The purpose of this study is to assess the effects of RLY5016 on serum potassium in heart failure patients. This study will also assess the safety and tolerability of RLY5016 in heart failure patients.

• Hyperkalemia
• Heart Failure

• Drug: Spironolactone + RLY5016
  Active investigational drug
• Drug: Spironolactone + Placebo
  Placebo

• RLY5016: Active Comparator
  Intervention: Drug: Spironolactone + RLY5016
• Placebo: Placebo Comparator
  Intervention: Drug: Spironolactone + Placebo

Inclusion Criteria:

• Heart failure patients clinically indicated to receive spironolactone therapy, with serum potassium levels of 4.3 - 5.1 mEq/L AND chronic kidney disease (GFR <60 mL/min) OR documented history of hyperkalemia within the last 6 months
• Females of child-bearing potential must be non-lactating, must have a negative serum pregnancy test at screening, and must have used a highly effective form of contraception for at least 3 months before study drug administration, during the study, and for one month after study completion
• Male patients and/or their female partners of child-bearing potential must use a highly effective form of contraception during the study and for 3 months after study completion
• Must sign informed consent document

Exclusion Criteria:

• History of bowel obstruction, swallowing disorders, severe gastrointestinal disorders or major gastrointestinal surgery
• Uncorrected hemodynamically significant primary valvular disease, known obstructive or restrictive cardiomyopathy, uncontrolled or hemodynamically unstable arrhythmia
• Coronary-artery bypass graft, percutaneous intervention (e.g. cardiac, cerebrovascular, aortic), or major surgery including thoracic and cardiac, within 3 months prior to baseline or anticipated need during study participation
• Heart transplant recipient, or anticipated need for transplant during study participation
• Any of the following events having occurred within 3 months prior to baseline: unstable angina as judged by the Investigator, unresolved acute coronary syndrome, transient ischemic attack or stroke
• Current dialysis patient, or anticipated need for dialysis during study participation
• Prior kidney transplant, or anticipated need for transplant during study participation
• Metastatic, late-stage or end-stage cancer with < 12 months life expectancy
• History of alcoholism or drug/chemical abuse within 1 year
• QTcB interval > 500 msec (Bazett's correction formula)
• Sustained systolic blood pressure > 170 or < 90 mmHg
• Liver enzymes (ALT, AST) > 3 times upper limit of normal
• Use of oral cardiac medications (including loop and thiazide diuretics) that have not been stable for at least 21 days prior to baseline and are not anticipated to remain stable during study participation
• Use of any IV cardiac medications within 21 days prior to baseline, or their anticipated need during study participation.
• Current use of polymer-based drugs (e.g. Renagel, Kayexalate, Welchol, Colestid), other phosphate binders or potassium binders, calcium supplements, antacids (eg TUMS, Maalox), or their anticipated need during study participation
• Use of aldosterone antagonist in the last 30 days prior to baseline, unless was discontinued due to hyperkalemia
• Use of potassium sparing medication and/or potassium supplements in the last 30 days prior to baseline
• Use of any investigational medication, 30 days or 5 half-lives whichever is longer, prior to baseline
• Patients who have taken investigational product in this study, or a previous RLY5016 study
• Inability to consume the study medication, or, in the opinion of the Investigator, inability to comply with the protocol
• In the opinion of the Investigator, any medical condition, uncontrolled systemic disease, serious intercurrent illness, or extenuating circumstance occurring or persisting, within 30 days prior to baseline, that would significantly decrease study compliance or jeopardize the safety of the patient or affect the validity of the trial results