Diabetes and Glandular Disease Research, Cetero Company, San Antonio, TX 78229, USA.
Diabetes Obes Metab. 2010 Jun;12(6):517-31. doi: 10.1111/j.1463-1326.2009.01188.x.
To evaluate the efficacy and safety of taranabant in overweight and obese patients with type 2 diabetes mellitus (T2DM).
This was a multicenter, double-blind, randomized, placebo-controlled study in overweight and obese patients with T2DM (ages > or = 18 and < or = 75 years) with a BMI > or = 27 kg/m(2) and < or = 43 kg/m(2) and HbA1c > or =7.0 and < or = 10.0%, who were either not on an antihyperglycaemic agent or on a stable dose of metformin (> or = 1500 mg/day). After a 2-week placebo run-in, patients were randomized to placebo (N = 156) or taranabant 0.5-mg (N = 155), 1-mg (N = 157), or 2-mg (N = 155) once daily for 52 weeks. Primary efficacy endpoints were changes from baseline in body weight (BW) and HbA1c at Week 36, with results at Week 52 being key secondary endpoints.
In the all-patients-treated population, using a last-observation-carried-forward analysis, reductions in BW were -2.5, -3.7, -4.5 and -5.1 kg at Week 36 and -2.4, -4.0, -4.6 and -5.3 kg at Week 52 in the placebo, 0.5-, 1- and 2-mg groups, respectively (all doses significant vs. placebo at both time points). The proportion of patients who lost > or = 5 and > or = 10% of their baseline BW was significantly greater in the 1- and 2-mg groups vs. placebo at Week 36 and all taranabant groups vs. placebo at Week 52. Reductions in HbA1c were -0.40, -0.47, -0.68 and -0.71% at Week 36 and -0.30, -0.43, -0.65 and -0.64% at Week 52, in the placebo, 0.5-, 1- and 2-mg groups, respectively (1- and 2-mg doses significant vs. placebo at both time points). After 52 weeks, the incidences of adverse experiences classified in the gastrointestinal (diarrhoea, nausea, vomiting), nervous system-related (dizziness, sensory-related), and psychiatric (irritability, depression-related) organ systems were numerically higher or statistically significantly higher in all taranabant groups compared with the placebo group.
After 36 and 52 weeks, treatment with taranabant at the 1- and 2-mg doses led to clinically significant weight loss and improvement in glycaemic parameters in overweight and obese patients with T2DM that was associated with dose-related increases in adverse experiences. Based on these data and data from other Phase III clinical studies, it was determined that the overall safety and efficacy profile of taranabant did not support further development for the treatment of obesity.
评估 taranabant 在超重和肥胖 2 型糖尿病（T2DM）患者中的疗效和安全性。
这是一项多中心、双盲、随机、安慰剂对照研究，纳入超重和肥胖的 T2DM 患者（年龄≥18 岁且＜75 岁），BMI 为 27kg/m²至 43kg/m²，HbA1c 为 7.0%至 10.0%，且未使用抗高血糖药物或使用稳定剂量二甲双胍（≥1500mg/天）。经过 2 周的安慰剂导入期后，患者被随机分配至安慰剂（N=156）或 taranabant 0.5mg（N=155）、1mg（N=157）或 2mg（N=155）组，每日一次，共 52 周。主要疗效终点为第 36 周时体重（BW）和 HbA1c 与基线相比的变化，第 52 周时的结果为关键次要终点。
在所有患者治疗人群中，采用最后观察值结转分析，安慰剂、0.5mg、1mg 和 2mg 组在第 36 周时的 BW 分别降低了 2.5kg、3.7kg、4.5kg 和 5.1kg，在第 52 周时的 BW 分别降低了 2.4kg、4.0kg、4.6kg 和 5.3kg（所有剂量在两个时间点均与安慰剂相比均有显著差异）。在第 36 周时，1mg 和 2mg 组与安慰剂组相比，BW 降低≥5%和≥10%的患者比例显著更高，在第 52 周时，所有 taranabant 组与安慰剂组相比，BW 降低≥5%和≥10%的患者比例显著更高。第 36 周时，HbA1c 分别降低了 0.40%、0.47%、0.68%和 0.71%，第 52 周时，HbA1c 分别降低了 0.30%、0.43%、0.65%和 0.64%，在安慰剂、0.5mg、1mg 和 2mg 组中，1mg 和 2mg 剂量与安慰剂相比均有显著差异。52 周后，所有 taranabant 组与安慰剂组相比，胃肠道（腹泻、恶心、呕吐）、神经系统相关（头晕、感觉相关）和精神科（易怒、抑郁相关）器官系统的不良事件发生率更高或统计学上更高。
在第 36 周和第 52 周时，1mg 和 2mg 剂量的 taranabant 治疗可导致超重和肥胖的 T2DM 患者体重显著减轻和血糖参数改善，且与剂量相关的不良事件增加有关。基于这些数据和其他 III 期临床研究的数据，确定 taranabant 的总体安全性和疗效特征不支持进一步开发用于肥胖的治疗。
