A Randomized Clinical Trial, Multicentre, Open-label, Parallel-group, to define the best Strategy for the management of hEart failure aNd chronic kidney disease among elderly patients with or at high risk of hyperKalemia in spAin by optimizing the use of RAASi with SZC: SENEKA Study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hospital Clinico Universitario De Valencia

Participant type

Patients

Age range

65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

1 Oct 2024 → ongoing

Decision date (initial)

2024-08-12

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

AstraZeneca

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To comparethe number of patients achieving an increase of at least 25% of RAASi according to guideline-recommended target doses, in the arm treated with Lokelma plus RAASi versus the arm treated with RAASi without K+ binder, at 3 months after study inclusion.

Secondary objectives 19

1. To assess the number of patients achieving at least 50% of the target dose of RAASi recommended in the guidelines.
2. To evaluate the safety and tolerability of SZC in this patient population.
3. To evaluate the combined safety endpoint of renal congestion in both experimental groups determined by increased weight between pre- discharge and 3 months afterwards > 2kg OR oedema OR rise in CA125 levels higher than 30%, as a combined safety endpoint and each adverse event alone.
4. To assess the number of patients that achieve at least 50% of the target dose recommended in guidelines of Mineralocorticoid receptor antagonist (MRA).
5. To analyse the number of patients achievingat least 50% of the guidelines recommended target dose of MRA and achieving at least 50% of the guidelines recommended target dose of RAASi.
6. To evaluate the number of patients achieving the target dose recommended in guidelines of RAASi.
7. To evaluate the number of patients requiring down titration and discontinuation of RAASi and/or MRA during the study.
8. To analyse the number of patients achieving 50% of target doses of RAASi at 1 month after study inclusion.
9. To determine surrogate short-term (90 days) efficacy objective of changes in biomarker levels (NT-proBNP and CA125) evaluated as a decrease of at least 5% from baseline to 3 months after study inclusion.
10. To explore changes in systolic arterial blood pressure at baseline and 3 months after study inclusion.
11. To explore the effect of treatment with SZC versus none on Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score
12. To evaluate changes in renal function at baseline visit (V1) and 3 months after study inclusion between both groups.
13. To analyse the number of patients that decrease at least 40% in estimated glomerular filtration rate (eGFR) by the CDK-EPI formula.
14. To explore the effect of treatment with SZC versus none on the Kidney Disease Questionnaire of life (KDQoL) Overall Summary Score
15. To determine the number of visits to the emergency department for HF/HK/impaired renal function/hypertension (defined as BP over 200 and/or 100 mmHg) and hyperkalemia diagnosed in the outpatient clinic.
16. To analyse the number of admissions for HF/HK/impaired renal function.
17. To evaluate in both experimental groups the combined endpoint of visits to the emergency department or admission for HF/HK/impaired renal function or decrease of at least 40% in estimated glomerular filtration rate (eGFR) by the CDK-EPI formula or death from cardiovascular causes.
18. To analyse the percentage of patients with HF treated with and without sodium-glucose cotransporter-2 (SGLT2) inhibitors
19. To explore changes in Mg levels at baseline and 3 months after study inclusion

Conditions and MedDRA coding

Chronic heart failure (NYHA I-III) and non-dialysis CKD

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2. Provision of informed consent form prior to any study specific procedures, sampling and analysis.
3. Individuals must be ≥ 70 years of age at the time of signing the informed consent form.
4. Individuals must have a confirmed diagnosis of Heart Failure (HF) according to clinical practice guidelines NYHA functional class I-III (with HFrEF or HFpEF).
5. Individuals must have previously been admitted to hospital due to HF decompensation requiring intravenous diuretics.
6. Individuals must have been stabilised for at least 24-48h of their HF decompensation before randomisation.
7. Individuals must have a confirmed diagnosis of Chronic Kidney Disease defined as a renal impairment of eGFR less than 60ml/min/1.73 m2.
8. Individuals receiving background standard of care for HF and treated according to international guidelines. Specific treatment should include RAASi and/or MRA treatment and at least should have been stable for ≥ 4 weeks at maximum tolerated doses.
9. Patients on RAASi blocker treatment with less than or equal to 75% of the maximum recommended dose.
10. Hyperkalemic patients (sK+ 5.1–5.9 mmol/L at screening / study enrolment) or Normokalemic

Exclusion criteria 21

1. Limited life expectancy (less than 1 year) according to clinician’s criteria, such as but not limited to malignancy, with life expectancy of less than 2 years based on investigator’s clinical judgement.
2. sK >6 mEq/litre or <4.5mEq/litre or history of hypokalemic episodes (S-K<3.5 mEq/L) during the last year.
3. Patients on haemodialysis or haemofiltration
4. NYHA functional class IV
5. Patients undergoing treatment with potassium binders.
6. Active tumour undergoing chemotherapy or metastasis or malignancy requiring treatment.
7. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted.
8. QTc(f) > 550 msec.
9. History of QT prolongation associated with other medications that required discontinuation of that medication.
10. Congenital long QT syndrome.
11. Prior history of hypersensitivity to a RAAS blocker drug, including but not limited to development of angioedema, icterus, hepatitis, or neutropenia or thrombocytopenia requiring treatment modification. Addison’s disease or other causes of hypoaldosteronism.
12. Patients with a known hypersensitivity to SZC or any of the excipients of the product.
13. Individuals treated with potassium binding resins such as sodium polystyrene sulfonate (SPS, e.g. Kayexalate®) or calcium polystyrene sulfonate (CPS; e.g. Resonium®) or the cation exchange polymer, patiromer sorbitex calcium (Veltassa®) within 7 days prior to the first dose of study drug.
14. Treated with potassium supplements within 7 days prior to randomization.
15. Positive hepatitis C antibody hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening.
16. Known to have tested positive for human immunodeficiency virus.
17. Known history of drug or alcohol abuse within 3 year of screening.
18. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).
19. Judgment by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements.
20. Previous enrolment in the present study.
21. Participation in another clinical study with an investigational product during the last 3 months.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Number of patients increasing at least 25% of the target doses of RAASi since the screening visit (V0) to 3 months after study inclusion (V9), considering the target dose of each RAASi drug in the ESC guidelines (1).

