Percutaneous or Surgical Repair In Mitral Prolapse And Regurgitation for ≥60 Year-olds (PRIMARY)

Study Overview
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Brief Summary
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This is a prospective, multicenter, open-label, randomized trial comparing mitral valve (MV) transcatheter edge-to-edge repair (TEER) to surgical repair (1:1 ratio) in patients with primary, degenerative mitral regurgitation (MR). The trial will be conducted in the U.S., Canada, Germany and the United Kingdom, and is designed as a strategy trial. Thus, all devices legally marketed for TEER of primary degenerative MR in a particular country are eligible to be used in this trial.

Detailed Description
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The primary aim of this study is to evaluate the long-term effectiveness and safety of MV TEER compared with surgical repair in patients with primary, degenerative MR. The secondary aim is to analyze the relationship between the adequacy of MR correction at one-year post intervention and longer-term clinical outcomes (death, heart failure hospitalizations/urgent care visits, valve re-interventions, and quality of life). The tertiary aim of this trial is to evaluate a range of patient-centered outcomes (quality of life, functional status, and discharge location) of transcatheter edge-to-edge MV repair compared with MV surgical repair in patients with primary, degenerative mitral regurgitation. The patient population for this trial consists of adult patients with severe, primary degenerative MR for whom the local heart team has verified that an indication for MV intervention is present and for whom both transcatheter edge-to-edge and surgical repair strategies are anatomically feasible. Because the use of the commercial edge-to-edge mitral repair device in the U.S. is approved only in patients considered to be at prohibitive risk of MV surgery by a heart team, use of such devices in this trial is considered investigational by the FDA. As such, this trial will be conducted under an Investigational Device Exemption (IDE ). Outcomes will be measured from randomization over a period of 5 years post intervention. The estimated enrollment period is 36 months, and all patients will be followed from randomization for up to 10 years post intervention for particular endpoints. Long-term follow-up will include leveraging administrative datasets linked to clinical trial data.

Official Title
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Percutaneous or Surgical Repair In Mitral Prolapse And Regurgitation for ≥60 Year-olds (PRIMARY)

Conditions
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Mitral Valve Regurgitation

Intervention / Treatment
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* Procedure: Mitral valve repair
* Device: Transcatheter edge-to-edge repair


Participation Criteria
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Eligibility Criteria
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The patient population for this trial consists of adults with severe, primary degenerative MR for whom the local heart team has verified that an indication for MV intervention is present and for whom both transcatheter edge-to-edge and surgical repair strategies are anatomically feasible. Specific inclusion and exclusion criteria are listed below. All patients who meet eligibility criteria will be included in the study regardless of gender, race, or ethnicity. Inclusion Criteria: Adult patients ≥65 yrs with moderately-severe or severe (3+ or 4+/4+) primary degenerative (Carpentier type II) MR defined by transthoracic echocardiography Clinical indication for MV intervention and anatomic candidate for both MV transcatheter edge-to-edge and surgical repair per local heart team assessment Patients across the surgical risk spectrum (low, intermediate, and high risk) depending on the local heart team assessment (see 2020 ACC/AHA guidelines for the management of patients with valvular heart disease) Patients with AF who meet an indication for concomitant ablation may be included provided the local heart team verifies they are eligible for both catheter-based and surgical ablation. Ability to perform 6-minute walk test (6MWT) and complete Kansas City Cardiomyopathy Questionnaire (KCCQ) instrument Exclusion Criteria: Non-degenerative types of primary MR (e.g., cleft leaflet) Secondary or functional MR Hypertrophic obstructive cardiomyopathy Presence of an IVC filter or pacing/ICD leads that would interfere with TEER per local heart team assessment Known allergic reactions to intravenous contrast Febrile illness within 30-days prior to randomization Any absolute contraindication to transesophageal echocardiography Any contraindication to systemic heparinization including active bleeding diatheses, and heparin induced thrombocytopenia Patients with CAD requiring revascularization Any prior mitral valve intervention or any prior repair of atrial septal defect Any prior MV intervention or any prior repair of atrial septal defect Need for any of the following concomitant procedures: aortic valve or aortic surgery, tricuspid valve surgery Need for any emergency intervention or surgery Active endocarditis Hemodynamic instability defined as cardiac index <2.0 l/min/m2 or systolic blood pressure <90mmHg or need for inotropic support or any mechanical circulatory support Left ventricular ejection fraction <25% Intracardiac mass or thrombus Co-morbid medical or oncologic condition for which local heart team believes that meaningful survival beyond 2 years is unlikely Active substance abuse Suspected inability to adhere to follow-up Treatment with another investigational drug or other intervention, assessment of which has not completed its primary endpoint or that clinically interferes with the present study endpoints.

