Acute Heart Failure
Conditions
Keywords
Acute heart failure (AHF),, Japanese,, Safety and tolerability, Pharmacokinetics,, Renal Impairment
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled study to assess safety, tolerability and pharmacokinetics and to explore efficacy of IV infusion of 10 µg/kg/day and 30 µg/kg/day serelaxin for 48 hours compared to placebo, when added to the standard therapy, in approximately 45 Japanese AHF patients.
Interventions
DRUGSerelaxin
Intravenous infusion
DRUGPlacebo
Placebo
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
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Written informed consent must be obtained before any study-specific assessment is performed. * Male or female ≥20 years of age, with body weight ≥30 kg and ≤160 kg * Hospitalized for AHF; AHF is defined as including all of the followings measured at any time between presentation (including the emergency department) and the end of screening: * Dyspnea at rest or with minimal exertion * Pulmonary congestion on chest radiograph * BNP ≥350 pg/mL or NT-proBNP ≥1,400 pg/mL * SBP ≥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 (IV) furosemide of at least 40 mg (or equivalent) at any time between presentation (this include outpatient clinic, ambulance, or hospital including emergency department) and the start of screening for the study for the treatment of the current acute heart failure (HF) episode. * Impaired renal function defined as an estimated glomerular filtration rate (eGFR) between presentation and randomization of ≥ 25 and≤ 75 mL/min/1.73 m2, calculated using the Japanese formula Key
Exclusion criteria
* Dyspnea primarily due to non-cardiac causes * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | From start of study treatment up to Day 5 (for AEs); From start of study treatment up to Day 14 (for SAEs) | AEs were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. AEs leading to discontinuations, or requiring dose adjustment or interruptions and additional therapy were assessed. |
| Maximum Plasma Concentration (Cmax) of Serelaxin | Baseline (pre-dose), 1, 2, 24, 48, 49, 52 and 56 hours (post-dose) | Maximum plasma concentration (Cmax) was defined as the peak level of serelaxin, derived from plasma concentration-time data, using a non-compartmental model approach. |
| Weight Adjusted Clearance (CL) of Serelaxin | Baseline (pre-dose), 1, 2, 24, 48, 49, 52 and 56 hours (post-dose) | Weight adjusted clearance (CL) was defined as the total body clearance of serelaxin after drug administration. CL was calculated as nominal infusion rate divided by Css, using a non-compartmental model approach. |
| Concentration at Steady-state (Css) of Serelaxin | Baseline (pre-dose), 1, 2, 24, 48, 49, 52 and 56 hours (post-dose) | Concentration at steady-state (Css) was defined as concentration at the state of equilibrium obtained at the end of a certain number of administrations. Css of serelaxin in plasma was calculated by using a non-compartmental model approach. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in NT-proBNP Levels Through Day 14 | Baseline, Day 1, Day 2, Day 5, Day 14 | NT-proBNP biomarker was used to assess the effect of serelaxinin on degree of cardiac wall stress and congestion. Geometric means of the ratio of post-Baseline values to baseline values of NT-proBNP was calculated by treatment for the full analysis set. |
| Change From Baseline in Area Under the Curve (AUC) for Systolic Blood Pressure (SBP) Through 48 Hours of Infusion at Day 5 | Baseline, 48 hours, Day 5 | The area under the curve (AUC) was defined as area under the plasma concentration-time curve from time zero to time of the last time point with measurable concentration, calculated by a trapezoidal method. Systolic blood pressure was measured using a calibrated standard sphygmomanometer after the subject remained in sitting position for 3 minutes at clinic during the visit. Sample collected at: Baseline; 30 & 60 minutes and then every hour for the first 6 hours of study drug infusion, and then every 3 hours during 48 hours of study drug infusion; every 3 hours until 12 hours following end of infusion, then every 6 hours for 48 hours and then every 24 hours until the earlier of Day 5 or discharge. AUC for SBP is standardized by dividing by the length of respective time ranges. |
| Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Baseline, Day 1, Day 2, Day 5, Day 14 | Neutrophil gelatinase-asc lipocalin (NGAL) biomarker was used to assess the effect of serelaxin on kidney function. Geometric means of the ratio of post-Baseline values to baseline values of NGAL was calculated by treatment for the full analysis set. |
| Change From Baseline in Aldosterone Levels Through Day 14 | Baseline, Day 1, Day 2, Day 5, Day 14 | Aldosterone biomarker was used to assess the effect of serelaxinin on fluid retention. Geometric means of the ratio of post-Baseline values to baseline values of aldosterone was calculated by treatment for the full analysis set. |
| Change From Baseline in Cystatin-C Levels Through Day 14 | Baseline, Day 1, Day 2, Day 5, Day 14 | Cystatin-C biomarker was used to assess the effect of serelaxinin on worsening of renal function. Geometric means of the ratio of post-Baseline values to baseline values of Cystatin-C was calculated by treatment for the full analysis set. |
| Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Baseline, Day 1, Day 2, Day 5, Day 14 | High sensitivity Troponin-T biomarker was used to assess the effect of serelaxin on myocardial damage. Geometric means of the ratio of post-Baseline values to baseline values of high sensitivity troponin-t was calculated by treatment for the full analysis set. |
Countries
Japan
Participant flow
Recruitment details
The study was conducted at 15 centers in Japan.
