Evaluation of Tricuspid Valve Percutaneous Repair System in the Treatment of Severe Secondary Tricuspid Disorders

Study Overview
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Brief Summary
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Tricuspid regurgitation (TR) is a long-overdue valvular pathology. Its prevalence is significant and increasing with the aging of the population. It is often a consequence of chronic left cardiac pathologies or atrial fibrillation. Surgical treatment is recommended in severe symptomatic TR or when the tricuspid annulus is dilated with TR identified prior to scheduled left heart valve surgery. TR are mainly secondary (complicating left heart disease, pulmonary hypertension, atrial fibrillation and atrial dilatation) and pose a difficult problem related to the prognosis. The risk of death or hospitalization is high under medical treatment. Nevertheless, the surgical results are disappointing with significant morbidity and mortality, which are increased by associated comorbidities that are frequent in these sorts of patients. The benefit-risk assessment of surgery is limited by multiple confounders. This justifies the evaluation of alternative methods aimed at correcting TR with less interventional risk. The Clip for the tricuspid valve has been evaluated in the TRILUMINATE trial (inclusion of 85 patients with moderate-to-severe symptomatic TR with a 6-month follow-up). The Triclip system appears to be safe and effective at reducing tricuspid regurgitation by at least one grade. This reduction could translate to significant clinical improvement at 6 months post-procedure. It justified the European Conformity (CE) mark obtention. A very similar system for the mitral valve (Mitraclip) was previously tested in the randomized EVEREST II study against conventional surgery. The results of the EVEREST II trial justified the recourse to percutaneous edge-to edge mitral repair in patients with primary mitral regurgitation when the patient is contraindicated to conventional surgery. The Mitra-FR study made it possible to study the role of Mitraclip for treating patient suffering from a secondary mitral insufficiency. It leads to the implementation of this technique in selected patients. For secondary TR, several series underscored its prevalence and its clinical consequences. TR treatment justifies the proposal for a randomized study. As a matter of fact, evidence for treating are seriously lacking. Surgical surveys report hospital mortality   8.8%. It, therefore, seems necessary to conduct a study as robust as possible to evaluate the contribution of clip for the tricuspid valve (as an innovative percutaneous technique) compared to conventional pharmacological treatment in patients who are unsuitable for a surgical isolated correction of the TR and who has suitable anatomy for clip for the tricuspid valve. It will be necessary to demonstrate clinical, functional (quality of life), echocardiographic and biological benefit of the percutaneous treatment vs optimized medical treatment alone.

Detailed Description
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The principal objective is to demonstrate, over a period of 12-month after randomization, that, on the Packer composite clinical endpoint (CCS) (combining NYHA class, patient global assessment (PGA) and major cardio-vascular events), the tricuspid valve percutaneous repair strategy with clip for the tricuspid valve is superior to best (optimized) medical treatment (BMT) in symptomatic patients with at least severe secondary TR. The Packer clinical composite score is eventually a three-level ordered categorical endpoint, each randomized patient being classifying as improved, unchanged, or worsen, depending on the clinical response over the follow-up period and at 12 months.

Official Title
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TRI-FR : Multicentric Randomized Evaluation of Tricuspid Valve Percutaneous Repair System (Clip for the Tricuspid Valve) in the Treatment of Severe Secondary Tricuspid Disorders

Conditions
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Tricuspid Regurgitation

