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

Hypertension Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01371747
• Other study ID #: RLY5016-205
• Secondary ID: 2011-000165-12
• Status: Completed
• Phase: Phase 2
• Start date: June 2011
• Est. completion date: June 2013

Study information

• Verified date: May 2021
• Source: Vifor Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 324
• Est. completion date: June 2013
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Chronic Kidney Disease
• Diabetic Nephropathies
• Hyperkalemia
• Hypertension
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

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)
• 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)
• 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)
• 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)
• 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)
• 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)
• losartan
losartan dose: 100 mg/d, oral, once daily (initiated during Run-In Period; Cohort 1)
• spironolactone
Spironolactone dose: 25 mg/d or up to 50 mg/d, oral, once daily (initiated during Run-In Period; Cohort 2)

Locations

Country	Name	City	State
Croatia	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
Georgia	Investigator site 301	Tbilisi
Georgia	Investigator Site 302	Tbilisi
Georgia	Investigator Site 303	Tbilisi
Georgia	Investigator Site 304	Tbilisi
Georgia	Investigator Site 305	Tbilisi
Georgia	Investigator Site 306	Tbilisi
Georgia	Investigator Site 307	Tbilisi
Georgia	Investigator Site 308	Tbilisi
Georgia	Investigator Site 309	Tbilisi
Georgia	Investigator Site 310	Tbilisi
Georgia	Investigator Site 311	Tbilisi
Hungary	Investigator Site 502	Budapest
Hungary	Investigator Site 508	Budapest
Hungary	Investigator Site 513	Budapest
Hungary	Investigator Site 514	Budapest
Hungary	Investigator Site 517	Budapest
Hungary	Investigator Site 522	Gyor
Hungary	Investigator Site 523	Hatvan
Hungary	Investigator Site 515	Jaszbereny
Hungary	Investigator Site 506	Kistarcsa
Hungary	Investigator Site 503	Kisvarda
Hungary	Investigator Site 510	Mosonmagyarovar
Hungary	Investigator Site 504	Szekesfehervar
Hungary	Investigator Site 505	Szikszo
Hungary	Investigator Site 507	Veszprem
Serbia	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
Slovenia	Investigator Site 707	Šempeter pri Gorici
Slovenia	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

Sponsors (1)

Lead Sponsor	Collaborator
Relypsa, Inc.

Countries where clinical trial is conducted

Croatia,  Georgia,  Hungary,  Serbia,  Slovenia, 

References & Publications (1)

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. Erratum in: JAMA. 2015 Aug 18;314(7):731. Dosage error in article text. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Relypsa company website