Clinical trial NCT01371747: Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy (AMETHYST-DN)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Kidney Disease
Hypertension
Hyperkalemia
Keywords: Hyperkalemia
Chronic Kidney Disease
Treatment of Hyperkalemia
Hypertension
Diabetic Nephropathy
Lead sponsor: Vifor Pharma
Sponsor class: INDUSTRY
First posted: 2011-06-13
Enrollment: 324
Sex: ALL
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Primary outcomes:
measure: Least Squares Mean Change in Serum Potassium From Baseline to Week 4 or Time of First Titration for Each Individual Starting Dose Group
timeFrame: Baseline to Week 4 or First Titration which could occur at any scheduled study visit after patiromer initiation.
Secondary outcomes:
measure: Least Squares Mean Change in Serum Potassium From Baseline to Week 8 or Time of First Titration for Each Individual Starting Dose Group
timeFrame: Baseline to Week 8 or First Titration which could occur at any scheduled study visit after patiromer initiation.
measure: Least Squares Mean Change in Serum Potassium From Baseline to Day 3 During the Treatment Initiation Period for Each Individual Starting Dose Group
timeFrame: Baseline to Day 3
measure: Mean Change in Serum Potassium From Baseline to Week 52 During the Long-term Maintenance Period for Each Individual Starting Dose Group
timeFrame: Baseline to Week 52
measure: Mean Change in Serum Potassium From Week 52 or Last Patiromer Dose (if Occurred Before Week 52) to Follow-up Visits Plus 7 Days
timeFrame: Week 52 or Last Patiromer Dose (if Occurred before Week 52) to Following up Visit Plus 7 Days
measure: Proportion of Participants Achieving Serum Potassium Levels Within 3.5 to 5.5 mEq/L at Week 8 for Each Individual Starting Dose Group
timeFrame: Baseline to Week 8
measure: Proportion of Participants Achieving Serum Potassium Levels Within 4.0 to 5.0 mEq/L at Week 8 for Each Individual Starting Dose Group
timeFrame: Baseline to Week 8
measure: Time to First Serum Potassium Measurement of 4.0 - 5.0 mEq/L During Treatment Initiation Period for Each Individual Starting Dose Group
timeFrame: Baseline to Week 8
measure: Proportions of Participants Achieving Serum Potassium Levels Within 3.8 to 5.0 mEq/L at Week 52 for Each Individual Starting Dose Group
timeFrame: Baseline to Week 52
Other outcomes:
Locations:
city: Karlovac
country: Croatia
facility: Investigator Site 201
city: Osijek
country: Croatia
facility: Investigator Site 207
city: Rijeka
country: Croatia
facility: Investigator Site 203
city: Zagreb
country: Croatia
facility: Investigator Site 202
city: Zagreb
country: Croatia
facility: Investigator Site 204
city: Zagreb
country: Croatia
facility: Investigator Site 208
city: Tbilisi
country: Georgia
facility: Investigator Site 305
city: Tbilisi
country: Georgia
facility: Investigator Site 309
city: Tbilisi
country: Georgia
facility: Investigator site 301
city: Tbilisi
country: Georgia
facility: Investigator Site 302
city: Tbilisi
country: Georgia
facility: Investigator Site 303
city: Tbilisi
country: Georgia
facility: Investigator Site 304
city: Tbilisi
country: Georgia
facility: Investigator Site 306
city: Tbilisi
country: Georgia
facility: Investigator Site 307
city: Tbilisi
country: Georgia
facility: Investigator Site 310
city: Tbilisi
country: Georgia
facility: Investigator Site 311
city: Tbilisi
country: Georgia
facility: Investigator Site 308
city: Budapest
country: Hungary
facility: Investigator Site 508
city: Budapest
country: Hungary
facility: Investigator Site 502
city: Budapest
country: Hungary
facility: Investigator Site 514
city: Budapest
country: Hungary
facility: Investigator Site 513
city: Budapest
country: Hungary
facility: Investigator Site 517
city: Gyor
country: Hungary
facility: Investigator Site 522
city: Hatvan
country: Hungary
facility: Investigator Site 523
city: Jaszbereny
country: Hungary
facility: Investigator Site 515
city: Kistarcsa
country: Hungary
facility: Investigator Site 506
city: Kisvarda
country: Hungary
facility: Investigator Site 503
city: Mosonmagyarovar
country: Hungary
facility: Investigator Site 510
city: Szekesfehervar
country: Hungary
facility: Investigator Site 504
city: Szikszo
country: Hungary
facility: Investigator Site 505
city: Veszprem
country: Hungary
facility: Investigator Site 507
city: Belgrade
country: Serbia
facility: Investigator Site 601
city: Belgrade
country: Serbia
facility: Investigator Site 602
city: Belgrade
country: Serbia
facility: Investigator Site 604
city: Belgrade
country: Serbia
facility: Investigator Site 605
city: Novi Sad
country: Serbia
facility: Investigator Site 603
city: Zrenjanin
country: Serbia
facility: Investigator Site 607
city: Celje
country: Slovenia
facility: Investigator Site 703
city: Golnik
country: Slovenia
facility: Investigator Site 706
city: Jesenice
country: Slovenia
facility: Investigator Site 708
city: Maribor
country: Slovenia
facility: Investigator Site 701
city: Slovenj Gradec
country: Slovenia
facility: Investigator Site 704
city: Šempeter pri Gorici
country: Slovenia
facility: Investigator Site 707
Study officials:
affiliation: Relypsa, Inc.
name: Director Clinical Operations
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.