Efficacy, Safety and Tolerability of Sexelaxin When Added to Standard Therapy in AHF (RELAX-AHF-ASIA)

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

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.

Study Overview

• Status: Terminated
• Conditions: Acute Heart Failure
• Intervention / Treatment: Drug: Placebo; Other: Standard of CareTherapy; Drug: Serelaxin

• Study Type: Interventional
• Enrollment (Actual): 876
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100050
    • Novartis Investigative Site
  • Chongqing, China, 400037
    • Novartis Investigative Site
  • Shanghai City, China
    • Novartis Investigative Site
  • Beijing
    • Beijing, Beijing, China, 100039
      • Novartis Investigative Site
    • Beijing, Beijing, China, 100037
      • Novartis Investigative Site
  • Gansu
    • Lanzhou, Gansu, China, 730030
      • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 51000
      • Novartis Investigative Site
    • Guangzhou, Guangdong, China, 510515
      • Novartis Investigative Site
  • Jiangsu
    • Suzhou, Jiangsu, China, 215006
      • Novartis Investigative Site
    • Yangzhou, Jiangsu, China
      • Novartis Investigative Site
  • Liaoning
    • Shenyang, Liaoning, China, 110000
      • Novartis Investigative Site
    • Shenyang, Liaoning, China, 110003
      • Novartis Investigative Site
  • Shanghai
    • Jinshan, Shanghai, China, 201508
      • Novartis Investigative Site
    • Shanghai, Shanghai, China, 200032
      • Novartis Investigative Site
  • Shanxi
    • Xian, Shanxi, China, 710061
      • Novartis Investigative Site
  • Tianjin
    • Tianjin, Tianjin, China, 300121
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310013
      • Novartis Investigative Site
    • Wenzhou, Zhejiang, China, 325000
      • Novartis Investigative Site
• India
  • Rajasthan, India, 334003
    • Novartis Investigative Site
  • Delhi
    • New Delhi, Delhi, India, 110029
      • Novartis Investigative Site
  • Gujarat
    • Ahmedabad, Gujarat, India, 380054
      • Novartis Investigative Site
    • Vadodara, Gujarat, India, 390022
      • Novartis Investigative Site
  • Maharashtra
    • Nagpur, Maharashtra, India, 440010
      • Novartis Investigative Site
    • Nagpur, Maharashtra, India, 440012
      • Novartis Investigative Site
  • Tamil Nadu
    • Chennai, Tamil Nadu, India, 600101
      • Novartis Investigative Site
  • Telangana
    • Hyderabad, Telangana, India, 500082
      • Novartis Investigative Site
• Japan
  • Osaka, Japan, 534-0021
    • Novartis Investigative Site
  • Saitama, Japan, 330 8503
    • Novartis Investigative Site
  • Aichi
    • Nagakute-city, Aichi, Japan, 480-1195
      • Novartis Investigative Site
    • Seto-city, Aichi, Japan, 489-8642
      • Novartis Investigative Site
  • Chiba
    • Kamogawa-city, Chiba, Japan, 2968602
      • Novartis Investigative Site
  • Ehime
    • Saijo-city, Ehime, Japan, 793-0027
      • Novartis Investigative Site
  • Fukuka
    • Chikushino-city, Fukuka, Japan, 818-8516
      • Novartis Investigative Site
  • Fukuoka
    • Fukuoka-city, Fukuoka, Japan, 810-0001
      • Novartis Investigative Site
    • Fukuoka-city, Fukuoka, Japan, 811-0213
      • Novartis Investigative Site
    • Fukuoka-city, Fukuoka, Japan, 815-8588
      • Novartis Investigative Site
    • Iizuka-city, Fukuoka, Japan, 820-8505
      • Novartis Investigative Site
    • Kurume-city, Fukuoka, Japan, 830-8543
      • Novartis Investigative Site
    • Kurume-city, Fukuoka, Japan, 830-8577
      • Novartis Investigative Site
