An Open Label, Randomized, Multiple-dose, Crossover Study to Compare the OralPharmacokinetics and Safety of TRC041266 Powder with TRC4186 Tablet in HealthyHuman Subjects.
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 34
- 试验地点
- 1
- 主要终点
- To compare the oral pharmacokinetics of TRC041266
研究概览
简要总结
Despite considerable progress in the treatment of hyperglycaemia and hypertension, clinical trials reported the prevalence of Heart Failure in approximately 13-47% in diabetic patients . Even mild diastolic dysfunction has been found to be associated with eight times more risk of mortality compared with normal cardiac function i.e. after 1 year the mortality rate was around 20-30 while after 5 years the mortality increases up to 45-60%.
One of the major causes of these complications is the formation of Advanced Glycosylation End (AGE) products. AGE is formed by a complex chain of reactions between reducing sugar such as glucose with proteins, forming multimeric complexes that trigger several pathological events.
There are three main mechanisms responsible for the AGE-related complications :
- non-receptor-mediated mechanisms including enhanced synthesis of extracellular matrix proteins, cross linking of structural proteins etc.
- receptor-mediated mechanisms such as promoting inflammation, endothelial dysfunction etc. and
- an increase in oxidative stress.
These underlying pathways lead to the complications of diabetes. An impaired vasodilatory reserve at the microvascular bed coupled to autonomic dysfunction contributing to a non-nutritive distribution of flow on one hand and a
compromised myocardial diastolic reserve and contractile capacity along with impaired perfusion on the other, trigger a homeostatic imbalance and ultimately contribute to the accelerated progression of heart failure associated with diabetes. It is becoming increasingly clear that anti-AGE strategies have an important role to play in the treatment of people with diabetes.
Torrent Pharmaceuticals Limited has developed a novel compound to address the main underlying mechanisms related to AGE-mediated complications. By reducing the preformed AGE and preventing AGE accumulation, the drug candidate TRC4186 would provide clinical benefit in heart failure secondary to diabetes by correcting the endothelial dysfunction, leading to an improved microvascular flow, and also by preserving function of myocardial calcium handling and preventing the deterioration in myocardial systolic and diastolic function.
TRC4186 bioavailability is significantly reduced in the presence of food necessitating administration under fasting condition. Therefore, the parent molecule has been conjugated with decanoic acid as TRC041266 to form co-crystal to circumvent this problem
Multiple dose comparative bioavailability study with TRC041266 powder and TRC4186 tablet in healthy volunteer is planned to evaluate pharmacokinetics and assess safety.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 65.00 Year(s)（—）
- 性别
- All
入选标准
- •Male and/or female subjects aged 18-65 years (both inclusive)
- •Volunteer with BMI of 18.5-30 kg/m2 (inclusive both) with minimum weight of 50 kg
- •Volunteer willing to provide written informed consent.
- •Ability to adhere to the study restrictions and assessments schedule.
排除标准
- •Inability to communicate or co-operate
- •History of angina, myocardial infarction (MI) or stroke within last 3 months prior to screening
- •Volunteers suffering from any chronic illness such as arthritis, asthma etc.
- •History of pre-existing bleeding disorder
- •Clinically relevant abnormal physical findings at the screening examination, which would interfere with the objectives of the study
- •Clinically significant abnormalities in the results of the clinical laboratory tests (at screening or check-in day (i.e. Day-0))
- •Clinically significant abnormal ECG (at screening), 2D Echo or Chest X-ray
- •Pregnant or lactating women or female subjects who are of childbearing potential and who are neither surgically sterilized nor willing to use reliable contraceptive methods {i) bilateral tubal occlusion; ii) vasectomised partner and iii) sexual abstinence iv) barrier method of contraception} and/or female volunteer with positive urine pregnancy test
- •Smokers who are unable to stop tobacco consumption during each study period, or smokers who smokes >10 cigarettes (or equivalent) per Day during last 3 months prior to Day 1
- •Positive for HIV, HCV and HbsAg.
- •History of significant blood loss due to any reason, including blood donation in the past 3 months; or the total blood loss in the last 3 months, including for this study, exceeds 450 ml.
- •Participation in any study within past 3 months
- •Addiction to alcohol or history of alcohol or drug abuse
- •Intake of hepatic microsomal enzyme inducer/inhibitor drugs in the period within 3 months prior to the first dose of study drug
- •History of consumption of prescribed medication since last 14 days or OTC medication/ herbal remedies since last 7 days before beginning of the study.
- •Volunteer found to be positive for breath alcohol test.
- •History of malignancy
- •Systolic blood pressure less than 100 mmHg or more than 139 mmHg and diastolic blood pressure less than 60 mmHg or more than 89 mmHg.
- •Pulse rate less than 60/minute or more than 100/minute.
- •Respiratory rate less than 10/minute or more than 20/minute.
- •History of hypersensitivity reaction/allergy to the investigational product or any drug chemically similar to the drug under investigation or any of the excipients.
- •Recent history of kidney or liver dysfunction.
- •Volunteers suffering from any psychiatric (acute or chronic) disorder.
- •Existence of any surgical or medical condition, which, in the judgment of the chief investigator and/or clinical investigator /physician, might interfere with the absorption, distribution, metabolism or excretion of the drug or likely to compromise the safety of volunteers
- •Volunteers with left ventricular ejection fraction (LVEF) < 55%
- •Serum magnesium level more than 2.6 mg/dl in male and 2.5 mg/dl in female.
结局指标
主要结局
To compare the oral pharmacokinetics of TRC041266
时间窗: Day 1: 0.00 (pre-dose),0.25, 0.50, 1.00, 1.50, 2.00,2.50, | 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 12.00 (pre-dose) (15 samples) | Day 2-6: 0.00 pre-dose (morning) and 12.00 pre-dose | (evening) (10 samples) | Day 7: 0.00 (pre-dose),0.25, 0.50, 1.00, 1.50, 2.00, 2.50,3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 12.00, 24.00 hr(Day 8), 48 hr (Day 9) (17 samples).
powder with TRC4186 tablet
时间窗: Day 1: 0.00 (pre-dose),0.25, 0.50, 1.00, 1.50, 2.00,2.50, | 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 12.00 (pre-dose) (15 samples) | Day 2-6: 0.00 pre-dose (morning) and 12.00 pre-dose | (evening) (10 samples) | Day 7: 0.00 (pre-dose),0.25, 0.50, 1.00, 1.50, 2.00, 2.50,3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 12.00, 24.00 hr(Day 8), 48 hr (Day 9) (17 samples).
次要结局
- a) To evaluate the safety and tolerability of TRC041266 powder in healthy human subjects.(b) To evaluate the pharmacokinetic parameters of metabolite M4)