Prospective ARNI versus ACE inhibitor trial to Determine Superiority in reducing heart failure Events after Myocardial Infarction

• Register: EUCTR
• Last refreshed on: 19 April 2021
• Main ID: EUCTR2016-002154-20-NL
• Date of registration: 09/11/2016
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: Prospective ARNI versus ACE inhibitor trial to Determine Superiority in reducing heart failure Events after Myocardial Infarction
• 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: 14/12/2016
• Target sample size: 5650
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-002154-20
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

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

Contacts

• Name: Clinical Trial Information Desk
• Affiliation: Novartis Pharma Services AG

• Name: Clinical Trial Information Desk
• Affiliation: Novartis Pharma Services AG

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female patients = 18 years of age.
2. Diagnosis of spontaneous AMI based on the universal MI definition with randomization to occur between 12 hours and 7 days after index event presentation.
3. Evidence of LV systolic dysfunction and/or pulmonary congestion requiring intravenous treatment associated with the index MI event defined as:
• LVEF =40% after index MI presentation and prior to randomization and/or
• Pulmonary congestion requiring intravenous treatment during the index hospitalization
4. At least one of the following 8 risk factors:
• Age = 70 years
• eGFR <60 mL/min/1.73 m2 based on MDRD formula at screening visit
• Type I or II diabetes mellitus
• Documented history of prior MI
• 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
5. Hemodynamically stable defined as:
• SBP = 100 mmHg at randomization for patients who received ACEi/ARB during the last 24 hours prior to randomization
• SBP = 110 mmHg at randomization for patients who did not receive ACEi/ARB during the last 24 hours prior to randomization
• No IV treatment with diuretics, vasodilators, vasopressors and/or inotropes during the 24 hours prior to randomization
Other protocol-defined inclusion criteria may apply.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 2797
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2853

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 rand or planned cardiac surgery w/in the 3 months prior to rand
12. eGFR < 30 ml/min/1.73 m2 as measured by MDRD at screening
13. Serum potassium > 5.2 mmol /L at (or equivalent plasma potassium value) randomization
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 esophageal varices
15. Previous use of LCZ696 or Entresto
16. 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 1year.
17. History of hypersensitivity to the study drugs or drugs of similar chemical classes or known intolerance or contraindications to study drugs or drugs of similar chemical classes including ACE inhibitors, ARB or NEP inhibitors
18. Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception

Other protocol-defined exclusion criteria may apply.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Left ventricular dysfunction following an acute myocardial infarction.
MedDRA version: 20.0 Level: PT Classification code 10000891 Term: Acute myocardial infarction System Organ Class: 10007541 - Cardiac disorders

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Trade Name: Entresto
Product Name: LCZ696 50 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
Other descriptive name: SACUBITRIL VALSARTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Entresto
Product Name: LCZ696 100 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
Other descriptive name: SACUBITRIL VALSARTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Entresto
Product Name: LCZ696 200 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
Other descriptive name: SACUBITRIL VALSARTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Diovan
Product Name: Diovan 40 mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VALSARTAN
CAS Number: 137862-53-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Diovan
Product Name: Diovan 80 mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VALSARTAN
CAS Number: 137862-53-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80-
Pharmaceutical form of the placebo: Film-coated tablet
Route o

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Time from randomization to first occurrence (up to approximately 32 months).

Primary end point(s): Time to the first occurrence of a confirmed composite endpoint. A confirmed composite endpoint includes cardiovascular death, heart failure hospitalization, or outpatient heart failure.

Secondary Objective: -To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time-to-first occurrence of CV death or HF hospitalization
-To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the new onset of symptomatic HF defined as time-to-first occurrence of HF hospitalization or outpatient HF
-To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time-to-first occurrence of CV death, non-fatal spontaneous MI or non-fatal stroke
-To demonstrate the 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
-To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time to all-cause mortality
-To evaluate the safety and tolerability of LCZ696 compared to ramipril

Main Objective: To demonstrate that LCZ696 is superior to ramipril in delaying the time-to-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.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1. Time from randomization to first occurrence (up to approximately 32 months)
2. Time from randomization to first occurrence (up to approximately 32 months).
3. Time from randomization to first occurrence (up to approximately 32 months).
4. The cumulative number.
5. Time from randomization

Secondary end point(s): 1. Time to the first occurrence of the confirmed composite endpoint. A confirmed composite endpoint includes cardiovascular death or heart failure hospitalization.
2. Time to the first occurrence of the confirmed composite endpoint. A confirmed composite endpoint includes heart failure hospitalization or outpatient heart failure.
3. Time to the first occurrence of the confirmed composite endpoint. A confirmed composite endpoint includes cardiovascular death, non-fatal spontaneous myocardial infarction or non-fatal stroke.
4. The total number of recurrent composite endpoints (count) and patient-specific follow-up time from randomization to end of study/death (days). A confirmed composite endpoint includes cardiovascular death, heart failure hospitalization, nonfatal spontaneous MI hospitalization, and non-fatal stroke hospitalization.
5. All-cause mortality

Secondary ID(s)

CLCZ696G2301

2016-002154-20-DE

NCT02924727

Source(s) of Monetary Support

Novartis Pharma Services AG

Ethics review

Status: Approved
Approval date: 14/12/2016
Contact: