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| ID | Type | Description | Link |
|---|---|---|---|
| 2018-003662-14 | EudraCT Number |
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The study was stopped due to low recruitment, which the Steering Committee and funder agreed could not be rectified.
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| Name | Class |
|---|---|
| University of Glasgow | OTHER |
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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard dose MRA | No Intervention | Participants in this arm will have titration to guideline-recommended doses of MRA attempted. | |
| Patiromer and high dose MRA | Experimental | Participants assigned to patiromer may be titrated to 200mg/day spironolactone or the highest licensed dose of eplerenone (50mg/day). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Patiromer | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| "Congestion Index" on Day 60 | 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 |
| Morbidity/Mortality | 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 |
| Morbidity and Mortality | Composite of time to (re-)hospitalisation or death | Periodically up to 10 years |
| Measure | Description | Time Frame |
|---|---|---|
| Dose of MRA | Dose of MRA achieved for all trial participants | Days 7 and 60 |
| Congestion Index | Congestion Index score for all trial participants |
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Inclusion Criteria
A. For the Screening Log (no follow-up envisaged nor linkage to electronic medical records)
≥18 years
Heart failure in the investigators opinion (new onset or decompensated chronic heart failure)
Planned to receive>80mg/day of furosemide or equivalent (IV, SC or oral) in the next 24 hours.
Worsening symptoms & signs of congestion in the prior 10 days requiring at least one of the following:
B. For the Consented Registry (with linkage to electronic medical records)
C. For Randomised Trial Run-in
Fulfils criteria for the consented registry
Clinical diagnosis of heart failure for at least 4 weeks
Congestion as shown by at least one of the following:
Cardiac dysfunction documented by at least one of the following in the previous three years:
Able and willing to provide written informed consent for the randomised trial
D. For Randomisation
Serum potassium >5.0mmol/L
After ingestion of a test-dose of patiromer,
the patient is willing to continue in the trial
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
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)
Systolic BP <90mmHg
Uncorrected valve disease as the main cause of heart failure in the investigators opinion
Hepatic encephalopathy or known severe liver disease
Infection currently requiring intravenous antibiotics or temperature >38°C
Myocardial ischaemia currently requiring intravenous therapy or coronary intervention in the previous 7 days
Arrhythmia requiring urgent cardioversion or intravenous therapy
Severe hyperkalaemia requiring, in the investigator's opinion, intravenous treatment or a potassium-binding agent
The patient is already receiving a potassium-binding agent (this includes patiromer) or the treating physician has already decided to use one
Known hypersensitivity to patiromer or any of the excipients
Known intolerance to both spironolactone and eplerenone (not including hyperkalaemia)
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)
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
Patients taking the following systemic medicines:
The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB)
Rare hereditary problems of galactose or fructose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
Known amyloid heart disease
Cancer likely to cause death or major disability within the next three years
Patients requiring mechanical circulatory support and
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.
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| Name | Affiliation | Role |
|---|---|---|
| John Cleland | University of Glasgow | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Glasgow Royal Infirmary | Glasgow | Strathclyde | G4 0SF | United Kingdom | ||
| Basildon University Hospital |
139 participants entered the registry but the trial was stopped because of low recruitment into the run-in phase (due, in part at least, the COVID pandemic), and because of the 19 patients who did enter the run-in phase, despite receiving up to spironolactone 100mg/day or eplerenone 50mg/day, only 4 patients developed a serum potassium >5.0 mmol/L, which was a requirement to enter the randomised phase of the trial.
Participants were screened across 12 sites between 13/03/2020 and 16/03/2022. The first participant to the registry was consented on 26/08/2020 and the last participant was consented to the registry on 17/03/2022. Participants to the trial that successfully completed run-in were randomised between 14/10/2021 and 16/03/2022.
