EXHIBIT B

EXHIBIT B
Protocol Synopsis
Exhibit B to the Clinical Trial Agreement dated March 2, 2026, by and between Thornwick Medical Research Institute, Inc. ("Sponsor") and Hargrove University Medical Center, Inc. ("Institution")
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1. Protocol Title
Cadence-3: A Prospective, Single-Arm, Open-Label Feasibility Study of the ThornValve MV-200 System for Transcatheter Mitral Valve Repair in Patients with Moderate-to-Severe Mitral Regurgitation
The Cadence-3 Trial represents the third in a planned sequence of investigator-initiated feasibility studies designed to evaluate the safety, technical feasibility, and preliminary clinical performance of the ThornValve MV-200 System in patients with clinically significant mitral regurgitation. The study is intended to generate the safety and performance data necessary to inform the design of a future pivotal trial and to support a subsequent premarket approval (PMA) submission to the United States Food and Drug Administration.
2. Protocol Identifiers
The following identifiers have been assigned to the Cadence-3 Trial:
All correspondence relating to this study, whether directed to the Sponsor, the Institution, the FDA, or any regulatory body, should reference the applicable identifiers listed above to ensure accurate identification and tracking of study-related communications.
3. Sponsor
Name: Thornwick Medical Research Institute, Inc.
Address: 280 Longmeadow Drive, Cambridge, MA 02139
Entity Type: Massachusetts nonprofit corporation organized under Section 501(c)(3) of the Internal Revenue Code. Thornwick Medical Research Institute, Inc. is a mission-driven research organization dedicated to the development and clinical translation of novel cardiovascular technologies. The Sponsor assumes all responsibilities of an IDE sponsor as defined under 21 CFR Part 812.
Sponsor Representative — Clinical Development: Dr. Elaine K. Sutherland, M.D. Vice President of Clinical Development Thornwick Medical Research Institute, Inc. 280 Longmeadow Drive, Cambridge, MA 02139 Telephone: (617) 555-4200
Email: esutherland@thornwickmri.org
Dr. Sutherland serves as the primary Sponsor representative responsible for the day-to-day clinical development activities associated with the Cadence-3 Trial, including protocol oversight, regulatory submissions, safety surveillance, and coordination with the clinical site, the Contract Research Organization, and all independent study committees.
Sponsor Representative — Executive: Dr. Ansel R. Varnham, M.D., Ph.D. President & Chief Executive Officer Thornwick Medical Research Institute, Inc. 280 Longmeadow Drive, Cambridge, MA 02139 Telephone: (617) 555-4100
Email: avarnham@thornwickmri.org
Dr. Varnham provides executive-level oversight of the Cadence-3 program and is authorized to execute agreements and make strategic decisions on behalf of the Sponsor in connection with the trial.
4. Investigational Site
Institution: Hargrove University Medical Center, Inc.
Address: 1400 Sterling Heights Boulevard, New Haven, CT 06510
Entity Type: Connecticut nonprofit corporation, academically affiliated with Hargrove University. Hargrove University Medical Center operates as a tertiary care academic medical center and serves as the primary teaching hospital for the Hargrove University School of Medicine.
Study Configuration: The Cadence-3 Trial is designed and authorized as a single-site study. All subject enrollment, index procedures, and scheduled follow-up assessments will be conducted at Hargrove University Medical Center. The decision to conduct this feasibility study at a single site reflects both the early-stage nature of the investigational device program and the exceptional institutional capabilities of Hargrove University Medical Center in the area of structural heart interventions.
Institutional Experience: Hargrove University Medical Center's Structural Heart Center is a nationally recognized program with extensive experience in transcatheter valve therapies. The Structural Heart Center performs approximately 650 transcatheter valve procedures annually, encompassing transcatheter aortic valve replacement (TAVR), transcatheter mitral valve repair, transcatheter tricuspid valve interventions, and related structural heart procedures. This volume of procedural activity provides the Institution with the depth of institutional experience, clinical infrastructure, specialized imaging capabilities, and dedicated support staff necessary to conduct the procedures contemplated in the Cadence-3 Trial safely and effectively. The Structural Heart Center maintains dedicated catheterization and hybrid operating room suites equipped with state-of-the-art fluoroscopic imaging systems, intraoperative transesophageal echocardiographic capabilities, and advanced hemodynamic monitoring.
5. Principal Investigator and Sub-Investigator
5.1 Principal Investigator
Name: Dr. Julian M. Castañeda, M.D., FACC
Title: Professor of Cardiovascular Medicine, Hargrove University School of Medicine; Director, Structural Heart Interventions Program, Hargrove University Medical Center
Qualifications: Dr. Castañeda is a board-certified interventional cardiologist with over 18 years of experience in transcatheter valve therapies, including transcatheter aortic valve replacement, transcatheter mitral valve repair, and emerging transcatheter tricuspid and pulmonary valve interventions. He has served as the principal investigator on nine prior medical device clinical trials, including multi-center pivotal studies for two commercially available transcatheter heart valve systems. Dr. Castañeda is the author of over 140 peer-reviewed publications in the field of structural heart disease and interventional cardiology. He is a Fellow of the American College of Cardiology (FACC) and has received multiple national and international awards recognizing his contributions to the advancement of transcatheter valve therapies. Dr. Castañeda will serve as the Principal Investigator for the Cadence-3 Trial and will assume overall responsibility for the conduct of the study at Hargrove University Medical Center, including subject enrollment, procedural performance, data integrity, regulatory compliance, and safety reporting, in accordance with the obligations set forth in the Clinical Trial Agreement, the Protocol, and applicable FDA regulations.
5.2 Sub-Investigator.  Name: Dr. Hannah L. Forsberg, M.D.
Title: Associate Professor of Cardiovascular Medicine, Hargrove University School of Medicine; Associate Director, Structural Heart Interventions Program, Hargrove University Medical Center
Qualifications: Dr. Forsberg is a board-certified interventional cardiologist with specialized expertise in mitral valve disease. She has been designated as Co-PI for the Cadence-3 Trial and will serve as the primary sub-investigator under the supervision of Dr. Castañeda. Dr. Forsberg has extensive experience in catheter-based mitral valve interventions, including clip-based repair, annuloplasty, and chordal replacement technologies. She will assist the Principal Investigator in the conduct of study procedures, subject evaluations, and safety assessments, and will assume the responsibilities of the Principal Investigator in the event of his absence or unavailability, as authorized under the Clinical Trial Agreement and the delegation of authority log maintained at the study site.
Additional sub-investigators and qualified study personnel may be added by the Principal Investigator with appropriate delegation and documentation, as required by 21 CFR Part 812 and GCP guidelines.
6. Investigational Device
Device Name: ThornValve MV-200 System
Device Type: Transcatheter Mitral Valve Repair Device
Description: The ThornValve MV-200 System is a proprietary transcatheter mitral valve repair system developed by Thornwick Medical Research Institute, Inc. The system consists of a catheter-based delivery platform designed for percutaneous, transseptal repair of the mitral valve in patients with clinically significant mitral regurgitation. The device is delivered via the femoral venous approach, advanced through the interatrial septum under fluoroscopic and echocardiographic guidance, and deployed at the mitral valve leaflets to achieve leaflet coaptation and reduction in mitral regurgitation severity. The ThornValve MV-200 System is intended to reduce mitral regurgitation severity without the need for open-heart surgery, offering a less invasive alternative for patients who are considered high-risk or inoperable for conventional surgical mitral valve repair or replacement.
The ThornValve MV-200 System comprises the following principal components:
(a) Delivery Catheter: A steerable, multi-lumen catheter designed for transseptal access and precise positioning at the mitral valve annulus. The delivery catheter incorporates proprietary deflection and stabilization mechanisms to facilitate accurate device deployment under real-time imaging guidance.
(b) Implant Device: A self-expanding, nitinol-based leaflet repair element designed to grasp and approximate the anterior and posterior mitral valve leaflets, restoring effective leaflet coaptation and reducing regurgitant flow. The implant is available in multiple sizes to accommodate varying mitral valve anatomies.
(c) Guiding Sheath and Accessories: A transseptal guiding sheath and associated accessories necessary for femoral venous access, interatrial septum crossing, and device delivery.
Regulatory Status: The ThornValve MV-200 System is an investigational device that has not been cleared or approved by the United States Food and Drug Administration for commercial distribution. The device is authorized for investigational use exclusively within the context of the Cadence-3 Trial under FDA Investigational Device Exemption (IDE) Number G260012, granted by the FDA's Center for Devices and Radiological Health (CDRH). The Cadence-3 Trial is the third in a series of investigator-initiated feasibility studies designed to generate the safety and performance data necessary to support a future pivotal trial submission to the FDA. Prior feasibility studies (Cadence-1 and Cadence-2) have been completed and their data have been reviewed by the FDA in connection with the approval of the current IDE.
Device Supply: All ThornValve MV-200 System devices, including delivery catheters, implant devices, guiding sheaths, and all associated accessories, will be supplied by the Sponsor at no cost to the Institution or to enrolled study subjects. The Sponsor will maintain an adequate inventory of devices at the study site or arrange for timely shipment in advance of each scheduled procedure. All devices will be tracked through the Sponsor's device accountability system in compliance with 21 CFR § 812.140. Unused or explanted devices will be returned to the Sponsor in accordance with the procedures set forth in the Protocol and the Clinical Trial Agreement.
7. Study Design
The design of the Cadence-3 Trial is summarized as follows:
The single-arm, open-label design is appropriate for the feasibility stage of the device development program. The primary purpose of the Cadence-3 Trial is to establish the initial safety profile and technical performance of the ThornValve MV-200 System in a carefully selected patient population, rather than to demonstrate comparative effectiveness. The data generated from this feasibility study, combined with data from the prior Cadence-1 and Cadence-2 studies, will inform the design of a subsequent randomized, controlled pivotal trial.
Because this is a single-arm, non-randomized study, outcome data will be interpreted in the context of published benchmarks for mitral valve interventions and natural history data for the target patient population. Independent adjudication of all primary endpoint events by the Clinical Events Committee and centralized echocardiographic assessment by an independent core laboratory will mitigate potential bias inherent in the open-label study design.
8. Study Objectives
8.1 Primary Objective
The primary objective of the Cadence-3 Trial is to evaluate the safety and technical feasibility of the ThornValve MV-200 System for transcatheter mitral valve repair in patients with moderate-to-severe mitral regurgitation. This objective encompasses both an assessment of the acute and short-term safety of the device implantation procedure and an evaluation of the ability of the device to be successfully delivered, deployed, and positioned at the mitral valve to achieve a clinically meaningful reduction in mitral regurgitation severity.
8.2 Secondary Objectives
The secondary objectives of the Cadence-3 Trial are as follows:
(a) To assess the procedural success rate, defined as successful device implantation with reduction of mitral regurgitation severity by at least one grade at 30 days post-procedure, as confirmed by independent echocardiographic core laboratory assessment.
(b) To evaluate clinical outcomes, including improvement in New York Heart Association (NYHA) functional class, change in 6-minute walk test distance, and change in patient-reported quality of life measures (Kansas City Cardiomyopathy Questionnaire, 12-item version [KCCQ-12] and Short Form Health Survey [SF-36]) at 12 and 24 months post-procedure.
(c) To characterize the safety profile of the ThornValve MV-200 System through systematic assessment of major adverse events (MAEs), including all-cause mortality, stroke, device embolization, emergent cardiac surgery for device-related complications, and major bleeding, through 24-month follow-up.
8.3 Exploratory Objectives
The exploratory objectives of the Cadence-3 Trial are designed to generate hypothesis-generating data and to inform the design of a future pivotal trial. These objectives include:
(a) To evaluate echocardiographic parameters of mitral valve function and left ventricular remodeling over time, including changes in left ventricular dimensions, volumes, and ejection fraction following device implantation.
(b) To assess biomarker trends, including serial measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, following device implantation, as an objective measure of neurohormonal response and hemodynamic improvement.
(c) To generate sufficient data regarding safety, performance, and clinical outcomes to support the design of a future randomized, controlled pivotal trial, including estimation of effect sizes and variability for sample size calculations.
9. Study Population
9.1 Planned Enrollment
The Cadence-3 Trial plans to enroll a total of 45 evaluable subjects at Hargrove University Medical Center. An evaluable subject is defined as a subject who provides informed consent, meets all eligibility criteria, and in whom the ThornValve MV-200 System implantation procedure is attempted. To account for potential screen failures and early withdrawals, the site may screen a larger number of potential subjects as necessary to achieve the target of 45 evaluable subjects.
9.2 Key Inclusion Criteria
To be eligible for enrollment in the Cadence-3 Trial, a subject must meet all of the following inclusion criteria:
1.  Age ≥ 18 years at the time of informed consent.
2.  Moderate-to-severe (3+) or severe (4+) mitral regurgitation, as confirmed by an independent echocardiographic core laboratory based on standardized echocardiographic grading criteria (integrative assessment per American Society of Echocardiography guidelines).
3.  Symptomatic mitral regurgitation (NYHA Functional Class II, III, or IV) despite optimal medical therapy, as determined by the treating heart team. Optimal medical therapy is defined as maximal tolerated doses of guideline-directed medical therapy for heart failure, including, as appropriate, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (or angiotensin receptor-neprilysin inhibitors), mineralocorticoid receptor antagonists, and diuretics, administered for a minimum of 30 days prior to screening.
4.  Suitable mitral valve anatomy for transcatheter repair with the ThornValve MV-200 System, as assessed by pre-procedural transesophageal echocardiography (TEE) and/or cardiac computed tomography (CT), evaluated in accordance with the anatomic eligibility criteria set forth in the full Protocol (Version 3.0).
5.  The subject (or the subject's legally authorized representative, where applicable under state law) provides written informed consent to participate in the study in accordance with 21 CFR Part 50 and the informed consent procedures approved by the HUMC IRB.
6.  The subject is a candidate for the study procedure in the opinion of the local heart team, which must include at a minimum one interventional cardiologist and one cardiac surgeon.
9.3 Key Exclusion Criteria
A subject who meets any of the following exclusion criteria will not be eligible for enrollment in the Cadence-3 Trial:
1.  Prior mitral valve surgery (including surgical repair, surgical replacement, or any prior open surgical intervention on the mitral valve) or prior transcatheter mitral valve intervention (including any prior transcatheter repair or replacement device implantation).
2.  Severe mitral annular calcification, as determined by pre-procedural imaging (TEE and/or cardiac CT), that in the judgment of the heart team precludes safe and effective deployment of the ThornValve MV-200 System.
3.  Active endocarditis or other active systemic infection at the time of screening or at any time prior to the planned procedure.
4.  Severe, uncompensated heart failure requiring inotropic support, mechanical circulatory support (e.g., intra-aortic balloon pump, percutaneous ventricular assist device, or extracorporeal membrane oxygenation), or hospitalization for acute decompensated heart failure within 7 days prior to the planned procedure.
5.  Life expectancy of less than 12 months due to non-cardiac comorbidities, as assessed by the Principal Investigator in consultation with the heart team.
6.  Known hypersensitivity or allergy to any material used in the manufacture of the ThornValve MV-200 System, including but not limited to nickel, titanium, polyester, or other device component materials, as identified in the Investigator's Brochure.
7.  Current participation in another investigational device or investigational drug clinical trial that, in the opinion of the Principal Investigator, may confound study results or interfere with the subject's participation in the Cadence-3 Trial. Participation in observational registries or post-market surveillance studies is not exclusionary.
8.  Pregnancy at the time of screening or planned pregnancy during the study period (from enrollment through the 24-month follow-up visit). Women of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days prior to the index procedure.
9.  Inability or unwillingness to comply with the study follow-up requirements, including all scheduled follow-up visits through 24 months post-procedure, as determined by the Principal Investigator.
Additional inclusion and exclusion criteria are specified in the full Protocol (Version 3.0), which is maintained on file with the Sponsor and the Institution and is incorporated by reference into the Clinical Trial Agreement.
