Aortic Stenosis, SeverePhase 3Reduce-MFANCT05230901
Effect of Antifibrotic Therapy on Regression of Myocardial Fibrosis After Transcatheter Aortic Valve Implantation (TAVI) in Aortic Stenosis Patients With High Fibrotic Burden
A Phase 3 study testing Spironolactone 25mg and Dihydralazine in people with Aortic Stenosis, Severe, run by University Medical Center Goettingen at 1 site in Germany.
Trial summary
The aim of the study is to evaluate the effect of antifibrotic therapy on regression of myocardial fibrosis after TAVI in patients with baseline high fibrotic burden. Therefore, patients will be treated with Spironolactone in addition to standard of care, Spioronolactone + Dihydralazine in addition to standard of care… Read more about this study
- Who is it for?
- Ages 60 years and older
- Conditions the study is for
- Aortic Stenosis, Severe
- What is being tested?
- Spironolactone 25mg and Dihydralazine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 300 participants
- Where
- 1 siteGermany
- Study dates
- 23 Feb 2022to Mar 2026
- 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 60 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male, female age ≥ 60
- Diagnosis of severe symptomatic aortic stenosis
- Transcatheter aortic valve implantation (TAVI) scheduled
- Written informed consent
Who cannot join
- 1. Pre-existing dilative or ischemic heart disease with EF<35% and guideline indication for spironolactone
- Patient on current medication with spironolactone, eplerenone, or dihydralazine
- Presence of coexistent myocardial pathology such as cardiac amyloidosis, hypertrophic cardiomyopathy, or myocarditis
- Presence of coexistent severe aortic regurgitation or severe mitral stenosis
- Previous surgical valve replacement or repair
- Pacemaker or ICD implanted
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- Renal impairment (serum creatinine > 1,8 mg/dl and/ or GFR < 30 ml/min/1,73 m² BSA)
- Significant hypotension (blood pressure < 90 mm Hg systolic and/or < 50 mm Hg diastolic
- Serum potassium > 5,1 mmol/l
- Contraindications for Spironolactone (anuria, acute renal failure, serum creatinine > 1.8 mg/dl, hyperkalemia, pregnancy)
- Contraindications for Dihydralazine (known allergy or hypersensitivity, systemic lupus erythematodes, adrenocortical disorders)
- Known active malignant disease with life expectancy < 1 year
- Women with child-bearing potential
- Simultaneous participation (including a waiting period of 4 weeks) in other interventional clinical trials
- Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial
- Person who is in a relationship of dependence/employment with the sponsor or the investigator
Trial locations and contacts
1 site in 1 country.
Germany1 site, 1 recruiting
- Recruiting
University Medical Center Göttingen
Göttingen, Lower Saxony, 37075
Miriam Puls, Prof. Dr., dr.m.puls@med.uni-goettingen.de
About this study
The aim of the study is to evaluate the effect of antifibrotic therapy on regression of myocardial fibrosis after TAVI in patients with baseline high fibrotic burden. Therefore, patients will be treated with Spironolactone in addition to standard of care, Spioronolactone + Dihydralazine in addition to standard of care or according to standard of care alone without any study medication. First, differences between patients in the control arm and patients randomized to anti-fibrotic therapy will be analyzed. The second analysis will determine, whether dihydralazine medication in addition to spironolactone is able to increase a potential antifibrotic effect. Myocardial fibrosis will be assessed by cardiac magnetic resonance imaging (CMR) before TAVI and 1 year after. Quantification of potentially irreversible replacement fibrosis will be carried out by late gadolinium enhancement (LGE), and quantification of the potentially reversible diffuse interstitial fibrosis will be performed by measurement of the extracellular volume fraction (ECV), thereby deriving matrix volume and cell volume.
- Conditions
- Aortic Stenosis, Severe
- Being tested
- Standard of Care, Spironolactone 25mg, Dihydralazine
- Medical subject headings
- Aortic Valve Stenosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Standard of CareOther
Patients with CMR-derived ECV% levels ≥25.9% will be treated with standard of care according to current guidelines (Control group).
