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

Acute Myocardial Infarction Clinical Trial

— PARADISE-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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02924727
• Other study ID #: CLCZ696G2301
• Secondary ID: 2016-002154-20
• Status: Completed
• Phase: Phase 3
• Start date: December 9, 2016
• Est. completion date: February 26, 2021

Study information

• Verified date: June 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5669
• Est. completion date: February 26, 2021
• Est. primary completion date: February 26, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myocardial Infarction
• Infarction
• 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
• Ramipril
Ramipril 1.25 mg, 2.5 mg, and 5 mg oral capsules
• Placebo of LCZ696
Matching placebo of LCZ696 tablets
• Placebo of ramipril
Matching placebo of ramipril capsule
• 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
• Placebo of valsartan
matching placebo of valsartan for one day to patients who will be randomized to received ramipril

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires	Caba
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad de Salta	Provincia De Salta
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Corrientes
Argentina	Novartis Investigative Site	Formosa
Argentina	Novartis Investigative Site	La Plata	Buenos Aires
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	San Luis
Argentina	Novartis Investigative Site	San Miguel de Tucuman	Tucuman
Argentina	Novartis Investigative Site	Santa Fe
Argentina	Novartis Investigative Site	Tucuman	San Miguel De Tucuman
Australia	Novartis Investigative Site	Bedford Park	South Australia
Australia	Novartis Investigative Site	Chemside	Queensland
Australia	Novartis Investigative Site	Geelong	Victoria
Australia	Novartis Investigative Site	Herston	Queensland
Australia	Novartis Investigative Site	Hobart	Tasmania
Australia	Novartis Investigative Site	Murdoch	Western Australia
Austria	Novartis Investigative Site	Braunau
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Belgium	Novartis Investigative Site	Aalst
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Bulgaria	Novartis Investigative Site	Sofia
Bulgaria	Novartis Investigative Site	Sofia
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Bulgaria	Novartis Investigative Site	Varna
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Greece	Novartis Investigative Site	Athens
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Hungary	Novartis Investigative Site	Budapest
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Italy	Novartis Investigative Site	Cona	FE
Italy	Novartis Investigative Site	Grosseto	GR
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Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
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Italy	Novartis Investigative Site	Rimini	RN
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Sanremo	IM
Italy	Novartis Investigative Site	Trieste	TS
Korea, Republic of	Novartis Investigative Site	Cheongju si	Chungcheongbuk Do
Korea, Republic of	Novartis Investigative Site	Gwangju
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Wonju	Gangwon-do
Mexico	Novartis Investigative Site	Ciudad de Mexico
Mexico	Novartis Investigative Site	Culiacan Sinaloa	Distrito Federal
Mexico	Novartis Investigative Site	Guadalajara	Jalisco
Mexico	Novartis Investigative Site	Guadalajara	Jalisco
Mexico	Novartis Investigative Site	Queretaro
Mexico	Novartis Investigative Site	San Luis Potosi
Mexico	Novartis Investigative Site	Torreon	Coahulia
Netherlands	Novartis Investigative Site	Alkmaar
Netherlands	Novartis Investigative Site	Almelo
Netherlands	Novartis Investigative Site	Amersfoort
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Beverwijk
Netherlands	Novartis Investigative Site	Breda
Netherlands	Novartis Investigative Site	Ede
Netherlands	Novartis Investigative Site	Gouda
Netherlands	Novartis Investigative Site	Groningen
Netherlands	Novartis Investigative Site	Heemstede
Netherlands	Novartis Investigative Site	Leeuwarden
Netherlands	Novartis Investigative Site	Leiderdorp
Netherlands	Novartis Investigative Site	Rotterdam
Netherlands	Novartis Investigative Site	Rotterdam
Netherlands	Novartis Investigative Site	Rotterdam
Netherlands	Novartis Investigative Site	Sneek	The Netherlands
Netherlands	Novartis Investigative Site	Tilburg
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Netherlands	Novartis Investigative Site	Veldhoven
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Netherlands	Novartis Investigative Site	Zwolle
Norway	Novartis Investigative Site	Gralum
Norway	Novartis Investigative Site	Oslo
