Acute Heart Failure (AHF)
Conditions
Keywords
AHF,, RLX030,, SOC,, WHF,, RELAX-AHF-EU, Renal Impairment
Brief summary
This was a multinational, multicenter, randomized, open-label study to confirm and expand the efficacy, safety and tolerability evidence of 48 hours intravenous infusion of serelaxin (30 micrograms/kg/day) when added to Standard of Care (SoC) in patients admitted to hospital for Acute Heart Failure (AHF).
Detailed description
This study was aimed at generating clinical evidence, especially on the short term period (in-hospital and at 30 days) to complement existing and future serelaxin data sets in Acute Heart Failure (AHF).
Interventions
DRUGSerelaxin
30 µg/kg/day IV infusion
DRUGStandard of Care
This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Systolic blood pressure ≥ 125 mmHg * Admitted for Acute Heart Failure (AHF) * Received intravenous furosemide (or equivalent) at any time between presentation and the start of screening * eGFR on admission: ≥ 25 and ≤75 mL/min/1.73 m\^2
Exclusion criteria
* Dyspnea (non-cardiac causes) * T \> 38.5°C * Clinical evidence of acute coronary syndrome currently or within 30 days prior to enrollment. * Significant left ventricular outflow obstruction, uncorrected, such as obstructive hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area \<1.0 cm\^2 or mean gradient \>50 mmHg on prior or current echocardiogram), severe aortic regurgitation and severe mitral stenosis. * AHF due to significant arrhythmias * Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy (does not include restrictive mitral filling patterns seen on Doppler echocardiographic assessments of diastolic function).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Worsening Heart Failure (WHF) / All Cause of Deaths Through Day 5 | 5 days | In-hospital WHF through Day 5 post-randomization included worsening signs and/or symptoms of heart failure that required an intensification of intravenous therapy for heart failure or mechanical ventilation, renal or circulatory support. A central event adjudication committee was appointed to oversee the WHF primary endpoint adjudication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Persistent Sign or Symptoms of Heart Failure / Non-Improvement at Any Post Baseline Visit Through Day 5 | 5 days | Persistent or non-improvement in any signs or symptoms of HF at any post baseline visit up to Day 5. |
| Percentage of Participants With Renal Deterioration at Any Post Baseline Visit Through Day 14 | 14 days | Renal deterioration is defined as \> or = 0.3 mg/dL increase from screening in serum creatinine. |
| Percentage of Participants With In-hospital Worsening Heart Failure/All-Cause Death/Readmission for Heart Failure Through Day 14 | 14 days | WHF/death/readmission for heart failure through Day 14. WHF/deaths through Day 5 were adjudicated and confirmed by the Clinical Endpoint Committee, WHF/deaths after Day 5 through Day 14 and readmission through Day 14 were as reported by the investigators. |
| Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients | Adverse Events (AE): 5 Days / Serious Adverse Events (SAE): 14 days / All cause deaths 30 days | — |
| Change From Baseline in Health-related Quality of Life Index Value, Assessed by EuroQoL EQ-5D-5L Questionnaire. | Baseline, Day 5, Day 14 | EQ-5D-5L is a questionnaire designed to assess health status in adults consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). The results were converted into a single index value using UK as the reference country for all countries. Range -0.3 (worst possible state) to 1 (best possible state). |
| Length of Index Hospital Stay | 30 Days | Length of stay (in hours) is defined as the index hospitalization discharge date and time minus the index hospitalization start date and time. |
Countries
Austria, Belgium, Bulgaria, Croatia, Czechia, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Italy, Latvia, Lithuania, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, Switzerland, United Kingdom
Participant flow
Pre-assignment details
The initial target was to randomize 3183 patients. This study was prematurely terminated (due to the neutral read-out of study RELAX-AHF-2) after 2666 patients were randomized. 16 patients had not qualified for randomization but were inadvertently randomized. These 16 patients did not enter the treatment phase and were not counted as started.
