E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hyperkalemia in Patients with Symptomatic Heart Failure. |
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E.1.1.1 | Medical condition in easily understood language |
Hyperkalemia means that the potassium level in the blood is higher than normal. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020646 |
E.1.2 | Term | Hyperkalaemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 evaluate the efficacy of SZC as compared with placebo in keeping potassium levels within the normal range (3.5-5.0 mEq/L) while on spironolactone ≥25 mg daily without assistance of rescue therapy for hyperkalaemia (HK) |
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E.2.2 | Secondary objectives of the trial |
- To compare the SZC and placebo arms with respect to keeping potassium levels within a normal range (3.5-5.0 mEq/L), keeping same spironolactone dose as used at randomisation, and without having had assistance of rescue therapy for HK - To compare the SZC and placebo arms with respect to spironolactone dose - To evaluate the efficacy of SZC as compared to placebo in keeping potassium levels ≤5.0 mEq/L - To compare the SZC and placebo arms with respect to ability to prevent decreases in spironolactone dose - To compare the SZC and placebo arms with respect to change from randomisation in Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) - To assess the safety and tolerability of SZC as compared to placebo in patients with HFrEF and HK, who are on RAASi treatment |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Adults aged ≥18 years - Potassium and estimated glomerular filtration rate (eGFR): - Cohort 1: sK+ 5.1-5.9 mEq/L at screening/study enrolment and eGFR ≥ 30 mL/min/1.73 m2; or - Cohort 2: Normokalaemic (sK+ 3.5-5.0 mEq/L) at screening and 'at risk' of developing HK defined as any of the following: - Have a history of HK (sK+ >5.0 mEq/L) within the prior 36 months and eGFR ≥30 mL/min/1.73 m2, or - sK+ 4.5-5.0 mEq/L and eGFR 30 to 60 mL/min/1.73 m2, or - sK+ 4.5-5.0 mEq/L and age >75 years - Symptomatic HFrEF (New York Heart Association [NYHA] class II-IV), which has been present for at least 3 months - Left ventricular ejection fraction (LVEF) ≤40% - Receiving angiotensin-converting enzyme inhibitor (ACEi), angiotensin II receptor blocker (ARB), or angiotensin receptor-Neprilysin inhibitor (ARNi) - Not on or on low-dose spironolactone or eplerenone (<25 mg daily). - Receiving beta-blocker unless contraindicated.
Inclusion Criteria for Proceeding to the 6-month Randomised-Withdrawal Treatment Phase: - NK (3.5-5.0 mEq/L) on SZC and receiving spironolactone ≥25 mg daily at the end of the 4- to 6-week run-in phase. Sex - Female: - Female participants of childbearing potential must have a negative pregnancy test (serum). - Female participants must be 1 year post-menopausal, surgically sterile, or using one highly effective form of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly). They should have been stable on their chosen method of birth control for a minimum of 4 months before entering the study and willing to remain on the birth control until 4 weeks after the last dose.
Informed Consent: - Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this CSP - Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative. |
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E.4 | Principal exclusion criteria |
- Heart failure due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, or severe stenotic valve disease as a primary cause of HF - Current inpatient hospitalisation due to HF with unstable HF, defined as any of the following: a.SBP <95 mmHg during the 6 hours prior to screening. b.Intravenous diuretic therapy during the 12 hours prior to screening. c.Use of intravenous inotropic drugs during the 24 hours prior to screening. d.Received mechanical circulatory support during the 48 hours prior to screening. - Type 1 myocardial infarction (MI), unstable angina, or stroke within 12 weeks prior to enrolment - Coronary revascularisation (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or valvular repair/replacement within 12 weeks prior to enrolment or planned to undergo any of these procedures - Implantation of a Cardiac Resynchronisation Therapy (CRT) device within 12 weeks prior to enrolment or intent to perform atrial fibrillation ablation or to implant a CRT device - Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted. - Clinically significant bradycardia, as per investigator's judgement, or second- or thirddegree heart block without a pacemaker - Previous cardiac transplantation or implantation of a ventricular assistance device (VAD) or similar device, or transplantation or implantation expected after randomisation - History of gynecomastia due to spironolactone therapy requiring down-titration or discontinuation of spironolactone, or switch to a different MRA
Other Exclusions: - Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). - Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements. - Previous enrolment in the present study. - For women only - breast-feeding or planning to become pregnant during the study. - If the participant has evidence of Coronavirus disease 2019 (COVID-19) within 2 weeks prior to enrolment (see Appendix E), the participant cannot be enrolled in the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of patients on SZC compared to placebo who, at the end of treatment visit, have serum potassium within 3.5-5.0 mEq/L, are on spironolactone ≥25 mg daily, and did not use rescue therapy for HK at any point during the randomised-withdrawal phase. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From randomisation to the end of treatment (EOT) visit (approximately 6 months post-randomisation) |
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E.5.2 | Secondary end point(s) |
- Proportion of patients on SZC compared to placebo who, at the EOT visit (approximately 8 months post-randomisation), have sK+ within 3.5-5.0 mEq/L are on the same dose of spironolactone as they were on at randomisation, and did not use rescue therapy for HK at any point during the randomised-withdrawal phase.
- Proportion of patients on SZC compared to placebo who, at the EOT visit are on spironolactone ≥25 mg daily.
- Time to first HK episode for patients on SZC compared to placebo during the randomised-withdrawal phase, with HK defined as sK+ >5.0 mEq/L
- Time to first instance of decrease or discontinuation of spironolactone dose due to HK for patients on SZC compared to placebo during the randomised-withdrawal phase
- Change in KCCQ-TSS at EOT visit (approximately 8 monthspost-randomisation) from randomisation for patients on SZC compared to placebo |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From randomisation to the end of treatment (EOT) visit (approximately 8 months post-randomisation). |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 |
Brazil |
Canada |
Hungary |
Poland |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |