Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy (AMETHYST-DN)
Condition: Chronic Kidney Disease; Hypertension; Hyperkalemia
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Diabetic Nephropathies; Hypertension; Hyperkalemia
Intervention: patiromer; patiromer; patiromer; patiromer; patiromer; patiromer; losartan; spironolactone
Intervention description: Cohorts 1, 2 and 3 - Patiromer starting dose: 8.4 g/day, orally, as a divided dose, twice daily. The dose of patiromer could be titrated based on participant's serum potassium response (Stratum 1); Cohorts 1, 2 and 3 - Patiromer starting dose: 16.8 g/day, orally, as a divided dose, twice daily. The dose of patiromer could be titrated based on participant's serum potassium response. (Stratum 2); Cohorts 1, 2 and 3 - Patiromer starting dose: 16.8 g/day, orally, as a divided dose, twice daily. The dose of patiromer could be titrated based on participant's serum potassium response (Stratum 1); Cohorts 1, 2 and 3 - Patiromer starting dose: 25.2 g/day, orally, as a divided dose, twice daily. The dose of patiromer could be titrated based on participant's serum potassium response (Stratum 1); Cohorts 1, 2 and 3 - Patiromer starting dose: 25.2 g/day, orally, as a divided dose, twice daily. The dose of patiromer could be titrated based on participant's serum potassium response. (Stratum 2); Cohorts 1, 2 and 3 - Patiromer starting dose: 33.6 g/day, orally, as a divided dose, twice daily. The dose of patiromer could be titrated based on participant's serum potassium response. (Stratum 2); losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1); Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)
Intervention MeSH terms: Losartan; Spironolactone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 324.0
Sex: All
Minimum age: 30 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Hyperkalemia; Chronic Kidney Disease; Treatment of Hyperkalemia; Hypertension; Diabetic Nephropathy

Summary:

      This study determined the optimal starting dose of patiromer in treating hyperkalemia in
      participants with hypertension and diabetic nephropathy who were already receiving ACEI
      and/or ARB drugs, with or without spironolactone. This study also evaluated the efficacy and
      safety of patiromer and the long term use of patiromer.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age 30 - 80 years old at screening (S1)

          2. Type 2 diabetes mellitus (T2DM) diagnosed after age 30 which has been treated with
             oral medications or insulin for at least 1 year prior to S1

          3. Chronic kidney disease (CKD): estimated glomerular filtration rate (eGFR) 15 - < 60
             mL/min/1.73m2 at screening based on central lab serum creatinine measurement (except
             for participants with hyperkalemia at S1), whose eligibility will be assessed based on
             local lab eGFR value)

          4. Urine albumin/creatinine ratio (ACR):

               1. Cohorts 1 and 2: urine ACR ≥ 30 mg/g at S1 AND average urine ACR ≥ 30 mg/g at the
                  beginning of Run-In Period (R0) based on up to three ACR values obtained starting
                  at S1 and ending at the R0 Visit

               2. Cohort 3: not applicable

          5. Local laboratory serum potassium (K+) values of:

               1. Cohorts 1 and 2: 4.3 - 5.0 mEq/L at S1; AND 4.5 - 5.0 mEq/L at R0; AND > 5.0 - <
                  6.0 mEq/L at randomization to patiromer (Baseline, T0 Visit)

               2. Cohort 3: > 5.0 - < 6.0 mEq/L at S1 OR at R0 after same day confirmation

          6. Must be receiving an ACEI and/or ARB for at least 28 days prior to screening

          7. Average systolic blood pressure (SBP) ≥ 130 - < 180 mmHg AND average DBP ≥ 80 - < 110
             mmHg (sitting) at both screening and R0 (as applicable)

          8. 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 patiromer administration, during the study,
             and for one month after study completion

          9. Provide their written informed consent prior to participation in the study

        Exclusion Criteria:

          1. Type 1 diabetes mellitus

          2. Central lab hemoglobin A1c > 12% at Screening 1 (S1) (except for Cohort 3 participants
             who are hyperkalemic at S1)

          3. Emergency treatment for T2DM within the last 3 months

          4. A confirmed SBP > 180 mmHg or diastolic blood pressure (DBP) > 110 mmHg at any time
             during SI or Run-In Period or at Baseline T0 Visit

          5. Central lab serum magnesium < 1.4 mg/dL (< 0.58 mmol/L) at screening (Cohort 3
             participants will be evaluated based on local lab serum magnesium measurement)

          6. Central lab urine ACR ≥ 10000 mg/g at screening (except for Cohort 3 participants who
             are hyperkalemic at S1)

          7. Confirmed diagnosis or history of renal artery stenosis (unilateral or bilateral)

          8. Diabetic gastroparesis

          9. Non-diabetic chronic kidney disease

         10. History of bowel obstruction, swallowing disorders, severe gastrointestinal disorders
             or major gastrointestinal surgery (e.g., large bowel resection)

         11. Current diagnosis of NYHA (New York Heart Association) Class III or IV heart failure

         12. Body mass index (BMI) ≥ 40 kg/m2

         13. Any of the following events having occurred within 2 months prior to screening:
             unstable angina as judged by the Principal Investigator (PI), unresolved acute
             coronary syndrome, cardiac arrest or clinically significant ventricular arrhythmias,
             transient ischemic attack or stroke, use of any intravenous cardiac medication

         14. Prior kidney transplant, or anticipated need for transplant during study participation

         15. Active cancer, currently on cancer treatment or history of cancer in the past 2 years
             except for non-melanocytic skin cancer which is considered cured

         16. History of alcoholism or drug/chemical abuse within 1 year

         17. Central lab liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase
             (AST)] > 3 times upper limit of normal at S1 (except for Cohort 3 patients with
             hyperkalemia at S1, who will have local lab ALT and AST)

         18. Loop and thiazide diuretics or other antihypertensive medications (calcium channel
             blocker, beta-blocker, alpha-blocker, or centrally acting agent) that have not been
             stable for at least 28 days prior to screening or not anticipated to remain stable
             during study participation

         19. Current use of polymer-based drugs (e.g., sevelamer, sodium polystyrene sulfonate,
             colesevelam, colestipol, cholestyramine), phosphate binders (e.g., lanthanum
             carbonate), or other potassium binders, or their anticipated need during study
             participation

         20. Current use of lithium

         21. Use of potassium sparing medications, including aldosterone antagonists (e.g.,
             spironolactone), drospirenone, potassium supplements, bicarbonate or baking soda in
             the last 7 days prior to screening

         22. Use of any investigational product within 30 days or 5 half-lives, whichever is
             longer, prior to screening

         23. Inability to consume the investigational product, or, in the opinion of the
             Investigator, inability to comply with the protocol

         24. In the opinion of the Investigator, any medical condition, uncontrolled systemic
             disease, or serious intercurrent illness that would significantly decrease study
             compliance or jeopardize the safety of the participant or affect the validity of the
             trial results