PB125 + Exercise Rehabilitation for Peripheral Artery Disease
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: VA Office of Research and Development
Must not be taking: Hormone therapy
Disqualifiers: Bleeding disorders, Complex atherosclerosis, others
Trial Summary
What is the purpose of this trial?Physical activity is the most beneficial and cost-effective treatment for Veterans with PAD, however, issues with oxygen delivery and utilization dramatically impair exercise compliance. The cause of these oxygen delivery and utilization impairments is likely increased oxidative stress and inflammation. The proposed project will comprehensively examine the novel strategy of Nuclear Factor Erythroid-2-like 2 (Nrf2) activation using PB125, aimed at diminishing oxidative stress and inflammation, and thereby lessening the negative impacts of the disease. This therapeutic will be evaluated in isolation and in combination with exercise rehabilitation to determine if there is a complimentary benefit. The ultimate goal is to provide insight into a potential novel therapeutic treatment for this disease, therefore, improving exercise tolerance and quality of life in this growing population.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, if you have a complex atherosclerotic lesion, you may not be able to stop certain medications due to increased risk.
What data supports the effectiveness of the treatment PB125 + Exercise Rehabilitation for Peripheral Artery Disease?
Research shows that exercise rehabilitation can significantly improve walking ability in patients with peripheral artery disease (PAD), and dietary supplements that increase nitric oxide, especially antioxidants, can improve walking distances in PAD patients. This suggests that combining exercise with a supplement like PB125, which may have antioxidant properties, could be beneficial.
12345Is the combination of PB125 and exercise rehabilitation safe for humans?
Exercise rehabilitation is generally safe and can reduce inflammation and oxidative stress in patients with peripheral artery disease. While specific safety data for PB125 is not provided, exercise therapy has been shown to improve health outcomes without significant adverse effects.
16789How does the PB125 + Exercise Rehabilitation treatment for peripheral artery disease differ from other treatments?
The PB125 + Exercise Rehabilitation treatment is unique because it combines a specific Nrf2 activator (PB125) with exercise rehabilitation, potentially reducing oxidative stress and enhancing the benefits of exercise for improving walking ability in peripheral artery disease. This approach is different from traditional treatments that focus solely on exercise or pharmacological interventions without targeting oxidative stress.
210111213Eligibility Criteria
This trial is for Veterans aged 40+ with Peripheral Artery Disease (PAD), who understand the study and can consent, or have a caregiver to assist. It's open to women not pregnant or likely to become so within six months. Excluded are those with bleeding disorders, complex atherosclerotic lesions requiring medication, or on hormone replacement therapy.Inclusion Criteria
Patients with mild cognitive impairment (i.e., montreal cognitive assessment (MOCA) <26) will be included but must have a responsible caregiver or spouse present during the informed consent
Must understand the study requirements and be willing and able to sign an informed consent document
I am not pregnant, breastfeeding, nor planning to become pregnant soon.
+1 more
Exclusion Criteria
I have a serious blockage in my arteries that makes stopping my medication risky.
Any other condition or event considered exclusionary by the PI and faculty physician
I do not have a bleeding disorder that prevents muscle biopsy.
+1 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Baseline
Initial assessments of functional capacity, cognitive function, vascular function, and mitochondrial respiration
1 week
1 visit (in-person)
Supplement Loading
Participants receive PB125 or placebo supplementation
4 weeks
1 visit (in-person)
Exercise Rehabilitation
Participants undergo 12 weeks of exercise rehabilitation with continued supplementation
12 weeks
Monthly assessments (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial tests PB125, a drug aimed at reducing oxidative stress and inflammation in PAD patients. It will be evaluated alone and alongside exercise rehabilitation to see if they work better together. The goal is improving exercise tolerance and life quality by addressing oxygen delivery issues.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Exercise Rehabilitation+PB125Experimental Treatment2 Interventions
Participants will be assigned to the Exercise+Placebo or Exercise+PB125 rehabilitation interventions using block randomization.
Group II: Exercise Rehabilitation with PlaceboPlacebo Group2 Interventions
Participants will be assigned to the Exercise+Placebo rehabilitation interventions using block randomization.
Exercise Rehabilitation is already approved in United States for the following indications:
🇺🇸 Approved in United States as Exercise Rehabilitation for:
- Peripheral Artery Disease (PAD)
- Claudication
- Vascular Health Improvement
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Utah Dept of Vascular SurgerySalt Lake City, UT
VA Salt Lake City Health Care System, Salt Lake City, UTSalt Lake City, UT
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Who Is Running the Clinical Trial?