Spironolactone 25mgDrug
Patients with CMR-derived ECV% levels ≥25.9% in Arm "Spironolactone" will receive spironolactone 25 mg/d in addition to standard of care medication .
DihydralazineDrug
Patients with CMR-derived ECV% levels ≥25.9% in arm "Spironolactone + Dihydralazine" will receive spironolactone 25 mg/d + dihydralazine (2x12.5 mg/d p.o. in slow acethylators, and 2x25mg/d p.o. in fast acethylators, confirmed by genetic testing)
| Study group | Role | What they receive |
|---|---|---|
| Control group | Other | Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care Receives: Other: Standard of Care |
| Spironolactone | Experimental | Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care + Spironolactone (25 mg/d, p.o.) Receives: Other: Standard of Care; Drug: Spironolactone 25mg |
| Spironolactone + Dihydralazine | Experimental | Patients with CMR-derived ECV% levels ≥25.9% will receive Standard of care + Spironolactone (25 mg/d, p.o.) + Dihydralazine (2x12.5 mg/d p.o. in slow acethylators, and 2x25mg / d p.o. in fast acethylators, confirmed by genetic testing) Receives: Other: Standard of Care; Drug: Spironolactone 25mg; Drug: Dihydralazine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Extracellular volume (ECV)-derived matrix volume (measured by CMR)
Differences between treatment groups in reduction of extracellular volume (ECV)- derived matrix volume (measured by CMR) after 12 months
Measured: 12 months
Secondary outcomes (28)
Left ventricular ejection fraction
Differences in recovery of left ventricular ejection fraction (EF) in % (measured by CMR) after 12 months
Measured: 12 months
Global longitudinal strain
Differences in recovery of global longitudinal strain (GLS) in % (measured by CMR) after 12 months
Measured: 12 months
diastolic function
Differences in recovery of diastolic function (measured by CMR) after 12 months
Measured: 12 months
Left ventricular myocardial tissue volumes
Differences in reduction of left ventricular myocardial tissue volumes (measured by CMR) after 12 months
Measured: 12 months
Left ventricular blood volumes
Differences in reduction of left ventricular blood volumes (measured by CMR) after 12 months
Measured: 12 months
Kansas City Cardiomyopathy Questionnaire
Differences in quality of life changes according to 23-items Kansas City Cardiomyopathy Questionnaire (KCCQ) after 12 months
Measured: 12 months
NYHA status
Differences in NYHA status after 12 months
Measured: 12 months
6min-walking test distance (6MWT)
Differences in 6min-walking test distance (6MWT; in m) after 12 months
Measured: 12 months
NT-proBNP-levels
Differences in NT-proBNP-levels (in pg/ml) after 12 months
Measured: 12 months
Heart failure hospitalizations
Rate of Heart failure hospitalizations within 12 months
Measured: 12 months
Total mortality
Rate of total mortality within 12 months
Measured: 12 months
Cardiovascular mortality
Rate of Cardiovascular mortality within 12 months
Measured: 12 months
Biomarker Procollagen type I carboxy-terminal propeptide (PICP)
Measurement of PICP in ng/ml
Measured: 12 months
Biomarker Procollagen III N-terminal propeptid (PIIINP)
Measurement of PIIINP in ng/ml
Measured: 12 months
Ratio of Increased collagen degradation (CITP) vs. matrix metalloproteinase-1 (MMP-1)
Measurement of CITP (in ng/l) and MMP-1 (in ng/ml)
Measured: 12 months
Methylation of Iroquois Homeobox 3 (IRX3)
Measurement of Methylation of IRX3 in %
Measured: 12 months
Methylation of rfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 3 (ACAP3)
Measurement of Methylation of ACAP3 in %
Measured: 12 months
Methylation of Growth Arrest And DNA Damage Inducible Gamma (GADD45G)
Measurement of Methylation of GADD45G in %
Measured: 12 months
Methylation of Chordin (CHRD)
Measurement of Methylation of CHRD in %
Measured: 12 months
Methylation of Klotho
Measurement of Methylation of Klotho in %
Measured: 12 months
Methylation of RAS Protein Activator Like 1 (RASAL1)
Measurement of Methylation of RASAL1 in %
Measured: 12 months
Methylation of ATPase Sarcoplasmic/Endoplasmic Reticulum Ca2+ Transporting 2 (ATP2A2)
Measurement of Methylation of ATP2A2 in %
Measured: 12 months
Methylation of B9 Domain Containing 1 (B9D1)
Measurement of Methylation of B9D1 in %
Measured: 12 months
Methylation of Bone Morphogenetic Protein 7 (BMP7)
Measurement of Methylation of BMP7 in %
Measured: 12 months
Methylation of Latency associated peptide (LAP)
Measurement of Methylation of LAP in %
Measured: 12 months
Serum creatinine
Change in serum creatinine (in mg/dl) after 12 months
Measured: 12 months
Cystatin c
Change in cystatin c (in mg/l) after 12 months
Measured: 12 months
Phosphate
Change in phosphate (in mmol/l) after 12 months
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Feb 2022
- Study start23 Feb 2022
- Primary completionJun 2025 (estimated)
- Study completionMar 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Aortic Stenosis, SevereStudies of the same condition, open and under way.
- 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
- Masking
- None (open label)
- Enrolment
- 300 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Medical Center Goettingen
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Karsten Gavenis, University Medical Center Goettingen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05230901
- Sponsor's protocol ID
- 02717
- Acronym
- Reduce-MFA
- Status last verified
- Jun 2022
- First submitted
- 12 Jan 2022
- Last updated
- 28 Jun 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 28 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Antifibrotic Therapy on Regression of Myocardial Fibrosis After Transcatheter Aortic Valve Implantation (TAVI) in Aortic Stenosis Patients With High Fibrotic Burden
- ClinicalTrials.gov ID
- NCT05230901
- Acronym / sponsor ID
- Reduce-MFA / 02717
- Conditions
- Aortic Stenosis, Severe
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 300 participants (estimated)
- Lead sponsor
- University Medical Center GoettingenUniversity, hospital or other
- Study start
- 23 Feb 2022 (actual)
- Primary completion
- Jun 2025 (estimated)
- Study completion
- Mar 2026 (estimated)
- First posted
- 9 Feb 2022 (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.
The aim of the study is to evaluate the effect of antifibrotic therapy on regression of myocardial fibrosis after TAVI in patients with baseline high fibrotic burden. Therefore, patients will be treated with Spironolactone in addition to standard of care, Spioronolactone + Dihydralazine in addition to standard of care or according to standard of care alone without any study medication. First, differences between patients in the control arm and patients randomized to anti-fibrotic therapy will be analyzed. The second analysis will determine, whether dihydralazine medication in addition to spironolactone is able to increase a potential antifibrotic effect. Myocardial fibrosis will be assessed by cardiac magnetic resonance imaging (CMR) before TAVI and 1 year after. Quantification of potentially irreversible replacement fibrosis will be carried out by late gadolinium enhancement (LGE), and quantification of the potentially reversible diffuse interstitial fibrosis will be performed by measurement of the extracellular volume fraction (ECV), thereby deriving matrix volume and cell volume.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Control group | Other | Other: Standard of CarePatients with CMR-derived ECV% levels ≥25.9% will receive Standard of care |
| Spironolactone | Experimental | Other: Standard of Care, Drug: Spironolactone 25mgPatients with CMR-derived ECV% levels ≥25.9% will receive Standard of care + Spironolactone (25 mg/d, p.o.) |
| Spironolactone + Dihydralazine | Experimental | Other: Standard of Care, Drug: Spironolactone 25mg, Drug: DihydralazinePatients with CMR-derived ECV% levels ≥25.9% will receive Standard of care + Spironolactone (25 mg/d, p.o.) + Dihydralazine (2x12.5 mg/d p.o. in slow acethylators, and 2x25mg / d p.o. in fast acethylators, confirmed by genetic testing) |
Who may qualify
- Ages
- 60 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Male, female age ≥ 60
- Diagnosis of severe symptomatic aortic stenosis
- Transcatheter aortic valve implantation (TAVI) scheduled
- Written informed consent
Key exclusion criteria (16 listed)
- 1. Pre-existing dilative or ischemic heart disease with EF<35% and guideline indication for spironolactone
- Patient on current medication with spironolactone, eplerenone, or dihydralazine
- Presence of coexistent myocardial pathology such as cardiac amyloidosis, hypertrophic cardiomyopathy, or myocarditis
- Presence of coexistent severe aortic regurgitation or severe mitral stenosis
