Acute Heart Failure
Conditions
Keywords
Serelaxin,, WHF,, Likert Scale,, RELAX-AHF-ASIA,, RLX030,, AHF,, acute heart failure
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.
Interventions
OTHERStandard of CareTherapy
This treatment can include but is not limited to intravenous and/or oral diuretics, ACE inhibitors/angiotensin receptor antagonists, β blockers, and aldosterone receptor antagonists, etc.
DRUGSerelaxin
Intravenous infusion
DRUGPlacebo
Intravenous infusion
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
* Male or female ≥ 18 years of age, with body weight ≤160 kg * Hospitalized for AHF; AHF is defined as including all of the following measured at any time between presentation (including the emergency department and outpatient clinic) and at the end of screening: * Persistent dyspnea at rest or with minimal exertion at screening and at the time of randomization * Pulmonary congestion on chest radiograph * Brain natriuretic peptide (BNP) ≥500 pg/mL or NT-proBNP ≥2,000 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 and outpatient clinic * 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 * Renal impairment defined as an estimate glomerular filtration rate using the between presentation and randomization of ≥ 25 and ≤75mL/min/1.73m2, calculated using the Modification of Diet in Renal Disease formula (or modified sMDRD formula according to specific ethnic groups and local practice guidelines).
Exclusion criteria
* Dyspnea primarily due to non-cardiac causes * Temperature \>38.5°C (oral or equivalent), sepsis, active and clinically significant infection requiring IV anti-microbial treatment or known presence or evidence of Human Immunodeficiency Virus (HIV) infection (based on history and/or clinical findings, including laboratory results obtained during screening period). * Clinical evidence of acute coronary syndrome currently or within 30 days prior to enrollment \*Patients with systolic blood pressure \>180 mmHg at the end of screening * 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 * Hepatic disease unrelated to Heart Failure etiology and as determined by any one of the following: AST and/or ALT values exceeding 3 X ULN and/or bilirubin \> 1.5 X ULN at screening or history of hepatic encephalopathy, esophageal varices, or portacaval shunt, or a diagnosis of cirrhosis by any means, or evidence of chronic Hepatitis B (presence of hepatitis B surface antigen production: positive HBsAg), or chronic Hepatitis C infection (presence of Hepatitis C genetic replication: positive Hepatitis C viral RNA, based on history and/or clinical findings, including laboratory results obtained during screening period). \*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 \>50 mmHg on prior or current echocardiogram), and severe mitral stenosis * History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past year with a life expectancy less than 1 year
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With a Clinical Composite Endpoint of Treatment Success, Treatment Failure, or no Change. | through day 5 | The trichotomous clinical composite endpoint of treatment success, treatment failure, or no change. Treatment success defined as improvement of dyspnea by Likert scale and at least 2 points improvement by at least 2 physician assessed signs and symptoms (orthopnea, rales edema, and jugular venous pulse) at Day 2; treatment failure defined as worsening heart failure, death, or re-hospitalization due to heart failure or renal failure through Day 5; no change defined as neither the criteria for treatment success nor the criteria for treatment failure was met through Day 5. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to CV Death | Through Day 180 | analysis of time to CEC CV death through day 180 : results are given in terms of number of participants with CV death event through day 180 (pre-defined timeframe). |
| Time to All-cause Death | Through Day 180 | Results are given in terms of number of participants with all cause death event through day 180 (pre-defined timeframe). |
| Time to Moderate or Marked Improvements in Dyspnea by Likert Scale, Expressed in Days | Through Day 5 | Time to event is computed as the number of days from randomization to moderate or marked improvements in dyspnea by Likert scale |
| Dyspnea by VAS-AUC Changes | Through Day 5 | Change from baseline in Dyspena by VAS-AUC through Day 5, expressed in mm-hours |
| Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization | Up to day 30 | Length of stay will be defined as the hospitalization discharge date and the time minus the baseline date and time plus 1 day |
| Renal Dysfunction and Prevention of Worsening of Renal Function | Through Day 5 | number of participants with renal dysfunction or in-hospital worsening of renal function through Day 5 |
| Time to WHF | Through Day 5 | Results are given in terms of number of participants with at least one worsening heart failure (WHF) event through day 5 (pre-defined timeframe). |
| Time to CV Death or Re-hospitalization Due to Heart Failure/ Renal Failure | Through Day 180 | Results are given in terms of number of participants with CV death or at least one re-hospitalization due to Heart Failure through day 180 (pre-defined timeframe). |
| Time to In-hospital Worsening Heart Failure Through Day 5 | Through Day 5 | Results are given in terms of number of participants with at least one in-hospital worsening heart failure through day 5 (pre-defined timeframe). In-hospital worsening heart failure is defined by symptoms only, signs only, and both symptoms and signs. |
| Use of Loop Diuretic and Vasoactive Agents | Through Day 5 | Number of patients reported with use of loop diuretic and vasoactive agents from randomization through Day 5 |
| Change From Baseline in Cardio-renal Biomarkers | Day 2 and Day 5 | — |
| Number of Patients Reported With Total Adverse Events, Serious Adverse Events and Death. | For the safety evaluation, all adverse events will be collected from signing of the informed consent form through Day 5 for non-serious AEs and through Day 14 for serious AEs. | To evaluate the safety and tolerability of intravenous serelaxin in AHF patients, number of patients with total adverse events, serious adverse events and death will be analyzed. |
| Time to Re-hospitalization Due to Heart Failure and Renal Impairment | Through Day 180 | Time to event is computed as the number of days from randomization to re-hospitalization due to Heart Failure and renal impairment |
Countries
China, India, Japan, Jordan, Lebanon, Malaysia, Philippines, Singapore, South Korea, Taiwan, Thailand
Participant flow
Recruitment details
* patient randomized : participants who signed ICF (876 participants) * Full analyis set: participants who received at least one dose of study drug (870 participants) * safety set (858 participtants): participants who received at least one dose of study drug and completed at least one post baseline assessment
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients who received continuous intravenous infusion of matching placebo serelaxin for 48 hours. | 433 |
| Serelaxin Patients who receivedcontinuous intravenous infusion of serelaxin for 48 hours. | 437 |
| Total | 870 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | patient followd less than 165 days | 11 | 5 |
| Overall Study | study terminated by sponsor | 58 | 54 |
| Overall Study | technical problem | 4 | 2 |
| Overall Study | Withdrawal by Subject | 9 | 11 |
Baseline characteristics
| Characteristic | Serelaxin | Total | Placebo |
|---|---|---|---|
| Age, Continuous full analysis set 870 participants | 68.9 years STANDARD_DEVIATION 14.4 | 69.6 years STANDARD_DEVIATION 14.14 | 70.2 years STANDARD_DEVIATION 13.86 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 420 Participants | 838 Participants | 418 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 32 Participants | 15 Participants |
| Sex: Female, Male Female | 147 Participants | 312 Participants | 165 Participants |
| Sex: Female, Male Male | 290 Participants | 558 Participants | 268 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 34 / 432 | 41 / 426 | 75 / 858 |
| other Total, other adverse events | 65 / 432 | 82 / 426 | 147 / 858 |
| serious Total, serious adverse events | 37 / 432 | 50 / 426 | 87 / 858 |
Outcome results
Primary
Percentage of Patients With a Clinical Composite Endpoint of Treatment Success, Treatment Failure, or no Change.
The trichotomous clinical composite endpoint of treatment success, treatment failure, or no change. Treatment success defined as improvement of dyspnea by Likert scale and at least 2 points improvement by at least 2 physician assessed signs and symptoms (orthopnea, rales edema, and jugular venous pulse) at Day 2; treatment failure defined as worsening heart failure, death, or re-hospitalization due to heart failure or renal failure through Day 5; no change defined as neither the criteria for treatment success nor the criteria for treatment failure was met through Day 5.
