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. )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Hyperkalemia
• Interventions: Drug: Patiromer; Drug: Placebos
• Enrollment: 1195

Participant Flow

Recruitment Details

Pre-assignment Details

From a total of 1642 screened participants, 1195 entered the Run-in Phase. The Run-in Phase Set includes participants who signed the informed consent and received at least 1 dose of patiromer during the Run-in Phase but were not eligible to be randomized. A total of 1168 participants received patiromer during Run-in Phase, and 878 of these participants were randomized to receive patiromer or placebo during the Treatment Phase

Arm/Group Title	Patiromer	Placebo
Arm/Group Description	Randomized participants who received a daily dose of patiromer, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of patiromer was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, patiromer was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of patiromer were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose). mEq/l = Milliequivalents Per Liter	Randomized participants who received a daily dose of placebo, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of placebo was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, placebo was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down-titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of placebo were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose). mEq/l = Milliequivalents Per Liter
Period Title: Run-in Phase
Started	1195	0
Completed	878	0
Not Completed	317	0
Reason Not Completed
Randomization Criterion #1	24	0
Randomization Criteria #1, #2	5	0
Randomization Criteria #1, #2 #4; AE; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L	1	0
Randomization Criteria #1, #3	1	0
Randomization Criteria #1, #4	1	0
Randomization Crit #1, #4; Withdraw By Subject; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L	1	0
Randomization Criteria #1, #4; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L	1	0
Randomization Criterion #1; AE	4	0
Randomization Criterion #1; AE; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L	1	0
Randomization Criterion #1; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L	2	0
Randomization Criterion #2	5	0
Randomization Criteria #2, #3	1	0
Randomization Criteria #2, #3, #4	1	0
Randomization Criteria #2, #4	4	0
Randomization Criterion #3	11	0
Randomization Criteria #3, #4	1	0
Randomization Criteria #3, #4; 2 Wks After Taking Min 0 Packet/Day, sK+ Is < 4.0 Meq/L	2	0
Randomization Criterion #3; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L	1	0
Randomization Criterion #4	3	0
Randomization Criterion #3; Physician Decision	1	0
Randomization Criterion #4; AE	4	0
Randomization Criterion #4; AE; 2 Wks After Taking Min 0 Packet/Day, sK+ Is < 4.0 Meq/L	1	0
Randomization Criterion #3; Exceeded 12 Weeks Of Run In	1	0
Randomization Criterion #4; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L	2	0
Randomization Criterion #4; 2 Wks After Taking Min 0 Packet/Day, sK+ Is < 4.0 Meq/L	1	0
AE (Adverse Event)	17	0
AE; Withdrawal By Subject	3	0
AE; Withdrawal By Subject; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L	1	0
AE; 1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L	1	0
AE; 2 Wks After Taking Min 0 Packet/Day, sK+ Is < 4.0 Meq/L	2	0
Withdrawal by Subject	43	0
AE; Physician Decision	1	0
1 Wk After 3 Patiromer Packets/Day, sK+ >5.0 Meq/L	10	0
Withdrawal By Subject; Withdrawal Of Consent	1	0
2 Wks After Taking Min 0 Packet/Day, sK+ Is < 4.0 Meq/L	6	0
Death	1	0
Non-Compliance With Study Drug	2	0
Physician Decision	1	0
Protocol Violation	13	0
Sponsor Request	34	0
Study Terminated By Sponsor	71	0
Withdrawal Of Consent	1	0
Exceeded 12 Weeks Of Run In	2	0
Not treated with Patiromer during Run-in	27	0
Period Title: Treatment Phase (Overall Study)
Started	439	439
Completed	360	367
Not Completed	79	72
Reason Not Completed
Protocol Violation	0	1
Physician Decision	20	13
Adverse Event	27	21
Lost to Follow-up	1	0
Consent withdrawn by subject	21	25
End of study visit not completed/delayed	1	3
Early study termination	0	1
Treatment discontinuation	2	2
Delayed visit and insufficient study	6	6
Sponsor's decision	1	0

