Study is to evaluate the efficacy and safety of LCZ696 compared to ramipril when added to standard therapy, in reducing the occurrence of cardiovascular (CV) death, heart failure (HF) hospitalization and outpatient HF (time-to-first event analysis)

• Register: CTRI
• Last refreshed on: 24 November 2021
• Main ID: CTRI/2017/06/008867
• Date of registration: 19-06-2017
• Prospective Registration: Yes
• Primary sponsor: Novartis Healthcare Pvt Ltd
• Public title: Study is to evaluate the efficacy and safety of LCZ696 compared to ramipril when added to standard therapy, in reducing the occurrence of cardiovascular (CV) death, heart failure (HF) hospitalization and outpatient HF (time-to-first event analysis)
• Scientific title: A multi-center, 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 an acute myocardial infarction - PARADISE-MI
• Date of first enrolment: 14-07-2017
• Target sample size: 4650
• Recruitment status: Closed to Recruitment of Participants
• URL: http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=15962
• Study type: Interventional
• Study design: Randomized, Parallel Group, Active Controlled Trial; Method of generating randomization sequence:Computer generated randomization Method of allocation concealment:Centralized Blinding and masking:Double Blind Double Dummy
• Phase: Phase 3

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Croatia, Czech Republic, Denmark, Finland, France, Germany, Greece, Guatemala, Hungary, India, Israel, Italy, Mexico, Netherlands, Norway, Peru, Philippines, Poland, Portugal, Republic of Korea, Romania, Russian Federation, Singapore, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, United Kingdom, United States of America

Contacts

• Name: Murugananthan K
• Affiliation: Novartis Healthcare Private Limited

• Name: Murugananthan K
• Affiliation: Novartis Healthcare Private Limited

Key inclusion & exclusion criteria

Inclusion criteria: Written informed consent must be obtained before any assessment is performed.

Male or female patients greater than equal to 18 years of age.

At least one of the following 8 risk factors:

Age greater than equal to 70 years

eGFR less than 60 mL per min per1.73 m2 based on 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 less than 30percent 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.

Hemodynamically stable defined as:

SBP greater than equal to 100 mmHg at randomization for patients who received ACE inhibitor or ARB during the last 24 hours prior to randomization (ACE inhibitor/ARB Yes patients)

SBP greater than equal to 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.

Evidence of LV systolic dysfunction and/or pulmonary congestion requiring intravenous

treatment associated with the index MI event defined as:

LVEF less than equal to 40percent 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-of-care. 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; see Appendix 3 for

Killip class definition) 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.
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.

Age minimum:
Age maximum:
Gender:

Health Condition(s) or Problem(s) studied

Health Condition 1: null- Acute Myocardial Infarction Health Condition 2: I219- Acute myocardial infarction, unspecified

Intervention(s)

Intervention1: LCZ696. LCZ696
50mg, 100mg and 200
mg dosage strengths will
be available for dose
adjustments: LCZ696 at dose levels 1-3 (50, 100 and 200 mg twice daily).
LCZ696 50 mg b.i.d. at V101 for duration of 7 days.
LCZ696 100 mg bid at V 102 for 7days.
200 mg bid at V 103 and continues for 959 days.
Control Intervention1: Rampril.
Ramipril 1.25mg, 2.5mg
and 5 mg dosage
strengths will be
available for dose
adjustments.: LCZ696 at dose levels 1-3 (Ramipril 1.25mg, 2.5mg
and 5 mg twice daily). -Ramipril 1.25 mg b.i.d. at V101 for duration of 7 days.
Ramipril 2.5 mg bid at V 102 for 7days.
Ramipril 5 mg bid at V 103 and continues for 959 days.

Primary Outcome(s)

To Demonstrate that LCZ696 is superior 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 function and or pulmonary congestion following the AMITimepoint: 32 months

Secondary Outcome(s)

To demonstrate the superiority of LCZ696 compared to ramipril, in delaying the time-tofirst

occurrence of CV death, non-fatal spontaneous MI or non-fatal strokeTimepoint: 32 months

To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time to

all-cause mortalityTimepoint: 32 months

To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time-tofirst

occurrence of CV death or HF hospitalizationTimepoint: 32 months

To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time to

new onset of symptomatic HF defined as time-to-first occurrence of HF hospitalization or

outpatient HFTimepoint: 32 months

Secondary ID(s)

CLCZ696G2301, Version 01 dated: 29-Jun-2016

Source(s) of Monetary Support

Novartis Pharma AG, CH-4002 Basel, Switzerland.

Ethics review

Status: Approved
Approval date: 21/11/2016
Contact:

Magna-Care Ethics Committee, hopda Medicare and Research Centre Pvt. Ltd., Dr. Manoj Chopada

Status: Approved
Approval date: 20/12/2016
Contact:

Institutional Ethics Commitee,Lisie Hospital Dr. Jabir Abdullakutty

Status: Approved
Approval date: 25/12/2016
Contact:

Ethics Committee, S. P. Medical College & A. G. Hospital, Dr. D K Agarwal

Status: Approved
Approval date: 09/01/2017
Contact:

Medanta Institutional Ethics Committee, Dr. V K Chopra

Status: Approved
Approval date: 14/01/2017
Contact:

Insitutional Ethics Committee,RUBY HALL CLINIC,Dr. Shireesh Hiremath

Status: Approved
Approval date: 25/01/2017
Contact:

Insititutional Ethics Committee,Shree Krishna Hospital & Medical Research Centre, Dr. Sunil Karna

Status: Approved
Approval date: 02/02/2017
Contact:

Ethic Committee of CIMS Hospital, Dr. Urmil Shah

Status: Approved
Approval date: 07/02/2017
Contact:

Institutional Ethics Committee, Government Medical College, Dr. Pradeep Deshmukh

Status: Approved
Approval date: 15/02/2017
Contact:

Institutional Ethics Committee, Maharaja Agrasen Hospital, Dr. B B Chanana

Status: Approved
Approval date: 28/02/2017
Contact:

Rhythm Heart Institute Ethics Committee, Dr. Nirav Bhalani

Status: Approved
Approval date: 25/03/2017
Contact:

Institutional Ethics committee, Meenakshi Mission Hospital and Research Center, Dr Sivakumar R.

Status: Approved
Approval date: 06/05/2017
Contact:

Institutional Ethics committee, St. Theresa Hospital, Dr Krutika Kulkarni

Status: Approved
Approval date: 21/06/2017
Contact:

Institutional Ethics Committee,Yashoda Academy of Medical Education & Research, Dr. Ravikanth

Status: Approved
Approval date: 27/12/2017
Contact:

Institutional Ethics Committee,Seth G S Medical College & KEM Hospital, Dr. Prafulla Kerkar

Status: Approved
Approval date: 17/07/2019
Contact:

KIMS Ethics Committee, Dr. Premchand

Status: Approved
Approval date: 06/08/2019
Contact:

Ethics Commitee_Sir Ganga Ram Hospital

Status: Approved
Approval date: 24/09/2019
Contact:

Institutional Ethics Committee, Shri Mahant Indiresh Hospital, Dr. Tanuj Bhatia