E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Management of hyperkalemia due to renin-angiotension-aldosterone system medications in patients treated for heart failure. |
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E.1.1.1 | Medical condition in easily understood language |
Serum potassium levels increase in patients with heart failure. |
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E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10005725 |
E.1.2 | Term | Blood potassium increased |
E.1.2 | System Organ Class | 10022891 - Investigations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the effects of patiromer on serum K+ in HF patients compared with placebo. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject provides written informed consent prior to study participation 2. Age at least 18 years or greater 3. Current New York Heart Association (NYHA) Class II–IV 4. Left ventricular ejection fraction ≤40%, measured by any echocardiographic, radionuclide, magnetic resonance imaging (MRI), angiographic, or computerized tomography method in the last 12 months (without subsequent measured ejection fraction >40% during this interval) 5. Receiving any dose of a beta-blocker for the treatment of HF or unable to tolerate beta-blocker (reason documented) 6. eGFR ≥30 mL/min/1.73 m2 at Screening (based on a single local laboratory analysis of serum creatinine and calculation using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; see Section 9.2) 7. Hyperkalemia at Screening (defined by 2 local serum K+ values of >5.0 mEq/L each obtained from a separate venipunctures, e.g., one in each arm or 2 separate venipunctures in the same arm) while receiving ACEi/ ARB/ ARNi, and/or MRA OR Normokalemia at Screening (defined by 2 local serum K+ ≥4.0-≤5.0 mEq/L each obtained from a separate venipuncture, e.g., one in each arm or two separate venipunctures in the same arm) but with a history of hyperkalemia documented by a usual care serum K+ measurement >5.0 mEq/L while on RAASi treatment in the 12 months prior to Screening leading to a subsequent and permanent dose decrease or discontinuation of one or more RAASi medications 8. Females of child-bearing potential must be non-lactating, must have a negative pregnancy test at Screening, and must agree to continue using contraception (see Section 9.8) throughout the study and for 4 weeks after study completion 9. With hospitalization for HF or equivalent (e.g., emergency room or outpatient visit for worsening HF during which the subject received intravenous medications for the treatment of HF) within the last 12 months before Screening a) Without atrial fibrillation at Screening, brain natriuretic peptide (BNP*) level must be greater than 150 pcg/mL (18 pmol/L) or N-terminal pro b-type BNP (NT-proBNP) must be greater than 600 pcg/mL (71 pmol/L) b) With atrial fibrillation at Screening, BNP level must be greater than 300 pcg/mL (35 pmol/L) or NT-proBNP must be greater than 1,200 pcg/mL (142 pmol/L) OR Without hospitalization for HF or equivalent (e.g., emergency room or outpatient visit for worsening HF during which the subject received intravenous medications for the treatment of HF) within the last 12 months before Screening a) Without atrial fibrillation at Screening, BNP level must be greater than 300 pcg/mL (35 pmol/L) or NT-proBNP must be greater than 1,200 pcg/mL (142 pmol/L) b) With atrial fibrillation at Screening, BNP level must be greater than 600 pcg/mL (71 pmol/L) or NT-proBNP must be greater than 2400 pcg/mL (284 pmol/L) *For subjects treated with ARNi (sacubitril/valsartan) in the previous 4 weeks before Screening, only NT-proBNP values are to be considered. |
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E.4 | Principal exclusion criteria |
1. 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 2. Symptomatic hypotension or systolic blood pressure <90 mmHg 3. Significant primary aortic or mitral valvular heart disease (except secondary mitral regurgitation due to left ventricular dilatation) 4. Heart transplantation or planned heart transplantation (i.e., currently on a heart transplant waiting list) during the study period 5. Diagnosis of peripartum or chemotherapy-induced cardiomyopathy or acute myocarditis in the previous 12 months 6. Implantation of a cardiac resynchronization therapy device in the previous 4 weeks before Screening 7. Restrictive, constrictive, hypertrophic, or obstructive cardiomyopathy 8. Untreated ventricular arrhythmia with syncope in the previous 4 weeks 9. History of, or current diagnosis of, a severe swallowing disorder, moderate-to-severe gastroparesis, or major gastrointestinal (GI) surgery (e.g., bariatric surgery or large bowel resection) 10. A major CV event within 4 weeks prior to Screening, including acute myocardial infarction, stroke (or transient ischemic attack), a lifethreatening atrial or ventricular arrhythmia, or resuscitated cardiac arrest 11. Note: This exclusion criterion is included in the new Inclusion Criterion 9 12. Liver enzymes (alanine aminotransferase, aspartate aminotransferase) >5 times upper limit of normal at Screening based on the local laboratory 13. Diagnosis or treatment of a malignancy in the past 2 years, excluding non-melanoma skin cancer and carcinoma in situ of the cervix, prostate cancer with Gleason score <7, or a condition highly likely to transform into a malignancy during the study 14. Presence of any condition (e.g., drug/alcohol abuse; acute illness), in the opinion of the Investigator, that places the subject at undue risk, or prevents complete participation in the trial procedures, or potentially jeopardizes the quality of the study data 15. Use of any investigational product for an unapproved indication within 4 weeks prior to Screening or currently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study 16. Known hypersensitivity to patiromer (RLY5016) or its components 17. Note: This exclusion criterion is modified and partially incorporated in Exclusion Criterion 18 18. Subjects currently being treated with or having taken any one of the following medications in the 7 days prior to Screening: sodium or calcium polystyrene sulfonate or sodium zirconium cyclosilicate, or patiromer 19. An employee, spouse, or family member of the Sponsor (Vifor Pharma), investigational site or the Contract Research Organization (CRO) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Changes in serum K+ levels from Baseline |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
