Peripheral Arterial DiseasePhase 4NCT02842424
Ramipril Treatment of Claudication: Oxidative Damage and Muscle Fibrosis
A Phase 4 study testing Ramipril in people with Peripheral Arterial Disease, run by University of Nebraska at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Peripheral Arterial Disease
- What is being tested?
- Ramipril
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 70 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Feb 2016to Jun 2027
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- A positive history of chronic claudication,
- Exercise-limiting claudication established by history and direct observation during a screening walking test administered by the evaluating vascular surgeon,
- Arterial occlusive disease per ankle Brachial index measurements and/or other imaging modalities,
- Stable blood pressure regimen, stable lipid regimen, stable diabetes regimen and risk factor control for 6 weeks.
Who cannot join
- Rest pain or tissue loss due to PAD (Fontaine stage III and IV),
- acute lower extremity ischemic event secondary to thromboembolic disease or acute trauma,
- Walking capacity significantly limited by conditions other than claudication including leg (joint/musculoskeletal, neurologic) and systemic (heart, lung disease) pathology,
- Current use of either ACE inhibitors or angiotensin II receptor blockers,
- Chronic kidney disease with estimated Glomerular Filtration Rate < 30 ml/min/1.73 m2,
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
VA Medical Center
Omaha, Nebraska, 68105
Holly DeSpiegelaere, 402-995-4171, Holly.DeSpiegelaere@va.gov
About this study
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.
Read the 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.
- Conditions
- Peripheral Arterial Disease
- Being tested
- Ramipril
- Keywords
- Ramipril, Angiotensin-converting enzyme, Claudication, Myopathy, Peripheral Arterial Disease
- Medical subject headings
- Peripheral Arterial Disease, Intermittent Claudication, Muscular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RamiprilDrug
Also called Altace
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.
| Study group | Role | What they receive |
|---|---|---|
| Ramipril Treatment | Experimental | 6 months treatment with the medication Ramipril Receives: Drug: Ramipril |
What is being measured
The primary outcome is the main question the study is designed to answer.
Absolute Claudication Distance
Maximum walking distance in meters per Gardner protocol
Measured: 6 months
Secondary outcomes (23)
6-minute Walking Distance
Maximum Distance in meters the patient can walk in 6 minutes on a flat, hard surface
Measured: 6 months
Initial Claudication Distance
The distance in meters the patient can walk before he experiences claudication pain, per Gardner protocol
Measured: 6 months
Average Daily Steps Taken
Monitored with an accelerometer at home
Measured: 6 months
Quality of life measured by the Walking Impairment Questionnaire
There are 14 questions across three categories of walking distance, walking speed and stair climbing. The WIQ is graded on a scale of 0-4; 0 represents no difficulty; 4 represents inability to walk. 0 score represents no difficulty, 1 score is slight difficulty, 2 score is some difficulty, 3 score is much difficulty, 4 score is unable to complete the task in question.
Measured: 6 months
Quality of life measured by the Medical Outcomes Study Short Form 36 Healthy Survey
- (The Short Form 36 Health Survey Questionnaire) has 8 scale (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health) that measures quality of life. The SF-36 scoring ranges from 0-100. Higher scores indicate better health; lower scores indicate more disability
Measured: 6 months
Leg biomechanics measured as Vertical ground reaction force
measured as Vertical ground reaction force
Measured: 6 months
Leg hemodynamics measured as Ankle Brachial Index (ABI)
Ratio of the blood pressure at the level of the ankle to the blood pressure at the level of the arm
Measured: 6 months
Leg hemodynamics
measured as Calf blood flow via contrast-enhanced ultrasound
Measured: 6 months
Leg hemodynamics measured as Calf blood flow via stress ABI testing
measured as Calf blood flow via stress ABI testing
Measured: 6 months
Leg hemodynamics measured as Calf muscle hemoglobin oxygen saturation
Measured with Near Infrared Spectroscopy
Measured: 6 months
Myofiber Mitochondrial Respiration, measured by polarography
measured by polarography
Measured: 6 months
Muscle Mitochondrial Function, measured by spectrophotometry
measured by spectrophotometry
Measured: 6 months
Myofiber Oxidative Damage
Myofiber content of HNE adducts and protein carbonyls
Measured: 6 months
Myofiber Morphology, Cross-Sectional Area
Area in square microns, measured by immunofluorescence microscopy
Measured: 6 months
Myofiber Morphology, Roundness
Measured as ratio of major axis in microns to minor axis in microns
Measured: 6 months
Myofiber Morphology, Solidity
Measured as the ratio of myofiber area in square microns to the area of a fitted convex hull in square microns
Measured: 6 months
Muscle Fibrosis, Muscle TGF-β1
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.
Measured: 6 months
Muscle Fibrosis, Total collagen deposited.
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.
Measured: 6 months
Microvascular Fibrosis, Capillary wall thickness.
Measured in microns by immunofluorescence microscopy of vessels labeled for collagen.
Measured: 6 months
Capillary density.
Number of capillaries per unit area (in square microns) of the tissue sample analyzed.
Measured: 6 months
Serum biomarker of fibrosis, serum procollagen type I c-peptide in picograms of peptide per ml
serum procollagen type I c-peptide in picograms of peptide
Measured: 6 months
Serum biomarker of fibrosis, serum procollagen type III n-terminal peptide in picograms of peptide per ml
serum procollagen type III n-terminal peptide in picograms of peptide per ml
Measured: 6 months
Plasma biomarker of fibrosis, plasma TGF-β1 in picograms per ml
plasma TGF-β1 in picograms per ml
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jul 2016 (estimated)
- Study start25 Feb 2016
- Primary completionJun 2027 (estimated)
- Study completionJun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Peripheral Arterial DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 70 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Nebraska
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Iraklis I Pipinos, MD, Principal investigator, University of NebraskaGeorge P Casale, PhD, Principal investigator, University of Nebraska
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02842424
- Sponsor's protocol ID
- 0139-16-ET
- Other IDs
- 00991
- Status last verified
- May 2025
- First submitted
- 17 Jun 2016
- Last updated
- 23 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No