A Double-blind, Placebo Controlled, Parallel Group Comparative Study to Evaluate the Efficacy and Safety of BRL 49653C With Concurrent Sulphonylurea Therapy, When Administered to Patients With Non-insulin Dependent Diabetes Mellitus.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 77
- 试验地点
- 1
- 主要终点
- To determine the effectiveness of BRL 49653C (2 mg bd) compared to placebo when added to sulphonylurea therapy, for 24 weeks in out-patients with NIDDM.
研究概览
简要总结
At least 30% of patients initially treated with sulphonylureas for NIDOM will have a poor response, and in the remaining 70% the subsequent failure rate is approximately 4% to 5% per year. BRL 49653C has a different mechanism of action to the sulphonylureas, and therefore the effects on fasting plasma glucose and Hb A1c are expected to be additive. Since circulatory insulin levels should decrease, and plasma glucose should be regulated, these combinations are also anticipated to slow both the progression of diabetic complications and delay the need for exogenous insulin.
The proposed study is intended primarily to determine the effectiveness of BRL 49653C by measure of glucose homeostasis as determined by Hb A1c and fasting plasma glucose, when added to sulphonylurea therapy (sulphonylureas are limited to: glibenclamide, glipazide and gliclazide). In addition, the clinical safety of BRL 49653C will be assessed in this patient population. The starting doses have been selected based on dose response studies examining safety, tolerability and efficacy in the U.S.A.
详细描述
Non-insulin dependent diabetes mellitus (NIDDM) is the most common form of the hyperglycaemic state. Although NIDDM exists in all populations, its prevalence varies greatly, depending upon age and race, and appears to be increasing. It is estimated that NIDOM occurs in 5% of 50-year-old-adults and 20% of the 80-year-old population with a linear progression between these age groups. Aberrant insulin secretion from pancreatic p-cells, and insulin resistance in peripheral tissues with reduced glucose uptake (particularly in muscle and liver) are the primary pathogenic mechanisms believed to be responsible for the metabolic abnormalities associated with NIDDM. Insulin resistance progresses to overt diabetes at the rate of approximately 5% of patients per year.
Patients with insulin resistance, but no overt diabetes mellitus, are generally overweight, usually have a sedentary lifestyle, and frequently have a family history of diabetes mellitus. Insulin-resistant phenotype is commonly associated with cardiovascular risk factors such as hypertension and dyslipidemia (decreased HDL and increased VLDL, LDL and triglycerides). Current available therapies for NIDOM include insulin and oral hypoglycemic agents (e.g. sulphonylurea compounds and biguanides). Sulphonylureas achieve blood glucose control by enhancing pancreatic insulin secretion. However, a significant failure rate does exist for this mode of treatment, and many patients who have received long term treatment with sulphonylureas do require exogenous insulin therapy when there is no longer adequate pancreatic insulin secretion (even in response to sulphonylureas). Single therapy with the biguanide, metformin, or combination therapy with an additional sulphonylurea may also be administered to NIDDM patients. However, the overall effect of metformin on glycemic control seems to be smaller than that of sulphonylureas, and in many cases, combination therapy does not stop the need for insulin after a period of time.
BRL 49653C is a highly potent and orally active anti-diabetic thiazolidinedione compound. The thiazolidinediones such as BRL 49653C represent a novel class of compounds that act as "insulin sensitizers" in target tissues. Unlike sulphonylureas, BRL 49653C improves the sensitivity of muscle and liver to insulin. An agent that enhances insulin sensitivity may be effective in regulating elevated blood glucose in patients with NIDDM and theoretically may be beneficial in reducing the frequency and severity of morbid complications of this disease. BRL 49653C does not increase pancreatic insulin secretion; therefore, treatment with BRL 49653C should not have the potential to exhaust pancreatic function, or produce the untoward effect of hypoglycemia (a potential complication of treatment with sulphonylureas).
In animal testing, repeat oral administration of BRL 49653C has been effective in reducing hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and free fatty acids associated with insulin-resistant models of NIDDM2. In the genetically obese mouse, the potency of BRL49653C as an anti-hyperglycemic agent, was compared with competitor insulin sensitizers, and BRL 49653C was proven to be at least 100 times more potent than CS-045 (troglitazone) and at least 30 times more potent than pioglitazone.
Six month toxicological findings were similar to those observed in one month studies. Please refer to the Investigator Brochure for more detailed information about pre-clinical studies and the pharmacology, metabolism, and toxicology of BRL 49653C.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 30 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men or women between 30-80 years of age inclusive at time of enrolment.
