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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

PHRR140804-000214

CRLX030A2302

2014-CT0199

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

Efficacy, safety and tolerability of serelaxin when added to standard therapy in Asian patients with acute heart failure (AHF)

Start Date Duration in Months Target Completion Date Actual Completion Date
2014-09-01 24 2016-09-01 2017-05-30

Terminated

program stopped

Institution Classification Region LTO #
Novartis Healthcare Philippines, Inc. Private Business NCR
Institution Region
Novartis Healthcare Philippines, Inc. NCR
Name E-Mail Institution and Institution Address
Carina Barlongo carina.barlongo@novartis.com 2/F Asian Reinsurance Bldg.Salcedo & Gamboa Streets, Legaspi Village Makati
Name E-Mail Institution and Institution Address
Carina Barlongo carina.barlongo@novartis.com 2/F Asian Reinsurance Bldg.Salcedo & Gamboa Streets, Legaspi Village Makati
Name Expertise Affiliation
Annette Borromeo, MD Cardiologist Philippine Heart Center
Eduardo Vicente Caguioa, MD Cardiologist University of Santo Tomas Hospital
Emiliano Canonigo, Jr., MD Cardiologist Asian Hospital and Medical Center
Eugenio Jose Ramos, MD Cardiologist The Medical City
Henry Chan, MD Cardiologist Chinese General Hospital and Medical Center
John C. Anonuevo, MD Cardiologist University of the Philippines - Philippine General Hospital
Loewe Go, MD Cardiologist St. Luke's Medical Center - Quezon City
Maria Adelaida M. Iboleon-Dy, MD Cardiologist St. Luke's Medical Center - Quezon City
Noe A. Babilonia, MD Cardiologist Philippine Heart Center
Rody G. Sy Cardiologist Cardinal Santos Medical Center
Romeo A. Divinagracia, MD Cardiologist University of the East Ramon Magsaysay Memorial Medical Center
Saturnino Javier, MD Cardiologist Makati Medical Center
Project Location Institutional Ethics Review Board
Philippine Heart Center Philippine Heart Center Ethics Review Committee
University of Santo Tomas Hospital University of Santo Tomas Hospital Institutional Review Board
Asian Hospital and Medical Center Asian Hospital and Medical Center Institutional Review Board
The Medical City The Medical City - Institutional Review Board
Chinese General Hospital and Medical Center Chinese General Hospital and Medical Center Institutional Review Board/Independent Ethics Committee
University of the Philippines - Philippine General Hospital N/A
St. Luke's Medical Center - Quezon City St. Luke's Medical Center Institutional Ethics Review Board
St. Luke's Medical Center - Quezon City St. Luke's Medical Center Institutional Ethics Review Board
Philippine Heart Center Philippine Heart Center Ethics Review Committee
Cardinal Santos Medical Center Cardinal Santos Medical Center Ethics Review Committee
University of the East Ramon Magsaysay Memorial Medical Center N/A
Makati Medical Center Makati Medical Center Institutional Review Board

acute heart failure

Primary objective(s) • To demonstrate that serelaxin is superior to placebo in improving the clinical composite of “treatment success,” “treatment failure” and “ unchanged” • Treatment success is defined as moderate or marked improvement in patient reported dyspnea by Likert scale AND ≥ 2 points improvement for at least 2 out of 4 physician assessed signs and symptoms including orthopnea, rales, edema and JVP and none of them deteriorating (≥ 0 point improvement) at Day 2. • Treatment failure is defined as worsening of heart failure or re-hospitalization due to HF or RF or death through Day 5. • All remaining patients are classified as having unchanged treatment status if they meet neither the criteria for treatment success nor the criteria for treatment failure through Day 5. Worsening heart failure (WHF) is defined as worsening signs and/or symptoms of heart failure that require an intensification of intravenous therapy for heart failure or mechanical ventilator, renal or circulatory support. Such treatment can include the institution or uptitration of IV furosemide, IV nitrates or any other IV medication for heart failure, or institution of mechanical support such as mechanical ventilation, ultrafiltration, hemodialysis, intra-aortic balloon pump or ventricular assist device.

• To evaluate the effect of serelaxin as compared to placebo on reducing time to worsening heart failure through Day 5 • To evaluate the effect of serelaxin as compared to placebo on reducing cardiovascular deaths through a follow-up period of 180 days • To evaluate the effect of serelaxin as compared to placebo on reducing all-cause deaths during a follow-up period of 180 days

Terminated

  • Philippines

Clinical Trial

CRLX030A2302

Unspecified

2014-05-09

0000-00-00

84

63

program stopped

2014-09-01

1. Written informed consent must be obtained before any study-specific assessment is performed* 2. Male or female ≥ 18 years of age, with body weight ≥ 30kg and ≤160 kg 3. Hospitalized for AHF; AHF is defined as including all of the following measured at any time between presentation (including the emergency department) and the end of screening: • Dyspnea at rest or with minimal exertion • Pulmonary congestion on chest radiograph • BNP ≥350 pg/mL or NT-proBNP ≥1,400 pg/mL 4. Systolic BP ≥125 mmHg at the start and at the end of screening 5. Able to be randomized within 16 hours from presentation to the hospital, including the emergency department 6. 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 7. Impaired renal function defined as an eGFR between presentation and randomization of ≥ 25 and ≤75mL/min/1.73m2, calculated using the sMDRD formula. * Patient assessments of AHF that are per current local institutional/hospital standard protocol or part of routine clinical care are allowed before signing informed consent, and can be used to support patient screening. Exclusion criteria 1. Dyspnea primarily due to non-cardiac causes 2. Temperature >38.5°C (oral or equivalent) or sepsis or active infection requiring IV antimicrobial treatment 3. Clinical evidence of acute coronary syndrome currently or within 30 days prior to enrollment. (Note that the diagnosis of acute coronary syndrome is a clinical diagnosis and that the sole presence of elevated troponin concentrations is not sufficient for a diagnosis of acute coronary syndrome, given that troponin concentrations may be significantly increased in the setting of AHF.) 4. AHF due to significant arrhythmias, which include any of the following: sustained ventricular tachycardia, bradycardia with sustained ventricular rate 130 beats per minute 5. Patients with Hematocrit <25%, or a history of blood transfusion within the 14 days prior to screening, or active life-threatening gastrointestinal (GI) bleeding 6. Significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area 50 mmHg on prior or current echocardiogram), and severe mitral stenosis 7. Current (within 2 hours prior to randomization) or planned (through the completion of study drug infusion) treatment with any IV vasoactive therapies, including vasodilators (including nesiritide and carperitide), positive inotropic agents and vasopressors, or mechanical support (endotracheal intubation, mechanical ventilation; intra-aortic balloon pump or any ventricular assist device; hemofiltration, ultrafiltration or dialysis), with the exception of IV furosemide (or equivalent), or IV nitrates at a dose of ≤ 0.1 mg/kg/hour if the patient has a systolic BP >150 mmHg at screening. 8. Hepatic disease unrelated to HF 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, history of hepatic encephalopathy, esophageal varices, or portacaval shunt, diagnosis of cirrhosis, chronic Hepatitis B or chronic Hepatitis C infection by any means (e.g. based on history, clinical findings, laboratory results or imaging) 9. Known presence of active or recurrent bacterial, fungal or viral infection at the time of enrollment, e.g. evidence of Human Immunodeficiency Virus (HIV) infection (based on history and/or clinical findings, including laboratory results obtained during screening period 10. Any organ transplant recipient, or patient currently listed for imminent transplant (i.e., do not exclude patients on an administrative transplant waiting list), or planned/admitted for any transplantation 11. Major surgery, including implantable devices (e.g. ICD, CRT), or major neurologic event including cerebrovascular events, within 30 days prior to screening 12. Any major solid organ transplant recipient or planned/anticipated organ transplant within 1 year. 13. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test 14. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment. Effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptom thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception: • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment • Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that subject • Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository • Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception • Placement of an intrauterine device (IUD) or intrauterine system (IUS) • In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment 15. Use of other investigational drugs within 30 days prior to screening 16. History of hypersensitivity to serelaxin 17. History of participating in serelaxin clinical studies 18. Inability to follow instructions or comply with follow-up procedures 19. Any other medical conditions that may put the patient at risk or influence study results in the investigator's opinion, or that the investigator deems unsuitable for the study

Interventional

Serelaxin (and/or matching placebo)

Serelaxin (and/or matching placebo) will be administered according to a weight-range adjusted dosing regimen at a nominal dose of 30 μg/kg/day (refer to the details in Section 5.5.4), as a continuous intravenous infusion for 48 hours. The study drug is provided as a 1 mg/mL solution in 6 mL vials (with 3.5 mL fill). For the randomized patients to receive the study drug infusion, it can be withdrawn from the vials contained in the blinded kits, injected into a 250 mL intravenous bag of 5% dextrose solution, and then infused through a dedicated IV line according to instructions in the Pharmacy Manual.

None

Randomized

Double Blind

randomized, double-blind, placebo controlled

Parallel

The purpose of this study is to evaluate the efficacy, safety and tolerability of intravenous infusion of 30 μg/kg/day serelaxin for 48 hours within 16 hours of clinical presentation, when added to standard therapy, in approximately 1,520 Asian AHF patients randomized to receive serelaxin or placebo to demonstrate superiority in early improvement in signs and symptoms of congestion and reduction in worsening heart failure as evaluated by a clinical composite as the primary endpoint. In addition the study will also assess the effect of serelaxin on the cardiovascular and all-cause deaths as listed as secondary endpoint; the results of which will be interpreted along with the results from other global studies.

Phase III

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