Participants by arm
| Arm | Count |
|---|---|
| Serelaxin 10 mcg/kg/Day Participants received 10 micrograms/kilogram/day (mcg/kg/day) serelaxin as continuous intravenous (i.v.) infusion for 48 hours. | 16 |
| Serelaxin 30 mcg/kg/Day Participants received 30 mcg/kg/day serelaxin as continuous i.v. infusion for 48 hours. | 15 |
| Placebo Participants received continuous i.v. infusion of placebo matched to serelaxin for 48 hours. | 15 |
| Total | 46 |
Baseline characteristics
| Characteristic | Serelaxin 10 mcg/kg/Day | Serelaxin 30 mcg/kg/Day | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 70.2 years STANDARD_DEVIATION 11.77 | 79.7 years STANDARD_DEVIATION 9.01 | 76.4 years STANDARD_DEVIATION 12.08 | 75.3 years STANDARD_DEVIATION 11.54 |
| Age, Customized < 65 years | 6 participants | 1 participants | 3 participants | 10 participants |
| Age, Customized ≥ 65 years | 10 participants | 14 participants | 12 participants | 36 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 3 Participants | 12 Participants |
| Sex: Female, Male Male | 12 Participants | 10 Participants | 12 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 16 | 9 / 15 | 9 / 15 |
| serious Total, serious adverse events | 1 / 16 | 3 / 15 | 0 / 15 |
Outcome results
Primary
Concentration at Steady-state (Css) of Serelaxin
Concentration at steady-state (Css) was defined as concentration at the state of equilibrium obtained at the end of a certain number of administrations. Css of serelaxin in plasma was calculated by using a non-compartmental model approach.
Time frame: Baseline (pre-dose), 1, 2, 24, 48, 49, 52 and 56 hours (post-dose)
Population: The analysis was performed in the PK population. Here, Number of participants analyzed signifies participants evaluable for this PK parameter at the specified time points for each arm, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serelaxin 10 mcg/kg/Day | Concentration at Steady-state (Css) of Serelaxin | 7.81 ng/mL | Standard Deviation 1.96 |
| Serelaxin 30 mcg/kg/Day | Concentration at Steady-state (Css) of Serelaxin | 19.1 ng/mL | Standard Deviation 4.61 |
Primary
Maximum Plasma Concentration (Cmax) of Serelaxin
Maximum plasma concentration (Cmax) was defined as the peak level of serelaxin, derived from plasma concentration-time data, using a non-compartmental model approach.
Time frame: Baseline (pre-dose), 1, 2, 24, 48, 49, 52 and 56 hours (post-dose)
Population: The analysis was performed in the pharmacokinetic (PK) set, defined as all participants who received study treatment and had at least one evaluable PK parameter data. Here, Number of participants analyzed signifies participants evaluable for this PK parameter at the specified time points for each arm, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serelaxin 10 mcg/kg/Day | Maximum Plasma Concentration (Cmax) of Serelaxin | 8.01 nanogram(s)/milliliter (ng/mL) | Standard Deviation 2.07 |
| Serelaxin 30 mcg/kg/Day | Maximum Plasma Concentration (Cmax) of Serelaxin | 19.2 nanogram(s)/milliliter (ng/mL) | Standard Deviation 4.69 |
Primary
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy
AEs were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. AEs leading to discontinuations, or requiring dose adjustment or interruptions and additional therapy were assessed.
