Acute Heart Failure
Conditions
Keywords
acute heart failure,, AHF,, multi-center,, randomized,, double-blind
Brief summary
The purpose of the study was to evaluate the efficacy, safety and tolerability of intravenous infusion of serelaxin, when added to standard therapy, in acute heart failure (AHF) patients.
Detailed description
This Phase IIIb outcome study in AHF patients was designed as a multicenter, randomized, double-blind, placebo-controlled, event-driven study in order to assess the efficacy, safety and tolerability of intravenous infusion of serelaxin or placebo. The AHF patients randomized to either serelaxin or placebo in the study were followed for a period of 180 days, and were required to receive standard-of-care background HF management during both the index hospitalization and post discharge according to regional or local guidelines/institutional standards.
Interventions
DRUGRLX030
1 mg/mL solution in 6 mL vials
DRUGPlacebo
Matching placebo solution to serelaxin
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male or female 18 years of age, with body weight ≤160 kg * Hospitalized for AHF with anticipated requirement of IV therapy for at least 48 hours; AHF is defined as including all of the following measured at any time between presentation (including the emergency department) and the end of screening: * Persistent dyspnea at rest or with minimal exertion * Pulmonary congestion on chest radiograph * B-type natriuretic peptide (BNP) ≥500 pg/mL or N-terminal (NT)-proBNP ≥2000 pg/mL; for patients ≥ 75 years of age or with current atrial fibrillation (at the time of randomization), BNP ≥ 750 pg/mL or NT-proBNP ≥ 3,000 pg/mL * Systolic BP ≥125 mmHg at the start and at the end of screening * Able to be randomized within 16 hours from presentation to the hospital, including the emergency department * Received intravenous furosemide of at least 40 mg total (or equivalent) at any time between presentation (this includes outpatient clinic, ambulance, or hospital including emergency department) and the start of screening for the study for the treatment of the current acute HF episode. Key
Exclusion criteria
* Dyspnea primarily due to non-cardiac causes * Known history of respiratory disorders requiring the daily use of IV or oral steroids (does not include inhaled steroids); need for intubation or the current use of IV or oral steroids for chronic obstructive pulmonary disease (COPD) * Temperature \>38.5°C (oral or equivalent) or sepsis or active infection requiring IV anti-microbial treatment * Clinical evidence of acute coronary syndrome currently or within 30 days prior to enrollment. * AHF due to significant arrhythmias, which include any of the following: sustained ventricular tachycardia, bradycardia with sustained ventricular rate \<45 beats per minute, or atrial fibrillation/flutter with sustained ventricular response of \>130 beats per minute * Patients with severe renal impairment defined as pre-randomization estimated glomerular filtration rate (eGFR) \< 25 mL/min/1.73m2 calculated using the Simplified Modification of Diet in Renal Disease (sMDRD) equation, and/or those receiving current or planned dialysis or ultrafiltration * Patients with hematocrit \<25%, or a history of blood transfusion within the 14 days prior to screening, or active life-threatening GI bleeding. * Known hepatic impairment (as evidenced by total bilirubin \> 3 mg/dL, or increased ammonia levels, if performed) or history of cirrhosis with evidence of portal hypertension such as varices. * Significant, uncorrected, left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area \<1.0 cm2 or mean gradient \>40 mmHg on prior or current echocardiogram), and severe mitral stenosis * Severe aortic insufficiency or severe mitral regurgitation for which surgical or percutaneous intervention is indicated. * Documented, prior to or at the time of randomization, restrictive amyloid myocardiopathy, OR 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 Confirmed Cardiovascular (CV) Death Through Day 180 | 180 days | The percentage of participants with an adjudicated CV death through day 180 was assessed. |
| Percentage of Participants With Worsening of Heart Failure (WHF) Through Day 5 | Day 5 | The percentage of participants with WHF through day 5 was assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With First Occurrence of Adjudicated CV Death or Adjudicated Re-hospitalization | 180 days | The percentage of participants with adjudicated CV death or adjudicated re-hospitalization through day 180 was assessed. |
| Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization | 180 days (Patients still in the hospital at Day 60 were censored at Day 60) | Length of stay was defined as the hospitalization discharge date and the time minus the baseline date and time plus 1 day. |
| Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure | From baseline to Day 5 | The percentage of participants with first improvement since baseline in congestive signs and symptoms was assessed. The signs and symptoms included exertional dyspnea, orthopnea, rales, jugular venous pressure and peripheral edema/pre-sacral edema. |
