Mineralocorticoid Receptor Antagonism Clinical Evaluation in Atherosclerosis Trial

Atherosclerotic disease, or hardening of the arteries, is characterized by the thickening of the arterial walls due to fatty deposits in wall and inflammation in the wall of arteries. High cholesterol, high blood pressure, diabetes, obesity and genetics play an important role in developing clinical symptoms of atherosclerosis disease. The complications of advanced atherosclerosis are chronic, slowly progressive and cumulative, resulting in heart attack, stroke and/or death and blockage of arteries.

This study is being done to assess the effectiveness of Spironolactone therapy to slow down the worsening of atherosclerotic disease (hardening of the arteries) in aorta (this is a large vessel coming out of your heart) compared to placebo (look alike sugar pill). This will be checked by comparing before and after therapy magnetic resonance imaging (MRI) pictures of your aortic wall.

Spironolactone is an FDA approved drug used to treat heart failure and in the management of hypertension (high blood pressure), but in this study it is used for another unapproved reason. In this study, we would like to evaluate the effects of Spironolactone in people with diabetes and atherosclerotic disease.

Study Overview

• Status: Completed
• Conditions: Atherosclerosis
• Intervention / Treatment: Drug: Placebo; Drug: Spironolactone

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 41 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female patients >45 or >40 years with known atherosclerotic events (examples include MI, Stroke) and able to provide informed consent (females must be either post-menopausal for one year, surgically sterile, or using effective contraception. Oral contraceptives are disallowed.
2. Patients with Type II Diabetes with HbA1c ≤ 9.0 on stable anti-glycemic regimen that may include oral and/or injectable therapy (GLP-1/Insulin etc.). Changes in dose of glycemic regimen is allowed during the course of the trial if felt to be clinically appropriate.
3. GFR <90 and evidence of proteinuria (Urine albumin/creatinine ratio of >30 mg/g or equivalent) in a urine specimen within 12 months OR GFR <60 mg/g regardless of proteinuria.
4. Patients must be on ACE and/or ARB therapy with no planned dose adjustments.

Exclusion Criteria:

1. Uncontrolled hypertension (SBP>160 and/or DBP>95 mmHg at visit 0 (screening) and SBP >145 mm Hg at visit 2).
2. GFR (MDRD) of <15 at Visit 0 (screening).
3. Hyperkalemia defined as serum K+≥ 5.1 meq/L at visit 0 (screening).
4. LDL cholesterol >150 mg/dl.
5. Plasma triglycerides >400 mg/dl.
6. Contraindications to MRI (metallic implants, severe claustrophobia).
7. Acute coronary syndrome, Transient ischemic attack, CVA or critical limb ischemia during the last 6 months or coronary/peripheral revascularization within the last 3 months.
8. Evidence of a secondary form of hypertension.
9. Initiation of new therapy with statins, ACEI/ARB, anti-oxidants, CCBs, diuretics, β blockers.
10. Type I diabetes mellitus
11. Known contraindication, including history of allergy to Spironolactone.
12. . Any surgical or medical condition which might alter pharmacokinetics of drug (e.g. renal transplant, liver failure, liver transplant).
13. Concurrent potentially life threatening arrhythmia or symptomatic arrhythmia.
14. Significant hyponatremia defined as Na <130 meq/L.
15. History of prior malignancy including leukemia and lymphoma (but not basal cell skin cancer, cured squamous cell cancer and localized Prostate cancer).
16. History of any severe, life-threatening disease.
17. Any surgical or medical conditions which places the patient at higher risk derived from his/her participation into the study, or likely to prevent patient from complying with requirements.
18. History of drug abuse within the last 2 years, noncompliance and unwillingness/inability to consent.
19. Pregnant women and nursing mothers.
20. Class III or IV Congestive Heart Failure.
21. Primary Hyperaldosteronism.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo
Experimental: Spironolactone	Drug: Spironolactone; Patients will be given Spironolactone 12.5 mg on week 0 (visit 2). Patients will be escalated to 25 mg daily Spironolactone or maximal tolerated dose over a 4-week period. Patients will continue treatment for an additional 48 weeks.; Other Names: Aldactone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change in Atheroma Volume (PAV) in the Thoracic Aorta of Spironolactone vs. Placebo	56 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Left Ventricular Mass Index of Spironolactone vs. Placebo.	56 weeks
Myocardial Fibrosis (Change in Native T1) Spironolactone vs. Placebo	56 weeks
Change in 24-hour Ambulatory Systolic Blood Pressure of Spironolactone vs. Placebo	11 weeks
Measures of Insulin Resistance (HOMA-IR) of Spironolactone vs. Placebo	56 weeks

Collaborators and Investigators

• Sponsor: University Hospitals Cleveland Medical Center
• Collaborators: University of Maryland; University of Toronto; Winthrop University
• Investigators: Principal Investigator: Sanjay Rajagopalan, Chief, Cardiovascular Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): April 29, 2022
• Study Completion (Actual): April 29, 2022

Study Registration Dates

• First Submitted: June 18, 2014
• First Submitted That Met QC Criteria: June 18, 2014
• First Posted (Estimated): June 20, 2014

Study Record Updates

• Last Update Posted (Actual): August 1, 2023
• Last Update Submitted That Met QC Criteria: July 10, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: 57047