  • Gifu
    • Ogaki-city, Gifu, Japan, 503-8502
      • Novartis Investigative Site
  • Hokkaido
    • Kushiro-city, Hokkaido, Japan, 085-0062
      • Novartis Investigative Site
    • Sapporo-city, Hokkaido, Japan, 006-8555
      • Novartis Investigative Site
  • Hyogo
    • Amagasaki city, Hyogo, Japan, 660 8550
      • Novartis Investigative Site
    • Kobe-City, Hyogo, Japan, 654-0155
      • Novartis Investigative Site
  • Ibaraki
    • Mito-city, Ibaraki, Japan, 311-4198
      • Novartis Investigative Site
  • Ishikawa
    • Kanazawa, Ishikawa, Japan, 920 8650
      • Novartis Investigative Site
  • Kagawa
    • Kanonji-city, Kagawa, Japan, 769-1695
      • Novartis Investigative Site
    • Takamatsu city, Kagawa, Japan, 760 8557
      • Novartis Investigative Site
  • Kanagawa
    • Kawasaki-city, Kanagawa, Japan, 211-8533
      • Novartis Investigative Site
    • Yokohama city, Kanagawa, Japan, 232 0024
      • Novartis Investigative Site
    • Yokohama-city, Kanagawa, Japan, 236 0051
      • Novartis Investigative Site
    • Yokohama-city, Kanagawa, Japan, 227-8501
      • Novartis Investigative Site
    • Yokohama-city, Kanagawa, Japan, 231-8682
      • Novartis Investigative Site
  • Kochi
    • Kochi city, Kochi, Japan, 781 8555
      • Novartis Investigative Site
  • Kumamoto
    • Kumamoto-city, Kumamoto, Japan, 861-4193
      • Novartis Investigative Site
    • Yatsushiro-city, Kumamoto, Japan, 866-8660
      • Novartis Investigative Site
  • Kyoto
    • Kyoto-city, Kyoto, Japan, 607-8062
      • Novartis Investigative Site
    • Uji-city, Kyoto, Japan, 611-0042
      • Novartis Investigative Site
  • Miyagi
    • Sendai-city, Miyagi, Japan, 981-3133
      • Novartis Investigative Site
  • Nagano
    • Nakano-city, Nagano, Japan, 383-8505
      • Novartis Investigative Site
    • Saku-city, Nagano, Japan, 3850051
      • Novartis Investigative Site
    • Ueda-city, Nagano, Japan, 386-8610
      • Novartis Investigative Site
  • Niigata
    • Niigata-city, Niigata, Japan, 950-1197
      • Novartis Investigative Site
  • Osaka
    • Osaka-city, Osaka, Japan, 540-0006
      • Novartis Investigative Site
  • Saitama
    • Kawaguchi-city, Saitama, Japan, 333-0842
      • Novartis Investigative Site
    • Sayama-city, Saitama, Japan, 350-1323
      • Novartis Investigative Site
    • Wako-city, Saitama, Japan, 351-0102
      • Novartis Investigative Site
  • Shiga
    • Kusatsu city, Shiga, Japan, 525 8585
      • Novartis Investigative Site
  • Shizuoka
    • Hamamatsu-city, Shizuoka, Japan, 430-8558
      • Novartis Investigative Site
    • Kakegawa-city, Shizuoka, Japan, 436-8555
      • Novartis Investigative Site
  • Tokyo
    • Akishima-city, Tokyo, Japan, 196-0003
      • Novartis Investigative Site
    • Chuo ku, Tokyo, Japan, 104-8560
      • Novartis Investigative Site
    • Hachioji-city, Tokyo, Japan, 192-0918
      • Novartis Investigative Site
    • Itabashi-ku, Tokyo, Japan, 173-8610
      • Novartis Investigative Site
    • Musashino-city, Tokyo, Japan, 180-8610
      • Novartis Investigative Site
    • Shinagawa ku, Tokyo, Japan, 141 8625
      • Novartis Investigative Site
    • Shinagawa-ku, Tokyo, Japan, 142-8666
      • Novartis Investigative Site
  • Wakayama
    • Tanabe-city, Wakayama, Japan, 646-8558
      • Novartis Investigative Site
• Jordan
  • Amman, Jordan, 11183
    • Novartis Investigative Site
  • Amman, Jordan, 11184
    • Novartis Investigative Site
  • JOR
    • Amman, JOR, Jordan, 11152
      • Novartis Investigative Site
