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Angiotensin-(1-7) in Peripheral Arterial Disease

Primary Purpose

Peripheral Arterial Disease

Status
Terminated
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Angiotensin 1-7
Saline
Sponsored by
Milton S. Hershey Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Peripheral Arterial Disease focused on measuring Renin-Angiotensin System, Inflammation, Cardiovascular, Atherosclerosis

Eligibility Criteria

21 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Sex: Male or Female
  • Age: 21-80 years of age
  • Diagnosed with PAD (e.g. ankle-brachial index below 0.9)
  • Fontaine stage II or less (no rest pain)
  • Capable of giving informed consent
  • Fluent in written and spoken English

Exclusion Criteria:

  • Age less than or equal to 20 years or greater than or equal to 81 years
  • Pregnant or nursing woman
  • Decisional impairment
  • Prisoners
  • Alcohol or drug abuse
  • Evidence of type I or type II diabetes (fasting glucose >126 mg/dl or use of anti-diabetic medications)
  • History of serious cardiovascular disease (e.g. myocardial infarction within 6 months, symptomatic coronary artery disease, presence of angina pectoris, significant arrhythmia, congestive heart failure, deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis, hypertrophic cardiomyopathy) or cerebrovascular disease (e.g. cerebral hemorrhage, stroke, transient ischemic attack).
  • History or presence of immunological or hematological disease
  • Impaired hepatic function [aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > 2 times the upper limit of normal range)
  • Impaired renal function (serum creatinine >2.0 mg/dl)
  • Anemia
  • Treatment with serotonin-norepinephrine reuptake inhibitors (SNRI) or norepinephrine transporter (NET) inhibitors
  • Treatment with phosphodiesterase-5 inhibitors
  • Treatment with anticoagulants
  • Treatment with chronic systemic glucocorticoid therapy (>7 consecutive days in 1 month)
  • Treatment with any investigational drug in the 1-month preceding the study
  • Inability to give, or withdraw, informed consent

Sites / Locations

  • Penn State Milton S. Hershey Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Angiotensin-(1-7)

Saline

Arm Description

Subjects will receive intravenous infusion of five ascending doses of angiotensin-(1-7). The doses are: 1, 2, 4, 8, and 12 ng/kg/min. Each dose will be maintained for 10 minutes, for a total infusion period of 50 minutes.

Subjects will receive intravenous infusion of saline that is matched in volume to the angiotensin-(1-7) arm. Saline infusion will be maintained for a total infusion period of 50 minutes.

Outcomes

Primary Outcome Measures

Leg Blood Flow
The change in measures of leg blood flow (e.g. femoral blood flow and conductance, calf muscle oxygen saturation) following angiotensin-(1-7) versus saline infusion.
Inflammatory Markers
The change in blood levels of inflammatory markers C-Reactive Protein and Interleukin-6 following angiotensin-(1-7) versus saline infusion.

Secondary Outcome Measures

Blood Pressure
The change in arm and finger cuff blood pressure following angiotensin-(1-7) versus saline infusion.
Heart Rate
The change in heart rate following angiotensin-(1-7) versus saline infusion.

