Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure (DIAMOND) (DIAMOND)

• ClinicalTrials.gov Identifier: NCT03888066
• Recruitment Status: Completed
• First Posted: March 25, 2019
• Results First Posted: February 24, 2023
• Last Update Posted: February 24, 2023
• Sponsor: Vifor Pharma, Inc.
• Collaborator: Syneos Health, LLC
• Information provided by (Responsible Party): Vifor Pharma ( Vifor Pharma, Inc. )

Tracking Information

• First Submitted Date: March 12, 2019
• First Posted Date: March 25, 2019
• Results First Submitted Date: August 25, 2022
• Results First Posted Date: February 24, 2023
• Last Update Posted Date: February 24, 2023
• Actual Study Start Date: April 24, 2019
• Actual Primary Completion Date: September 2, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 17, 2022)

Changes in Serum K+ Levels From Baseline [ Time Frame: Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo ]

Adjusted mean changes in serum K+ from Baseline.

Original Primary Outcome Measures (submitted: March 21, 2019)

Time to first occurrence of CV death or CV hospitalization (or equivalent in outpatient clinic) [ Time Frame: 6 months to 2.5 years ]

To determine if patiromer treatment of subjects who developed hyperkalemia while receiving RAASi medications will result in continued use of RAASi medications in accordance with heart failure (HF) treatment guidelines and thereby decrease the occurrence of the combined endpoint of cardiovascular (CV) death and CV hospitalization events compared with placebo treatment.

Current Secondary Outcome Measures (submitted: February 22, 2023)

• CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time [ Time Frame: From Day 1/Baseline to week 90 ]
  Cumulative incidence of the first event of hyperkalemia with a serum K+ value >5.5 mEq/l taking death as competing and calculated as CIF Estimates (95% CI) over time. Aalen-Johansen estimators of the cumulative incidence function with death as a competing event. CIF = cumulative incidence function; mEq/l = Milliequivalents Per Liter
• CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time [ Time Frame: From Day 1/Baseline to week 102 ]
  Cumulative incidence of the reduction of the MRA dose below target dose calculated as CIF Estimates (95% CI) over time. Note: The reduction below the MRA target dose must last for at least 14 days (orless if at the end of study) to confirm this endpoint. CIF = cumulative incidence function; mEq/l = Milliequivalents Per Liter
• Investigator-reported Events of Hyperkalemia [ Time Frame: Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo ]
  Participant's follow-up is from the date of the first dose of randomized study medication up to the participant's end of study date or 24 Jun 2021, whichever comes first. Annualized event rate per 100 subject-years= The total number of events for all subjects in the treatment group divided by the total subject-years of follow-up in that treatment group multiplied by 100.
• Hyperkalemia-related Hard Outcomes Endpoints [ Time Frame: Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo ]
  Analyzed using Win Ratio approach with the following hierarchical components:

  1. Time to CV death
  2. Total number of CV hospitalizations
  3. Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/l
  4. Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/l
  5. Total number of hyperkalemia events with serum K+ >5.0 mEq/l

  MHTE=More hyperkalemia toxicity events; MHE=More hyperkalemia events; CV=Cardiovascular
• RAASi Use Score [ Time Frame: Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo ]
  RAASi use score (0 to 8 points) analyzed using the Win Ratio approach for each pair of participants with the following additive components:

  1. All-cause death
  2. Occurrence of a CV hospitalization
  3. HF medication use and dose for i) an ACEi/ARB/ARNi, ii) a MRA, and iii) a beta-blocker

  Each participant in each comparison can have 0-8 points and all participants are compared using this score at the respective appropriate follow-up time point. RAASi=renin-angiotensin-aldosterone system inhibitor; ACEi=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blocker; ARNi=angiotensin receptor/neprilysin inhibitor; MRA=mineralocorticoid receptor antagonist.

Original Secondary Outcome Measures (submitted: March 21, 2019)

• Proportion of subjects on ≥ 50% of guideline-recommended target dose of RAASi medications [ Time Frame: Through End of Study Visit, approximately 2.5 years ]
  Proportion of subjects on ≥ 50% of guideline-recommended target dose of angiotensin-converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB), or ARNi and ≥ 50% of guideline-recommended target dose of MRA at the End of Study Visit
• Total HF hospitalizations [ Time Frame: Through End of Study Visit, approximately 2.5 years ]
  Total HF hospitalizations (or equivalent in outpatient clinic)
• Kansas City Cardiomyopathy Questionnaire (KCCQ) [ Time Frame: Through End of Study Visit, approximately 2.5 years ]
  Patient reported outcome: Kansas City Cardiomyopathy Questionnaire (KCCQ)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure (DIAMOND)
• Official Title: A Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal, Parallel Group Study of Patiromer for the Management of Hyperkalemia in Subjects Receiving Renin Angiotensin Aldosterone System Inhibitor (RAASi) Medications for the Treatment of Heart Failure (DIAMOND)
• Brief Summary: The purpose of this study is to assess the effects of patiromer compared with placebo on serum K+ in HF patients.

Detailed Description

Prospective Phase 3b multinational, multicenter, double-blind, placebo-controlled, randomized withdrawal, parallel group study that includes screening and up to 12 weeks Run-in Phase (all subjects will have patiromer initiated and RAASi medications, including mineralocorticoid receptor antagonist (MRA) optimized) and a randomized withdrawal Blinded Treatment Phase.

