Impact of Nrf2 Activation on Macrovascular, Microvascular & Leg Function & Walking Capacity in Peripheral Artery Disease

NCT06319339 | Recruiting Early Phase 1 FDA Drug

• 1 other identifier: 0419-23-FB
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Peripheral artery disease (PAD) is associated with elevated oxidative stress, and oxidative stress has been implicated as the cause of reduced endothelial reactivity in individuals with PAD. Endothelial function is important because the endothelium contributes to the dilation of arteries during exercise, thereby implicating impaired endothelial function as a mechanism contributing to exacerbated exercise-induced ischemia. Therefore, the purpose of this study is to test the hypothesis that acute exogenous diroximel fumarate (Vumerity) intake will improve antioxidant capacity, thereby reducing oxidative stress and improving vascular function and walking capacity in those with PAD. During this study, participants will be administered diroximel fumarate or a placebo, and the acute effects of diroximel fumarate on vascular function and walking capacity will be assessed. Vascular function and walking capacity will be assessed with flow-mediated dilation, arterial stiffness, head-up tilt test, blood biomarkers, near-infrared spectroscopy, and a treadmill test. There will be a follow-up visit to assess blood work after diroximel fumarate.

Conditions

Peripheral Artery Disease; Peripheral Vascular Diseases; Peripheral Arterial Disease; Peripheral Arterial Occlusive Disease

Outcome Measures

Primary Outcomes (4)

• Macrovascular Endothelial Function

  Macrovascular endothelial function will be measured non-invasively using the flow-mediated dilation (FMD) technique in the brachial and popliteal arteries using a Doppler ultrasound. These measures will be performed before and after vumerity or placebo on the first visit, and these measures will be performed before and after Vumerity or placebo on the second visit.

  Day 1: before and after intervention. Day 7: before and after intervention.

• Oxygen Transfer and Utilization

  Oxygen transfer and utilization will be measured as the near-infrared spectroscopy (NIRS) reoxygenation rate in the medial gastrocnemius after an arterial occlusion. These measures will be performed before and after Vumerity or placebo on the first visit, and these measures will be performed before and after Vumerity or placebo on the second visit.

  Day 1: before and after intervention. Day 7: before and after intervention.

• Femoral and Popliteal Artery Blood Flow

  Femoral and popliteal artery blood flow will be measured in both legs using Doppler ultrasound. These measures will be performed before and after Vumerity or placebo on the first visit, and these measures will be performed before and after Vumerity or placebo on the second visit.

  Day 1: before and after intervention. Day 7: before and after intervention.

• Walking capacity

  Physical walking capacity will be measured during the Gardner treadmill protocol. Participants will walk on a treadmill at 2.0 miles per hour (mph). Grade will began at zero and will be increased by two percent every two minutes. Participants unable to walk at least 2.0 mph begin walking at 0.5 mph and their speed is increased by 0.50 mph every two minutes until the participant reaches 2.0 mph. After reaching 2.0 mph, treadmill grade is increased by two percent every two minutes. Participants are asked to continue walking without stopping until they cannot continue because of leg symptoms, exhaustion, or other symptoms. These measures will be performed before and after Vumerity or placebo on the first visit, and these measures will be performed before and after Vumerity or placebo on the second visit.

  Day 1: before and after intervention. Day 7: before and after intervention.

Secondary Outcomes (1)

• Circulating blood markers of Oxidative Stress and Antioxidants

  Day 1: before and after intervention. Day 7: before and after intervention.

Study Arms (4)

Control: Vumerity intake, then Placebo

EXPERIMENTAL

Participants will receive a single dose of VUMERITY (diroximal fumarate, 462mg). After a minimum period of 7 days, they will then receive a single dose of the placebo (microcrystalline cellulose, 462 mg).

Drug: Vumerity; Other: Placebo

Control: Placebo intake, then Vumerity

PLACEBO COMPARATOR

Participants will receive a single dose of placebo (microcrystalline cellulose, 462 mg). After a minimum period of 7 days, they will then receive a single dose of VUMERITY (diroximal fumarate, 462mg).

Drug: Vumerity; Other: Placebo

PAD: Vumerity intake, then Placebo

EXPERIMENTAL

Participants with peripheral artery disease (PAD) will receive a single dose of VUMERITY (diroximal fumarate, 462mg). After a minimum period of 7 days, they will then receive a single dose of the placebo (microcrystalline cellulose, 462 mg).

Drug: Vumerity; Other: Placebo

PAD: Placebo intake, then Vumerity

PLACEBO COMPARATOR

Participants with peripheral artery disease (PAD) will receive a single dose of placebo (microcrystalline cellulose, 462 mg). After a minimum period of 7 days, they will then receive a single dose of VUMERITY (diroximal fumarate, 462mg).