Time frame: through day 5
Population: Full analysis set (FAS) - All patients in the randomized population who were not misrandomized patients. Following the intent-to-treat (ITT) principle, patients were analyzed according to the treatment they had been assigned to at the randomization
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Percentage of Patients With a Clinical Composite Endpoint of Treatment Success, Treatment Failure, or no Change. | No Change | 314 Participants |
| Placebo | Percentage of Patients With a Clinical Composite Endpoint of Treatment Success, Treatment Failure, or no Change. | Treatment Success | 83 Participants |
| Placebo | Percentage of Patients With a Clinical Composite Endpoint of Treatment Success, Treatment Failure, or no Change. | Treatment Failure | 36 Participants |
| Serelaxin | Percentage of Patients With a Clinical Composite Endpoint of Treatment Success, Treatment Failure, or no Change. | Treatment Failure | 18 Participants |
| Serelaxin | Percentage of Patients With a Clinical Composite Endpoint of Treatment Success, Treatment Failure, or no Change. | No Change | 333 Participants |
| Serelaxin | Percentage of Patients With a Clinical Composite Endpoint of Treatment Success, Treatment Failure, or no Change. | Treatment Success | 86 Participants |
Secondary
Change From Baseline in Cardio-renal Biomarkers
Time frame: Day 2 and Day 5
Population: The data was not collected, and analysis not performed, as the trial was terminated prematurely
Secondary
Dyspnea by VAS-AUC Changes
Change from baseline in Dyspena by VAS-AUC through Day 5, expressed in mm-hours
Time frame: Through Day 5
Population: full analysis set with measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Dyspnea by VAS-AUC Changes | 2284.6 mm-hours | Standard Deviation 2702.34 |
| Serelaxin | Dyspnea by VAS-AUC Changes | 2358.2 mm-hours | Standard Deviation 2321.17 |
Secondary
Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization
Length of stay will be defined as the hospitalization discharge date and the time minus the baseline date and time plus 1 day
Time frame: Up to day 30
Population: full analysis set with measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization | 3.2 days | Standard Deviation 5.13 |
| Serelaxin | Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization | 2.5 days | Standard Deviation 4.26 |
Secondary
Number of Patients Reported With Total Adverse Events, Serious Adverse Events and Death.
To evaluate the safety and tolerability of intravenous serelaxin in AHF patients, number of patients with total adverse events, serious adverse events and death will be analyzed.
Time frame: For the safety evaluation, all adverse events will be collected from signing of the informed consent form through Day 5 for non-serious AEs and through Day 14 for serious AEs.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Patients Reported With Total Adverse Events, Serious Adverse Events and Death. | number of participants with SAE | 50 Participants |
| Placebo | Number of Patients Reported With Total Adverse Events, Serious Adverse Events and Death. | number of participants with AE | 253 Participants |
| Placebo | Number of Patients Reported With Total Adverse Events, Serious Adverse Events and Death. | number of patients with death | 41 Participants |
| Serelaxin | Number of Patients Reported With Total Adverse Events, Serious Adverse Events and Death. | number of patients with death | 34 Participants |
| Serelaxin | Number of Patients Reported With Total Adverse Events, Serious Adverse Events and Death. | number of participants with SAE | 37 Participants |
| Serelaxin | Number of Patients Reported With Total Adverse Events, Serious Adverse Events and Death. | number of participants with AE | 219 Participants |
Secondary
Renal Dysfunction and Prevention of Worsening of Renal Function
number of participants with renal dysfunction or in-hospital worsening of renal function through Day 5
Time frame: Through Day 5
Population: Full analysis set with measure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Renal Dysfunction and Prevention of Worsening of Renal Function | 120 participants |
| Serelaxin | Renal Dysfunction and Prevention of Worsening of Renal Function | 59 participants |
Secondary
Time to All-cause Death
Results are given in terms of number of participants with all cause death event through day 180 (pre-defined timeframe).
Time frame: Through Day 180
Population: Full analysis set (FAS) - All patients in the randomized population who were not misrandomized patients\*. Following the intent-to-treat (ITT) principle, patients were analyzed according to the treatment they had been assigned to at the randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Time to All-cause Death | 41 Participants |
| Serelaxin | Time to All-cause Death | 33 Participants |
Secondary
Time to CV Death
analysis of time to CEC CV death through day 180 : results are given in terms of number of participants with CV death event through day 180 (pre-defined timeframe).