Full Information

First Posted
August 2, 2017
Last Updated
August 31, 2023
Sponsor
Milton S. Hershey Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03240068
Brief Title
Angiotensin-(1-7) in Peripheral Arterial Disease
Official Title
Protective Effects of Angiotensin-(1-7) in Peripheral Arterial Disease
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Terminated
Why Stopped
Study funding ended prior to completion.
Study Start Date
September 1, 2017 (Actual)
Primary Completion Date
August 30, 2023 (Actual)
Study Completion Date
August 30, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Milton S. Hershey Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Peripheral arterial disease (PAD) affects over 8 million individuals in the United States alone. This is a form of atherosclerosis in which plaques preferentially build up inside the arteries of the legs to limit blood flow. These patients are at high risk for heart attack and stroke, with at least half dying from coronary artery disease. Our understanding of the causes of PAD remains incomplete. The renin-angiotensin hormone system is one mechanism known to contribute to atherosclerosis. Pharmacologic blockade of the hormone angiotensin II is beneficial in forms of atherosclerosis, including peripheral arterial disease, to improve blood vessel damage and functional outcomes. These therapies also increase circulating levels of angiotensin-(1-7), a hormone that dilates blood vessels. Angiotensin-(1-7) improves blood vessel function and reduces inflammation to protect against atherosclerosis in animal models; however, there are no clinical data in patients with atherosclerosis. The overall goal of this project is to examine the cardiovascular effects of angiotensin-(1-7) in PAD.
Detailed Description
This is a randomized, double blind, placebo-controlled, crossover study to determine if acute intravenous Ang-(1-7) infusion can reduce systemic inflammation and improve measures of leg blood flow in subjects with PAD. The investigators will also measure for changes in blood pressure and circulating hormones in response to angiotensin-(1-7) infusion. This is an outpatient study that will be conducted in the Clinical Research Center at the Penn State Milton S. Hershey Medical Center. Subjects with PAD will participate in a screening visit, and if eligible, in two separate study visits in which they will receive intravenous angiotensin-(1-7) or saline infusion. Each study visit will last approximately 4 hours, with at least one week of washout between study visits. During study visits, subjects will be instrumented with two intravenous catheters (one for drug infusion and one for blood sampling), arm and finger blood pressure cuffs, sticky patches to measure heart rate, a belt around the stomach to measure breathing, an ultrasound probe on each leg to measure blood flow, a probe on the ear to measure blood oxygen saturation, a probe on each calf muscle to measure oxygen levels, and probes on the skin to measure temperature and blood flow. The investigators will obtain baseline measures of blood pressure and heart rate and collect blood samples to measure hormones in the blood. After baseline measurements, the investigators will infuse angiotensin-(1-7) or saline for 50 minutes. Finger cuff blood pressure, leg blood flow, and calf muscle oxygen levels will be measured continuously during infusions. The investigators will measure blood pressure and heart rate and collect blood samples at the end of the infusion period.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Peripheral Arterial Disease
Keywords
Renin-Angiotensin System, Inflammation, Cardiovascular, Atherosclerosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Angiotensin-(1-7)
Arm Type
Experimental
Arm Description
Subjects will receive intravenous infusion of five ascending doses of angiotensin-(1-7). The doses are: 1, 2, 4, 8, and 12 ng/kg/min. Each dose will be maintained for 10 minutes, for a total infusion period of 50 minutes.
Arm Title
Saline
Arm Type
Placebo Comparator
Arm Description
Subjects will receive intravenous infusion of saline that is matched in volume to the angiotensin-(1-7) arm. Saline infusion will be maintained for a total infusion period of 50 minutes.
Intervention Type
Drug
Intervention Name(s)
Angiotensin 1-7
Other Intervention Name(s)
Angiotensin I (1-7), Angiotensin I/II (1-7) Acetate
Intervention Description
This is a biologically active hormone of the renin-angiotensin system. It may play a beneficial role in regulation of blood pressure by dilating blood vessels and reducing inflammation.
Intervention Type
Drug
Intervention Name(s)
Saline
Other Intervention Name(s)
normal saline, 0.9% sodium chloride
Intervention Description
Normal saline will be used as the placebo comparator.
Primary Outcome Measure Information:
Title
Leg Blood Flow
Description
The change in measures of leg blood flow (e.g. femoral blood flow and conductance, calf muscle oxygen saturation) following angiotensin-(1-7) versus saline infusion.
Time Frame
50 minutes
Title
Inflammatory Markers
Description
The change in blood levels of inflammatory markers C-Reactive Protein and Interleukin-6 following angiotensin-(1-7) versus saline infusion.
Time Frame
50 minutes
Secondary Outcome Measure Information:
Title
Blood Pressure
Description
The change in arm and finger cuff blood pressure following angiotensin-(1-7) versus saline infusion.
Time Frame
50 minutes
Title
Heart Rate
Description
The change in heart rate following angiotensin-(1-7) versus saline infusion.
Time Frame
50 minutes
Other Pre-specified Outcome Measures:
Title
Renin-Angiotensin System Hormones
Description
The change in circulating levels of renin-angiotensin system hormones (e.g. plasma renin activity, angiotensin peptides, aldosterone) following angiotensin-(1-7) versus saline infusion.
Time Frame
50 minutes
Title
Nitric Oxide Bioavailability
Description
The change in circulating levels of nitrate and nitrite following angiotensin-(1-7) versus saline infusion.
Time Frame
50 minutes
Title
Lipids
Description
The change in circulating lipids (e.g. cholesterol, triglycerides) following angiotensin-(1-7) versus saline infusion.
Time Frame
50 minutes

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Sex: Male or Female Age: 21-80 years of age Diagnosed with PAD (e.g. ankle-brachial index below 0.9) Fontaine stage II or less (no rest pain) Capable of giving informed consent Fluent in written and spoken English Exclusion Criteria: Age less than or equal to 20 years or greater than or equal to 81 years Pregnant or nursing woman Decisional impairment Prisoners Alcohol or drug abuse Evidence of type I or type II diabetes (fasting glucose >126 mg/dl or use of anti-diabetic medications) History of serious cardiovascular disease (e.g. myocardial infarction within 6 months, symptomatic coronary artery disease, presence of angina pectoris, significant arrhythmia, congestive heart failure, deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis, hypertrophic cardiomyopathy) or cerebrovascular disease (e.g. cerebral hemorrhage, stroke, transient ischemic attack). History or presence of immunological or hematological disease Impaired hepatic function [aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > 2 times the upper limit of normal range) Impaired renal function (serum creatinine >2.0 mg/dl) Anemia Treatment with serotonin-norepinephrine reuptake inhibitors (SNRI) or norepinephrine transporter (NET) inhibitors Treatment with phosphodiesterase-5 inhibitors Treatment with anticoagulants Treatment with chronic systemic glucocorticoid therapy (>7 consecutive days in 1 month) Treatment with any investigational drug in the 1-month preceding the study Inability to give, or withdraw, informed consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Amy C Arnold, PhD
Organizational Affiliation
Penn State College of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Penn State Milton S. Hershey Medical Center
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Angiotensin-(1-7) in Peripheral Arterial Disease

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