Baseline Characteristics

Arm/Group Title		Patiromer	Placebo	Total
Arm/Group Description		Randomized participants who received a daily dose of patiromer, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of patiromer was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, patiromer was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of patiromer were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).	Randomized participants who received a daily dose of placebo, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of placebo was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, placebo was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down-titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of placebo were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).	Total of all reporting groups
Overall Number of Baseline Participants		439	439	878
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	439 participants	439 participants	878 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	181 41.2%	169 38.5%	350 39.9%
	>=65 years	258 58.8%	270 61.5%	528 60.1%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	439 participants	439 participants	878 participants
		66.6 (10.0)	67.1 (9.9)	66.9 (10.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	439 participants	439 participants	878 participants
	Female	112 25.5%	126 28.7%	238 27.1%
	Male	327 74.5%	313 71.3%	640 72.9%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	439 participants	439 participants	878 participants
	Hispanic or Latino	56 12.8%	57 13.0%	113 12.9%
	Not Hispanic or Latino	381 86.8%	379 86.3%	760 86.6%
	Unknown or Not Reported	2 0.5%	3 0.7%	5 0.6%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	439 participants	439 participants	878 participants
Argentina		16	16	32
Belgium		0	2	2
Brazil		6	10	16
Bulgaria		43	48	91
Canada		1	0	1
Czechia		2	7	9
France		1	1	2
Georgia		139	118	257
Germany		4	2	6
Hungary		8	11	19
Israel		8	4	12
Italy		3	4	7
Mexico		6	4	10
Netherlands		3	1	4
Poland		37	43	80
Russia		37	42	79
Serbia		3	5	8
Spain		11	14	25
Ukraine		81	75	156
United States		30	32	62

Outcome Measures

1. Primary Outcome

Title	Changes in Serum K+ Levels From Baseline
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patiromer	Placebo
Arm/Group Description:	Randomized participants who received a daily dose of patiromer, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of patiromer was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, patiromer was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of patiromer were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).	Randomized participants who received a daily dose of placebo, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of placebo was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, placebo was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down-titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of placebo were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).
Overall Number of Participants Analyzed	439	439
Least Squares Mean (Standard Error); Unit of Measure: Milliequivalents Per Liter (mEq/l)
	0.029 (0.019)	0.127 (0.019)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Patiromer, Placebo
	Comments	Difference in adjusted mean changes (SE)
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	[Not Specified]
	Method	Mixed model for repeated measures (MMRM)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.097
	Confidence Interval	(2-Sided) 95%; -0.128 to -0.067
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.015
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	CIF Estimates of the Time to First Hyperkalemia Event With Serum K+ Level > 5.5 mEq/l Over Time
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patiromer	Placebo
Arm/Group Description:	Randomized participants who received a daily dose of patiromer, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of patiromer was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, patiromer was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of patiromer were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).	Randomized participants who received a daily dose of placebo, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of placebo was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, placebo was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down-titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of placebo were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).
Overall Number of Participants Analyzed	439	439
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Probability
Week 1	0.02; (0.01 to 0.04)	0.04; (0.03 to 0.06)
Week 2	0.04; (0.02 to 0.06)	0.08; (0.06 to 0.11)
Week 6	0.05; (0.03 to 0.07)	0.10; (0.08 to 0.13)
Week 18	0.08; (0.06 to 0.12)	0.14; (0.11 to 0.18)
Week 30	0.13; (0.10 to 0.17)	0.20; (0.15 to 0.24)
Week 42	0.17; (0.12 to 0.22)	0.24; (0.19 to 0.29)
Week 54	0.21; (0.15 to 0.27)	0.29; (0.23 to 0.35)
Week 66	0.25; (0.18 to 0.32)	0.34; (0.26 to 0.42)
Week 78	0.30; (0.22 to 0.40)	0.34; (0.26 to 0.42)
Week 90	0.34; (0.23 to 0.44)	0.34; (0.26 to 0.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Patiromer, Placebo
	Comments	Hazard Ratio patiromer vs placebo. The HR for the time to first hyperkalemia event for patiromer vs placebo was calculated. HR and p-value come from a Cox proportional regression model adjusted for geographic region, sex, Baseline T2DM status, Baseline K+ value, and Baseline eGFR. HR = Hazard Ratio; T2DM=Type 2 diabetes mellitus; eGFR=Estimated glomerular filtration rate
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	= 0.006
	Comments	Threshold for statistical significance = 0.05
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.87
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	CIF Estimates of the Reduction of the MRA Dose Below Target Dose Over Time
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patiromer	Placebo
Arm/Group Description:	Randomized participants who received a daily dose of patiromer, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of patiromer was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, patiromer was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of patiromer were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).	Randomized participants who received a daily dose of placebo, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of placebo was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, placebo was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down-titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of placebo were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).
Overall Number of Participants Analyzed	439	439
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Probability
Week 1	0.02; (0.01 to 0.04)	0.04; (0.03 to 0.07)
Week 2	0.03; (0.02 to 0.05)	0.08; (0.06 to 0.11)
Week 6	0.06; (0.04 to 0.08)	0.12; (0.09 to 0.15)
Week 18	0.10; (0.08 to 0.14)	0.15; (0.12 to 0.19)
Week 30	0.14; (0.10 to 0.18)	0.19; (0.15 to 0.23)
Week 42	0.16; (0.12 to 0.21)	0.23; (0.18 to 0.28)
Week 54	0.19; (0.14 to 0.24)	0.26; (0.20 to 0.32)
Week 66	0.22; (0.16 to 0.29)	0.27; (0.21 to 0.33)
Week 78	0.27; (0.20 to 0.35)	0.29; (0.22 to 0.36)
Week 90	0.27; (0.20 to 0.35)	0.29; (0.22 to 0.36)
Week 102	0.27; (0.20 to 0.35)	NA [1]; (0 to 0)

