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This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure (PARADIGM-HF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01035255
Recruitment Status : Terminated (Early termination was approved due to compelling efficacy of LCZ696 in patients with HF & reduced EF after final pre-specified interim analysis 28-Mar-2014.)
First Posted : December 18, 2009
Results First Posted : September 7, 2015
Last Update Posted : August 15, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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Brief Summary:
The study will evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic heart failure (NYHA Class II - IV and EF =< 35%).

Condition or disease Intervention/treatment Phase
Heart Failure With Reduced Ejection Fraction Drug: LCZ696 200 mg BID Drug: Enalapril 10 mg BID Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8442 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double-blind, Parallel Group, Active-controlled Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality in Patients With Chronic Heart Failure and Reduced Ejection Fraction
Study Start Date : December 2009
Actual Primary Completion Date : May 2014
Actual Study Completion Date : May 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arms and Interventions
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Arm Intervention/treatment
Experimental: LCZ696
single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. LCZ696 200mg BID during double blind treatment period
 Drug: LCZ696 200 mg BID
LCZ696 200 mg BID
Active Comparator: Enalapril
single-blind active run-in period consisted of treatment with enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a total duration of 5 to 10 weeks. Temporary down-titration from LCZ696 200 mg bid to LCZ696 100 mg bid was allowed provided the patient was up-titrated back to LCZ696 200 mg bid and tolerated this dose for at least two weeks before being eligible for randomization. Enalapril 10 mg BID during double blind treatment period
 Drug: Enalapril 10 mg BID
Enalapril 10 mg BID


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants That Had First Occurrence of the Composite Endpoint, Which is Defined as Either Cardiovascular (CV) Death or Heart Failure (HF) Hospitalization [ Time Frame: up to 51 months ]
    Number of participants that had first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization due to HF.


Secondary Outcome Measures :
  1. Number of Patients - All-cause Mortality [ Time Frame: up to 51 months ]
    Number of patients - All-cause mortality. All-cause mortality is common in Heart Failure HF patients this measures how many patients had this event. The data is on FAS population up to March 31, 2014

  2. Number of Patients Reported With Adjudicated Primary Causes of Death [ Time Frame: up to 51 months ]
    Number of patients reported with adjudicated primary causes of death. The data is on Randomization population up to March 31, 2014

  3. Change From Baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score [ Time Frame: Baseline, Month 8 ]
    Change from baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. KCCQ clinical summary score is a composite assessment of physical limitations and total symptom scores. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.

  4. Number of Patients With First Confirmed Renal Dysfunction [ Time Frame: up to 51 months ]
    Number of patients with first confirmed renal dysfunction

  5. Percentage of Participants With New Onset of Atrial Fibrillation (AF) [ Time Frame: up to 51 months ]
    Percentage of participants with New Onset of Atrial Fibrillation The new onset atrial fibrillation (AF) analysis was based on a subset of FAS: i.e., for patients without a history of AF at baseline (patients with a history of AF were excluded from this analysis).


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:

  • Patients must give written informed consent before any assessment is performed.
  • Outpatients ≥ 18 years of age, male or female.
  • Patients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction (EF =< 35%) and elevated BNP.
  • Patients must be on an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks.
  • Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks.

Exclusion Criteria:

  • Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
  • History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs.
  • Previous history of intolerance to recommended target doses of ACEIs or ARBs
  • Known history of angioedema.
  • Requirement of treatment with both ACEIs and ARBs.
  • Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy).
  • Symptomatic hypotension and/or a SBP < 100 mmHg.
  • Estimated GFR < 30 mL/min/1.73m2 as measured by the simplified MDRD formula
  • Serum potassium > 5.2 mmol/L.

Other protocol-defined inclusion/exclusion criteria may apply.

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): NCT01035255


Locations
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Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Packer M, McMurray JJ, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile M, Andersen K, Arango JL, Arnold JM, Belohlavek J, Bohm M, Boytsov S, Burgess LJ, Cabrera W, Calvo C, Chen CH, Dukat A, Duarte YC, Erglis A, Fu M, Gomez E, Gonzalez-Medina A, Hagege AA, Huang J, Katova T, Kiatchoosakun S, Kim KS, Kozan O, Llamas EB, Martinez F, Merkely B, Mendoza I, Mosterd A, Negrusz-Kawecka M, Peuhkurinen K, Ramires FJ, Refsgaard J, Rosenthal A, Senni M, Sibulo AS Jr, Silva-Cardoso J, Squire IB, Starling RC, Teerlink JR, Vanhaecke J, Vinereanu D, Wong RC; PARADIGM-HF Investigators and Coordinators. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015 Jan 6;131(1):54-61. doi: 10.1161/CIRCULATIONAHA.114.013748. Epub 2014 Nov 17.

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01035255    
Other Study ID Numbers: CLCZ696B2314
2009-015834-31
First Posted: December 18, 2009    Key Record Dates
Results First Posted: September 7, 2015
Last Update Posted: August 15, 2016
Last Verified: July 2016
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
chronic heart failure
cardiovascular death
hospitalization
outcome study
 BNP
KCCQ
eGFR
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Enalapril
Sacubitril and valsartan sodium hydrate drug combination
Angiotensin-Converting Enzyme Inhibitors
 Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Angiotensin Receptor Antagonists