- •Patients who had non-independent diabetes mellitus (NIDDM) defined by the criteria of the National Diabetes Data Group.
- •Patients who had sulphonylurea therapy for at least 6 months and a constant dose for at least 2 months prior to visit
- •Patients who had fasting plasma glucose <= 15.0 mmol/L at screening. Hemoglobin A1c >= 7.5%.
- •Female patients must be (1) post-menopausal, i.e. > 6 months without menstrual period, surgically sterile, or (2) using hormonal contraceptives or intrauterine contraceptive devices. Female patients who were taking hormonal contraceptives must also use an additional barrier form or intrauterine form of birth control.
- •Patients who had given their written informed consent to participate.
排除标准
- •Female patients who were pregnant, breast feeding or planning a pregnancy during the course of the study.
- •Patients who had a fasting plasma glucose > 15.0 mmol/L at screening, or severity of diabetes mellitus requiring administration of insulin, or patients with ketonuria.
- •Patients who had clinically significant renal or hepatic disease (i.e., patients with serum creatinine > 160 micromol/L (1.8 mg/dL); ALT, AST, total bilirubin, gamma GT, or alkaline phosphatase more than 2.5 times the upper limit of the normal laboratory range).
- •Any clinically significant abnormality identified on the screening physical examination, laboratory tests, electrocardiogram which in the judgment of the investigator would preclude safe completion of the study.
- •Patients who had leukocyte count < 3000/mm3 or platelet count <120,000/mm
- •Systolic blood pressure >180mmHg or diastolic blood pressure >114mmHg while on appropriate hypertensive therapy.
- •Significant anemia (hemoglobin < 11 g/dL for males or < 10g/dL for females) or diagnosis of porphyria.
- •Symptomatic diabetic neuropathy of sufficient severity to require treatment for control of symptoms (eg, painful peripheral neuropathy, symptomatic orthostatic hypotension, urinary retention, gastric stasis, pedal ulcers).
- •Diabetic retinopathy imminently requiring treatment for preserving or restoring vision.
- •Body mass index(BMI) < 22 and >38 kg/m2 (Formula: BMI= weight, kg ÷height, m2)and variation in body weight of >=5% between screening and visit2.
研究组 & 干预措施
BRL 49653C
Eligible patients may enter the study at visit 1 according to the inclusion/exclusion criteria. At the screening visit, patients will enter a single blind placebo run-in period to establish baseline characteristics. Patients must have been stable on sulphonylurea therapy for at least 2 months prior to the screening visit to be included. For the duration of the run-in period, patients will receive BRL 49653C placebo in addition to their constant dose of sulphonylurea. Patients eligible to enter the double-blind phase of the study will be randomized in equal numbers at visit 2, to one of two treatment groups (BRL 49653C 2 mg bid. or placebo bid). Patients will then continue to take their study medication arid the constant dose of sulphonylurea through visits 3 to 8 (weeks 4 to 24).
干预措施: BRL 49653C (Drug)
placebo
Eligible patients may enter the study at visit 1 according to the inclusion/exclusion criteria. At the screening visit, patients will enter a single blind placebo run-in period to establish baseline characteristics. Patients must have been stable on sulphonylurea therapy for at least 2 months prior to the screening visit to be included. For the duration of the run-in period, patients will receive BRL 49653C placebo in addition to their constant dose of sulphonylurea. Patients eligible to enter the double-blind phase of the study will be randomized in equal numbers at visit 2, to one of two treatment groups (BRL 49653C 2 mg bid. or placebo bid). Patients will then continue to take their study medication arid the constant dose of sulphonylurea through visits 3 to 8 (weeks 4 to 24).
干预措施: Placebo (Drug)
结局指标
主要结局
To determine the effectiveness of BRL 49653C (2 mg bd) compared to placebo when added to sulphonylurea therapy, for 24 weeks in out-patients with NIDDM.
时间窗: 7 months
Primary: Change from baseline for Hb A1c at week 24. Secondary: Mean change from baseline for: fasting plasma glucose,insulin levels, immune reactive,lipid levels (ie.total cholesterol, HDL-cholesterol, LDL cholesterol, triglycerides), body weight (WHR), vital signs (systolic, diastolic blood pressure and heart rate)
次要结局
- To assess the clinical safety of BRL 49653C (2 mg bd) compared to placebo when added to sulphonylurea therapy, for 24 weeks in out-patients with NIDOM.(7 months)