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

• 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: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: October 4, 2016
• First Posted Date: October 5, 2016
• Results First Submitted Date: January 20, 2022
• Results First Posted Date: June 22, 2023
• Last Update Posted Date: June 22, 2023
• Actual Study Start Date: December 9, 2016
• Actual Primary Completion Date: February 26, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 16, 2023)

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

Original Primary Outcome Measures (submitted: October 4, 2016)

Time to the first occurrence of a confirmed composite endpoint [ Time Frame: Time from randomization to first occurrence (up to approximately 32 months) ]

A confirmed composite endpoint includes cardiovascular (CV) death, heart failure (HF) hospitalization, or outpatient heart failure

Current Secondary Outcome Measures (submitted: June 16, 2023)

• 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.
• 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
• 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
• 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
• 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.

Original Secondary Outcome Measures (submitted: October 4, 2016)

• Time to the first occurrence of a confirmed composite of CV death or HF hospitalization [ Time Frame: Time from randomization to first occurrence (up to approximately 32 months) ]
  A confirmed composite endpoint for this outcome measure includes cardiovascular death or heart failure hospitalization.
• Time to the first occurrence of a confirmed composite of HF hospitalization or outpatient HF [ Time Frame: Time from randomization to first occurrence (approximately up to 32 months) ]
  A confirmed composite endpoint includes first occurrence of heart failure hospitalization or outpatient heart failure
• Time to the first occurrence of 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 32 months) ]
  A confirmed composite endpoint for this outcome measure includes cardiovascular death, non-fatal spontaneous myocardial infarction or non-fatal stroke
• Total number of recurrent confirmed composite endpoints [ Time Frame: Time from randomization to end of study (approximately up to 32 months) ]
  A confirmed composite endpoint includes cardiovascular death, heart failure hospitalization, non-fatal spontaneous MI hospitalization, and non-fatal stroke hospitalization
• Time to all-cause mortality [ Time Frame: Time from randomization to death (approximately up to 32 months) ]
  All-cause mortality defined as death related to CV and non-CV events.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Prospective ARNI vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI
• 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)
• 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.
• 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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Acute Myocardial Infarction

Intervention

• Drug: LCZ696 (sacubitril/valsartan)
  LCZ696 (sacubitril/valsartan) tablet will be available in 24/26 mg, 49/51 mg and 97/103 mg, respectively
• 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 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
• Drug: Placebo of valsartan
  matching placebo of valsartan for one day to patients who will be randomized to received ramipril

Study Arms

• 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.

  Interventions:

  • Drug: LCZ696 (sacubitril/valsartan)
  • Drug: Placebo of ramipril
  • Drug: Valsartan
• 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.

  Interventions:

  • Drug: Ramipril
  • Drug: Placebo of LCZ696
  • Drug: Placebo of valsartan

Publications *

• Mehran R, Steg PG, Pfeffer MA, Jering K, Claggett B, Lewis EF, Granger C, Kober L, Maggioni A, Mann DL, McMurray JJV, Rouleau JL, Solomon SD, Ducrocq G, Berwanger O, De Pasquale CG, Landmesser U, Petrie M, Leng DSK, van der Meer P, Lefkowitz M, Zhou Y, Braunwald E. The Effects of Angiotensin Receptor-Neprilysin Inhibition on Major Coronary Events in Patients With Acute Myocardial Infarction: Insights From the PARADISE-MI Trial. Circulation. 2022 Dec 6;146(23):1749-1757. doi: 10.1161/CIRCULATIONAHA.122.060841. Epub 2022 Nov 2.
• Shah AM, Claggett B, Prasad N, Li G, Volquez M, Jering K, Cikes M, Kovacs A, Mullens W, Nicolau JC, Kober L, van der Meer P, Jhund PS, Ibram G, Lefkowitz M, Zhou Y, Solomon SD, Pfeffer MA. Impact of Sacubitril/Valsartan Compared With Ramipril on Cardiac Structure and Function After Acute Myocardial Infarction: The PARADISE-MI Echocardiographic Substudy. Circulation. 2022 Oct 4;146(14):1067-1081. doi: 10.1161/CIRCULATIONAHA.122.059210. Epub 2022 Sep 9.
• Pfeffer MA, Claggett B, Lewis EF, Granger CB, Kober L, Maggioni AP, Mann DL, McMurray JJV, Rouleau JL, Solomon SD, Steg PG, Berwanger O, Cikes M, De Pasquale CG, Fernandez A, Filippatos G, Jering K, Landmesser U, Menon V, Merkely B, Petrie MC, Petrov I, Schou M, Senni M, Sim D, van der Meer P, Lefkowitz M, Zhou Y, Wang Y, Braunwald E. Impact of Sacubitril/Valsartan Versus Ramipril on Total Heart Failure Events in the PARADISE-MI Trial. Circulation. 2022 Jan 4;145(1):87-89. doi: 10.1161/CIRCULATIONAHA.121.057429. Epub 2021 Nov 19. No abstract available.
• Pfeffer MA, Claggett B, Lewis EF, Granger CB, Kober L, Maggioni AP, Mann DL, McMurray JJV, Rouleau JL, Solomon SD, Steg PG, Berwanger O, Cikes M, De Pasquale CG, East C, Fernandez A, Jering K, Landmesser U, Mehran R, Merkely B, Vaghaiwalla Mody F, Petrie MC, Petrov I, Schou M, Senni M, Sim D, van der Meer P, Lefkowitz M, Zhou Y, Gong J, Braunwald E; PARADISE-MI Investigators and Committees. Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction. N Engl J Med. 2021 Nov 11;385(20):1845-1855. doi: 10.1056/NEJMoa2104508. Erratum In: N Engl J Med. 2021 Dec 30;385(27):2592.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 16, 2023): 5669
• Original Estimated Enrollment (submitted: October 4, 2016): 4650
• Actual Study Completion Date: February 26, 2021
• Actual Primary Completion Date: February 26, 2021 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Croatia, 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

Administrative Information

• NCT Number: NCT02924727
• Other Study ID Numbers: CLCZ696G2301; 2016-002154-20 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: June 2023