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出境医 / 临床实验 / LCZ696 in Advanced LV Hypertrophy and HFpEF

LCZ696 in Advanced LV Hypertrophy and HFpEF

Study Description
Brief Summary:
Patients with advanced LVH and HFpEF will be randomly assigned in open-label fashion to receive LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and will be treated for 24 weeks.

Condition or disease Intervention/treatment Phase
Heart Failure Essential Hypertension Drug: LCZ 696 Drug: Valsartan Phase 2

Detailed Description:
Heart failure with preserved ejection fraction (HFpEF) has a significant morbidity and mortality, and therapies that have proven effective in HF with reduced EF have not been shown to improve long-term prognosis in HFpEF. Inhibition of circulating neprilysin could augment deficient NP-receptor GC signaling and therefore be beneficial in HFpEF, as suggested by the decrease in NP following administration of valsartan/sacubitril in the phase 2 (PARAMOUNT study). Use of valsartan/sacubitril is currently being tested in the multicenter PARAGON-HF trial with HFpEF patients. The investigators suppose the best candidates for LCZ696 therapy will be patients with HFpEF and advanced concentric LV hypertrophy and obesity, i.e. having the lowest BNP bioavailability.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Sacubitril/Valsartan (LCZ696) in Patients With Advanced Hypertensive Left Ventricular Hypertrophy and Heart Failure With Preserved Ejection Fraction: Clinical, Haemodynamic and Neurohumoral Effects (a Phase 2, Randomized, Single-center, Parallel Group Study)
Actual Study Start Date : May 31, 2019
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : November 2020
Arms and Interventions
Arm Intervention/treatment
Experimental: LCZ 696
Initial dose - 50 mg twice daily, up-titration to 200 mg twice daily. Patients will also receive standard therapy for heart failure (β-blockers, diuretics, MRAs)
 Drug: LCZ 696
50-100-200 mg tablet
Active Comparator: Valsatran
Initial dose - 40 mg twice daily, up-titration to 160 mg twice daily. Patients also will receive standard therapy for heart failure (β-blockers, diuretics, MRAs)
 Drug: Valsartan
40-80-160 mg tablet
Outcome Measures
Primary Outcome Measures :
  1. Change in 6-minute walking distance (6MWD) [ Time Frame: 24 weeks ]
    Difference in distance walked during 6-minute walking test (6MWT) between 24 weeks after baseline and at baseline


Secondary Outcome Measures :
  1. Change in exercise time during diastolic stress-test (DST) [ Time Frame: 24 weeks ]
    Difference in exercise time during DST between 24 weeks after baseline and at baseline

  2. Change in left atrial volume index (LAVI) [ Time Frame: 24 weeks ]
    Difference in LAVI assessed by echocardiography between 24 weeks after baseline and at baseline

  3. Change in average E/e' ratio [ Time Frame: 24 weeks ]
    Difference in E/e' ratio assessed by echocardiography both at rest and at peak exercise during diastolic stress test (DST) between 24 weeks after baseline and at baseline

  4. Change estimated pulmonary artery systolic pressure (PASP) [ Time Frame: 24 weeks ]
    Difference in PASP assessed by echocardiography at peak exercise both at rest and at peak exercise during diastolic stress test (DST) between 24 weeks after baseline and at baseline

  5. Change in left ventricular mass index (LVMI) [ Time Frame: 24 weeks ]
    Difference in LVMI assessed by echocardiography between 24 weeks after baseline and at baseline

  6. Change of New York Heart Association (NYHA) functional classification [ Time Frame: 24 weeks ]
    Difference in NYHA class between 24 weeks after baseline and at baseline

  7. Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) score [ Time Frame: 24 weeks ]
    Difference in MLHFQ score between 24 weeks after baseline and at baseline. The questionnaire is comprised of 21 important physical, emotional and socioeconomic ways heart failure can adversely affect a patient's life. After receiving brief standardized instructions, the patient marks a 0 (zero) to 5 scale to indicate how much each itemized adverse of heart failure has prevented the patient from living as he or she wanted to live during the past 4 weeks. The questionnaire is simply scored by summation of all 21 responses. Score ranges from 0 (best quality of life) to 105 (worst quality of life).

  8. Change in N-terminal pro b-type natriuretic peptide (NT-proBNP) [ Time Frame: 24 weeks ]
    Difference in NT-proBNP plasma levels between 24 weeks after baseline and at baseline

  9. Change in high-sensitivity C-reactive protein (hsCRP) [ Time Frame: 24 weeks ]
    Difference in hsCRP plasma levels between 24 weeks after baseline and at baseline

  10. Change in carboxyterminal propeptide of type I collagen (PICP) [ Time Frame: 24 weeks ]
    DIfference in PICP plasma levels between 24 weeks after baseline and at baseline

  11. Change in carboxyterminal telopeptide of type I collagen (CITP) [ Time Frame: 24 weeks ]
    Difference in CITP plasma levels between 24 weeks after baseline and at baseline

  12. Change in N-Propeptide Of Type III Procollagen (PIIINP) [ Time Frame: 24 weeks ]
    Difference in PIIINP plasma levels between 24 weeks after baseline and at baseline

  13. Change in Growth/differentiation factor 15 (GDF-15) [ Time Frame: 24 weeks ]
    Difference in GDF-15 plasma levels between 24 weeks after baseline and at baseline

  14. Change in sST2 [ Time Frame: 24 weeks ]
    Difference in sST2 plasma levels between 24 weeks after baseline and at baseline

  15. Change in Galectin-3 [ Time Frame: 24 weeks ]
    Difference in Galectin-3 plasma levels between 24 weeks after baseline and at baseline

  16. Change in monocyte chemoattractant-1 (MCP-1) [ Time Frame: 24 weeks ]
    DIfference in MCP-1 plasma levels between 24 weeks after baseline and at baseline


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Moderate/severe hypertensive left ventricular (LV) hypertrophy (LVMi ≥109 g/m² in women and ≥132 g/m² in men);
  2. New York Heart Association (NYHA) class II-III heart failure;
  3. Left ventricular ejection fraction > 50%;
  4. Increased LV filling pressures assessed at rest or at peak exercise by echocardiography
  5. Body mass index (BMI) > 30 kg/m²
  6. Signed and data informed consent

Exclusion Criteria:

  1. Age ≤ 18 years;
  2. Evidence of myocardial ischemia during stress echocardiography;
  3. Chronic atrial flutter or atrial fibrillation;
  4. Alternative cause of left ventricular hypertrophy and impaired diastolic function (hypertrophic/restictive cardiomyopathy, aortic stenosis, constrictive pericarditis and etc.);
  5. NYHA classification I or decompensated heart failure at screening;
  6. Systolic blood pressure < 110 mmHg or > 180 mmHg;
  7. Diastolic blood pressure < 40 mmHg or > 100 mmHg;
  8. Anemia (Hb < 100 g/l);
  9. Significant left sided structural valve disease;
  10. Secondary hypertension;
  11. Dyspnea due to non-cardiac causes such as pulmonary disease, anemia, severe obesity, primary valvular, or myocardial diseases;
  12. Myocardial infarction or myocardial revascularization within the last 3 months of screening;
  13. Stroke or TIA within the last 3 months of screening;
  14. Autoimmunic and oncological diseases;
  15. Impaired renal function, defined as eGFR < 30 ml/min/1.73 m²;
  16. Impaired liver function;
  17. Potassium concentration >5.2 mmol/L.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Artem Ovchinnikov, MD, PhD +74954146612 artcardio@mail.ru

Locations
Layout table for location information
Russian Federation
National Medical Research Center for Cardiology Recruiting
Moscow, Russian Federation, 121552
Contact: Nursiyat Ibragimova, MD       nursik0205@gmail.com   
Principal Investigator: Nursiyat Ibragimova, MD         
Sponsors and Collaborators
National Medical Research Center for Cardiology, Ministry of Health of Russian Federation
Ministry of Health of Russian Federation
Tracking Information
First Submitted Date  ICMJE April 23, 2019
First Posted Date  ICMJE April 26, 2019
Last Update Posted Date December 23, 2019
Actual Study Start Date  ICMJE May 31, 2019
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 23, 2019) 		Change in 6-minute walking distance (6MWD) [ Time Frame: 24 weeks ]
Difference in distance walked during 6-minute walking test (6MWT) between 24 weeks after baseline and at baseline
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 25, 2019)
  • Change in exercise time during diastolic stress-test (DST) [ Time Frame: 24 weeks ]
    Difference in exercise time during DST between 24 weeks after baseline and at baseline
  • Change in left atrial volume index (LAVI) [ Time Frame: 24 weeks ]
    Difference in LAVI assessed by echocardiography between 24 weeks after baseline and at baseline
  • Change in average E/e' ratio [ Time Frame: 24 weeks ]
    Difference in E/e' ratio assessed by echocardiography both at rest and at peak exercise during diastolic stress test (DST) between 24 weeks after baseline and at baseline
  • Change estimated pulmonary artery systolic pressure (PASP) [ Time Frame: 24 weeks ]
    Difference in PASP assessed by echocardiography at peak exercise both at rest and at peak exercise during diastolic stress test (DST) between 24 weeks after baseline and at baseline
  • Change in left ventricular mass index (LVMI) [ Time Frame: 24 weeks ]
    Difference in LVMI assessed by echocardiography between 24 weeks after baseline and at baseline
  • Change of New York Heart Association (NYHA) functional classification [ Time Frame: 24 weeks ]
    Difference in NYHA class between 24 weeks after baseline and at baseline
  • Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) score [ Time Frame: 24 weeks ]
    Difference in MLHFQ score between 24 weeks after baseline and at baseline. The questionnaire is comprised of 21 important physical, emotional and socioeconomic ways heart failure can adversely affect a patient's life. After receiving brief standardized instructions, the patient marks a 0 (zero) to 5 scale to indicate how much each itemized adverse of heart failure has prevented the patient from living as he or she wanted to live during the past 4 weeks. The questionnaire is simply scored by summation of all 21 responses. Score ranges from 0 (best quality of life) to 105 (worst quality of life).
  • Change in N-terminal pro b-type natriuretic peptide (NT-proBNP) [ Time Frame: 24 weeks ]
    Difference in NT-proBNP plasma levels between 24 weeks after baseline and at baseline
  • Change in high-sensitivity C-reactive protein (hsCRP) [ Time Frame: 24 weeks ]
    Difference in hsCRP plasma levels between 24 weeks after baseline and at baseline
  • Change in carboxyterminal propeptide of type I collagen (PICP) [ Time Frame: 24 weeks ]
    DIfference in PICP plasma levels between 24 weeks after baseline and at baseline
  • Change in carboxyterminal telopeptide of type I collagen (CITP) [ Time Frame: 24 weeks ]
    Difference in CITP plasma levels between 24 weeks after baseline and at baseline
  • Change in N-Propeptide Of Type III Procollagen (PIIINP) [ Time Frame: 24 weeks ]
    Difference in PIIINP plasma levels between 24 weeks after baseline and at baseline
  • Change in Growth/differentiation factor 15 (GDF-15) [ Time Frame: 24 weeks ]
    Difference in GDF-15 plasma levels between 24 weeks after baseline and at baseline
  • Change in sST2 [ Time Frame: 24 weeks ]
    Difference in sST2 plasma levels between 24 weeks after baseline and at baseline
  • Change in Galectin-3 [ Time Frame: 24 weeks ]
    Difference in Galectin-3 plasma levels between 24 weeks after baseline and at baseline
  • Change in monocyte chemoattractant-1 (MCP-1) [ Time Frame: 24 weeks ]
    DIfference in MCP-1 plasma levels between 24 weeks after baseline and at baseline
Original Secondary Outcome Measures  ICMJE
 (submitted: April 23, 2019)
  • Change in exercise time during diastolic stress-test (DST) [ Time Frame: 24 weeks ]
    Difference in exercise time during DST between 24 weeks after baseline and at baseline
  • Change in left atrial volume index (LAVI) [ Time Frame: 24 weeks ]
    Difference in LAVI assessed by echocardiography between 24 weeks after baseline and at baseline
  • Change in average E/e' ratio [ Time Frame: 24 weeks ]
    Difference in E/e' ratio assessed by echocardiography both at rest and at peak exercise during diastolic stress test (DST) between 24 weeks after baseline and at baseline
  • Change estimated pulmonary artery systolic pressure (PASP) [ Time Frame: 24 weeks ]
    Difference in PASP assessed by echocardiography at peak exercise both at rest and at peak exercise during diastolic stress test (DST) between 24 weeks after baseline and at baseline
  • Change in left ventricular mass index (LVMI) [ Time Frame: 24 weeks ]
    Difference in LVMI assessed by echocardiography between 24 weeks after baseline and at baseline
  • Change of New York Heart Association (NYHA) functional classification [ Time Frame: 24 weeks ]
    Difference in NYHA class between 24 weeks after baseline and at baseline
  • Change in Minnesota Living With Heart Failure Questionnaire (MLHFQ) score [ Time Frame: 24 weeks ]
    Difference in MLHFQ score between 24 weeks after baseline and at baseline
  • Change in N-terminal pro b-type natriuretic peptide (NT-proBNP) [ Time Frame: 24 weeks ]
    Difference in NT-proBNP plasma levels between 24 weeks after baseline and at baseline
  • Change in high-sensitivity C-reactive protein (hsCRP) [ Time Frame: 24 weeks ]
    Difference in hsCRP plasma levels between 24 weeks after baseline and at baseline
  • Change in carboxyterminal propeptide of type I collagen (PICP) [ Time Frame: 24 weeks ]
    DIfference in PICP plasma levels between 24 weeks after baseline and at baseline
  • Change in carboxyterminal telopeptide of type I collagen (CITP) [ Time Frame: 24 weeks ]
    Difference in CITP plasma levels between 24 weeks after baseline and at baseline
  • Change in N-Propeptide Of Type III Procollagen (PIIINP) [ Time Frame: 24 weeks ]
    Difference in PIIINP plasma levels between 24 weeks after baseline and at baseline
  • Change in Growth/differentiation factor 15 (GDF-15) [ Time Frame: 24 weeks ]
    Difference in GDF-15 plasma levels between 24 weeks after baseline and at baseline
  • Change in sST2 [ Time Frame: 24 weeks ]
    Difference in sST2 plasma levels between 24 weeks after baseline and at baseline
  • Change in Galectin-3 [ Time Frame: 24 weeks ]
    Difference in Galectin-3 plasma levels between 24 weeks after baseline and at baseline
  • Change in monocyte chemoattractant-1 (MCP-1) [ Time Frame: 24 weeks ]
    DIfference in MCP-1 plasma levels between 24 weeks after baseline and at baseline
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE LCZ696 in Advanced LV Hypertrophy and HFpEF
Official Title  ICMJE Sacubitril/Valsartan (LCZ696) in Patients With Advanced Hypertensive Left Ventricular Hypertrophy and Heart Failure With Preserved Ejection Fraction: Clinical, Haemodynamic and Neurohumoral Effects (a Phase 2, Randomized, Single-center, Parallel Group Study)
Brief Summary Patients with advanced LVH and HFpEF will be randomly assigned in open-label fashion to receive LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and will be treated for 24 weeks.
Detailed Description Heart failure with preserved ejection fraction (HFpEF) has a significant morbidity and mortality, and therapies that have proven effective in HF with reduced EF have not been shown to improve long-term prognosis in HFpEF. Inhibition of circulating neprilysin could augment deficient NP-receptor GC signaling and therefore be beneficial in HFpEF, as suggested by the decrease in NP following administration of valsartan/sacubitril in the phase 2 (PARAMOUNT study). Use of valsartan/sacubitril is currently being tested in the multicenter PARAGON-HF trial with HFpEF patients. The investigators suppose the best candidates for LCZ696 therapy will be patients with HFpEF and advanced concentric LV hypertrophy and obesity, i.e. having the lowest BNP bioavailability.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Heart Failure
  • Essential Hypertension
Intervention  ICMJE
  • Drug: LCZ 696
    50-100-200 mg tablet
  • Drug: Valsartan
    40-80-160 mg tablet
Study Arms  ICMJE
  • Experimental: LCZ 696
    Initial dose - 50 mg twice daily, up-titration to 200 mg twice daily. Patients will also receive standard therapy for heart failure (β-blockers, diuretics, MRAs)
    Intervention: Drug: LCZ 696
  • Active Comparator: Valsatran
    Initial dose - 40 mg twice daily, up-titration to 160 mg twice daily. Patients also will receive standard therapy for heart failure (β-blockers, diuretics, MRAs)
    Intervention: Drug: Valsartan
Publications * Not Provided

