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

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ClinicalTrials.gov Identifier: NCT02924727
Recruitment Status : Completed
First Posted : October 5, 2016
Results First Posted : June 22, 2023
Last Update Posted : June 22, 2023
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myocardial Infarction Drug: LCZ696 (sacubitril/valsartan) Drug: Ramipril Drug: Placebo of LCZ696 Drug: Placebo of ramipril Drug: Valsartan Drug: Placebo of valsartan Phase 3

Detailed Description:
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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5669 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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 (AMI)
Actual Study Start Date : December 9, 2016
Actual Primary Completion Date : February 26, 2021
Actual Study Completion Date : February 26, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Attack

Arms and Interventions
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Arm Intervention/treatment
Experimental: LCZ696 (sacubitril/valsartan)

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)
LCZ696 (sacubitril/valsartan) tablet will be available in 24/26 mg, 49/51 mg and 97/103 mg, respectively

Drug: Placebo of ramipril
Matching placebo of ramipril capsule

Drug: Valsartan
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
Active Comparator: Ramipril

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
Ramipril 1.25 mg, 2.5 mg, and 5 mg oral capsules

Drug: Placebo of LCZ696
Matching placebo of LCZ696 tablets

Drug: Placebo of valsartan
matching placebo of valsartan for one day to patients who will be randomized to received ramipril


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


Secondary Outcome Measures :
  1. Number of Participants With a Confirmed Composite of CV Death or HF Hospitalization [ Time Frame: Time from randomization to first occurrence (up to approximately 43 months) ]
    A confirmed composite endpoint for this outcome measure includes cardiovascular death or heart failure hospitalization.

  2. Number of Participants With a Confirmed Composite of HF Hospitalization or Outpatient HF [ Time Frame: Time from randomization to first occurrence (approximately up to 43 months) ]
    A confirmed composite endpoint includes first occurrence of heart failure hospitalization or outpatient heart failure

  3. Number of Participants With a Confirmed Composite of CV Death, Non-fatal Spontaneous Myocardial Infarction or Non-fatal Stroke [ Time Frame: Time from randomization to first occurrence (approximately up to 43 months) ]
    A confirmed composite endpoint for this outcome measure includes cardiovascular death, non-fatal spontaneous myocardial infarction or non-fatal stroke

  4. Total Number of Confirmed Composite Endpoints [ Time Frame: Time from randomization to end of study (approximately up to 43 months) ]
    A confirmed composite endpoint includes cardiovascular death, heart failure hospitalization, non-fatal spontaneous MI hospitalization, and non-fatal stroke hospitalization

  5. All-cause Mortality for Full Analysis Set (FAS) [ Time Frame: Time from randomization to death (approximately up to 43 months) ]
    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.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. (*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)

  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 with diuretics, vasodilators, vasopressors and/or inotropes, during the index hospitalization

  4. 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

  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

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 w/in the 3 months prior to randomization
  12. eGFR < 30 ml/min/1.73 m^2 as measured by MDRD at screening
  13. Serum potassium > 5.2 mmol /L (or equivalent plasma potassium value) at 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
  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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02924727


Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] May 18, 2016
Statistical Analysis Plan  [PDF] November 12, 2016

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02924727    
Other Study ID Numbers: CLCZ696G2301
2016-002154-20 ( EudraCT Number )
First Posted: October 5, 2016    Key Record Dates
Results First Posted: June 22, 2023
Last Update Posted: June 22, 2023
Last Verified: June 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Spontaneous AMI
HF hospitalization
outpatient HF
LV systolic dysfunction
pulmonary congestion
 STEMI
NSTEMI
randomized clinical trial
LCZ696
ramipril
Additional relevant MeSH terms:
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Myocardial Infarction
Infarction
Ischemia
Pathologic Processes
Necrosis
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Valsartan
 Ramipril
Sacubitril and valsartan sodium hydrate drug combination
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors