Clinical trial NCT02842424: Ramipril Treatment of Claudication: Oxidative Damage and Muscle Fibrosis
Official title: Ramipril Treatment of Claudication: Oxidative Damage and Muscle Fibrosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Peripheral Arterial Disease
Keywords: Ramipril
Angiotensin-converting enzyme
Claudication
Myopathy
Peripheral Arterial Disease
Lead sponsor: University of Nebraska
Sponsor class: OTHER
First posted: 2016-07-22
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Absolute Claudication Distance
timeFrame: 6 months
Secondary outcomes:
measure: 6-minute Walking Distance
timeFrame: 6 months
measure: Initial Claudication Distance
timeFrame: 6 months
measure: Average Daily Steps Taken
timeFrame: 6 months
measure: Quality of life measured by the Walking Impairment Questionnaire
timeFrame: 6 months
measure: Quality of life measured by the Medical Outcomes Study Short Form 36 Healthy Survey
timeFrame: 6 months
measure: Leg biomechanics measured as Vertical ground reaction force
timeFrame: 6 months
measure: Leg hemodynamics measured as Ankle Brachial Index (ABI)
timeFrame: 6 months
measure: Leg hemodynamics
timeFrame: 6 months
measure: Leg hemodynamics measured as Calf blood flow via stress ABI testing
timeFrame: 6 months
measure: Leg hemodynamics measured as Calf muscle hemoglobin oxygen saturation
timeFrame: 6 months
measure: Myofiber Mitochondrial Respiration, measured by polarography
timeFrame: 6 months
measure: Muscle Mitochondrial Function, measured by spectrophotometry
timeFrame: 6 months
measure: Myofiber Oxidative Damage
timeFrame: 6 months
measure: Myofiber Morphology, Cross-Sectional Area
timeFrame: 6 months
measure: Myofiber Morphology, Roundness
timeFrame: 6 months
measure: Myofiber Morphology, Solidity
timeFrame: 6 months
measure: Muscle Fibrosis, Muscle TGF-β1
timeFrame: 6 months
measure: Muscle Fibrosis, Total collagen deposited.
timeFrame: 6 months
measure: Microvascular Fibrosis, Capillary wall thickness.
timeFrame: 6 months
measure: Capillary density.
timeFrame: 6 months
measure: Serum biomarker of fibrosis, serum procollagen type I c-peptide in picograms of peptide per ml
timeFrame: 6 months
measure: Serum biomarker of fibrosis, serum procollagen type III n-terminal peptide in picograms of peptide per ml
timeFrame: 6 months
measure: Plasma biomarker of fibrosis, plasma TGF-β1 in picograms per ml
timeFrame: 6 months
Other outcomes:
Locations:
city: Omaha
country: United States
facility: VA Medical Center
state: Nebraska
Study officials:
affiliation: University of Nebraska
name: Iraklis I Pipinos, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Nebraska
name: George P Casale, PhD
role: PRINCIPAL_INVESTIGATOR
References: