Safety and Efficacy from an 8 Week Double-Blind Trial and a 26 Week Open-Label Extension of Asenapine in Adolescents with Schizophrenia

Abstract

Objective: The purpose of this study was to evaluate the safety and efficacy of asenapine in adolescents with schizophrenia.

Methods: In an 8 week, randomized, double-blind placebo-controlled trial, subjects (12-17 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria for schizophrenia were randomized 1:1:1 to placebo, asenapine 2.5 mg b.i.d., or asenapine 5 mg b.i.d. Subjects who completed the 8 week acute study could participate in a 26 week flexible-dose asenapine-only open-label extension (OLE).

Results: A similar percentage of subjects completed treatment on day 56 (2.5 mg b.i.d. (n=98): 83%; 5 mg b.i.d. [n=106]: 79%; placebo [n=102]: 79%). In the mixed model for repeated measures analysis of the primary end-point (with Hochberg correction for multiplicity), least squares (LS) mean differences between asenapine and placebo on the Positive and Negative Syndrome Scale (PANSS) total score at day 56 were not significant (-4.8 for 2.5 mg b.i.d., p=0.070; -5.6 for 5 mg b.i.d., p=0.064). Significant improvement in the Clinical Global Impressions-Severity score was observed in the 5 mg b.i.d. group versus placebo on day 56 (LS mean -0.3, p=0.024). In the acute phase, ≥7% weight gain and the composite event of somnolence, sedation, and hypersomnia were more common in both asenapine groups than in the placebo group. Akathisia, fasting glucose elevation, and extrapyramidal syndrome were more common in the 5 mg b.i.d. group than in the placebo group. There were no unexpected adverse events in the OLE, and PANSS total scores decreased by -16.1 points in the group previously treated with placebo (n=62) and by -11.2 points in the continuous asenapine group (n=131) from OLE baseline to week 26.

Conclusions: Although improvements in PANSS total score at day 56 of the acute phase were numerically greater for both asenapine 2.5 and 5 mg b.i.d. than for placebo and were maintained in the OLE, the primary end-point did not achieve statistical significance in the acute phase. No new or unexpected safety concerns were detected during the acute phase or after an additional 26 weeks of asenapine treatment in the adolescent population with schizophrenia.

Clinical trials registry: NCT01190254 and NCT1190267 at ClinicalTrials.gov.

Trial registration: ClinicalTrials.gov NCT01190254 NCT01190267 NCT01190254.

FIG. 1.

Subject disposition. ^aOf the AEs in the 8 week acute phase, three in patients randomized to placebo, three in patients randomized to asenapine 2.5 mg, and four in patients randomized to asenapine 5 mg were caused by the disease under study. ^bThe analysis population included all randomized subjects <18 years of age who received one osr more dose of trial medication; eight subjects (two in the placebo/asenapine group and six in the asenapine/asenapine group) who were 18 year old entered and were treated in the OLE but were not included in the primary analysis. ^cThree of the AEs in the placebo/asenapine group in the OLE were caused by the disease under study. ^dFour of the AEs in the continuous asenapine group in the OLE were caused by the disease under study. AE, adverse event; OLE, open-label extension.

FIG. 2.

Efficacy during the acute phase (MMRM, full analysis set). (A) LS mean change from baseline in PANSS total score at day 56 of treatment. P values were adjusted using the Hochberg procedure. Δ=asenapine minus placebo. (B) LS mean change from baseline (with 95% CI) in PANSS total score by visit. Unadjusted p values for treatment comparisons with placebo. (C) LS mean change from baseline in CGI-S score at day 56 of treatment. Unadjusted p values for treatment comparisons with placebo. Δ=asenapine minus placebo. CGI-S, Clinical Global Impressions-Severity; CI, confidence interval; LS, least squares; MMRM, mixed model for repeated measures; PANSS, Positive and Negative Syndrome Scale.

FIG. 3.

Efficacy during the OLE (OC, full analysis set). (A) Mean change in PANSS total score from open-label baseline to end of OLE by visit. (B) Mean (SD) change in CGI-S score from open-label baseline to end of OLE by visit. CGI-S, Clinical Global Impressions-Severity; OC, observed cases; OLE, open-label extension; PANSS, Positive and Negative Syndrome Scale.