Intervention / Treatment
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* Procedure: Tricuspid valve
* Other: Best medical treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pre-Inclusion Criteria: Age ≥ 18 years Symptomatic secondary (at least) severe TR (Carpentier Type IIIB (restrictive) and / or I (tricuspid annulus dilation)) stable for at least 30 days NYHA functional class II to IV without cirrhosis and/or ascites Signs of heart failure in the previous 12-months with or without having been hospitalized Stable optimized medical and/or interventional treatment Ineligible for corrective action on the valve by surgical approach after a specialized multidisciplinary consultation (heart team) including at least a cardio-thoracic surgeon, an interventional cardiologist, an imaging-cardiologist and an Anesthesiologist). Signature of an informed consent Definitive Inclusion Criteria: Central core-laboratory analysis : TR characterized before Implantation by at least one of the following criteria: Regurgitation volume > 45 mL / beat Surface of the regurgitant orifice > 40 mm² Vena contracta> 7mm Gap between leaflets ≤ 10 mm (at the presumed location of the clip) Then after the TR severity grading; the Clinical eligibility Committee will valid the inclusion. Non Inclusion Criteria: Patient treated with Mitraclip or other percutaneous approach on the mitral valve in the past 3-month Any prior tricuspid valve procedure that would interfere with placement of the Triclip device Tricuspid valve leaflet anatomy which may preclude clip implantation, proper clip positioning on the leaflets or sufficient reduction in TR. This may include: Tricuspid valve anatomy not evaluable by TTE and TEE Active endocarditis Evidence of calcification in the grasping area Evidence of stenosis (mean pressure gradient > 5 mmHg or surface area ≤1cm² Presence of a severe coaptation defect (> 1cm) of the tricuspid leaflets Severe leaflet defect(s) preventing proper device placement Epstein anomaly - identified by having a normal annulus position while the valve leaflets are attached to the walls and septum of the right ventricle Myocardial infarction or coronary bypass surgery in the past 3-month Left ventricular ejection fraction ≤35% Cardiac Resynchronization therapy for less than 3-month and patients having a TR that is clearly related to the right ventricular lead positioning Cardioversion for less than 6 weeks Life expectancy irrespective of the valvular heart disease <1 year (due to co-morbidities) Other scheduled cardiac surgery (including registration in cardiac transplant list) Coronary angioplasty in the preceding month Current infection requiring prescription of antibiotics End-stage renal failure (dialysis patient) Severe hepatic insufficiency (disruption of liver metabolism associated with coagulation disorders (factor V <50%)) Stroke in the previous 3-month Uncontrolled pre- capillary pulmonary hypertension (right catheterization required) (systolic pulmonary pressure > 60 mmHg) Tricuspid prosthetic valve Pace maker lead or ICD lead that would prevent appropriate placement of the Triclips Nitinol allergy Contraindication, allergy or hypersensibility to dual anti-platelet and anticoagulant therapy Ongoing infection requiring antibiotic therapy Evidence of intra vascular or intra cardiac thrombus Patient who are included in another research protocol Protected person (adults legally protected (under judicial protection, guardianship or supervision), person deprived of their liberty, pregnant woman, lactating woman and minor) Absence of coverage by a social security scheme

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tricuspid valve<br>tricuspid valve percutaneous repair strategy with clip for the tricuspid valve | Procedure: Tricuspid valve<br>* Clip for the tricuspid valve implantation on top of best medical therapy<br>|
| Other: Best medical treatment<br> | Other: Best medical treatment<br>* Best medical therapy alone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Milton Packer clinical composite score | Milton Packer clinical composite score classifies each patient into 1 of 3 categories (improved, worsened, unchanged), and is determined aggregating evaluation functional using NYHA class, quality of life score using patient global assessment and number of major cardio-vascular events | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of participants with all-cause mortality |  | 12 months | 
| number of participants with tricuspid valve surgery |  | 12 months | 
| rate of heart failure hospitalizations |  | 12 months | 
| assessment of quality of life improvement | Kansas City Cardiomyopathy Questionnaire score (KCCQ) The responses are categorized under 3 subscales (symptom burden, physical limitation and quality of life) with a range of possible subscale scores from 0 to 100, with 100 representing the least burden of symptoms. The total KCCQ score represents the mean of the three subscale scores. | 0 and 12 months | 
| quality of life score | Kansas City Cardiomyopathy Questionnaire (KCCQ) The responses are categorized under 3 subscales (symptom burden, physical limitation and quality of life) with a range of possible subscale scores from 0 to 100, with 100 representing the least burden of symptoms. The total KCCQ score represents the mean of the three subscale scores. | 6 and 12 months | 
| quality of life score | Minnesota Living with Heart Failure (MLHF) | 6 and 12 months | 
| quality of life score | EQ5D-5L The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system : 5 dimensions : mobility, self-care, usual activities, pain/discomfort, anxiety/depression. 5 levels : no problems,slight problems, moderate, problems and extreme. Each level corresponds to 1 digit number. The digits for the 5 dimensions are combined into a 5-digit number. The EQ VAS : on a vertical visual analogue scale, 100 'The best health you can imagine' 0 'The worst health you can imagine'. | 6 and 12 months | 
| quality of life score | Patient global assessment (PGA) | 6 and 12 months | 
| functional evaluation | NYHA functional class | 6 and 12 months | 
| severity of the Tricuspid Regurgitation (TR) | TR grade | 6 and 12 months | 
| walking distance | 6-minute walk test | 6 and 12 months | 
| echocardiography parameters | right heart function | 6 and 12 months | 
| echocardiography parameters | right heart cavities sizes | 6 and 12 months | 
| echocardiography parameters | degree of tricuspid regurgitation | 6 and 12 months | 
| echocardiography parameters | stenosis | 6 and 12 months | 
| biological parameters | parameters renal : creatinine, clearance, AST | 6 and 12 months | 
| biological parameters | hepatic function | 6 and 12 months | 
| biological parameters | NT-proBNP | 6 and 12 months | 
| overall survival |  | 6 and 12 months | 
| number of cardiovascular death |  | 6 and 12 months | 
| number of major cardiovascular events |  | 6 and 12 months | 
| Incremental Cost-Effectiveness Ratio expressed as cost per QALY |  | 12 and 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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secondary Tricuspid Regurgitation, least severe Tricuspid Regurgitation, symptomatic patients