Ages Eligible for Study
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Minimum Age: 65 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
Interventional Model Description: Eligible and consented patients will be randomized 1:1 to a TEER versus surgical repair. Patient randomization will be stratified by clinical site and by surgical risk profile, namely low, intermediate, and high surgical risk. Primary effectiveness will be analyzed by intention-to-treat; that is, the patients will be grouped by their assignment at randomization whether or not they actually received the treatment to which they were assigned.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Surgical mitral valve repair<br>Patients who are randomized to the surgical arm will undergo mitral surgery. | Procedure: Mitral valve repair<br>* Patients who are randomized to the surgical arm will undergo mitral surgery. Mitral surgery will be conducted using general anesthesia and cardiopulmonary bypass. Mitral surgery may be performed via a sternotomy or a right thoracotomy approach with or without robotic assistance. Standard techniques commonly include a ring or band annuloplasty to correct and prevent annular dilatation; leaflet prolapse and redundancy may be corrected by leaflet resection techniques and / or chordal reconstruction.<br>* Other names: Mitral valve surgery;|
| Active Comparator: Transcatheter edge-to-edge repair<br>In the transcatheter edge-to-edge repair arm, patients will be treated with a commercially-approved edge-to-edge mitral repair device. | Device: Transcatheter edge-to-edge repair<br>* Patients will be treated with a commercially-approved edge-to-edge mitral repair device. The steerable guide catheter (guide) is inserted into the femoral vein and advanced across the inter-atrial septum using image guided puncture. Fluoroscopic and echocardiographic guidance will be used to visualize the devices and assess the repair. The guide is positioned over the MV and the clip/clasp delivery system is inserted into the guide and positioned over the MV in accordance with the manufacturer's instructions. The delivery catheter is advanced until the clip/clasp emerges from the tip of the guide into the left atrium. The catheter is manipulated using the control handle until the clip/clasp is correctly oriented with respect to the line of coaptation of the mitral valve. The clip/clasp is opened, and advanced across the mitral valve into the left ventricle then pulled back to grasp the leaflets.<br>* Other names: TEER;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality, valve re-intervention, hospitalizations and urgent visits for heart failure, or onset of ≥ 3+ MR (by transthoracic echocardiogram (TTE)) composite score. | Composite score of all-cause mortality, valve re-intervention, hospitalizations and urgent visits for heart failure, or onset of ≥ 3+ MR (by transthoracic echocardiogram (TTE)) from randomization to a minimum follow-up of 3 years post randomization (including a one-month post intervention blanking period for HF hospitalizations/urgent visits). Composite score will be expressed as a Z-score - The Z-Score is a statistical measurement of a score's relationship to the mean in a group of scores. A Z-score of 0 is equal to the mean, with negative numbers indicating values lower than the mean and positive values higher than the mean. | 3 years post intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adequacy of MR correction | Adequacy of MR correction at one year post intervention, defined as < 2+ MR as assessed by TTE | one year post intervention | 
| Kansas City Cardiomyopathy Questionnaire (KCCQ) | Disease-specific quality of life as measured by the KCCQ at 6-month time intervals up to 5 years. KCCQ has 23 items that map to 7 domains: symptom frequency; symptom burden; symptom stability; physical limitations; social limitations; quality of life; and self-efficacy. The symptom frequency and symptom burden domains are merged into a total symptom score, which can be combined with the physical limitation domain to create a clinical summary score. All scores are scaled 0 to 100, with higher scores indicating better health outcome. | up to 10 years post intervention | 
| Procedure failure | Procedure failure defined as residual moderately severe or severe (3+ or 4+/4+) MR at the end of the procedure, or conversion of a TEER to an open surgical repair or replacement, or conversion of a surgical mitral valve repair to a mitral valve replacement procedure. | End of procedure | 
| Procedure failure | Procedure failure defined as residual moderately severe or severe (3+ or 4+/4+) MR at the end of the procedure, or conversion of a TEER to an open surgical repair or replacement, or conversion of a surgical mitral valve repair to a mitral valve replacement procedure. | 10 years post randomization | 
| All-cause mortality | All-cause mortality through 5 years post randomization | 5 years post randomization | 