Norway	Novartis Investigative Site	Stavanger
Peru	Novartis Investigative Site	Bellavista	Lima
Peru	Novartis Investigative Site	Cercado De Lima	Lima
Peru	Novartis Investigative Site	Jesus Maria	Lima
Peru	Novartis Investigative Site	Lima
Philippines	Novartis Investigative Site	Iloilo city	Iloilo
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Philippines	Novartis Investigative Site	Quezon City	Manila
Poland	Novartis Investigative Site	Bialystok
Poland	Novartis Investigative Site	Lubin
Poland	Novartis Investigative Site	Lublin
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa
Portugal	Novartis Investigative Site	Almada
Portugal	Novartis Investigative Site	Braga
Portugal	Novartis Investigative Site	Carnaxide	Lisboa
Portugal	Novartis Investigative Site	Coimbra
Portugal	Novartis Investigative Site	Covilha
Portugal	Novartis Investigative Site	Faro
Portugal	Novartis Investigative Site	Guimaraes
Portugal	Novartis Investigative Site	Leiria
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Portugal	Novartis Investigative Site	Vila Real
Romania	Novartis Investigative Site	Baia Mare
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Romania	Novartis Investigative Site	Bucharest
Romania	Novartis Investigative Site	Bucharest
Romania	Novartis Investigative Site	Bucharest
Romania	Novartis Investigative Site	Bucuresti
Romania	Novartis Investigative Site	Bucuresti
Romania	Novartis Investigative Site	Bucuresti	District 4
Romania	Novartis Investigative Site	Cluj Napoca	Jud Cluj
Romania	Novartis Investigative Site	Craiova
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Romania	Novartis Investigative Site	Sibiu
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Romania	Novartis Investigative Site	Targu Mures	Mures
Romania	Novartis Investigative Site	Timisoara	Timis
Romania	Novartis Investigative Site	Timisoara
Romania	Novartis Investigative Site	Timisoara
Russian Federation	Novartis Investigative Site	Barnaul
Russian Federation	Novartis Investigative Site	Kemerovo
Russian Federation	Novartis Investigative Site	Krasnodar
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Murmansk
Russian Federation	Novartis Investigative Site	N.Novgorod
Russian Federation	Novartis Investigative Site	Nizhnii Novgorod
Russian Federation	Novartis Investigative Site	Rostov on Don
Russian Federation	Novartis Investigative Site	S.-Petersburg
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	Saint-Petersburg
Russian Federation	Novartis Investigative Site	Saratov
Russian Federation	Novartis Investigative Site	Sestroretsk
Russian Federation	Novartis Investigative Site	Sochy
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	Tomsk
Russian Federation	Novartis Investigative Site	Yekaterinburg
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Slovakia	Novartis Investigative Site	Banska Bystrica	SVK
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Bratislava	Slovak Republic
Slovakia	Novartis Investigative Site	Kosice
Slovakia	Novartis Investigative Site	Nitra	Slovak Republic
Slovakia	Novartis Investigative Site	Presov
South Africa	Novartis Investigative Site	Cape Town	Western Cape
South Africa	Novartis Investigative Site	Cape Town
South Africa	Novartis Investigative Site	George	Western Cape
South Africa	Novartis Investigative Site	Pinelands	Cape Town
South Africa	Novartis Investigative Site	Worcester
Spain	Novartis Investigative Site	A Coruna	Galicia
Spain	Novartis Investigative Site	Badalona	Catalunya
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Caceres	Extremadura
Spain	Novartis Investigative Site	El Palmar	Murcia
Spain	Novartis Investigative Site	La Coruna	Galicia
Spain	Novartis Investigative Site	Leon	Castilla Y Leon
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Villamartin	Cadiz
Sweden	Novartis Investigative Site	Goethenburg
Sweden	Novartis Investigative Site	Helsingborg
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Sweden	Novartis Investigative Site	Malmo
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Sweden	Novartis Investigative Site	Stockholm	SE
Sweden	Novartis Investigative Site	Uppsala
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Switzerland	Novartis Investigative Site	Bern
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Taiwan	Novartis Investigative Site	New Taipei
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Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
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Thailand	Novartis Investigative Site	Bangkok
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Turkey	Novartis Investigative Site	Ankara-Cankaya
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United Kingdom	Novartis Investigative Site	Basingstoke	Hampshire
