Trial Outcomes & Findings for Safety of Repeat Doses of IV Serelaxin in Subjects With Chronic Heart Failure (NCT NCT01982292)

NCT ID: NCT01982292

Last Updated: 2016-11-09

Results Overview

A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. A patient is considered antibody negative during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were negative. A patient's antibody status is considered to be undetermined during the study if it is not defined as positive or negative.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

321 participants

Primary outcome timeframe

16 weeks

Results posted on

2016-11-09

Participant Flow

A total of 323 patients were randomized to the serelaxin or placebo treatment in a 2:1 ratio. 2 patients from serelaxin were mis-randomized, hence 321 received study drug.

Participant milestones

Participant milestones
Measure	RLX030 (Serelaxin) Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
Overall Study STARTED	215	108
Overall Study Full Analaysis Set (FAS)	213	108
Overall Study Safety Set	212	108
Overall Study COMPLETED	203	107
Overall Study NOT COMPLETED	12	1

Reasons for withdrawal

Reasons for withdrawal
Measure	RLX030 (Serelaxin) Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
Overall Study Adverse Event	2	0
Overall Study Death	1	0
Overall Study Lost to Follow-up	2	0
Overall Study Non-Compliance With Study Treatment	1	0
Overall Study Protocol Deviation	1	0
Overall Study Patient/Guardian Decision	3	1
Overall Study Technical Problems	2	0

Baseline Characteristics

Safety of Repeat Doses of IV Serelaxin in Subjects With Chronic Heart Failure

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	RLX030 (Serelaxin) n=213 Participants Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo n=108 Participants Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Total n=321 Participants Total of all reporting groups
Age, Continuous	66.7 Years STANDARD_DEVIATION 8.99 • n=93 Participants	65.2 Years STANDARD_DEVIATION 11.18 • n=4 Participants	66.2 Years STANDARD_DEVIATION 9.79 • n=27 Participants
Sex: Female, Male Female	46 Participants n=93 Participants	26 Participants n=4 Participants	72 Participants n=27 Participants
Sex: Female, Male Male	167 Participants n=93 Participants	82 Participants n=4 Participants	249 Participants n=27 Participants

PRIMARY outcome

Timeframe: 16 weeks

Population: Safety Set: All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment. In this reported analysis, patients with undetermined antibody status are excluded from analysis population

Outcome measures

Outcome measures
Measure	RLX030 (Serelaxin) n=200 Participants Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo n=106 Participants Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
Percentage of Participants With Chronic Heart Failure (CHF) Who Develop Anti-serelaxin Antibodies at Any Time Following Repeat Administration of IV Continuous Infusions of Serelaxin Administered for up to 48 Hours in 16 Weeks Positive	0.50 Percentage of participants Interval 0.03 to 2.35	0.00 Percentage of participants Interval 0.0 to 2.79
Percentage of Participants With Chronic Heart Failure (CHF) Who Develop Anti-serelaxin Antibodies at Any Time Following Repeat Administration of IV Continuous Infusions of Serelaxin Administered for up to 48 Hours in 16 Weeks Negative	99.50 Percentage of participants Interval 97.65 to 99.97	100 Percentage of participants Interval 97.21 to 100.0

SECONDARY outcome

Timeframe: Randomization to Week 4, Week 4 to Week 8, Week 8 to Week 12, week 12 to week 16

Population: All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.

A patient is considered antibody positive during the study if he/she had at least two infusions and had at least one evaluable measurement to test for anti-serelaxin antibodies after each infusion and all evaluable antibody test results were positive. Each time period is defined as the time frame from study drug initiation (or the visit if there is no infusion) to prior to study drug initiation of the next period (or the visit if no there is no infusion). n= The total number of subjects with evaluable antibody status during the defined period.

Outcome measures

Outcome measures
Measure	RLX030 (Serelaxin) n=212 Participants Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo n=108 Participants Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 Randomization to week 4 (n= 209, 107)	0.48 Percentage of patients Interval 0.02 to 2.25	0.00 Percentage of patients Interval 0.0 to 2.76
Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 Week 4 to week 8 (n= 204, 108)	0.49 Percentage of patients Interval 0.03 to 2.3	0.00 Percentage of patients Interval 0.0 to 2.74
Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 Week 8 to week 12 (n= 204, 107)	0.49 Percentage of patients Interval 0.03 to 2.3	0.00 Percentage of patients Interval 0.0 to 2.76
Percentage of Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies After a Single Infusion of Serelaxin Over Time up to Week 16 Week 12 to week 16 (n= 2, 2)	0 Percentage of patients Interval 0.0 to 0.0	0 Percentage of patients Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: Week 4, Week 8, Week 12

Population: Safety set:All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment

Outcome measures

Outcome measures
Measure	RLX030 (Serelaxin) n=1 Participants Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
Antibody Titers in Participants With Chronic Heart Failure Who Develop Positive Anti-serelaxin Antibodies (Neutralizing, Non-neutralizing or Both) at Any Time Following 3 Repeated Infusions and at Week 4, Week 8 and Week 12	NA In international Units Standard Deviation NA Antibody titers unavailable as positive antibodies patients were very low in number	—

SECONDARY outcome

Timeframe: At Week 4, Week 8, Week 12

Population: All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment

Outcome measures

Outcome measures
Measure	RLX030 (Serelaxin) n=212 Participants Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo n=108 Participants Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12) after 1 infusion (at week 4) [n=209,108]	0.48 Percentage of participants Interval 0.02 to 2.25	0.0 Percentage of participants Interval 0.0 to 2.74
Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12) after 2 infusions (at week 8) [n=200,106]	0.50 Percentage of participants Interval 0.03 to 2.35	0.0 Percentage of participants Interval 0.0 to 2.79
Percentage of Participants With Chronic Heart Failure With Positive Antibody Status Who Develop Non-neutralizing Anti-serelaxin Antibodies Following 3 Repeated Infusions (i.e. at Week 4, Week 8, and Week 12) after 3 infusions (at week 12) [n=184, 102]	0.54 Percentage of participants Interval 0.03 to 2.55	0.0 Percentage of participants Interval 0.0 to 2.89

SECONDARY outcome

Timeframe: 16 weeks

Population: Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.

Incidence rate of special interest, indicative of hypersensitivity reactions which occur during and after administration of repeated infusions of serelaxin relative to placebo in subjects with chronic heart failure is reported. Hypersensitivity reactions or infusion reactions can be headache, nausea, fever, chills, dizziness, flush, pruritus, chest and/or back pain.

Outcome measures

Outcome measures
Measure	RLX030 (Serelaxin) n=212 Participants Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo n=108 Participants Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions Submitted for adjudication	32 Participants	14 Participants
Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions Confirmed with no hypersensitivity reactions	32 Participants	14 Participants
Number of Participants With Adverse Events Such as Adjudicated Potential Hypersensitivity or Infusion Reactions Hypersensitivity reactions confirmed	0 Participants	0 Participants

SECONDARY outcome

Timeframe: pre-infusion and 8, 24 and 48 hours post each infusion.

Population: Due to sparse PK sampling, this analysis was not done.

Due to sparse PK sampling, AUC 0-48 hours was not analyzed.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: pre-infusion and 24, 48 hours post each infusion

Population: PK analysis set (PK) - All patients with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug and experienced no protocol deviations with relevant impact on PK data.

Concentration at steady state (Css) was estimated using C48 or C24 for patients who received the intended rate of infusion for at least 24hours. n: Number of patients with valid PK parameters available

Outcome measures

Outcome measures
Measure	RLX030 (Serelaxin) n=211 Participants Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
Pharmacokinetics of RLXL030: Actual Concentrations at Steady State (Css) First infusion (n=174)	31.6 ng/ml Standard Deviation 70.1	—
Pharmacokinetics of RLXL030: Actual Concentrations at Steady State (Css) Second Infusion (n=174)	53.5 ng/ml Standard Deviation 234	—
Pharmacokinetics of RLXL030: Actual Concentrations at Steady State (Css) Third (n = 181)	38.9 ng/ml Standard Deviation 95.2	—

SECONDARY outcome

Timeframe: 48 hours post each infusion

Population: Due to sparse PK sampling, this analysis was not done.

This analysis was not done due to sparse PK sampling.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 48 hours post each infusion

Clearance (CL) was calculated using concentration at steady state (Css) and the actual delivered dose rate. n: Number of patients with valid PK parameters available within 48 hours post each infusion.

Outcome measures

Outcome measures
Measure	RLX030 (Serelaxin) n=211 Participants Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
Pharmacokinetics of RLX030: Clearance of Serelaxin (CL) First Infusion (n= 173)	106 mL/hr/kg Standard Deviation 55.8	—
Pharmacokinetics of RLX030: Clearance of Serelaxin (CL) Second Infusion (n=173)	97.4 mL/hr/kg Standard Deviation 41.4	—
Pharmacokinetics of RLX030: Clearance of Serelaxin (CL) Third Infusion (n= 180)	202 mL/hr/kg Standard Deviation 1290	—

Adverse Events

RLX030 (Serelaxin)

Serious events: 30 serious events

Other events: 65 other events

Deaths: 0 deaths

Placebo

Serious events: 15 serious events

Other events: 39 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER

Measure	RLX030 (Serelaxin) n=212 participants at risk Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo n=108 participants at risk Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
Blood and lymphatic system disorders ANAEMIA	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Cardiac disorders ACUTE MYOCARDIAL INFARCTION	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Cardiac disorders ANGINA UNSTABLE	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Cardiac disorders ATRIAL FIBRILLATION	0.94% 2/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Cardiac disorders ATRIAL FLUTTER	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Cardiac disorders ATRIOVENTRICULAR BLOCK SECOND DEGREE	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Cardiac disorders CARDIAC FAILURE	1.9% 4/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	1.9% 2/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Cardiac disorders CARDIAC FAILURE ACUTE	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Cardiac disorders CARDIAC FAILURE CHRONIC	0.94% 2/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Cardiac disorders CARDIAC FAILURE CONGESTIVE	0.94% 2/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Cardiac disorders CARDIOGENIC SHOCK	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Cardiac disorders VENTRICULAR TACHYCARDIA	0.94% 2/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Gastrointestinal disorders DIARRHOEA	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Gastrointestinal disorders HAEMORRHOIDAL HAEMORRHAGE	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
General disorders MEDICAL DEVICE SITE PAIN	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
General disorders MULTI-ORGAN FAILURE	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
General disorders SYSTEMIC INFLAMMATORY RESPONSE SYNDROME	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations APPENDICITIS	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations BRONCHITIS	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations DIARRHOEA INFECTIOUS	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations EPIDIDYMITIS	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations GANGRENE	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations GASTROENTERITIS	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations OSTEOMYELITIS	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations PERITONSILLAR ABSCESS	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations PNEUMONIA	1.4% 3/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations PNEUMONIA STREPTOCOCCAL	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations SEPSIS	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations STREPTOCOCCAL SEPSIS	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations URINARY TRACT INFECTION	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Injury, poisoning and procedural complications ALCOHOL POISONING	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Injury, poisoning and procedural complications POST PROCEDURAL HAEMORRHAGE	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Musculoskeletal and connective tissue disorders OSTEOARTHRITIS	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) BASAL CELL CARCINOMA	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) SQUAMOUS CELL CARCINOMA OF SKIN	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Nervous system disorders CAROTID ARTERY STENOSIS	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Nervous system disorders SYNCOPE	0.94% 2/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Nervous system disorders VOCAL CORD PARALYSIS	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Psychiatric disorders ACUTE PSYCHOSIS	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Psychiatric disorders SUICIDAL IDEATION	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Renal and urinary disorders ACUTE KIDNEY INJURY	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Renal and urinary disorders HYDRONEPHROSIS	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Respiratory, thoracic and mediastinal disorders ACUTE RESPIRATORY DISTRESS SYNDROME	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Respiratory, thoracic and mediastinal disorders CHRONIC OBSTRUCTIVE PULMONARY DISEASE	0.94% 2/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Respiratory, thoracic and mediastinal disorders EPISTAXIS	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Respiratory, thoracic and mediastinal disorders RESPIRATORY FAILURE	0.94% 2/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.00% 0/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Vascular disorders HYPERTENSIVE EMERGENCY	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Vascular disorders HYPOTENSION	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Vascular disorders PERIPHERAL ARTERIAL OCCLUSIVE DISEASE	0.00% 0/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.

Measure	RLX030 (Serelaxin) n=212 participants at risk Randomized patients received an IV infusion of 30 μg/kg/day of serelaxin for 48 hours at randomization and at Weeks 4 and 8	Placebo n=108 participants at risk Randomized patients received an IV infusion of placebo of serelaxin for 48 hours at randomization and at Weeks 4 and 8
Blood and lymphatic system disorders ANAEMIA	2.8% 6/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	1.9% 2/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
General disorders INFUSION SITE EXTRAVASATION	2.4% 5/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
General disorders NON-CARDIAC CHEST PAIN	2.8% 6/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
General disorders OEDEMA PERIPHERAL	1.9% 4/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	2.8% 3/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations BRONCHITIS	0.94% 2/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	3.7% 4/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations NASOPHARYNGITIS	8.5% 18/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	7.4% 8/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Infections and infestations PNEUMONIA	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	2.8% 3/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Metabolism and nutrition disorders HYPOKALAEMIA	1.4% 3/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	4.6% 5/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Musculoskeletal and connective tissue disorders BACK PAIN	0.47% 1/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	3.7% 4/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Musculoskeletal and connective tissue disorders MUSCLE SPASMS	1.9% 4/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	2.8% 3/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Nervous system disorders DIZZINESS	4.7% 10/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	0.93% 1/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Nervous system disorders HEADACHE	4.2% 9/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	2.8% 3/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Psychiatric disorders INSOMNIA	1.4% 3/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	2.8% 3/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Respiratory, thoracic and mediastinal disorders DYSPNOEA	1.4% 3/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	2.8% 3/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.
Vascular disorders HYPERTENSION	3.3% 7/212 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.	4.6% 5/108 Safety set (SAF) - All patients who received at least one dose of study drug and had at least one post-Baseline safety assessment.