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

0419-23-FB

Purpose: 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. Eligibility: Individuals with PAD will be deemed eligible for this study if they 1) are 50-75 years old and postmenopausal, 2) have a positive history of exercise-limiting claudication (Fontaine II or III), 3) do not have renal impairments, 4) do not have Fontaine stage IV PAD, and 5) are not currently pregnant or nursing. Age-matched controls will be deemed eligible for this study if they 1) are 50-75 years old and postmenopausal, 2) have an ABI greater than 0.9 (no PAD), 3) do not have exercise-limiting diseases or injuries, 4) do not have renal impairments, and 5) are not currently pregnant or nursing. Intervention and Evaluation: 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. Follow-up: There will be a follow-up visit to assess blood work after diroximel fumarate.

2024-08-01

2025-08-01

2025-08-01

Not yet recruiting

Early phase I

20

Inclusion Criteria: At entry into the study, peripheral artery disease (PAD) subjects must: 1. be able to provide written informed consent 2. be between the ages of 50-75 3. be diagnosed as Fontaine stage II-III 4. women must be postmenopausal (cessation of menses for \> 24 mo) 5. demonstrate a history of exercise-induced claudication 6. must not have ulcers, gangrene, or necrosis of the foot (Fontaine stage IV PAD) 7. blood work and medical history 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), complete blood count indicating: red blood cell (Males: 4-6 trillion cells/L, Females: 4-5 trillion cells/L), hemoglobin (Males: 13-17 g/dL, Females: 12-15 g/dL), hematocrit (Males: 38-49%, Females: 34-45%), white blood cell count (Males \& Females: 3-10 billion cells/L), and platelet count (Males: 135-320 billion/L, Females: 160-380 billion/L), and normal lymphocyte count (1-4.8 billion lymphocytes/L) (this is the most important parameter as the drug can cause lymphopenia, albeit not with a single dose). no diagnosis of multiple sclerosis or psoriasis no diagnosis of gastrointestinal disorders (e.g., moderate IBS, Crohn's disease, etc.) no concomitant use of dimethyl fumarate no indication of hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of VUMERITY. At entry into the study, age-matched control subjects must: 1. be able to provide written informed consent 2. be between the ages of 50-75 3. have no evidence of peripheral occlusive disease (ankle-brachial index \> 0.90) 4. women must be postmenopausal (cessation of menses for \> 24 mo) 5. blood work and medical history 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), complete blood count indicating: red blood cell (Males: 4-6 trillion cells/L, Females: 4-5 trillion cells/L), hemoglobin (Males: 13-17 g/dL, Females: 12-15 g/dL), hematocrit (Males: 38-49%, Females: 34-45%), white blood cell count (Males \& Females: 3-10 billion cells/L), and platelet count (Males: 135-320 billion/L, Females: 160-380 billion/L), and normal lymphocyte count (1-4.8 billion lymphocytes/L) (this is the most important parameter as the drug can cause lymphopenia, albeit not with a single dose). no diagnosis of multiple sclerosis or psoriasis no diagnosis of gastrointestinal disorders (e.g., moderate IBS, Crohn's disease, etc.) no concomitant use of dimethyl fumarate no indication of hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of VUMERITY. Exclusion Criteria: Potential subjects with PAD will be deemed ineligible if they: 1. have pain at rest and/or tissue loss due to PAD (Fontaine stage IV PAD) 2. have an acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma 3. have limited walking capacity due to conditions other than PAD 4. have not had a physical exam to assess exercise limitations in the past year. 5. are currently pregnant or nursing 6. 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), complete blood count indicating: red blood cell (Males: 4-6 trillion cells/L, Females: 4-5 trillion cells/L), hemoglobin (Males: 13-17 g/dL, Females: 12-15 g/dL), hematocrit (Males: 38-49%, Females: 34-45%), white blood cell count (Males \& Females: 3-10 billion cells/L), and platelet count (Males: 135-320 billion/L, Females: 160-380 billion/L), and normal lymphocyte count (1-4.8 billion lymphocytes/L) (this is the most important parameter as the drug can cause lymphopenia, albeit not with a single dose). no diagnosis of multiple sclerosis or psoriasis no diagnosis of gastrointestinal disorders (e.g., moderate IBS, Chrohns disease, etc.) no concomitant use of dimethyl fumarate no indication of hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of VUMERITY. Potential age-matched control subjects will be deemed ineligible if they: 1. have a positive diagnosis of PAD 2. have any exercise limitations as determined by a doctor at their last physical exam (at or before 1 year prior to the study) 3. have not had a physical exam to assess exercise limitations in the past year. 4. have limited walking capacity from musculoskeletal injury 5. are currently pregnant or nursing 6. 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), complete blood count indicating: red blood cell (Males: 4-6 trillion cells/L, Females: 4-5 trillion cells/L), hemoglobin (Males: 13-17 g/dL, Females: 12-15 g/dL), hematocrit (Males: 38-49%, Females: 34-45%), white blood cell count (Males \& Females: 3-10 billion cells/L), and platelet count (Males: 135-320 billion/L, Females: 160-380 billion/L), and normal lymphocyte count (1-4.8 billion lymphocytes/L) (this is the most important parameter as the drug can cause lymphopenia, albeit not with a single dose). no diagnosis of multiple sclerosis or psoriasis no diagnosis of gastrointestinal disorders (e.g., moderate IBS, Chrohns disease, etc.) no concomitant use of dimethyl fumarate no indication of hypersensitivity to diroximel fumarate, dimethyl fumarate, or to any of the excipients of VUMERITY.

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2024-05-02