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

Study Overview
=================
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.

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)

Conditions
-----------------
Hyperkalemia

Intervention / Treatment
-----------------
* Drug: Patiromer
* Drug: Placebos


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Patiromer<br>Subjects will be randomized to receive a daily dose of patiromer with possible dose adjustments based on subsequent local serum potassium levels. | Drug: Patiromer<br>* 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).<br>* Other names: Veltassa;|
| Placebo Comparator: Group 2: Placebo<br>Subjects will be randomized to receive a daily dose of placebo with possible dose adjustments based on subsequent local serum potassium levels. | Drug: Placebos<br>* 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).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Serum K+ Levels From Baseline | Adjusted mean changes in serum K+ from Baseline. | Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time | 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 | From Day 1/Baseline to week 90 | 
| CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time | 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 | From Day 1/Baseline to week 102 | 
| Investigator-reported Events of Hyperkalemia | 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. | Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo | 
| Hyperkalemia-related Hard Outcomes Endpoints | Analyzed using Win Ratio approach with the following hierarchical components: Time to CV death Total number of CV hospitalizations Total number of hyperkalemia toxicity events with serum K+ >6.5 mEq/l Total number of hyperkalemia events with serum K+ >6.0-6.5 mEq/l Total number of hyperkalemia events with serum K+ >5.0 mEq/l MHTE=More hyperkalemia toxicity events; MHE=More hyperkalemia events; CV=Cardiovascular | Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo | 
| RAASi Use Score | RAASi use score (0 to 8 points) analyzed using the Win Ratio approach for each pair of participants with the following additive components: All-cause death Occurrence of a CV hospitalization 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. | Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
treatment of hyperkalemia, chronic kidney disease, hypertension, hyperkalemia, potassium, spironolactone, heart failure, Renin Angiotensin-Aldosterone System Inhibitor (RAASi), RAASi, high potassium, eplerenone, reduced ejection fraction