10. Study Endpoints
10.1 Primary Safety Endpoint
The primary safety endpoint of the Cadence-3 Trial is the rate of major adverse events (MAEs) occurring within 30 days post-procedure. The 30-day MAE rate is defined as a composite of the following events:
(a) All-cause death;
(b) Stroke (ischemic or hemorrhagic), as adjudicated by the Clinical Events Committee;
(c) Device embolization (defined as migration of the implant device from its intended position at the mitral valve to another location within the cardiovascular system);
(d) Emergent cardiovascular surgery for device-related complications (defined as any unplanned cardiovascular surgical procedure performed during or within 30 days of the index procedure that is directly attributable to a complication related to the ThornValve MV-200 System);
(e) Life-threatening bleeding, defined as Bleeding Academic Research Consortium (BARC) Type 3b, 3c, or Type 5 bleeding; and
(f) Acute kidney injury requiring new-onset renal replacement therapy (dialysis) within 30 days of the index procedure.
All events contributing to the primary safety endpoint will be independently adjudicated by the Clinical Events Committee in accordance with prespecified endpoint definitions set forth in the CEC Charter.
10.2 Primary Feasibility/Performance Endpoint
The primary feasibility and performance endpoint is the technical success rate, defined as the proportion of subjects in whom the following criteria are met at the time of the index procedure:
(a) Successful delivery and deployment of the ThornValve MV-200 System at the intended mitral valve location; and
(b) Reduction of mitral regurgitation severity to ≤ 2+ (moderate or less) at the time of the index procedure, as assessed by intra-procedural transesophageal echocardiography (TEE) and confirmed by the independent echocardiographic core laboratory.
Technical success will be assessed on a per-subject basis and reported as a proportion with exact binomial 95% confidence intervals.
10.3 Secondary Endpoints
The following secondary endpoints will be assessed in the Cadence-3 Trial:
(a) Freedom from MAEs (as defined in Section 10.1) at 6, 12, and 24 months post-procedure, analyzed using Kaplan-Meier time-to-event methods.
(b) Reduction in mitral regurgitation severity from baseline at 6, 12, and 24 months, as assessed by transthoracic echocardiography and evaluated by the independent echocardiographic core laboratory.
(c) Change in NYHA functional class from baseline to 6, 12, and 24 months post-procedure.
(d) Change in 6-minute walk test distance from baseline to 12 and 24 months post-procedure.
(e) Change in patient-reported quality of life scores, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ-12) and the Short Form Health Survey (SF-36), from baseline to 12 and 24 months post-procedure.
(f) Rates of rehospitalization for heart failure at 12 and 24 months post-procedure.
10.4 Exploratory Endpoints
The following exploratory endpoints will be assessed to generate hypothesis-generating data and inform future study design:
(a) Echocardiographic parameters: Changes from baseline in left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left atrial volume (LAV), and left ventricular ejection fraction (LVEF), assessed at 6, 12, and 24 months post-procedure by the independent echocardiographic core laboratory.
(b) Biomarker analysis: Changes in NT-proBNP levels from baseline through 30 days, 6 months, 12 months, and 24 months post-procedure.
(c) Device durability: Echocardiographic assessment of device integrity, device position stability, and sustained device function at 12 and 24 months post-procedure, including evaluation for device fracture, detachment, or significant device-related mitral stenosis.
11. Study Procedures and Schedule of Assessments
11.1 Screening / Baseline (Pre-Procedure)
The screening and baseline assessment period begins with the provision of written informed consent and continues through the day of the index procedure. The following assessments will be performed during the screening and baseline period:
•  Provision and documentation of written informed consent
•  Comprehensive medical history review, including cardiovascular history, comorbid conditions, prior surgeries, current medications, and allergy history
•  Complete physical examination, including vital signs (blood pressure, heart rate, respiratory rate, temperature, and oxygen saturation)
•  Laboratory testing, including complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), coagulation studies (PT/INR, aPTT), liver function tests, renal function (serum creatinine, estimated glomerular filtration rate), NT-proBNP, and other tests as specified in the Protocol
•  12-lead electrocardiogram (ECG)
•  Transthoracic echocardiography (TTE) for baseline assessment of mitral regurgitation severity, left ventricular function, and cardiac chamber dimensions
•  Transesophageal echocardiography (TEE) for detailed assessment of mitral valve anatomy, leaflet morphology, and suitability for transcatheter repair with the ThornValve MV-200 System
•  Cardiac computed tomography (CT), if applicable, for supplementary anatomic assessment as determined by the heart team
•  6-minute walk test
•  NYHA functional class assessment
•  Quality of life questionnaires: Kansas City Cardiomyopathy Questionnaire (KCCQ-12) and Short Form Health Survey (SF-36)
•  Pregnancy test (serum or urine beta-hCG) for women of childbearing potential
•  Assessment of inclusion and exclusion criteria by the Principal Investigator or qualified designee
•  Heart team evaluation and confirmation of procedural candidacy
11.2 Index Procedure
The ThornValve MV-200 System implantation procedure will be performed in a dedicated cardiac catheterization laboratory or hybrid operating room at Hargrove University Medical Center. The procedure will be performed under general anesthesia, with continuous transesophageal echocardiographic (TEE) guidance and fluoroscopic imaging throughout. The Principal Investigator (Dr. Julian M. Castañeda) or the Sub-Investigator (Dr. Hannah L. Forsberg), under the supervision of the Principal Investigator, will perform the implantation procedure.
The index procedure will include:
•  Administration of general anesthesia and endotracheal intubation
•  Femoral venous access and transseptal puncture under fluoroscopic and echocardiographic guidance
•  Advancement of the guiding sheath and delivery catheter to the mitral valve
•  Positioning and deployment of the ThornValve MV-200 System implant at the mitral valve leaflets
•  Intra-procedural assessment of device positioning, leaflet grasping, and reduction of mitral regurgitation severity by TEE
•  Confirmation of technical success criteria (reduction of mitral regurgitation to ≤ 2+)
•  Catheter and sheath removal, hemostasis, and post-procedural monitoring
All procedural data, including procedure duration, fluoroscopy time, contrast volume, and intra-procedural complications, will be documented in the electronic data capture system.
11.3 Post-Procedure Follow-Up Visits
Follow-up assessments will be performed at the following time points after the index procedure:
Discharge / 7 Days Post-Procedure:
•  Clinical assessment, including physical examination and vital signs
•  Transthoracic echocardiography (TTE) for assessment of device position and mitral regurgitation severity
•  Laboratory testing, including CBC, CMP, and renal function
•  Adverse event monitoring and documentation
•  Medication reconciliation
30 Days Post-Procedure:
•  Clinical assessment, including physical examination and vital signs
•  Transthoracic echocardiography (TTE)
•  6-minute walk test
•  NYHA functional class assessment
•  Quality of life questionnaires (KCCQ-12, SF-36)
•  NT-proBNP level
•  Adverse event monitoring and documentation
•  Medication review
6 Months Post-Procedure:
•  Clinical assessment, including physical examination and vital signs
•  Transthoracic echocardiography (TTE)
•  NYHA functional class assessment
•  Adverse event monitoring and documentation
•  Medication review
12 Months Post-Procedure:
•  Comprehensive clinical assessment, including complete physical examination and vital signs
•  Transthoracic echocardiography (TTE)
•  Transesophageal echocardiography (TEE) for detailed assessment of device integrity and function
•  6-minute walk test
•  NYHA functional class assessment
•  Quality of life questionnaires (KCCQ-12, SF-36)
•  NT-proBNP level
•  Laboratory testing as specified in the Protocol
•  Adverse event monitoring and documentation
•  Medication review
Completion of all 12-month assessments for a given subject, with satisfactory data quality as confirmed by the CRO, triggers the second per-subject payment installment of $28,500, as set forth in Exhibit A (Study Budget) to the Clinical Trial Agreement.
18 Months Post-Procedure:
•  Clinical assessment, including physical examination and vital signs
•  Transthoracic echocardiography (TTE)
•  NYHA functional class assessment
•  Adverse event monitoring and documentation
•  Medication review
24 Months Post-Procedure (End of Study Visit):
•  Comprehensive clinical assessment, including complete physical examination and vital signs
•  Transthoracic echocardiography (TTE)
•  Transesophageal echocardiography (TEE) for detailed assessment of device integrity and long-term function
•  6-minute walk test
•  NYHA functional class assessment
•  Quality of life questionnaires (KCCQ-12, SF-36)
•  NT-proBNP level
•  Laboratory testing as specified in the Protocol
•  Adverse event monitoring and documentation
•  Medication review
•  End-of-study documentation and subject disposition
Completion of all 24-month assessments for a given subject, with satisfactory data quality as confirmed by the CRO, triggers the third and final per-subject payment installment of $28,500, as set forth in Exhibit A (Study Budget) to the Clinical Trial Agreement.
11.4 Unscheduled Visits
Any unscheduled visits, interim hospitalizations, emergency department encounters, or adverse events occurring between scheduled study visits will be documented and reported in accordance with the Protocol and the safety monitoring procedures established for the Cadence-3 Trial. The study site will make reasonable efforts to capture all clinically relevant events occurring during the study period, including events that come to the attention of the study team through routine clinical care, subject self-reporting, or review of medical records. All unscheduled events will be entered into the electronic data capture system and assessed for potential relationship to the investigational device or the index procedure.
12. Data Safety Monitoring Board (DSMB)
DSMB Chair: Dr. Garrett P. Lindholm, M.D., Ph.D., Professor of Biostatistics and Cardiology, Ellsworth University, Chicago, Illinois.
Constitution: The independent Data Safety Monitoring Board for the Cadence-3 Trial was formally constituted in November 2025 by the Sponsor, in consultation with the Principal Investigator. The DSMB operates under a separate, written DSMB Charter that defines the composition, responsibilities, operating procedures, and decision-making authority of the Board. The DSMB Charter is maintained on file with the Sponsor and is available for review by the Institution, the IRB, and the FDA upon request.
Role: The DSMB will provide independent safety oversight of the Cadence-3 Trial by reviewing unblinded safety data at predetermined intervals. The DSMB will evaluate accumulating safety data, including all adverse events, serious adverse events, device-related complications, and mortality, to assess whether the safety profile of the ThornValve MV-200 System remains acceptable in light of the potential clinical benefits. The DSMB will conduct scheduled reviews after enrollment of the 5th, 15th, 30th, and 45th subjects. Additional ad hoc meetings may be convened at the discretion of the DSMB Chair at any time if safety concerns arise that warrant immediate review.
Authority: Based on its review of safety data, the DSMB may issue one of the following recommendations to the Sponsor:
(a) Continue the trial without modification;
(b) Continue the trial with modifications, including but not limited to changes to the Protocol, eligibility criteria, enrollment pace, or follow-up procedures;
(c) Suspend enrollment temporarily pending further safety evaluation; or
(d) Terminate the trial if the DSMB determines that continued enrollment would expose subjects to unacceptable risk.
The Sponsor retains ultimate decision-making authority regarding trial continuation, modification, or termination; however, the Sponsor will give serious consideration to all DSMB recommendations and will document the rationale for any decision that departs from a DSMB recommendation.
Independence: All members of the DSMB are independent of both the Sponsor and the Institution. DSMB members have no financial interest in the ThornValve MV-200 System or in Thornwick Medical Research Institute, Inc., no intellectual property rights related to the device, and no other conflicts of interest that could compromise their ability to provide objective, unbiased safety oversight. Conflict of interest disclosures for all DSMB members are maintained on file with the Sponsor.
13. Data Management and Biostatistical Analysis
Contract Research Organization (CRO): Meridian Clinical Sciences, Inc. 900 Weston Parkway, Suite 400 Cary, NC 27513
CRO Contact: Victoria Reeves, Vice President, Cardiovascular Programs Telephone: (919) 555-7800
Email: vreeves@meridiancs.com
Scope of CRO Services: Meridian Clinical Sciences, Inc. has been engaged by the Sponsor to provide comprehensive data management and biostatistical analysis services for the Cadence-3 Trial. The scope of services includes, but is not limited to:
(a) Design, development, validation, and maintenance of the electronic data capture (EDC) system for the Cadence-3 Trial;
(b) Database design, including case report form (CRF) development and data dictionary creation;
(c) Data management, including data entry monitoring, query generation and resolution, medical coding (MedDRA for adverse events, WHO Drug Dictionary for concomitant medications), and data quality assurance procedures;
(d) Biostatistical analysis, including preparation and finalization of the Statistical Analysis Plan (SAP), programming of statistical analyses, and generation of statistical tables, listings, and figures;
(e) Safety monitoring support, including preparation of periodic safety data summaries for the DSMB and safety reports for regulatory submissions;
(f) Preparation of statistical analysis reports, including the final clinical study report.
Data Capture: All clinical data collected during the Cadence-3 Trial will be entered into a validated electronic data capture (EDC) system designed and maintained by Meridian Clinical Sciences. The EDC system will comply with 21 CFR Part 11 requirements for electronic records and electronic signatures. Source data verification will be performed by Sponsor-designated monitors in accordance with the monitoring plan established for the trial. All data entered into the EDC system will be subject to programmed edit checks, manual data review, and query resolution procedures to ensure data quality and integrity.
Statistical Analysis Plan (SAP): A formal Statistical Analysis Plan will be developed by Meridian Clinical Sciences in collaboration with the Sponsor and the Principal Investigator and will be finalized prior to the enrollment of the first subject. The SAP will describe in detail all planned primary, secondary, and exploratory endpoint analyses, including definitions of analysis populations, statistical methods, handling of missing data, subgroup analyses, and sensitivity analyses.
Analysis Population: The primary analysis will be conducted on the intent-to-treat (ITT) population, defined as all enrolled subjects in whom the ThornValve MV-200 System implantation procedure is attempted, regardless of whether the procedure is completed successfully. A per-protocol (PP) population, defined as subjects who complete the implantation procedure without major protocol deviations and complete the 30-day follow-up visit, will be analyzed as a prespecified sensitivity analysis to assess the robustness of the primary results.
14. Regulatory Considerations
The ThornValve MV-200 System is an investigational device that has not been approved or cleared by the United States Food and Drug Administration for commercial distribution. The device is authorized for use in the Cadence-3 Trial exclusively under FDA Investigational Device Exemption (IDE) Number G260012, in accordance with the requirements of 21 CFR Part 812.
The Cadence-3 Trial protocol (Version 3.0) and the associated informed consent form were reviewed and approved by the Hargrove University Medical Center Institutional Review Board (IRB) on December 18, 2025, under IRB Protocol Number HUMC-IRB-2025-0847. The IRB approval encompasses the Protocol, the informed consent form, all subject-facing materials, and the HIPAA authorization form.
All amendments to the Protocol will require review and approval by the HUMC IRB prior to implementation, unless the amendment is necessary to eliminate an immediate hazard to study subjects, in which case the amendment may be implemented immediately with prompt notification to the IRB and the Sponsor. Protocol amendments that affect the scientific basis, study design, subject safety, or risk-benefit assessment of the trial will also require submission to the FDA as IDE supplements in accordance with 21 CFR § 812.35.
The Sponsor will submit an IDE supplement to the FDA by March 15, 2026, incorporating the executed Clinical Trial Agreement and all site-specific documentation required to authorize enrollment at Hargrove University Medical Center. Enrollment of the first subject will not commence until the IDE supplement has been submitted and any FDA comments or conditions have been addressed.
Adverse event reporting will comply in all respects with FDA IDE regulations set forth in 21 CFR Part 812, including the timely reporting of unanticipated adverse device effects (UADEs) to the FDA, all reviewing IRBs, and all participating investigators within the timeframes specified in 21 CFR § 812.150.
The Cadence-3 Trial will be conducted in accordance with the following regulatory and ethical standards:
(a) Applicable FDA regulations, including 21 CFR Part 50 (Protection of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 CFR Part 56 (Institutional Review Boards), and 21 CFR Part 812 (Investigational Device Exemptions);
(b) International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP), as adopted by the FDA;
(c) The Declaration of Helsinki, as adopted by the World Medical Association (most recent revision); and
(d) All applicable federal, state, and local laws and regulations, including but not limited to the Health Insurance Portability and Accountability Act (HIPAA) and Connecticut state privacy and research laws.
