Joshi Deepa, Gj Prashant, Ghosh Shohini, Mohanan Anookh, Joshi Shashank, Mohan Viswanathan, Chowdhury Subhankar, Dutt Chaitanya, Tandon Nikhil
Torrent Pharmaceuticals Ltd., Ahmedabad, Gujarat, India.
Lilavati Hospital, Mumbai, India.
Diabetes Metab Syndr Obes. 2022 Feb 25;15:615-631. doi: 10.2147/DMSO.S330515. eCollection 2022.
TRC150094, a novel mitochondrial modulator, reduces insulin resistance and is expected to improve the trinity of dysglycemia, dyslipidemia, and hypertension. In this multi-dose phase-2 study, we evaluated the safety and efficacy of TRC150094 in diabetic subjects with dyslipidemia receiving standard of care.
A randomized, multicenter, double-blind, placebo-controlled, parallel-group, Phase 2 study was conducted in 225 subjects from July 2013 to August 2015. The key inclusion criteria were body mass index of 23-35 kg/m, age between 30 and 65 years, fasting glucose of ≥126 or glycated hemoglobin (HbA1c) of ≥6.4% stabilized on treatment with ≤2 oral hypoglycemic agents, apolipoprotein-B (apo-B) ≥100 mg/dL, serum triglyceride (TG) ≥150 mg/dL, systolic blood pressure (SBP) ≥130 mmHg, and diastolic blood pressure (DBP) ≥85 mmHg with/without antihypertensive treatment. The subjects were randomly assigned to one of three TRC150094 doses (25, 50, or 75 mg) or placebo for 24 weeks. The outcomes assessed included fasting plasma glucose (FPG), insulin, mean arterial blood pressure (MAP), and apoB. In addition, safety and tolerability were assessed.
A reduction for dose up to 50 mg was noted for FPG in the range of 13.9 to 21.7 mg/dL (p < 0.05 for TRC150094 25 and 50 mg), fasting insulin reduction in the range 2.7 to 6.0 mU/L (all doses, p > 0.05), and improved HOMA-IR (-2.0 to -2.5) (all doses, p > 0.05) compared to placebo after 24 weeks of treatment. Furthermore, a significant reduction in MAP in the range 3.1 to 4.2 mmHg (p < 0.05 for TRC150094 25 and 75 mg) was noted. In addition, TRC150094 treatment was weight neutral, had a favorable effect on lowering atherogenic lipid fractions, including non-HDL cholesterol (-6.8 mg/dL at 50 mg dose). Adverse events were mild to moderate in nature and not dose-related. One adverse event not related to treatment led to the discontinuation of the study. Overall, TRC150094 was safe and well tolerated for up to 24 weeks.
In this study, TRC150094 treatment in the dose range of 25 to 50 mg showed improvement in various components of CMBCD, ie, dysglycemia, dyslipidemia, and hypertension.
This study was registered in the Clinical Trial Registry of India. Trial registration number: CTRI/2013/03/003444. Date of registration: 4th March 2013.
新型线粒体调节剂TRC150094可降低胰岛素抵抗，有望改善血糖异常、血脂异常和高血压这“三联征”。在这项多剂量2期研究中，我们评估了TRC150094在接受标准治疗的血脂异常糖尿病患者中的安全性和疗效。
2013年7月至2015年8月，对225名受试者进行了一项随机、多中心、双盲、安慰剂对照、平行组2期研究。主要纳入标准为体重指数23 - 35kg/m，年龄30至65岁，使用≤2种口服降糖药治疗稳定后空腹血糖≥126或糖化血红蛋白（HbA1c）≥6.4%，载脂蛋白B（apo - B）≥100mg/dL，血清甘油三酯（TG）≥150mg/dL，收缩压（SBP）≥130mmHg，舒张压（DBP）≥85mmHg（无论是否接受抗高血压治疗）。受试者被随机分配至三种TRC150094剂量（25、50或75mg）之一或安慰剂组，为期24周。评估的结局指标包括空腹血糖（FPG）、胰岛素、平均动脉压（MAP）和apoB。此外，还评估了安全性和耐受性。
治疗24周后，与安慰剂相比，TRC150094剂量达50mg时，FPG降低幅度为13.9至21.7mg/dL（TRC150094 25mg和50mg组p < 0.05），空腹胰岛素降低幅度为2.7至6.0mU/L（所有剂量组，p > 0.05），HOMA - IR改善幅度为 - 2.0至 - 2.5（所有剂量组，p > 0.05）。此外，MAP显著降低幅度为3.1至4.2mmHg（TRC150094 25mg和75mg组p < 0.05）。此外，TRC150094治疗对体重无影响，对降低致动脉粥样硬化脂质成分有良好效果，包括非高密度脂蛋白胆固醇（50mg剂量时降低6.8mg/dL）。不良事件性质为轻至中度，且与剂量无关。一项与治疗无关的不良事件导致研究中断。总体而言，TRC150094在长达24周的时间内是安全且耐受性良好的。
在本研究中，25至50mg剂量范围的TRC150094治疗显示出在CMBCD的各个组成部分，即血糖异常、血脂异常和高血压方面有所改善。
本研究在印度临床试验注册中心注册。试验注册号：CTRI/2013/03/003444。注册日期：2013年3月4日。
