Spironolactone With Patiromer in the Treatment of Resistant Hypertension in Chronic Kidney Disease (AMBER)

A Randomized, Double-Blind, Placebo Controlled, Parallel Group Study of Patiromer for the Enablement of Spironolactone Use for Blood Pressure Control in Patients With Resistant Hypertension and Chronic Kidney Disease

The purpose of this study is to determine if patiromer treatment in chronic kidney disease (CKD) subjects receiving spironolactone for the treatment of resistant hypertension will result in more persistent use of spironolactone through prevention of hyperkalemia and lead to improved blood pressure control compared with treatment with spironolactone alone (placebo).

Study Overview

• Status: Completed
• Conditions: Hyperkalemia; Resistant Hypertension
• Intervention / Treatment: Drug: Patiromer; Drug: Spironolactone; Drug: Placebo

Detailed Description

Approximately 290 eligible participants with [chronic kidney disease (CKD) on stable doses of medication] will be randomly assigned to receive a patiromer or placebo starting dose of two packets a day, once a day.

All eligible participants will undergo a screening/run-in period (up to 4 weeks) to determine eligibility for study entry. Eligible participants will be randomized and treated for 12 weeks (Treatment Period) and followed for 2 weeks after completing the patiromer or placebo treatment. There are 8 planned clinic visits during the Treatment Period and one planned visit two weeks after the last dose of patiromer or placebo (Follow-up Period).

The dose of patiromer or placebo may be increased or decreased (titrated) based on participants' individual potassium response.

• Study Type: Interventional
• Enrollment (Actual): 295
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bulgaria
  • Sofia, Bulgaria, 1612
    • Investigator Site 1402
• Croatia
  • Zagreb, Croatia, 10000
    • Investiagor Site 2205
  • Zagreb, Croatia, 10000
    • Investigator Site 2201
  • Zagreb, Croatia, 10000
    • Investigator Site 2202
  • Zagreb, Croatia, 10000
    • Investigator Site 2203
• Georgia
  • Tbilisi, Georgia, 0102
    • Investigator Site 3806
  • Tbilisi, Georgia, 0112
    • Investigator Site 3811
  • Tbilisi, Georgia, 0144
    • Investigator Site 3802
  • Tbilisi, Georgia, 0159
    • Investigator Site 3801
  • Tbilisi, Georgia, 0159
    • Investigator Site 3804
  • Tbilisi, Georgia, 0159
    • Investigator Site 3805
  • Tbilisi, Georgia, 0159
    • Investigator Site 3807
  • Tbilisi, Georgia, 0159
    • Investigator Site 3808
  • Tbilisi, Georgia, 0159
    • Investigator Site 3810
  • Tbilisi, Georgia, 0159
    • Investigator Site 3812
  • Tbilisi, Georgia, 0159
    • Investigator Site 3813
  • Tbilisi, Georgia, 0186
    • Investigator Site 3809
• Germany
  • Gottingen, Germany, 37075
    • Investigator Site 4202
• Hungary
  • Balatonfured, Hungary, H-8230
    • Investigator Site 4607
  • Budapest, Hungary, H-1097
    • Investigator Site 4606
  • Debrecen, Hungary, 4032
    • Investigator Site 4611
  • Hatvan, Hungary, H-3000
    • Investigator Site 4601
  • Kistarcsa, Hungary, H-2143
    • Investigator Site 4605
  • Miskolc, Hungary, H-3529
    • Investigator Site 4602
  • Miskolc, Hungary, H-3530
    • Investigator Site 4610
  • Mosonmagyarovar, Hungary, H-9200
    • Investigator Site 4608
• South Africa
  • Johannesburg, South Africa
    • Investigator Site 7403
• Ukraine
  • Khar'kov, Ukraine, 61006
    • Investigator Site 7803
  • Kharkiv, Ukraine, 61002
    • Investiagor Site 7809
  • Kharkiv, Ukraine, 61039
    • Investigator Site 7808
  • Kharkiv, Ukraine, 61103
    • Investigator Site 7802
  • Kiev, Ukraine, 03680
    • Investigator Site 7805
  • Kiev, Ukraine, 04114
    • Investigator Site 7801
  • Zaporizhzhia, Ukraine, 69001
    • Investigator Site 7804
  • Zaporizhzhia, Ukraine, 69118
    • Investigator Site 7807
• United Kingdom
  • Leicester, United Kingdom, LE5 4QF
    • Investigator Site 8202
  • London, United Kingdom, Se5 9RS
    • Investigator Site 8205
• United States
  • Florida
    • Hollywood, Florida, United States, 33021
      • Investigator site 1012
    • Miami Lakes, Florida, United States, 33014
      • Investigator Site 1023
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Investigator Site 1022

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years
• Taking at least three medications for blood pressure (one a diuretic)
• Uncontrolled high blood pressure
• Abnormal kidney function (with-eGFR, a measure of kidney function, of 25 - ≤ 45 mL/min/1.73m2
• Normal Blood serum Potassium in a specific range (4.3 - 5.1 mEq/L)

Exclusion Criteria:

• History of untreated known causes of high blood pressure, excluding kidney disease (not CKD)
• Inability to measure BP
• Not taking high blood pressure medications as prescribed medications
• Recent change in renal function (in the past 3 months) which has required hospitalization or dialysis
• Renal transplant
• History of cancer within past 12 months
• Recent cardiovascular event with last 3 months
• Clinically significant abnormalities of heart rhythm (ventricular arrhythmia or atrial fibrillation with uncontrolled heart rate)
• Inability to take study medication
• Alcoholism