The study population includes subjects with heart failure (HF) with reduced ejection fraction (HFrEF) who are hyperkalemic (serum potassium [K+] > 5.0 mEq/L) while receiving treatment with renin angiotensin aldosterone system inhibitor (RAASi) medications or who are normokalemic (serum K+ 4.0 - 5.0 mEq/L) but have a history of hyperkalemia prior to screening with subsequent reduction or discontinuation of a RAASi medication.

Each subject's participation includes a Run-in Phase (maximum 12 weeks) followed by the Treatment Phase (variable per subject). Study duration for individual subjects will vary, depending on their individual enrollment date. Subjects who prematurely discontinue patiromer/placebo will remain in the study for the collection of clinical events data and will receive usual care.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Prospective Phase 3b multinational, multicenter, double-blind, placebo-controlled, randomized withdrawal, parallel group study that includes screening and 12 weeks Run-in Phase and a randomized withdrawal Blinded Treatment Phase.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention

• Condition: Hyperkalemia

Intervention

• Drug: Patiromer
  The starting dose of patiromer will be 1 packet/day and may be taken either with food or without food. Based upon the patiromer treatment algorithm patiromer may be increased by 1 packet per day in intervals of at least 1 week (± 3 days). For subjects who become hypokalemic, patiromer may be decreased to a minimum of 0 packets/day. Doses of patiromer will be 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).
  Other Name: Veltassa
• Drug: Placebos
  The starting dose of placebo will be 1 packet/day and may be taken either with food or without food. Based upon the placebo treatment algorithm placebo may be increased by 1 packet per day in intervals of at least 1 week (± 3 days). For subjects who become hypokalemic, placebo may be decreased to a minimum of 0 packets/day. Doses of placebo will be 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).

Study Arms

• Experimental: Group 1: Patiromer
  Subjects will be randomized to receive a daily dose of patiromer with possible dose adjustments based on subsequent local serum potassium levels.
  Intervention: Drug: Patiromer
• Placebo Comparator: Group 2: Placebo
  Subjects will be randomized to receive a daily dose of placebo with possible dose adjustments based on subsequent local serum potassium levels.
  Intervention: Drug: Placebos

Publications *

• Butler J, Anker SD, Lund LH, Coats AJS, Filippatos G, Siddiqi TJ, Friede T, Fabien V, Kosiborod M, Metra M, Pina IL, Pinto F, Rossignol P, van der Meer P, Bahit C, Belohlavek J, Bohm M, Brugts JJ, Cleland JGF, Ezekowitz J, Bayes-Genis A, Gotsman I, Goudev A, Khintibidze I, Lindenfeld J, Mentz RJ, Merkely B, Montes EC, Mullens W, Nicolau JC, Parkhomenko A, Ponikowski P, Seferovic PM, Senni M, Shlyakhto E, Cohen-Solal A, Szecsody P, Jensen K, Dorigotti F, Weir MR, Pitt B. Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial. Eur Heart J. 2022 Nov 1;43(41):4362-4373. doi: 10.1093/eurheartj/ehac401.
• Bolanos JA, Seliger SL. Recurrent Hyperkalemia in Renin-Angiotensin-Aldosterone System Inhibitor (RAASi) Treatment: Stuck between a Rock and a Hard Place. Clin J Am Soc Nephrol. 2021 Mar 8;16(3):345-347. doi: 10.2215/CJN.00950121. Epub 2021 Feb 19. No abstract available.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 22, 2023): 1195
• Original Estimated Enrollment (submitted: March 21, 2019): 2388
• Actual Study Completion Date: September 2, 2021
• Actual Primary Completion Date: September 2, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age at least 18 years or greater
• Symptomatic low ejection fraction heart failure (weak heart muscle)
• Receiving any dose of a beta blocker for the treatment of HF (unless not able to tolerate)
• Kidney function not more than mild or moderately impaired
• High blood potassium (>5.0 mEq/L) currently while receiving medications for heart failure OR normal blood potassium currently but previously had high potassium in the12 months prior to screening which caused a permanent reduction or discontinuation of heart failure medications
• Hospitalization for heart failure or treatment in an out patient setting with intravenous medications within the last 12 months before screening.

Exclusion Criteria:

• Current acute decompensated HF, within 4 weeks before screening. Subjects with a discharge from a hospitalization for acute decompensation of HF longer than 4 weeks before screening may be included
• Significant primary aortic or mitral valvular heart disease (except secondary mitral regurgitation due to left ventricular dilatation)
• Heart transplantation or planned heart transplantation (i.e., currently on a heart transplant waiting list) during the study period

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Belgium, Brazil, Bulgaria, Canada, Czechia, France, Georgia, Germany, Hungary, Israel, Italy, Mexico, Netherlands, Poland, Russian Federation, Serbia, Spain, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03888066
• Other Study ID Numbers: PAT-CR-302; 2018-005030-38 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)

Time Frame

Data can be requested 6 months after the primary publication and approval of the indication studied in the US and European Union (EU), whichever is later.

Data will be indefinitely available for requesting

• Access Criteria: A research proposal must be approved by an independent review panel and the study sponsor and researchers must sign a data sharing agreement.

• Current Responsible Party: Vifor Pharma ( Vifor Pharma, Inc. )
• Original Responsible Party: Relypsa, Inc.
• Current Study Sponsor: Vifor Pharma, Inc.
• Original Study Sponsor: Relypsa, Inc.
• Collaborators: Syneos Health, LLC

Investigators

• Study Director: Peter Szecsödy, MD; Vifor Pharma

• PRS Account: Vifor Pharma
• Verification Date: February 2023