VA Office of Research and DevelopmentLead Sponsor
References
Effect of Dietary Supplements Which Upregulate Nitric Oxide on Walking and Quality of Life in Patients with Peripheral Artery Disease: A Meta-Analysis. [2023]This systematic review pooled evidence from randomised controlled trials (RCTs) on the effectiveness of dietary upregulators of nitric oxide (NO) in improving the walking and quality of life of patients with peripheral artery disease (PAD). RCTs examining the effect of dietary upregulators of NO in patients with PAD were included. The primary outcome was the maximum walking distance. Secondary outcomes were the initial claudication distance, the six-minute walking distance, quality of life, the ankle-brachial pressure index (ABI), adverse events and risk of mortality, revascularisation or amputation. Meta-analyses were performed using random effects models. The risk of bias was assessed using Cochrane's ROB-2 tool. Leave-one-out and subgroup analyses were conducted to assess the effect of individual studies, the risk of bias and intervention type on pooled estimates. Thirty-four RCTs involving 3472 participants were included. Seven trials tested NO donors, nineteen tested antioxidants, three tested NO synthase inducers and five tested enhancers of NO availability. Overall, the dietary supplements significantly improved the initial claudication (SMD 0.34; 95%CI 0.04, 0.64; p = 0.03) but not maximum walking (SMD 0.13; 95%CI -0.17, 0.43; p = 0.39) distances. Antioxidant supplements significantly increased both the maximum walking (SMD 0.36; 95%CI 0.14, 0.59; p = 0.001) and initial claudication (SMD 0.58; 95%CI 0.26, 0.90; p < 0.001) distances. The dietary interventions did not improve the physical function domain of the Short Form-36 (SMD -0.16; 95%CI -0.32, 0.00; p = 0.38), ABI or risk of adverse events, mortality, revascularisation or amputation. Dietary NO upregulators, especially antioxidants, appear to improve the initial claudication distance in patients with PAD. Larger high-quality RCTs are needed to fully examine the benefits and risks of these treatments. PROSPERO Registration: CRD42022256653.
Beet the Best? [2020]A primary goal of therapy for patients with peripheral artery disease (PAD) and intermittent claudication is increased ambulatory function. Supervised exercise rehabilitation was recently shown to confer superior walking benefits to pharmacological or surgical interventions. Increases in plasma inorganic nitrite, via oral nitrate, have been shown to increase exercise performance in both human and animal models, especially in hypoxic conditions.
Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. [2022]To identify the components of exercise rehabilitation programs that were most effective in improving claudication pain symptoms in patients with peripheral arterial disease.
Local and Systemic Inflammation and Oxidative Stress After a Single Bout of Maximal Walking in Patients With Symptomatic Peripheral Artery Disease. [2021]The aim of this study was to assess the effects of a single bout of maximal walking on blood and muscle nitric oxide (NO) bioavailability, oxidative stress, and inflammation in symptomatic peripheral artery disease (PAD) patients.
Peripheral artery disease, redox signaling, oxidative stress - Basic and clinical aspects. [2018]Reactive oxygen and nitrogen species (ROS and RNS, e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. At higher concentrations, ROS and RNS lead to oxidative stress and oxidative damage of biomolecules (e.g. via formation of peroxynitrite, fenton chemistry). Peripheral artery disease (PAD) is characterized by severe ischemic conditions in the periphery leading to intermittent claudication and critical limb ischemia (end stage). It is well known that redox biology and oxidative stress play an important role in this setting. We here discuss the major pathways of oxidative stress and redox signaling underlying the disease progression with special emphasis on the contribution of inflammatory processes. We also highlight therapeutic strategies comprising pharmacological (e.g. statins, angiotensin-converting enzyme inhibitors, phosphodiesterase inhibition) and non-pharmacological (e.g. exercise) interventions. Both of these strategies induce potent indirect antioxidant and anti-inflammatory mechanisms that may contribute to an improvement of PAD associated complications and disease progression by removing excess formation of ROS and RNS (e.g. by ameliorating primary complications such as hyperlipidemia and hypertension) as well as the normalization of the inflammatory phenotype suppressing the progression of atherosclerosis.
Vascular surgical society of great britain and ireland: angioplasty reverses the systemic effects of exercise in intermittent claudication [2019]BACKGROUND: The choice between exercise training and percutaneous transluminal angioplasty (PTA) in the treatment of intermittent claudication (IC) remains controversial. Exercise is known to induce systemic effects in claudicants. This study aimed to determine whether such systemic effects are reversed by PTA. METHODS: Ten patients with IC were recruited before PTA. Having emptied the bladder and rested for 1 h, pre-exercise blood and urine samples were collected. Patients underwent treadmill exercise to their maximum walking time and further blood samples were collected at 10, 20 and 30 min. A second urine sample was collected at 60 min. Total antioxidant capacity (TAC) and von Willebrand factor (vWF) were measured in blood, and albumin : creatinine ratio (ACR) and retinol binding protein : creatinine ratio (RBP : Cr) in urine. Patients were recalled 2 weeks after successful angioplasty and the protocol was repeated. Statistical analysis was by Wilcoxon signed rank test. RESULTS: Following PTA, all patients walked for 5 min on the treadmill. All patients had a significant exercise-induced fall in ankle pressure that was reversed by PTA. Changes in TAC are shown in the Table. There was no significant change in vWF. Exercise in claudicants induced a significant increase in median ACR (pre/post exercise (pre-exercise value divided by post-exercise value) 0.8; P = 0.03) and in median RBP : Cr (pre/post exercise 1.8; P = 0.04). These changes were no longer evident after successful PTA. CONCLUSION: Exercise-induced changes in renal glomerular (ACR) and tubular function (RBP : Cr) in claudicants were reversed by successful angioplasty. PTA reduced the systemic TAC before and after exercise suggesting a reduced free radical challenge.
Influence of Peripheral Transluminal Angioplasty Alongside Exercise Training on Oxidative Stress and Inflammation in Patients with Peripheral Arterial Disease. [2021]In patients with intermittent claudication, exercise training ameliorates inflammation by reducing oxidative stress. A total of 41 patients with intermittent claudication (Rutherford 3) were included in the study (with 21 patients treated by endovascular revascularization (ER), and 20 patients without ER). All patients were referred to home-based exercise training. Absolute and initial claudication distance (ACD, ICD) and ABI (ankle-brachial index) were measured. ROS (reactive oxygen species) formation was measured using the luminol analogue L-012. Follow-up was performed after 3 months. ROS production after NOX2 (NAPDH oxidase 2) stimulation showed a significant reduction in both groups at follow-up (PTA group: p = 0.002, control group: p = 0.019), with a higher relative reduction in ROS in the PTA group than in the control group (p = 0.014). ABI measurements showed a significant increase in the PTA (peripheral transluminal angioplasty) group (p = 0.001), but not in the control group (p = 0.127). Comparing both groups at follow-up, ABI was higher in the PTA group (p = 0.047). Both groups showed a significant increas ACD and ICD at follow-up (PTA group: ACD: p = 0.001, ICD: p < 0.0001; control group: ACD: p = 0.041, ICD: p = 0.002). There was no significant difference between both groups at follow-up (ACD: p = 0.421, ICD: p = 0.839). Endovascular therapy in combination with exercise training leads to a lower leukocyte activation state with a reduced NOX2-derived ROS production paralleled by an improved ABI, ACD and ICD. Our data support the strategy to combine exercise training with preceding endovascular therapy.
Local Injections of Superoxide Dismutase Attenuate the Exercise Pressor Reflex in Rats with Femoral Artery Occlusion. [2020]The exercise pressor reflex is amplified in patients with peripheral artery disease (PAD) and in an experimental PAD model of rats induced by femoral artery occlusion. Heightened blood pressure worsens the restricted blood flow directed to the limbs in this disease. The purpose of this study was to determine the role played by muscle oxidative stress in regulating the augmented pressor response to static exercise in PAD. We hypothesized that limb ischemia impairs muscle superoxide dismutase (SOD) thereby leading to abnormal autonomic responsiveness observed in PAD animals, and a chronic compensation of SOD for anti-oxidation improves the exaggerated exercise pressor reflex. Our data show that femoral occlusion decreased the protein levels of SOD in ischemic muscle as compared with control muscle. Downregulation of SOD appeared to a greater degree in the oxidative (red) muscle than in the glycolytic (white) muscle under the condition of muscle ischemia. In addition, the exercise pressor response was assessed during electrically induced static contraction. The data demonstrates that the enhancement of the exercise pressor reflex was significantly attenuated after tempol (a mimetic of SOD, 30 mg over a period of 72 h) was administered into the occluded hindlimb. In the occluded rats, mean arterial pressure (MAP) response was 26 ± 3 mmHg with no tempol and 12 ± 2 mmHg with tempol application (P < 0.05 vs. group with no tempol; n = 6 in each group). There were no differences in muscle tension development (time-tension index: 12.1 ± 1.2 kgs with no tempol and 13.5 ± 1.1 kgs with tempol; P > 0.05 between groups). In conclusion, SOD is lessened in the ischemic muscles and supplement of SOD improves the amplified exercise pressor reflex, which is likely beneficial to the restricted blood flow to the limbs in PAD.