[1]

Not feasible to estimate the cumulative incidence at a time beyond the largest observed time

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Patiromer, Placebo
	Comments	Hazard Ratio patiromer vs placebo. The HR for the time to first hyperkalemia event for patiromer vs placebo was calculated. HR and p-value come from a Cox proportional regression model adjusted for geographic region, sex, Baseline T2DM status, Baseline K+ value, and Baseline eGFR. HR = Hazard Ratio; T2DM=Type 2 diabetes mellitus; eGFR=Estimated glomerular filtration rate
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	= 0.006
	Comments	Threshold for statistical significance = 0.05
	Method	Regression, Cox
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.87
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Investigator-reported Events of Hyperkalemia
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patiromer	Placebo
Arm/Group Description:	Randomized participants who received a daily dose of patiromer, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of patiromer was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, patiromer was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of patiromer were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).	Randomized participants who received a daily dose of placebo, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of placebo was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, placebo was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down-titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of placebo were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).
Overall Number of Participants Analyzed	439	439
Measure Type: Number; Unit of Measure: Ann. event rate per 100 subject-years
	82.38	114.65

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Patiromer, Placebo
	Comments	NBMAC Annualized event RR patiromer vs placebo. NBMAC adjusted for geographical region, sex, Baseline T2DM status, Baseline K+ value, and Baseline eGFR. Rate ratio less than 1 favors patiromer. NBMAC=Negative binomial model adjusted for covariates; RR=Rate Ratio; T2DM=Type 2 diabetes mellitus; eGFR=Estimated glomerular filtration rate
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	[Not Specified]
	Method	Negative binomial model adjusted for cov
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Annualized event rate ratio
	Estimated Value	0.658
	Confidence Interval	(2-Sided) 95%; 0.534 to 0.81
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Hyperkalemia-related Hard Outcomes Endpoints
Description	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
Time Frame	Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description:	All participants randomized to patiromer or placebo arm.
Overall Number of Participants Analyzed	878
Measure Type: Number; Unit of Measure: Events
CV death in Placebo Group First	3491
CV death in Patiromer Group First	4609
More CV hospitalizations in Placebo Group	4539
More CV hospitalizations in Patiromer Group	4178
MHTE with serum K+>6.5 in Placebo Group	419
MHTE with serum K+>6.5 in Patiromer Group	401
MHE with serum K+>6.0-6.5 in Placebo Group	4283
MHE with serum K+>6.0-6.5 in Patiromer Group	1446
MHE with serum K+>5.0-6.0 in Placebo Group	55633
MHE with serum K+>5.0-6.0 in Patiromer Group	34156
None of the above	79566
Total number of pairs	192721