• Korea, Republic of
  • Busan, Korea, Republic of, 602739
    • Novartis Investigative Site
  • Gwangju, Korea, Republic of, 61469
    • Novartis Investigative Site
  • Incheon, Korea, Republic of, 405 760
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 02841
    • Novartis Investigative Site
  • Bucheon Si
    • Gyeonggi do, Bucheon Si, Korea, Republic of, 422-711
      • Novartis Investigative Site
  • Chungcheongbuk Do
    • Cheongju si, Chungcheongbuk Do, Korea, Republic of, 28644
      • Novartis Investigative Site
  • Gangwon-do
    • Wonju, Gangwon-do, Korea, Republic of, 26427
      • Novartis Investigative Site
  • Gyeonggi Do
    • Bundang Gu, Gyeonggi Do, Korea, Republic of, 13620
      • Novartis Investigative Site
  • Korea
    • Seoul, Korea, Korea, Republic of, 05505
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 06351
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 08308
      • Novartis Investigative Site
  • Seocho Gu
    • Seoul, Seocho Gu, Korea, Republic of, 06591
      • Novartis Investigative Site
• Lebanon
  • Ashrafieh, Lebanon, 166830
    • Novartis Investigative Site
  • Beirut, Lebanon, 1107 2020
    • Novartis Investigative Site
  • Beirut, Lebanon
    • Novartis Investigative Site
  • Hazmieh, Lebanon, 470
    • Novartis Investigative Site
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Novartis Investigative Site
  • Kuala Lumpur, Malaysia, 50400
    • Novartis Investigative Site
  • MYS
    • Kuala Lumpur, MYS, Malaysia, 56000
      • Novartis Investigative Site
  • Sabah
    • Kota Kinabalu, Sabah, Malaysia, 88300
      • Novartis Investigative Site
  • Sarawak
    • Kuching, Sarawak, Malaysia, 94300
      • Novartis Investigative Site
  • Selangor Darul Ehsan
    • Kuala Lumpur, Selangor Darul Ehsan, Malaysia, 43000
      • Novartis Investigative Site
    • Sungai Buloh, Selangor Darul Ehsan, Malaysia, 47000
      • Novartis Investigative Site
• Philippines
  • Makati City, Philippines, 1229
    • Novartis Investigative Site
  • Manila, Philippines, 1003
    • Novartis Investigative Site
  • Pasig City, Philippines, 1605
    • Novartis Investigative Site
  • Quezon City, Philippines, 1102
    • Novartis Investigative Site
  • Quezon City, Philippines, 1113
    • Novartis Investigative Site
  • San Juan City, Philippines, 1500
    • Novartis Investigative Site
  • Manila
    • Quezon City, Manila, Philippines, 1100
      • Novartis Investigative Site
  • Metro Manila
    • Manila, Metro Manila, Philippines, 1000
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169609
    • Novartis Investigative Site
  • Singapore, Singapore, 117549
    • Novartis Investigative Site
• Taiwan
  • Changhua, Taiwan, 50006
    • Novartis Investigative Site
  • Kaohsiung, Taiwan, 80756
    • Novartis Investigative Site
  • Kaohsiung City, Taiwan, 83301
    • Novartis Investigative Site
  • New Taipei, Taiwan, 22060
    • Novartis Investigative Site
  • Taichung, Taiwan, 40447
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
  • Taipei, Taiwan, 10449
    • Novartis Investigative Site
  • Taoyuan, Taiwan, 33305
    • Novartis Investigative Site
  • Yilan, Taiwan, 26058
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
  • Bangkok, Thailand, 10400
    • Novartis Investigative Site
  • Chiang Mai, Thailand, 50200
    • Novartis Investigative Site
  • Muang, Thailand, 40002
    • Novartis Investigative Site
  • Hat Yai
    • Songkhla, Hat Yai, Thailand, 90110
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

