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

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

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.

Study Overview

• Status: Completed
• Conditions: Peripheral Arterial Disease; Type II Diabetes Mellitus
• Intervention / Treatment: Other: Placebo Comparator Beverage (Beet-It Stamina Shot) & Exercise Training; Drug: Beetroot Juice (Beet-It Stamina Shot) and Exercise Training

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Diet & Fitness Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: BR Juice Placebo and Exercise Training; 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; 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.; Other Names: James White Drinks
Experimental: BR Juice (Beet-It Stamina Shot) & Supervised Exercise Training; 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; 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.; Other Names: James White Drinks

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Woessner M, VanBruggen MD, Pieper CF, Sloane R, Kraus WE, Gow AJ, Allen JD. Beet the Best? Circ Res. 2018 Aug 31;123(6):654-659. doi: 10.1161/CIRCRESAHA.118.313131.

Helpful Links

• Frederick R. Cobb Non-Invasive Vascular Research Laboratory
• Duke Clinical Trials Listing

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: February 5, 2013
• First Submitted That Met QC Criteria: February 6, 2013
• First Posted (Estimate): February 7, 2013

Study Record Updates

• Last Update Posted (Actual): July 27, 2017
• Last Update Submitted That Met QC Criteria: July 26, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Diabetes; Exercise; Vascular Diseases; Cardiovascular Diseases; Functional Capacity; Arterial Occlusive Diseases
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Diabetes Mellitus; Atherosclerosis; Diabetes Mellitus, Type 2; Peripheral Arterial Disease; Peripheral Vascular Diseases
• Other Study ID Numbers: Pro00039608; 5R21HL113717-02 (U.S. NIH Grant/Contract)