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants
	Comments	Win ratio for composite. Win ratio approach: Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. For each matched pair, the new treatment patient is labelled winner/loser depending on CV/hyperkalemia event first. The win ratio is the total number of winners divided by the total numbers of losers.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Win Ratio
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Win Ratio
	Estimated Value	1.526
	Confidence Interval	(2-Sided) 95%; 1.231 to 1.906
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	All Participants
	Comments	Win ratio CV death and hospitalization. Win ratio approach: Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. For each matched pair, the new treatment patient is labelled winner/loser depending on CV/hyperkalemia event first. The win ratio is the total number of winners divided by the total numbers of losers. Unmatched win ratio is presented for this endpoint. Win ratio above 1 favors patiromer.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	= 0.744
	Comments	[Not Specified]
	Method	Win Ratio
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Win Ratio
	Estimated Value	0.914
	Confidence Interval	(2-Sided) 95%; 0.526 to 1.578
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	RAASi Use Score
Description	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.
Time Frame	Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description:	All participants randomized to patiromer or placebo arm.
Overall Number of Participants Analyzed	878
Measure Type: Number; Unit of Measure: Events
Number of wins in Patiromer Group	62073
Number of wins in Placebo Group	49733
Number of ties	80915
Total number of pairs	192721

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants
	Comments	Win ratio for composite. Win ratio approach: Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. For each matched pair, the new treatment patient is labelled winner/loser depending on CV/hyperkalemia event first. The win ratio is the total number of winners divided by the total numbers of losers. Unmatched win ratio is presented for this endpoint. Win ratio above 1 favors patiromer.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	= 0.048
	Comments	[Not Specified]
	Method	Win Ratio
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Win Ratio
	Estimated Value	1.248
	Confidence Interval	(2-Sided) 95%; 1.003 to 1.564
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Mean duration of exposure: 227.9 days for Patiromer and 234.5 days for Placebo
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Patiromer		Placebo
Arm/Group Description	Randomized participants who received a daily dose of patiromer, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of patiromer was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, patiromer was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of patiromer were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).		Randomized participants who received a daily dose of placebo, with possible dose adjustments based on subsequent local serum potassium level, during the Treatment Phase. The starting dose of placebo was 1 packet/day taken either with food or without food. Based upon the K+ management algorithms, placebo was to be increased by 1 packet per day in intervals of at least 1 week (±3 days). If hypokalemia developed during the Treatment Phase, then the study drug was to be down-titrated (lowest acceptable dose was 0 packets/day) until local serum K+ ≥4.0 mEq/l. Doses of placebo were 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose).
All-Cause Mortality
	Patiromer		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	24/439 (5.47%)		18/439 (4.10%)
Serious Adverse Events
	Patiromer		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	54/439 (12.30%)		58/439 (13.21%)
Blood and lymphatic system disorders
