Fleseriu Maria, Iweha Chioma, Salgado Luiz, Mazzuco Tania Longo, Campigotto Federico, Maamari Ricardo, Limumpornpetch Padiporn
Departments of Medicine and Neurological Surgery, Northwest Pituitary Center, Oregon Health and Science University, Portland, OR, United States.
Panda Medical Associates, Peoria, AZ, United States.
Front Endocrinol (Lausanne). 2019 Jul 16;10:436. doi: 10.3389/fendo.2019.00436. eCollection 2019.
The efficacy and safety of subcutaneous (sc) pasireotide have been evaluated in a Phase III trial. Here, we report safety and efficacy results from a multinational, expanded-access study of pasireotide sc in patients with Cushing's disease (CD) in a real-world setting (clinicaltrials.gov, identifier: NCT01582061). Adults with active CD previously untreated with pasireotide were enrolled; pasireotide sc was initiated at 600 μg twice daily (bid; EU countries) or 900 μg bid (non-EU countries; 600 μg bid in patients with impaired glucose metabolism). Pasireotide dose could be adjusted in 300 μg increments/decrements to a maximum of 900 μg bid or minimum of 300 μg bid for sustained urinary free cortisol (UFC) normalization/tolerability issues. Primary objective: document the safety of pasireotide sc in patients with CD. Key secondary objectives: assess the proportion of patients with mean UFC (mUFC) not exceeding the upper limit of normal (ULN) and changes from baseline in clinical signs/symptoms and quality of life (QoL) to weeks 12, 24, and 48. One hundred and four patients received pasireotide: female, = 84 (80.8%); median duration of pasireotide exposure, 25.1 weeks; median (range) baseline mUFC, 321.2 nmol/24 h (142-10,920; 2.3 × ULN [1.0-79.2]). Forty (38.5%) patients completed the study. The most common reasons for premature discontinuation of pasireotide were unsatisfactory therapeutic effect ( = 26, 25.0%) and adverse events (AEs; = 20, 19.2%). Drug-related grade 3/4 AEs or drug-related serious AEs (primary endpoint) were documented in 42 (40.4%) patients, most commonly diabetes mellitus ( = 12, 11.5%) and hyperglycemia ( = 8, 7.7%). All patients experienced ≥1 AE and most ( = 102; 98.1%) reported ≥1 drug-related AE; six (5.8%) patients discontinued treatment because of hyperglycemia-related AEs. At weeks 12, 24, and 48, respectively, 36/66 (54.5%), 22/46 (47.8%), and 9/21 (42.9%) evaluable patients had normalized mUFC levels. Clinical signs/symptoms and QoL were also improved. In an international, real-world, clinical-practice setting, pasireotide sc was generally well-tolerated (no new safety signals were identified), effectively reduced UFC (normalization in ~50% of evaluable patients) and improved clinical signs and QoL in patients with CD. While hyperglycemia-related AEs were common, consistent with previous studies, most were manageable, with <6% of patients discontinuing treatment because of these events.
皮下注射帕西瑞肽的疗效和安全性已在一项III期试验中进行了评估。在此，我们报告一项在现实环境中针对库欣病（CD）患者开展的帕西瑞肽皮下注射的多国扩大准入研究的安全性和疗效结果（clinicaltrials.gov，标识符：NCT01582061）。招募了此前未接受过帕西瑞肽治疗的成年活动性CD患者；帕西瑞肽皮下注射起始剂量为600μg，每日两次（bid；欧盟国家）或900μg bid（非欧盟国家；糖代谢受损患者为600μg bid）。帕西瑞肽剂量可根据持续尿游离皮质醇（UFC）正常化/耐受性问题以300μg的增量/减量进行调整，最大剂量为900μg bid，最小剂量为300μg bid。主要目标：记录帕西瑞肽皮下注射在CD患者中的安全性。关键次要目标：评估平均UFC（mUFC）不超过正常上限（ULN）的患者比例，以及至第12、24和48周时临床体征/症状和生活质量（QoL）相对于基线的变化。104例患者接受了帕西瑞肽治疗：女性84例（80.8%）；帕西瑞肽暴露的中位持续时间为25.1周；基线mUFC的中位数（范围）为321.2nmol/24小时（142 - 10920；2.3×ULN [1.0 - 79.2]）。40例（38.5%）患者完成了研究。帕西瑞肽提前停药的最常见原因是治疗效果不理想（26例，25.0%）和不良事件（AE；20例，19.2%）。42例（40.4%）患者记录到与药物相关的3/4级AE或与药物相关的严重AE（主要终点），最常见的是糖尿病（12例，11.5%）和高血糖（8例，7.7%）。所有患者均经历了≥1次AE，大多数（102例；98.1%）报告了≥1次与药物相关的AE；6例（5.8%）患者因高血糖相关AE而停药。在第12、24和48周时，分别有36/66（54.5%）、22/46（47.8%）和9/21（42.9%）可评估患者的mUFC水平恢复正常。临床体征/症状和QoL也得到了改善。在国际现实临床实践环境中，帕西瑞肽皮下注射总体耐受性良好（未发现新的安全信号），有效降低了UFC（约50%的可评估患者恢复正常），并改善了CD患者的临床体征和QoL。虽然高血糖相关AE很常见，与既往研究一致，但大多数是可控的，因这些事件停药的患者<6%。
