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Nitrites, Exercise, and Peripheral Arterial Disease (NO-PAD)

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ClinicalTrials.gov Identifier: NCT01684930
Recruitment Status : Completed
First Posted : September 13, 2012
Results First Posted : January 1, 2016
Last Update Posted : August 29, 2017
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Jason Allen, Ph.D., Duke University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Outcomes Assessor);   Primary Purpose: Treatment
Condition Peripheral Arterial Disease
Interventions Drug: Beetroot Juice (Beet-It Stamina Shot) & Supervised Exercise Training
Other: Placebo Comparator Beverage (Beet-It Stamina Shot) & Exercise Training
Enrollment 32
Recruitment Details 10,817 patients were screened, 898 potential study candidates were identified, and 32 subjects signed consent and were enrolled from June 2012 through July 2014. Of the 32 subjects who signed consent, 5 subjects were screen failures and 1 withdrew consent. 26 subjects were randomized and 22 subjects completed all study testing.
Pre-assignment Details  
Arm/Group Title BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training
Hide Arm/Group Description

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.

Beetroot Juice (Beet-It Stamina Shot) & Supervised 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.

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.

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.

Period Title: Overall Study
Started 12 14
Completed 9 13
Not Completed 3 1
Reason Not Completed
Withdrawal by Subject             3             1
Arm/Group Title BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training Total
Hide Arm/Group Description

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.

Beetroot Juice (Beet-It Stamina Shot) & Supervised 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.

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.

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.

Total of all reporting groups
Overall Number of Baseline Participants 12 14 26
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 12 participants 14 participants 26 participants
63.25  (8.9) 71.85  (7.9) 67.88  (9.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 14 participants 26 participants
Female
3
  25.0%
6
  42.9%
9
  34.6%
Male
9
  75.0%
8
  57.1%
17
  65.4%
1.Primary Outcome
Title Change in Exercise Capacity: VO2peak (Maximal Oxygen Consumption)
Hide Description Exercise capacity will be assessed using a maximal cardiopulmonary exercise (CPX) test with expired gas analysis, for determination of peak oxygen consumption, claudication onset time and peak walking time.
Time Frame Baseline and 16 Weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants who completed study.
Arm/Group Title BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training
Hide Arm/Group Description:

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.

Beetroot Juice (Beet-It Stamina Shot) & Supervised 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.

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.

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.

Overall Number of Participants Analyzed 9 13
Mean (Standard Deviation)
Unit of Measure: ml/kg/min
1.48  (2.69) 0.23  (2.21)
2.Primary Outcome
Title Change In Time To Exhaustion
Hide Description Exercise capacity will be assessed using a maximal cardiopulmonary exercise (CPX) test with expired gas analysis, for determination of total time to exhaustion.
Time Frame Baseline and 16 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training
Hide Arm/Group Description:

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.

Beetroot Juice (Beet-It Stamina Shot) & Supervised 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.

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.

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.

Overall Number of Participants Analyzed 9 13
Mean (Standard Deviation)
Unit of Measure: seconds
289.56  (175.44) 254.92  (210.48)
3.Secondary Outcome
Title Change in Functional Ability
Hide Description 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.
Time Frame Baseline and 16 Weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training
Hide Arm/Group Description:

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.

Beetroot Juice (Beet-It Stamina Shot) & Supervised 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.

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.

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.

Overall Number of Participants Analyzed 9 13
Mean (Standard Deviation)
Unit of Measure: feet
172.89  (166.05) 95  (173.7)
4.Secondary Outcome
Title Change In Claudication Onset Time
Hide Description Exercise capacity will be assessed using a maximal cardiopulmonary exercise (CPX) test with expired gas analysis, for determination of claudication onset time.
Time Frame Baseline and 16 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training
Hide Arm/Group Description:

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.

Beetroot Juice (Beet-It Stamina Shot) & Supervised 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.

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.

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.

Overall Number of Participants Analyzed 9 13
Mean (Standard Deviation)
Unit of Measure: seconds
199.22  (143.47) 48.58  (198.75)
5.Secondary Outcome
Title Change In Vascular Function (BAFMD)
Hide Description Vascular Function is measured as Brachial artery flow-mediated dilation (BAFMD). BAFMD is a measure of change in artery diameter after a stimulus .
Time Frame Baseline and 16 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
participants with analyzable data
Arm/Group Title BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training
Hide Arm/Group Description:

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.

Beetroot Juice (Beet-It Stamina Shot) & Supervised 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.

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.

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.

Overall Number of Participants Analyzed 4 6
Mean (Standard Deviation)
Unit of Measure: % dilation
-1.14  (3.02) -0.19  (1.80)
6.Secondary Outcome
Title Change in Angiogenesis
Hide Description Gastrocnemious muscle biopsy will be performed to measure the number of capillaries per fibre as a marker of change in angiogenesis between groups
Time Frame Baseline and 16 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants who had a gastrocnemius muscle biopsy with enough tissue to analyze.
Arm/Group Title BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training
Hide Arm/Group Description:

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.

Beetroot Juice (Beet-It Stamina Shot) & Supervised 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.

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.

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.

Overall Number of Participants Analyzed 5 8
Mean (Standard Deviation)
Unit of Measure: capillaries per fibrer
0.38  (0.54) 0.26  (0.51)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training
Hide Arm/Group Description

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.

Beetroot Juice (Beet-It Stamina Shot) & Supervised 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.

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.

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.

All-Cause Mortality
BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training
Affected / at Risk (%) Affected / at Risk (%)
Total   0/12 (0.00%)   0/14 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
BR Juice (Beet-It Stamina Shot) and Exercise Training BR Juice Placebo and Exercise Training
Affected / at Risk (%) Affected / at Risk (%)
Total   1/12 (8.33%)   0/14 (0.00%) 
Cardiac disorders     
hypotensive episode with exercise *  1/12 (8.33%)  0/14 (0.00%) 
*
Indicates events were collected by non-systematic assessment
The largest limitation to the study was the evolving knowledge on conversion rates of oral inorganic nitrate to nitrite. We found a good deal of unexpected inter and intra-subject variation in conversion rates.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Jason D. Allen, PhD
Organization: Victoria University
Phone: 61 3 9919 4264
Responsible Party: Jason Allen, Ph.D., Duke University
ClinicalTrials.gov Identifier: NCT01684930     History of Changes
Other Study ID Numbers: Pro00031918
1R21HL111972-01 ( U.S. NIH Grant/Contract )
First Submitted: September 11, 2012
First Posted: September 13, 2012
Results First Submitted: November 25, 2015
Results First Posted: January 1, 2016
Last Update Posted: August 29, 2017