Heart Failure
Conditions
Keywords
HF, Heart failure, hyperkalemia, chronic kidney disease, prevention of hyperkalemia in heart failure participants
Brief summary
The purpose of this study was to evaluate the feasibility of individualized titration of patiromer according to serum potassium. This study also assessed the safety and tolerability of patiromer and the effects of patiromer on serum potassium in heart failure (HF) participants with chronic kidney disease (CKD).
Detailed description
This was an open-label, single-arm study to evaluate a titration regimen for patiromer in approximately 63 HF participants with CKD receiving one or more of the following: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), or beta blockers (BBs). This study was considered to be exploratory. Upon successful completion of screening evaluations (-10 to -5 days prior to enrollment), all eligible participants were assigned at Baseline (Day 0 visit) to an initial dose of patiromer (20 g/day) and spironolactone (25 mg/day). Study visits for enrolled participants were scheduled for Days 3, 7, 14, 21, 28, 35, 42, 49 and 56. A follow-up visit occurred on Day 63. At selected study visits, patiromer or spironolactone doses may have been titrated. The study dosing algorithm was designed to maintain an individual's serum potassium value in the range of 4.0 - 5.1 mEq/L (based on local lab data). Any participant with a local laboratory serum potassium value \< 3.5 or \> 5.5 mEq/L on two consecutive scheduled study visits, despite titration of patiromer or spironolactone, were withdrawn from the study, permanently discontinued patiromer and spironolactone, and returned for a follow-up visit within 7 days.
Interventions
DRUGpatiromer
Active investigational drug
DRUGspironolactone
Sponsors
Relypsa, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Chronic HF clinically indicated to receive spironolactone therapy 2. Age 18 years or older 3. Local laboratory serum potassium values of 4.3 - 5.1 mEq/L at screening and baseline 4. CKD (estimated glomerular filtration rate \[eGFR\] \< 60 mL/min/1.73m2 at screening based on central lab creatinine measurement) 5. On at least one of the following HF therapies: ACEI, ARB, or BB 6. Females of child-bearing potential must be non-lactating, must have a negative serum pregnancy test at screening, and must have used a highly effective form of contraception for at least 3 months before study drug administration, during the study, and for one month after study completion 7. Male participants and/or their female partners of child-bearing potential must use a highly effective form of contraception during the study and for 3 months after study completion 8. Provide their written informed consent prior to participation in the study
Exclusion criteria
1. History of bowel obstruction, swallowing disorders, severe gastrointestinal disorders or major gastrointestinal surgery 2. Uncorrected primary severe valvular disease, known obstructive or restrictive cardiomyopathy, uncontrolled or hemodynamically unstable arrhythmia 3. Coronary-artery bypass graft, percutaneous intervention (e.g., cardiac, cerebrovascular, aortic), or major surgery including thoracic and cardiac, within 3 months prior to baseline or anticipated need during study participation 4. Heart transplant recipient, or anticipated need for transplant during study participation 5. Any of the following events having occurred within 2 months prior to baseline: unstable angina as judged by the Investigator, unresolved acute coronary syndrome, transient ischemic attack or stroke 6. Current dialysis participant, or anticipated need for dialysis during study participation 7. Prior kidney transplant, or anticipated need for transplant during study participation 8. Metastatic, late-stage or end-stage cancer with \< 12 months life expectancy or at risk for tumor lysis syndrome 9. History of alcoholism or drug/chemical abuse within 1 year 10. Sustained systolic blood pressure \> 180 or \< 90 mmHg 11. Liver enzymes \[alanine aminotransferase (ALT), aspartate aminotransferase (AST)\] \> 3 times upper limit of normal 12. Loop and thiazide diuretics that have not been stable for at least 21 days prior to baseline or not anticipated to remain stable during study participation 13. Use of any intravenous cardiac medications within 21 days prior to baseline, or their anticipated need during study participation 14. Current use of polymer-based drugs (e.g., sevelamer, sodium polystyrene sulfonate, colesevelam, colestipol), phosphate binders (e.g., lanthanum carbonate), or other potassium binders, or their anticipated need during study participation 15. Use of potassium sparing medication including aldosterone antagonists or potassium supplements in the last 21 days prior to baseline 16. Use of any investigational medication within 30 days or 5 half-lives, whichever is longer, prior to baseline 17. Participants who have taken investigational product in this study, or a previous patiromer study 18. Inability to consume the study medication, or, in the opinion of the Investigator, inability to comply with the protocol 19. In the opinion of the Investigator, any medical condition, uncontrolled systemic disease, serious intercurrent illness, or extenuating circumstance occurring or persisting, within 30 days prior to baseline, that would significantly decrease study compliance or jeopardize the safety of the participant or affect the validity of the trial results
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Serum Potassium in the Range of 3.5 - 5.5 mEq/L at the End of Treatment | 56 days |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Serum Potassium in the Range of 3.5 - 5.5 mEq/L at Week 8 | 56 Days |
| Percentage of Participants With Serum Potassium in the Range of 4.0 - 5.1 mEq/L at Week 4 | 28 Days |
| Percentage of Participants With Serum Potassium in the Range of 4.0 - 5.1 mEq/L at Week 8 | 56 Days |
| Percentage of Participants With Serum Potassium in the Range of 4.0 - 5.1 mEq/L at the End of Treatment | 56 Days |
| Mean Dose of Patiromer at End of Treatment | 56 Days |
| Percentage of Participants Requiring Patiromer Uptitration | 56 Days |
| Percentage of Participants Requiring Patiromer Downtitration | 56 Days |
| Median Time to First Patiromer Dose Titration | 56 Days |
| Percentage of Participants With Serum Potassium in the Range of 3.5 - 5.5 mEq/L at Week 4 | 28 Days |
| Mean Patiromer Dose at Week 1 | Up to Week 1 |
| Mean Patiromer Dose at Week 4 | Up to Week 4 |
| Mean Patiromer Dose at Week 8 | Up to Week 8 |
| Mean Change From Baseline in Serum Potassium to End of Treatment | 56 Days |
| Percentage of Participants Discontinuing Due to Hyperkalemia (Serum Potassium > 5.5 mEq/L) | 56 Days |
| Percentage of Patients Whose Spironolactone Dose Was Increased Up to 50 mg/Day | 56 Days |
| Change in Urine Albumin to Creatinine Ratio (ACR) From Baseline to Week 4 Among Participants With ACR ≥ 30 mg/g at Baseline | Baseline and Day 28 |
| Change in ACR From Baseline to Week 8 Among Participants With Urine ACR ≥ 30 mg/g at Baseline | Baseline and Day 56 |
| Mean Number of Patiromer Titrations | 56 Days |
Countries
Georgia, Slovenia
Participant flow
Pre-assignment details
Eligible participants were ≥ 18 years old, had a history of chronic HF, were clinically indicated to initiate spironolactone therapy, had a serum potassium measurement of 4.3 - 5.1 mEq/L at screening and baseline, had CKD (eGFR \< 60 mL/min/1.73 m2 at screening), and were taking one or more HF therapies (ACEIs, ARBs, or BBs).
Participants by arm
| Arm | Count |
|---|---|
| Patiromer Spironolactone + Patiromer
Participants received patiromer (20 g/day, administered as a divided dose of 10 g in the morning and 10 g in the evening) and spironolactone (25 mg/day, administered once daily), orally. After Day 3, at the first occurrence of a serum potassium value of ≤ 5.1 mEq/L, the spironolactone dose was increased once to 50 mg/day; dose reductions were not allowed. | 63 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Death | 1 |
| Overall Study | Protocol-specified (High K+) | 1 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Patiromer |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 46 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age, Continuous | 70.8 years |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 4 / 63 |
| serious Total, serious adverse events | 6 / 63 |
Outcome results
Primary
Percentage of Participants With Serum Potassium in the Range of 3.5 - 5.5 mEq/L at the End of Treatment
Time frame: 56 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Percentage of Participants With Serum Potassium in the Range of 3.5 - 5.5 mEq/L at the End of Treatment | 90.5 percentage of participants |
95% CI: [80.4, 96.4]
Secondary
Change in ACR From Baseline to Week 8 Among Participants With Urine ACR ≥ 30 mg/g at Baseline
Time frame: Baseline and Day 56
Population: Participants with urine ACR ≥ 30 mg/g at baseline and available data at Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patiromer | Change in ACR From Baseline to Week 8 Among Participants With Urine ACR ≥ 30 mg/g at Baseline | -291.06 mg/g | Standard Error 141.5644 |
Secondary
Change in Urine Albumin to Creatinine Ratio (ACR) From Baseline to Week 4 Among Participants With ACR ≥ 30 mg/g at Baseline
Time frame: Baseline and Day 28
Population: Participants with urine ACR ≥ 30 mg/g at baseline and available data at Week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patiromer | Change in Urine Albumin to Creatinine Ratio (ACR) From Baseline to Week 4 Among Participants With ACR ≥ 30 mg/g at Baseline | -291.01 mg/g | Standard Error 130.7973 |
Secondary
Mean Change From Baseline in Serum Potassium to End of Treatment
Time frame: 56 Days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patiromer | Mean Change From Baseline in Serum Potassium to End of Treatment | -0.13 mEq/L | Standard Deviation 0.686 |
Secondary
Mean Dose of Patiromer at End of Treatment
Time frame: 56 Days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patiromer | Mean Dose of Patiromer at End of Treatment | 22.5 grams | Standard Deviation 7.8 |
Secondary
Mean Number of Patiromer Titrations
Time frame: 56 Days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patiromer | Mean Number of Patiromer Titrations | 1.3 patiromer titrations | Standard Deviation 1.1 |
Secondary
Mean Patiromer Dose at Week 1
Time frame: Up to Week 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patiromer | Mean Patiromer Dose at Week 1 | 20.0 grams | Standard Deviation 0 |
Secondary
Mean Patiromer Dose at Week 4
Time frame: Up to Week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patiromer | Mean Patiromer Dose at Week 4 | 21.9 grams | Standard Deviation 8.5 |
Secondary
Mean Patiromer Dose at Week 8
Time frame: Up to Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patiromer | Mean Patiromer Dose at Week 8 | 23.0 grams | Standard Deviation 12.4 |
Secondary
Median Time to First Patiromer Dose Titration
Time frame: 56 Days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Patiromer | Median Time to First Patiromer Dose Titration | 21 days |
Secondary
Percentage of Participants Discontinuing Due to Hyperkalemia (Serum Potassium > 5.5 mEq/L)
Time frame: 56 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Percentage of Participants Discontinuing Due to Hyperkalemia (Serum Potassium > 5.5 mEq/L) | 1.6 percentage of participants |
Secondary
Percentage of Participants Requiring Patiromer Downtitration
Time frame: 56 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Percentage of Participants Requiring Patiromer Downtitration | 12.7 percentage of participants |
Secondary
Percentage of Participants Requiring Patiromer Uptitration
Time frame: 56 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Percentage of Participants Requiring Patiromer Uptitration | 33.3 percentage of participants |
Secondary
Percentage of Participants With Serum Potassium in the Range of 3.5 - 5.5 mEq/L at Week 4
Time frame: 28 Days
Population: Participants with available data at Week 4.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Percentage of Participants With Serum Potassium in the Range of 3.5 - 5.5 mEq/L at Week 4 | 96.7 percentage of participants |
Secondary
Percentage of Participants With Serum Potassium in the Range of 3.5 - 5.5 mEq/L at Week 8
Time frame: 56 Days
Population: Participants with available data at Week 8.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Percentage of Participants With Serum Potassium in the Range of 3.5 - 5.5 mEq/L at Week 8 | 93.0 percentage of participants |
Secondary
Percentage of Participants With Serum Potassium in the Range of 4.0 - 5.1 mEq/L at the End of Treatment
Time frame: 56 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Percentage of Participants With Serum Potassium in the Range of 4.0 - 5.1 mEq/L at the End of Treatment | 84.1 percentage of participants |
95% CI: [72.7, 92.1]
Secondary
Percentage of Participants With Serum Potassium in the Range of 4.0 - 5.1 mEq/L at Week 4
Time frame: 28 Days
Population: Participants with available data at Week 4.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Percentage of Participants With Serum Potassium in the Range of 4.0 - 5.1 mEq/L at Week 4 | 78.7 percentage of participants |
Secondary
Percentage of Participants With Serum Potassium in the Range of 4.0 - 5.1 mEq/L at Week 8
Time frame: 56 Days
Population: Participants with available data at Week 8.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Percentage of Participants With Serum Potassium in the Range of 4.0 - 5.1 mEq/L at Week 8 | 86.0 percentage of participants |
Secondary
Percentage of Patients Whose Spironolactone Dose Was Increased Up to 50 mg/Day
Time frame: 56 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patiromer | Percentage of Patients Whose Spironolactone Dose Was Increased Up to 50 mg/Day | 100 percentage of participants |