| Percentage of Participants With All-cause Death Through Day 180 | 180 days | The percentage of participants with all-cause death through day 180 was assessed. |
| Change From Baseline in NT-proBNP Biomarker | Baseline, Day 2, Day 5 and Day 14 | Blood samples were collected to assess the change from baseline in NT-proBNP. The ratio of the post-baseline value to the baseline value is presented. |
| Change From Baseline in Cystatin C Biomarker | Baseline, Day 2, Day 5 and Day 14 | Blood samples were collected to assess the change from baseline in Cystatin C. The ratio of the post-baseline value to the baseline value is presented. |
| Change From Baseline in hsTroponin T Biomarker | Baseline, Day 2, Day 5 and Day 14 | Blood samples were collected to assess the change from baseline in hsTroponin T. The geometric least square mean (LSM) of the ratio of the post-baseline value to the baseline value is presented. |
| Length of Total Hospital Stay (LOS) During the Index Acute Heart Failure (AHF) Hospitalization | 180 days (Participants still in the hospital at Day 60 were censored at Day 60) | Length of stay was defined as the index hospitalization discharge date and time minus the baseline date and time plus 1 day. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Czechia, Denmark, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Mexico, Netherlands, Norway, Peru, Poland, Portugal, Puerto Rico, Romania, Russia, Slovakia, South Africa, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
6600 participants were randomized into the trial. Only 6545 participants were eligible for analysis. Therefore, the participants flow and baseline characteristics are based on 6545 participants.
Participants by arm
| Arm | Count |
|---|---|
| Serelaxin (RLX030) Participants received continuous intravenous infusion of serelaxin 30 ug/kg/day for 48 hours. | 3,274 |
| Placebo Participants received continuous intravenous infusion of matching placebo to serelaxin for 48 hours. | 3,271 |
| Total | 6,545 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Withdrawal by Subject | 8 | 7 |
Baseline characteristics
| Characteristic | Placebo | Total | Serelaxin (RLX030) |
|---|---|---|---|
| Age, Continuous | 72.8 Years STANDARD_DEVIATION 11.17 | 73.0 Years STANDARD_DEVIATION 11.2 | 73.1 Years STANDARD_DEVIATION 11.24 |
| Race (NIH/OMB) American Indian or Alaska Native | 18 Participants | 31 Participants | 13 Participants |
| Race (NIH/OMB) Asian | 16 Participants | 30 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 171 Participants | 334 Participants | 163 Participants |
| Race (NIH/OMB) More than one race | 46 Participants | 92 Participants | 46 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants | 8 Participants | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 17 Participants | 34 Participants | 17 Participants |
| Race (NIH/OMB) White | 2999 Participants | 6016 Participants | 3017 Participants |
| Sex: Female, Male Female | 1341 Participants | 2637 Participants | 1296 Participants |
| Sex: Female, Male Male | 1930 Participants | 3908 Participants | 1978 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 363 / 3,257 | 386 / 3,248 |
| other Total, other adverse events | 1,336 / 3,257 | 1,277 / 3,248 |
| serious Total, serious adverse events | 412 / 3,257 | 424 / 3,248 |
Outcome results
Primary
Percentage of Participants With Confirmed Cardiovascular (CV) Death Through Day 180
The percentage of participants with an adjudicated CV death through day 180 was assessed.
Time frame: 180 days
Population: The Full Analysis Set, which included all randomized participants who were not mis-randomized or excluded due to GCP reasons, was analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serelaxin (RLX030) | Percentage of Participants With Confirmed Cardiovascular (CV) Death Through Day 180 | 8.7 Percentage of participants |
| Placebo | Percentage of Participants With Confirmed Cardiovascular (CV) Death Through Day 180 | 8.9 Percentage of participants |
p-value: 0.385795% CI: [0.83, 1.15]Log Rank
Primary
Percentage of Participants With Worsening of Heart Failure (WHF) Through Day 5
The percentage of participants with WHF through day 5 was assessed.
Time frame: Day 5
Population: The Full Analysis Set, which included all randomized participants who were not mis-randomized or excluded due to GCP reasons, was analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serelaxin (RLX030) | Percentage of Participants With Worsening of Heart Failure (WHF) Through Day 5 | 6.9 Percentage of participants |
| Placebo | Percentage of Participants With Worsening of Heart Failure (WHF) Through Day 5 | 7.7 Percentage of participants |
p-value: 0.096895% CI: [0.75, 1.07]Gehan's generalized Wilcoxon test
Secondary
Change From Baseline in Cystatin C Biomarker
Blood samples were collected to assess the change from baseline in Cystatin C. The ratio of the post-baseline value to the baseline value is presented.
Time frame: Baseline, Day 2, Day 5 and Day 14
Population: Participants from the biomarker analysis set, who had both baseline and post baseline values for a given time point, were analyzed at that time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Serelaxin (RLX030) | Change From Baseline in Cystatin C Biomarker | Day 2 | 1.0261 mg/L |
| Serelaxin (RLX030) | Change From Baseline in Cystatin C Biomarker | Day 5 | 1.1171 mg/L |
| Serelaxin (RLX030) | Change From Baseline in Cystatin C Biomarker | Day 14 | 1.1186 mg/L |
| Placebo | Change From Baseline in Cystatin C Biomarker | Day 14 | 1.1342 mg/L |
| Placebo | Change From Baseline in Cystatin C Biomarker | Day 2 | 1.0648 mg/L |
| Placebo | Change From Baseline in Cystatin C Biomarker | Day 5 | 1.1259 mg/L |
Comparison: Day 2p-value: 0.000395% CI: [0.9447, 0.983]Repeated measures model
Comparison: Day 5p-value: 0.536195% CI: [0.9677, 1.0172]Repeated measures model
Comparison: Day 14p-value: 0.37595% CI: [0.9567, 1.0169]Repeated measures model
Secondary
Change From Baseline in hsTroponin T Biomarker
Blood samples were collected to assess the change from baseline in hsTroponin T. The geometric least square mean (LSM) of the ratio of the post-baseline value to the baseline value is presented.
Time frame: Baseline, Day 2, Day 5 and Day 14
Population: Participants from the biomarker analysis set, who had both baseline and post baseline values for a given time point, were analyzed at that time point.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Serelaxin (RLX030) | Change From Baseline in hsTroponin T Biomarker | Day 2 | 0.9808 ug/L |
| Serelaxin (RLX030) | Change From Baseline in hsTroponin T Biomarker | Day 5 | 0.9589 ug/L |
| Serelaxin (RLX030) | Change From Baseline in hsTroponin T Biomarker | Day 14 | 0.7813 ug/L |
| Placebo | Change From Baseline in hsTroponin T Biomarker | Day 2 | 1.0432 ug/L |
| Placebo | Change From Baseline in hsTroponin T Biomarker | Day 5 | 1.0678 ug/L |
| Placebo | Change From Baseline in hsTroponin T Biomarker | Day 14 | 0.8611 ug/L |
Comparison: Day 2p-value: 0.020995% CI: [0.8921, 0.9907]Repeated measures model
Comparison: Day 5p-value: 0.003495% CI: [0.8358, 0.9649]Repeated measures model
Comparison: Day 14p-value: 0.020995% CI: [0.8355, 0.9854]Repeated measures model
Secondary
Change From Baseline in NT-proBNP Biomarker
Blood samples were collected to assess the change from baseline in NT-proBNP. The ratio of the post-baseline value to the baseline value is presented.
Time frame: Baseline, Day 2, Day 5 and Day 14
Population: Participants from the biomarker analysis set, who had both baseline and post baseline values for a given time point, were analyzed at that time point.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Serelaxin (RLX030) | Change From Baseline in NT-proBNP Biomarker | Day 2 | 0.4902 pg/mL |
| Serelaxin (RLX030) | Change From Baseline in NT-proBNP Biomarker | Day 5 | 0.4249 pg/mL |
| Serelaxin (RLX030) | Change From Baseline in NT-proBNP Biomarker | Day 14 | 0.4265 pg/mL |
| Placebo | Change From Baseline in NT-proBNP Biomarker | Day 2 | 0.5702 pg/mL |
| Placebo | Change From Baseline in NT-proBNP Biomarker | Day 5 | 0.4454 pg/mL |
| Placebo | Change From Baseline in NT-proBNP Biomarker | Day 14 | 0.4469 pg/mL |
Comparison: Day 2p-value: 0.000795% CI: [0.7876, 0.9385]Repeated measures model
Comparison: Day 5p-value: 0.370995% CI: [0.86, 1.0579]Repeated measures model
Comparison: Day 14p-value: 0.389395% CI: [0.8578, 1.0617]Repeated measures model
Secondary
Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization
Length of stay was defined as the hospitalization discharge date and the time minus the baseline date and time plus 1 day.