Participants by arm
| Arm | Count |
|---|---|
| Serelaxin + Standard of Care Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care. | 1,756 |
| Standard of Care (SOC) All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc. | 894 |
| Total | 2,650 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 14 | 8 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Technical Problems or Missing | 5 | 2 |
| Overall Study | Withdrawal by Subject | 14 | 3 |
Baseline characteristics
| Characteristic | Serelaxin + Standard of Care | Standard of Care (SOC) | Total |
|---|---|---|---|
| Age, Continuous | 75.24 Years STANDARD_DEVIATION 10.349 | 75.95 Years STANDARD_DEVIATION 9.905 | 75.48 Years STANDARD_DEVIATION 10.205 |
| Race/Ethnicity, Customized Asian | 5 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Black | 4 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized Caucasian | 1706 Participants | 869 Participants | 2575 Participants |
| Race/Ethnicity, Customized Other | 25 Participants | 12 Participants | 37 Participants |
| Race/Ethnicity, Customized Unknown | 16 Participants | 7 Participants | 23 Participants |
| Sex: Female, Male Female | 760 Participants | 383 Participants | 1143 Participants |
| Sex: Female, Male Male | 996 Participants | 511 Participants | 1507 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 63 / 1,729 | 43 / 894 |
| other Total, other adverse events | 637 / 1,729 | 324 / 894 |
| serious Total, serious adverse events | 214 / 1,729 | 107 / 894 |
Outcome results
Primary
Percentage of Participants With Worsening Heart Failure (WHF) / All Cause of Deaths Through Day 5
In-hospital WHF through Day 5 post-randomization included worsening signs and/or symptoms of heart failure that required an intensification of intravenous therapy for heart failure or mechanical ventilation, renal or circulatory support. A central event adjudication committee was appointed to oversee the WHF primary endpoint adjudication.
Time frame: 5 days
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serelaxin + Standard of Care | Percentage of Participants With Worsening Heart Failure (WHF) / All Cause of Deaths Through Day 5 | 4.95 Percentage of Participants |
| Standard of Care (SOC) | Percentage of Participants With Worsening Heart Failure (WHF) / All Cause of Deaths Through Day 5 | 6.94 Percentage of Participants |
p-value: 0.017295% CI: [0.51, 0.98]Gehan's generalized Wilcoxon test
Secondary
Change From Baseline in Health-related Quality of Life Index Value, Assessed by EuroQoL EQ-5D-5L Questionnaire.
EQ-5D-5L is a questionnaire designed to assess health status in adults consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). The results were converted into a single index value using UK as the reference country for all countries. Range -0.3 (worst possible state) to 1 (best possible state).
Time frame: Baseline, Day 5, Day 14
Population: Full Analysis Set (only evaluable patients with non-missing information included)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Serelaxin + Standard of Care | Change From Baseline in Health-related Quality of Life Index Value, Assessed by EuroQoL EQ-5D-5L Questionnaire. | Day 5 | 0.28 units on a scale | Standard Deviation 0.298 |
| Serelaxin + Standard of Care | Change From Baseline in Health-related Quality of Life Index Value, Assessed by EuroQoL EQ-5D-5L Questionnaire. | Day 14 | 0.32 units on a scale | Standard Deviation 0.328 |
| Standard of Care (SOC) | Change From Baseline in Health-related Quality of Life Index Value, Assessed by EuroQoL EQ-5D-5L Questionnaire. | Day 5 | 0.27 units on a scale | Standard Deviation 0.292 |
| Standard of Care (SOC) | Change From Baseline in Health-related Quality of Life Index Value, Assessed by EuroQoL EQ-5D-5L Questionnaire. | Day 14 | 0.31 units on a scale | Standard Deviation 0.317 |
Comparison: Day 5p-value: 0.3115Mixed Models Analysis
Comparison: Day 14p-value: 0.1236Mixed Models Analysis
Secondary
Length of Index Hospital Stay
Length of stay (in hours) is defined as the index hospitalization discharge date and time minus the index hospitalization start date and time.