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United Kingdom	Novartis Investigative Site	Norwich
United Kingdom	Novartis Investigative Site	Worcester
United States	Novartis Investigative Site	Alexandria	Louisiana
United States	Novartis Investigative Site	Bakersfield	California
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Bangor	Maine
United States	Novartis Investigative Site	Baton Rouge	Louisiana
United States	Novartis Investigative Site	Bellevue	Washington
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Novartis Investigative Site	Boise	Idaho
United States	Novartis Investigative Site	Brandon	Florida
United States	Novartis Investigative Site	Canton	Ohio
United States	Novartis Investigative Site	Carmichael	California
United States	Novartis Investigative Site	Chapel Hill	North Carolina
United States	Novartis Investigative Site	Charleston	South Carolina
United States	Novartis Investigative Site	Charlotte	North Carolina
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Coeur d'Alene	Idaho
United States	Novartis Investigative Site	Columbia	South Carolina
United States	Novartis Investigative Site	Covington	Louisiana
United States	Novartis Investigative Site	Cumming	Georgia
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Danville	Virginia
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Duluth	Minnesota
United States	Novartis Investigative Site	Durham	North Carolina
United States	Novartis Investigative Site	Erie	Pennsylvania
United States	Novartis Investigative Site	Falls Church	Virginia
United States	Novartis Investigative Site	Flushing	New York
United States	Novartis Investigative Site	Gilbert	Arizona
United States	Novartis Investigative Site	Grand Forks	North Dakota
United States	Novartis Investigative Site	Greenville	South Carolina
United States	Novartis Investigative Site	Hackensack	New Jersey
United States	Novartis Investigative Site	Hammond	Louisiana
United States	Novartis Investigative Site	Hattiesburg	Mississippi
United States	Novartis Investigative Site	Hershey	Pennsylvania
United States	Novartis Investigative Site	Hollywood	Florida
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Huntsville	Alabama
United States	Novartis Investigative Site	Iowa City	Iowa
United States	Novartis Investigative Site	Jackson	Mississippi
United States	Novartis Investigative Site	Jacksonville Beach	Florida
United States	Novartis Investigative Site	Johns Creek	Georgia
United States	Novartis Investigative Site	Kalamazoo	Michigan
United States	Novartis Investigative Site	Knoxville	Tennessee
United States	Novartis Investigative Site	Lansing	Michigan
United States	Novartis Investigative Site	Lebanon	New Hampshire
United States	Novartis Investigative Site	Lee's Summit	Missouri
United States	Novartis Investigative Site	Lincoln	Nebraska
United States	Novartis Investigative Site	Lincoln	Nebraska
United States	Novartis Investigative Site	Los Alamitos	California
United States	Novartis Investigative Site	Lynchburg	Virginia
United States	Novartis Investigative Site	Manassas	Virginia
United States	Novartis Investigative Site	Medford	Oregon
United States	Novartis Investigative Site	Muncie	Indiana
United States	Novartis Investigative Site	Munster	Indiana
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	North Kansas City	Missouri
United States	Novartis Investigative Site	Northridge	California
United States	Novartis Investigative Site	Ocala	Florida
United States	Novartis Investigative Site	Omaha	Nebraska
United States	Novartis Investigative Site	Orange	California
United States	Novartis Investigative Site	Petoskey	Michigan
United States	Novartis Investigative Site	Rapid City	South Dakota
United States	Novartis Investigative Site	Richmond	Indiana
United States	Novartis Investigative Site	Robbinsdale	Minnesota
United States	Novartis Investigative Site	Rockville	Maryland
United States	Novartis Investigative Site	Saginaw	Michigan
United States	Novartis Investigative Site	Saint Cloud	Minnesota
United States	Novartis Investigative Site	Saint Paul	Minnesota
United States	Novartis Investigative Site	San Francisco	California
United States	Novartis Investigative Site	Slidell	Louisiana
United States	Novartis Investigative Site	Southfield	Michigan
United States	Novartis Investigative Site	Springfield	Missouri
United States	Novartis Investigative Site	Sylmar	California
United States	Novartis Investigative Site	Thomasville	Georgia
United States	Novartis Investigative Site	Valhalla	New York
United States	Novartis Investigative Site	Webster	Texas
United States	Novartis Investigative Site	York	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  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, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)