Prospective ARNI vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of LCZ696 titrated to a target dose of 200 mg twice daily, compared to ramipril titrated to a target dose of 5 mg twice daily.

Detailed Description
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The purpose of this study is to evaluate the efficacy and safety of LCZ696 titrated to a target dose of 200 mg twice daily, compared to ramipril titrated to a target dose of 5 mg twice daily, in addition to conventional post-AMI treatment, in reducing the occurrence of composite endpoint of CV death, HF hospitalization and outpatient HF (time-to-first event analysis) in post-AMI patients with evidence of LV systolic dysfunction and/or pulmonary congestion, with no known prior history of chronic HF.

Official Title
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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 (AMI)

Conditions
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Acute Myocardial Infarction

Intervention / Treatment
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* Drug: LCZ696 (sacubitril/valsartan)
* Drug: Ramipril
* Drug: Placebo of LCZ696
* Drug: Placebo of ramipril
* Drug: Valsartan
* Drug: Placebo of valsartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥ 18 years of age. Diagnosis of spontaneous AMI based on the universal MI definition* with randomization to occur between 12 hours and 7 days after index event presentation. (*patients with spontaneous MI event determined to be secondary to another medical condition such as anemia, hypotension, or arrhythmia OR thought to be caused by coronary vasospasm with document normal coronary arteries are not eligible; patients with clinical presentation thought to be related to Takotsubo cardiomyopathy are also not eligible) 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 with diuretics, vasodilators, vasopressors and/or inotropes, during the index hospitalization At least one of the following 8 risk factors: Age ≥ 70 years eGFR <60 mL/min/1.73 m^2 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 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 Key Exclusion Criteria: Known history of chronic HF prior to randomization Cardiogenic shock within the last 24 hours prior to randomization Persistent clinical HF at the time of randomization Coronary artery bypass graft (CABG) performed or planned for index MI Clinically significant right ventricular MI as index MI Symptomatic hypotension at screening or randomization Patients with a known history of angioedema Stroke or transient ischemic attack within one month prior to randomization Known or suspected bilateral renal artery stenosis Clinically significant obstructive cardiomyopathy Open-heart surgery performed within one month prior to randomization or planned cardiac surgery w/in the 3 months prior to randomization eGFR < 30 ml/min/1.73 m^2 as measured by MDRD at screening Serum potassium > 5.2 mmol /L (or equivalent plasma potassium value) at randomization 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 Previous use of LCZ696 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. 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 Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCZ696 (sacubitril/valsartan)<br>Following randomization, patients will receive LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Patients will be required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from ramipril matching placebo pack) twice a day for the duration of the study. Patients randomized to LCZ who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization will receive a valsartan bridge for one day. These patients will receive two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment. | Drug: LCZ696 (sacubitril/valsartan)<br>* LCZ696 (sacubitril/valsartan) tablet will be available in 24/26 mg, 49/51 mg and 97/103 mg, respectively<br>Drug: Placebo of ramipril<br>* Matching placebo of ramipril capsule<br>Drug: Valsartan<br>* Valsartan (VAL489) 40 mg and 80 mg tablets, two doses for 1 day to patients who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization<br>|
| Active Comparator: Ramipril<br>Following randomization, patients will receive the Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients will be required to take a total of two pills, (one capsule from the ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to ramipril who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization will immediately start on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients will receive two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo. | Drug: Ramipril<br>* Ramipril 1.25 mg, 2.5 mg, and 5 mg oral capsules<br>Drug: Placebo of LCZ696<br>* Matching placebo of LCZ696 tablets<br>Drug: Placebo of valsartan<br>* matching placebo of valsartan for one day to patients who will be randomized to received ramipril<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With First CEC (Clinical Endpoint Committee) Confirmed Primary Composite Endpoint | A confirmed composite endpoint includes cardiovascular (CV) death, heart failure (HF) hospitalization, or outpatient heart failure | From randomization to first occurrence (up to approximately 43 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Confirmed Composite of CV Death or HF Hospitalization | A confirmed composite endpoint for this outcome measure includes cardiovascular death or heart failure hospitalization. | Time from randomization to first occurrence (up to approximately 43 months) | 
| Number of Participants With a Confirmed Composite of HF Hospitalization or Outpatient HF | A confirmed composite endpoint includes first occurrence of heart failure hospitalization or outpatient heart failure | Time from randomization to first occurrence (approximately up to 43 months) | 
| Number of Participants With a Confirmed Composite of CV Death, Non-fatal Spontaneous Myocardial Infarction or Non-fatal Stroke | A confirmed composite endpoint for this outcome measure includes cardiovascular death, non-fatal spontaneous myocardial infarction or non-fatal stroke | Time from randomization to first occurrence (approximately up to 43 months) | 
| Total Number of Confirmed Composite Endpoints | A confirmed composite endpoint includes cardiovascular death, heart failure hospitalization, non-fatal spontaneous MI hospitalization, and non-fatal stroke hospitalization | Time from randomization to end of study (approximately up to 43 months) | 
| All-cause Mortality for Full Analysis Set (FAS) | All-cause mortality defined as deaths related to Cardiovascular (CV) and non-CV events for patients in the Full Analysis Set up to a cut-off date of 31-Dec-2020. | Time from randomization to death (approximately up to 43 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spontaneous AMI, HF hospitalization, outpatient HF, LV systolic dysfunction, pulmonary congestion, STEMI, NSTEMI, randomized clinical trial, LCZ696, ramipril