Time frame: 30 Days
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serelaxin + Standard of Care | Length of Index Hospital Stay | 251.28 hours | Standard Deviation 162.368 |
| Standard of Care (SOC) | Length of Index Hospital Stay | 243.59 hours | Standard Deviation 160.27 |
p-value: 0.1392Wilcoxon (Mann-Whitney)
Secondary
Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients
Time frame: Adverse Events (AE): 5 Days / Serious Adverse Events (SAE): 14 days / All cause deaths 30 days
Population: Safety Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Serelaxin + Standard of Care | Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients | Patients with any SAE through Day 14 | 12.38 Percentage of participants |
| Serelaxin + Standard of Care | Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients | All cause deaths through Day 14 | 1.91 Percentage of participants |
| Serelaxin + Standard of Care | Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients | All cause deaths through Day 5 | 0.58 Percentage of participants |
| Serelaxin + Standard of Care | Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients | All cause deaths through Day 30 | 3.30 Percentage of participants |
| Serelaxin + Standard of Care | Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients | Patients with any AE through Day 5 | 58.13 Percentage of participants |
| Standard of Care (SOC) | Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients | All cause deaths through Day 30 | 4.25 Percentage of participants |
| Standard of Care (SOC) | Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients | Patients with any AE through Day 5 | 56.04 Percentage of participants |
| Standard of Care (SOC) | Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients | Patients with any SAE through Day 14 | 11.97 Percentage of participants |
| Standard of Care (SOC) | Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients | All cause deaths through Day 5 | 0.67 Percentage of participants |
| Standard of Care (SOC) | Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients | All cause deaths through Day 14 | 2.01 Percentage of participants |
Secondary
Percentage of Participants With In-hospital Worsening Heart Failure/All-Cause Death/Readmission for Heart Failure Through Day 14
WHF/death/readmission for heart failure through Day 14. WHF/deaths through Day 5 were adjudicated and confirmed by the Clinical Endpoint Committee, WHF/deaths after Day 5 through Day 14 and readmission through Day 14 were as reported by the investigators.
Time frame: 14 days
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serelaxin + Standard of Care | Percentage of Participants With In-hospital Worsening Heart Failure/All-Cause Death/Readmission for Heart Failure Through Day 14 | 8.49 Percentage of Patients |
| Standard of Care (SOC) | Percentage of Participants With In-hospital Worsening Heart Failure/All-Cause Death/Readmission for Heart Failure Through Day 14 | 10.63 Percentage of Patients |
p-value: 0.063495% CI: [0.61, 1.02]Gehan's generalized Wilcoxon test
Secondary
Percentage of Participants With Persistent Sign or Symptoms of Heart Failure / Non-Improvement at Any Post Baseline Visit Through Day 5
Persistent or non-improvement in any signs or symptoms of HF at any post baseline visit up to Day 5.
Time frame: 5 days
Population: Full Analysis Set (only evaluable patients with non-missing information included)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serelaxin + Standard of Care | Percentage of Participants With Persistent Sign or Symptoms of Heart Failure / Non-Improvement at Any Post Baseline Visit Through Day 5 | 86 Percentage of Participants |
| Standard of Care (SOC) | Percentage of Participants With Persistent Sign or Symptoms of Heart Failure / Non-Improvement at Any Post Baseline Visit Through Day 5 | 91 Percentage of Participants |
p-value: <0.0001Chi-squared
Secondary
Percentage of Participants With Renal Deterioration at Any Post Baseline Visit Through Day 14
Renal deterioration is defined as \> or = 0.3 mg/dL increase from screening in serum creatinine.
Time frame: 14 days
Population: Full Analysis Set (only evaluable patients with non-missing information included)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serelaxin + Standard of Care | Percentage of Participants With Renal Deterioration at Any Post Baseline Visit Through Day 14 | 36 Percentage of Participants |
| Standard of Care (SOC) | Percentage of Participants With Renal Deterioration at Any Post Baseline Visit Through Day 14 | 44 Percentage of Participants |
p-value: 0.0002Chi-squared