Time frame: From start of study treatment up to Day 5 (for AEs); From start of study treatment up to Day 14 (for SAEs)
Population: The analysis was performed on the safety population, defined as all participants who received at least one dose of study treatment and had at least one post-baseline assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Serelaxin 10 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs | 10 participants |
| Serelaxin 10 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | SAEs | 1 participants |
| Serelaxin 10 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | Death | 0 participants |
| Serelaxin 10 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | Discontinuation due to AE(s) | 0 participants |
| Serelaxin 10 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | Discontinuation due to SAE(s) | 0 participants |
| Serelaxin 10 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs requiring dose adjustment or interruption | 0 participants |
| Serelaxin 10 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs requiring additional therapy | 8 participants |
| Serelaxin 10 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs related to study drug | 2 participants |
| Serelaxin 30 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | Death | 0 participants |
| Serelaxin 30 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs requiring additional therapy | 10 participants |
| Serelaxin 30 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | Discontinuation due to AE(s) | 2 participants |
| Serelaxin 30 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | Discontinuation due to SAE(s) | 0 participants |
| Serelaxin 30 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs requiring dose adjustment or interruption | 1 participants |
| Serelaxin 30 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs | 11 participants |
| Serelaxin 30 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | SAEs | 3 participants |
| Serelaxin 30 mcg/kg/Day | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs related to study drug | 2 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | Death | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | SAEs | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs | 9 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | Discontinuation due to AE(s) | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs requiring additional therapy | 9 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs requiring dose adjustment or interruption | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | Discontinuation due to SAE(s) | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs and SAEs, AEs Requiring Dose Adjustment or Interruption and Additional Therapy | AEs related to study drug | 0 participants |
Primary
Weight Adjusted Clearance (CL) of Serelaxin
Weight adjusted clearance (CL) was defined as the total body clearance of serelaxin after drug administration. CL was calculated as nominal infusion rate divided by Css, using a non-compartmental model approach.
Time frame: Baseline (pre-dose), 1, 2, 24, 48, 49, 52 and 56 hours (post-dose)
Population: The analysis was performed in the PK population. Here, Number of participants analyzed signifies participants evaluable for this PK parameter at the specified time points for each arm, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Serelaxin 10 mcg/kg/Day | Weight Adjusted Clearance (CL) of Serelaxin | 56.8 mL/hr/kg | Standard Deviation 15.4 |
| Serelaxin 30 mcg/kg/Day | Weight Adjusted Clearance (CL) of Serelaxin | 70.2 mL/hr/kg | Standard Deviation 23.2 |
Secondary
Change From Baseline in Aldosterone Levels Through Day 14
Aldosterone biomarker was used to assess the effect of serelaxinin on fluid retention. Geometric means of the ratio of post-Baseline values to baseline values of aldosterone was calculated by treatment for the full analysis set.
Time frame: Baseline, Day 1, Day 2, Day 5, Day 14
Population: The analysis was performed in the FAS population. Only participants with a value at both baseline and the post-dose time point were included.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Aldosterone Levels Through Day 14 | Day 1 | 0.985 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Aldosterone Levels Through Day 14 | Day 2 | 0.975 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Aldosterone Levels Through Day 14 | Day 5 | 0.895 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Aldosterone Levels Through Day 14 | Day 14 | 1.510 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Aldosterone Levels Through Day 14 | Day 14 | 1.114 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Aldosterone Levels Through Day 14 | Day 1 | 0.816 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Aldosterone Levels Through Day 14 | Day 5 | 0.825 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Aldosterone Levels Through Day 14 | Day 2 | 0.721 Ratio |
| Placebo | Change From Baseline in Aldosterone Levels Through Day 14 | Day 14 | 1.179 Ratio |
| Placebo | Change From Baseline in Aldosterone Levels Through Day 14 | Day 2 | 0.911 Ratio |
| Placebo | Change From Baseline in Aldosterone Levels Through Day 14 | Day 5 | 0.816 Ratio |
| Placebo | Change From Baseline in Aldosterone Levels Through Day 14 | Day 1 | 0.791 Ratio |
Secondary
Change From Baseline in Area Under the Curve (AUC) for Systolic Blood Pressure (SBP) Through 48 Hours of Infusion at Day 5
The area under the curve (AUC) was defined as area under the plasma concentration-time curve from time zero to time of the last time point with measurable concentration, calculated by a trapezoidal method. Systolic blood pressure was measured using a calibrated standard sphygmomanometer after the subject remained in sitting position for 3 minutes at clinic during the visit. Sample collected at: Baseline; 30 & 60 minutes and then every hour for the first 6 hours of study drug infusion, and then every 3 hours during 48 hours of study drug infusion; every 3 hours until 12 hours following end of infusion, then every 6 hours for 48 hours and then every 24 hours until the earlier of Day 5 or discharge. AUC for SBP is standardized by dividing by the length of respective time ranges.
Time frame: Baseline, 48 hours, Day 5
Population: The analysis was performed in the full analysis set (FAS) population, defined as all participants who were randomized in the study.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Area Under the Curve (AUC) for Systolic Blood Pressure (SBP) Through 48 Hours of Infusion at Day 5 | 48 hours | -8.21 mmHg | Standard Error 2.903 |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Area Under the Curve (AUC) for Systolic Blood Pressure (SBP) Through 48 Hours of Infusion at Day 5 | Day 5 | -8.79 mmHg | Standard Error 2.761 |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Area Under the Curve (AUC) for Systolic Blood Pressure (SBP) Through 48 Hours of Infusion at Day 5 | 48 hours | -18.6 mmHg | Standard Error 3.018 |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Area Under the Curve (AUC) for Systolic Blood Pressure (SBP) Through 48 Hours of Infusion at Day 5 | Day 5 | -22.14 mmHg | Standard Error 2.871 |
| Placebo | Change From Baseline in Area Under the Curve (AUC) for Systolic Blood Pressure (SBP) Through 48 Hours of Infusion at Day 5 | 48 hours | -10.88 mmHg | Standard Error 3.018 |
| Placebo | Change From Baseline in Area Under the Curve (AUC) for Systolic Blood Pressure (SBP) Through 48 Hours of Infusion at Day 5 | Day 5 | -14.77 mmHg | Standard Error 2.871 |
Secondary
Change From Baseline in Cystatin-C Levels Through Day 14
Cystatin-C biomarker was used to assess the effect of serelaxinin on worsening of renal function. Geometric means of the ratio of post-Baseline values to baseline values of Cystatin-C was calculated by treatment for the full analysis set.
Time frame: Baseline, Day 1, Day 2, Day 5, Day 14
Population: The analysis was performed in the FAS population. Only participants with a value at both baseline and the post-dose time point were included.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 1 | 0.921 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 2 | 0.930 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 5 | 1.062 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 14 | 1.195 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 14 | 1.136 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 1 | 0.988 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 5 | 1.115 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 2 | 0.852 Ratio |
| Placebo | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 14 | 1.125 Ratio |
| Placebo | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 2 | 0.965 Ratio |
| Placebo | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 5 | 1.038 Ratio |
| Placebo | Change From Baseline in Cystatin-C Levels Through Day 14 | Day 1 | 0.985 Ratio |
Secondary
Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14
High sensitivity Troponin-T biomarker was used to assess the effect of serelaxin on myocardial damage. Geometric means of the ratio of post-Baseline values to baseline values of high sensitivity troponin-t was calculated by treatment for the full analysis set.
Time frame: Baseline, Day 1, Day 2, Day 5, Day 14
Population: The analysis was performed in the FAS population. Only participants with a value at both baseline and the post-dose time point were included.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Serelaxin 10 mcg/kg/Day | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 1 | 0.899 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 2 | 0.856 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 5 | 0.849 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 14 | 0.820 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 14 | 0.813 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 1 | 1.060 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 5 | 0.972 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 2 | 1.040 Ratio |
| Placebo | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 14 | 0.685 Ratio |
| Placebo | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 2 | 0.894 Ratio |
| Placebo | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 5 | 0.779 Ratio |
| Placebo | Change From Baseline in High Sensitivity Troponin-T Levels Through Day 14 | Day 1 | 0.956 Ratio |
Secondary
Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14
Neutrophil gelatinase-asc lipocalin (NGAL) biomarker was used to assess the effect of serelaxin on kidney function. Geometric means of the ratio of post-Baseline values to baseline values of NGAL was calculated by treatment for the full analysis set.
Time frame: Baseline, Day 1, Day 2, Day 5, Day 14
Population: The analysis was performed in the FAS population. Only participants with a value at both baseline and the post-dose time point were included.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 1 | 1.011 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 2 | 0.929 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 5 | 1.129 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 14 | 1.434 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 14 | 1.520 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 1 | 1.083 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 5 | 1.238 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 2 | 1.172 Ratio |
| Placebo | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 14 | 1.433 Ratio |
| Placebo | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 2 | 1.099 Ratio |
| Placebo | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 5 | 1.135 Ratio |
| Placebo | Change From Baseline in Neutrophil Gelatinase-asc Lipocalin (NGAL) Levels Through Day 14 | Day 1 | 1.054 Ratio |
Secondary
Change From Baseline in NT-proBNP Levels Through Day 14
NT-proBNP biomarker was used to assess the effect of serelaxinin on degree of cardiac wall stress and congestion. Geometric means of the ratio of post-Baseline values to baseline values of NT-proBNP was calculated by treatment for the full analysis set.
Time frame: Baseline, Day 1, Day 2, Day 5, Day 14
Population: The analysis was performed in the FAS population. Only participants with a value at both baseline and the post-dose time point were included.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Serelaxin 10 mcg/kg/Day | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 2 | 0.492 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 14 | 0.295 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 5 | 0.388 Ratio |
| Serelaxin 10 mcg/kg/Day | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 1 | 0.585 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 2 | 0.451 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 1 | 0.646 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 14 | 0.419 Ratio |
| Serelaxin 30 mcg/kg/Day | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 5 | 0.386 Ratio |
| Placebo | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 1 | 0.673 Ratio |
| Placebo | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 14 | 0.277 Ratio |
| Placebo | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 5 | 0.526 Ratio |
| Placebo | Change From Baseline in NT-proBNP Levels Through Day 14 | Day 2 | 0.581 Ratio |