Lei Sun1, Sergey Yagoda2, Hongqi Xue3, Randy Brown3, Narinder Nangia2, David McDonnell4, Bhaskar Rege2, Lisa von Moltke2, Borje Darpo3. 1. Alkermes, Inc., 852 Winter Street, Waltham, MA 02451, USA. Electronic address: lei.sun@alkermes.com. 2. Alkermes, Inc., 852 Winter Street, Waltham, MA 02451, USA. 3. ERT, 150 Allens Creek Road, Rochester, NY 14618, USA. 4. Alkermes Pharma Ireland Limited, Connaught House, 1 Burlington Road, Dublin 4 D04 C5Y6, Ireland.
Abstract
BACKGROUND:OLZ/SAM is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, and is in development for the treatment of schizophrenia and bipolar I disorder. OLZ/SAM is under development with the intent to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. This thorough QT study assessed the effects of therapeutic and supratherapeutic doses of OLZ/SAM on cardiac repolarization in patients with schizophrenia. METHODS: In this randomized, double-blind, placebo- and positive (moxifloxacin)-controlled, parallel-group study, 100 patients aged 18 to 60 years with stable schizophrenia were randomized 3:2 to the active arm and control arm. Subjects in the active arm received a therapeutic dose of 10/10 mg (10 mg olanzapine/10 mg samidorphan) on days 2-4, 20/20 mg on days 5-8, and a supratherapeutic dose of 30/30 mg (1.5 times and 3 times the maximum recommended daily dose of olanzapine and samidorphan, respectively) on days 9-13, and moxifloxacin-matched placebo on days 1 and 14. Subjects in the control arm received a single oral dose of moxifloxacin 400 mg and moxifloxacin-matched placebo on days 1 and 14 in a nested crossover fashion, along with OLZ/SAM-matched placebo on days 2-13. Serial electrocardiograms (ECGs) and simultaneous plasma drug concentrations were determined pre- and post-dose. The effects of OLZ/SAM on heart rate and ECG parameters (QT interval with Fridericia's correction [QTcF], PR and QRS interval, and T-wave morphology) were evaluated, and the primary endpoint was change from baseline in QTcF (ΔQTcF). The relationship between drug concentration and ΔQTcF (C-QTc) was evaluated using a linear mixed-effects model. Safety monitoring included adverse events reporting and clinical laboratory assessments. RESULTS: Based on primary analysis using C-QTc modeling, no clinically concerning QTc effect (ie, placebo-corrected ΔQTcF [ΔΔQTcF] ≥10 msec) was observed across the OLZ/SAM dose range tested (10/10 to 30/30 mg), up to olanzapine and samidorphan concentrations of approximately 110 and 160 ng/mL, respectively. The slope (90% confidence interval [CI]) of the C-QTc relationship was shallow and not significant for either olanzapine or samidorphan (0.03 [-0.01, 0.08] and 0.01 [-0.01, 0.04] msec per ng/mL, respectively). The predicted ΔΔQTcF (90% CI) was 2.33 (-2.72, 7.38) and 1.38 (-3.37, 6.12) msec at the observed geometric mean maximal concentration (Cmax) of olanzapine (62.6 ng/mL) and samidorphan (75.1 ng/mL) on day 13, respectively. The study's assay sensitivity was confirmed by the C-QTc relationship of moxifloxacin. OLZ/SAM was well tolerated at all doses; adverse events occurring in >5% of subjects treated with OLZ/SAM were somnolence, weight increased, nausea, and dizziness. CONCLUSIONS: This thorough QT study in patients with stable schizophrenia demonstrated that OLZ/SAM, in doses and plasma concentrations up to supratherapeutic levels, does not have a clinically relevant effect on ECG parameters, including QT/QTc prolongation.
RCT Entities:
BACKGROUND:OLZ/SAM is a combination of olanzapine, an atypical antipsychotic, and samidorphan, an opioid antagonist, and is in development for the treatment of schizophrenia and bipolar I disorder. OLZ/SAM is under development with the intent to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. This thorough QT study assessed the effects of therapeutic and supratherapeutic doses of OLZ/SAM on cardiac repolarization in patients with schizophrenia. METHODS: In this randomized, double-blind, placebo- and positive (moxifloxacin)-controlled, parallel-group study, 100 patients aged 18 to 60 years with stable schizophrenia were randomized 3:2 to the active arm and control arm. Subjects in the active arm received a therapeutic dose of 10/10 mg (10 mg olanzapine/10 mg samidorphan) on days 2-4, 20/20 mg on days 5-8, and a supratherapeutic dose of 30/30 mg (1.5 times and 3 times the maximum recommended daily dose of olanzapine and samidorphan, respectively) on days 9-13, and moxifloxacin-matched placebo on days 1 and 14. Subjects in the control arm received a single oral dose of moxifloxacin 400 mg and moxifloxacin-matched placebo on days 1 and 14 in a nested crossover fashion, along with OLZ/SAM-matched placebo on days 2-13. Serial electrocardiograms (ECGs) and simultaneous plasma drug concentrations were determined pre- and post-dose. The effects of OLZ/SAM on heart rate and ECG parameters (QT interval with Fridericia's correction [QTcF], PR and QRS interval, and T-wave morphology) were evaluated, and the primary endpoint was change from baseline in QTcF (ΔQTcF). The relationship between drug concentration and ΔQTcF (C-QTc) was evaluated using a linear mixed-effects model. Safety monitoring included adverse events reporting and clinical laboratory assessments. RESULTS: Based on primary analysis using C-QTc modeling, no clinically concerning QTc effect (ie, placebo-corrected ΔQTcF [ΔΔQTcF] ≥10 msec) was observed across the OLZ/SAM dose range tested (10/10 to 30/30 mg), up to olanzapine and samidorphan concentrations of approximately 110 and 160 ng/mL, respectively. The slope (90% confidence interval [CI]) of the C-QTc relationship was shallow and not significant for either olanzapine or samidorphan (0.03 [-0.01, 0.08] and 0.01 [-0.01, 0.04] msec per ng/mL, respectively). The predicted ΔΔQTcF (90% CI) was 2.33 (-2.72, 7.38) and 1.38 (-3.37, 6.12) msec at the observed geometric mean maximal concentration (Cmax) of olanzapine (62.6 ng/mL) and samidorphan (75.1 ng/mL) on day 13, respectively. The study's assay sensitivity was confirmed by the C-QTc relationship of moxifloxacin. OLZ/SAM was well tolerated at all doses; adverse events occurring in >5% of subjects treated with OLZ/SAM were somnolence, weight increased, nausea, and dizziness. CONCLUSIONS: This thorough QT study in patients with stable schizophrenia demonstrated that OLZ/SAM, in doses and plasma concentrations up to supratherapeutic levels, does not have a clinically relevant effect on ECG parameters, including QT/QTc prolongation.
Authors: Syeda Tayyaba Rehan; Abdul Hannan Siddiqui; Zayeema Khan; Laiba Imran; Abdul Ahad Syed; Muhammad Junaid Tahir; Zahra Jassani; Manjeet Singh; Muhammad Sohaib Asghar; Ali Ahmed Journal: Ann Med Surg (Lond) Date: 2022-06-30