i

A multicenter, randomized, double-blind, active-controlled, parallel-group phase 3 study to evaluate the efficacy and safety of LCZ696 compared to ramipril on morbidity and mortality in high risk patients following acute myocardial infarction

PHRR170707-001595

CLCZ696G2301

2017-CT0399

A multicenter, randomized, double-blind, active-controlled, parallel-group phase 3 study to evaluate the efficacy and safety of LCZ696 compared to ramipril on morbidity and mortality in high risk patients following acute myocardial infarction

A multicenter, randomized, double-blind, active-controlled, parallel-group phase 3 study to evaluate the efficacy and safety of LCZ696 compared to ramipril on morbidity and mortality in high risk patients following acute myocardial infarction

Regime Classification Priority
2010 - 2016 Health Technology Development Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2017-06-23 36 2020-06-23 2021-01-28

Completed

Institution Classification Region LTO #
Novartis Healthcare Philippines, Inc. Private Business NCR 3000006283930
Institution Classification Region LTO #
PAREXEL Clinical Research (Philippines) Ltd. Corp. Private Business NCR CDRR-NCR-CRO-4
Institution Region
Novartis Healthcare Philippines, Inc. NCR
Name E-Mail Institution and Institution Address
Anna Liza Calingasin anna_liza.calingasin@novartis.com 5/F Ayala North Exchange Tower 1 Salcedo corner Amorsolo Streets Legaspi Village, Makati City
Name E-Mail Institution and Institution Address
Ivy Emily Peneyro-Vergara ivy_emily.peneyro-vergara@novartis.com 5/F Ayala North Exchange Tower 1 Salcedo corner Amorsolo Streets Legaspi Village, Makati City
Name Expertise Affiliation
John C. Anonuevo, MD Cardiology University of the Philippines - Philippine General Hospital
Jorge Sison, MD Cardiology Medical Center Manila
Louie S. Tirador, MD Cardiology St. Paul's Hospital of Iloilo, Inc.
Maria Teresa B. Abola, MD Cardiology Philippine Heart Center
Project Location Institutional Ethics Review Board
University of the Philippines - Philippine General Hospital N/A
Medical Center Manila Manila Medical Ethics Review Committee
St. Paul's Hospital of Iloilo, Inc. St. Paul’s Hospital Iloilo – Institutional Ethics Review Board
Philippine Heart Center Philippine Heart Center Ethics Review Committee

post acute myocardial infarction

LCZ696 superiority to ramipril in delaying the timeto- first occurrence of the composite endpoint of CV death, HF hospitalization or outpatient HF* in patients with LV systolic dysfunction and/or pulmonary congestion following an AMI.

 

The outpatient HF endpoint event is defined as an adjudicated event of clinical development of symptomatic HF (either urgent/unscheduled or non-urgent) in the outpatient setting with symptoms and signs requiring initiation/intensification of intravenous or qualifying oral HF treatment

1. Superiority of LCZ696, compared to ramipril, in delaying the time-to-first occurrence of CV death or HF hospitalization

2. Superiority of LCZ696, compared to ramipril, in delaying the new-onset of symptomatic HF defined as time-to-first occurence of HF hospitalization or outpatient HF

 

3. Superiority of LCZ696, compared to ramipril, in delaying the time-to-first occurrence of CV death, non-fatal spontaneous MI or non-fatal stroke

4. superiority of LCZ696, compared to ramipril, in reducing the rate of the composite endpoint of CV death and total (first and recurrent) hospitalizations due to HF, non-fatal spontaneous MI or non-fatal stroke

5. superiority of LCZ696, compared to ramipril, in delaying the time to all-cause mortality

6. 
safety and tolerability of LCZ696 compared to ramipri;

 

Completed

  • Argentina
  • Australia
  • Austria
  • Belgium
  • Brazil
  • Bulgaria
  • Canada
  • China
  • Colombia
  • Croatia
  • Czech Republic
  • Denmark
  • Germany
  • Greece
  • Guatemala
  • Hungary
  • India
  • Israel
  • Italy
  • Mexico
  • Netherlands
  • Philippines
  • Poland
  • Portugal
  • Romania
  • Russia
  • Singapore
  • Slovakia
  • South Korea
  • Spain
  • Switzerland
  • Taiwan
  • Thailand
  • Turkey
  • United Kingdom

Clinical Trial

CLCZ696G2301

20170302104617

2017-06-22

0000-00-00

54

51

51 is the number of actual randomized patients.

2017-06-23

KEY INCLUSION CRITERIA

1. Written informed consent must be obtained before any assessment is performed.
2. Male or female patients ≥ 18 years of age.
3. Diagnosis of spontaneous AMI based on the universal myocardial infarction (MI) definition* with randomization to occur between 12 hours and 7 days after index event presentation**.
Spontaneous AMI is defined when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia due to primary coronary event. Under these conditions, the following criteria have to be met for the diagnosis of spontaneous AMI:

Detection of rise and/or fall of cardiac enzymes (cardiac troponin, cTn or the MB fraction of creatinine kinase, CKMB) with at least one value above the 99th percentile of the upper reference limit  or the local laboratory MI diagnosis cut-off value, together with evidence of myocardial ischemia with at least one of the following:
    • Ischemic discomfort or other ischemia symptom(s)
   
Electrocardiogram (ECG) characteristics of STEMI or NSTEMI including new or presumably new significant ST-segment-T wave (ST-T) changes
    • Newly developed pathological Q waves or left bundle branch block (LBBB) in the ECG
(*Patients with a spontaneous MI event determined to be secondary to another medical condition such as anemia, hypotension, or an arrhythmia OR thought to be caused by coronary vasospasm with documented normal coronary arteries are not eligible)

