To determine if patiromer treatment of subjects who developed hyperkalemia while receiving RAASi medications will result in continued use of RAASi medications in accordance with HF treatment guidelines and thereby decrease the occurrence of the…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Blood potassium increased
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Time to first occurrence of CV death or CV hospitalization
Secondary outcome
• Proportion of subjects on >=50% of guideline-recommended target dose of ACEi,
ARB, or ARNi and >=50% of guideline-recommended target dose of MRA at the EoS
Visit
• Total HF hospitalizations (or equivalent in outpatient clinic)
• Change from randomization in the clinical summary score of Kansas City
Cardiomyopathy Questionnaire (KCCQ) at 8 months
Background summary
Please refer to background and rational in the protocol: section 1 and 2, page
27-30
Twenty-six (26) million people worldwide have a diagnosis of (HF. In their
Heart Disease and Stroke Statistics*2017 Update, the American Heart Association
(AHA) reported data from National Health and Nutrition Examination Survey 2011-
2014, which estimates that 6.5 million Americans >=20 years of age have HF.
Projections show that with improved survival and the aging of the population,
the prevalence of HF in the US will increase 46% from 2012 to 2030, resulting
in more than 8 million people >=18 years of age with HF. Currently, HF accounts
for nearly 1 million annual hospitalizations in the US and more than 3 million
physician office visits. By 2030, 1 in every 33 US citizens will have a
diagnosis of HF. Accordingly, it is in the public interest that therapies which
have shown reductions in cardiovascular (CV) mortality, reductions in HF
hospitalizations, and improvements in patient quality of life be optimally
implemented.
HF mortality remains high. Approximately 50% of people diagnosed with HF will
die within 5 years, but mortality rates have improved in the past 20 years, and
this has been primarily because of evidence-based approaches to treating HF
risk factors and comorbidities, as well as use of ACEi, BB, MRA, coronary
revascularization, implantable cardioverter-defibrillators, and cardiac
resynchronization therapeutic strategies.
However, evidence suggests that these treatments are not being implemented as
recommended in HF treatment guidelines. Data from the Get With The
Guidelines-Heart Failure (GWTG-HF) registry suggests that approximately 47% of
individuals admitted to the hospital with HF should have had initiation of at
least 1 new medication on discharge. The GWTG-HF registry 2008-2013 collected
prescribing, indications, and
contraindications for ACEi or ARB, BB, MRA, hydralazine/isosorbide dinitrate,
and anticoagulants. The difference between a patient*s medication regimen at
hospital admission and that which was recommended by HF quality measures at
discharge was calculated. Among 158,922 patients from 271 hospitals with a
primary discharge diagnosis of HF, initiation of ACEi/ARB was indicated in 18.1%
of all patients, 55.5% of whom had not been receiving ACEi/ARB at admission. BB
were indicated in 20.3%, 50.5% of whom had not been receiving BB at admission,
and initiation of MRA was indicated in 24.1%, 87.4% of whom had not been
receiving MRA at admission. A quarter of patients hospitalized with HF needed
to start more than 1 medication to meet HF quality measures, and a significant
proportion of these patients
were not taking these medications at admission, excluding them from the
mortality and morbidity benefits attributed to these treatments which have
earned Class I recommendations in the HF treatment guidelines.
Similar findings have been seen in the European Society of Cardiology Heart
Failure Long-Term Registry. In patients with chronic HFrEF, renin-angiotensin
system blockers, BB, and MRA were used in 92.2, 92.7, and 67.0% of patients,
respectively. About 70% of patients did not receive the target dosage of these
drugs. Among reasons for non-adherence or not achieving the target dose with
ACEi,
ARB, or MRA were contraindication or lack of tolerance, most often due to
worsening renal function, symptomatic hypotension, or hyperkalemia. The
reduction in renal function associated with HF, older age, and comorbidities
such as diabetes mellitus hampers K+ excretion and so makes patients with HF
more likely to develop hyperkalemia. Additionally, the guideline-recommended
pharmacologic treatments, which include multiple neurohormonal antagonists of
the renin-angiotensin-aldosterone system (RAAS), increase the risk of
hyperkalemia, especially when used in combination. Epstein et al., 2015
examined renin-angiotensin-aldosterone system inhibitor (RAASi) dose levels in
a US patient population. They investigated the impact of hyperkalemia on RAASi
dose and the association between dose levels and clinical outcomes. Patients
were classified by comorbidities (chronic kidney disease (CKD), HF, or
diabetes) and RAASi dose level at index date, as determined by prescription
information (supramaximal = above labeled dose; maximal = labeled dose;
submaximal = less than labeled dose; or discontinued). One-third (32.8%) of all
qualifying subjects experienced at least 1 hyperkalemic event (serum K+ >5.0
mEq/L). Among subjects with HF and Stage
3-4 CKD, maximum doses were prescribed in 19% of subjects; 64% of subjects were
prescribed submaximal doses, and 16% of patients discontinued treatment with
RAASi medications as of the index date. Analysis of RAASi dosing before and
after hyperkalemia events revealed that a substantial proportion of subjects
had changes in their dose following an episode of elevated serum K+, with dose
changes occurring more
frequently after moderate-to-severe hyperkalemia events (serum K+ >5.5 mEq/L).
Patients on a maximum dose of a RAASi were down-titrated to a submaximal dose
or discontinued the RAASi nearly half the time (47%) after moderate-to-severe
hyperkalemia events and 38% of the time after mild events. Among patients on
submaximal doses of RAASi, moderate-to-severe hyperkalemia events were followed
by submaximal dose maintenance in 55% of patients and discontinuation in 27% of
patients, compared with dose maintenance in 61% after mild hyperkalemia events
and discontinuation in 24% after mild events. Nearly 60% of subjects with HF
who discontinued RAASi experienced an adverse outcome or mortality compared
with 52.3% of patients on submaximal doses and 44.3% of patients on maximum
doses (all comparisons p<0.05). Patients on submaximal doses or who
discontinued RAASi therapy showed consistently worse outcomes compared with
patients on maximum doses, irrespective of comorbidity status (CKD, HF,
diabetes mellitus) or patient age, suggesting that patients may benefit from
continuing maximal, guideline-directed doses of medications, if hyperkalemia
can be managed.
Although these data are taken from a retrospective database analysis with many
limitations, they are consistent with other observational and retrospective
studies that have reported a meaningful gap between recommendations in
guidelines and real-world practice. Closing this gap between the number of
guideline-RAASi-eligible patients with HFrEF and the actual number receiving
RAASi may provide an opportunity
to further reduce CV mortality, hospitalizations for CV events (including HF),
and healthcare costs.
New treatments for hyperkalemia may offer a solution to intolerance or
contraindication due to hyperkalemia while on RAASi medications and may help
close this gap. Veltassa® (patiromer) for Oral Suspension is a nonabsorbed,
polymeric K+ binder that is approved for the treatment of hyperkalemia.
Study objective
To determine if patiromer treatment of subjects who developed hyperkalemia
while receiving RAASi medications will result in continued use of RAASi
medications in accordance with HF treatment guidelines and thereby decrease the
occurrence of the combined endpoint of cardiovascular (CV) death and CV
hospitalization events compared with placebo treatment.
Study design
Prospective Phase 3b multinational, multicenter, double-blind,
placebo-controlled, randomized withdrawal, parallel group study that includes
Screening, an up to 12 weeks Run-in Phase (all subjects will have patiromer
initiated and RAASi medications, including mineralocorticoid receptor
antagonist (MRA), optimized) and a randomized withdrawal Blinded Treatment
Phase.
Intervention
All enrolled subjects will be treated with patiromer single-blinded during the
Run-in Phase. After the Run-in Phase, eligible subjects will be randomized in a
1:1 ratio to treatment with patiromer or placebo in a double-blinded fashion.
The starting dose will be 1 packet/day . Based upon the potassium management
algorithms, patiromer/placebo may be increased by 1 packet per day in intervals
of at least 1 week (±3 days). For subjects who become hypokalemic,
patiromer/placebo may be decreased to a minimum of 0 packets/day.
Doses of patiromer/placebo will be 0 packets/day, 1 packet/day, 2 packets/day,
and 3 packets/day (maximum dose).
Study burden and risks
For full details see schedule of assessments in the protocol page 17-18
The patient participation in this study will last approximately 2.5 years.
During this time the patient will visit the hospital
approximately 13-20 times. The visits will take about hours.
During these visits the following tests and procedures will take place:
- physical examinations will be done and questions will be asked about medical
history.
- ECGs will be done
- weight, height, blood pressure, temperature, heartbeat will be measured
- blood and urine sampling will be taken.
- The research physician will also test female participants of childbearing
potential for pregnancy.
- Subjects need to complete several questionnaires
Possible side effects that are already known are described in the IB and
patient information letter.
