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LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction

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ClinicalTrials.gov Identifier: NCT00887588
Recruitment Status : Completed
First Posted : April 24, 2009
Results First Posted : August 13, 2015
Last Update Posted : August 25, 2015
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE April 22, 2009
First Posted Date  ICMJE April 24, 2009
Results First Submitted Date  ICMJE July 16, 2015
Results First Posted Date  ICMJE August 13, 2015
Last Update Posted Date August 25, 2015
Study Start Date  ICMJE November 2009
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 12, 2015)
Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) [ Time Frame: Baseline, 12 weeks ]
Evaluation of NT-proBNP was performed by a central laboratory. Change from baseline in NT-proBNP was presented as a ratio where the ratio was calculated as the NT-proBNP value at 12 weeks over the NT-proBNP value at baseline. A ratio < 1 indicates improvement.
Original Primary Outcome Measures  ICMJE
 (submitted: April 23, 2009)
Change in log-scale in NT-proBNP [ Time Frame: 12 weeks ]
Change History Complete list of historical versions of study NCT00887588 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 12, 2015)
  • Change From Baseline in NT-proBNP and Brain Natriuretic Peptide (BNP) [ Time Frame: baseline, 36 weeks ]
    Evaluation of NT-proBNP and BNP was performed by a central laboratory. Change from baseline in NT-proBNP and in BNP was presented as a ratio where the ratio for NT-proBNP was calculated as the NT-proBNP value at 36 weeks over the NT-proBNP value at baseline, and the ratio for BNP was calculated as the BNP value at 36 weeks over the BNP value at baseline. A ratio < 1 indicates improvement.
  • Change From Baseline in Plasma Cyclic Guanine Monophosphate (cGMP) [ Time Frame: baseline, 36 weeks ]
    Evaluation of cGMP was performed by a central laboratory. Change from baseline in cGMP was presented as a ratio where the ratio was calculated as the cGMP value at 36 weeks over the cGMP value at baseline. A ratio < 1 indicates improvement.
  • Change From Baseline in Echocardiography (ECHO) Parameters: Left Ventricular End (LVE) Diastolic Diameter, LVE Systolic Diameter, Septal End Diastolic Thickness, Posterior LV Wall End Diastolic Thickness, Relative Wall Thickness, Left Atrial Dimension [ Time Frame: Baseline, 36 weeks ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.
  • Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume [ Time Frame: Baseline, 36 weeks ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.
  • Change From Baseline in Echocardiography Parameters: Left Ventricular Ejection Fraction [ Time Frame: Baseline, 36 weeks ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.
  • Change From Baseline in Echocardiography Parameters: Left Ventricular Mass [ Time Frame: Baseline, 36 weeks ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.
  • Change From Baseline in Echocardiography Parameters: Left Ventricular Mass Index [ Time Frame: Baseline, 36 weeks ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.
  • Change From Baseline in Echocardiography Parameters: Left Atrial Volume Index [ Time Frame: Baseline, 36 weeks ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.
  • Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus [ Time Frame: Baseline, 36 weeks ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.
  • Change From Baseline in Echocardiography Parameters: Ratio of E to A Velocity, E/e' Ratio [ Time Frame: Baseline, 36 weeks ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A ratio < 1 indicates improvement.
  • Change in Echocardiography Parameters: Isovolumic Relaxation Time [ Time Frame: Baseline, 36 weeks ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.
  • Change From Baseline in Echocardiography Parameters: Tricuspid Regurgitation Velocity [ Time Frame: Baseline, 36 weeks ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.
  • Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores [ Time Frame: baseline, 36 weeks ]
    The KCCQ is a self-administered questionnaire. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and quality of life, each with different Likert scale wording, including limitations, frequency, bother, change in condition, understanding, levels of enjoyment and satisfaction. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. A positive change from baseline indicates improvement.
  • Percentage of Participants With Clinical Composite Assessment of Improved, Unchanged or Worsened [ Time Frame: 36 weeks ]
    The clinical composite assessment is defined as follows: Improved = a) participant improved (markedly or moderately) in the global assessment of disease activity with no worsening of NYHA functional class and no major adverse cardiovascular event or b) participant improved in NYHA functional class with no worsening (markedly or moderately) in the global assessment of disease activity and no major adverse cardiovascular event. Worsened = participant worsened (markedly or moderately) in the global assessment of disease activity or in NYHA functional class or experienced a major adverse cardiovascular event. Unchanged = participant does not meet the definition for improved or worsened.
  • Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV [ Time Frame: baseline, 36 weeks ]
    The NYHA Functional Classification classifies patients' heart failure according to the severity of their symptoms. The classification is as follows: Class I: no limitation of physical activity, ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath); Class II: slight limitation to physical activity, comfortable at rest, ordinary physical activity results in fatigue, palpitation or dyspnea; Class III: marked limitation of physical activity, comfortable at rest, less than ordinary activity causes fatigue, palpitation or dyspnea; Class IV: unable to carry on any physical activity without discomfort, symptoms of heart failure at rest, if any physical activity is undertaken, discomfort increases.
  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: baseline, 36 weeks ]
    eGFR was calculated from the serum creatinine concentration determined by central laboratory assessment. A positive change from baseline indicates improvement.
  • Change From Baseline in Serum Creatinine [ Time Frame: baseline, 36 weeks ]
    Evaluation of serum creatinine was performed by central laboratory. A negative change from baseline indicates improvement.
  • Change From Baseline in Albumin/Creatinine Ratio [ Time Frame: baseline, 36 weeks ]
    Evaluation of albumin/creatinine was performed by central laboratory. A ratio < 1 indicates improvement.
  • Change From Baseline in Arterial Stiffness Parameters: Brachial Systolic Blood Pressure (SBP), Brachial Diastolic Blood Pressure (DBP), Central Augmentation Pressure, Central Pressure at T1-DP, Central SBP, Central DBP, Central Mean Pressure [ Time Frame: baseline, 36 weeks ]
    A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement.
  • Change From Baseline in Arterial Stiffness Parameters: Heart Rate Correct Cen Aug/Pulse Ht [ Time Frame: baseline, 36 weeks ]
    A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement.
  • Change From Baseline in Arterial Stiffness Parameters: Heart Rate [ Time Frame: baseline, 36 weeks ]
    A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement.
  • Change From Baseline in Arterial Stiffness Parameters: Pulse Wave Velocity [ Time Frame: baseline, 36 weeks ]
    A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement.
  • Change From Baseline in Sitting SBP, Sitting DBP and Sitting Pulse Pressure (PP) [ Time Frame: baseline, 36 weeks ]
    Sitting blood pressure and sitting pulse pressure were assessed. A negative change from baseline indicates improvement.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2009)
  • Change in log-scale in BNP, MR-proBNP, cGMP [ Time Frame: 12 weeks ]
  • Change in echocardiography parameters [ Time Frame: 12 weeks ]
  • class indicators of signs and symptoms of heart failure at each visit [ Time Frame: 12 weeks ]
  • Change in the overall summary score and individual domain score of the Kansas City Cardiomyopathy questionnaire [ Time Frame: 12 weeks ]
  • Change in clinical composite score (NYHA and global patient assessment score) time frame [ Time Frame: 12 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction
Official Title  ICMJE A 36-week, Randomized, Double-blind, Multi-center, Parallel Group, Active Controlled Study to Evaluate the Efficacy, Safety and Tolerability of LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction
Brief Summary The study will assess the effects of 36 weeks of treatment with LCZ696 compared to valsartan on N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) in patients with chronic heart failure and preserved left-ventricular ejection fraction.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Chronic Heart Failure
Intervention  ICMJE
  • Drug: LCZ696
    50 mg, 100 mg and 200 mg tablets
  • Drug: Valsartan
    40 mg, 80 mg and 160 mg tablets
  • Drug: Placebo
    matching placebo to LCZ696 and Valsartan
Study Arms  ICMJE
  • Experimental: LCZ696
    During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.
    Interventions:
    • Drug: LCZ696
    • Drug: Placebo
  • Active Comparator: Valsartan
    During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
    Interventions:
    • Drug: Valsartan
    • Drug: Placebo
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 Completed
Actual Enrollment  ICMJE
 (submitted: June 25, 2014)
307
Original Estimated Enrollment  ICMJE
 (submitted: April 23, 2009)
290
Actual Study Completion Date  ICMJE December 2011
Actual Primary Completion Date December 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with documented stable chronic heart failure (NYHA II-IV):