- Previous surgical valve replacement or repair
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 |
|---|---|---|
| Standard of CarePatients with CMR-derived ECV% levels ≥25.9% will be treated with standard of care according to current guidelines (Control group). | Other | Control group, Spironolactone, Spironolactone + Dihydralazine |
| Spironolactone 25mgPatients with CMR-derived ECV% levels ≥25.9% in Arm "Spironolactone" will receive spironolactone 25 mg/d in addition to standard of care medication . | Drug | Spironolactone, Spironolactone + Dihydralazine |
| DihydralazinePatients with CMR-derived ECV% levels ≥25.9% in arm "Spironolactone + Dihydralazine" will receive spironolactone 25 mg/d + dihydralazine (2x12.5 mg/d p.o. in slow acethylators, and 2x25mg/d p.o. in fast acethylators, confirmed by genetic testing) | Drug | Spironolactone + Dihydralazine |
Primary outcome
Extracellular volume (ECV)-derived matrix volume (measured by CMR)
Time frame: 12 months
Differences between treatment groups in reduction of extracellular volume (ECV)- derived matrix volume (measured by CMR) after 12 months
28 secondary outcomes
Left ventricular ejection fraction
Time frame: 12 months
Global longitudinal strain
Time frame: 12 months
diastolic function
Time frame: 12 months
Left ventricular myocardial tissue volumes
Time frame: 12 months
Left ventricular blood volumes
Time frame: 12 months
Kansas City Cardiomyopathy Questionnaire
Time frame: 12 months
NYHA status
Time frame: 12 months
6min-walking test distance (6MWT)
Time frame: 12 months
NT-proBNP-levels
Time frame: 12 months
Heart failure hospitalizations
Time frame: 12 months
Total mortality
Time frame: 12 months
Cardiovascular mortality
Time frame: 12 months
Biomarker Procollagen type I carboxy-terminal propeptide (PICP)
Time frame: 12 months
Biomarker Procollagen III N-terminal propeptid (PIIINP)
Time frame: 12 months
Ratio of Increased collagen degradation (CITP) vs. matrix metalloproteinase-1 (MMP-1)
Time frame: 12 months
Methylation of Iroquois Homeobox 3 (IRX3)
Time frame: 12 months
Methylation of rfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 3 (ACAP3)
Time frame: 12 months
Methylation of Growth Arrest And DNA Damage Inducible Gamma (GADD45G)
Time frame: 12 months
Methylation of Chordin (CHRD)
Time frame: 12 months
Methylation of Klotho
Time frame: 12 months
Methylation of RAS Protein Activator Like 1 (RASAL1)
Time frame: 12 months
Methylation of ATPase Sarcoplasmic/Endoplasmic Reticulum Ca2+ Transporting 2 (ATP2A2)
Time frame: 12 months
Methylation of B9 Domain Containing 1 (B9D1)
Time frame: 12 months
Methylation of Bone Morphogenetic Protein 7 (BMP7)
Time frame: 12 months
Methylation of Latency associated peptide (LAP)
Time frame: 12 months
Serum creatinine
Time frame: 12 months
Cystatin c
Time frame: 12 months
Phosphate
Time frame: 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jun 2022.
- 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.
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 Spironolactone 25mg and Dihydralazine in people with Aortic Stenosis, Severe, run by University Medical Center Goettingen at 1 site in Germany.
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 4 inclusion and 16 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 28 Jun 2022. 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 Germany. 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. 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 Miriam Puls, Prof. (+49 551 3910958, dr.m.puls@med.uni-goettingen.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Extracellular volume (ECV)-derived matrix volume (measured by CMR) (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 28 Jun 2022.