ENAC Blockade and Arterial Stiffness

May 30, 2023 updated by: Camila Manrique, MD, University of Missouri-Columbia

Estrogen Receptor Alpha Signaling in Endothelial Cells Exacerbates Arterial Stiffening Via Upregulation of ENaC in Insulin Resistant Females

To determine whether treatment with the ENaC inhibitor, amiloride, improves endothelial function and arterial stiffness in obese insulin resistant subjects in a randomized placebo-controlled trial examining pre and postmenopausal women and age-matched men.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Overweight/obese males, pre- and post-menopausal females with insulin resistance, 30-70 years of age will be recruited. Following screening, eligible men and women will be randomly assigned to either amiloride (max dose 5mg) or placebo in a double-blinded design manner.

After randomization, subjects will be scheduled for an outpatient visit to the undergo baseline assessment of arterial stiffness (carotid femoral pulse wave velocity - cfPWV) and endothelial function (brachial popliteal artery flow mediated dilation). Subject assessment will be repeated at 12 weeks and at 24 weeks.

Study Type

Interventional

Enrollment (Estimated)

157

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

30 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 30 to 70 years of age at randomization
  • Body mass index (BMI) 25.1-50 kg/m2 or waist circumference > 88 cm (> 35 in) in women and >102 cm (>40 in) in men. 3, 4
  • One other characteristic of metabolic syndrome (elevated triglycerides ≥150 mg/dl; HDL cholesterol <40 mg/dl in men and <50 mg/dl in women; blood pressure ≥130/85 mm Hg or treatment for hypertension; impaired fasting glucose (≥100 mg/dl)) or fasting insulin level >10 mU/L (correlates with insulin resistance).

Exclusion Criteria:

  1. History of type 1 or type 2 diabetes
  2. Known cardiovascular events within the last 12 months (stroke, acute coronary event, revascularization, heart failure hospitalization).
  3. History of uncontrolled thyroid disease, chronic liver disease (cirrhosis) or GFR <50 ml/min.
  4. Use of potassium sparing medications (angiotensin II receptor blockers, angiotensin converting enzymes inhibitors or mineralocorticoid receptor blockers) or use of potassium supplements.
  5. Active cancer (This criterion does not apply to those subjects with basal cell carcinoma or stage 1 squamous cell carcinoma of the skin)
  6. Excessive alcohol consumption (>14 drinks/week for men, >7 drinks/week for women)
  7. Current tobacco use
  8. Non controlled hypertension
  9. Participation in regular exercise > 3 days/wk per week at a moderate or vigorous intensity
  10. Pregnancy or lactation in women (or women not using contraceptives)
  11. Women who plan to become pregnant during the duration of the trial
  12. Chronic use of NSAIDs
  13. Potassium level > 5.0 mqE/L at time of screening
  14. Blood pressure at screening <110/70

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
6 months of daily placebo
Drug: Placebo - Cap
6 months of 1 pill a day
Experimental: Amiloride
6 months of amiloride (max dose 5 mg) treatment
Drug: Amiloride Pill
Max dose of 5 mg a day for 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Carotid femoral PWV
Time Frame: Baseline, 3 months (interim) and 6 months (final)
It is the gold standard non-invasive index of arterial stiffness. Transit time between carotid and femoral pressure waves is calculated using the foot-to-foot method. cfPWV is calculated as distance traveled by the pulse wave (i.e., femoral location-sternal notch minus sternal notch-carotid location) divided by pulse transit time. All the measurements will be done by the same blinded technician.The goal is to assess changes from baseline when compared to interim and final time point.
Baseline, 3 months (interim) and 6 months (final)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Brachial artery flow mediated dilation (FMD)
Time Frame: Baseline, 3 months (interim) and 6 months (final)
The goal is to assess changes from baseline when compared to interim and final time point. ] Brachial artery FMD will be assessed at baseline and at 12-wk. FMD is a measurement of conduit artery endothelial function. FMD is assessed immediately after each PWV measurement. Shear rate AUC until peak diameter is calculated as stimulus for FMD and used in covariate analysis as described. All measurements will be performed, under co-I supervision by the same blinded technician.
Baseline, 3 months (interim) and 6 months (final)
Popliteal artery flow mediated dilation (FMD)
Time Frame: Baseline, 3 months (interim) and 6 months (final)
The goal is to assess changes from baseline when compared to interim and final time point. ] Popliteal artery FMD will be assessed at baseline and at 12-wk. FMD is a measurement of conduit artery endothelial function. FMD is assessed immediately after each PWV measurement. Shear rate AUC until peak diameter is calculated as stimulus for FMD and used in covariate analysis as described. All measurements will be performed, under co-I supervision by the same blinded technician.
Baseline, 3 months (interim) and 6 months (final)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Missouri-Columbia

Investigators

  • Principal Investigator: Camila Manrique Acevedo, MD, University of Missouri-Columbia

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 15, 2019

Primary Completion (Estimated)

June 1, 2024

Study Completion (Estimated)

June 1, 2024

Study Registration Dates

First Submitted

February 8, 2019

First Submitted That Met QC Criteria

February 8, 2019

First Posted (Actual)

February 12, 2019

Study Record Updates

Last Update Posted (Actual)

May 31, 2023

Last Update Submitted That Met QC Criteria

May 30, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2012990

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.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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