    • LVEF ≥ 45% (local measurement, assessed by echocardiography, MUGA, CT scan, MRI or ventricular angiography)
    • the ejection fraction must have been obtained within 6 months prior to randomization or after any MI or other event that would affect ejection fraction.
  • Plasma NT-proBNP > 500 pg/ml at Visit 1.
  • Patients with documented stable chronic heart failure (NYHA II-IV).
  • Patients receiving ACE inhibitors (ACEi), an angiotensin receptor blockers (ARB) and/or a beta blockers must be on a stable dose of these medications stable for the 1 month period prior to Visit 1.
  • Patients must be on diuretic therapy prior to Visit 1 (flexible dosing is permitted).
  • Patients with a controlled systolic BP, defined as a target systolic BP less than 140 mm Hg; participants with BP up to and including 160 mm Hg are eligible for enrollment if they are on three or more medications to control BP at randomization (Visit 2).
  • Patients with at least one of the following symptoms at the time of screening (Visit 1):

    • Dyspnea on exertion
    • Orthopnea
    • Paroxysmal nocturnal dyspnea
    • Peripheral edema
  • Patients must have an eGFR ≥ 30 ml/min/1.73 m2 at Visit 1 (calculated by the Modification of Diet in Renal Disease formula).
  • Patients with a potassium ≤5.2 mmol/l at Visit 1.

Exclusion Criteria:

  • Patients with a prior LVEF reading <45%, at any time.
  • Patients who require treatment with both an ACE inhibitor and an ARB.
  • Isolated right heart failure due to pulmonary disease.
  • Dyspnea and/or edema from non-cardiac causes, such as lung disease, anemia, or severe obesity.
  • Presence of hemodynamically significant mitral and /or aortic valve disease.
  • Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic stenosis.
  • Presence of hypertrophic obstructive cardiomyopathy.
  • Other protocol-defined inclusion/exclusion criteria may apply
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 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,   Brazil,   Canada,   Germany,   India,   Italy,   Netherlands,   Poland,   Romania,   Russian Federation,   Singapore,   Spain,   United States,   Venezuela
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00887588
Other Study ID Numbers  ICMJE CLCZ696B2214
2009-010208-27
Has Data Monitoring Committee Yes
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
Study Director: Novartis Novartis
PRS Account Novartis
Verification Date August 2015

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