Aortic Valve StenosisPhase 2/3ARISTOTENCT03315832
Efficacy of Angiotensin Receptor Blocker Following aortIc Valve Intervention for Aortic STenOsis: a Randomized mulTi-cEntric Double-blind Phase II Study
A Phase 2/3 study testing Valsartan in people with Aortic Valve Stenosis and Valsartan, run by University Hospital, Limoges at 1 site in France.
Trial summary
Aortic stenosis (AS) is the most frequent valvular heart disease in Western countries, with increasing prevalence. Recent guidelines recommend aortic valve intervention (surgical aortic valve replacement [SAVR] or transcatheter aortic valve replacement [TAVR]) in severe AS, as soon as symptoms or left ventricular (LV)… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Aortic Valve Stenosis, Valsartan, Angiotensin Receptor Antagonists
- What is being tested?
- Valsartan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 1 siteFrance
- Study dates
- 2 Jan 2023to 2 Jul 2025
- Phase
- Phase 2/3
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Men with age ≥18 years
- Women at postmenopausal state as defined by absence of menses for the last 12 months without alternative medical cause.
- Severe AS, defined according most recent guidelines (aortic valve area <1.0cm² or <0.6cm²/m² and aortic mean pressure gradient ≥40mmHg or aortic maximal velocity >4m/s, as assessed using transthoracic echocardiography [TTE]).
- Indication for aortic valve intervention
- Affiliation to the French Social Security system
- Signed informed consent.
Who cannot join
- Patients already under any Renin-Angiotensin-Aldosterone System blockers (RAASb) prior to randomization.
- Concomitant coronary artery bypass graft or other valvular intervention
- Other significant left-sided valvular heart diseases (≥moderate), even without concomitant procedure
- Any contra-indication to CMR
- Chronic kidney disease with estimated glomerular filtration rate (GFR) <30 ml/min
- Prior or planned organ transplantation
Show all 23Show fewer
- Hyperkaliemia (kaliemia >5.5 mmol/L at inclusion visit)
- Severe hepatic failure, biliary cirrhosis, cholestasis
- Combined use of aliskiren and concomitant diabetes mellitus or renal failure with GFR<60mL/min/1.73m²
- Low systolic blood pressure (<100mmHg)
- History of angioedema
- History of hypersensitivity or allergy to Angiotensin-II Receptor Blockers or excipient
- Under legal authority.
- Unwilling to consent
- Secondary Exclusion Criteria:
- Patients not under RAASb prior to randomization but who should benefit from this treatment to improve outcome:
- Heart failure with reduced ejection fraction (<40%)
- Coronary artery disease
- Clinical peripheral artery disease
- History of cerebrovascular disease
- Uncontrolled hypertension despite the use of other therapeutic classes
- Diabetes mellitus
- Impossibility to perform randomization into the 9-day post-intervention period due to per procedural complication with prolonged stay in intensive cardiac care unit (including death).
Trial locations and contacts
1 site in 1 country.
About this study
Aortic stenosis (AS) is the most frequent valvular heart disease in Western countries, with increasing prevalence. Recent guidelines recommend aortic valve intervention (surgical aortic valve replacement [SAVR] or transcatheter aortic valve replacement [TAVR]) in severe AS, as soon as symptoms or left ventricular (LV) dysfunction occur, in order to improve clinical outcome and achieve LV mass (LVM) regression. The highest amount of LVM regression is obtained during the first year. Nevertheless, there is heterogeneity in LV remodeling and residual LV hypertrophy is associated with poorer postoperative improvement in cardiac function and morphology. Incomplete regression of LV hypertrophy at 12 months after SAVR is a powerful predictor of adverse outcome. Yet, the use of specific pharmacological therapy to improve postoperative LVM regression could be an appealing therapeutic option after aortic valve intervention.
