Clinical trial NCT04142788: RELieving Increasing oEdema Due to Heart Failure
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Heart Failure，Congestive
Lead sponsor: NHS Greater Glasgow and Clyde
Sponsor class: OTHER
Collaborators: name: University of Glasgow
First posted: 2019-10-29
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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

Eligibility criteria: 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.

Primary outcomes:
measure: "Congestion Index" on Day 60
timeFrame: After 400 patients have been evaluated at Day 60
measure: Morbidity/Mortality
timeFrame: Through study completion
measure: Morbidity and Mortality
timeFrame: Periodically up to 10 years
Secondary outcomes:
measure: Dose of MRA
timeFrame: Days 7 and 60
measure: Congestion Index
timeFrame: Days 7 and 60
measure: Days Dead or Hospitalised During the First 60 Days
timeFrame: Through 60 days
measure: Quality of Life (EQ-5D)
timeFrame: Days 7 and 60
measure: Quality of Life Kansas City Cardiomyopathy Questionnaire (KCCQ-12)
timeFrame: Days 7 and 60
measure: NYHA Class
timeFrame: Days 7 and 60
measure: Patient Global Assessment
timeFrame: Days 7 and 60
measure: Reduced All-cause Mortality
timeFrame: Through study completion, up to 5 years
measure: Reduced Non-cancer Mortality
timeFrame: Through study completion, up to 5 years
measure: Reduced Cardiovascular Mortality
timeFrame: Through study completion, up to 5 years
measure: Reduced Mortality/Morbidity - HF/Non-cancer
timeFrame: During first year
measure: Reduced Mortality/Morbidity - Any
timeFrame: During first year
measure: QALY
timeFrame: Through study completion, up to 5 years
measure: Proportion Alive and Well at 12 Months
timeFrame: At 12 months
measure: Dose of MRA
timeFrame: At 6 months and 12 months
measure: Dose of Oral Diuretics Other Than MRA
timeFrame: At 6 months and 12 months
measure: NYHA Class
timeFrame: At 6 months and 12 months
measure: Patient Global Assessment
timeFrame: At 6 months and 12 months
measure: Participant Characteristics and Assessment of Morbidity and Mortality
timeFrame: Periodically up to 10 years
measure: Participant Characteristics/Assessment of Morbidity/Mortality
timeFrame: Periodically up to 10 years
measure: Characteristics and Assessment of Morbidity/Mortality
timeFrame: Periodically up to 10 years
measure: Characteristics/Assessment of Morbidity/Mortality
timeFrame: Periodically up to 10 years
Other outcomes:
Locations:
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
state: Strathclyde
city: Basildon
country: United Kingdom
facility: Basildon University Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Bridgend
country: United Kingdom
facility: Princess of Wales Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Hull
country: United Kingdom
facility: Castle Hill Hospital
city: Kirkcaldy
country: United Kingdom
facility: Victoria Hospital
city: London
country: United Kingdom
facility: Guy's and St Thomas's Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: St George's Hospital
Study officials:
affiliation: University of Glasgow
name: John Cleland
role: PRINCIPAL_INVESTIGATOR
References: