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

NCT ID: NCT01371747

Last Updated: 2021-06-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 324 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-06-30
• Study Completion Date: 2013-06-30

Brief 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.

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

Conditions

Chronic Kidney Disease; Hypertension; Hyperkalemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Stratum 1: 8.4 g/d patiromer

Participants with baseline serum potassium \> 5.0 to 5.5 mEq/L (milliequivalent)

Group Type: EXPERIMENTAL

patiromer

Intervention Type: DRUG

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)

losartan

Intervention Type: DRUG

losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)

spironolactone

Intervention Type: DRUG

Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)

Stratum 1: 16.8 g/d patiromer

Participants with baseline serum potassium \> 5.0 to 5.5 mEq/L

Group Type: EXPERIMENTAL

patiromer

Intervention Type: DRUG

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)

losartan

Intervention Type: DRUG

losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)

spironolactone

Intervention Type: DRUG

Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)

Stratum 1: 25.2 g/d patiromer

Participants with baseline serum potassium \> 5.0 to 5.5 mEq/L

Group Type: EXPERIMENTAL

patiromer

Intervention Type: DRUG

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)

losartan

Intervention Type: DRUG

losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)

spironolactone

Intervention Type: DRUG

Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)

Stratum 2: 16.8 g/d patiromer

Participants with baseline serum potassium \> 5.5 to \< 6.0 mEq/L

Group Type: EXPERIMENTAL

patiromer

Intervention Type: DRUG

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)

losartan

Intervention Type: DRUG

losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)

spironolactone

Intervention Type: DRUG

Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)

Stratum 2: 25.2 g/d patiromer

Participants with baseline serum potassium \> 5.5 to \< 6.0 mEq/L

Group Type: EXPERIMENTAL

patiromer

Intervention Type: DRUG

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)

losartan

Intervention Type: DRUG

losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)

spironolactone

Intervention Type: DRUG

Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)

Stratum 2: 33.6 g/d patiromer

Participants with baseline serum potassium \> 5.5 to \< 6.0 mEq/L

Group Type: EXPERIMENTAL

patiromer

Intervention Type: DRUG

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

Intervention Type: DRUG

losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)

spironolactone

Intervention Type: DRUG

Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)

Interventions

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)

Intervention Type: 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)

Intervention Type: 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)

Intervention Type: 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)

Intervention Type: 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)

Intervention Type: 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)

Intervention Type: DRUG

losartan

losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)

Intervention Type: DRUG

spironolactone

Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)

Intervention Type: DRUG

Other Intervention Names

RLY5016 for Oral Suspension; Veltassa; RLY5016 for Oral Suspension; Veltassa; RLY5016 for Oral Suspension; Veltassa; RLY5016 for Oral Suspension; Veltassa; RLY5016 for Oral Suspension; Veltassa; RLY5016 for Oral Suspension; Veltassa

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

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Relypsa, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Director Clinical Operations

Role: STUDY_DIRECTOR

Relypsa, Inc.

Locations

Investigator Site 201

Karlovac, , Croatia

Investigator Site 207

Osijek, , Croatia

Investigator Site 203

Rijeka, , Croatia

Investigator Site 202

Zagreb, , Croatia

Investigator Site 204

Zagreb, , Croatia

Investigator Site 208

Zagreb, , Croatia

Investigator Site 305

Tbilisi, , Georgia

Investigator Site 309

Tbilisi, , Georgia

Investigator site 301

Tbilisi, , Georgia

Investigator Site 302

Tbilisi, , Georgia

Investigator Site 303

Tbilisi, , Georgia

Investigator Site 304

Tbilisi, , Georgia

Investigator Site 306

Tbilisi, , Georgia

Investigator Site 307

Tbilisi, , Georgia

Investigator Site 310

Tbilisi, , Georgia

Investigator Site 311

Tbilisi, , Georgia

Investigator Site 308

Tbilisi, , Georgia

Investigator Site 508

Budapest, , Hungary

Investigator Site 502

Budapest, , Hungary

Investigator Site 514

Budapest, , Hungary

Investigator Site 513

Budapest, , Hungary

Investigator Site 517

Budapest, , Hungary

Investigator Site 522

Győr, , Hungary

Investigator Site 523

Hatvan, , Hungary

Investigator Site 515

Jászberény, , Hungary

Investigator Site 506

Kistarcsa, , Hungary

Investigator Site 503

Kisvárda, , Hungary

Investigator Site 510

Mosonmagyaróvár, , Hungary

Investigator Site 504

Székesfehérvár, , Hungary

Investigator Site 505

Szikszó, , Hungary

Investigator Site 507

Veszprém, , Hungary

Investigator Site 601

Belgrade, , Serbia

Investigator Site 602

Belgrade, , Serbia

Investigator Site 604

Belgrade, , Serbia

Investigator Site 605

Belgrade, , Serbia

Investigator Site 603

Novi Sad, , Serbia

Investigator Site 607

Zrenjanin, , Serbia

Investigator Site 703

Celje, , Slovenia

Investigator Site 706

Golnik, , Slovenia

Investigator Site 708

Jesenice, , Slovenia

Investigator Site 701

Maribor, , Slovenia

Investigator Site 704

Slovenj Gradec, , Slovenia

Investigator Site 707

Šempeter pri Gorici, , Slovenia

Countries

Croatia; Georgia; Hungary; Serbia; Slovenia

References

Bakris GL, Pitt B, Weir MR, Freeman MW, Mayo MR, Garza D, Stasiv Y, Zawadzki R, Berman L, Bushinsky DA; AMETHYST-DN Investigators. Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial. JAMA. 2015 Jul 14;314(2):151-61. doi: 10.1001/jama.2015.7446.

Reference Type: BACKGROUND

PMID: 26172895 (View on PubMed)

Bakris GL, Woods SD, Alvarez PJ, Arthur SP, Kumar R. Hyperkalemia Management in Older Adults With Diabetic Kidney Disease Receiving Renin-Angiotensin-Aldosterone System Inhibitors: A Post Hoc Analysis of the AMETHYST-DN Clinical Trial. Kidney Med. 2021 Mar 13;3(3):360-367.e1. doi: 10.1016/j.xkme.2021.01.005. eCollection 2021 May-Jun.

Reference Type: DERIVED

PMID: 34136782 (View on PubMed)

Natale P, Palmer SC, Ruospo M, Saglimbene VM, Strippoli GF. Potassium binders for chronic hyperkalaemia in people with chronic kidney disease. Cochrane Database Syst Rev. 2020 Jun 26;6(6):CD013165. doi: 10.1002/14651858.CD013165.pub2.

Reference Type: DERIVED

PMID: 32588430 (View on PubMed)

Pitt B, Bakris GL, Weir MR, Freeman MW, Lainscak M, Mayo MR, Garza D, Zawadzki R, Berman L, Bushinsky DA. Long-term effects of patiromer for hyperkalaemia treatment in patients with mild heart failure and diabetic nephropathy on angiotensin-converting enzymes/angiotensin receptor blockers: results from AMETHYST-DN. ESC Heart Fail. 2018 Aug;5(4):592-602. doi: 10.1002/ehf2.12292. Epub 2018 May 16.

Reference Type: DERIVED

PMID: 29767459 (View on PubMed)

Other Identifiers

2011-000165-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

RLY5016-205

Identifier Type: -

Identifier Source: org_study_id