Clinical trial NCT03597035: Mineralocorticoid Receptor Antagonism Clinical Evaluation in Atherosclerosis Add-On
Official title: Mineralocorticoid Receptor Antagonism Clinical Evaluation in Atherosclerosis Add-On
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Type2 Diabetes
Hyperkalemia
Lead sponsor: University Hospitals Cleveland Medical Center
Sponsor class: OTHER
Collaborators: name: Relypsa, Inc.
First posted: 2018-07-24
Enrollment: 8
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: An open label proof-of-concept clinical trial in 50 patients with Type II diabetes evaluating the effects of MRA + Patiromer on LV mass and plaque regression over 12 months of treatment by magnetic resonance imaging (MRI).
Primary purpose: TREATMENT

Brief summary: Patiromer add-on to a mineralocorticoid receptor antagonist (MRA) in patients with Type 2 diabetes mellitus and chronic kidney disease (CKD) will reduce blood pressure and left ventricular (LV) mass to a greater extent compared to patients with MRA alone and favorably affect key secondary hemodynamic and inflammatory variables including atherosclerosis progression.

Atherosclerosis is the leading cause of morbidity and mortality in Type II diabetes. A cell type called the monocyte/macrophage is critical to development and complications of atherosclerosis.

This project will evaluate the effectiveness of a medication called Spironolactone in addition to Patiromer in preventing atherosclerosis in Type II diabetes through its effects on cells such as the monocyte. Spironolactone has been demonstrated to be effective for the treatment of patients after a heart attack and stroke. The investigators will evaluate the impact of Spironolactone in combination with Patiromer in reducing atherosclerosis plaque and additionally evaluate its potential in changing inflammation.

The investigators envision that a strategy of simultaneously probing effect of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design hard event (heart attack, stroke etc.) based trials.

Detailed description: There is substantial interest in preventing cardiovascular (CV) and renal disease progression in the Type 2 diabetic. Activation of the renin angiotensin aldosterone axis (RAS) and the mineralocorticoid receptor (MR) results in pro-inflammatory effects. Further the phenomenon of aldosterone escape provides a rationale for MR antagonism in addition to an ACEI/ARB agent. Agents that target the renin-angiotensin aldosterone system (RAAS) cascade have shown benefit in Type 2 Diabetics although combined RAS blockade such as using ACEI+ARB or ACEI/ARB+Renin inhibition have met with failure primarily owing to adverse effects such as hypotension and renal failure/hyperkalemia requiring dialysis. It has been speculated that dual RAS blockade or use of ACEI/ARB in conjunction with MRA may potentially be beneficial if one controls hyperkalemia and/or avoid excess hypotension. As a foundation for this current proposal, the investigators have demonstrated an important role for RAAS and MR antagonism in reducing atherosclerosis and inflammation in experimental animal models and limited studies in humans. The investigators are currently testing the efficacy of Spironolactone in reducing atherosclerosis on top of ACEI/ARB in high-risk patients with type 2 diabetes (T2DM) with concomitant CKD as part of a Randomized Double-blind controlled clinical trial. Given the fact that as much as 20-40% of a diabetic patient population with CKD may have problems of hyperkalemia on spironolactone, particularly those already on angiotensin converting enzyme inhibitor (ACEI)/ARB therapy, that would preclude their participation in this trial, the investigators would like to propose an open label supplemental arm to where patients who are ineligible for participation owing to baseline hyperkalemia or hyperkalemia on the dose escalation phase will be eligible to participate in the PRIMARY-Add on trial. The addition of Patiromer will enable introduction of MRA therapy at therapeutic doses and avoidance of hyperkalemia. The investigators thus propose a prospective open label trial with blinded assessment of end-points (PROBE) study which test the relative safety and efficacy of Patiromer on top of Spironolactone in T2DM on LV mass regression and occurrence of hypokalemia (Co-Primary End-points) as well as its effect on 24-hour ambulatory blood pressure (ABP) at 6 weeks, central aortic blood pressure at 6 weeks, atherosclerosis progression at 12 months and measures of monocyte inflammatory potential. If successful, the studies outlined in this proposal will extend the utility of Patiromer in high-risk diabetics at risk for future CV events and provide new information.

Eligibility criteria: Inclusion Criteria

1. Male or female patients \>= 45 years 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. Glomerular filtration rate (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 angiotensin-converting-enzyme inhibitor (ACE) and/or angiotensin-resistance-blocker (ARB) therapy with no planned dose adjustments.
5. Hyperkalemia defined as serum K+≥ 5.1 meq/L at visit 0 (screening).

Exclusion Criteria

1. Uncontrolled hypertension (Systolic Blood Pressure (SBP)\>160 and/or Diastolic Blood Pressure (DBP)\>95 mmHg at visit 0 (screening) and SBP \>145 mm Hg at visit 2).
2. GFR (MDRD) of \<20 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, cardiovascular accident (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, ACE/ARB, antioxidants, calcium channel blockers (CCBs), diuretics, β blockers.
10. Type I diabetes mellitus
11. Known contraindication, including history of allergy to Spironolactone or Patiromer
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 cured prostate cancer).
16. History of any severe, life-threatening disease.
17. Any surgical or medical conditions which place 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

Primary outcomes:
measure: Left Ventricular Mass
timeFrame: Time 0: study baseline, beginning of treatment. Time 1: 12 months follow-up, end of treatment.
Secondary outcomes:
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
Study officials:
affiliation: University Hospitals Cleveland Medical Center
name: Sanjay Rajagopalan, MBBS
role: PRINCIPAL_INVESTIGATOR
References: