RLY5016 in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy (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: September 13, 2013
Last verified: September 2013
  Purpose

RLY5016-205 is an open-label, randomized, dose ranging study to determine the optimal starting dose, efficacy and safety of RLY5016 in treating hyperkalemia in hypertensive patients with nephropathy due to type 2 diabetes mellitus (T2DM) receiving Angiotensin-converting Enzyme Inhibitor (ACEI) and/or Angiotensin II Receptor Blocker (ARB) drugs, with or without spironolactone.

The study consists of the following periods:

  • Screening: Up to 10 days (1 visit)
  • Run-in: up to 4 weeks (1 to 4 visits)
  • RLY5016 Treatment Initiation: first 8 weeks of RLY5016 treatment (a minimum of 10 visits)
  • Long-Term Maintenance: additional 44 weeks of RLY5016 treatment up to a total of one year (minimum of 11 additional visits)
  • Follow-up (after RLY5016 discontinuation): 1 week (2 visits) OR 4 weeks (5 visits) depending on the final serum potassium level

Condition Intervention Phase
Chronic Kidney Disease
Hypertension
Hyperkalemia
Drug: RLY5016 + Losartan
Drug: RLY5016 + ACEi and/or ARB + Spironolactone
Drug: RLY5016 + ACEi and/or ARB + 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 RLY5016 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:
  • Mean change in serum potassium from baseline to week 4 or prior to the initiation of RLY5016 dose titration (if occurs before week 4) [ Time Frame: 28 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Mean change in serum potassium from baseline to week 8 or prior to the initiation of RLY5016 dose titration [ Time Frame: Up to 8 weeks ] [ Designated as safety issue: No ]
  • Proportion of patients maintaining the starting RLY5016 dose at week 4 and 8 [ Time Frame: Up to 8 weeks ] [ Designated as safety issue: No ]
  • Mean change in serum potassium from baseline to post-baseline visits [ Time Frame: Up to 8 weeks ] [ Designated as safety issue: No ]
  • Proportion of patients requiring RLY5016 titration [ Time Frame: up to 8 weeks ] [ Designated as safety issue: No ]
  • Mean time to first RLY5016 titration [ Time Frame: Up to 8 weeks ] [ Designated as safety issue: No ]
  • Mean number of RLY5016 titrations [ Time Frame: Up to 8 weeks ] [ Designated as safety issue: No ]
  • Proportion of patients who maintain serum potassium (K+) in the range of 3.5 - 5.5 mEq/L by visit and during the entire study treatment period [ Time Frame: Up to 8 weeks ] [ Designated as safety issue: No ]
  • Proportion of patients who maintain serum K+ in the range of 4.0 - 5.0 mEq/L by visit and during the entire study treatment period [ Time Frame: up to 8 weeks ] [ Designated as safety issue: No ]
  • Proportion of patients who discontinue from the study due to high serum potassium withdrawal criteria [ Time Frame: Up to 8 weeks ] [ Designated as safety issue: No ]
  • Mean change in blood pressure from screening to week 4 and 8 [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
  • Mean change in urine albumin to creatinine ratio (ACR) from screening to week 4 and 8 [ Time Frame: up to 12 weeks ] [ Designated as safety issue: No ]
  • Proportion of patients with ≥ 35% reduction in urine ACR from screening to week 4 and 8 [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]
  • Proportion of patients with urine ACR ≥ 500 mg/g at screening who achieve ACR < 500 mg/g at week 4 and 8 [ Time Frame: Up to 12 weeks ] [ Designated as safety issue: No ]

Enrollment: 306
Study Start Date: May 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
patients with serum potassium >5.0-5.5 mEq/L
Drug: RLY5016 + Losartan
RLY5016 dose: 10 g/d, 20 g/d, and 30 g/d, oral, twice daily; Losartan dose: 100 mg/d, oral, once daily
Drug: RLY5016 + ACEi and/or ARB + Spironolactone
RLY5016 dose: 10 g/d, 20 g/d, and 30 g/d, oral, twice daily; ACEi and/or ARB dose: current; Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily
Experimental: Stratum 2
patients with serum potassium >5.5-<6.0 mEq/L
Drug: RLY5016 + Losartan
RLY5016 dose: 30 g/d and 40 g/d, oral, twice daily; Losartan dose: 100 mg/d, oral, once daily
Drug: RLY5016 + ACEi and/or ARB + Spironolactone
RLY5016 dose: 30 g/d and 40 g/d, oral, twice daily; ACEi and/or ARB dose: current; Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily

  Eligibility

Ages Eligible for Study:   30 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 1. Age 30 - 80 years old at screening
  2. Type 2 diabetes mellitus (T2DM) diagnosed after age 30 which has been treated with oral medications or insulin for at least one year prior to screening
  3. Chronic kidney disease: eGFR 15 - < 60 mL/min/1.73m2 at screening based on central lab serum creatinine measurement (except for patients with hyperkalemia at S1, whose eligibility will be assessed based on local lab eGFR value)
  4. 4. Urine ACR:

    1. Cohorts 1 and 2: urine ACR ≥ 30 mg/g at screening (S1) AND average urine ACR ≥ 30 mg/g at the beginning of Run-In Period (R0) based on up to 3 ACR values obtained starting at S1 and ending at the R0 Visit
    2. Cohort 3: not applicable
  5. Local laboratory serum 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 RLY5016 (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 SBP ≥ 140 - < 180 mmHg OR average DBP ≥ 90 - < 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 RLY5016 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 S1 (except for Cohort 3 patients who are hyperkalemic at S1)
  3. Emergency treatment for T2DM within the last 3 months
  4. Diabetic gastroparesis
  5. Non-diabetic chronic kidney disease
  6. History of bowel obstruction, swallowing disorders, severe gastrointestinal disorders or major gastrointestinal surgery (e.g., cholectomy)
  7. Current diagnosis of NYHA Class III or IV heart failure
  8. Body mass index (BMI) ≥ 40 kg/m2
  9. Any of the following events having occurred within 2 months prior to screening: unstable angina as judged by the Investigator, unresolved acute coronary syndrome, cardiac arrest or clinically significant ventricular arrhythmias, transient ischemic attack or stroke, use of any intravenous cardiac medication
  10. Prior kidney transplant, or anticipated need for transplant during study participation
  11. Active cancer, currently on cancer treatment or history of cancer in the past two years except for non-melanocytic skin cancer which is considered cured
  12. History of alcoholism or drug/chemical abuse within 1 year
  13. Central lab liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST)] > 3 times upper limit of normal (except for Cohort 3 patients with hyperkalemia at S1, who will have local lab ALT and AST)
  14. 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
  15. 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
  16. Current use of lithium
  17. 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
  18. Use of any investigational product within 30 days or 5 half-lives, whichever is longer, prior to screening
  19. Inability to consume the investigational product, or, in the opinion of the Investigator, inability to comply with the protocol
  20. 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 patient 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

  Hide Study Locations
Locations
Croatia
Investigator Site 201
Karlovac, Croatia, 47000
Investigator Site 207
Osijek, Croatia, 31000
Investigator Site 203
Rijeka, Croatia, 51000
Investigator Site 204
Zagreb, Croatia, 10000
Investigator Site 202
Zagreb, Croatia, 10000
Investigator Site 208
Zagreb, Croatia, 10000
Georgia
Investigator site 301
Tbilisi, Georgia, 0159
Investigator Site 302
Tbilisi, Georgia, 0159
Investigator Site 303
Tbilisi, Georgia, 0159
Investigator Site 304
Tbilisi, Georgia, 0141
Investigator Site 305
Tbilisi, Georgia, 0102
Investigator Site 306
Tbilisi, Georgia, 0179
Investigator Site 307
Tbilisi, Georgia, 0164
Investigator Site 308
Tbilisi, Georgia, 0186
Investigator Site 309
Tbilisi, Georgia, 0144
Investigator Site 310
Tbilisi, Georgia, 0159
Investigator Site 311
Tbilisi, Georgia, 0141
Hungary
Investigator Site 516
Baja, Hungary, H-6500
Investigator Site 501
Budapest, Hungary, 1083
Investigator Site 502
Budapest, Hungary, 1106
Investigator Site 508
Budapest, Hungary, 1097
Investigator Site 513
Budapest, Hungary, 1097
Investigator Site 514
Budapest, Hungary, H-1041
Investigator Site 517
Budapest, Hungary, H-1115
Investigator Site 518
Debrecen, Hungary, H-4032
Investigator Site 522
Gyor, Hungary, H-9024
Investigator Site 515
Jaszbereny, Hungary, H-5100
Investigator Site 511
Kecskemet, Hungary, 6000
Investigator Site 506
Kistarcsa, Hungary, 2143
Investigator Site 503
Kisvarda, Hungary, 4600
Investigator Site 510
Mosonmagyarovar, Hungary, 9200
Investigator Site 520
Pecs, Hungary, H-7624
Investigator Site 504
Szekesfehervar, Hungary, 8000
Investigator Site 505
Szikszo, Hungary, 3800
Investigator Site 507
Veszprem, Hungary, 8200
Serbia
Investigator Site 601
Belgrade, Serbia, 11000
Investigator Site 602
Belgrade, Serbia, 11000
Investigator Site 604
Belgrade, Serbia, 11000
Investigator Site 605
Belgrade, Serbia, 11000
Investigator Site 606
Belgrade, Serbia, 11000
Investigator Site 603
Novi Sad, Serbia, 21000
Slovenia
Investigator Site 706
Golnik, Slovenia, 4204
Investigator Site 705
Izola, Slovenia, 6310
Investigator Site 708
Jesenice, Slovenia, 4270
Investigator Site 702
Ljubljana, Slovenia, 1000
Investigator Site 701
Maribor, Slovenia, 2000
Investigator Site 704
Slovenj Gradec, Slovenia, 2380
Investigator Site 707
Šempeter pri Gorici, Slovenia, 5290
Sponsors and Collaborators
Relypsa, Inc.
Investigators
Study Director: Yuri Stasiv Relypsa, Inc.
  More Information

Additional Information:
No publications provided

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
Last Updated: September 13, 2013
Health Authority: Austria: Austrian Federal Office for Safety in Health Care
Croatia: Ministry of Health and Social Welfare of the Republic of Croatia
Georgia: State Regulation Agency for Medical Activities of Ministry of Labour, Health & Social Affairs of Georia
Hungary: National Institute of Pharmacy
Serbia: Medicines and Medical Devices Agency of Serbia
Slovenia: Agency for Medicinal products and Medical Devices

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
Spironolactone
Angiotensin-Converting Enzyme Inhibitors
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing

ClinicalTrials.gov processed this record on September 18, 2014