Drug: Vumerity; Other: Placebo

Interventions

Vumerity DRUG

diroximal fumarate 462 mg (2 capsules)

Also known as: diroximal fumarate

Control: Placebo intake, then Vumerity; Control: Vumerity intake, then Placebo; PAD: Placebo intake, then Vumerity; PAD: Vumerity intake, then Placebo

Placebo OTHER

Microcrystalline cellulose 462 mg (2 capsules)

Control: Placebo intake, then Vumerity; Control: Vumerity intake, then Placebo; PAD: Placebo intake, then Vumerity; PAD: Vumerity intake, then Placebo

Eligibility Criteria

• Age: 50 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Peripheral artery disease (PAD) participants:
• Able to provide written informed consent
• years of age
• Diagnosed as Fontaine stage II-III
• History of exercise-induced claudication
• Females must be postmenopausal (cessation of menses for \> 24 months)
• Normal renal function (serum creatinine-estimated glomerular filtration rate \>= 60 mL/min) or evidence of stable renal function within the last 6 months
• Normal hepatic function (alanine transaminase \< 87.5 U/L, alkaline phosphatase \< 260 U/L, total bilirubin 1.8 mg/dL) or evidence of stable hepatic function within the last 6 months
• Complete blood count:
• Females: red blood cell 4-5 trillion cells/L, hemoglobin 12-15 g/dL, hematocrit 34-45%, white blood cell count 3-10 billion cells/L, platelet count 160-380 billion/L, and normal lymphocyte count \> 700 million lymphocytes/L, or evidence of stable blood counts within the last 6 months
• Males: red blood cell 4-6 trillion cells/L, hemoglobin 13-17 g/dL, hematocrit 38-49%, white blood cell count 3-10 billion cells/L, platelet count 135-320 billion/L, and normal lymphocyte count \> 700 million lymphocytes/L, or evidence of stable blood counts within the last 6 months
• Age-matched control participants:
• Able to provide written informed consent
• years of age
• No evidence of peripheral occlusive disease (ankle-brachial index \> 0.90)

You may not qualify if:

• Peripheral artery disease (PAD) participants:
• Pain at rest and/or tissue loss due to PAD (Fontaine stage IV PAD)
• Acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma
• Limited walking capacity from conditions other than PAD
• No physical exam to assess exercise limitations in the past year
• Currently pregnant or nursing
• Blood work and medical history NOT demonstrating:
• Normal renal function (serum creatinine-estimated glomerular filtration rate \>\> 60 mL/min)
• Normal hepatic function (alanine transaminase 0-35 IU/L, alkaline phosphatase 30-120 IU/L, total bilirubin 2-17 micromoles/L),
• Diagnosis of multiple sclerosis or psoriasis
• Diagnosis of gastrointestinal disorders (e.g., moderate IBS, Crohn's disease, etc.
• Concomitant use of dimethyl fumarate
• Hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of VUMERITY
• Ulcers, gangrene, or necrosis of the foot (Fontaine stage IV PAD)
• Complete blood count NOT within ranges:

Sponsors & Collaborators

• University of Nebraska: lead

Study Sites (1)

University of Nebraska - Omaha

Omaha, Nebraska, 68182, United States

RECRUITING

Related Publications (15)

• Loffredo L, Marcoccia A, Pignatelli P, Andreozzi P, Borgia MC, Cangemi R, Chiarotti F, Violi F. Oxidative-stress-mediated arterial dysfunction in patients with peripheral arterial disease. Eur Heart J. 2007 Mar;28(5):608-12. doi: 10.1093/eurheartj/ehl533. Epub 2007 Feb 13.

  PMID: 17298965 BACKGROUND

• Segal SS, Jacobs TL. Role for endothelial cell conduction in ascending vasodilatation and exercise hyperaemia in hamster skeletal muscle. J Physiol. 2001 Nov 1;536(Pt 3):937-46. doi: 10.1111/j.1469-7793.2001.00937.x.

  PMID: 11691885 BACKGROUND

• Hamburg NM, Creager MA. Pathophysiology of Intermittent Claudication in Peripheral Artery Disease. Circ J. 2017 Feb 24;81(3):281-289. doi: 10.1253/circj.CJ-16-1286. Epub 2017 Jan 26.

  PMID: 28123169 BACKGROUND

• Pipinos II, Judge AR, Selsby JT, Zhu Z, Swanson SA, Nella AA, Dodd SL. The myopathy of peripheral arterial occlusive disease: Part 2. Oxidative stress, neuropathy, and shift in muscle fiber type. Vasc Endovascular Surg. 2008 Apr-May;42(2):101-12. doi: 10.1177/1538574408315995. Epub 2008 Apr 7.

  PMID: 18390972 BACKGROUND

• Pipinos II, Judge AR, Selsby JT, Zhu Z, Swanson SA, Nella AA, Dodd SL. The myopathy of peripheral arterial occlusive disease: part 1. Functional and histomorphological changes and evidence for mitochondrial dysfunction. Vasc Endovascular Surg. 2007 Dec-2008 Jan;41(6):481-9. doi: 10.1177/1538574407311106.

