Atherosclerosis
Conditions
Brief summary
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.
Interventions
DRUGSpironolactone
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.
DRUGPlacebo
Placebo
Sponsors
University of Maryland
University of Toronto
Winthrop University
University Hospitals Cleveland Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
41 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change in Atheroma Volume (PAV) in the Thoracic Aorta of Spironolactone vs. Placebo | 56 weeks |
Secondary
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Spironolactone Spironolactone
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. | 37 |
| Placebo Placebo
Placebo: Placebo | 42 |
| Total | 79 |
Baseline characteristics
| Characteristic | Placebo | Total | Spironolactone |
|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 8.7 | 64.3 years STANDARD_DEVIATION 8.6 | 65.5 years STANDARD_DEVIATION 8.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 26 Participants | 46 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 14 Participants | 30 Participants | 16 Participants |
| Sex: Female, Male Female | 17 Participants | 33 Participants | 16 Participants |
| Sex: Female, Male Male | 25 Participants | 46 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 37 | 1 / 42 |
| other Total, other adverse events | 9 / 37 | 8 / 42 |
| serious Total, serious adverse events | 7 / 37 | 8 / 42 |
Outcome results
Primary
Percent Change in Atheroma Volume (PAV) in the Thoracic Aorta of Spironolactone vs. Placebo
Time frame: 56 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Spironolactone | Percent Change in Atheroma Volume (PAV) in the Thoracic Aorta of Spironolactone vs. Placebo | 0.5 percentage change | Standard Deviation 10.3 |
| Placebo | Percent Change in Atheroma Volume (PAV) in the Thoracic Aorta of Spironolactone vs. Placebo | 7.3 percentage change | Standard Deviation 11.4 |
p-value: 0.0293Wilcoxon (Mann-Whitney)
Secondary
Change in 24-hour Ambulatory Systolic Blood Pressure of Spironolactone vs. Placebo
Time frame: 11 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Spironolactone | Change in 24-hour Ambulatory Systolic Blood Pressure of Spironolactone vs. Placebo | -5.95 mmHg | Standard Deviation 10.9 |
| Placebo | Change in 24-hour Ambulatory Systolic Blood Pressure of Spironolactone vs. Placebo | 2 mmHg | Standard Deviation 17.59 |
p-value: 0.1276Wilcoxon (Mann-Whitney)
Secondary
Left Ventricular Mass Index of Spironolactone vs. Placebo.
Time frame: 56 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Spironolactone | Left Ventricular Mass Index of Spironolactone vs. Placebo. | -3.5 g/m^2 | Standard Deviation 3.7 |
| Placebo | Left Ventricular Mass Index of Spironolactone vs. Placebo. | 2.1 g/m^2 | Standard Deviation 4.5 |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Measures of Insulin Resistance (HOMA-IR) of Spironolactone vs. Placebo
Time frame: 56 weeks
Population: Data not collected for this outcome measure.
Secondary
Myocardial Fibrosis (Change in Native T1) Spironolactone vs. Placebo
Time frame: 56 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Spironolactone | Myocardial Fibrosis (Change in Native T1) Spironolactone vs. Placebo | -10.3 ms | Standard Deviation 35.9 |
| Placebo | Myocardial Fibrosis (Change in Native T1) Spironolactone vs. Placebo | 17.1 ms | Standard Deviation 35.6 |
p-value: 0.0189Wilcoxon (Mann-Whitney)