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1 - Patiromer; spironolactone + blinded patiromer	Drug: Patiromer; 2 packets/day starting dose, administered orally; Other Names: Veltassa; RLY5016 for Oral Suspension; Patiromer for Oral Suspension; Drug: Spironolactone; 25 mg tablet/day starting dose, administered orally
Experimental: Group 2 - Placebo; spironolactone + blinded placebo	Drug: Spironolactone; 25 mg tablet/day starting dose, administered orally; Drug: Placebo; 2 packets/day starting dose, administered orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Remaining on Spironolactone at Week 12	The proportion of subjects remaining on spironolactone at Week 12 will be compared between treatment groups (spironolactone/patiromer versus spironolactone/placebo). Subjects who discontinued from the study early or discontinued study spironolactone prior to Week 12, for any reason, were considered as not having remained on spironolactone until Week 12.	At week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in AOBP SBP From Baseline to Week 12 or Last Available AOBP SBP Prior to Addition of Any New BP Medications or Increase From Any Baseline BP Medications	AOBP: Automated Office Blood Pressure SBP: Systolic Blood Pressure BP: Blood Pressure	From baseline to Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in AOBP SBP From Baseline to Week 12 Regardless of Increase in Antihypertensives	AOBP SBP: Automated Office Systolic Blood Pressure	From baseline to Week 12
Central Serum Potassium Change From Baseline to Week 12 by Baseline Serum Potassium Category	The two baseline potassium subgroups, 4.3-<4.7 mEq/L versus 4.7-5.1 mEq/L, are based on central laboratory data. If a participant's serum potassium result at baseline was not in one of the two subgroups reported below, the participant's potassium stratum at randomization was used. Therefore, participants with BCSP <4.3 mEq/L or >5.1 mEq/L at baseline (Day 0) have been classified according to their serum potassium values at the Screening period.	From baseline to Week 12
Participants With Central Serum Potassium <5.5 mEq/L Over Time	Baseline Central Serum Potassium: BCSP. The symbols > and ≤ included in the row titles are used to indicate the time interval [">Week1 and ≤Week2" meaning from day 8 until day 14 (included)]. If a participant's serum potassium result at baseline was not in one of the two subgroups reported below, the participant's potassium stratum at randomization was used. Therefore, participants with BCSP <4.3 mEq/L or >5.1 mEq/L at baseline (Day 0) have been classified according to their serum potassium values at the Screening period.	From baseline to Week 12
Participants Having Spironolactone Titrations Over Time	The titration was performed according to the following criteria: Spironolactone was increased in cases of hypertension, decreased or stopped in cases of hypotension and maintained if the blood pressure results were adequate The symbols > and ≤ included in the row titles are used to indicate the time interval [">Week1 and ≤Week2" meaning from day 8 until day 14 (included)].	From baseline to Week 12
Number of Participants by Spironolactone Dose Prescribed at Each Visit	QD: Once daily QOD: Once every other day	From baseline to Week 10
Shifts in Selected Laboratory Tests From Baseline to End of Treatment	The end of treatment value is defined as the last non-missing value on or prior to the last spironolactone dose date (from End of Treatment - Case report form) + 3 days LLN=Lower limit of the normal range. ULN=Upper limit of the normal range. EoT=End of Treatment	From Baseline to End of Treatment, up to 12 weeks.
Spironolactone Dose Level at End of 12 Weeks of Study Treatment	Row title: Participants not completing 12W of study treatment: Participants who had not completed 12 weeks of study treatment.	12 Weeks of Study Treatment

Collaborators and Investigators

• Sponsor: Relypsa, Inc.
• Investigators: Study Director: Study Director or VP Clinical Development, Relypsa, Inc.

Publications and helpful links

General Publications

• 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.
• Agarwal R, Rossignol P, Budden J, Mayo MR, Arthur S, Williams B, White WB. Patiromer and Spironolactone in Resistant Hypertension and Advanced CKD: Analysis of the Randomized AMBER Trial. Kidney360. 2021 Jan 15;2(3):425-434. doi: 10.34067/KID.0006782020. eCollection 2021 Mar 25.
• Agarwal R, Rossignol P, Romero A, Garza D, Mayo MR, Warren S, Ma J, White WB, Williams B. Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2019 Oct 26;394(10208):1540-1550. doi: 10.1016/S0140-6736(19)32135-X. Epub 2019 Sep 15.
• Agarwal R, Rossignol P, Garza D, Mayo MR, Warren S, Arthur S, Romero A, White WB, Williams B. Patiromer to Enable Spironolactone Use in the Treatment of Patients with Resistant Hypertension and Chronic Kidney Disease: Rationale and Design of the AMBER Study. Am J Nephrol. 2018;48(3):172-180. doi: 10.1159/000492622. Epub 2018 Sep 3.

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2017
• Primary Completion (Actual): November 27, 2018
• Study Completion (Actual): November 27, 2018

Study Registration Dates

• First Submitted: March 1, 2017
• First Submitted That Met QC Criteria: March 1, 2017
• First Posted (Actual): March 6, 2017

Study Record Updates

• Last Update Posted (Actual): May 12, 2021
• Last Update Submitted That Met QC Criteria: May 10, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Hypertension; Chronic Kidney Disease; Resistant Hypertension; Potassium; Treatment of Hyperkalemia; Hyperkalemia; Spironolactone
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Urologic Diseases; Renal Insufficiency; Water-Electrolyte Imbalance; Hypertension; Kidney Diseases; Renal Insufficiency, Chronic; Hyperkalemia; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: RLY5016-207; 2016-002657-38 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No