Dietary Nitrate and Exercise to Augment Exercise Training Benefits in Subjects With DM+PAD

Study Overview
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Brief Summary
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The hypothesis of this proposal is that in subjects with Type II diabetes mellitus (T2D) and peripheral arterial disease (PAD) with intermittent claudication (IC), regular consumption of a high nitrate supplement which raises plasma nitrite, in conjunction with 12 weeks of supervised exercise training at the limb ischemic threshold (SET) will produce a greater clinical benefit (increases in claudication onset time [COT] and peak walking time [PWT] relative to a group with the same exercise training but supplemented with placebo .This study is essentially exploratory in nature and designed to provide us with information to adequately develop power and execute a larger study. We have previously seen benefits from nitrate supplementation on function in PAD.

Official Title
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Dietary Nitrate to Augment Exercise Training Benefits in Subjects With Type II Diabetes (DM) and Peripheral Arterial Disease (PAD)

Conditions
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Peripheral Arterial Disease, Type II Diabetes Mellitus

Intervention / Treatment
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* Drug: Beetroot Juice (Beet-It Stamina Shot) and Exercise Training
* Other: Placebo Comparator Beverage (Beet-It Stamina Shot) & Exercise Training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Peripheral Arterial Disease (ABI of less than 0.9) Diagnosed Type II Diabetes Intermittent Claudication for 3 or more months Exclusion Criteria: Individuals with known alcohol or drug abuse problems Individuals who have suffered a heart attack or stroke, or have changes on a resting ECG, in the last 3 months Those classified as American Heart Association Class D Gangrene, impending limb loss or osteomyelitis Lower extremity vascular surgery, angioplasty or lumbar sympathectomy within 3 months of enrollment Severe peripheral neuropathy Any condition other than PAD that limits walking Chest pain during treadmill exercise which appears before the onset of claudication, or >3mm ST depression during exercise Subjects taking nitrates or nitroglycerin products Must not be taking protein pump inhibitor medications

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 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 |
| --- | --- |
| Experimental: BR Juice (Beet-It Stamina Shot) & Supervised Exercise Training<br>Subjects consume 70 ml of Beetroot Juice (Beet-It Stamina Shot) to assess acute effects of beverage supplementation at the start (between Testing Visits 1 & 2) and at the end of the trial (between Visits 3 & 4). It also allows for comparisons of the combination of beetroot juice and chronic training effects (between Visits 2 & 3) to when the subject has not consumed the beverage (Visits 1 & 4). All subjects will consume Beet-It Stamina Shot 3 hours prior to all beverage tolerance visits, Testing Visits 2 & 3 and for all supervised exercise training visits during the 12 week intervention. | Drug: Beetroot Juice (Beet-It Stamina Shot) and Exercise Training<br>* The beverage is high in inorganic nitrate and bottled and supplied by James White Drinks. This supplement will be used in conjunction with supervised exercise training.<br>* Other names: James White Drinks;|
| Placebo Comparator: BR Juice Placebo and Exercise Training<br>Subjects consume 70 ml of Beetroot Juice (Beet-It Stamina Shot; Placebo) to assess acute effects of beverage supplementation at the start (between Testing Visits 1 & 2) and at the end of the trial (between Visits 3 & 4). It also allows for comparisons of the combination of placebo beverage and chronic training effects (between Visits 2 & 3) to when the subject has not consumed the beverage (Visits 1 & 4). All subjects will consume Beet-It Stamina Shot (Placebo) 3 hours prior to all beverage tolerance visits, Testing Visits 2 & 3 and for all supervised exercise training visits during the 12 week intervention. | Other: Placebo Comparator Beverage (Beet-It Stamina Shot) & Exercise Training<br>* The beverage is identical in look and taste to Beet-It Stamina Shot but with active ingredient removed. It is also bottled and supplied by James White Drinks. This placebo supplement will be used in conjunction with supervised exercise training.<br>* Other names: James White Drinks;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Exercise Capacity - Maximal Oxygen Capacity (VO2peak) | Exercise capacity will be assessed using a maximal cardiopulmonary exercise (CPX) test with expired gas analysis, for determination of peak oxygen consumption | Baseline & 16 Weeks | 
| Change in Exercise Capacity - Time to Exhaustion (TTE) | Exercise capacity will be assessed using a maximal cardiopulmonary exercise (CPX) test for determination of Time to Exhaustion (TTE) | Baseline & 16 Weeks | 
| Change in Exercise Capacity - Claudication Onset Time (COT) | Exercise capacity will be assessed using a maximal cardiopulmonary exercise (CPX) test for determination of Claudication Onset Time (COT) | Baseline & 16 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Functional Ability | Six-Minute Walk test. This test simple and practical assessment of functional capacity. The test measures the distance that a patient can walk on a flat, hard surface in a period of 6 minutes. The test is self-paced and assesses the submaximal level of functional capacity. The subjects choose their own intensity and are allowed to stop and rest if necessary during the test. | Baseline and 16 Weeks | 
| Change in Angiogenesis | Gastrocnemious muscle biopsy will be performed to measure the number of capillaries per fibre as a marker of change in angiogenesis between groups. | Baseline and 16 weeks | 
| Change In Vascular Function | Vascular Function will be measured as the Brachial artery flow-mediated dilation (BAFMD) | Baseline and 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular Diseases, Vascular Diseases, Arterial Occlusive Diseases, Diabetes, Exercise, Functional Capacity