Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF

Acute Heart Failure Clinical Trial

— RELAX-AHF-2  

Official title:

A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Study to Evaluate the Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in Acute Heart Failure Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01870778
• Other study ID #: CRLX030A2301
• Secondary ID: 2013-001498-25
• Status: Completed
• Phase: Phase 3
• First received: June 3, 2013
• Last updated: March 2, 2018
• Start date: October 2, 2013
• Est. completion date: February 1, 2017

Study information

• Verified date: March 2018
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study was to evaluate the efficacy, safety and tolerability of intravenous infusion of serelaxin, when added to standard therapy, in acute heart failure (AHF) patients.

Description:

This Phase IIIb outcome study in AHF patients was designed as a multicenter, randomized, double-blind, placebo-controlled, event-driven study in order to assess the efficacy, safety and tolerability of intravenous infusion of serelaxin or placebo. The AHF patients randomized to either serelaxin or placebo in the study were followed for a period of 180 days, and were required to receive standard-of-care background HF management during both the index hospitalization and post discharge according to regional or local guidelines/institutional standards.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6600
• Est. completion date: February 1, 2017
• Est. primary completion date: January 23, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Male or female 18 years of age, with body weight =160 kg

• Hospitalized for AHF with anticipated requirement of IV therapy for at least 48 hours; AHF is defined as including all of the following measured at any time between presentation (including the emergency department) and the end of screening:

• Persistent dyspnea at rest or with minimal exertion

• Pulmonary congestion on chest radiograph

• B-type natriuretic peptide (BNP) =500 pg/mL or N-terminal (NT)-proBNP =2000 pg/mL; for patients = 75 years of age or with current atrial fibrillation (at the time of randomization), BNP = 750 pg/mL or NT-proBNP = 3,000 pg/mL

• Systolic BP =125 mmHg at the start and at the end of screening

• Able to be randomized within 16 hours from presentation to the hospital, including the emergency department

• Received intravenous furosemide of at least 40 mg total (or equivalent) at any time between presentation (this includes outpatient clinic, ambulance, or hospital including emergency department) and the start of screening for the study for the treatment of the current acute HF episode.

Key Exclusion Criteria:

• Dyspnea primarily due to non-cardiac causes

• Known history of respiratory disorders requiring the daily use of IV or oral steroids (does not include inhaled steroids); need for intubation or the current use of IV or oral steroids for chronic obstructive pulmonary disease (COPD)

• Temperature >38.5°C (oral or equivalent) or sepsis or active infection requiring IV anti-microbial treatment

• Clinical evidence of acute coronary syndrome currently or within 30 days prior to enrollment.

• AHF due to significant arrhythmias, which include any of the following: sustained ventricular tachycardia, bradycardia with sustained ventricular rate <45 beats per minute, or atrial fibrillation/flutter with sustained ventricular response of >130 beats per minute

• Patients with severe renal impairment defined as pre-randomization estimated glomerular filtration rate (eGFR) < 25 mL/min/1.73m2 calculated using the Simplified Modification of Diet in Renal Disease (sMDRD) equation, and/or those receiving current or planned dialysis or ultrafiltration

• Patients with hematocrit <25%, or a history of blood transfusion within the 14 days prior to screening, or active life-threatening GI bleeding.

• Known hepatic impairment (as evidenced by total bilirubin > 3 mg/dL, or increased ammonia levels, if performed) or history of cirrhosis with evidence of portal hypertension such as varices.

• Significant, uncorrected, left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area <1.0 cm2 or mean gradient >40 mmHg on prior or current echocardiogram), and severe mitral stenosis

• Severe aortic insufficiency or severe mitral regurgitation for which surgical or percutaneous intervention is indicated.

• Documented, prior to or at the time of randomization, restrictive amyloid myocardiopathy, OR acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy (does NOT include restrictive mitral filling patterns seen on Doppler echocardiographic assessments of diastolic function).

Related Conditions & MeSH terms

• Acute Heart Failure
• Heart Failure

Intervention

Drug:
• RLX030
1 mg/mL solution in 6 mL vials
• Placebo
Matching placebo solution to serelaxin

