Trial Outcomes & Findings for Effect of Serelaxin Versus Standard of Care in Acute Heart Failure (AHF) Patients (NCT NCT02064868)

NCT ID: NCT02064868

Last Updated: 2019-03-22

Results Overview

In-hospital WHF through Day 5 post-randomization included worsening signs and/or symptoms of heart failure that required an intensification of intravenous therapy for heart failure or mechanical ventilation, renal or circulatory support. A central event adjudication committee was appointed to oversee the WHF primary endpoint adjudication.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

2666 participants

Primary outcome timeframe

5 days

Results posted on

2019-03-22

Participant Flow

The initial target was to randomize 3183 patients. This study was prematurely terminated (due to the neutral read-out of study RELAX-AHF-2) after 2666 patients were randomized. 16 patients had not qualified for randomization but were inadvertently randomized. These 16 patients did not enter the treatment phase and were not counted as started.

Participant milestones

Participant milestones
Measure	Serelaxin + Standard of Care Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.	Standard of Care (SOC) All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
Overall Study STARTED	1756	894
Overall Study Full Analysis Set	1756	894
Overall Study Safety Set	1729	894
Overall Study Per Protocol Set	1155	627
Overall Study COMPLETED	1722	881
Overall Study NOT COMPLETED	34	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Serelaxin + Standard of Care Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.	Standard of Care (SOC) All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
Overall Study Lost to Follow-up	14	8
Overall Study Physician Decision	1	0
Overall Study Withdrawal by Subject	14	3
Overall Study Technical Problems or Missing	5	2

Baseline Characteristics

Full Analysis Set

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Serelaxin + Standard of Care n=1756 Participants Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.	Standard of Care (SOC) n=894 Participants All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.	Total n=2650 Participants Total of all reporting groups
Age, Continuous	75.24 Years STANDARD_DEVIATION 10.349 • n=5 Participants	75.95 Years STANDARD_DEVIATION 9.905 • n=7 Participants	75.48 Years STANDARD_DEVIATION 10.205 • n=5 Participants
Sex: Female, Male Female	760 Participants n=5 Participants • Full Analysis Set	383 Participants n=7 Participants • Full Analysis Set	1143 Participants n=5 Participants • Full Analysis Set
Sex: Female, Male Male	996 Participants n=5 Participants • Full Analysis Set	511 Participants n=7 Participants • Full Analysis Set	1507 Participants n=5 Participants • Full Analysis Set
Race/Ethnicity, Customized Caucasian	1706 Participants n=5 Participants • Full Analysis Set	869 Participants n=7 Participants • Full Analysis Set	2575 Participants n=5 Participants • Full Analysis Set
Race/Ethnicity, Customized Black	4 Participants n=5 Participants • Full Analysis Set	4 Participants n=7 Participants • Full Analysis Set	8 Participants n=5 Participants • Full Analysis Set
Race/Ethnicity, Customized Asian	5 Participants n=5 Participants • Full Analysis Set	2 Participants n=7 Participants • Full Analysis Set	7 Participants n=5 Participants • Full Analysis Set
Race/Ethnicity, Customized Unknown	16 Participants n=5 Participants • Full Analysis Set	7 Participants n=7 Participants • Full Analysis Set	23 Participants n=5 Participants • Full Analysis Set
Race/Ethnicity, Customized Other	25 Participants n=5 Participants • Full Analysis Set	12 Participants n=7 Participants • Full Analysis Set	37 Participants n=5 Participants • Full Analysis Set

PRIMARY outcome

Timeframe: 5 days

Population: Full Analysis Set

Outcome measures

Outcome measures
Measure	Serelaxin + Standard of Care n=1756 Participants Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.	Standard of Care (SOC) n=894 Participants All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
Percentage of Participants With Worsening Heart Failure (WHF) / All Cause of Deaths Through Day 5	4.95 Percentage of Participants	6.94 Percentage of Participants

SECONDARY outcome

Timeframe: 14 days

Population: Full Analysis Set

WHF/death/readmission for heart failure through Day 14. WHF/deaths through Day 5 were adjudicated and confirmed by the Clinical Endpoint Committee, WHF/deaths after Day 5 through Day 14 and readmission through Day 14 were as reported by the investigators.

Outcome measures

Outcome measures
Measure	Serelaxin + Standard of Care n=1756 Participants Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.	Standard of Care (SOC) n=894 Participants All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
Percentage of Participants With In-hospital Worsening Heart Failure/All-Cause Death/Readmission for Heart Failure Through Day 14	8.49 Percentage of Patients	10.63 Percentage of Patients

SECONDARY outcome

Timeframe: 5 days

Population: Full Analysis Set (only evaluable patients with non-missing information included)

Persistent or non-improvement in any signs or symptoms of HF at any post baseline visit up to Day 5.

Outcome measures

Outcome measures
Measure	Serelaxin + Standard of Care n=1744 Participants Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.	Standard of Care (SOC) n=894 Participants All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
Percentage of Participants With Persistent Sign or Symptoms of Heart Failure / Non-Improvement at Any Post Baseline Visit Through Day 5	86 Percentage of Participants Interval 84.0 to 87.0	91 Percentage of Participants Interval 89.0 to 93.0

SECONDARY outcome

Timeframe: 14 days

Population: Full Analysis Set (only evaluable patients with non-missing information included)

Renal deterioration is defined as \> or = 0.3 mg/dL increase from screening in serum creatinine.