| All-cause mortality | All-cause mortality from randomization through 10 years post intervention | 10 years post intervention | 
| Cardiovascular and non-cardiovascular mortality | Cardiovascular and non-cardiovascular mortality from randomization through 5 years post intervention | 5 years post intervention | 
| Cardiovascular and non-cardiovascular mortality | Cardiovascular and non-cardiovascular mortality from randomization through 10 years post intervention | 10 years post intervention | 
| Valve re-interventions | Valve re-interventions through 5 years post intervention | 5 years post intervention | 
| Valve re-interventions | Valve re-interventions through 10 years post intervention | 10 years post intervention | 
| Serious or protocol-defined adverse events | Serious or protocol-defined adverse events, including stroke, acute kidney injury (AKI), and renal failure, through 5 years | 5 years post intervention | 
| MR grade | Mitral Regurgitation (MR) grade as mild, moderate, or severe. (grade I-IV, with higher grade indicating poorer health outcomes.) | through 5 years post intervention | 
| Left Ventricular Ejection Fraction (LVEF) | Left ventricular ejection fraction (LVEF) is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. | through 5 years post intervention | 
| Left Ventricular End Diastolic Dimension (LVEDD) | Left ventricular end diastolic dimension (LVEDD) is the diameter across the left ventricle of the heart at the end of diastole, that is, when the heart muscle is maximally relaxed, and usually corresponds to its largest diameter. | through 5 years post intervention | 
| Left Ventricular End Systolic Dimension (LVESD) | Left ventricular end systolic dimension (LVESD) is the diameter across the left ventricle of the heart at the end of systole, that is, when the heart muscle is maximally contracted, and usually corresponds to its smallest diameter. | through 5 years post intervention | 
| Left Ventricular End Diastolic Volume (LVEDV) | Left Ventricular end diastolic volume (LVEDV) is the volume of blood in the left ventricle at the end of the diastole or ventricular filling. | through 5 years post intervention | 
| Left Ventricular End Systolic Volume (LVESV) | Left Ventricular end systolic volume (LVESV) is the volume of blood in the left ventricle at the end of the systolic ejection phase immediately before the beginning of diastole or ventricular filling. | through 5 years post intervention | 
| Mitral valve gradient | The valve gradient is the difference in pressure on each side of the valve. When a valve is narrowed (a condition called stenosis), the pressure on the front of the valve builds up as blood is forced through the narrow opening. This causes a larger pressure difference between the front and back of the valve. The valve gradient can be used to determine the severity of the valve disorder. | through 5 years post intervention | 
| Forward stroke volume | The forward stroke volume is the volume entering the aorta. | through 5 years post intervention | 
| 6 Minute Walk Test (6MWT) | Functional status as measured by the 6MWT at yearly time intervals over 5 years. 6MT - The distance covered over a time of 6 minutes | through 5 years post intervention | 
| EuroQol- 5 Dimension (EQ-5D) | Generic QoL as measured by the EuroQol-5D (EQ-5D). The EQ-5D descriptive system is a preference-based HRQL measure with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The answers given to ED-5D permit to find 243 unique health states or can be converted into EQ- 5D index an utility scores anchored at 0 for death and 1 for perfect health. The EQ-5D questionnaire also includes a Visual Analog Scale (VAS), by which respondents can report their perceived health status with a grade ranging from 0 (the worst possible health status) to 100 (the best possible health status). | through 10 years post intervention | 
| Length of stay (LOS) | Length of stay as measured by number of days hospitalized. | through 10 years post intervention | 
| ICU days of index hospitalization | Number of ICU days of index hospitalization | through 10 years post intervention | 
| Number and reasons for readmissions | Number and reasons for readmissions, including for valve re-intervention and readmissions/urgent visits for heart failure | through 10 years post intervention | 
| Cost | Costs associated with the index hospitalization as well as follow-up readmissions will be measured. | through 10 years post intervention | 
| Cost-effectiveness | A cost-effectiveness analysis (CEA) comparing cumulative costs and quality-adjusted life years (QALYs) of transcatheter edge-to-edge repair vs surgical repair will be performed from U.S., Canadian, German and United Kingdom health care sector perspectives according to national guidelines. | through 10 years post intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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surgical mitral valve repair, transcatheter edge-to-edge repair