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

• Sponsor: University of Minnesota (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02636283
• Collaborator: American Heart Association (Other)
• Enrollment: 6
• Location: 1
• Arms: 2
• Actual Duration (Months): 10
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Dec 31, 2017
• Actual Primary Completion Date: Nov 1, 2018
• Actual Study Completion Date: Nov 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Entresto oral route	Drug: Entresto; Oral pills
Placebo Comparator: Placebo group Oral placebo	Drug: Placebo group; The placebo pills

Outcome Measures

Primary Outcome Measures

1. Treadmill Walk Until Pain Initiated in Minutes [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 [12 weeks]

   Post-contraction measures of mitochondrial and microvascular function using MR spectroscopy and functional MRI

2. Insulin Sensitivity [12 weeks]

   Using Homeostasis Model Assessment (HOMA) index

3. Arterial Elasticity [12 weeks]

   Pulse wave pressure analysis

4. Quality of Life Questionnaires [12 weeks]

   Questionnaires describing independent living and quality of life

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Minnesota Medical Center	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• University of Minnesota
• American Heart Association

Investigators

• Principal Investigator: Otto A Sanchez, M.D., Ph.D., University of Minnesota

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 21, 2017

More Information

Publications

None provided.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT02636283
• Other Study ID Numbers: 15SDG25360025
• First Posted: Dec 21, 2015
• Last Update Posted: Dec 17, 2019
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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: Peripheral Arterial Disease; Peripheral Vascular Diseases; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Arm/Group Title	Entresto	Placebo Group
Arm/Group Description	oral route Entresto: Oral pills	Oral placebo Placebo group: The placebo pills
Period Title: Overall Study
STARTED	3	3
COMPLETED	1	0
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Entresto	Placebo Group	Total
Arm/Group Description	oral route Entresto: Oral pills	Oral placebo Placebo group: The placebo pills	Total of all reporting groups
Overall Participants	3	3	6
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	2 66.7%	5 83.3%
>=65 years	0 0%	1 33.3%	1 16.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.7 (4.16)	62.7 (3.06)	61.7 (3.45)
Sex: Female, Male (Count of Participants)
Female	1 33.3%	2 66.7%	3 50%
Male	2 66.7%	1 33.3%	3 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	00 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 33.3%	1 16.7%
White	3 100%	2 66.7%	5 83.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%	3 100%	6 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Study terminated prematurely; outcome measure data was not collected.

Arm/Group Title	Entresto	Placebo Group
Arm/Group Description	oral route Entresto: Oral pills	Oral placebo Placebo group: The placebo pills
Measure Participants	0	0

2. Secondary Outcome

Title	Mitochondrial and Microvascular Function Arterial Elasticity
Description	Post-contraction measures of mitochondrial and microvascular function using MR spectroscopy and functional MRI
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Study terminated prematurely; outcome measure data was not collected.

Arm/Group Title	Entresto	Placebo Group
Arm/Group Description	oral route Entresto: Oral pills	Oral placebo Placebo group: The placebo pills
Measure Participants	0	0

3. Secondary Outcome

Title	Insulin Sensitivity
Description	Using Homeostasis Model Assessment (HOMA) index
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Study terminated prematurely; outcome measure data was not collected.

Arm/Group Title	Entresto	Placebo Group
Arm/Group Description	oral route Entresto: Oral pills	Oral placebo Placebo group: The placebo pills
Measure Participants	0	0

4. Secondary Outcome

Title	Arterial Elasticity
Description	Pulse wave pressure analysis
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Study terminated prematurely; outcome measure data was not collected.

Arm/Group Title	Entresto	Placebo Group
Arm/Group Description	oral route Entresto: Oral pills	Oral placebo Placebo group: The placebo pills
Measure Participants	0	0

5. Secondary Outcome

Title	Quality of Life Questionnaires
Description	Questionnaires describing independent living and quality of life
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Study terminated prematurely; outcome measure data was not collected.

Arm/Group Title	Entresto	Placebo Group
Arm/Group Description	oral route Entresto: Oral pills	Oral placebo Placebo group: The placebo pills
Measure Participants	0	0

Adverse Events

Time Frame	12 weeks
Arm/Group Title	Entresto		Placebo Group
Arm/Group Description	oral route Entresto: Oral pills		Oral placebo Placebo group: The placebo pills
All Cause Mortality
	Entresto		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)
Serious Adverse Events
	Entresto		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Entresto		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		0/3 (0%)
Cardiac disorders
Hypotension	1/3 (33.3%)	1	0/3 (0%)	0
General disorders
Chest Discomfort	1/3 (33.3%)	1	0/3 (0%)	0
Pain	1/3 (33.3%)	1	0/3 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/3 (33.3%)	1	0/3 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.