Renin-angiotensin-aldosterone system blockers (RAASb) and more particularly angiotensin-II receptor blockers (ARBs) are efficient in reducing LVM in hypertensive patients, as emphasized by several meta-analyses. In addition, ARBs improve myocardial relaxation, diastolic function, decreased hypertrophy and may have anti-fibrotic effects. In a recent retrospective study from our group, RAASb prescription after SAVR was associated with increased survival, but confirmation through a randomized trial is mandatory. In a prospective randomized single-center study, the use of candesartan was associated both with LV and LA remodeling as compared to the conventional management. Nevertheless, these results are based on echocardiographic data, which is not the gold standard for the assessment cardiac remodeling, and no placebo or active comparator was tested to control the impact of ARBs in these patients.
Read more
The primary objective of this Phase II study is to investigate the efficacy of valsartan, introduced postoperatively, as compared to placebo, on 1-year changes in indexed LVM, as assessed by CMR, in patients undergoing aortic valve intervention (SAVR or TAVR) for AS.
The secondary objectives are to compare the efficacy of valsartan vs. placebo in terms of one-year changes (difference from baseline) in cardiac function and in cardiac morphology, one-year exercise capacity and one-year changes in biomarkers related to cardiac function. In addition, the assessment of the safety of valsartan will also be considered as secondary objective.
The ARISTOTE trial is a multicenter prospective phase II, randomized, double-blind study including patients with the diagnosis of severe AS and indication for valve intervention.
The active treatment is valsartan, an orally active, potent, and specific angiotensin II receptor antagonist.
Patients will be randomized between 2 groups (valsartan versus placebo) and the treatment will be initiated (80 mg daily) at 5±4 days following aortic valve intervention. The comparative treatment will be a placebo; tablets of valsartan and placebo have a similar appearance and administration mode. Patient in the control group will receive a placebo using the same protocol as the valsartan group.
The patients will be cautiously monitored and any adverse events will be collected. The dose will be increased at 160 mg daily 13±2 days after aortic valve intervention and, if well tolerated, for the remaining period of the study. The tolerance will be regularly assessed and dose adjusted according to a pre-specified algorithm.
- Conditions
- Aortic Valve Stenosis, Valsartan, Angiotensin Receptor Antagonists, Transcatheter Aortic Valve Replacement, Heart Valve Prosthesis Implantation, Hypertrophy, Left Ventricular
- Being tested
- Valsartan, Placebo Oral Tablet
- Keywords
- Aortic Valve Stenosis, Valsartan, Angiotensin Receptor Antagonists, Transcatheter Aortic Valve Replacement, Heart Valve Prosthesis Implantation, double-blind phase II study, left ventricular mass
- Medical subject headings
- Aortic Valve Stenosis, Hypertrophy, Left Ventricular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ValsartanDrug
The active treatment is valsartan, an orally active, potent, and specific angiotensin II receptor antagonist. The treatment will be initiated (80 mg, daily) at 5±4 days following aortic valve intervention. The dose will be increased at 160 mg daily 13±2 days after aortic valve intervention and, if well tolerated, for the remaining period of the study.
Placebo Oral TabletDrug
The comparative treatment will be a placebo; tablets of valsartan and placebo have a similar appearance and administration mode. Patient in the control group will receive a placebo using the same protocol as the valsartan group.
