Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy (AMETHYST-DN)

Study Overview
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Brief Summary
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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.

Detailed Description
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RLY5016-205 was an open-label, randomized, dose ranging study to determine the optimal starting dose, efficacy and safety of patiromer in treating hyperkalemia in hypertensive patients with nephropathy due to type 2 diabetes mellitus (T2DM) who were already receiving Angiotensin-converting Enzyme Inhibitor (ACEI) and/or Angiotensin II Receptor Blocker (ARB) drugs, with or without spironolactone. The study consisted of the following periods: Screening: Up to 10 days (1 visit) Run-in for those who were not hyperkalemic at screening (Cohorts 1 and 2): up to 4 weeks (1 to 4 visits) Patiromer Treatment Initiation: first 8 weeks of patiromer treatment (a minimum of 10 visits) Patiromer Long-Term Maintenance: additional 44 weeks of patiromer treatment up to a total of one year (minimum of 11 additional visits) Follow-up (after patiromer discontinuation): 1 week (2 visits) OR 4 weeks (5 visits) depending on the final serum potassium level

Official Title
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A Multicenter, Randomized, Open-Label, Dose Ranging Study to Evaluate the Efficacy and Safety of Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy Receiving Angiotensin-converting Enzyme Inhibitor (ACEI) and/or Angiotensin II Receptor Blocker (ARB) Drugs, With or Without Spironolactone

Conditions
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Chronic Kidney Disease, Hypertension, Hyperkalemia

Intervention / Treatment
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* Drug: patiromer
* Drug: patiromer
* Drug: patiromer
* Drug: patiromer
* Drug: patiromer
* Drug: patiromer
* Drug: losartan
* Drug: spironolactone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 30 - 80 years old at screening (S1) 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 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) Urine albumin/creatinine ratio (ACR): 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 Cohort 3: not applicable Local laboratory serum potassium (K+) values of: 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) Cohort 3: > 5.0 - < 6.0 mEq/L at S1 OR at R0 after same day confirmation Must be receiving an ACEI and/or ARB for at least 28 days prior to screening Average systolic blood pressure (SBP) ≥ 130 - < 180 mmHg AND average DBP ≥ 80 - < 110 mmHg (sitting) at both screening and R0 (as applicable) 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 Provide their written informed consent prior to participation in the study Exclusion Criteria: Type 1 diabetes mellitus Central lab hemoglobin A1c > 12% at Screening 1 (S1) (except for Cohort 3 participants who are hyperkalemic at S1) Emergency treatment for T2DM within the last 3 months 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 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) Central lab urine ACR ≥ 10000 mg/g at screening (except for Cohort 3 participants who are hyperkalemic at S1) Confirmed diagnosis or history of renal artery stenosis (unilateral or bilateral) Diabetic gastroparesis Non-diabetic chronic kidney disease History of bowel obstruction, swallowing disorders, severe gastrointestinal disorders or major gastrointestinal surgery (e.g., large bowel resection) Current diagnosis of NYHA (New York Heart Association) Class III or IV heart failure Body mass index (BMI) ≥ 40 kg/m2 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 Prior kidney transplant, or anticipated need for transplant during study participation 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 History of alcoholism or drug/chemical abuse within 1 year 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) 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 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 Current use of lithium 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 Use of any investigational product within 30 days or 5 half-lives, whichever is longer, prior to screening Inability to consume the investigational product, 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, 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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum 1: 8.4 g/d patiromer<br>Participants with baseline serum potassium > 5.0 to 5.5 mEq/L (milliequivalent) | Drug: patiromer<br>* 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)<br>* Other names: Veltassa;Drug: losartan<br>* losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)<br>Drug: spironolactone<br>* Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)<br>|
| Experimental: Stratum 1: 16.8 g/d patiromer<br>Participants with baseline serum potassium > 5.0 to 5.5 mEq/L | Drug: patiromer<br>* 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)<br>* Other names: Veltassa;Drug: losartan<br>* losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)<br>Drug: spironolactone<br>* Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)<br>|
| Experimental: Stratum 1: 25.2 g/d patiromer<br>Participants with baseline serum potassium > 5.0 to 5.5 mEq/L | Drug: patiromer<br>* 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)<br>* Other names: Veltassa;Drug: losartan<br>* losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)<br>Drug: spironolactone<br>* Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)<br>|
| Experimental: Stratum 2: 16.8 g/d patiromer<br>Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L | Drug: patiromer<br>* 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)<br>* Other names: Veltassa;Drug: losartan<br>* losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)<br>Drug: spironolactone<br>* Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)<br>|
| Experimental: Stratum 2: 25.2 g/d patiromer<br>Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L | Drug: patiromer<br>* 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)<br>* Other names: Veltassa;Drug: losartan<br>* losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)<br>Drug: spironolactone<br>* Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)<br>|
| Experimental: Stratum 2: 33.6 g/d patiromer<br>Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L | Drug: patiromer<br>* 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)<br>* Other names: Veltassa;Drug: losartan<br>* losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)<br>Drug: spironolactone<br>* Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Squares Mean Change in Serum Potassium From Baseline to Week 4 or Time of First Titration for Each Individual Starting Dose Group | Least square mean changes from Baseline to Week 4/first titration were derived from parallel lines ANCOVA model with randomized starting dose and baseline serum potassium value as covariates. | Baseline to Week 4 or First Titration which could occur at any scheduled study visit after patiromer initiation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Squares Mean Change in Serum Potassium From Baseline to Week 8 or Time of First Titration for Each Individual Starting Dose Group | Least squares mean changes from Baseline to Week 8/first titration were derived from parallel lines ANCOVA model with randomized starting dose and baseline serum potassium value as covariates. | Baseline to Week 8 or First Titration which could occur at any scheduled study visit after patiromer initiation. | 
| Least Squares Mean Change in Serum Potassium From Baseline to Day 3 During the Treatment Initiation Period for Each Individual Starting Dose Group | Least squares mean changes from Baseline to Day 3 were derived from parallel lines ANCOVA model with randomized starting dose and baseline serum potassium value as covariates. | Baseline to Day 3 | 
| Mean Change in Serum Potassium From Baseline to Week 52 During the Long-term Maintenance Period for Each Individual Starting Dose Group |  | Baseline to Week 52 | 
| Mean Change in Serum Potassium From Week 52 or Last Patiromer Dose (if Occurred Before Week 52) to Follow-up Visits Plus 7 Days |  | Week 52 or Last Patiromer Dose (if Occurred before Week 52) to Following up Visit Plus 7 Days | 
| Proportion of Participants Achieving Serum Potassium Levels Within 3.5 to 5.5 mEq/L at Week 8 for Each Individual Starting Dose Group |  | Baseline to Week 8 | 
| Proportion of Participants Achieving Serum Potassium Levels Within 4.0 to 5.0 mEq/L at Week 8 for Each Individual Starting Dose Group |  | Baseline to Week 8 | 
| Time to First Serum Potassium Measurement of 4.0 - 5.0 mEq/L During Treatment Initiation Period for Each Individual Starting Dose Group |  | Baseline to Week 8 | 
| Proportions of Participants Achieving Serum Potassium Levels Within 3.8 to 5.0 mEq/L at Week 52 for Each Individual Starting Dose Group |  | Baseline to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperkalemia, Chronic Kidney Disease, Treatment of Hyperkalemia, Hypertension, Diabetic Nephropathy