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Use of Entresto Sacubitril/Valsartan for the Treatment of Peripheral Arterial Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02636283
Recruitment Status : Terminated (Recruitment)
First Posted : December 21, 2015
Results First Posted : December 17, 2019
Last Update Posted : December 17, 2019
American Heart Association
Information provided by (Responsible Party):
University of Minnesota

Brief Summary:
This study proposes the use of Entresto (sacubitril/valsartan) to test the effects on pain free walking duration on patients with peripheral arterial disease, a condition caused by decreased blood flow to the muscles in the legs.

Condition or disease Intervention/treatment Phase
Peripheral Arterial Disease Drug: Entresto Drug: Placebo group Phase 2

Detailed Description:

Current approaches for the treatment of peripheral arterial disease (PAD) lack the success observed in the treatment of other forms of vascular diseases. A potential reason for this may be that available treatments do not target the pathological mechanisms implicated in the development of PAD. These mechanisms include obstruction of aortic-iliac arteries and its branches due to the formation of atherosclerotic plaques and mitochondrial and microvascular dysfunction. Although blood flow improves following surgical revascularization, pain free and maximal walking duration does not improve to the same degree. This suggests that in addition to blood flow obstruction, mitochondrial and microvascular dysfunction are significant factors implicated in the development of PAD.

Therefore, any treatment designed for patients with PAD should be aimed at improving mitochondrial and microvascular function. In this regard, natriuretic peptides (NP) have been shown to increase mitochondrial and microvascular density and these two findings have been associated with increases in oxygen consumption and perfusion of skeletal muscles.

The Investigator proposes that an increase in endogenous natriuretic peptides by inhibiting the enzyme that degrades it in blood will increase mitochondrial and microvascular function and this will be associated with an increase in maximal and pain free walking duration. To test this hypothesis the investigators have designed a double blind randomized controlled clinical trial providing sacubitril/valsartan for 12 weeks trial period.The improvements in mitochondrial and microvascular function will be measured using magnetic resonance (MR) spectroscopy and functional MR imaging and an exercise stress test will be used to assess maximal and pain free walking duration. This trial will provide patients with PAD with a non-surgical, cause-specific treatment option.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Use of Entresto (Sacubitril/Valsartan) for the Treatment of Peripheral Arterial Disease
Actual Study Start Date : December 31, 2017
Actual Primary Completion Date : November 1, 2018
Actual Study Completion Date : November 1, 2018

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Active Comparator: Entresto
oral route
Drug: Entresto
Oral pills

Placebo Comparator: Placebo group
Oral placebo
Drug: Placebo group
The placebo pills

Primary Outcome Measures :
  1. Treadmill Walk Until Pain Initiated in Minutes [ Time Frame: 12 weeks ]
    Time in minutes on a standardized treadmill test to initiation of pain and time until pain requires patient to stop walking

Secondary Outcome Measures :
  1. Mitochondrial and Microvascular Function Arterial Elasticity [ Time Frame: 12 weeks ]
    Post-contraction measures of mitochondrial and microvascular function using MR spectroscopy and functional MRI

  2. Insulin Sensitivity [ Time Frame: 12 weeks ]
    Using Homeostasis Model Assessment (HOMA) index

  3. Arterial Elasticity [ Time Frame: 12 weeks ]
    Pulse wave pressure analysis

  4. Quality of Life Questionnaires [ Time Frame: 12 weeks ]
    Questionnaires describing independent living and quality of life

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Subject with symptoms of intermittent claudication, such as exercise-induced pain, cramps, fatigue, or other equivalent discomfort, involving large muscle groups of the leg(s) (calf, thigh, buttocks), relieved by rest.
  2. Ankle-brachial index ≤ 0.90 acquired according to the American Heart Association guidelines.
  3. Highest ankle pressure reduced by at least 25 mm Hg after exercise compared to resting pressure (or loss of previously present Doppler signal for both the posterior tibial and anterior tibial arteries immediately after exercise if arteries were incompressible).
  4. Patients on medical treatment for PAD without significant improvement in intermittent claudication within the last 6 months.

Exclusion Criteria:

  1. Age < 18 and > 80 years.
  2. Patients with physician diagnosed chronic kidney disease or heart failure stage II or IV or unstable angina.
  3. Echocardiographic evidence of cardiomyopathies and pulmonary hypertension.
  4. Patients that have received cancer treatment within the last year (except skin cancer).
  5. Severe limitations in mobility due to osteomuscular disorders present at time of interview.
  6. Dementia or other mental disorders that prevent patients from following a research protocol present at time of interview
  7. Patients engaged in an exercise rehabilitation program within the past 6 months.
  8. Patients schedule to undergo an arterial revascularization procedure during the study or have undergone one within the past 6 months.
  9. Inconsistent maximal walking distance on the treadmill test.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02636283

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United States, Minnesota
University of Minnesota Medical Center
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
University of Minnesota
American Heart Association
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Principal Investigator: Otto A Sanchez, M.D., Ph.D. University of Minnesota
  Study Documents (Full-Text)

Documents provided by University of Minnesota:
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Responsible Party: University of Minnesota Identifier: NCT02636283    
Other Study ID Numbers: 15SDG25360025
First Posted: December 21, 2015    Key Record Dates
Results First Posted: December 17, 2019
Last Update Posted: December 17, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Peripheral Arterial Disease
Peripheral Vascular Diseases
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Sacubitril and valsartan sodium hydrate drug combination
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action