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| ID | Title | Description |
|---|---|---|
| FG000 | Standard Dose MRA | Participants in this arm will have titration to guideline-recommended doses of MRA attempted. |
| FG001 | Patiromer and High Dose MRA | Participants assigned to patiromer may be titrated to 200mg/day spironolactone or the highest licensed dose of eplerenone (50mg/day). 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Standard Dose MRA | Participants in this arm will have titration to guideline-recommended doses of MRA attempted. |
| BG001 | Patiromer and High Dose MRA | Participants assigned to patiromer may be titrated to 200mg/day spironolactone or the highest licensed dose of eplerenone (50mg/day). 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | "Congestion Index" on Day 60 | To find out whether administering patiromer and higher-dose MRA improves evidence of congestion on Day 60 compared to standard care. | Data were not collected due to early termination of the study. | Posted | After 400 patients have been evaluated at Day 60 |
|
15 months due to early study termination
Serious Adverse Event data were collected for all individuals entering run-in, regardless of whether or not they were subsequently randomised. Other [non-serious] adverse events were not collected as part of the study for the Run-in and Not Randomised Arm.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Run-in and Not Randomised | Participants with a serum potassium <=5.0mmol/L who are not currently receiving an MRA will first be given spironolactone (or eplerenone#) 25mg once daily and randomised to patiromer or not, if and when their serum potassium is >5.0mmol/L. If serum potassium does not exceed 5.0mmol/L within 72 hours, the dose of spironolactone may be increased to 50mg/day and after a further 72 hours to 100mg/day. Those intolerant of or unwilling to take spironolactone should be offered eplerenone (maximum dose 50mg/day). Participants with a serum potassium <=5.0mmol/L who are currently receiving an MRA at a dose of <50mg/day will be initiated on spironolactone 50mg once daily (or eplerenone#) or if currently already receiving 50mg/day, spironolactone 100mg/day (the maximum dose of eplerenone is 50mg/day). They will be randomised to receive patiromer or not, only once their serum potassium is >5.0mmol/L. [# only those intolerant of, or unwilling to take, spironolactone should be offered eplerenone] |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardioversion | Surgical and medical procedures | Systematic Assessment |
Early termination of the trial resulted in small numbers of patients recruited and no available analysis
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof John Cleland | University of Glasgow | 0141 330 7774 | john.cleland@glasgow.ac.uk |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 22, 2021 | Jun 5, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 24, 2023 | Jun 6, 2024 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C568789 | patiromer |
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|
| Days 7 and 60 |
| 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 |
| 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 |
| 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 |
| NYHA Class | NYHA class (I-IV) for all trial participants | Days 7 and 60 |
| 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 |
| Reduced All-cause Mortality | All-cause mortality for all trial participants | Through study completion, up to 5 years |
| Reduced Non-cancer Mortality | Non-cancer mortality for all trial participants | Through study completion, up to 5 years |
| Reduced Cardiovascular Mortality | Cardiovascular mortality for all trial participants | Through study completion, up to 5 years |
| Reduced Mortality/Morbidity - HF/Non-cancer | Days lost to hospitalisation for heart failure or non-cancer deaths over 12 months for all trial participants | During first year |
| Reduced Mortality/Morbidity - Any | Days lost to any hospitalisation or any death over 12 months for all trial participants | During first year |
| QALY | Quality adjusted life-years for duration of the trial for all trial participants | Through study completion, up to 5 years |
| 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 |
| Dose of MRA | Dose of MRA for all trial participants | At 6 months and 12 months |
| Dose of Oral Diuretics Other Than MRA | Dose of oral diuretics other than MRA for all trial participants | At 6 months and 12 months |
| NYHA Class | NYHA class (I-IV) for all trial participants | At 6 months and 12 months |
| Patient Global Assessment | Patient Global Assessment to measure quality of life for all trial participants | At 6 months and 12 months |
| Participant Characteristics and Assessment of Morbidity and Mortality | Time to cardiovascular (re-)hospitalisation or non-cancer death for registry/trial participants | Periodically up to 10 years |
| Participant Characteristics/Assessment of Morbidity/Mortality | Time to heart failure (re-)hospitalisation or non-cancer death for registry/trial participants | Periodically up to 10 years |
| Characteristics and Assessment of Morbidity/Mortality | Incidence rate for hospitalisation for registry/trial participants | Periodically up to 10 years |
| Characteristics/Assessment of Morbidity/Mortality | Time to death (all-causes, cardiovascular causes, heart failure causes, cancer causes, and other) for registry and trial participants | Periodically up to 10 years |
| Basildon |
| United Kingdom |
| Blackpool Victoria Hospital | Blackpool | United Kingdom |
