Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study of Metformin for the Assessment of Changes in Functional Capacity, Endothelial Function, and Hemodynamics in Individuals With Peripheral Artery Disease-Related Intermittent Claudication
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Change in pain-free walking time
研究概览
简要总结
The purpose of this study is to determine the effects of metformin on functional capacity (pain-free and maximum walking times) in individuals with peripheral artery disease (PAD)-related intermittent claudication.
详细描述
Background and Rationale:
Metformin has demonstrable efficacy in slowing or reversing the progression of various insulin-resistant disease states - most notably type 2 diabetes and pre-diabetes. In seeking to establish proof-of-concept that insulin resistance is a suitable pathophysiological target in the treatment of PAD-related intermittent claudication (pain in the leg muscles during walking, which resolves on exercise cessation), this study will determine whether the known insulin-sensitizing effects of metformin translate to alleviation of the functional limitations imposed by claudication.
Study Design:
A total of 80 individuals with PAD-related intermittent claudication will be randomised (1:1) to either metformin or matching placebo for 16-18 weeks (double-blind, parallel group design). The maximum daily dose of metformin will be 2000mg (up-titrated from half this dose at 2 weeks if tolerated).
Primary Hypothesis:
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥40 years old.
- •Resting ankle-brachial index (ABI) ≤0.90 in the limiting leg(s), or a >20% reduction in the ABI measured immediately post-exercise where the resting ABI is >0.
- •In cases of incompressible arteries in the limiting leg(s) (i.e. ABI ≥1.40), a toe-brachial index (TBI) of ≤0.70 is required.
- •Peripheral artery stenosis/occlusion in the limiting leg(s), documented by duplex ultrasonography or other imaging tests.
- •Stable (i.e. 3-month history) intermittent claudication in at least one PAD-affected leg.
- •Maximum walking time during graded treadmill exercise testing (Gardner-Skinner protocol) ≥1 minute and ≤16 minutes.
- •Concurrent medications that may affect primary, secondary or exploratory endpoints have remained stable over the previous 3 months.
- •Have given signed informed consent to participate in the study.
排除标准
- •Identification of any other medical condition requiring immediate therapeutic intervention.
- •Clinically significant abnormal electrocardiogram (ECG) at rest or during exercise that represents a contraindication to study procedures or the study drug.
- •Myocardial infarction, unstable angina, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass graft surgery (CABG), or other major surgery within the previous 6 months.
- •Exercise capacity limited by a factor other than PAD-related intermittent claudication.
- •Any condition that precludes valid completion of a treadmill exercise test.
- •Critical limb ischemia in either leg, defined as PAD-related chronic ischemic rest pain or skin lesions (ulcers, gangrene).
- •Previous peripheral revascularisation or other surgical treatment for PAD in the previous 6 months.
- •Known non-atherosclerotic cause of PAD.
- •Active cancer.
- •Uncontrolled hypertension (resting brachial blood pressure ≥160/100 mmHg).
- •Evidence of pharmacologically-treated or poorly controlled (i.e. HbA1c ≥7.5%) type 2 diabetes or other class of diabetes (e.g. type 1 diabetes).
- •Known intolerance or contraindication(s) to metformin.
- •Known contraindication(s) to "Definity" (perflutren lipid microsphere).
- •Participation or intention to participate in another clinical research study during the study period.
- •History of non-compliance to medical regimens or unwillingness to comply with the study protocol.
- •Any other condition that in the opinion of the Investigators would confound the evaluation and interpretation of the data.
- •Persons directly involved in the execution of the protocol.
- •Incapable of providing written informed consent due to cognitive, language, or other reasons.
研究组 & 干预措施
Metformin
Metformin at a maximum dose of 1000mg twice daily for 16-18 weeks (i.e. maximum of 2000mg per day).
干预措施: Metformin (Drug)
Placebo
Matching placebo twice daily for 16-18 weeks.
干预措施: Placebo (Drug)
结局指标
主要结局
Change in pain-free walking time
时间窗: Measured at baseline and following 16-18 weeks treatment
Pain-free walking time (time to onset of claudication) will be measured during a graded treadmill exercise test.
Change in maximum walking time
时间窗: Measured at baseline and following 16-18 weeks treatment
Maximum walking time will be measured during a graded treadmill exercise test.
次要结局
- Change in insulin sensitivity(Measured at baseline and following 16-18 weeks treatment)
- Change in objectively measured physical activity / sedentary behaviour in the daily life setting.(Measured at baseline and following 16-18 weeks treatment)
- Change in endothelial function(Measured at baseline and following 16-18 weeks treatment)
- Change in questionnaire-based markers of quality of life / perceived functional capacity(Measured at baseline and following 16-18 weeks treatment)
- Change in skeletal muscle blood flow response to insulin(Measured at baseline and following 16-18 weeks treatment)
- Change in skeletal muscle blood flow response to acute exercise(Measured at baseline and following 16-18 weeks treatment)