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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)

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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 )

Tracking Information
First Submitted Date  ICMJE December 16, 2009
First Posted Date  ICMJE December 18, 2009
Results First Submitted Date  ICMJE August 6, 2015
Results First Posted Date  ICMJE September 7, 2015
Last Update Posted Date August 15, 2016
Study Start Date  ICMJE December 2009
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 9, 2015)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 17, 2009)
Time to first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization [ Time Frame: up to 4yrs ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 9, 2015)
  • 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: December 17, 2009)
  • Change in the clinical summary score for HF symptoms and physical limitations (as assessed by KCCQ). [ Time Frame: up to 4yrs ]
  • Time to all-cause mortality [ Time Frame: up to 4yrs ]
  • Time to occurrence of renal dysfunction [ Time Frame: up to 4yrs ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure
Official Title  ICMJE 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
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%).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Heart Failure With Reduced Ejection Fraction
Intervention  ICMJE
  • Drug: LCZ696 200 mg BID
    LCZ696 200 mg BID
  • Drug: Enalapril 10 mg BID
    Enalapril 10 mg BID
Study Arms  ICMJE
  • 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
    Intervention: Drug: 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
    Intervention: Drug: Enalapril 10 mg BID
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 9, 2015)
8442
Original Estimated Enrollment  ICMJE
 (submitted: December 17, 2009)
7980
Actual Study Completion Date  ICMJE May 2014
Actual Primary Completion Date May 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Belgium,   Brazil,   Bulgaria,   Canada,   Chile,   China,   Colombia,   Czech Republic,   Denmark,   Dominican Republic,   Ecuador,   Estonia,   Finland,   France,   Germany,   Guatemala,   Hong Kong,   Hungary,   Iceland,   India,   Israel,   Italy,   Korea, Republic of,   Latvia,   Lithuania,   Malaysia,   Mexico,   Netherlands,   Panama,   Peru,   Philippines,   Poland,   Portugal,   Romania,   Russian Federation,   Singapore,   Slovakia,   South Africa,   Spain,   Sweden,   Taiwan,   Thailand,   Turkey,   United Kingdom,   United States,   Venezuela
Removed Location Countries Australia,   New Zealand,   Serbia,   Ukraine
 
Administrative Information
NCT Number  ICMJE NCT01035255
Other Study ID Numbers  ICMJE CLCZ696B2314
2009-015834-31
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date July 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP