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

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

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.

Study Overview

• Status: Terminated
• Conditions: Peripheral Arterial Disease
• Intervention / Treatment: Drug: Entresto; Drug: Placebo group

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Entresto; oral route	Drug: Entresto; Oral pills
PLACEBO_COMPARATOR: Placebo group; Oral placebo	Drug: Placebo group; The placebo pills

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treadmill Walk Until Pain Initiated in Minutes	Time in minutes on a standardized treadmill test to initiation of pain and time until pain requires patient to stop walking	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mitochondrial and Microvascular Function Arterial Elasticity	Post-contraction measures of mitochondrial and microvascular function using MR spectroscopy and functional MRI	12 weeks
Insulin Sensitivity	Using Homeostasis Model Assessment (HOMA) index	12 weeks
Arterial Elasticity	Pulse wave pressure analysis	12 weeks
Quality of Life Questionnaires	Questionnaires describing independent living and quality of life	12 weeks

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: American Heart Association
• Investigators: Principal Investigator: Otto A Sanchez, M.D., Ph.D., University of Minnesota

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 31, 2017
• Primary Completion (ACTUAL): November 1, 2018
• Study Completion (ACTUAL): November 1, 2018

Study Registration Dates

• First Submitted: October 29, 2015
• First Submitted That Met QC Criteria: December 18, 2015
• First Posted (ESTIMATE): December 21, 2015

Study Record Updates

• Last Update Posted (ACTUAL): December 17, 2019
• Last Update Submitted That Met QC Criteria: December 5, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Arterial Disease; Peripheral Vascular Diseases; Molecular Mechanisms of Pharmacological Action; Angiotensin Receptor Antagonists; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: 15SDG25360025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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