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

• Hospitalized for AHF; AHF is defined as including all of the following measured at any time between presentation (including the emergency department and outpatient clinic) and at the end of screening:

  • Persistent dyspnea at rest or with minimal exertion at screening and at the time of randomization
  • Pulmonary congestion on chest radiograph
  • Brain natriuretic peptide (BNP) ≥500 pg/mL or NT-proBNP ≥2,000 pg/mL
• Systolic BP ≥125 mmHg at the start and at the end of screening
• Able to be randomized within 16 hours from presentation to the hospital, including the emergency department and outpatient clinic
• Received intravenous furosemide of at least 40 mg total (or equivalent) at any time between presentation (this includes outpatient clinic, ambulance, or hospital including emergency department) and the start of screening for the study for the treatment of the current acute HF episode
• Renal impairment defined as an estimate glomerular filtration rate using the between presentation and randomization of ≥ 25 and ≤75mL/min/1.73m2, calculated using the Modification of Diet in Renal Disease formula (or modified sMDRD formula according to specific ethnic groups and local practice guidelines).

Exclusion Criteria:

• Dyspnea primarily due to non-cardiac causes
• Temperature >38.5°C (oral or equivalent), sepsis, active and clinically significant infection requiring IV anti-microbial treatment or known presence or evidence of Human Immunodeficiency Virus (HIV) infection (based on history and/or clinical findings, including laboratory results obtained during screening period).

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

  *Patients with systolic blood pressure >180 mmHg at the end of screening

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

• Hepatic disease unrelated to Heart Failure etiology and as determined by any one of the following: AST and/or ALT values exceeding 3 X ULN and/or bilirubin > 1.5 X ULN at screening or history of hepatic encephalopathy, esophageal varices, or portacaval shunt, or a diagnosis of cirrhosis by any means, or evidence of chronic Hepatitis B (presence of hepatitis B surface antigen production: positive HBsAg), or chronic Hepatitis C infection (presence of Hepatitis C genetic replication: positive Hepatitis C viral RNA, based on history and/or clinical findings, including laboratory results obtained during screening period).

  *Significant uncorrected left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area <1.0 cm2 or mean gradient >50 mmHg on prior or current echocardiogram), and severe mitral stenosis

• History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past year with a life expectancy less than 1 year