Time frame: 180 days (Patients still in the hospital at Day 60 were censored at Day 60)
Population: The Full Analysis Set, which included all randomized participants who were not mis-randomized or excluded due to GCP reasons, was analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serelaxin (RLX030) | Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization | 3.8 days | Standard Deviation 8.29 |
| Placebo | Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization | 4.1 days | Standard Deviation 8.77 |
p-value: 0.2103Wilcoxon rank sum test
Secondary
Length of Total Hospital Stay (LOS) During the Index Acute Heart Failure (AHF) Hospitalization
Length of stay was defined as the index hospitalization discharge date and time minus the baseline date and time plus 1 day.
Time frame: 180 days (Participants still in the hospital at Day 60 were censored at Day 60)
Population: The Full Analysis Set, which included all randomized participants who were not mis-randomized or excluded due to GCP reasons, was analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serelaxin (RLX030) | Length of Total Hospital Stay (LOS) During the Index Acute Heart Failure (AHF) Hospitalization | 9.362 days | Standard Deviation 9.3581 |
| Placebo | Length of Total Hospital Stay (LOS) During the Index Acute Heart Failure (AHF) Hospitalization | 9.545 days | Standard Deviation 9.6739 |
p-value: 0.2204Wilcoxon rank sum test
Secondary
Percentage of Participants With All-cause Death Through Day 180
The percentage of participants with all-cause death through day 180 was assessed.
Time frame: 180 days
Population: The Full Analysis Set, which included all randomized participants who were not mis-randomized or excluded due to GCP reasons, was analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serelaxin (RLX030) | Percentage of Participants With All-cause Death Through Day 180 | 11.2 Percentage of participants |
| Placebo | Percentage of Participants With All-cause Death Through Day 180 | 11.9 Percentage of participants |
p-value: 0.38995% CI: [0.81, 1.08]Log Rank
Secondary
Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure
The percentage of participants with first improvement since baseline in congestive signs and symptoms was assessed. The signs and symptoms included exertional dyspnea, orthopnea, rales, jugular venous pressure and peripheral edema/pre-sacral edema.
Time frame: From baseline to Day 5
Population: The Full Analysis Set, which included all randomized participants who were not mis-randomized or excluded due to GCP reasons, was considered for the analysis. For each symptom, only participants with observed baseline signs and symptoms and non-missing baseline and post baseline signs and symptoms were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Serelaxin (RLX030) | Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure | Orthopnea | 92.9 Percentage of participants |
| Serelaxin (RLX030) | Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure | Jugular venous pressure | 90.4 Percentage of participants |
| Serelaxin (RLX030) | Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure | Rales | 94.1 Percentage of participants |
| Serelaxin (RLX030) | Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure | Peripheral edema, pre-sacral edema | 91.6 Percentage of participants |
| Serelaxin (RLX030) | Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure | Exertional dyspnea | 94.1 Percentage of participants |
| Placebo | Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure | Peripheral edema, pre-sacral edema | 90.7 Percentage of participants |
| Placebo | Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure | Exertional dyspnea | 92.6 Percentage of participants |
| Placebo | Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure | Orthopnea | 91.2 Percentage of participants |
| Placebo | Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure | Rales | 93.7 Percentage of participants |
| Placebo | Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure | Jugular venous pressure | 88.0 Percentage of participants |
Comparison: Exertional dyspneap-value: 0.00595% CI: [1.02, 1.14]Log Rank
Comparison: Orthopneap-value: 0.005195% CI: [1.02, 1.14]Log Rank
Comparison: Ralesp-value: 0.996295% CI: [0.95, 1.05]Log Rank
Comparison: Jugular venous pressurep-value: 0.019695% CI: [1.01, 1.15]Log Rank
Comparison: Peripheral edema, pre-sacral edemap-value: 0.215895% CI: [0.98, 1.1]Log Rank
Secondary
Percentage of Participants With First Occurrence of Adjudicated CV Death or Adjudicated Re-hospitalization
The percentage of participants with adjudicated CV death or adjudicated re-hospitalization through day 180 was assessed.
Time frame: 180 days
Population: The Full Analysis Set, which included all randomized participants who were not mis-randomized or excluded due to GCP reasons, was analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Serelaxin (RLX030) | Percentage of Participants With First Occurrence of Adjudicated CV Death or Adjudicated Re-hospitalization | 24.3 Percentage of participants |
| Placebo | Percentage of Participants With First Occurrence of Adjudicated CV Death or Adjudicated Re-hospitalization | 24.9 Percentage of participants |
p-value: 0.274495% CI: [0.88, 1.07]Log Rank