| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| People with heart failure, worsening symptoms and signs of congestion and serum potassium >5mmol/L |
|
| E.1.1.1 | Medical condition in easily understood language |
| People with heart failure, worsening symptoms and signs of congestion and serum potassium >5mmol/L |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010684 |
| E.1.2 | Term | Congestive heart failure |
| E.1.2 | System Organ Class | 100000004849 |
|
| 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 |
A. Primary Objective
To find out whether giving Patiromer (an agent that binds potassium in the gut) to patients with worsening fluid overload (also known as congestion) due to heart failure who have a high blood potassium concentration will enable the use of higher doses of medicines called mineralo-corticoid antagonists (namely spironolactone or eplerenone) and whether this will reduce the rate of worsening heart failure [defined as a composite of need for diuretic injections for heart failure after discharge from the initial episode of care], re-hospitalisation for worsening heart failure or deaths for reasons other than cancer (treatment is not expected to influence cancer rates or cancer deaths).
Patients will be randomly assigned to receive Patiromer (+ high-dose MRA) or not (+ standard-dose MRA) and outcomes compared. Both patients and investigators will be aware of which group they are assigned to. There is no placebo.
B. Other Primary Objectives
For The Registry:
To assess |
|
| E.2.2 | Secondary objectives of the trial |
For The Registry:
To describe the characteristics and outcome of participants with worsening heart failure who require higher doses of diuretics to control worsening symptoms and signs of fluid overload (congestion).
For The Randomised Trial until Day 60:
To find out whether people with worsening congestion due to heart failure and a high blood potassium who are randomised to patiromer receive higher doses of MRA and have less severe symptoms and signs of congestion, quality of life and hospital length of stay compared to patients assigned to those who are randomised to standard care.
Randomised Trial including All Follow-up:
To find out whether people with worsening congestion due to heart failure and a high blood potassium who are randomised to patiromer receive higher doses of MRA, have improved long-term quality of life, spend less time in hospital and have lower all-cause mortality compared to patients assigned to those who are randomised to standard care.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For the Screening Log (no linkage to electronic medical records or follow-up)
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 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:
a) hospitalisation
b) administration of intravenous diuretics
c) doubling of the dose of loop diuretic (e.g.:- from 40mg to 80mg/day or 80mg to 160mg/day)
d) addition of a thiazide diuretic to treatment with a loop diuretic
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
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:
a) Peripheral oedema
b) Raised venous pressure
c) Inferior vena cava diameter >20mm
4. Cardiac dysfunction documented by at least one of the following in the previous three years:
a) Left ventricular ejection fraction <50% or a report of moderate or severe left ventricular dysfunction
b) Left atrial diameter >3.0cm/m2 (body surface area)
c) Elevated BNP or NT-proBNP
(i) BNP >150ng/L if in sinus rhythm or >450ng/L if not in sinus rhythm
(ii) 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
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,
• the patient is willing to continue in the trial
• the investigator considers the patient can follow instructions on preparing patiromer.
|
|
| E.4 | Principal exclusion criteria |
For the Screening Log and Consented Registry
- None
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 >38oC
6. Myocardial ischaemia currently requiring intravenous therapy or coronary intervention 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 spironolactone or 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 child bearing 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
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Composite of time to need for IV diuretics for worsening or recalcitrant heart failure (subsequent to discharge from index episode of care), (re-)hospitalisation for worsening heart failure or non-cancer deaths. The study is powered on time-to-first event but analysis will include first and recurrent events for the primary endpoint.
There is also a primary endpoint for the registry:
# Time to first (re)-hospitalisation or death
And an ancillary primary endpoint at Day 60:
# Congestion Index
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The trial is event driven and will continue until 719 primary outcome events have occurred overall in the two randomised groups.
The registry outcome will be evaluated periodically up to 10 years.
Congestion Index will be evaluated at Day 60. |
|
| E.5.2 | Secondary end point(s) |
RANDOMISED TRIAL (LONG-TERM FOLLOW-UP):
# Mortality (all-cause; non-cancer; cardiovascular)
# Days lost to hospitalisation for heart failure or non-cancer mortality
# Days lost to any hospitalisation or death
# Proportion alive & well (defined by KCCQ)
# Quality adjusted life-years using EQ5D
# Dose of MRA
# Dose of oral diuretics other than MRA
# NYHA
# Patient Global Assessment (PGA)
UNTIL DAY 60:
# Dose of MRA
# Congestion Index
# Individual Components of Congestion Index
# Days dead or hospitalised
# Quality of Life (EQ5D & KCCQ)
# NYHA
# Patient Global Assessment (PGA)
REGISTRY:
# Composite of time to cardiovascular (re)-hospitalisation or non-cancer death
# Composite of time to heart failure (re)-hospitalisation or non-cancer death
# Incidence rate for hospitalisation (all-causes, cardiovascular causes, heart failure causes, cancer causes – separately)
# Time to death (all-causes, cardiovascular causes, heart failure causes, cancer causes, and other) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
RANDOMISED TRIAL (LONG-TERM FOLLOW-UP):
# Mortality (all-cause; non-cancer; cardiovascular) - END TRIAL
# Days lost to hospitalisation for heart failure/non-cancer mortality - 12 MONTH
# Days lost to any hospitalisation/death - 12 MONTH
# Proportion alive & well (defined by KCCQ)- 12 MONTH
# QUALY using EQ5D - END OF TRIAL
# Dose MRA - 6&12 MONTH
# Dose oral diuretics other than MRA - 6&12 MONTH
# NYHA - 6&12 MONTH
# Patient Global Assessment (PGA)- 6&12 MONTH
UNTIL DAY 60:
# Dose MRA - DAYS 7&60
# Congestion Index (CI) - DAYS 7&60
# Individual components of CI - DAYS 7&60
# Days dead/hospitalised - DAY 60
# Quality of Life (EQ5D & KCCQ)- DAYS 7&60
# NYHA - DAYS 7&60
# PGA - DAYS 7&60
REGISTRY: PERIODICALLY UP TO 10 YEARS |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Test: Combination of Partiromer and Spironolactone or Eplerenone |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Comparator: Spironolactone or Eplerenone |
|
| 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 | 100 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| End of trial is final database lock. After last patient last visit record linkages will have to be carried out, all study outcomes identified and adjudicated. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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