Rheumatic Heart DiseasePhase 3NCT03991910
The Effect of Ramipril in Suppressing ST2 Expression in Rheumatic Mitral Stenosis Patients
A Phase 3 study testing Ramipril 5Mg Oral Capsule in people with Rheumatic Heart Disease and Mitral Stenosis, run by Universitas Indonesia at 1 site in Indonesia.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Rheumatic Heart Disease, Mitral Stenosis, Rheumatic Mitral Stenosis
- What is being tested?
- Ramipril 5Mg Oral Capsule
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 66 participants
- Where
- 1 siteIndonesia
- Study dates
- 27 Jun 2019to 8 Aug 2024
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- Patients with congenital heart disease
- patients with non-mitral valve surgery
- patients with coronary artery bypass surgery
- patients who refuse to join this study.
- adults aged over 65 years or older
- pregnant women
Show all 11Show fewer
- patients with autoimmune disease.
- Patients with persistent hypotension (systolic blood pressure (BP) < 100 mm Hg)
- severe aortic stenosis (aortic valve orifice < 0.75 cm2 )
- chronic renal dysfunction with serum creatinine > 2.5 mg/ dL,
- known ACEI intolerance.
Trial locations and contacts
1 site in 1 country.
Indonesia1 site, 1 recruiting
- Recruiting
Ade Meidian Ambari
Jakarta, DKI Jakarta, 1140
Ade Meidian Ambari, MD,FIHA, 021-5684085 ext. 2209, dr_ade_meidian@yahoo.co.id
About this study
Official title: Randomised Controlled Trial Into the Role of Ramipril in Fibrosis Reduction in Rheumatic Heart Disease: The RamiRHeD Trial Protocol
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.
Read the 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
- Conditions
- Rheumatic Heart Disease, Mitral Stenosis, Rheumatic Mitral Stenosis, Fibrosis; Heart, ACE Inhibitor
- Being tested
- Placebos, Ramipril 5Mg Oral Capsule
- Keywords
- Rheumatic Heart Disease, Mitral Stenosis, Rheumatic Mitral Stenosis, Valve Fibrosis, ramipril, ST2
- Medical subject headings
- Rheumatic Heart Disease, Mitral Valve Stenosis, Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlacebosDrug
Also called control group
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). Placebo will be given until 5 days prior to Mitral valve replacement surgery.
Ramipril 5Mg Oral CapsuleDrug
Also called treatment group
the treatment group will be given each Ramipril 2,5 mg inside a capsule as an initial dose, for 2 weeks. If there is no serious adverse effect in the observation period of 2 weeks, Ramipril 5 mg inside a capsule will be given for the next weeks until 5 days before the mitral valve surgery date. Study participant won't be able to know the drug and doses inside the capsule (for masking)
| Study group | Role | What they receive |
|---|---|---|
| control | Placebo comparator | control patients will be given a placebo Receives: Drug: Placebos |
| treatment | Experimental | Ramipril 5 mg treatment group Receives: Drug: Ramipril 5Mg Oral Capsule |
What is being measured
The primary outcome is the main question the study is designed to answer.
ST2 expression in mitral valve tissue and papillary muscle
expression of ST2 in mitral valve tissue, using immunohistochemistry method
Measured: a year
Secondary outcomes (13)
ST2 Plasma concentration
plasma level of ST2 measured by ELISA
Measured: a year
NT-proBNP concentration (pg/ml)
concentration of NT-proBNP, plasma markers for cardiac dysfunction.
Measured: a year
NYHA class
related symptoms will be graded in class I to IV according to NYHA.
Measured: a year
cardiovascular mortality
Study participants will be followed up until 1 year after the surgery for any mortality that is caused by progression of the cardiac disease
Measured: 1 year
All-cause mortality
Study participants will be followed up until 1 year after the surgery for mortality of any cause.
Measured: 1 year
End diastolic dimension
The diameter across a ventricle at the end of diastole, if not else specified then usually referring to the transverse (left-to-right) internal (luminal) distance, excluding thickness of walls, although it can also be measured as the external distance.
Measured: 1 year
End systolic dimension
The diameter across a ventricle at the end of systole, if not else specified then usually referring to the transverse (left-to-right) internal (luminal) distance, excluding thickness of walls, although it can also be measured as the external distance.
Measured: 1 year
Mitral valve area
mitral valve area is the area of mitral valve, measured by the Gorlin formula MVA (cm2) = (CO ÷ DFP) ÷ (38.0 x MPG) where MVA is the mitral valve area, CO is cardiac output, DFP is the diastolic flow period, 38.0 is the constant and MPG is pressure gradient.
Measured: 1 year
Mitral valve gradient
mitralvalve graient is a echocardiographic parameters of the pressure gradient in the mitral valve
Measured: 1 year
Tricuspid maximal velocity (Vmax)
Tricuspid maximal velocity (Vmax) is the echocardiographic parameters of the maximal velocity in tricuspid valve annulus
Measured: 1 year
Tricuspid regurgitation severity
TRicuspid regurgitation severity is classified ad mild, moderate, and severe, according to European Association of Echocardiography measurement year 2010 for Tricuspid Valve regusrgitation severity.
Measured: 1 year
Ejection fraction
echocardiographic parameter to asses ventricular function
Measured: 1 year
TAPSE (tricuspid annular plane systolic excursion)
echocardiography parameter to asses right ventricular function
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jun 2019
- Study start27 Jun 2019
- Primary completion8 Aug 2024 (estimated)
- Study completion8 Aug 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Rheumatic Heart DiseaseStudies of the same condition, open and under way.
- More trials run by Universitas IndonesiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- pre post test design with placebo control
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 66 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Universitas Indonesia
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Ade Meidian Ambari, Universitas Indonesia
- Investigators
- Ade Meidian Ambari, MD,FIHA, Principal investigator, Universitas Indonesia, RSPJN harapan kita
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03991910
- Sponsor's protocol ID
- RamiRHeD
- Status last verified
- Aug 2021
- First submitted
- 17 Jun 2019
- Last updated
- 16 Aug 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 27642098Shi 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.
PubMed 23079082Ciccone 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.
PubMed 24335613Ambari 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.
PubMed 32850979Ambari AM, Setianto B, Santoso A, Radi B, Dwiputra B, Susilowati E, Tulrahmi F, Wind A, Cramer MJM, Doevendans P. Randomised controlled trial into the role of ramipril in fibrosis reduction in rheumatic heart disease: the RamiRHeD trial protocol. BMJ Open. 2021 Sep 13;11(9):e048016. doi: 10.1136/bmjopen-2020-048016.
PubMed 34518254
Study at a glance
From the registry record, last updated by the sponsor on 16 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomised Controlled Trial Into the Role of Ramipril in Fibrosis Reduction in Rheumatic Heart Disease: The RamiRHeD Trial Protocol
- ClinicalTrials.gov ID
- NCT03991910
- Acronym / sponsor ID
- RamiRHeD
- Conditions
- Rheumatic Heart Disease, Mitral Stenosis, Rheumatic Mitral Stenosis, Fibrosis; Heart, ACE Inhibitor
- Keywords
- Rheumatic Heart Disease, Mitral Stenosis, Rheumatic Mitral Stenosis, Valve Fibrosis, ramipril, ST2
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 66 participants (estimated)
- Lead sponsor
- Universitas IndonesiaUniversity, hospital or other
- Study start
- 27 Jun 2019 (actual)
- Primary completion
- 8 Aug 2024 (estimated)
- Study completion
- 8 Aug 2024 (estimated)
- First posted
- 19 Jun 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- pre post test design with placebo control
| Arm | Type | Receives |
|---|---|---|
| control | Placebo comparator | Drug: Placeboscontrol patients will be given a placebo |
| treatment | Experimental | Drug: Ramipril 5Mg Oral CapsuleRamipril 5 mg treatment group |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (11 listed)
- Patients with congenital heart disease
- patients with non-mitral valve surgery
- patients with coronary artery bypass surgery
- patients who refuse to join this study.
- adults aged over 65 years or older
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlacebosAlso: control groupthe 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). Placebo will be given until 5 days prior to Mitral valve replacement surgery. | Drug | control |
| Ramipril 5Mg Oral CapsuleAlso: treatment groupthe treatment group will be given each Ramipril 2,5 mg inside a capsule as an initial dose, for 2 weeks. If there is no serious adverse effect in the observation period of 2 weeks, Ramipril 5 mg inside a capsule will be given for the next weeks until 5 days before the mitral valve surgery date. Study participant won't be able to know the drug and doses inside the capsule (for masking) | Drug | treatment |
Primary outcome
ST2 expression in mitral valve tissue and papillary muscle
Time frame: a year
expression of ST2 in mitral valve tissue, using immunohistochemistry method
13 secondary outcomes
ST2 Plasma concentration
Time frame: a year
NT-proBNP concentration (pg/ml)
Time frame: a year
NYHA class
Time frame: a year
cardiovascular mortality
Time frame: 1 year
All-cause mortality
Time frame: 1 year
End diastolic dimension
Time frame: 1 year
End systolic dimension
Time frame: 1 year
Mitral valve area
Time frame: 1 year
Mitral valve gradient
Time frame: 1 year
Tricuspid maximal velocity (Vmax)
Time frame: 1 year
Tricuspid regurgitation severity
Time frame: 1 year
Ejection fraction
Time frame: 1 year
TAPSE (tricuspid annular plane systolic excursion)
Time frame: 1 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Aug 2021.
- Background: PubMed 27642098Wei 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.
- Background: PubMed 23079082Shi 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.
- Background: PubMed 24335613Ciccone 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.
- Background: PubMed 32850979Ambari 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.
- Derived from this study: PubMed 34518254Ambari AM, Setianto B, Santoso A, Radi B, Dwiputra B, Susilowati E, Tulrahmi F, Wind A, Cramer MJM, Doevendans P. Randomised controlled trial into the role of ramipril in fibrosis reduction in rheumatic heart disease: the RamiRHeD trial protocol. BMJ Open. 2021 Sep 13;11(9):e048016. doi: 10.1136/bmjopen-2020-048016.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ade Meidian Ambari, MD,FIHA principal investigator
Universitas Indonesia, RSPJN harapan kita
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Ramipril 5Mg Oral Capsule in people with Rheumatic Heart Disease and Mitral Stenosis, run by Universitas Indonesia at 1 site in Indonesia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 16 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Indonesia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Ade Meidian Ambari, MD, FIHA (021-5684085 ext. 2209, dr_ade_meidian@yahoo.co.id), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
ST2 expression in mitral valve tissue and papillary muscle (time frame: a year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03991910, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Aug 2021.