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出境医 / 临床实验 / The Effect of Ramipril in Suppressing ST2 Expression in Rheumatic Mitral Stenosis Patients

The Effect of Ramipril in Suppressing ST2 Expression in Rheumatic Mitral Stenosis Patients

Study Description
Brief Summary:
Objective propose: to investigate the effect of Ramipril in suppressing ST2 (suppression of tumorigenicity 2) in the cardiac mitral valve in patients with Rheumatic Heart Disease. We hypothesized that we hypothesized that ramipril will improve rheumatic mitral valve fibrosis through the downregulation of ST2.

Condition or disease Intervention/treatment Phase
Rheumatic Heart Disease Mitral Stenosis Rheumatic Mitral Stenosis Fibrosis; Heart ACE Inhibitor Drug: Placebos Drug: Ramipril 5Mg Oral Capsule Phase 3

Detailed Description:
The efficacy of secondary prevention is limited in the prevention of RHD progression. For this reason, new strategies and therapies are needed to prevent the progression of RHD. Neutralizing inflammatory cytokines or antagonizing their receptor function has been considered as a useful therapeutic strategy to treat autoimmune diseases. In this respect, new therapies targeting ST 2 and their receptors as studied in some autoimmune diseases may promise a new approach for patients with RHD. Angiotensin II induces the upregulation of Transforming growth factor β (TGF-β) and latter the binding of IL-33 to sST2 and not to the natural ligand (ST2L). The binding of IL-33 to sST2 will cause fibrogenesis even more. Thus, ACEI is hypothesized to attenuate this vicious cycle through the inhibition of Angiotensin II and consequently increase Bradykinin that furtherly inhibits fibrosis through the negative regulation of angiotensin II activity in Mitogen Activator Protein Kinase (MAPK) pathways through the suppression of the Ca2+ response and the Na+ transportACE inhibitor were agents with anti-fibrosis effects. The investigators keen to investigate the effect of Ramipril in suppressing ST2 expression as biomarkers of fibrosis in cardiac mitral valve in patients with Rheumatic Heart Disease in the National Cardiac Center Harapan Kita hospital Jakarta Indonesia. This study was designed as a randomized clinical trial. Patients with mitral stenosis valvular dysfunction due to rheumatic process planned for cardiac valve replacement surgery were given Ramipril or placebo for a minimum of 12 weeks (3 months). ST2 expression will be analyzed as the fibrosis biomarker in the mitral valve. This study will be conducted in the Department of Cardiology and Vascular Medicine, University Indonesia, National Cardiac Center Harapan Kita Hospital, Jakarta, Indonesia from June 2019
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: pre post test design with placebo control
Masking: Double (Participant, Investigator)
Masking Description: study participants do not know whether they become treatment group or control group the investigator does not know which participant in each group
Primary Purpose: Treatment
Official Title: The Effect of Ramipril in Suppressing Gene Expression of Fibrosis in Cardiac Mitral Stenosis in Patients With Rheumatic Heart Disease
Actual Study Start Date : June 27, 2019
Estimated Primary Completion Date : August 8, 2021
Estimated Study Completion Date : August 8, 2021
Arms and Interventions
Arm Intervention/treatment
Placebo Comparator: control
control patients will be given a placebo
 Drug: Placebos
the control group will be given placebo inside a capsule, so study participant won't be able to know the drug and doses inside the capsule (for masking)
Other Name: control group
Experimental: treatment
Ramipril 5 mg treatment group
 Drug: Ramipril 5Mg Oral Capsule
the treatment group will be given Ramipril 5 mg inside a capsule, so study participant won't be able to know the drug and doses inside the capsule (for masking)
Other Name: treatment group
Outcome Measures
Primary Outcome Measures :
  1. ST2 expression in mitral valve tissue [ Time Frame: a year ]
    expression of ST2 in mitral valve tissue, using immunohistochemistry method


Secondary Outcome Measures :
  1. ST2 Plasma concentration [ Time Frame: a year ]
    plasma level of ST2 measured by ELISA

  2. NT-proBNP concentration (pg/ml) [ Time Frame: a year ]
    concentration of NT-proBNP, plasma markers for cardiac dysfunction.

  3. Ejection fraction [ Time Frame: a year ]
    echocardiographic parameter to asses ventricular function

  4. TAPSE (tricuspid annular plane systolic excursion) [ Time Frame: a year ]
    echocardiography parameter to asses right ventricular function

  5. NYHA class [ Time Frame: a year ]
    related symptoms will be graded in class I to IV according to NYHA.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with mitral valve stenosis or a combination
  • aged more than 18 years
  • undergo cardiac valve replacement operation with or without a tricuspid valve repair,
  • patients with systolic blood pressure (SBP) ≥ 100 mmHg and diastolic blood pressure (DBP) ≥ 60 mmHg
  • passed in medication phase without side effect minimum 4 weeks until operation schedule

Exclusion Criteria:

  1. Patients with congenital heart disease
  2. patients with non-mitral valve surgery
  3. patients with coronary artery bypass surgery
  4. patients who refuse to join this study.
  5. adults aged over 65 years or older
  6. pregnant women
  7. patients with autoimmune disease.
  8. Patients with persistent hypotension (systolic blood pressure (BP) < 100 mm Hg)
  9. severe aortic stenosis (aortic valve orifice < 0.75 cm2 )
  10. chronic renal dysfunction with serum creatinine > 2.5 mg/ dL,
  11. known ACEI intolerance.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Ade Meidian Ambari, MD, FIHA 021-5684085 ext 2209 dr_ade_meidian@yahoo.co.id

Locations
Layout table for location information
Indonesia
Ade Meidian Ambari Recruiting
Jakarta, DKI Jakarta, Indonesia, 1140
Contact: Ade Meidian Ambari, MD,FIHA    021-5684085 ext 2209    dr_ade_meidian@yahoo.co.id   
Sponsors and Collaborators
Indonesia University
Investigators
Layout table for investigator information
Principal Investigator: Ade Meidian Ambari, MD,FIHA Universitas Indonesia, RSPJN harapan kita
Tracking Information
First Submitted Date  ICMJE June 17, 2019
First Posted Date  ICMJE June 19, 2019
Last Update Posted Date December 7, 2020
Actual Study Start Date  ICMJE June 27, 2019
Estimated Primary Completion Date August 8, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 2, 2020) 		ST2 expression in mitral valve tissue [ Time Frame: a year ]
expression of ST2 in mitral valve tissue, using immunohistochemistry method
Original Primary Outcome Measures  ICMJE
 (submitted: June 18, 2019)
  • ST2 plasma level [ Time Frame: a year ]
    plasma level of ST2 measured by ELISA
  • ST2 expression in mitral valve tissue [ Time Frame: a year ]
    expression of ST2 in mitral valve tissue, using immunohistochemistry method
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 2, 2020)
  • ST2 Plasma concentration [ Time Frame: a year ]
    plasma level of ST2 measured by ELISA
  • NT-proBNP concentration (pg/ml) [ Time Frame: a year ]
    concentration of NT-proBNP, plasma markers for cardiac dysfunction.
  • Ejection fraction [ Time Frame: a year ]
    echocardiographic parameter to asses ventricular function
  • TAPSE (tricuspid annular plane systolic excursion) [ Time Frame: a year ]
    echocardiography parameter to asses right ventricular function
  • NYHA class [ Time Frame: a year ]
    related symptoms will be graded in class I to IV according to NYHA.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 18, 2019)
  • NT-proBNP concentration (pg/ml) [ Time Frame: a year ]
    concentration of NT-proBNP, plasma markers for cardiac dysfunction.
  • global strain [ Time Frame: a year ]
    echocardiography parameter
  • Ejection fraction [ Time Frame: a year ]
    echocardiography parameter
  • NYHA class [ Time Frame: a year ]
    related symptoms will be graded in class I to IV according to NYHA.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effect of Ramipril in Suppressing ST2 Expression in Rheumatic Mitral Stenosis Patients
Official Title  ICMJE The Effect of Ramipril in Suppressing Gene Expression of Fibrosis in Cardiac Mitral Stenosis in Patients With Rheumatic Heart Disease
Brief Summary Objective propose: to investigate the effect of Ramipril in suppressing ST2 (suppression of tumorigenicity 2) in the cardiac mitral valve in patients with Rheumatic Heart Disease. We hypothesized that we hypothesized that ramipril will improve rheumatic mitral valve fibrosis through the downregulation of ST2.
Detailed Description The efficacy of secondary prevention is limited in the prevention of RHD progression. For this reason, new strategies and therapies are needed to prevent the progression of RHD. Neutralizing inflammatory cytokines or antagonizing their receptor function has been considered as a useful therapeutic strategy to treat autoimmune diseases. In this respect, new therapies targeting ST 2 and their receptors as studied in some autoimmune diseases may promise a new approach for patients with RHD. Angiotensin II induces the upregulation of Transforming growth factor β (TGF-β) and latter the binding of IL-33 to sST2 and not to the natural ligand (ST2L). The binding of IL-33 to sST2 will cause fibrogenesis even more. Thus, ACEI is hypothesized to attenuate this vicious cycle through the inhibition of Angiotensin II and consequently increase Bradykinin that furtherly inhibits fibrosis through the negative regulation of angiotensin II activity in Mitogen Activator Protein Kinase (MAPK) pathways through the suppression of the Ca2+ response and the Na+ transportACE inhibitor were agents with anti-fibrosis effects. The investigators keen to investigate the effect of Ramipril in suppressing ST2 expression as biomarkers of fibrosis in cardiac mitral valve in patients with Rheumatic Heart Disease in the National Cardiac Center Harapan Kita hospital Jakarta Indonesia. This study was designed as a randomized clinical trial. Patients with mitral stenosis valvular dysfunction due to rheumatic process planned for cardiac valve replacement surgery were given Ramipril or placebo for a minimum of 12 weeks (3 months). ST2 expression will be analyzed as the fibrosis biomarker in the mitral valve. This study will be conducted in the Department of Cardiology and Vascular Medicine, University Indonesia, National Cardiac Center Harapan Kita Hospital, Jakarta, Indonesia from June 2019
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
pre post test design with placebo control
Masking: Double (Participant, Investigator)
Masking Description:
study participants do not know whether they become treatment group or control group the investigator does not know which participant in each group
Primary Purpose: Treatment
Condition  ICMJE
  • Rheumatic Heart Disease
  • Mitral Stenosis
  • Rheumatic Mitral Stenosis
  • Fibrosis; Heart
  • ACE Inhibitor
Intervention  ICMJE
  • Drug: Placebos
    the control group will be given placebo inside a capsule, so study participant won't be able to know the drug and doses inside the capsule (for masking)
    Other Name: control group
  • Drug: Ramipril 5Mg Oral Capsule
    the treatment group will be given Ramipril 5 mg inside a capsule, so study participant won't be able to know the drug and doses inside the capsule (for masking)
    Other Name: treatment group
Study Arms  ICMJE
  • Placebo Comparator: control
    control patients will be given a placebo
    Intervention: Drug: Placebos
  • Experimental: treatment
    Ramipril 5 mg treatment group
    Intervention: Drug: Ramipril 5Mg Oral Capsule
Publications *
  • Wei Q, Liu H, Liu M, Yang C, Yang J, Liu Z, Yang P. Ramipril attenuates left ventricular remodeling by regulating the expression of activin A-follistatin in a rat model of heart failure. Sci Rep. 2016 Sep 19;6:33677. doi: 10.1038/srep33677.
  • Shi Q, Abusarah J, Baroudi G, Fernandes JC, Fahmi H, Benderdour M. Ramipril attenuates lipid peroxidation and cardiac fibrosis in an experimental model of rheumatoid arthritis. Arthritis Res Ther. 2012 Oct 18;14(5):R223. doi: 10.1186/ar4062.
  • Ciccone MM, Cortese F, Gesualdo M, Riccardi R, Di Nunzio D, Moncelli M, Iacoviello M, Scicchitano P. A novel cardiac bio-marker: ST2: a review. Molecules. 2013 Dec 11;18(12):15314-28. doi: 10.3390/molecules181215314. Review.
  • Ambari AM, Setianto B, Santoso A, Radi B, Dwiputra B, Susilowati E, Tulrahmi F, Doevendans PA, Cramer MJ. Angiotensin Converting Enzyme Inhibitors (ACEIs) Decrease the Progression of Cardiac Fibrosis in Rheumatic Heart Disease Through the Inhibition of IL-33/sST2. Front Cardiovasc Med. 2020 Jul 28;7:115. doi: 10.3389/fcvm.2020.00115. eCollection 2020. Review.

*   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: June 18, 2019) 		66
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 8, 2021
Estimated Primary Completion Date August 8, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with mitral valve stenosis or a combination
  • aged more than 18 years
  • undergo cardiac valve replacement operation with or without a tricuspid valve repair,
  • patients with systolic blood pressure (SBP) ≥ 100 mmHg and diastolic blood pressure (DBP) ≥ 60 mmHg
  • passed in medication phase without side effect minimum 4 weeks until operation schedule

Exclusion Criteria:

  1. Patients with congenital heart disease
  2. patients with non-mitral valve surgery
  3. patients with coronary artery bypass surgery
  4. patients who refuse to join this study.
  5. adults aged over 65 years or older
  6. pregnant women
  7. patients with autoimmune disease.
  8. Patients with persistent hypotension (systolic blood pressure (BP) < 100 mm Hg)
  9. severe aortic stenosis (aortic valve orifice < 0.75 cm2 )
  10. chronic renal dysfunction with serum creatinine > 2.5 mg/ dL,
  11. known ACEI intolerance.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ade Meidian Ambari, MD, FIHA 021-5684085 ext 2209 dr_ade_meidian@yahoo.co.id
Listed Location Countries  ICMJE Indonesia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03991910
Other Study ID Numbers  ICMJE RamiRHeD
Has Data Monitoring Committee Yes
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
Plan to Share IPD: No
Responsible Party Ade Meidian Ambari, Indonesia University
Study Sponsor  ICMJE Indonesia University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ade Meidian Ambari, MD,FIHA Universitas Indonesia, RSPJN harapan kita
PRS Account Indonesia University
Verification Date December 2020

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

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