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
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Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Cordoba
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Argentina	Novartis Investigative Site	Cordoba
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United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Nottingham	Hampshire
United Kingdom	Novartis Investigative Site	Portsmouth
United Kingdom	Novartis Investigative Site	Swindon
United Kingdom	Novartis Investigative Site	Torquay	Devon
United States	Novartis Investigative Site	Abington	Pennsylvania
United States	Novartis Investigative Site	Alexandria	Louisiana
United States	Novartis Investigative Site	Anaheim	California
United States	Novartis Investigative Site	Annapolis	Maryland
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Atlantis	Florida
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Baton Rouge	Louisiana
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Bronx	New York
United States	Novartis Investigative Site	Bronx	New York
United States	Novartis Investigative Site	Brooklyn	New York
United States	Novartis Investigative Site	Brooklyn	New York
United States	Novartis Investigative Site	Canton	Ohio
United States	Novartis Investigative Site	Chapel Hill	North Carolina
United States	Novartis Investigative Site	Charlottesville	Virginia
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Cleveland	Ohio
United States	Novartis Investigative Site	Colorado Springs	Colorado
United States	Novartis Investigative Site	Columbus	Ohio
United States	Novartis Investigative Site	Covington	Louisiana
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Denver	Colorado
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Durham	North Carolina
United States	Novartis Investigative Site	Elk Grove Village	Illinois
United States	Novartis Investigative Site	Falls Church	Virginia
United States	Novartis Investigative Site	Fresno	California
United States	Novartis Investigative Site	Galveston	Texas
United States	Novartis Investigative Site	Greenville	South Carolina
United States	Novartis Investigative Site	Greenville	South Carolina
United States	Novartis Investigative Site	Hartford	Connecticut
United States	Novartis Investigative Site	Hartford	Connecticut
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Huntsville	Alabama
United States	Novartis Investigative Site	Indianapolis	Indiana
United States	Novartis Investigative Site	Indianapolis	Indiana
United States	Novartis Investigative Site	Jackson	Mississippi
United States	Novartis Investigative Site	Jacksonville	Florida
United States	Novartis Investigative Site	Jacksonville	Florida
United States	Novartis Investigative Site	Jacksonville	Florida
United States	Novartis Investigative Site	Kansas City	Missouri
United States	Novartis Investigative Site	Kansas City	Kansas
United States	Novartis Investigative Site	Kingston	New York
United States	Novartis Investigative Site	Loma Linda	California
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Lynchburg	Virginia
United States	Novartis Investigative Site	Marietta	Georgia
United States	Novartis Investigative Site	Minneapolis	Minnesota
United States	Novartis Investigative Site	Montgomery	Alabama
United States	Novartis Investigative Site	Morgantown	West Virginia
United States	Novartis Investigative Site	Muncie	Indiana
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	Natrona Heights	Pennsylvania
United States	Novartis Investigative Site	New Hyde Park	New York
United States	Novartis Investigative Site	New Orleans	Louisiana
United States	Novartis Investigative Site	Northridge	California
United States	Novartis Investigative Site	Oakbrook Terrace	Illinois
United States	Novartis Investigative Site	Omaha	Nebraska
United States	Novartis Investigative Site	Palo Alto	California
United States	Novartis Investigative Site	Peoria	Illinois
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Picayune	Mississippi
United States	Novartis Investigative Site	Portland	Oregon
United States	Novartis Investigative Site	Providence	Rhode Island
United States	Novartis Investigative Site	Raleigh	North Carolina
United States	Novartis Investigative Site	Roanoke	Virginia
United States	Novartis Investigative Site	Rochester	New York
United States	Novartis Investigative Site	Sacramento	California
United States	Novartis Investigative Site	Saint Louis	Missouri
United States	Novartis Investigative Site	Saint Louis	Missouri
United States	Novartis Investigative Site	Saint Louis	Missouri
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	Sanford	Florida
United States	Novartis Investigative Site	Sarasota	Florida
United States	Novartis Investigative Site	Seattle	Washington
United States	Novartis Investigative Site	Seattle	Washington
United States	Novartis Investigative Site	Stony Brook	New York
United States	Novartis Investigative Site	Sylmar	California
United States	Novartis Investigative Site	Tampa	Florida
United States	Novartis Investigative Site	Tampa	Florida
United States	Novartis Investigative Site	Toledo	Ohio
United States	Novartis Investigative Site	Tucson	Arizona
United States	Novartis Investigative Site	Walnut Creek	California
United States	Novartis Investigative Site	Warwick	Rhode Island
United States	Novartis Investigative Site	Winter Haven	Florida
United States	Novartis Investigative Site	Worcester	Massachusetts
United States	Novartis Investigative Site	Wynnewood	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Bulgaria,  Canada,  Chile,  Colombia,  Czechia,  Denmark,  France,  Germany,  Greece,  Hungary,  Ireland,  Israel,  Italy,  Mexico,  Netherlands,  Norway,  Peru,  Poland,  Portugal,  Puerto Rico,  Romania,  Russian Federation,  Slovakia,  South Africa,  Spain,  Sweden,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Confirmed Cardiovascular (CV) Death Through Day 180	The percentage of participants with an adjudicated CV death through day 180 was assessed.	180 days
Primary	Percentage of Participants With Worsening of Heart Failure (WHF) Through Day 5	The percentage of participants with WHF through day 5 was assessed.	Day 5
Secondary	Percentage of Participants With All-cause Death Through Day 180	The percentage of participants with all-cause death through day 180 was assessed.	180 days
Secondary	Length of Total Hospital Stay (LOS) During the Index Acute Heart Failure (AHF) Hospitalization	Length of stay was defined as the index hospitalization discharge date and time minus the baseline date and time plus 1 day.	180 days (Participants still in the hospital at Day 60 were censored at Day 60)
Secondary	Percentage of Participants With First Occurrence of Adjudicated CV Death or Adjudicated Re-hospitalization	The percentage of participants with adjudicated CV death or adjudicated re-hospitalization through day 180 was assessed.	180 days
Secondary	Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization	Length of stay was defined as the hospitalization discharge date and the time minus the baseline date and time plus 1 day.	180 days (Patients still in the hospital at Day 60 were censored at Day 60)
Secondary	Percentage of Participants With First Improvement Since Baseline in Congestive Signs and Symptoms of Heart Failure	The percentage of participants with first improvement since baseline in congestive signs and symptoms was assessed. The signs and symptoms included exertional dyspnea, orthopnea, rales, jugular venous pressure and peripheral edema/pre-sacral edema.	From baseline to Day 5
Secondary	Change From Baseline in hsTroponin T Biomarker	Blood samples were collected to assess the change from baseline in hsTroponin T. The geometric least square mean (LSM) of the ratio of the post-baseline value to the baseline value is presented.	Baseline, Day 2, Day 5 and Day 14
Secondary	Change From Baseline in NT-proBNP Biomarker	Blood samples were collected to assess the change from baseline in NT-proBNP. The ratio of the post-baseline value to the baseline value is presented.	Baseline, Day 2, Day 5 and Day 14
Secondary	Change From Baseline in Cystatin C Biomarker	Blood samples were collected to assess the change from baseline in Cystatin C. The ratio of the post-baseline value to the baseline value is presented.	Baseline, Day 2, Day 5 and Day 14