15. Informed Consent
Written informed consent will be obtained from each subject (or, where applicable under Connecticut state law, the subject's legally authorized representative) prior to the performance of any study-specific procedures, including screening assessments. The informed consent process will be conducted in accordance with 21 CFR Part 50 (Protection of Human Subjects), the requirements of the HUMC IRB, and the ethical principles set forth in the Belmont Report and the Declaration of Helsinki.
The informed consent form (ICF) for the Cadence-3 Trial has been reviewed and approved by the Hargrove University Medical Center Institutional Review Board as part of IRB Protocol Number HUMC-IRB-2025-0847. The ICF will not be modified without prior IRB approval, except as may be required to address an immediate safety concern.
During the informed consent process, subjects will be informed of the following:
(a) The investigational nature of the ThornValve MV-200 System and the purpose of the Cadence-3 Trial;
(b) The procedures involved in the study, including the index procedure and all scheduled follow-up assessments;
(c) The potential risks and discomforts associated with the investigational device and the study procedures, including the risks of the implantation procedure, the possibility of device malfunction or failure, and the risks associated with general anesthesia, transseptal puncture, and vascular access;
(d) The potential benefits of participation, including the possibility of reduced mitral regurgitation and improved symptoms, as well as the possibility that no direct benefit may be realized;
(e) The alternative treatments available, including continued medical therapy, surgical mitral valve repair or replacement, and other commercially available transcatheter mitral valve repair devices, as applicable;
(f) The subject's right to withdraw from the study at any time, for any reason, without prejudice to their ongoing clinical care at Hargrove University Medical Center; and
(g) The measures that will be taken to protect the confidentiality of the subject's personal health information.
The informed consent process will be conducted by qualified study personnel (investigators, sub-investigators, or trained research coordinators) under the supervision of the Principal Investigator. Adequate time will be provided for subjects to review the informed consent form, ask questions, and consult with family members or other advisors before making a decision regarding participation. Documentation of informed consent, including the signed and dated ICF, will be maintained in the subject's research file and the medical record.
16. Adverse Event Reporting and Safety Monitoring
All adverse events (AEs) and serious adverse events (SAEs) will be systematically collected, documented, assessed, and reported from the time of the ThornValve MV-200 System implantation procedure through the completion of the 24-month follow-up period for each subject. The Principal Investigator and study staff will assess each adverse event for severity, seriousness, relationship to the investigational device, and relationship to the study procedure, in accordance with the definitions and criteria set forth in the Protocol.
Serious Adverse Event Reporting: All SAEs will be reported by the study site to the Sponsor within 24 hours of the site's awareness of the event. SAE reports will be submitted using the standardized SAE reporting form provided by the Sponsor and entered into the EDC system. The Sponsor will evaluate all SAE reports and determine whether the event constitutes an unanticipated adverse device effect (UADE) or requires expedited regulatory reporting.
Unanticipated Adverse Device Effect Reporting: Any adverse event that constitutes an unanticipated adverse device effect (UADE), as defined in 21 CFR § 812.3(s), will be reported by the Sponsor to the FDA, the HUMC IRB, and the DSMB in accordance with the timelines and procedures specified in 21 CFR § 812.150. Specifically, the Sponsor will submit an initial report of any UADE to the FDA and all reviewing IRBs within 10 working days of first receiving notice of the event.
Clinical Events Committee (CEC): An independent Clinical Events Committee will be established to provide blinded adjudication of all events contributing to the primary safety endpoint, all serious adverse events, and all deaths occurring during the study period. The CEC will operate under a separate charter that defines the committee's composition, adjudication processes, endpoint definitions, and decision rules. CEC members will be independent of both the Sponsor and the Institution and will have no financial or intellectual conflicts of interest with the ThornValve MV-200 System. The CEC will be constituted and operational prior to the enrollment of the first subject.
Data Safety Monitoring Board (DSMB): The independent DSMB, chaired by Dr. Garrett P. Lindholm (see Section 12), will conduct periodic safety reviews at the intervals specified in the DSMB Charter. The DSMB will review cumulative safety data, including all adverse events, serious adverse events, and adjudicated endpoint events, and will provide recommendations to the Sponsor regarding the continuation, modification, or termination of the trial based on safety findings.
17. Study Duration and Key Milestones
The following table summarizes the estimated key milestones and timeline for the Cadence-3 Trial:
The enrollment period is estimated to be approximately 15 months (April 2026 through June 2027), during which 45 evaluable subjects will be enrolled at an anticipated rate of approximately 3 subjects per month. Each subject will be followed for 24 months from the date of device implantation, resulting in a total estimated study duration of approximately 36 months from first patient enrollment to last patient, last visit. The Sponsor and the Institution acknowledge that actual enrollment rates and study timelines may vary from these estimates and will cooperate in good faith to achieve the enrollment and follow-up objectives set forth in the Protocol.
18. Sample Size Justification
The Cadence-3 Trial is a feasibility study, and the sample size of 45 evaluable subjects has been selected to provide adequate preliminary safety and performance data to inform the design of a future pivotal trial, rather than to achieve definitive statistical hypothesis testing.
The sample size of 45 subjects provides the following statistical properties:
(a) Safety estimation: With 45 subjects, if the true 30-day major adverse event (MAE) rate is 10%, there is approximately 95% probability of observing at least one MAE during the study. The observed 30-day MAE rate can be estimated with a 95% confidence interval having a half-width of approximately ±8.8 percentage points, providing a reasonable degree of precision for feasibility-stage safety assessment.
(b) Performance estimation: With 45 subjects, if the true technical success rate is 85%, the observed success rate can be estimated with a 95% confidence interval having a half-width of approximately ±10.4 percentage points, providing sufficient precision to characterize the expected range of technical performance.