Anaemia † 1	0/439 (0.00%)	0	3/439 (0.68%)	4
Cardiac disorders
Cardiac failure † 1	9/439 (2.05%)	10	15/439 (3.42%)	18
Angina unstable † 1	3/439 (0.68%)	3	3/439 (0.68%)	3
Acute left ventricular failure † 1	2/439 (0.46%)	2	0/439 (0.00%)	0
Atrial fibrillation † 1	1/439 (0.23%)	1	2/439 (0.46%)	2
Acute coronary syndrome † 1	1/439 (0.23%)	2	1/439 (0.23%)	1
Acute myocardial infarction † 1	1/439 (0.23%)	1	1/439 (0.23%)	1
Cardiac failure congestive † 1	1/439 (0.23%)	1	1/439 (0.23%)	2
Ventricular tachycardia † 1	1/439 (0.23%)	1	1/439 (0.23%)	1
Angina pectoris † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Left ventricular failure † 1	1/439 (0.23%)	2	0/439 (0.00%)	0
Myocardial infarction † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Myocardial ischaemia † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Ventricular extrasystoles † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Cardiac arrest † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Cardiomyopathy † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Coronary artery disease † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Pulseless electrical activity † 1	0/439 (0.00%)	0	1/439 (0.23%)	2
Cardiac failure acute † 1	1/439 (0.23%)	1	4/439 (0.91%)	6
Cardiac failure chronic † 1	1/439 (0.23%)	1	1/439 (0.23%)	1
Ear and labyrinth disorders
Vertigo † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Gastrointestinal disorders
Intestinal pseudo-obstruction † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Vomiting † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Inflammatory bowel disease † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Rectal haemorrhage † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Umbilical hernia † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
General disorders
Sudden death † 1	10/439 (2.28%)	10	10/439 (2.28%)	10
Death † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Hepatobiliary disorders
Cholecystitis acute † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Infections and infestations
Pneumonia † 1	5/439 (1.14%)	5	6/439 (1.37%)	6
COVID-19 † 1	2/439 (0.46%)	2	3/439 (0.68%)	3
COVID-19 pneumonia † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Cellulitis † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Gangrene † 1	0/439 (0.00%)	0	2/439 (0.46%)	2
Endocarditis † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Injury, poisoning and procedural complications
Road traffic accident † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Traumatic intracranial haemorrhage † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Vascular procedure complication † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Investigations
Ultrasound pancreas abnormal † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Metabolism and nutrition disorders
Dehydration † 1	1/439 (0.23%)	1	1/439 (0.23%)	1
Decreased appetite † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Hypoglycaemia † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Hypokalaemia † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Hyperglycaemia † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Musculoskeletal and connective tissue disorders
Muscle atrophy † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancoast's tumour † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Plasmacytoma † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Thyroid neoplasm † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Nervous system disorders
Ischaemic stroke † 1	2/439 (0.46%)	2	1/439 (0.23%)	1
Cerebral haemorrhage † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Cerebral infarction † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Transient ischaemic attack † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Brain injury † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Cerebrovascular accident † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Status epilepticus † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Vascular encephalopathy † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Renal and urinary disorders
Renal failure † 1	2/439 (0.46%)	2	0/439 (0.00%)	0
Acute kidney injury † 1	1/439 (0.23%)	1	1/439 (0.23%)	1
Calculus urinary † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
End stage renal disease † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema † 1	1/439 (0.23%)	1	1/439 (0.23%)	1
Acute respiratory failure † 1	1/439 (0.23%)	1	1/439 (0.23%)	1
Chronic obstructive pulmonary disease † 1	1/439 (0.23%)	2	0/439 (0.00%)	0
Respiratory failure † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Respiratory arrest † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Vocal cord dysfunction † 1	0/439 (0.00%)	0	1/439 (0.23%)	1
Skin and subcutaneous tissue disorders
Diabetic foot † 1	1/439 (0.23%)	1	1/439 (0.23%)	1
Vascular disorders
Peripheral ischaemia † 1	1/439 (0.23%)	1	1/439 (0.23%)	1
Hypotension † 1	1/439 (0.23%)	1	0/439 (0.00%)	0
Orthostatic hypotension † 1	0/439 (0.00%)	0	2/439 (0.46%)	2
1 Term from vocabulary, MedDRA (23.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	1%
	Patiromer		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	320/439 (72.89%)		325/439 (74.03%)
Blood and lymphatic system disorders
Anaemia † 1	11/439 (2.51%)	11	5/439 (1.14%)	6
Iron deficiency anaemia † 1	9/439 (2.05%)	9	7/439 (1.59%)	7
Cardiac disorders
Cardiac failure † 1	10/439 (2.28%)	11	10/439 (2.28%)	11
Atrial fibrillation † 1	5/439 (1.14%)	6	3/439 (0.68%)	3
Gastrointestinal disorders
Diarrhoea † 1	19/439 (4.33%)	20	15/439 (3.42%)	15
Constipation † 1	11/439 (2.51%)	13	5/439 (1.14%)	5
Abdominal pain upper † 1	2/439 (0.46%)	2	5/439 (1.14%)	5
General disorders
Asthenia † 1	5/439 (1.14%)	5	8/439 (1.82%)	9
Oedema peripheral † 1	2/439 (0.46%)	2	5/439 (1.14%)	5
Infections and infestations
Pneumonia † 1	7/439 (1.59%)	8	1/439 (0.23%)	1
COVID-19 † 1	6/439 (1.37%)	6	6/439 (1.37%)	8
Respiratory tract infection viral † 1	0/439 (0.00%)	0	6/439 (1.37%)	6
Investigations
Glomerular filtration rate decreased † 1	15/439 (3.42%)	19	10/439 (2.28%)	14
Blood creatinine increased † 1	2/439 (0.46%)	2	5/439 (1.14%)	5
Metabolism and nutrition disorders
Hyperkalaemia † 1	197/439 (44.87%)	335	238/439 (54.21%)	412
Hypokalaemia † 1	66/439 (15.03%)	75	47/439 (10.71%)	53
Hypomagnesaemia † 1	19/439 (4.33%)	20	22/439 (5.01%)	25
Hyperglycaemia † 1	10/439 (2.28%)	11	3/439 (0.68%)	3
Diabetes mellitus † 1	7/439 (1.59%)	7	5/439 (1.14%)	5
Iron deficiency † 1	6/439 (1.37%)	6	2/439 (0.46%)	2
Hyponatraemia † 1	0/439 (0.00%)	0	5/439 (1.14%)	5
Musculoskeletal and connective tissue disorders
Back pain † 1	10/439 (2.28%)	11	6/439 (1.37%)	6
Arthralgia † 1	6/439 (1.37%)	6	3/439 (0.68%)	3
Nervous system disorders
Headache † 1	9/439 (2.05%)	9	11/439 (2.51%)	14
Renal and urinary disorders
Chronic kidney disease † 1	5/439 (1.14%)	7	8/439 (1.82%)	8
Renal impairment † 1	5/439 (1.14%)	5	7/439 (1.59%)	7
Reproductive system and breast disorders
Gynaecomastia † 1	6/439 (1.37%)	6	0/439 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Hydrothorax † 1	6/439 (1.37%)	7	2/439 (0.46%)	2
Acute respiratory failure † 1	5/439 (1.14%)	6	0/439 (0.00%)	0
Dyspnoea † 1	4/439 (0.91%)	4	5/439 (1.14%)	7
Vascular disorders
Hypotension † 1	15/439 (3.42%)	17	13/439 (2.96%)	14
Hypertension † 1	8/439 (1.82%)	8	2/439 (0.46%)	2
1 Term from vocabulary, MedDRA (23.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

 

Results Point of Contact

• Name/Title: DIAMOND Clinical Study Team
• Organization: Vifor Pharma, Inc.
• Phone: +41 588 518 000
• EMail: Diamond_Information@viforpharma.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Vifor Pharma ( Vifor Pharma, Inc. )
• ClinicalTrials.gov Identifier: NCT03888066
• Other Study ID Numbers: PAT-CR-302; 2018-005030-38 ( EudraCT Number )
• First Submitted: March 12, 2019
• First Posted: March 25, 2019
• Results First Submitted: August 25, 2022
• Results First Posted: February 24, 2023
• Last Update Posted: February 24, 2023