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 determine if patiromer treatment of subjects who developed hyperkalemia while receiving RAASi medications will result in continued use of RAASi medications in accordance with heart failure (HF) treatment guidelines and thereby decrease the occurrence of the combined endpoint of cardiovascular (CV) death and CV hospitalization events compared with placebo treatment. |
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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 HF 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 (BB) for the treatment of HF or unable to tolerate BB (reason documented) 6.Estimated glomerular filtration rate (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 of the protocol) 7. Hyperkalemia at Screening (defined by 2 local serum K+ values of >5.0 mEq/L each obtained from a separate venipuncture, e.g., one in each arm or two 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 of the protocol) throughout the study and for 4 weeks after study completion 9. With hospitalization for HF or equivalent (e.g., urgent emergency room or outpatient visit for worsening HF during which the patient received intravenous medications for the treatment of HF) within last 12 months before screening a) Without atrial fibrillation at Screening, 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) |
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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 life-threatening atrial or ventricular arrhythmia, or resuscitated cardiac arrest. 11. 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 (Relypsa, 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) |
Time to first occurrence of CV death or CV hospitalization (or equivalent in outpatient clinic) |
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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) |
•Proportion of subjects on ≥50% of guideline-recommended target dose of ACEi, ARB, or ARNi and ≥50% of guideline-recommended target dose of MRA at the End of Study (EoS) Visit • Total HF hospitalizations (or equivalent in outpatient clinic) • Change from randomization in the clinical summary score of Kansas City Cardiomyopathy Questionnaire (KCCQ) at 8 months |
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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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 156 |
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 |
Georgia |
Israel |
Mexico |
Russian Federation |
Serbia |
Ukraine |
United States |
Bulgaria |
Czechia |
Denmark |
France |
Germany |
Italy |
Netherlands |
Poland |
Spain |
Sweden |
United Kingdom |
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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 study will continue until the required number of composite endpoint events have occurred. |
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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 |