The Effects of Oral Inorganic Nitrate Supplementation on Lower Limb Perfusion During Exercise in Patients With PAD

NCT05036213 | Unknown Phase 1 FDA Drug

• 1 other identifier: 21774
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

Peripheral arterial disease (PAD) is a highly prevalent and costly condition. Intermittent claudication (IC), defined as ischemic leg pain that occurs with walking, results in functional impairment, reduced daily physical activity, and a lower quality of life. Although the mechanisms contributing to functional impairment are not fully delineated, current evidence suggests that the uncoupling of skeletal muscle cellular metabolism from tissue perfusion may be responsible for exercise intolerance. We have previously shown increases in plasma inorganic nitrite, via oral nitrate, produced clinically significant increases exercise performance in patients with PAD+IC. The hypothesis of this proposal is in patients with PAD+IC, 3-6 days of oral dietary nitrate consumption (in the form of concentrated beetroot juice) will produce a greater tissue perfusion, oxygen delivery, and enhanced muscle metabolism in comparison to placebo. This will translate into an increase in physical performance in both muscle specific plantar flexion exercise and treadmill measures of pain free ambulation. In order to test this hypothesis, we will recruit 10 patients PAD+IC in a randomized, double-blind, placebo controlled, cross over design.

Conditions

Peripheral Arterial Disease; Peripheral Vascular Diseases

Keywords

PAD; nitrate; nitric oxide

Outcome Measures

Primary Outcomes (1)

• Phosphocreatine kinetics after maximal exercise

  The primary outcomes to be analyzed will be treatment differences (BR v PL) in phosphocreatine recovery time constant (PCr) measured by Creatine chemical Exchange Saturation Transfer (CrCREST). The subjects will be positioned within the scanner feet first with the calf at the isocenter of the magnet and a flexible phased array coil will be positioned and wrapped around the calf of interest. Imaging of calf muscle energetics using creatine chemical exchange saturation transfer (CrCEST, no contrast agent used) will be performed after pedal ergometry until exhaustion or limiting symptoms

  After a minimum of 3 days of supplementation with either Placebo or nitrate rich beverage.

Secondary Outcomes (5)

• Maximal hyperemia in different lower limb compartments

  After a minimum of 3 days of supplementation with either Placebo or nitrate rich beverage.

• Peak exercise

  After a minimum of 3 days of supplementation with either Placebo or nitrate rich beverage.

• Claudication Onset Time

  After a minimum of 3 days of supplementation with either Placebo or nitrate rich beverage.

• Vascular Function - Brachial Flow Mediated Dilation

  After a minimum of 3 days of supplementation with either Placebo or nitrate rich beverage.

• Vascular stiffness

  After a minimum of 3 days of supplementation with either Placebo or nitrate rich beverage.

Study Arms (2)

Dietary nitrate

ACTIVE COMPARATOR

The active treatment, beetroot juice (BEET IT, James White Drinks, Ipswich, UK), contains 6.2mmol of inorganic nitrate. Participants will continue supplementation until they complete all testing visits.

Drug: BEET IT - Concentrate Beet root juice

concentrated beet root juice with depleted nitrate content

PLACEBO COMPARATOR

The placebo treatment is also beetroot juice provide by the same company (BEET IT, James White Drinks, Ipswich, UK), but it does not contain any inorganic nitrate. Participants will continue supplementation until they complete all testing visits.

Drug: BEET IT - Concentrate Beet root juice (nitrate depleted)

Interventions

BEET IT - Concentrate Beet root juice DRUG

Each bottle contains 75ml of concentrated beetroot juice with approximately 6.2mmol of inorganic nitrate. The product is provided by BEET IT, James White Drinks, Ipswich, UK.

Also known as: Dietary Nitrate supplementation (nitrate rich)

Dietary nitrate

BEET IT - Concentrate Beet root juice (nitrate depleted) DRUG

Each bottle contains 75ml of concentrated beetroot juice with depleted nitrate, thus, no inorganic nitrate is found in thisbeverage. The product is also provided by BEET IT, James White Drinks, Ipswich, UK.

Also known as: Dietary Nitrate supplementation (nitrate depleted)

concentrated beet root juice with depleted nitrate content

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- History of stable intermittent claudication for 3 or more months, and an Ankle-brachial index test (ABI) \<0.9 at rest.
• Symptomatic PAD (claudication or critical limb ischemia)

You may not qualify if:

• \- Limb threatening ischemia, including rest pain and/or gangrene; impending limb loss or chronic osteomyelitis.
• Lower extremity vascular surgery, angioplasty or lumbar sympathectomy within 3 months of enrollment;
• severe peripheral neuropathy or any condition other than PAD that limits walking such as unstable angina;
• history of significant left main or three vessel coronary artery disease (\>70% stenosis, unprotected by grafts) or recent myocardial infarction (6 weeks);
• chest pain during treadmill exercise which appears before the onset of claudication,
• chronic renal failure with an eGRF\<30; Type 1diabetes mellitus, a BMI\>40, and a HbA1c\>8.5%. Refusal to give or inability to give informed consent. Pregnancy (Self-reported).

Sponsors & Collaborators

• University of Virginia: lead

Study Sites (1)

University of Virginia

Charlottesville, Virginia, 22903, United States

RECRUITING

Related Publications (4)

• Isbell DC, Epstein FH, Zhong X, DiMaria JM, Berr SS, Meyer CH, Rogers WJ, Harthun NL, Hagspiel KD, Weltman A, Kramer CM. Calf muscle perfusion at peak exercise in peripheral arterial disease: measurement by first-pass contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging. 2007 May;25(5):1013-20. doi: 10.1002/jmri.20899.

  PMID: 17410566 BACKGROUND

• Isbell DC, Berr SS, Toledano AY, Epstein FH, Meyer CH, Rogers WJ, Harthun NL, Hagspiel KD, Weltman A, Kramer CM. Delayed calf muscle phosphocreatine recovery after exercise identifies peripheral arterial disease. J Am Coll Cardiol. 2006 Jun 6;47(11):2289-95. doi: 10.1016/j.jacc.2005.12.069. Epub 2006 May 15.

  PMID: 16750698 BACKGROUND

• Lopez D, Pollak AW, Meyer CH, Epstein FH, Zhao L, Pesch AJ, Jiji R, Kay JR, DiMaria JM, Christopher JM, Kramer CM. Arterial spin labeling perfusion cardiovascular magnetic resonance of the calf in peripheral arterial disease: cuff occlusion hyperemia vs exercise. J Cardiovasc Magn Reson. 2015 Feb 22;17(1):23. doi: 10.1186/s12968-015-0128-y.

  PMID: 25890198 BACKGROUND

• Kenjale AA, Ham KL, Stabler T, Robbins JL, Johnson JL, Vanbruggen M, Privette G, Yim E, Kraus WE, Allen JD. Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease. J Appl Physiol (1985). 2011 Jun;110(6):1582-91. doi: 10.1152/japplphysiol.00071.2011. Epub 2011 Mar 31.

  PMID: 21454745 BACKGROUND

MeSH Terms

Conditions

Peripheral Arterial Disease; Peripheral Vascular Diseases

Condition Hierarchy (Ancestors)

Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Jason D. Allen, PhD

  University of Virginia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Casey C Derella, PhD

CONTACT

434-243-8677; bxg7vn@virginia.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor in kinesiology

Model Details: This is a randomized, double-blind, placebo-controlled, cross-over design. This means that all subjects will complete both supplementation phases in a randomized order.

Study Record Dates

• First Submitted: September 1, 2021
• First Posted: September 5, 2021
• Study Start: February 1, 2020
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: November 29, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Beginning 9 months and ending 36 months following article publication.

Locations

US (1)