RELieving Increasing oEdema Due to Heart Failure

Heart Failure,Congestive Clinical Trial

— RELIEHF  

Official title:

A Phase IV, Registry-based, Randomised, Controlled, Open-label Trial Investigating the Potential for Patiromer-facilitated Use of Higher Doses of MRAs in Addition to Standard Care to Improve Congestion, Well-being, Morbidity and Mortality

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04142788
• Other study ID #: GN17CA082
• Secondary ID: 2018-003662-14
• Status: Terminated
• Phase: Phase 4
• Start date: July 28, 2020
• Est. completion date: December 20, 2022

Study information

• Verified date: January 2023
• Source: NHS Greater Glasgow and Clyde
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This trial will investigate the potential for patiromer-facilitated use of higher doses of mineralocorticoid antagonists in addition to standard care (compared to standard care alone) to improve congestion, well-being and mortality in people who have worsening congestion due to heart failure and hyperkalaemia.

Description:

People with worsening congestive heart failure may benefit from treatment with higher doses of MRA if they are administered patiromer to treat or prevent hyperkalaemia. Potential participants with worsening heart failure will be identified by their care teams and asked to participate in a research registry. If eligible, registry participants will be asked to take part in the RELIEHF randomised trial. The randomised trial will investigate whether patiromer allows patients with worsening heart failure to be titrated to higher doses of MRA (predominantly spironolactone). Participants assigned to patiromer may be titrated to 200mg/day spironolactone or the highest licensed dose of eplerenone (50mg/day). Participants who are not assigned to patiromer should have titration to guideline-recommended doses of MRA attempted. The registry and trial will take place in about 100 secondary care sites across the UK. At the end of the trial, participants will be followed through their electronic medical records via record linkage for up to 10 years

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: December 20, 2022
• Est. primary completion date: December 20, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria A. For the Screening Log (no follow-up envisaged nor linkage to electronic medical records)

1. =18 years

2. Heart failure in the investigators opinion (new onset or decompensated chronic heart failure)

3. Planned to receive>80mg/day of furosemide or equivalent (IV, SC or oral) in the next 24 hours.

4. Worsening symptoms & signs of congestion in the prior 10 days requiring at least one

of the following:

1. hospitalisation

2. administration of intravenous diuretics

3. an increase in the dose of loop diuretic by at least 40mg/day of furosemide (or equivalent) to a total of at least 80mg/day of furosemide (or equivalent)

4. addition of a thiazide diuretic to treatment with a loop diuretic B. For the Consented Registry (with linkage to electronic medical records)

1. Fulfils the criteria for the screening log

2. Able and willing to provide written informed consent for registry participation C. For Randomised Trial Run-in

1. Fulfils criteria for the consented registry

2. Clinical diagnosis of heart failure for at least 4 weeks

3. Congestion as shown by at least one of the following:

1. Peripheral oedema

2. Raised venous pressure

3. Inferior vena cava diameter >20mm

4. Cardiac dysfunction documented by at least one of the following in the previous three

years:

1. A LVEF<50%or a report of moderate or severe left ventricular dysfunction

2. Left atrial diameter >3.0cm/m2 (body surface area)

3. Elevated BNP or NT-proBNP (BNP >150ng/L if in sinus rhythm or >450ng/L if not in sinus rhythm; NT-proBNP >500ng/L if in sinus rhythm and >1500ng/L if not in sinus rhythm)

5. Able and willing to provide written informed consent for the randomised trial D. For Randomisation

1. Serum potassium >5.0mmol/L

• Patients with a serum potassium >5.0mmol/L may be randomised immediately unless they have severe hyperkalaemia requiring, in the investigators opinion, intravenous treatment or a potassium binding agent.
• Severe hyperkalaemia should be managed according to the UK Renal Association guidelines of 2014 (https://renal.org/wp-content/uploads/2017/06/hyperkalaemia-guideline-1.pdf). Participants may be reconsidered for the trial once such interventions are no longer considered necessary.
• Patients with a serum potassium =5.0mmol/L should be initiated on spironolactone or have the dose increased up to 100mg/day and randomised only if serum potassium exceeds 5.0mmol/L. Those intolerant of or unwilling to take spironolactone should be offered eplerenone titrated to a maximum dose of 50mg/day.
• A run-in period of up to 35 days is permitted (the run-in period will usually occur during hospitalisation or a course of day-care or intense management).

2. After ingestion of a test-dose of patiromer,

1. the patient is willing to continue in the trial

2. the investigator considers the patient can follow instructions on preparing patiromer Exclusion criteria A, For the Screening Log & Registry

• None B. For the Randomised Trial

1. eGFR <30ml/minute/1.73m2 (if clinically appropriate, the dose of other agents such as loop diuretics, ACE inhibitors, angiotensin receptor blockers, beta-blockers and sacubitril-valsartan may be adjusted to allow eGFR to increase)

2. Systolic BP <90mmHg

3. Uncorrected valve disease as the main cause of heart failure in the investigators opinion

4. Hepatic encephalopathy or known severe liver disease

5. Infection currently requiring intravenous antibiotics or temperature >38°C

6. Myocardial ischaemia currently requiring intravenous therapy or coronary intervention in the previous 7 days

7. Arrhythmia requiring urgent cardioversion or intravenous therapy

8. Severe hyperkalaemia requiring, in the investigator's opinion, intravenous treatment or a potassium-binding agent

9. The patient is already receiving a potassium-binding agent (this includes patiromer) or the treating physician has already decided to use one

10. Known hypersensitivity to patiromer or any of the excipients

11. Known intolerance to both spironolactone and eplerenone (not including hyperkalaemia)

12. Known hypersensitivity to the active substance or excipients of spironolactone and eplerenone as per the current Summary of Product Characteristics (Note: actual medicine supplied to participants will vary depending on local arrangements)

