PRIMARY Ancillary Substudy

Official title

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

Overview

The PRIMARY trial (NCT05051033), which compares mitral valve repair (MVr) to transcatheter-edge-to-edge-repair (TEER), offers a platform for conducting mechanistic studies to develop early insights into the pathophysiological processes by which mitral valve prolapse (MVP) can impact left ventricular (LV) myocardial structure and function, and, thereby, predispose to arrhythmias and sudden death. Such insights are key to identifying interventions to reduce the long-term sequelae of heart failure (HF) and arrhythmias, as well as delineate optimal therapeutic approaches for different patient sub-groups.

Detailed description

This is an ancillary study of a multicenter randomized clinical trial comparing MVr to TEER for degenerative mitral regurgitation (MR) involving up to 250 patients from the parent trial. All patients will receive rhythm monitoring, up to 200 patients will receive pre/post intervention CMR, all patients in the parent trial will undergo a transthoracic echocardiogram (TTE) (as part of the randomized controlled trial (RCT)), and 60 surgical patients will undergo tissue biopsies. The study is being conducted in highly experienced clinical centers in the U.S., Canada, Germany, the U.K. and Spain. The estimated enrollment period is 12-18 months. Outcomes will be measured from baseline to 12 months after randomization.

This mechanistic ancillary study has the following aims:

1. To compare the impact of MVr and TEER on disordered ventricular biomechanics and myocardial fibrosis that predispose to ventricular arrhythmias, using speckle tracking strain echocardiography, cardiac magnetic resonance imaging (CMR), and rhythm monitoring pre- and post-mitral valve (MV) intervention. The research team hypothesize's that a treatment strategy that more effectively and durably reduces MVP and MR will lead to improved ventricular mechanics, limit progression of myocardial fibrosis and decrease the burden of ventricular arrhythmias and HF. 2. To compare the impact of MVr and TEER on recurrent/residual MR, LV and left atrial (LA) reverse remodeling with baseline and 1-year post-intervention CMR, and to use quantitative CMR myocardial tissue phenotyping as a predictor of response to MVr and TEER. 3. To construct functional pre-operative CMR fingerprints that recapitulate the mechanical state of the heart to develop individualized computational models, which will be altered in silico based on the proposed treatment plan, to predict patients' response to therapy. These results will be validated against post-operative outcome data to test the validity of this approach for predicting treatment response. 4. To explore the relationships among gene products, structural variables, and post-operative clinical outcomes, including reverse remodeling, using tissue obtained at surgery from ventricular myocardium.

Interventions

• Procedure Cardiac Magnetic Resonance Imaging
  Non-invasive imaging test that uses powerful magnets and radio waves to create detailed pictures of the heart without using radiation.
• Device ZioPatch Monitoring
  ZioPatch is a small, wearable heart monitor that sticks to the chest and records the heart's electrical activity continuously for up to 14 days. It helps doctors detect irregular heart rhythms (arrhythmias) without the need for bulky wires or equipment.
• Procedure Myocardial Tissue Biopsy
  During the MVr procedure, surgeons will biopsy approximately 50 μg of tissue from the endocardial and subendocardial myocardium in the inferobasilar and control areas using a surgical rongeur.

Primary outcome measures

• Presence of Myocardial Fibrosis [Time frame: 1 year post index procedure.]
• Presence of Ventricular Arrythmia [Time frame: 1 year post index procedure.]
• Proteomics [Time frame: 1 year post index procedure.]

Secondary outcome measures (1)

• Computational and Predictive Models of Treatment Outcome [Time frame: 1 year post index procedure.]

Eligibility criteria

Inclusion criteria

• Patients who meet all eligibility criteria and are randomized in the parent PRIMARY trial.
• For the ancillary biospecimen study, patients who are randomized to MVr in the parent trial.

Exclusion criteria

• Severe claustrophobia not controlled with sedation.
• Prior adverse reaction to gadolinium administration.
• Patients with an implantable subcutaneous cardioverter defibrillator and/or cardiac resynchronization therapy device with defibrillator may be excluded as they typically produce substantial artifacts on cardiac MRI making assessment very challenging.
• Known allergic reaction to adhesives or hydrogels or with family history of adhesive skin allergies (for patients undergoing rhythm monitoring).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Basic science

Study locations

United States · 16 centers

• Keck Hospital of the University of Southern California — Los Angeles
• Cedars-Sinai — Los Angeles
• University of California San Francisco — San Francisco
• Stanford University — Stanford
• Piedmont Heart Institute — Atlanta
• Maine Medical Center — Portland
• The Johns Hopkins Hospital — Baltimore
• Massachusetts General Hospital — Boston
• … and 8 more centers

United Kingdom · 7 centers

• Royal Papworth Hospital NHS Foundation Trust — Trumpington
• The Leeds Teaching Hospitals NHS Trust — Leeds
• Barts Health NHS Trust — Whitechapel
• Manchester University NHS Foundation Trust — Oxford
• South Tees Hospitals NHS Foundation Trust — Marton-in-Cleveland
• Oxford University Hospitals NHS Foundation Trust — Oxford
• University Hospitals Sussex NHS Foundation Trust — Worthing

Germany · 2 centers

• Deutsches Herzzentrum der Charité — Berlin
• Herzzentrum Leipzig — Leipzig

Identifiers

NCT: NCT07103733 · GCO 08-1078 ANC · 5U01HL088942-17

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