adverse event (AE), 1 death, 2 lost to follow-up (FU) and 3 other]. cTwenty dropouts (12 withdrew consent, 3 AEs, 2 lost to FU, 1 study drug protocol violation and 2 other). dTwenty-seven dropouts (15 withdrew consent, 2 AEs and 10 other). eTwenty-nine dropouts (12 withdrew consent, 3 AEs and 14 other).
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Figure 1: Designs of the two studies used in the analysis. A Paliperidone extended release (ER) vs placebo study. B Paliperidone palmitate (PP) vs placebo study. aSubjects remained in the double-blind phase until they experienced a relapse, until they withdrew from the study or until the study was completed. The double-blind phase was followed by an open-label extension in each study. Based on significant efficacy, both studies were terminated early. At the time the studies were stopped, a total of 91 subjects in the paliperidone ER study and a total of 76 subjects in the PP study were in the stabilisation phase and were considered as completing the entire study per protocol. Subjects (n = 25) in the PP study who did not meet the more stringent stabilisation criteria employed in the paliperidone ER study were excluded to standardise the study criteria. bSeven dropouts [1 adverse event (AE), 1 death, 2 lost to follow-up (FU) and 3 other]. cTwenty dropouts (12 withdrew consent, 3 AEs, 2 lost to FU, 1 study drug protocol violation and 2 other). dTwenty-seven dropouts (15 withdrew consent, 2 AEs and 10 other). eTwenty-nine dropouts (12 withdrew consent, 3 AEs and 14 other).

Mentions: Two similarly designed randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention studies of paliperidone ER (NCT00086320) [13] and PP (NCT00111189) [14] were included (Figure 1). These trials had comparable study designs (i.e. run-in/transition, stabilisation, DB and optional open-label extension phases), comparable stabilisation and relapse criteria and similar inclusion and exclusion criteria. The paliperidone ER study had an 8-week run-in phase followed by a 6-week open-label stabilisation phase [13], and the PP trial had a 9-week run-in phase followed by a 24-week open-label stabilisation phase [14]. In both trials, subjects were first stabilised with paliperidone ER or PP [defined by Positive and Negative Syndrome Scale (PANSS) total scores ≤75 and select PANSS item scores ≤4] and were then randomly assigned to active treatment or placebo. The DB phase was variable in the two trials: subjects remained in the DB phase until they experienced a relapse, until they withdrew from the study or until the study was completed. Therefore, the length of time in the DB period differed for each patient. Based on significant improvements over placebo, both studies were terminated early. Analysis was performed on the DB relapse prevention phase of the two studies, using the DB intent-to-treat analysis set, consisting of all randomly assigned subjects who received at least one dose of DB medication. Both original studies were conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. The original study protocols were reviewed and approved by an independent ethics committee or an institutional review board at each study site, and all subjects provided written informed consent before entering the studies.


Long-acting injectable paliperidone palmitate versus oral paliperidone extended release: a comparative analysis from two placebo-controlled relapse prevention studies.

Markowitz M, Fu DJ, Levitan B, Gopal S, Turkoz I, Alphs L - Ann Gen Psychiatry (2013)

Designs of the two studies used in the analysis. A Paliperidone extended release (ER) vs placebo study. B Paliperidone palmitate (PP) vs placebo study. aSubjects remained in the double-blind phase until they experienced a relapse, until they withdrew from the study or until the study was completed. The double-blind phase was followed by an open-label extension in each study. Based on significant efficacy, both studies were terminated early. At the time the studies were stopped, a total of 91 subjects in the paliperidone ER study and a total of 76 subjects in the PP study were in the stabilisation phase and were considered as completing the entire study per protocol. Subjects (n = 25) in the PP study who did not meet the more stringent stabilisation criteria employed in the paliperidone ER study were excluded to standardise the study criteria. bSeven dropouts [1 adverse event (AE), 1 death, 2 lost to follow-up (FU) and 3 other]. cTwenty dropouts (12 withdrew consent, 3 AEs, 2 lost to FU, 1 study drug protocol violation and 2 other). dTwenty-seven dropouts (15 withdrew consent, 2 AEs and 10 other). eTwenty-nine dropouts (12 withdrew consent, 3 AEs and 14 other).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3722005&req=5

