Ramipril Treatment of Claudication

Overview

Peripheral artery disease (PAD) is a manifestation of atherosclerosis that produces progressive narrowing and occlusion of the arteries supplying the lower extremities. The most common clinical manifestation of PAD is claudication, i.e., a severe functional limitation identified as gait dysfunction and walking-induced leg muscle pain relieved by rest. The standard therapies for claudication include the medications cilostazol and pentoxifylline, supervised exercise therapy and operative revascularization. Recent data demonstrated that 24 weeks of treatment with the angiotensin-converting enzyme (ACE) inhibitor Ramipril produces improvements in the walking performance of patients with claudication that are higher than those of cilostazol and pentoxifylline and similar to those produced by supervised exercise therapy and operative revascularization. The mechanisms by which Ramipril therapy produces this impressive improvement in the functional capacity of claudicating patients remain unknown. The Investigators hypothesize that treatment of claudicating PAD patients with Ramipril will improve walking performance and quality of life by improving the myopathy of the gastrocnemius. Improved myopathy is a consequence of reduced oxidative damage, reduced TGF-β1 production by vascular smooth muscle cells and reduced collagen deposition in the affected gastrocnemius.

Full Title of Study: “Ramipril Treatment of Claudication: Oxidative Damage and Muscle Fibrosis”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 2020

Detailed Description

This is an interventional study of PAD patients that exhibit claudication. The purpose of this study is to determine the potential mechanisms by which Ramipril vastly improves the walking performance of these patients. The study will be achieved through these specific aims: Specific Aim #1: Test the hypothesis that Ramipril-mediated improvements of walking parameters among patients with PAD correlate with improvements in both the morphometrics and biochemistry of myofibers in the gastrocnemius of the impaired limb. Specific Aim #2: Test the hypothesis that Ramipril-mediated improvements of walking parameters in patients with PAD correlate with reduced fibrotic events in small vessels and microvasculature, in association with reduced generalized collagen deposition and improved tissue oxygenation, in the gastrocnemius of the impaired limb. Specific Aim #3: Using adult human arterial smooth muscle cells (AHASMC), in vitro, the Investigators will test the hypothesis that the ACE inhibitor Ramipril, which acts as an antagonist of Angiotensin II type 1 receptor (ART1) stimulation by reducing tissue Angiotensin II (Ang II), impedes a mechanism in which Ang II stimulation of ART1 and exposure to hypoxia enhance proliferation of AHASMC and their production of TGF-β1 and collagen, via stimulation of phosphoinositide-3-kinase signaling and suppression of phosphatase and tensin homologue, a master regulator of cell growth. If the above hypotheses are correct, Aims #1 and #2 will demonstrate for the first time that therapy with Ramipril improves the walking performance and quality of life of claudicating PAD patients by improving the myopathy in skeletal muscle of the ischemic lower limbs. The work in Aim #3 will determine the pathways by which hypoxia and Angiotensin II cooperate to induce myopathy in the ischemic muscle. Specific agents targeting these pathways could become new treatments for claudication and for the more advanced stages of PAD characterized by leg rest pain and gangrene.

Interventions

  • Drug: Ramipril
    • Ramipril therapy will start at 2.5mg/day for 1 week. Then 5mg/day for 1 week and will be increased to 10mg/day by the third week. The patients will stay on Ramipril 10mg/day for 22 weeks.

Arms, Groups and Cohorts

  • Experimental: Ramipril Treatment
    • 6 months treatment with the medication Ramipril

Clinical Trial Outcome Measures

Primary Measures

  • Absolute Claudication Distance
    • Time Frame: 6 months
    • Maximum walking distance in meters per Gardner protocol