13. Women of childbearing potential. For the purposes of this trial this means any woman aged <60 years unless they have had a hysterectomy or bilateral tubal ligation or are aged >50 years and have undergone the menopause and had amenorrhea for at least 3 years

14. Patients taking the following systemic medicines:

• strong inhibitors of CYP 3A4 (e.g. itraconazole, ketoconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazodone)
• Lithium
• Tacrolimus or Cyclosporin

15. The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB)

16. Rare hereditary problems of galactose or fructose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption

17. Known amyloid heart disease

18. Cancer likely to cause death or major disability within the next three years

19. Patients requiring mechanical circulatory support and

20. Patients who do not develop a serum potassium >5.0mmol/L despite receiving up to 100mg/day of spironolactone or 50mg/day of eplerenone during the run in phase.

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure,Congestive

Intervention

Drug:
• Patiromer
Patiromer (8.4g/day to 25.2g/day) and spironolactone (up to 200mg/day) or eplerenone (up to 50mg/day if spironolactone not acceptable). Treatments should be titrated to maintain serum potassium close to the target of 4.5mmol/L.

Locations

Country	Name	City	State
United Kingdom	Basildon University Hospital	Basildon
United Kingdom	Blackpool Victoria Hospital	Blackpool
United Kingdom	Princess of Wales Hospital	Bridgend
United Kingdom	Royal Devon and Exeter Hospital	Exeter
United Kingdom	Glasgow Royal Infirmary	Glasgow	Strathclyde
United Kingdom	Queen Elizabeth University Hospital	Glasgow
United Kingdom	Castle Hill Hospital	Hull
United Kingdom	Victoria Hospital	Kirkcaldy
United Kingdom	Guy's and St Thomas's Hospital	London
United Kingdom	King's College Hospital	London
United Kingdom	St George's Hospital	London

Sponsors (2)

Lead Sponsor	Collaborator
NHS Greater Glasgow and Clyde	University of Glasgow

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	"Congestion index" on Day 60 (trial participants)	To find out whether administering patiromer and higher-dose MRA improves evidence of congestion on Day 60 compared to standard care.	After 400 patients have been evaluated at Day 60
Primary	Morbidity/mortality (trial participants)	Composite of time to need for parenteral diuretic therapy (subsequent to initial discharge) for worsening or recalcitrant heart failure, (re-)hospitalisation for worsening heart failure or non-cancer deaths.	Through study completion
Primary	Morbidity/mortality (registry/trial participants)	Composite of time to (re-)hospitalisation or death	Periodically up to 10 years
Secondary	Dose of MRA	Dose of MRA achieved for all trial participants	Days 7 and 60
Secondary	Congestion Index	Congestion Index score for all trial participants	Days 7 and 60
Secondary	Days dead or hospitalised during the first 60 days	Days dead or hospitalised during the first 60 days for all trial participants	Through 60 days
Secondary	Quality of Life (EQ-5D)	Quality of Life using validated EQ-5D questionnaire for all trial participants (visual analogue score - min 0, max 100, higher means better outcome; calculated score min 0, max 1, higher means better outcome)	Days 7 and 60
Secondary	Quality of Life Kansas City Cardiomyopathy Questionnaire (KCCQ-12)	Quality of Life using validated KCCQ-12 questionnaire for all trial participants (score - min 0, max 100; higher means better outcome)	Days 7 and 60
Secondary	NYHA class	NYHA class (I-IV) for all trial participants	Days 7 and 60
Secondary	Patient Global Assessment	Patient Global Assessment to measure quality of life for all trial participants (ranges from markedly improved to markedly worsened; markedly improved means a better outcome)	Days 7 and 60
Secondary	Reduced mortality	All-cause mortality for all trial participants	Through study completion, up to 5 years
Secondary	Reduced mortality	Non-cancer mortality for all trial participants	Through study completion, up to 5 years
Secondary	Reduced mortality	Cardiovascular mortality for all trial participants	Through study completion, up to 5 years
Secondary	Reduced mortality/morbidity	Days lost to hospitalisation for heart failure or non-cancer deaths over 12 months for all trial participants	During first year
Secondary	Reduced mortality/morbidity	Days lost to any hospitalisation or any death over 12 months for all trial participants	During first year
Secondary	QALY	Quality adjusted life-years for duration of the trial for all trial participants	Through study completion, up to 5 years
Secondary	Proportion alive and well at 12 months	Proportion alive and well at 12 months (well-being defined by KCCQ-12 score) for all trial participants	At 12 months
Secondary	Dose of MRA	Dose of MRA for all trial participants	At 6 months and 12 months
Secondary	Dose of oral diuretics other than MRA	Dose of oral diuretics other than MRA for all trial participants	At 6 months and 12 months
Secondary	NYHA class	NYHA class (I-IV) for all trial participants	At 6 months and 12 months
Secondary	Patient Global Assessment	Patient Global Assessment to measure quality of life for all trial participants	At 6 months and 12 months
Secondary	Participant characteristics and assessment of morbidity/mortality	Time to cardiovascular (re-)hospitalisation or non-cancer death for registry/trial participants	Periodically up to 10 years
Secondary	Participant characteristics and assessment of morbidity/mortality	Time to heart failure (re-)hospitalisation or non-cancer death for registry/trial participants	Periodically up to 10 years
Secondary	Participant characteristics and assessment of morbidity/mortality	Incidence rate for hospitalisation for registry/trial participants	Periodically up to 10 years
Secondary	Participant characteristics and assessment of morbidity/mortality	Time to death for registry/trial participants	Periodically up to 10 years