Onset of efficacy with acute long-acting injectable paliperidone palmitate treatment in markedly to severely ill patients with schizophrenia: post hoc analysis of a randomized, double-blind clinical trial

Abstract

Background: This post hoc analysis (trial registration: ClinicalTrials.gov NCT00590577) assessed onset of efficacy and tolerability of acute treatment with once-monthly paliperidone palmitate (PP), a long-acting atypical antipsychotic initiated by day 1 and day 8 injections, in a markedly to severely ill schizophrenia population.

Methods: Subjects entering the 13-week, double-blind trial were randomized to PP (39, 156, or 234 mg [25, 100, and 150 mg eq of paliperidone, respectively]) or placebo. This subgroup analysis included those with a baseline Clinical Global Impressions-Severity (CGI-S) score indicating marked to severe illness. PP subjects received a 234-mg day 1 injection (deltoid), followed by their assigned dose on day 8 and monthly thereafter (deltoid or gluteal). Thus, data for PP groups were pooled for days 4 and 8. Measures included Positive and Negative Syndrome Scale (PANSS), CGI-S, Personal and Social Performance (PSP), and adverse events (AEs). Analysis of covariance (ANCOVA) and last-observation-carried-forward (LOCF) methodologies, without multiplicity adjustments, were used to assess changes in continuous measures. Onset of efficacy was defined as the first time point a treatment group showed significant PANSS improvement (assessed days 4, 8, 22, 36, 64, and 92) versus placebo, which was maintained through end point.

Results: A total of 312 subjects met inclusion criterion for this subgroup analysis. After the day 1 injection, mean PANSS total scores improved significantly with PP (all received 234 mg) versus placebo at day 4 (P = 0.012) and day 8 (P = 0.007). After the day 8 injection, a significant PANSS improvement persisted at all subsequent time points in the 234-mg group versus placebo (P < 0.05). PANSS improvements were greater from day 36 through end point in the 156-mg group (P < 0.05) and only at end point in the 39-mg group (P < 0.05). CGI-S and PSP scores improved significantly in the 234-mg and 156-mg PP groups versus placebo at end point (P < 0.05 for both, respectively); improvement in the 39-mg group was not significant. The most common AEs for PP-treated subjects (≥10%, any treatment group) were headache, insomnia, schizophrenia exacerbation, injection site pain, and agitation.

Conclusions: In this markedly to severely ill population, acute treatment with 234 mg PP improved psychotic symptoms compared with placebo by day 4. After subsequent injections, observed improvements are suggestive of a dose-dependent effect. No unexpected tolerability findings were noted.

Figure 1

Least-squares (LS) mean Positive and Negative Syndrome Scale (PANSS) total score change from baseline for the paliperidone palmitate dose groups versus placebo group (last-observation-carried-forward [LOCF] analysis). All paliperidone palmitate-treated subjects received paliperidone palmitate 234 mg on day 1 and then received their assigned treatment on days 8, 36, and 64. SE = standard error.

Figure 2

Effect size for change from baseline to end point on Positive and Negative Syndrome Scale (PANSS) total score for markedly to severely ill subjects and overall study population. CI = confidence interval.

Figure 3

Effect size for change from baseline to end point on Clinical Global Impressions-Severity (CGI-S) score for markedly to severely ill subjects and overall study population. CI = confidence interval.

Figure 4

Effect size for change from baseline to end point on Personal and Social Performance (PSP) score for markedly to severely ill subjects and overall study population. CI = confidence interval.