Secondary Measures

  • 6-minute Walking Distance
    • Time Frame: 6 months
    • Maximum Distance in meters the patient can walk in 6 minutes on a flat, hard surface
  • Initial Claudication Distance
    • Time Frame: 6 months
    • The distance in meters the patient can walk before he experiences claudication pain, per Gardner protocol
  • Average Daily Steps Taken
    • Time Frame: 6 months
    • Monitored with an accelerometer at home
  • Quality of life measured by the Walking Impairment Questionnaire
    • Time Frame: 6 months
  • Quality of life measured by the Medical Outcomes Study Short Form 36 Healthy Survey
    • Time Frame: 6 months
  • Leg biomechanics measured as Vertical ground reaction force
    • Time Frame: 6 months
  • Leg hemodynamics measured as Ankle Brachial Index (ABI)
    • Time Frame: 6 months
    • Ratio of the blood pressure at the level of the ankle to the blood pressure at the level of the arm
  • Leg hemodynamics measured as Calf blood flow via contrast-enhanced ultrasound
    • Time Frame: 6 months
  • Leg hemodynamics measured as Calf blood flow via stress ABI testing
    • Time Frame: 6 months
  • Leg hemodynamics measured as Calf muscle hemoglobin oxygen saturation
    • Time Frame: 6 months
    • Measured with Near Infrared Spectroscopy
  • Myofiber Mitochondrial Respiration, measured by polarography
    • Time Frame: 6 months
  • Muscle Mitochondrial Function, measured by spectrophotometry
    • Time Frame: 6 months
  • Myofiber Oxidative Damage
    • Time Frame: 6 months
    • Myofiber content of HNE adducts and protein carbonyls
  • Myofiber Morphology, Cross-Sectional Area
    • Time Frame: 6 months
    • Area in square microns, measured by immunofluorescence microscopy
  • Myofiber Morphology, Roundness
    • Time Frame: 6 months
    • Measured as ratio of major axis in microns to minor axis in microns
  • Myofiber Morphology, Solidity
    • Time Frame: 6 months
    • Measured as the ratio of myofiber area in square microns to the area of a fitted convex hull in square microns
  • Muscle Fibrosis, Muscle TGF-β1
    • Time Frame: 6 months
    • Measured as the sum of the products of mean pixel intensity (in gray scale units) and area (in square microns) of each TGF-β1 labeled event divided by the total area (in square microns) of the tissue sample analyzed. Measured by immunofluorescence microscopy.
  • Muscle Fibrosis, Total collagen deposited.
    • Time Frame: 6 months
    • Measured as the area-weighted mean pixel intensity (in gray scale units) of all the collagen labeled events per tissue sample. Measured by bright-field microscopy.
  • Microvascular Fibrosis, Capillary wall thickness.
    • Time Frame: 6 months
    • Measured in microns by immunofluorescence microscopy of vessels labeled for collagen.
  • Capillary density.
    • Time Frame: 6 months
    • Number of capillaries per unit area (in square microns) of the tissue sample analyzed.
  • Serum biomarker of fibrosis, serum procollagen type I c-peptide in picograms of peptide per ml
    • Time Frame: 6 months
  • Serum biomarker of fibrosis, serum procollagen type III n-terminal peptide in picograms of peptide per ml
    • Time Frame: 6 months
  • Plasma biomarker of fibrosis, plasma TGF-β1 in picograms per ml
    • Time Frame: 6 months

Participating in This Clinical Trial

Inclusion Criteria

1. A positive history of chronic claudication, 2. Exercise-limiting claudication established by history and direct observation during a screening walking test administered by the evaluating vascular surgeon, 3. Arterial occlusive disease per ankle Brachial index measurements and/or other imaging modalities, 4. Stable blood pressure regimen, stable lipid regimen, stable diabetes regimen and risk factor control for 6 weeks. Exclusion Criteria:

1. Rest pain or tissue loss due to PAD (Fontaine stage III and IV), 2. acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma, 3. Walking capacity significantly limited by conditions other than claudication including leg (joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology, 4. Current use of either ACE inhibitors or angiotensin II receptor blockers, 5. Chronic kidney disease with estimated Glomerular Filtration Rate < 30 ml/min/1.73 m2, 6. History of bilateral severe renal artery stenosis and 7) History of angioedema related to previous ACE-inhibitor treatment or known hypersensitivity to ramipril or other ACE inhibitors.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 90 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Nebraska
  • Provider of Information About this Clinical Study
    • Principal Investigator: Iraklis I Pipinos, MD, Professor of Surgery – University of Nebraska
  • Overall Official(s)
    • Iraklis I Pipinos, MD, Principal Investigator, University of Nebraska
    • George P Casale, PhD, Principal Investigator, University of Nebraska
  • Overall Contact(s)
    • Holly DeSpiegelaere, 402-995-4171, Holly.DeSpiegelaere@va.gov

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