Figure 1: Designs of the two studies used in the analysis. A Paliperidone extended release (ER) vs placebo study. B Paliperidone palmitate (PP) vs placebo study. aSubjects remained in the double-blind phase until they experienced a relapse, until they withdrew from the study or until the study was completed. The double-blind phase was followed by an open-label extension in each study. Based on significant efficacy, both studies were terminated early. At the time the studies were stopped, a total of 91 subjects in the paliperidone ER study and a total of 76 subjects in the PP study were in the stabilisation phase and were considered as completing the entire study per protocol. Subjects (n = 25) in the PP study who did not meet the more stringent stabilisation criteria employed in the paliperidone ER study were excluded to standardise the study criteria. bSeven dropouts [1 adverse event (AE), 1 death, 2 lost to follow-up (FU) and 3 other]. cTwenty dropouts (12 withdrew consent, 3 AEs, 2 lost to FU, 1 study drug protocol violation and 2 other). dTwenty-seven dropouts (15 withdrew consent, 2 AEs and 10 other). eTwenty-nine dropouts (12 withdrew consent, 3 AEs and 14 other).
Mentions: Two similarly designed randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention studies of paliperidone ER (NCT00086320) [13] and PP (NCT00111189) [14] were included (Figure 1). These trials had comparable study designs (i.e. run-in/transition, stabilisation, DB and optional open-label extension phases), comparable stabilisation and relapse criteria and similar inclusion and exclusion criteria. The paliperidone ER study had an 8-week run-in phase followed by a 6-week open-label stabilisation phase [13], and the PP trial had a 9-week run-in phase followed by a 24-week open-label stabilisation phase [14]. In both trials, subjects were first stabilised with paliperidone ER or PP [defined by Positive and Negative Syndrome Scale (PANSS) total scores ≤75 and select PANSS item scores ≤4] and were then randomly assigned to active treatment or placebo. The DB phase was variable in the two trials: subjects remained in the DB phase until they experienced a relapse, until they withdrew from the study or until the study was completed. Therefore, the length of time in the DB period differed for each patient. Based on significant improvements over placebo, both studies were terminated early. Analysis was performed on the DB relapse prevention phase of the two studies, using the DB intent-to-treat analysis set, consisting of all randomly assigned subjects who received at least one dose of DB medication. Both original studies were conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. The original study protocols were reviewed and approved by an independent ethics committee or an institutional review board at each study site, and all subjects provided written informed consent before entering the studies.

Bottom Line: This analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia.The safety profile of PP was similar to that of paliperidone ER.Future studies are needed to confirm these findings.

View Article: PubMed Central - HTML - PubMed

Affiliation: Janssen Scientific Affairs, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, USA. mmarkowi@its.jnj.com.

ABSTRACT

Background: Increasing availability and use of long-acting injectable antipsychotics have generated a need to compare these formulations with their oral equivalents; however, a paucity of relevant data is available.

Methods: This post hoc comparison of the long-term efficacy, safety and tolerability of maintenance treatment with paliperidone palmitate (PP) versus oral paliperidone extended release (ER) used data from two similarly designed, randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention trials. Assessments included measures of time to relapse, symptom changes/functioning and treatment-emergent adverse events (TEAEs). Time to relapse between treatment groups was evaluated using a Cox proportional hazards model. Between-group differences for continuous variables for change scores during the DB phase were assessed using analysis of co-variance models. Categorical variables were evaluated using Chi-square and Fisher's exact tests. No adjustment was made for multiplicity.

Results: Approximately 45% of enrolled subjects in both trials were stabilised and randomised to the DB relapse prevention phase. Risk of relapse was higher in subjects treated with paliperidone ER than in those treated with PP [paliperidone ER/PP hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.46-4.35; p < 0.001]. Similarly, risk of relapse after withdrawal of paliperidone ER treatment (placebo group of the paliperidone ER study) was higher than after withdrawal of PP (paliperidone ER placebo/PP placebo HR, 2.25; 95% CI, 1.59-3.18; p < 0.001). Stabilised schizophrenic subjects treated with PP maintained functioning demonstrated by the same proportions of subjects with mild to no difficulties in functioning at DB baseline and end point [Personal and Social Performance (PSP) scale total score >70, both approximately 58.5%; p = 1.000] compared with a 10.9% decrease for paliperidone ER (58.5% vs 47.6%, respectively; p = 0.048). The least squares mean change for Positive and Negative Syndrome Scale (PANSS) total score at DB end point in these previously stabilised subjects was 3.5 points in favour of PP (6.0 vs 2.5; p = 0.025). The rates of TEAEs and AEs of interest appeared similar.

Conclusions: This analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia. The safety profile of PP was similar to that of paliperidone ER. Future studies are needed to confirm these findings.

No MeSH data available.


Related in: MedlinePlus