Exploring the long-term safety of asenapine in adults with schizophrenia in a double-blind, fixed-dose, extension study

Abstract

Purpose: The primary objective of this study was to assess long-term safety with sublingual asenapine 2.5 or 5 mg twice daily (BID) in patients with schizophrenia.

Patients and methods: Actively treated patients on asenapine 2.5 mg BID, asenapine 5 mg BID, or olanzapine 15 mg once daily (QD) who completed a 6-week randomized, double-blind, placebo- and olanzapine-controlled study continued lead-in treatment in this 26-week, multicenter, double-blind, double-dummy, olanzapine-controlled Phase IIIB extension study; placebo patients were assigned to asenapine 2.5 mg BID treatment. Safety analyses were based on the all treated set (patients who received one or more doses of extension trial medication); change from baseline analyses used the acute study baseline. Treatment-emergent adverse events (TEAEs) and changes in laboratory parameters were monitored; weight change for asenapine versus olanzapine was the key secondary objective. Descriptive statistics were used; weight change was analyzed using a mixed-model repeated-measure approach.

Results: Of the 120 patients in the all-treated set, 60% completed treatment (asenapine 2.5 mg BID 66.1% overall, asenapine 5 mg BID 52.4%, olanzapine 15 mg QD 56.3%). The incidence of TEAEs was higher for placebo patients from the lead-in study who switched to asenapine 2.5 mg BID for extension treatment (71.0%) versus patients continuing asenapine 2.5 mg BID (38.7%), asenapine 5 mg BID (38.1%), or olanzapine 15 mg QD (25.0%). The most common TEAE (≥5% in every group) was worsening of schizophrenia. Least squares mean change in body weight from the acute study baseline to week 26 was +0.6 kg for overall asenapine 2.5 mg BID, +0.8 kg for asenapine 5 mg BID, and +1.2 kg for olanzapine 15 mg QD. There were no clinically relevant changes in metabolic parameters; values were generally similar across treatment groups.

Conclusion: Asenapine 2.5 mg BID and 5 mg BID were generally well tolerated in long-term treatment. Weight gain was less for overall asenapine 2.5 mg BID and 5 mg BID than for olanzapine 15 mg QD.

Keywords: asenapine; long-term; olanzapine; safety; schizophrenia; weight.

Figure 1

Trial design. Notes: ^aThe time of the active olanzapine dose (morning or afternoon/evening) was not disclosed in order to preserve blinding. If the active olanzapine dose was taken in the morning, the olanzapine-matched placebo was taken in the afternoon/evening; if the active olanzapine dose was taken in the afternoon/evening, the olanzapine-matched placebo was taken in the morning. The same number of film-coated tablets was taken in the morning and afternoon/evening. Abbreviations: BID, twice daily; EOT, end of treatment; QD, once daily.

Figure 2

Patient disposition and reasons for discontinuation. Note: One subject in the olanzapine 15 mg QD/olanzapine 15 mg QD group did not have a postbaseline PANSS total score measurement and was therefore not included in the FAS. Abbreviations: AE, adverse event; ATS, all treated set; BID, twice daily; FAS, full analysis set; PANSS, Positive and Negative Syndrome Scale; QD, once daily.

Figure 3

LS mean change in weight from acute study baseline to week 26 (MMRM, ATS). Note: Baseline was the last nonmissing assessment before the first dose of acute study medication. Abbreviations: ATS, all treated set; BID, twice daily; LS, least squares; MMRM, mixed-effect model for repeated measures; QD, once daily.