Secondary endpoints 29

1. Number of patients achieving at least 50% of the target doses of RAASi since the screening visit (V0) to 3 months after study inclusion (V9), considering the target dose of each RAASi drug recommended in the ESC guidelines.
2. Number of patients increasing 50% of RAASi doses since the screening visit (0) to 3 months after study inclusion (V9), considering the target dose of each RAASi drug recommended in the ESC guidelines.
3. Number of patients achieving at least 50% of the target doses of MRA since the screening visit (V0) to 3 months after study inclusion (V9), considering the target dose of each MRA drug recommended in the ESC guidelines.
4. Number of patients increasing 50% of MRA doses since the screening visit (V0) to 3 months after study inclusion (V9), considering the target dose of each MRA drug recommended in the ESC guidelines
5. Number of patients achieving at least 50% of the target doses of MRA and RAASi since the screening visit (0) to 3 months after study inclusion (V9), considering the target dose recommended in the ESC guidelines
6. Number of patients increasing 50% of MRA and RAASi doses since the screening visit (V0) to 3 months after study inclusion (V9), considering the target dose of each drug recommended in the ESC guidelines
7. Number of patients achieving the target doses of RAASi since the screening visit (V0) to 3 months after study inclusion (V9), considering the target dose of each RAASi drug recommended in the ESC guidelines
8. Proportion of patients in each group requiring down titration of RAASi and/or MRA over the study period.
9. Proportion of patients in each group that required up titration of RAASi and/or MRA following down titration of RAASi and/or MRA.
10. Proportion of patients in each group requiring discontinuation of RAASi and/or MRA over the study period.
11. Number of patients achieving at least 50% of the target doses of RAASi since the screening visit (V0) to 1 month after study inclusion, considering the target dose of each RAASi drug recommended in the ESC guidelines
12. Number of patients increasing 50% of RAASi doses since the screening visit (V0) to 1 month after study inclusion, considering the target dose of each RAASi drug recommended in the ESC guidelines
13. Number of patients achieving a decrease of at least 5% in NT-proBNP levels since the baseline visit (V1) to 3 months after study inclusion (V9).
14. Mean Change in NT-proBNP levels since the baseline visit (V1) to 3 months after study inclusion (V9).
15. Number of patients achieving a decrease of at least 5% in CA125 levels since the baseline visit (V1) to 3 months after study inclusion (V9).
16. Mean Change in CA125 levels since the baseline visit (V1) to 3 months after study inclusion (V9).
17. Mean change on Systolic arterial blood pressure measurement from baseline visit (V1) to 3 months after study inclusion (V9).
18. Mean change from baseline visit (V1) measured at 3 months after study inclusion (V9) in the overall summary score of KKCQ, as a specific HF patient reported outcome questionnaire.
19. To determine the change in renal function the following variables will be calculated between baseline visit (V1) and 3 months after study inclusion (V9): Mean Change in UACR and Mean change in HCO3
20. Number of patients decreasing at least 40% the eGFR since the screening visit (0) to 3 months after study inclusion (V9).
21. Mean change from baseline visit (V1) measured at 3 months after study inclusion (V9) (V9) in the overall summary score of KDQoL, as a specific CKD patient reported outcome questionnaire.
22. Number of visits for HF/HK/impaired renal function/hypertension or hyperkalemia diagnosed in the outpatient clinic.
23. Proportion of patients requiring hospitalization for HF/HK/impaired renal function over the study period.
24. Mean number of hospitalizations per patient for HF/HK/impaired renal function over the study period.
25. Proportion of patients presenting at least one clinical event over the study period
26. Proportion of patients presenting more than one clinical event over the study period
27. Proportion of patients presenting all clinical events over the study period
28. Percentage of patients treated with and without sodium-glucose cotransporter-2 (SGLT2) inhibitors over the study period in both arms
29. Mean Change in Mg levels since the baseline visit (V1) to 3 months after study inclusion (V9).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hospital Clinico Universitario De Valencia

Sponsor organisation

Hospital Clinico Universitario De Valencia

Address

Avenida Blasco Ibanez 17

City

Valencia

Postcode

46010

Country

Spain

Scientific contact point

Organisation

Hospital Clinico Universitario De Valencia

Contact name

Clara Bonanad Lozano

Public contact point

Organisation

Hospital Clinico Universitario De Valencia

Contact name

Clara Bonanad Lozano

Third parties 1

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications