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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)

This study has been 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.)
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01035255
First received: December 16, 2009
Last updated: July 13, 2016
Last verified: July 2016
  Purpose
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 Intervention Phase
Heart Failure With Reduced Ejection Fraction Drug: LCZ696 200 mg BID Drug: Enalapril 10 mg BID Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (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

Resource links provided by NLM:


Further study details as provided by Novartis ( Novartis Pharmaceuticals ):

Primary Outcome Measures:
  • 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:
  • 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

  • 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

  • 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.

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

  • 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).


Enrollment: 8442
Study Start Date: December 2009
Study Completion Date: May 2014
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01035255

  Show 1030 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

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, Bělohlávek J, Böhm M, Boytsov S, Burgess LJ, Cabrera W, Calvo C, Chen CH, Dukat A, Duarte YC, Erglis A, Fu M, Gomez E, Gonzàlez-Medina A, Hagège AA, Huang J, Katova T, Kiatchoosakun S, Kim KS, Kozan Ö, 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.

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01035255     History of Changes
Other Study ID Numbers: CLCZ696B2314
2009-015834-31
Study First Received: December 16, 2009
Results First Received: August 6, 2015
Last Updated: July 13, 2016

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
chronic heart failure
cardiovascular death
hospitalization
outcome study
BNP
KCCQ
eGFR

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Enalapril
Enalaprilat
LCZ 696
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Angiotensin Receptor Antagonists

ClinicalTrials.gov processed this record on July 21, 2017