Novel Treatment of Intermittent Claudication in Patients With Peripheral Arterial Disease Using Danshen Gegen (D&G) Capsule

Study Overview
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Brief Summary
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Peripheral arterial disease (PAD) due to lower limb arterial blockages affects significant proportion of the population with an age-adjusted prevalence of approximately 12%. Claudication induced walking impairment can be debilitating and adversely affects social, leisure, and occupational activities in many patients and is associated with higher mortality among PAD patients. Unfortunately, very few effective therapies are available to improve leg symptoms and exercise performance in PAD patients. Surgery is the last resort but results vary. Therefore, there is a large unmet need for medical therapies that can improve long-term walking performance and functional capacity in PAD patients. Danshen and Gegen (D&G) are commonly used Chinese herbal medicine in the treatment of cardiovascular diseases. D&G study has been extensively researched and continued at The Chinese University of Hong Kong (CUHK) for their antioxidative and vasodilator properties, modulate anti-atherosclerosis and improve arthrogenic athophysiology. Three randomized trials were completed at the CUHK showing D&G improved lipid profile, vascular function and thinned down the internal layer of the carotid artery. One may expect the same with lower limb arteries. Extensive clinical experiences of use in China and Hong Kong indicated that D&G are well tolerated and safe. This project is a randomized control trial to determine the efficacy and Safety of D&G in improving the functional capacity & QoL in patients with symptomatic PAD. The results of this study have the potential to change local and international practice in providing a much needed therapeutic option in the treatment of PAD.

Detailed Description
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Peripheral arterial disease involving the lower limbs is becoming an increasingly important health issue which places considerable burden on individuals, communities and health care resources. PAD affects an estimated 27 million adults >55 years of age in Europe and North America (1). The prevalence of PAD in Asia is expected to be similar and is likely to rise as the Chinese population ages. Intermittent claudication affects most patients with PAD. Although IC is not limb-threatening, the loss of walking ability and the experience of pain with ambulation can cause significant social, leisure, and occupational impairment in many patients (2-4). The decreased QoL experienced in patients with IC is on par with other cardiovascular diseases such as heart failure and heart attack. More alarmingly, physical disability is associated with higher risk of death among PAD patients. For these reasons and because patients are chronically disabled, the treatment of IC has increasingly become a major clinical focus in cardiovascular research. For PAD patients, it is critical to focus on therapies that can reduce the underlying cardiovascular risk as well as improving functional status and Qol. Although multiple therapies (antiplatelet agents, statins, anti-hypertensive agents) have been proven to reduce cardiovascular risk in PAD patients, very few therapeutic agents have been shown to improve symptoms of IC in PAD patients (5). As such there is a large unmet need in terms of leg-specific therapies that can improve walking performance and functional capacity for this debilitating disease. Traditional Chinese herbal medicine such as Danshen and Gegen are well established in the treatment of cardiovascular diseases and well tolerated by most patients. The studies done at the Institute of Chinese Medicine of the CUHK showed particularly encouraging results (6-8). The outcomes of this study have the potential to change local and international practice in providing a novel therapeutic option in the treatment of symptomatic PAD. As parallel laboratory research is being done to identify the most active components of the D&G formula in preparation for drug development, the efficacy of D&G in PAD will offer more assurance for the systemic efforts.

Official Title
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Novel Treatment of Intermittent Claudication in Patients With Peripheral Arterial Disease Using Danshen Gegen (D&G) Capsule

Conditions
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Peripheral Arterial Disease, Intermittent Claudication

Intervention / Treatment
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* Drug: Danshen Gegen Capsule
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women 40 years or older With stable intermittent claudication secondary to PAD defined as resting ABI <0.90 and a ≥10mmHg decrease in ankle artery blood pressure after exercise. No change in existing therapy for claudication within 3 months of study enrollment. Exclusion Criteria: Critical limb ischemia defined by ischemic rest pain, ulceration, or gangrene Major lower limb amputation Surgical or endovascular revascularization for PAD within 3 months prior to enrolment Exercise limitation due to significant concomitant disease (e.g. severe arthritis, cardiac or pulmonary disease) Pregnant women and women who are breastfeeding Patients who are currently on Warfarin Patients with resting systolic blood pressure below 100mmHg (SBP < 100mmHg)

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Danshen Gegen Capsule<br>3 capsules (500 mg per capsule) twice daily for 24 weeks | Drug: Danshen Gegen Capsule<br>* Danshen can dilate blood vessels, reduce the number of angina attacks and significantly improve endothelial function in patients with Coronary Angina Pectoris. Gegen is also effective in dilating cardiovascular and cerebrovascular of the brain, and improving blood circulation. The main active ingredient of Gegen isoflavones is effective in dilating the coronary arteries, improving metabolism in normal and ischemic myocardium and reducing blood pressure, heart rate and myocardial oxygen consumption.<br>* Other names: D&G;|
| Placebo Comparator: Placebo<br>3 capsules (500 mg per capsule) twice daily for 24 weeks | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in total distance walked on a standardized graded treadmill |  | between baseline and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in distance walked to onset of claudication |  | between baseline and 24 weeks | 
| Change in health related quality of life assessed by EuroQol-5 Dimension |  | between baseline and 24 weeks | 
| Change in functional status assessed by Walking Impairment Questionnaire |  | between baseline and 24 weeks | 
| Rates of combined cardiovascular events including vascular death, myocardial infarction, stroke, revascularization, or readmission to hospital for a vascular or atherosclerosis-related complication |  | At 24 weeks | 
| Change in ankle brachial index before and after exercise by brachial-to-ankle pulse wave velocity |  | between baseline and 24 weeks | 
| Changes in arterial stiffness assessed by brachial-to-ankle pulse wave velocity |  | between baseline and 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Danshen Gegen Capsule