4. Evidence of LV systolic dysfunction and/or pulmonary congestion requiring intravenous treatment associated with the index MI event defined as:
Left ventricular ejection fraction (LVEF) ≤ 40% assessed locally by echocardiography, magnetic resonance imaging, cardiac CT, radionuclide or contrast ventriculography after index MI presentation** and prior to randomization. (These examinations may be performed as part of patient standard-ofcare. In case multiple LVEF measurements have been performed during index event, the last one performed prior to randomization should be considered as the qualifying measurement), and/or
Pulmonary congestion requiring intravenous treatment during the index hospitalization supported by clinical assessment (worst Killip class, II or above) or radiological findings. Radiological evidence of pulmonary congestion is defined as pulmonary venous congestion with interstitial or alveolar edema and must be supported by at least one chest X-ray or CT scan.
(**Index MI presentation is the time of patient presentation at eitherthe ER/ED, ICU/CCU or hospital ward etc., at study center, for the treatment of the index MI.)

5. At least one of the following 8 risk factors:

Age ≥ 70 years
eGFR 2 based on Modification of Diet in Renal Disease (MDRD) formula at screening visit
Type I or II diabetes mellitus
Documented history of prior MI supported by ECG changes and/or elevation of cardiac enzymes consistent with MI diagnosis.
Atrial fibrillation as noted by ECG, associated with index MI
LVEF < 30% associated with index MI
Worst Killip class III or IV associated with index MI requiring intravenous treatment
STEMI without reperfusion therapy within the first 24 hours after presentation

6. Hemodynamically stable defined as:

Systolic blood pressure (SBP) ≥ 100 mmHg at randomization for patients who received ACE inhibitor/angiotensin receptor blocker (ARB) during the last 24 hours prior to randomization (ACE inhibitor/ARB Yes patients)
SBP ≥ 110 mmHg at randomization for patients who did not receive ACE inhibitor/ARB during the last 24 hours prior to randomization (ACE inhibitor/ARB No patients)
No intravenous treatment with diuretics, vasodilators, vasopressors and/or inotropes during the last 24 hours prior to randomization.

KEY EXCLUSION CRITERIA
1. Known history of chronic HF prior to randomization
2. Cardiogenic shock within the last 24 hours prior to randomization
3. Persistent clinical HF at the time of randomization
4. Coronary artery bypass graft (CABG) performed or planned for index MI
5. Clinically significant right ventricular MI as index MI
6. Symptomatic hypotension at screening or randomization
7. Patients with a known history of angioedema
8. Stroke or transient ischemic attack within one month prior to randomization
9. Known or suspected bilateral renal artery stenosis
10. Clinically significant obstructive cardiomyopathy
11. Open-heart surgery performed within one month prior to randomization or planned cardiac surgery within the 3 months after randomization
12. eGFR < 30 ml/min/1.73 m2 as measured by the Modification of Diet in Renal Disease (MDRD) formula at screening
13. Serum potassium > 5.2 mmol /L at screening
14. Known hepatic impairment (as evidenced by total bilirubin > 3.0 mg/dL or increased ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension such as varices
15. Previous use of LCZ696 or EntrestoTM
16. Use of other investigational drugs within 30 days prior to screening
17. History of hypersensitivity to the study drugs or drugs of similar chemical classes 18. Known intolerance or contraindications to study drugs or drugs of similar chemical classes including ACE inhibitors, ARB or NEP inhibitors
19. Patients taking medications prohibited by the protocol that cannot be discontinued for the duration of the study
20. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin) within the past 3 years with a life expectancy of less than 1 year 21. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or extraction of study drug at investigators’ discretion 22. History or evidence of drug or alcohol abuse within the last 12 months
23. Patients considered unsuitable for the study, including patients with psychiatric, behavioral or cognitive disorders, sufficient to interfere with the patient’s ability to understand and comply with the protocol instructions or follow-up procedures
24. 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 human chorionic gonadotropin (hCG) laboratory test
25. 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 investigational drug


Interventional

LCZ696

sacubitril-valsartan, oral

Date Amendment Classification Reason
2017-11-22 Amendments related to the protocol Informed consent
2018-09-10 Amendments related to the protocol Informed consent
2019-05-03 Amendments related to the protocol Informed consent
2020-12-11 Amendments related to the protocol Informed consent

Randomized

Double Blind

Unspecified

Parallel

The purpose of this study is to evaluate the efficacy and safety of LCZ696 compared to ramipril, in reducing the occurrence of cardiovascular (CV) death, heart failure (HF) hospitalization and outpatient HF (time-to-first event analysis) in post-AMI patients with evidence of left ventricular (LV) systolic dysfunction and/or pulmonary congestion, without a known prior history of chronic HF.

This is an event-driven study which is a well-established study design for long-term cardiovascular outcome trials in post-acute myocardial infarction (AMI) patients. While the composite of CV death or HF hospitalization is a well-established mortality and morbidity endpoint, the addition of the outpatient HF component, which in this study represents the confirmed diagnosis of new onset symptomatic HF, aims to capture the clinically important outpatient event that contributes to the totality of HF morbidity following an AMI presenting as either inpatient (i.e., HF hospitalization) or outpatient (i.e., outpatient HF) events.

Ramipril is chosen as an active comparator of the study representing the guideline-recommended standard-of-care angiotensin converting enzyme (ACE) inhibitors shown to improve survival and reduce HF morbidity in high-risk post-AMI patients.

Phase III

Utilization Utilization Info
Publication
Oral Presentation
Drug Literature
Posters
Others
©2022 HERDIN PLUS. All rights reserved. | Contact Us | Keep up to date