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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
Results First Received: August 6, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Heart Failure With Reduced Ejection Fraction
Interventions: Drug: LCZ696 200 mg BID
Drug: Enalapril 10 mg BID

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups
  Description
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
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

Participant Flow:   Overall Study
    LCZ696   Enalapril
STARTED   4209   4233 
GCP Violations   18   19 
Mis-randomized   4   2 
Full Analysis Set (FAS)   4187 [1]   4212 [1] 
COMPLETED   3468   3371 
NOT COMPLETED   741   862 
Death                724                844 
Lost to Follow-up                2                5 
patient's request                15                13 
[1] patents with GCP violation and mis-randomized are not included in FAS



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups
  Description
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
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
Total Total of all reporting groups

Baseline Measures
   LCZ696   Enalapril   Total 
Overall Participants Analyzed 
[Units: Participants]
 4209   4233   8442 
Age 
[Units: Years]
Mean (Standard Deviation)
 63.78  (11.520)   63.82  (11.25)   63.80  (11.385) 
Gender 
[Units: Participants]
     
Female   888   959   1847 
Male   3321   3274   6595 


  Outcome Measures
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1.  Primary:   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 ]

2.  Secondary:   Number of Patients - All-cause Mortality   [ Time Frame: up to 51 months ]

3.  Secondary:   Number of Patients Reported With Adjudicated Primary Causes of Death   [ Time Frame: up to 51 months ]

4.  Secondary:   Change From Baseline to Month 8 for the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score   [ Time Frame: Baseline, Month 8 ]

5.  Secondary:   Number of Patients With First Confirmed Renal Dysfunction   [ Time Frame: up to 51 months ]

6.  Secondary:   Percentage of Participants With New Onset of Atrial Fibrillation (AF)   [ Time Frame: up to 51 months ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
phone: 862-778-8300


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.


Responsible Party: Novartis ( 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