| Princess of Wales Hospital | Bridgend | United Kingdom |
| Royal Devon and Exeter Hospital | Exeter | 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 | United Kingdom |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
|
| Primary | Morbidity/Mortality | 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. | Data were not collected due to early termination of the study. | Posted | Through study completion |
|
|
| Primary | Morbidity and Mortality | Composite of time to (re-)hospitalisation or death | Data were not collected due to early termination of the study. | Posted | Periodically up to 10 years |
|
|
| Secondary | Dose of MRA | Dose of MRA achieved for all trial participants | Data were not collected due to early termination of the study. | Posted | Days 7 and 60 |
|
|
| Secondary | Congestion Index | Congestion Index score for all trial participants | Data were not collected due to early termination of the study. | Posted | 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 | Data were not collected due to early termination of the study. | Posted | 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) | Data were not collected due to early termination of the study. | Posted | 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) | Data were not collected due to early termination of the study. | Posted | Days 7 and 60 |
|
|
| Secondary | NYHA Class | NYHA class (I-IV) for all trial participants | Data were not collected due to early termination of the study. | Posted | 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) | Data were not collected due to early termination of the study. | Posted | Days 7 and 60 |
|
|
| Secondary | Reduced All-cause Mortality | All-cause mortality for all trial participants | Data were not collected due to early termination of the study. | Posted | Through study completion, up to 5 years |
|
|
| Secondary | Reduced Non-cancer Mortality | Non-cancer mortality for all trial participants | Data were not collected due to early termination of the study. | Posted | Through study completion, up to 5 years |
|
|
| Secondary | Reduced Cardiovascular Mortality | Cardiovascular mortality for all trial participants | Data were not collected due to early termination of the study. | Posted | Through study completion, up to 5 years |
|
|
| Secondary | Reduced Mortality/Morbidity - HF/Non-cancer | Days lost to hospitalisation for heart failure or non-cancer deaths over 12 months for all trial participants | Data were not collected due to early termination of the study. | Posted | During first year |
|
|
| Secondary | Reduced Mortality/Morbidity - Any | Days lost to any hospitalisation or any death over 12 months for all trial participants | Data were not collected due to early termination of the study. | Posted | During first year |
|
|
| Secondary | QALY | Quality adjusted life-years for duration of the trial for all trial participants | Data were not collected due to early termination of the study. | Posted | 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 | Data were not collected due to early termination of the study. | Posted | At 12 months |
|
|
| Secondary | Dose of MRA | Dose of MRA for all trial participants | Data were not collected due to early termination of the study. | Posted | 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 | Data were not collected due to early termination of the study. | Posted | At 6 months and 12 months |
|
|
| Secondary | NYHA Class | NYHA class (I-IV) for all trial participants | Data were not collected due to early termination of the study. | Posted | At 6 months and 12 months |
|
|
| Secondary | Patient Global Assessment | Patient Global Assessment to measure quality of life for all trial participants | Data were not collected due to early termination of the study. | Posted | At 6 months and 12 months |
|
|
| Secondary | Participant Characteristics and Assessment of Morbidity and Mortality | Time to cardiovascular (re-)hospitalisation or non-cancer death for registry/trial participants | Data were not collected due to early termination of the study. | Posted | Periodically up to 10 years |
|
|
| Secondary | Participant Characteristics/Assessment of Morbidity/Mortality | Time to heart failure (re-)hospitalisation or non-cancer death for registry/trial participants | Data were not collected due to early termination of the study. | Posted | Periodically up to 10 years |
|
|
| Secondary | Characteristics and Assessment of Morbidity/Mortality | Incidence rate for hospitalisation for registry/trial participants | Data were not collected due to early termination of the study. | Posted | Periodically up to 10 years |
|
|
| Secondary | Characteristics/Assessment of Morbidity/Mortality | Time to death (all-causes, cardiovascular causes, heart failure causes, cancer causes, and other) for registry and trial participants | Data were not collected due to early termination of the study. | Posted | Periodically up to 10 years |
|
|
| 0 |
| 15 |
| 2 |
| 15 |
| 0 |
| 0 |
| EG001 | Standard Dose MRA | Participants in this arm will have titration to guideline-recommended doses of MRA attempted. | 0 | 2 | 1 | 2 | 0 | 2 |
| EG002 | Patiromer and High Dose MRA | Participants assigned to patiromer may be titrated to 200mg/day spironolactone or the highest licensed dose of eplerenone (50mg/day). 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. | 0 | 2 | 1 | 2 | 1 | 2 |
| Cystoscopy | Investigations | Systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | Systematic Assessment | Acute hyponatremia |
|
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