See endpoint description. |
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E.5.2 | Secondary end point(s) |
1. Hyperkalemia events: The time to the first event of hyperkalemia with a serum K+ value >5.5 mEq/L as per the measured values from the central or local laboratories is analyzed using a Cox proportional hazards regression model. The event probabilities will be estimated using the Aalen- Johansen estimator of the cumulative incidence function accounting for competing events such as death. 2. Durable enablement to stay on the MRA target dose (of 50 mg spironolactone or eplerenone): The time to the event of reduction of the MRA dose below target is analyzed using a Cox proportional hazards regression model. The event probabilities will be estimated using Aalen-Johansen estimator of the cumulative incidence function accounting for competing events such as death. Note: Discontinuation of the target dose for at least 14 days (or less if at the EoS) is required to confirm this endpoint. 3. Investigator reported AEs of hyperkalemia (first and recurrent) are analyzed using a negative binomial regression with the logarithm of the individual follow-up time as offset. A joint frailty model of the total (first and recurrent) hyperkalemia events and time to death as terminating event. If all- cause mortality is substantial in number and differential between the treatment groups, then the joint frailty model would become the main analysis approach. Note: For analyses based upon the negative binomial distribution, the subject level count data will be modeled as function of treatment with the natural log of the subject level follow up time taken into account in the estimation of the event rate. 4. Hyperkalemia-related hard outcomes are analyzed using the Win Ratio approach with the following hierarchical components (all assessed during comparable follow-up times): 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 toxicity events with serum K+ >6.0- 6.5 mEq/L 5. Total number of hyperkalemia toxicity events with serum K+ >5.0- 6.0 mEq/L 5. RAASi Use Score which will be analyzed using the Win Ratio approach for each pair of patients at the end of the comparable follow-up period that is appropriate for that pair of patients with the following additive components. Points are accumulated from two components at the respective time for each patient in each comparison: Component A: •If during the follow-up (to the respective end of follow-up in the comparison) there was no CV hospitalization and the subject is alive at the end of that follow-up, the subject is assigned 2 points Component B: Further points are collected for the treatment status at the respective end of follow-up in the comparison: •For ACEi/ARB/ARNi use: >50% of the target dose = 2 points •For ACEi/ARB/ARNi use: >0 and up to 50% of the target dose = 1 point •For MRA use: >50% of the target dose = 2 points •For MRA use: >0 and up to 50% of the target dose = 1 point •For beta-blocker use: >50% of the target dose = 2 points •For beta-blocker use: >0 and up to 50% of the target dose = 1 point In summary, each subject in each comparison can have 0-8 points (sum of Components A and B) and all subjects are compared using this score at the respective appropriate follow-up time point. The regression analyses will be adjusted for geographic region as the stratification factor of the randomization and relevant baseline characteristics of the subjects. Other Secondary End Points Note: Discontinuation of the target dose for at least 14 days (or less if at the EoS) is required to confirm this endpoint • Durable hyperkalemia-free enablement to stay on the MRA target dose (days on 50 mg MRA without presence of hyperkalemia) • Hyperkalemia toxicity events with serum K+ >6.5 mEq/L • Hyperkalemia toxicity events with serum K+ >6.0-6.5 mEq/L • Emergency treatment for hyperkalemia (hospitalization or emergency room) • Total number of hyperkalemia toxicity events with serum K+ >5.0-6.0 mEq/L • KCCQ questionnaire - OSS, CSS and TSS • Investigator reported events of hyperkalemia (recurrent events) • Proportion of subjects on ≥50% of target dose of ACEi, ARB, or ARNi and ≥50% of target dose of MRA at the EoS Visit • Time to first occurrence of CV death or CV hospitalization |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
See endpoint description. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Single blind during Run-in phase and double blind during treatment phase |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 242 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Brazil |
Bulgaria |
Czechia |
Denmark |
France |
Georgia |
Germany |
Israel |
Italy |
Mexico |
Netherlands |
Poland |
Russian Federation |
Serbia |
Spain |
Sweden |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The common EoS will occur when 820 subjects have completed the Week 6 visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 5 |