The purpose of this study is to assess the effects of patiromer compared with placebo on serum K+ in HF patients.
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
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
1,195
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).
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).
Changes in Serum K+ Levels From Baseline
Adjusted mean changes in serum K+ from Baseline.
Time frame: Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo
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
Time frame: 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
Time frame: 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.
Time frame: 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: 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
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Investigator Site 11-080
Alexander City, Alabama, United States
Investigator Site 11-041
Huntsville, Alabama, United States
Investigator Site 11-153
Phoenix, Arizona, United States
Investigator Site 11-097
Tucson, Arizona, United States
Investigator Site 11-052
Bakersfield, California, United States
Investigator Site 11-174
Fremont, California, United States
Investigator Site 11-136
Fresno, California, United States
Investigator Site 11-102
Huntington Beach, California, United States
Investigator Site 11-162
La Jolla, California, United States
Investigator Site 11-048
La Mesa, California, United States
...and 405 more locations
Time frame: 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: 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.
Time frame: Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo