Onset of efficacy and tolerability following the initiation dosing of long-acting paliperidone palmitate: post-hoc analyses of a randomized, double-blind clinical trial

Abstract

Background: Paliperidone palmitate is a long-acting injectable atypical antipsychotic for the acute and maintenance treatment of adults with schizophrenia. The recommended initiation dosing regimen is 234 mg on Day 1 and 156 mg on Day 8 via intramuscular (deltoid) injection; followed by 39 to 234 mg once-monthly thereafter (deltoid or gluteal). These post-hoc analyses addressed two commonly encountered clinical issues regarding the initiation dosing: the time to onset of efficacy and the associated tolerability.

Methods: In a 13-week double-blind trial, 652 subjects with schizophrenia were randomized to paliperidone palmitate 39, 156, or 234 mg (corresponding to 25, 100, or 150 mg equivalents of paliperidone, respectively) or placebo (NCT#00590577). Subjects randomized to paliperidone palmitate received 234 mg on Day 1, followed by their randomized fixed dose on Day 8, and monthly thereafter, with no oral antipsychotic supplementation. The onset of efficacy was defined as the first timepoint where the paliperidone palmitate group showed significant improvement in the Positive and Negative Syndrome Scale (PANSS) score compared to placebo (Analysis of Covariance [ANCOVA] models and Last Observation Carried Forward [LOCF] methodology without adjusting for multiplicity) using data from the Days 4, 8, 22, and 36 assessments. Adverse event (AE) rates and relative risks (RR) with 95% confidence intervals (CI) versus placebo were determined.

Results: Paliperidone palmitate 234 mg on Day 1 was associated with greater improvement than placebo on Least Squares (LS) mean PANSS total score at Day 8 (p=0.037). After the Day 8 injection of 156 mg, there was continued PANSS improvement at Day 22 (p≤0.007 vs. placebo) and Day 36 (p<0.001). Taken together with results in the 39 mg and 234 mg Day 8 arms, these findings suggest a trend towards a dose-dependent response. During Days 1 to 7, AEs reported in ≥2% of paliperidone palmitate subjects (234 mg) and a greater proportion of paliperidone palmitate than placebo subjects were: agitation (3.2% vs. 1.3%; RR 2.52 [95% CI 0.583, 10.904]), headache (4.0% vs. 3.8%; RR 1.06 [95% CI 0.433, 2.619]), and injection site pain (6.7% vs. 3.8%; RR 1.79 [95% CI 0.764, 4.208]). Days 8 to 36 AEs meeting the same criteria in the 156 mg Day 8 arm were: anxiety (3.1% vs. 2.5%; RR 1.24 [95% CI 0.340, 4.542]), psychotic disorder (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]), dizziness (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]), and injection site pain (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]). Corresponding Days 8 to 36 AEs in the 39 mg Day 8 group were: agitation (4.5% vs. 4.4%; RR 1.03 [95% CI 0.371, 2.874]), anxiety (3.9% vs. 2.5%; RR 1.55 [95% CI 0.446, 5.381]), and psychotic disorder (2.6% vs. 1.3%; RR 2.07 [95% CI 0.384, 11.110]) while in the 234 mg Day 8 group it was anxiety (3.1% vs. 2.5%, RR 1.25 [95% CI 0.342, 4.570]).

Conclusions: Significantly greater symptom improvement was observed by Day 8 with paliperidone palmitate (234 mg on Day 1) compared to placebo; this effect was maintained after the 156 mg Day 8 injection, with a trend towards a dose-dependent response. No unexpected tolerability findings were noted in the first week or month after the initiation dosing.

Trial registration: ClinicalTrials.gov: NCT#00590577.

Trial registration: ClinicalTrials.gov NCT00590577.

Figure 1

Subject Randomization. Of 652 subjects enrolled in the double-blind treatment period, 488 were randomized (1:1:1:1) to paliperidone palmitate (fixed dose of 39, 156, or 234 mg) and 164 to placebo. All those randomized to the fixed doses of paliperidone palmitate received 234 mg as the first initiation dose on Day 1, followed by administration of their fixed dose on Days 8, 36, and 64.

Figure 2

Changes in PANSS Total Scores Over Time (LOCF) in the ITT Analysis Set (p-values for Paliperidone Palmitate vs. Placebo). The administration of paliperidone palmitate 234 mg on Day 1 was associated with a significantly greater improvement than placebo on mean PANSS total score at the Day 8 assessment (LS mean [SE] change from baseline -8.21 [0.87] vs. -5.79 [1.20], p = 0.037). In a dose-dependent fashion, all paliperidone palmitate groups continued to show greater PANSS total score improvement than placebo at subsequent timepoints.

Figure 3

Responders: ≥30% Improvement from Baseline in PANSS Total Scores. The responder rates were significantly higher with paliperidone palmitate (all dose groups) than with placebo by the Day 36 timepoint.

Figure 4

Adverse Events in ≥2% of Paliperidone Palmitate and in a Higher Percentage of Paliperidone Palmitate than Placebo Subjects. Adverse events meeting these criteria during Days 1 to 7 are shown in Panel A for subjects received paliperidone palmitate 234 mg Day 1 (rates and relative risks versus placebo with 95% CIs); none were statistically significant as determined by 95% CIs. Adverse events that met these criteria during Days 8 to 36 are shown in Panel B for the paliperidone palmitate 156 mg Day 8 group, Panel C for the 39 mg Day 8 group, and Panel D for the 234 mg Day 8 group. None were statistically significant as determined by 95% CIs.