Cardinal Way 100
Redwood City 94063
US
Cardinal Way 100
Redwood City 94063
US
Listed location countries
Age
Inclusion criteria
1. Subject provides written informed consent prior to study participation
2. Age at least 18 years or greater
3. Current New York Heart Association (NYHA) Class II-IV
4. Left ventricular ejection fraction <=40%, measured by any echocardiographic,
radionuclide, magnetic resonance imaging (MRI), angiographic, or computerized
tomography method in the last 12 months (without subsequent measured ejection
fraction >40% during this interval)
5. Receiving any dose of a beta blocker (BB) for the treatment of HF or unable
to tolerate BB (reason documented)
6. Estimated glomerular filtration rate (eGFR) >=30 mL/min/1.73 m2 at Screening
(based on a single local laboratory analysis of serum creatinine and
calculation using the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equation; see Section 9.2)
7. Hyperkalemia at Screening (defined by 2 local serum K+ values of >5.0 mEq/L
each obtained from a separate venipuncture, e.g., one in each arm or two
separate venipunctures in the same arm) while receiving ACEi, ARB, ARNi, and/or
MRA
OR
Normokalemia at Screening (defined by 2 local serum K+ >=4.0 <=5.0 mEq/L each
obtained from a separate venipuncture, e.g., one in each arm or two separate
venipunctures in the same arm) but with a history of hyperkalemia documented by
a usual care serum K+ measurement >5.0 mEq/L while on RAASi treatment in the 12
months prior to Screening leading to a subsequent and permanent dose decrease
or discontinuation of one or more RAASi medications
8. Females of child-bearing potential must be non-lactating, must have a
negative pregnancy test at Screening, and must agree to continue using
contraception (see Section 9.8) throughout the study and for 4 weeks after
study completion
9. With hospitalization for HF or equivalent (e.g., emergency room or
outpatient visit for worsening HF during which the patient received intravenous
medications for the treatment of HF) within the last 12 months before Screening
a) Without atrial fibrillation at Screening, BNP level must be greater than 150
pcg/mL (18 pmol/L) or N-terminal pro b-type BNP (NT proBNP) must be greater
than 600 pcg/mL (71 pmol/L)
b) With atrial fibrillation at Screening, BNP level must be greater than 300
pcg/mL (35 pmol/L) or NT proBNP must be greater than 1,200 pcg/mL (142 pmol/L)
OR
Without hospitalization for HF or equivalent (e.g., emergency room or
outpatient visit for worsening HF during which the subject received intravenous
medications for the treatment of HF) within the last 12 months before Screening
a) Without atrial fibrillation at Screening, BNP level must be greater than 300
pcg/mL (35 pmol/L) or NT proBNP must be greater than 1,200 pcg/mL (142 pmol/L)
b) With atrial fibrillation at Screening, BNP level must be greater than 600
pcg/mL (71 pmol/L) or NT proBNP must be greater than 2400 pcg/mL (284 pmol/L)
Exclusion criteria
1. Current acute decompensated HF within 4 weeks before Screening. Subjects
with a discharge from a hospitalization for acute decompensation of HF longer
than 4 weeks before Screening may be included
2. Symptomatic hypotension or systolic blood pressure <90 mmHg
3. Significant primary aortic or mitral valvular heart disease (except
secondary mitral regurgitation due to left ventricular dilatation)
4. Heart transplantation or planned heart transplantation (i.e., currently on a
heart transplant waiting list) during the study period
5. Diagnosis of peripartum or chemotherapy-induced cardiomyopathy or acute
myocarditis in the previous 12 months
6. Implantation of a cardiac resynchronization therapy device in the previous 4
weeks before Screening
7. Restrictive, constrictive, hypertrophic, or obstructive cardiomyopathy
8. Untreated ventricular arrhythmia with syncope in the previous 4 weeks
9. History of, or current diagnosis of, a severe swallowing disorder, moderate
to severe gastroparesis, or major gastrointestinal (GI) surgery (e.g.,
bariatric surgery or large bowel resection)
10. A major CV event within 4 weeks prior to Screening, including acute
myocardial infarction, stroke (or transient ischemic attack), a life
threatening atrial or ventricular arrhythmia, or resuscitated cardiac arrest
11. Note: This exclusion criterion is included in the new Inclusion Criterion 9
12. Liver enzymes (alanine aminotransferase, aspartate aminotransferase) >5
times upper limit of normal at Screening based on the local laboratory
13. Diagnosis or treatment of a malignancy in the past 2 years, excluding non
melanoma skin cancer and carcinoma in situ of the cervix, prostate cancer with
Gleason score <7, or a condition highly likely to transform into a malignancy
during the study
14. Presence of any condition (e.g., drug/alcohol abuse; acute illness), in the
opinion of the Investigator, that places the subject at undue risk, or prevents
complete participation in the trial procedures, or potentially jeopardizes the
quality of the study data
15. Use of any investigational product for an unapproved indication within 4
weeks prior to Screening or currently enrolled in any other type of medical
research judged not to be scientifically or medically compatible with this study
16. Known hypersensitivity to patiromer (RLY5016) or its components
17. Note: This exclusion criterion is modified and partially incorporated in
Exclusion Criterion 18
18. Subjects currently being treated with or having taken any one of the
following medications in the 7 days prior to Screening: sodium or calcium
polystyrene sulfonate or sodium zirconium cyclosilicate, or patiromer
19. An employee, spouse, or family member of the Sponsor (Relypsa, Vifor
Pharma), investigational site or the Contract Research Organization (CRO)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-005030-38-NL |
| ClinicalTrials.gov | NCT03888066 |
| CCMO | NL69752.078.19 |