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Patients will receive continuous intravenous infusion of matching placebo serelaxin for 48 hours.	Drug: Placebo; Intravenous infusion; Other: Standard of CareTherapy; This treatment can include but is not limited to intravenous and/or oral diuretics, ACE inhibitors/angiotensin receptor antagonists, β blockers, and aldosterone receptor antagonists, etc.
Experimental: Serelaxin; Patients will receive continuous intravenous infusion of serelaxin(30 µg/kg/day) for 48 hours.	Other: Standard of CareTherapy; This treatment can include but is not limited to intravenous and/or oral diuretics, ACE inhibitors/angiotensin receptor antagonists, β blockers, and aldosterone receptor antagonists, etc.; Drug: Serelaxin; Intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With a Clinical Composite Endpoint of Treatment Success, Treatment Failure, or no Change.	The trichotomous clinical composite endpoint of treatment success, treatment failure, or no change. Treatment success defined as improvement of dyspnea by Likert scale and at least 2 points improvement by at least 2 physician assessed signs and symptoms (orthopnea, rales edema, and jugular venous pulse) at Day 2; treatment failure defined as worsening heart failure, death, or re-hospitalization due to heart failure or renal failure through Day 5; no change defined as neither the criteria for treatment success nor the criteria for treatment failure was met through Day 5.	through day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to WHF	Results are given in terms of number of participants with at least one worsening heart failure (WHF) event through day 5 (pre-defined timeframe).	Through Day 5
Time to CV Death	analysis of time to CEC CV death through day 180 : results are given in terms of number of participants with CV death event through day 180 (pre-defined timeframe).	Through Day 180
Time to All-cause Death	Results are given in terms of number of participants with all cause death event through day 180 (pre-defined timeframe).	Through Day 180
Time to Moderate or Marked Improvements in Dyspnea by Likert Scale, Expressed in Days	Time to event is computed as the number of days from randomization to moderate or marked improvements in dyspnea by Likert scale	Through Day 5
Dyspnea by VAS-AUC Changes	Change from baseline in Dyspena by VAS-AUC through Day 5, expressed in mm-hours	Through Day 5
Length of Intensive Care Unit (ICU) and/or Coronary Care Unit (CCU) Stay for the Index AHF Hospitalization	Length of stay will be defined as the hospitalization discharge date and the time minus the baseline date and time plus 1 day	Up to day 30
Renal Dysfunction and Prevention of Worsening of Renal Function	number of participants with renal dysfunction or in-hospital worsening of renal function through Day 5	Through Day 5
Time to Re-hospitalization Due to Heart Failure and Renal Impairment	Time to event is computed as the number of days from randomization to re-hospitalization due to Heart Failure and renal impairment	Through Day 180
Time to CV Death or Re-hospitalization Due to Heart Failure/ Renal Failure	Results are given in terms of number of participants with CV death or at least one re-hospitalization due to Heart Failure through day 180 (pre-defined timeframe).	Through Day 180
Time to In-hospital Worsening Heart Failure Through Day 5	Results are given in terms of number of participants with at least one in-hospital worsening heart failure through day 5 (pre-defined timeframe). In-hospital worsening heart failure is defined by symptoms only, signs only, and both symptoms and signs.	Through Day 5
Use of Loop Diuretic and Vasoactive Agents	Number of patients reported with use of loop diuretic and vasoactive agents from randomization through Day 5	Through Day 5
Change From Baseline in Cardio-renal Biomarkers		Day 2 and Day 5
Number of Patients Reported With Total Adverse Events, Serious Adverse Events and Death.	To evaluate the safety and tolerability of intravenous serelaxin in AHF patients, number of patients with total adverse events, serious adverse events and death will be analyzed.	For the safety evaluation, all adverse events will be collected from signing of the informed consent form through Day 5 for non-serious AEs and through Day 14 for serious AEs.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Grand J, Miger K, Sajadieh A, Kober L, Torp-Pedersen C, Ertl G, Lopez-Sendon J, Pietro Maggioni A, Teerlink JR, Sato N, Gimpelewicz C, Metra M, Holbro T, Nielsen OW. Blood Pressure Drops During Hospitalization for Acute Heart Failure Treated With Serelaxin: A Patient-Level Analysis of 4 Randomized Controlled Trials. Circ Heart Fail. 2022 Apr;15(4):e009199. doi: 10.1161/CIRCHEARTFAILURE.121.009199. Epub 2022 Feb 21.
• Grand J, Miger K, Sajadieh A, Køber L, Torp-Pedersen C, Ertl G, López-Sendón J, Pietro Maggioni A, Teerlink JR, Sato N, Gimpelewicz C, Metra M, Holbro T, Nielsen OW. Systolic Blood Pressure and Outcome in Patients Admitted With Acute Heart Failure: An Analysis of Individual Patient Data From 4 Randomized Clinical Trials. J Am Heart Assoc. 2021 Sep 21;10(18):e022288. doi: 10.1161/JAHA.121.022288. Epub 2021 Sep 13.

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2014
• Primary Completion (Actual): March 27, 2017
• Study Completion (Actual): June 16, 2017

Study Registration Dates

• First Submitted: November 20, 2013
• First Submitted That Met QC Criteria: December 9, 2013
• First Posted (Estimate): December 11, 2013

Study Record Updates

• Last Update Posted (Actual): August 2, 2019
• Last Update Submitted That Met QC Criteria: June 12, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: acute heart failure; Serelaxin,; WHF,; Likert Scale,; RELAX-AHF-ASIA,; RLX030,; AHF,
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: CRLX030A2302

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No