Physical Exercise Reduces Cytotoxicity and Up-Regulates Nrf2 and UPR Expression in Circulating Cells of Peripheral Artery Disease Patients: An Hypoxic Adaptation? [2021]Ischemia-reperfusion (I-R) produces reactive oxygen species (ROS) that damage cells and favour cytotoxicity and apoptosis in peripheral artery disease (PAD) patients. Since brief episodes of I-R (ischemic conditioning) protect cells against ischemic harms, we evaluated whether a short-course of supervised treadmill training, characterized by repeated episodes of I-R, makes peripheral blood mononuclear cells (PBMCs) from PAD patients with intermittent claudication more resistant to I-R injuries by reducing oxidative stress and by inducing an adaptative response of unfolded protein response (UPR) and nuclear factor-E2-related factor (Nrf2) pathway expression.
Effects of exercise rehabilitation on cardiovascular risk factors in older patients with peripheral arterial occlusive disease. [2013]The purpose of this study was to determine whether a 6-month exercise rehabilitation program can improve cardiovascular risk factors in patients with peripheral arterial occlusive disease (PAOD).
Effect of propionyl-L-carnitine on a background of monitored exercise in patients with claudication secondary to peripheral artery disease. [2015]Exercise training is established for the treatment of peripheral artery disease; however the additional benefit of pharmacologic therapy with exercise has not been studied. This trial tested the hypothesis that propionyl-L-carnitine (PLC), in combination with monitored home-based exercise training, would improve treadmill peak walking time (PWT) over exercise training alone.
Training rather than walking: the test in -train out program for home-based rehabilitation in peripheral arteriopathy. [2019]Exercise training reduces walking disability in peripheral arterial disease (PAD). This non-randomized study evaluates the effects on walking ability and hemodynamic parameters of a novel approach to home-based rehabilitation, the test in -train out program (Ti-To), compared with the traditional home-based free walking exercise (Tr-E).
RTA-dh404 decreased oxidative stress in mice ischemic limbs and augmented efficacy of therapeutic angiogenesis by intramuscular injection of adipose-derived regenerative cells in the limbs. [2022]Although an intramuscular injection of angiogenic cells to ischemic limbs with peripheral artery disease is a therapeutic option to rescue patients by augmenting neovascularization in the limbs, oxidative stress in the limbs may accelerate apoptosis of the injected cells and thereby reduce the therapeutic effect. In this study involving mice with ischemic lower limbs, whether daily oral administration of RTA-dh404, which is an activator of nuclear factor erythroid 2-related factor 2 (Nrf2) with antioxidant activity, could reduce oxidative stress in the limbs and suppress apoptosis of adipose-derived regenerative cells (ADRCs) injected in the limbs, eventually augmenting neovascularization in the limbs, was evaluated. The tissue expression of Nrf2 and concentrations of total antioxidant capacity and superoxide dismutase in the mice ischemic limbs were higher in the RTA-dh404-treated mice than in the control treated mice, and oxidative stress in the limbs of the RTA-dh404 treated mice was decreased. The day after an intramuscular injection of human ADRCs into ischemic lower limbs of immunodeficient mice, the number of apoptotic ADRCs in the ischemic limbs was decreased by approximately 25% in the RTA-dh404-treated mice compared to the control mice. Fourteen days after cell injection, neovascularization and the salvage ratio were increased by approximately 10% and 63%, respectively, in the ischemic limbs in the RTA-dh404-treated mice compared to the control mice. Pretreatment of ischemic limbs by daily oral administration of RTA-dh404 may augment the effect of therapeutic angiogenesis using an intramuscular injection of ADRCs into the ischemic limbs.