Time frame: Through Day 180
Population: Full analysis set (FAS) - All patients in the randomized population who were not misrandomized patients\*. Following the intent-to-treat (ITT) principle, patients were analyzed according to the treatment they had been assigned to at the randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Time to CV Death | 27 Participants |
| Serelaxin | Time to CV Death | 27 Participants |
Secondary
Time to CV Death or Re-hospitalization Due to Heart Failure/ Renal Failure
Results are given in terms of number of participants with CV death or at least one re-hospitalization due to Heart Failure through day 180 (pre-defined timeframe).
Time frame: Through Day 180
Population: Full analysis set (FAS) - All patients in the randomized population who were not misrandomized patients\*. Following the intent-to-treat (ITT) principle, patients were analyzed according to the treatment they had been assigned to at the randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Time to CV Death or Re-hospitalization Due to Heart Failure/ Renal Failure | 87 Participants |
| Serelaxin | Time to CV Death or Re-hospitalization Due to Heart Failure/ Renal Failure | 82 Participants |
Secondary
Time to In-hospital Worsening Heart Failure Through Day 5
Results are given in terms of number of participants with at least one in-hospital worsening heart failure through day 5 (pre-defined timeframe). In-hospital worsening heart failure is defined by symptoms only, signs only, and both symptoms and signs.
Time frame: Through Day 5
Population: Full analysis set with measure
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Time to In-hospital Worsening Heart Failure Through Day 5 | WHF through day 5 by both | 20 Participants |
| Placebo | Time to In-hospital Worsening Heart Failure Through Day 5 | WHF through day 5 by symptoms | 2 Participants |
| Placebo | Time to In-hospital Worsening Heart Failure Through Day 5 | death through day 5 | 1 Participants |
| Placebo | Time to In-hospital Worsening Heart Failure Through Day 5 | WHF through day 5 by signs | 3 Participants |
| Serelaxin | Time to In-hospital Worsening Heart Failure Through Day 5 | death through day 5 | 1 Participants |
| Serelaxin | Time to In-hospital Worsening Heart Failure Through Day 5 | WHF through day 5 by signs | 0 Participants |
| Serelaxin | Time to In-hospital Worsening Heart Failure Through Day 5 | WHF through day 5 by symptoms | 1 Participants |
| Serelaxin | Time to In-hospital Worsening Heart Failure Through Day 5 | WHF through day 5 by both | 9 Participants |
Secondary
Time to Moderate or Marked Improvements in Dyspnea by Likert Scale, Expressed in Days
Time to event is computed as the number of days from randomization to moderate or marked improvements in dyspnea by Likert scale
Time frame: Through Day 5
Population: Full analysis set (FAS)with measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time to Moderate or Marked Improvements in Dyspnea by Likert Scale, Expressed in Days | 1.327 days | Standard Deviation 1.4418 |
| Serelaxin | Time to Moderate or Marked Improvements in Dyspnea by Likert Scale, Expressed in Days | 1.352 days | Standard Deviation 1.5071 |
Secondary
Time to Re-hospitalization Due to Heart Failure and Renal Impairment
Time to event is computed as the number of days from randomization to re-hospitalization due to Heart Failure and renal impairment
Time frame: Through Day 180
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Re-hospitalization Due to Heart Failure and Renal Impairment | 87 days |
| Serelaxin | Time to Re-hospitalization Due to Heart Failure and Renal Impairment | 82 days |
Secondary
Time to WHF
Results are given in terms of number of participants with at least one worsening heart failure (WHF) event through day 5 (pre-defined timeframe).
Time frame: Through Day 5
Population: Full analysis set (FAS) - All patients in the randomized population who were not misrandomized patients\*. Following the intent-to-treat (ITT) principle, patients were analyzed according to the treatment they had been assigned to at the randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Time to WHF | 26 Participants |
| Serelaxin | Time to WHF | 11 Participants |
Secondary
Use of Loop Diuretic and Vasoactive Agents
Number of patients reported with use of loop diuretic and vasoactive agents from randomization through Day 5
Time frame: Through Day 5
Population: full analysis set with measure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Use of Loop Diuretic and Vasoactive Agents | 58 participants |
| Serelaxin | Use of Loop Diuretic and Vasoactive Agents | 49 participants |