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 23, 2019) 		60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2020
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Moderate/severe hypertensive left ventricular (LV) hypertrophy (LVMi ≥109 g/m² in women and ≥132 g/m² in men);
  2. New York Heart Association (NYHA) class II-III heart failure;
  3. Left ventricular ejection fraction > 50%;
  4. Increased LV filling pressures assessed at rest or at peak exercise by echocardiography
  5. Body mass index (BMI) > 30 kg/m²
  6. Signed and data informed consent

Exclusion Criteria:

  1. Age ≤ 18 years;
  2. Evidence of myocardial ischemia during stress echocardiography;
  3. Chronic atrial flutter or atrial fibrillation;
  4. Alternative cause of left ventricular hypertrophy and impaired diastolic function (hypertrophic/restictive cardiomyopathy, aortic stenosis, constrictive pericarditis and etc.);
  5. NYHA classification I or decompensated heart failure at screening;
  6. Systolic blood pressure < 110 mmHg or > 180 mmHg;
  7. Diastolic blood pressure < 40 mmHg or > 100 mmHg;
  8. Anemia (Hb < 100 g/l);
  9. Significant left sided structural valve disease;
  10. Secondary hypertension;
  11. Dyspnea due to non-cardiac causes such as pulmonary disease, anemia, severe obesity, primary valvular, or myocardial diseases;
  12. Myocardial infarction or myocardial revascularization within the last 3 months of screening;
  13. Stroke or TIA within the last 3 months of screening;
  14. Autoimmunic and oncological diseases;
  15. Impaired renal function, defined as eGFR < 30 ml/min/1.73 m²;
  16. Impaired liver function;
  17. Potassium concentration >5.2 mmol/L.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Artem Ovchinnikov, MD, PhD +74954146612 artcardio@mail.ru
Listed Location Countries  ICMJE Russian Federation
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03928158
Other Study ID Numbers  ICMJE AAAA-A18-118022290061-2
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Nursiyat Ibragimova, National Medical Research Center for Cardiology, Ministry of Health of Russian Federation
Study Sponsor  ICMJE National Medical Research Center for Cardiology, Ministry of Health of Russian Federation
Collaborators  ICMJE Ministry of Health of Russian Federation
Investigators  ICMJE Not Provided
PRS Account National Medical Research Center for Cardiology, Ministry of Health of Russian Federation
Verification Date December 2019

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

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