  PMID: 18166628 BACKGROUND

• Beckman JA, Duncan MS, Damrauer SM, Wells QS, Barnett JV, Wasserman DH, Bedimo RJ, Butt AA, Marconi VC, Sico JJ, Tindle HA, Bonaca MP, Aday AW, Freiberg MS. Microvascular Disease, Peripheral Artery Disease, and Amputation. Circulation. 2019 Aug 6;140(6):449-458. doi: 10.1161/CIRCULATIONAHA.119.040672. Epub 2019 Jul 8.

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• Kiani S, Aasen JG, Holbrook M, Khemka A, Sharmeen F, LeLeiko RM, Tabit CE, Farber A, Eberhardt RT, Gokce N, Vita JA, Hamburg NM. Peripheral artery disease is associated with severe impairment of vascular function. Vasc Med. 2013 Apr;18(2):72-8. doi: 10.1177/1358863X13480551. Epub 2013 Mar 18.

  PMID: 23509089 BACKGROUND

• Allan RB, Vun SV, Spark JI. A Comparison of Measures of Endothelial Function in Patients with Peripheral Arterial Disease and Age and Gender Matched Controls. Int J Vasc Med. 2016;2016:2969740. doi: 10.1155/2016/2969740. Epub 2016 Jan 31.

  PMID: 26942010 BACKGROUND

• Maldonado FJ, Miralles Jde H, Aguilar EM, Gonzalez AF, Garcia JR, Garcia FA. Relationship between noninvasively measured endothelial function and peripheral arterial disease. Angiology. 2009 Dec-2010 Jan;60(6):725-31. doi: 10.1177/0003319708327787. Epub 2008 Dec 2.

  PMID: 19054793 BACKGROUND

• Sanada H, Higashi Y, Goto C, Chayama K, Yoshizumi M, Sueda T. Vascular function in patients with lower extremity peripheral arterial disease: a comparison of functions in upper and lower extremities. Atherosclerosis. 2005 Jan;178(1):179-85. doi: 10.1016/j.atherosclerosis.2004.08.013.

  PMID: 15585216 BACKGROUND

• Park SY, Pekas EJ, Headid RJ 3rd, Son WM, Wooden TK, Song J, Layec G, Yadav SK, Mishra PK, Pipinos II. Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease. Am J Physiol Heart Circ Physiol. 2020 Aug 1;319(2):H456-H467. doi: 10.1152/ajpheart.00235.2020. Epub 2020 Jul 24.

  PMID: 32706261 BACKGROUND

• Pekas EJ, Wooden TK, Yadav SK, Park SY. Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease. Am J Physiol Regul Integr Comp Physiol. 2021 Aug 1;321(2):R162-R173. doi: 10.1152/ajpregu.00121.2021. Epub 2021 Jun 23.

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• DePaola N, Gimbrone MA Jr, Davies PF, Dewey CF Jr. Vascular endothelium responds to fluid shear stress gradients. Arterioscler Thromb. 1992 Nov;12(11):1254-7. doi: 10.1161/01.atv.12.11.1254.

  PMID: 1420084 BACKGROUND

• Jonasson E, Sejbaek T. Diroximel fumarate in the treatment of multiple sclerosis. Neurodegener Dis Manag. 2020 Oct;10(5):267-276. doi: 10.2217/nmt-2020-0025. Epub 2020 Jul 20.

  PMID: 32686599 BACKGROUND

• Naismith RT, Wolinsky JS, Wundes A, LaGanke C, Arnold DL, Obradovic D, Freedman MS, Gudesblatt M, Ziemssen T, Kandinov B, Bidollari I, Lopez-Bresnahan M, Nangia N, Rezendes D, Yang L, Chen H, Liu S, Hanna J, Miller C, Leigh-Pemberton R. Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study. Mult Scler. 2020 Nov;26(13):1729-1739. doi: 10.1177/1352458519881761. Epub 2019 Nov 4.

  PMID: 31680631 BACKGROUND

MeSH Terms

Conditions

Peripheral Arterial Disease; Peripheral Vascular Diseases; Peripheral Arterial Occlusive Disease 1

Interventions

diroximel fumarate

Condition Hierarchy (Ancestors)

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

Study Officials

• Song-Young Park, PhD

  University of Nebraska

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Song-Young Park, PhD

CONTACT

402-554-3374; song-youngpark@unomaha.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Double-blinded study
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: There will be a peripheral artery disease (PAD) group and an age-matched healthy control group. Within each of these groups will be a 1:1 randomized, crossover, double-blinded study.

Study Record Dates

• First Submitted: March 5, 2024
• First Posted: March 20, 2024
• Study Start: November 14, 2024
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: October 3, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)