Outcome measures

Outcome measures
Measure	Serelaxin + Standard of Care n=1740 Participants Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.	Standard of Care (SOC) n=889 Participants All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
Percentage of Participants With Renal Deterioration at Any Post Baseline Visit Through Day 14	36 Percentage of Participants Interval 34.0 to 38.0	44 Percentage of Participants Interval 40.0 to 47.0

SECONDARY outcome

Timeframe: 30 Days

Population: Full Analysis Set

Length of stay (in hours) is defined as the index hospitalization discharge date and time minus the index hospitalization start date and time.

Outcome measures

Outcome measures
Measure	Serelaxin + Standard of Care n=1756 Participants Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.	Standard of Care (SOC) n=894 Participants All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
Length of Index Hospital Stay	251.28 hours Standard Deviation 162.368	243.59 hours Standard Deviation 160.270

SECONDARY outcome

Timeframe: Adverse Events (AE): 5 Days / Serious Adverse Events (SAE): 14 days / All cause deaths 30 days

Population: Safety Set

Outcome measures

Outcome measures
Measure	Serelaxin + Standard of Care n=1729 Participants Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.	Standard of Care (SOC) n=894 Participants All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients Patients with any AE through Day 5	58.13 Percentage of participants	56.04 Percentage of participants
Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients Patients with any SAE through Day 14	12.38 Percentage of participants	11.97 Percentage of participants
Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients All cause deaths through Day 5	0.58 Percentage of participants	0.67 Percentage of participants
Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients All cause deaths through Day 14	1.91 Percentage of participants	2.01 Percentage of participants
Percentage of Participants With Adverse Events as Assessment of Safety and Tolerability of Serelaxin in AHF Patients All cause deaths through Day 30	3.30 Percentage of participants	4.25 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, Day 5, Day 14

Population: Full Analysis Set (only evaluable patients with non-missing information included)

EQ-5D-5L is a questionnaire designed to assess health status in adults consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). The results were converted into a single index value using UK as the reference country for all countries. Range -0.3 (worst possible state) to 1 (best possible state).

Outcome measures

Outcome measures
Measure	Serelaxin + Standard of Care n=1545 Participants Serelaxin (30 µg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.	Standard of Care (SOC) n=793 Participants All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
Change From Baseline in Health-related Quality of Life Index Value, Assessed by EuroQoL EQ-5D-5L Questionnaire. Day 5	0.28 units on a scale Standard Deviation 0.298	0.27 units on a scale Standard Deviation 0.292
Change From Baseline in Health-related Quality of Life Index Value, Assessed by EuroQoL EQ-5D-5L Questionnaire. Day 14	0.32 units on a scale Standard Deviation 0.328	0.31 units on a scale Standard Deviation 0.317

Adverse Events

Serelaxin + Standard of Care

Serious events: 214 serious events

Other events: 637 other events

Deaths: 63 deaths

Standard of Care (SOC)

Serious events: 107 serious events

Other events: 324 other events

Deaths: 43 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	Serelaxin + Standard of Care n=1729 participants at risk Serelaxin (30 μg/kg/day) as continuous 48 hour intravenous infusion plus standard of care.	Standard of Care (SOC) n=894 participants at risk All patients were required to receive standard of care background heart failure (HF) management during the study, according to local guidelines/international standards. This treatment can include but is not limited to intravenous and/or oral diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor antagonists, beta blockers and aldosterone receptor antagonists, etc.
Blood and lymphatic system disorders Anaemia	2.8% 49/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	1.0% 9/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Cardiac disorders Atrial fibrillation	2.0% 34/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	2.6% 23/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Cardiac disorders Cardiac failure	4.7% 81/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	6.3% 56/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Cardiac disorders Mitral valve incompetence	1.6% 28/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	1.3% 12/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Gastrointestinal disorders Constipation	4.3% 74/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	3.6% 32/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Gastrointestinal disorders Diarrhoea	1.7% 29/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	2.3% 21/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Gastrointestinal disorders Nausea	2.3% 40/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	1.9% 17/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
General disorders Pyrexia	1.4% 24/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	2.3% 21/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Infections and infestations Bronchitis	1.4% 24/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	1.6% 14/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Infections and infestations Urinary tract infection	3.2% 56/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	2.9% 26/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Investigations Blood pressure systolic decreased	2.8% 49/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	0.22% 2/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Metabolism and nutrition disorders Hyperuricaemia	2.7% 47/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	3.9% 35/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Metabolism and nutrition disorders Hypokalaemia	6.9% 119/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	8.2% 73/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Musculoskeletal and connective tissue disorders Back pain	1.6% 28/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	1.2% 11/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Musculoskeletal and connective tissue disorders Muscle spasms	1.9% 33/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	0.89% 8/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Nervous system disorders Headache	2.6% 45/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	2.0% 18/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Psychiatric disorders Anxiety	1.6% 27/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	1.8% 16/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Psychiatric disorders Insomnia	3.4% 58/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	2.3% 21/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Renal and urinary disorders Renal failure	1.0% 18/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	2.0% 18/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Renal and urinary disorders Renal impairment	1.7% 30/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	2.0% 18/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days
Vascular disorders Hypotension	2.8% 48/1729 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days	2.0% 18/894 • All Cause Mortality: 30 days (additional deaths are included which occurred after the clinical trial reporting period of 30 days for up to 8 months post randomization); Serious Adverse Events: 14 days; Other non-serious Adverse Events (AEs): 5 days