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NCT06319339 | NOT YET RECRUITING | Peripheral Artery Disease

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

University of Nebraska

Brief Summary:

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.

Condition or disease

Peripheral Artery Disease

Peripheral Vascular Diseases

Peripheral Arterial Disease

Peripheral Arterial Occlusive Disease

Intervention/treatment

Vumerity

Placebo

Phase

EARLY_PHASE1

Detailed Description:

Peripheral artery disease (PAD), which affects an estimated 200 million individuals worldwide, is characterized by the development of atherosclerotic plaques in the conduit arteries of the back and legs, and leads to exercise-limiting ischemic muscle pain, soft tissue ulcers, gangrene, and ultimately amputation. The pathophysiology of PAD is multifaceted and includes macro-vascular dysfunction, micro-vascular dysfunction, and muscle myopathy. A popular hypothesis for the tissue damage that occurs after conduit artery stenosis is the ischemia-reperfusion hypothesis. Under this hypothesis, intermittent periods of ischemia and hypoxia, followed by rapid oxygen reperfusion, ultimately leads to the production of excessive reactive oxygen species (ROS) in the ischemic tissues, and the intermittent elevations in ROS may exacerbate the degradation of mitochondrial function. Damage to mitochondria may then lead to greater ROS production, thereby creating a vicious cycle of oxidative stress damage and subsequent damage to muscles and blood vessels distal to a stenosis. In alignment with this hypothesis, it has been demonstrated that those with PAD have impaired blood vessel function, demonstrated by low endothelial reactivity. Furthermore, it seems that the reduced vascular reactivity in those with PAD may be partially caused by elevated ROS production, since the introduction of mitochondrial targeted antioxidants and free nitrates can improve vascular reactivity in those with PAD. Reduced endothelial reactivity may have deleterious effects for those with PAD during walking, since the endothelium dilates the arteries when shear increases at the onset of exercise, thereby highlighting a potential mechanism that may exacerbate exercise-induced ischemia. Interestingly, improvements in vascular reactivity mediated by mitochondrial derived antioxidants and free nitrates are paralleled by improvements in walking performance. This highlights the potential importance of ROS management in the treatment of those with PAD and may indicate an effective pharmacological target to improve vascular health and functional capacity in those with PAD. A potentially effective pharmacological target for oxidative stress management in those with PAD may be the nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) complex because NRF2 is directly involved in the cellular response to oxidative stress. Keap1 promotes the ubiquitination and destruction of intracellular NRF2, which keeps the concentration of NRF2 low in the cytosol under normal conditions. However, molecules that react with Keap1, such as reactive oxygen species, impede Keap1s ability to prevent NRF2 from accumulating. When NRF2 accumulates, it is translocated into the cell nucleus and acts as a transcription factor for several cellular antioxidants, which bind to molecules that cause oxidative stress, thereby reducing cellular oxidative damage. Therefore, substances that target the Keap1-NRF2 complex may be useful for reducing oxidative stress in those with PAD. Of note, diroximel fumarate is a compound that directly interacts with the Keap1-NRF2 complex by its derivative monomethyl fumarate, and diroximel fumarate has been shown to reduce inflammation via this mechanism in those with multiple sclerosis. Therefore, the investigators postulate that diroximel fumarate may increase antioxidant capacity in those with PAD via the NRF2 mechanism, which may lead to improved endothelial function and walking capacity. However, there are currently no studies that have investigated the effects of acute diroximel fumarate intake on vascular function and walking capacity in individuals with PAD. Therefore, the investigators propose to test the hypothesis that acute exogenous diroximel fumarate intake will improve micro- and macro-vascular function, leg skeletal muscle mitochondrial function, and walking capacity in participants with PAD.

Study Type : INTERVENTIONAL
Estimated Enrollment : 20 participants
Masking : DOUBLE
Masking Description : Double-blinded study
Primary Purpose : TREATMENT
Official Title : Impact of Nrf2 Activation on Macrovascular Function, Microvascular Function, Leg Function, and Walking Capacity in Patients With Peripheral Artery Disease
Actual Study Start Date : 2024-12
Estimated Primary Completion Date : 2025-08
Estimated Study Completion Date : 2025-08

Information not available for Arms and Intervention/treatment

Ages Eligible for Study: 50 Years to 75 Years
Sexes Eligible for Study: ALL
Accepts Healthy Volunteers: 1
Criteria
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.
Impact of Nrf2 Activation on Macrovascular, Microvascular & Leg Function & Walking Capacity in Peripheral Artery Disease

Location Details

NCT06319339

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Locations

Not yet recruiting

United States, Nebraska

University of Nebraska - Omaha

Omaha, Nebraska, United States, 68182