| Study group | Role | What they receive |
|---|---|---|
| Valsartan | Experimental | The active treatment is valsartan, an orally active, potent, and specific angiotensin II receptor antagonist. The treatment will be initiated (80 mg, daily) at 5±4 days following aortic valve intervention. The dose will be increased at 160 mg daily 13±2 days after aortic valve intervention and, if well tolerated, for the remaining period of the study. Receives: Drug: Valsartan |
| Placebo Oral Tablet | Placebo comparator | The comparative treatment will be a placebo; tablets of valsartan and placebo have a similar appearance and administration mode. Patient in the control group will receive a placebo using the same protocol as the valsartan group. Receives: Drug: Placebo Oral Tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
Indexed left ventricular mass
the 1-year change from baseline in indexed LVM after aortic valve intervention as assessed using cardiac magnetic resonance (CMR)
Measured: Day 0 to Year 1
Secondary outcomes (21)
Left ventricular global longitudinal strain
The 1-year change from baseline in left ventricular global longitudinal strain quantified using CMR
Measured: Day 0 to Year 1
Left ventricular global longitudinal strain
The 1-year change from baseline in Left ventricular global longitudinal strain quantified using transthoracic echocardiography (TTE)
Measured: Day 0 to Year 1
Left atrial volume
The 1-year change from baseline in Left atrial volume quantified using CMR
Measured: Day 0 to Year 1
Left atrial volume
The 1-year change from baseline in Left atrial volume quantified using TTE
Measured: Day 0 to Year 1
Indexed left ventricular mass
the 1-year change from baseline in indexed LVM after aortic valve intervention as assessed using TTE (real-time 3D)
Measured: Day 0 to Year 1
Native T1
the 1-year change from baseline in native T1 using CMR
Measured: Day 0 to Year 1
Rate of late gadolinium enhancement (LGE)
the 1-year change from baseline in rate of LGE using CMR
Measured: Day 0 to Year 1
Volume of late gadolinium enhancement (LGE)
the 1-year change from baseline in volume of LGE using CMR
Measured: Day 0 to Year 1
Extra cellular volume
The 1-year change from baseline in extra cellular volume using CMR
Measured: Day 0 to Year 1
Indexed interstitial volume
The 1-year change from baseline in Indexed interstitial volume using CMR
Measured: Day 0 to Year 1
Electrocardiographic strain
The 1-year change from baseline in Electrocardiographic strain
Measured: Day 0 to Year 1
Left ventricular ejection fraction
The 1-year change from baseline in Left ventricular ejection fraction using CMR
Measured: Day 0 to Year 1
Left ventricular ejection fraction
The 1-year change from baseline in Left ventricular ejection fraction using TTE
Measured: Day 0 to Year 1
Peak exercise VO2
The 1-year measurement of Peak exercise VO2
Measured: Year 1
VE/VCO2 ratio
The 1-year measurement of VE/VCO2 ratio
Measured: 1 year
Maximal load
The 1-year maximal load reached
Measured: 1 year
New-York heart association functional class
The 1-year assessment of New-York heart association functional class
Measured: 1 year
Exercise oscillatory ventilation rate
The 1-year quantification of exercise oscillatory ventilation rate
Measured: 1 year
Nt-pro Brain natriuretic peptide
The 1-year change from baseline in level of Nt-pro Brain natriuretic peptide using immunoassay
Measured: Day 0 to Year 1
Plasma cardiac troponin I
The 1-year change from baseline in concentration of Plasma cardiac troponin I using high-sensitivity assay
Measured: Day 0 to Year 1
Incidence of treatment-Emergent Adverse Events
Clinical occurrence of adverse events (AEs) and serious adverse events (SAEs) during the duration of the study period ending month 13
Measured: Day 1 to Month 13
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Oct 2017
- Study start2 Jan 2023 (estimated)
- Primary completion2 Jul 2025 (estimated)
- Study completion2 Jul 2025 (estimated)
Why it stopped: problem of faisability
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Aortic Valve StenosisStudies of the same condition, open and under way.
- More trials run by University Hospital, LimogesThe 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Patients with the diagnosis of severe AS and indication for valve intervention (i.e. SAVR or TAVR) fulfilling all inclusion/exclusion criteria will be randomized using 1:1 ratio.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Limoges
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03315832
- Sponsor's protocol ID
- I16007 (ARISTOTE)
- Acronym
- ARISTOTE
- Status last verified
- Mar 2023
- First submitted
- 17 Oct 2017
- Last updated
- 17 Mar 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy of Angiotensin Receptor Blocker Following aortIc Valve Intervention for Aortic STenOsis: a Randomized mulTi-cEntric Double-blind Phase II Study
- ClinicalTrials.gov ID
- NCT03315832
- Acronym / sponsor ID
- ARISTOTE / I16007 (ARISTOTE)
- Conditions
- Aortic Valve Stenosis, Valsartan, Angiotensin Receptor Antagonists, Transcatheter Aortic Valve Replacement, Heart Valve Prosthesis Implantation, Hypertrophy, Left Ventricular
- Keywords
- Aortic Valve Stenosis, Valsartan, Angiotensin Receptor Antagonists, Transcatheter Aortic Valve Replacement, Heart Valve Prosthesis Implantation, double-blind phase II study, left ventricular mass
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: problem of faisability
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University Hospital, LimogesUniversity, hospital or other
- Study start
- 2 Jan 2023 (estimated)
- Primary completion
- 2 Jul 2025 (estimated)
- Study completion
- 2 Jul 2025 (estimated)
- First posted
- 20 Oct 2017 (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.
Aortic stenosis (AS) is the most frequent valvular heart disease in Western countries, with increasing prevalence. Recent guidelines recommend aortic valve intervention (surgical aortic valve replacement [SAVR] or transcatheter aortic valve replacement [TAVR]) in severe AS, as soon as symptoms or left ventricular (LV) dysfunction occur, in order to improve clinical outcome and achieve LV mass (LVM) regression. The highest amount of LVM regression is obtained during the first year. Nevertheless, there is heterogeneity in LV remodeling and residual LV hypertrophy is associated with poorer postoperative improvement in cardiac function and morphology. Incomplete regression of LV hypertrophy at 12 months after SAVR is a powerful predictor of adverse outcome. Yet, the use of specific pharmacological therapy to improve postoperative LVM regression could be an appealing therapeutic option after aortic valve intervention.
Renin-angiotensin-aldosterone system blockers (RAASb) and more particularly angiotensin-II receptor blockers (ARBs) are efficient in reducing LVM in hypertensive patients, as emphasized by several meta-analyses. In addition, ARBs improve myocardial relaxation, diastolic function, decreased hypertrophy and may have anti-fibrotic effects. In a recent retrospective study from our group, RAASb prescription after SAVR was associated with increased survival, but confirmation through a randomized trial is mandatory. In a prospective randomized single-center study, the use of candesartan was associated both with LV and LA remodeling as compared to the conventional management. Nevertheless, these results are based on echocardiographic data, which is not the gold standard for the assessment cardiac remodeling, and no placebo or active comparator was tested to control the impact of ARBs in these patients.
The primary objective of this Phase II study is to investigate the efficacy of valsartan, introduced postoperatively, as compared to placebo, on 1-year changes in indexed LVM, as assessed by CMR, in patients undergoing aortic valve intervention (SAVR or TAVR) for AS.
The secondary objectives are to compare the efficacy of valsartan vs. placebo in terms of one-year changes (difference from baseline) in cardiac function and in cardiac morphology, one-year exercise capacity and one-year changes in biomarkers related to cardiac function. In addition, the assessment of the safety of valsartan will also be considered as secondary objective.
The ARISTOTE trial is a multicenter prospective phase II, randomized, double-blind study including patients with the diagnosis of severe AS and indication for valve intervention.
The active treatment is valsartan, an orally active, potent, and specific angiotensin II receptor antagonist.
Patients will be randomized between 2 groups (valsartan versus placebo) and the treatment will be initiated (80 mg daily) at 5±4 days following aortic valve intervention. The comparative treatment will be a placebo; tablets of valsartan and placebo have a similar appearance and administration mode. Patient in the control group will receive a placebo using the same protocol as the valsartan group.
The patients will be cautiously monitored and any adverse events will be collected. The dose will be increased at 160 mg daily 13±2 days after aortic valve intervention and, if well tolerated, for the remaining period of the study. The tolerance will be regularly assessed and dose adjusted according to a pre-specified algorithm.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Patients with the diagnosis of severe AS and indication for valve intervention (i.e. SAVR or TAVR) fulfilling all inclusion/exclusion criteria will be randomized using 1:1 ratio.
| Arm | Type | Receives |
|---|---|---|
| Valsartan | Experimental | Drug: ValsartanThe active treatment is valsartan, an orally active, potent, and specific angiotensin II receptor antagonist. The treatment will be initiated (80 mg, daily) at 5±4 days following aortic valve intervention. The dose will be increased at 160 mg daily 13±2 days after aortic valve intervention and, if well tolerated, for the remaining period of the study. |
| Placebo Oral Tablet | Placebo comparator | Drug: Placebo Oral TabletThe comparative treatment will be a placebo; tablets of valsartan and placebo have a similar appearance and administration mode. Patient in the control group will receive a placebo using the same protocol as the valsartan group. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Men with age ≥18 years
- Women at postmenopausal state as defined by absence of menses for the last 12 months without alternative medical cause.
- Severe AS, defined according most recent guidelines (aortic valve area <1.0cm² or <0.6cm²/m² and aortic mean pressure gradient ≥40mmHg or aortic maximal velocity >4m/s, as assessed using transthoracic echocardiography [TTE]).
- Indication for aortic valve intervention
- Affiliation to the French Social Security system
Key exclusion criteria (23 listed)
- Patients already under any Renin-Angiotensin-Aldosterone System blockers (RAASb) prior to randomization.
- Concomitant coronary artery bypass graft or other valvular intervention
- Other significant left-sided valvular heart diseases (≥moderate), even without concomitant procedure
- Any contra-indication to CMR
- Chronic kidney disease with estimated glomerular filtration rate (GFR) <30 ml/min
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 |
|---|---|---|
| ValsartanThe active treatment is valsartan, an orally active, potent, and specific angiotensin II receptor antagonist. The treatment will be initiated (80 mg, daily) at 5±4 days following aortic valve intervention. The dose will be increased at 160 mg daily 13±2 days after aortic valve intervention and, if well tolerated, for the remaining period of the study. | Drug | Valsartan |
| Placebo Oral TabletThe comparative treatment will be a placebo; tablets of valsartan and placebo have a similar appearance and administration mode. Patient in the control group will receive a placebo using the same protocol as the valsartan group. | Drug | Placebo Oral Tablet |
Primary outcome
Indexed left ventricular mass
Time frame: Day 0 to Year 1
the 1-year change from baseline in indexed LVM after aortic valve intervention as assessed using cardiac magnetic resonance (CMR)
21 secondary outcomes
Left ventricular global longitudinal strain
Time frame: Day 0 to Year 1
Left ventricular global longitudinal strain
Time frame: Day 0 to Year 1
Left atrial volume
Time frame: Day 0 to Year 1
Left atrial volume
Time frame: Day 0 to Year 1
Indexed left ventricular mass
Time frame: Day 0 to Year 1
Native T1
Time frame: Day 0 to Year 1
Rate of late gadolinium enhancement (LGE)
Time frame: Day 0 to Year 1
Volume of late gadolinium enhancement (LGE)
Time frame: Day 0 to Year 1
Extra cellular volume
Time frame: Day 0 to Year 1
Indexed interstitial volume
Time frame: Day 0 to Year 1
Electrocardiographic strain
Time frame: Day 0 to Year 1
Left ventricular ejection fraction
Time frame: Day 0 to Year 1
Left ventricular ejection fraction
Time frame: Day 0 to Year 1
Peak exercise VO2
Time frame: Year 1
VE/VCO2 ratio
Time frame: 1 year
Maximal load
Time frame: 1 year
New-York heart association functional class
Time frame: 1 year
Exercise oscillatory ventilation rate
Time frame: 1 year
Nt-pro Brain natriuretic peptide
Time frame: Day 0 to Year 1
Plasma cardiac troponin I
Time frame: Day 0 to Year 1
Incidence of treatment-Emergent Adverse Events
Time frame: Day 1 to Month 13
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Mar 2023.
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Valsartan in people with Aortic Valve Stenosis and Valsartan, run by University Hospital, Limoges at 1 site in France.
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 6 inclusion and 23 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: withdrawn, as of the sponsor's last update on 17 Mar 2023. 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 France. 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 combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Indexed left ventricular mass (time frame: Day 0 to Year 1). 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 17 Mar 2023.