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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Relypsa, Inc.
ClinicalTrials.gov Identifier:
NCT01371747
First received: June 9, 2011
Last updated: June 17, 2016
Last verified: June 2016
  Purpose
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.

Condition Intervention Phase
Chronic Kidney Disease
Hypertension
Hyperkalemia
Drug: patiromer
Drug: losartan
Drug: spironolactone
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Relypsa, Inc.:

Primary Outcome Measures:
  • Least Squares Mean Change in Serum Potassium From Baseline to Week 4 or Time of First Titration for Each Individual Starting Dose Group [ Time Frame: Baseline to Week 4 or First Titration which could occur at any scheduled study visit after patiromer initiation. ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Least Squares Mean Change in Serum Potassium From Baseline to Week 8 or Time of First Titration for Each Individual Starting Dose Group [ Time Frame: Baseline to Week 8 or First Titration which could occur at any scheduled study visit after patiromer initiation. ] [ Designated as safety issue: No ]
    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.

  • Least Squares Mean Change in Serum Potassium From Baseline to Day 3 During the Treatment Initiation Period for Each Individual Starting Dose Group [ Time Frame: Baseline to Day 3 ] [ Designated as safety issue: No ]
    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.

  • Mean Change in Serum Potassium From Baseline to Week 52 During the Long-term Maintenance Period for Each Individual Starting Dose Group [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]
  • Mean Change in Serum Potassium From Week 52 or Last Patiromer Dose (if Occurred Before Week 52) to Follow-up Visits Plus 7 Days [ Time Frame: Week 52 or Last Patiromer Dose (if Occurred before Week 52) to Following up Visit Plus 7 Days ] [ Designated as safety issue: No ]
  • Proportion of Participants Achieving Serum Potassium Levels Within 3.5 to 5.5 mEq/L at Week 8 for Each Individual Starting Dose Group [ Time Frame: Baseline to Week 8 ] [ Designated as safety issue: No ]
  • Proportion of Participants Achieving Serum Potassium Levels Within 4.0 to 5.0 mEq/L at Week 8 for Each Individual Starting Dose Group [ Time Frame: Baseline to Week 8 ] [ Designated as safety issue: No ]
  • Time to First Serum Potassium Measurement of 4.0 - 5.0 mEq/L During Treatment Initiation Period for Each Individual Starting Dose Group [ Time Frame: Baseline to Week 8 ] [ Designated as safety issue: No ]
  • Proportions of Participants Achieving Serum Potassium Levels Within 3.8 to 5.0 mEq/L at Week 52 for Each Individual Starting Dose Group [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]

Enrollment: 324
Study Start Date: June 2011
Study Completion Date: June 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Stratum 1: 8.4 g/d patiromer
Participants with baseline serum potassium > 5.0 to 5.5 mEq/L (milliequivalent)
Drug: patiromer
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)
Other Names:
  • RLY5016 for Oral Suspension
  • Veltassa
Drug: losartan
losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)
Drug: spironolactone
Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)
Experimental: Stratum 1: 16.8 g/d patiromer
Participants with baseline serum potassium > 5.0 to 5.5 mEq/L
Drug: patiromer
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)
Other Names:
  • RLY5016 for Oral Suspension
  • Veltassa
Drug: losartan
losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)
Drug: spironolactone
Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)
Experimental: Stratum 1: 25.2 g/d patiromer
Participants with baseline serum potassium > 5.0 to 5.5 mEq/L
Drug: patiromer
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)
Other Names:
  • RLY5016 for Oral Suspension
  • Veltassa
Drug: losartan
losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)
Drug: spironolactone
Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)
Experimental: Stratum 2: 16.8 g/d patiromer
Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L
Drug: patiromer
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)
Other Names:
  • RLY5016 for Oral Suspension
  • Veltassa
Drug: losartan
losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)
Drug: spironolactone
Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)
Experimental: Stratum 2: 25.2 g/d patiromer
Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L
Drug: patiromer
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)
Other Names:
  • RLY5016 for Oral Suspension
  • Veltassa
Drug: losartan
losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)
Drug: spironolactone
Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)
Experimental: Stratum 2: 33.6 g/d patiromer
Participants with baseline serum potassium > 5.5 to < 6.0 mEq/L
Drug: patiromer
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)
Other Names:
  • RLY5016 for Oral Suspension
  • Veltassa
Drug: losartan
losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)
Drug: spironolactone
Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)

Detailed Description:

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
  Eligibility

Ages Eligible for Study:   30 Years to 80 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01371747

  Show 43 Study Locations
Sponsors and Collaborators
Relypsa, Inc.
Investigators
Study Director: Director Clinical Operations Relypsa, Inc.
  More Information

Additional Information:
Publications:
Responsible Party: Relypsa, Inc.
ClinicalTrials.gov Identifier: NCT01371747     History of Changes
Other Study ID Numbers: RLY5016-205  2011-000165-12 
Study First Received: June 9, 2011
Results First Received: November 11, 2015
Last Updated: June 17, 2016
Health Authority: Austria: Austrian Federal Office for Safety in Health Care
Croatia: Ministry of Health and Social Welfare of the Republic of Croatia
Georgia: Ministry of Health
Hungary: National Institute of Pharmacy
Serbia: Medicines and Medical Devices Agency of Serbia
Slovenia: Agency for Medicinal products and Medical Devices
Austria: Ethikkommission
Croatia: Ethics Committee
Hungary: Scientific and Medical Research Council Ethics Committee
Serbia: Ethics Committee
Slovenia: Ethics Committee

Keywords provided by Relypsa, Inc.:
Hyperkalemia
Chronic Kidney Disease
Treatment of Hyperkalemia
Hypertension
Diabetic Nephropathy

Additional relevant MeSH terms:
Hypertension
Kidney Diseases
Renal Insufficiency, Chronic
Diabetic Nephropathies
Hyperkalemia
Vascular Diseases
Cardiovascular Diseases
Urologic Diseases
Renal Insufficiency
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Water-Electrolyte Imbalance
Metabolic Diseases
Losartan
Angiotensin Receptor Antagonists
Spironolactone
Angiotensin-Converting Enzyme Inhibitors
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Molecular Mechanisms of Pharmacological Action
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents
Protease Inhibitors

ClinicalTrials.gov processed this record on August 25, 2016