(c) Clinical endpoint estimation: The sample size of 45 subjects is sufficient to provide meaningful estimates of secondary clinical endpoints, including changes in NYHA functional class, 6-minute walk test distance, quality of life scores, and echocardiographic parameters, with adequate precision to inform the sample size calculations and study design for a future pivotal trial.
The sample size is consistent with the guidance provided by the FDA in the IDE approval letter for the Cadence-3 program and reflects a balance between generating sufficient data for regulatory and clinical decision-making and minimizing the number of subjects exposed to the investigational device at this early feasibility stage of development.
19. Study Committees and Oversight
The following committees and oversight bodies will provide governance and monitoring for the Cadence-3 Trial:
Sponsor Oversight: Thornwick Medical Research Institute, Inc., through its Vice President of Clinical Development, Dr. Elaine K. Sutherland, will provide overall sponsor oversight of the Cadence-3 Trial. Sponsor oversight responsibilities include, but are not limited to, monitoring of Protocol compliance, clinical monitoring and site management, safety surveillance and pharmacovigilance, regulatory communications with the FDA and the HUMC IRB, device accountability, and financial administration. The Sponsor will designate qualified clinical monitors to conduct routine monitoring visits at the study site in accordance with a written monitoring plan, to verify source data, review regulatory documents, and ensure compliance with the Protocol, GCP, and applicable regulatory requirements.
Data Safety Monitoring Board (DSMB): The independent DSMB, as described in Section 12, will provide independent safety oversight of the trial. The DSMB is chaired by Dr. Garrett P. Lindholm, M.D., Ph.D., Professor of Biostatistics and Cardiology, Ellsworth University, Chicago, Illinois. The DSMB operates under a separate charter and will conduct scheduled safety reviews after enrollment of the 5th, 15th, 30th, and 45th subjects.
Clinical Events Committee (CEC): An independent Clinical Events Committee will be constituted to adjudicate all events contributing to the primary safety endpoint and all serious adverse events occurring during the study. CEC members will be appointed by the Sponsor prior to the enrollment of the first subject and will operate under a separate, written CEC Charter. The CEC members will be independent cardiologists and neurologists with expertise in the adjudication of cardiovascular events and will have no financial or intellectual conflicts of interest with the Sponsor, the Institution, or the ThornValve MV-200 System.
Echocardiographic Core Laboratory: An independent echocardiographic core laboratory will be designated by the Sponsor prior to the enrollment of the first subject to provide centralized, blinded assessment of all echocardiographic studies obtained during the Cadence-3 Trial. The core laboratory will evaluate mitral regurgitation severity, left ventricular dimensions and function, device integrity, and all other echocardiographic parameters specified in the Protocol and the SAP. Centralized echocardiographic assessment by an independent core laboratory is intended to reduce measurement variability and observer bias, enhancing the scientific rigor of the study.
20. Confidentiality and Data Protection
All subject data collected during the Cadence-3 Trial will be handled in strict accordance with the requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA), as amended, the HIPAA Privacy Rule (45 CFR Parts 160 and 164), applicable Connecticut state privacy laws, and the institutional policies of Hargrove University Medical Center governing the use and disclosure of protected health information (PHI) for research purposes.
Subjects will be identified in all study databases and case report forms by unique study identification numbers assigned at the time of enrollment. No personally identifiable information — including names, dates of birth, Social Security numbers, medical record numbers, or other direct identifiers — will be included in any study database transmitted to the Sponsor, the CRO (Meridian Clinical Sciences, Inc.), or any study committee. A master linking file connecting study identification numbers to subject identities will be maintained securely at the study site under the custody of the Principal Investigator and will not be disclosed to the Sponsor or any third party except as required by law or regulatory authority.
Ownership, licensing, and permitted uses of Trial Data (as defined in the Clinical Trial Agreement) are governed by the terms and conditions set forth in the Clinical Trial Agreement dated March 2, 2026, to which this Exhibit B is attached. Nothing in this Protocol Synopsis is intended to modify or supersede the data ownership and licensing provisions of the Clinical Trial Agreement.
21. Publication and Dissemination of Results
Publication and dissemination of the results of the Cadence-3 Trial are governed by the publication rights provisions set forth in the Clinical Trial Agreement dated March 2, 2026, between Thornwick Medical Research Institute, Inc. and Hargrove University Medical Center, Inc. The Principal Investigator and the Institution agree to comply with the publication review, authorship, and prepublication notification requirements specified in the Clinical Trial Agreement.
The Cadence-3 Trial is registered on ClinicalTrials.gov under identifier NCT06198234, in compliance with the requirements of Section 801 of the FDA Amendments Act of 2007 (FDAAA 801) and the Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11). Study results will be posted on ClinicalTrials.gov in accordance with the applicable timelines set forth in FDAAA 801 and any applicable NIH requirements. The Sponsor and the Principal Investigator will cooperate in the preparation and submission of results information to ClinicalTrials.gov.
22. Protocol Amendments
Any modifications to this Protocol — whether substantive or administrative — require written approval from the Sponsor (through its Vice President of Clinical Development or designee) and the Hargrove University Medical Center Institutional Review Board prior to implementation at the study site, except as provided below.
Amendments that affect the scientific basis of the study, the study design, subject eligibility criteria, study endpoints, the investigational device, or the risk-benefit assessment for subjects will be submitted to the FDA as IDE supplements in accordance with 21 CFR § 812.35. Such amendments will not be implemented until the IDE supplement has been submitted and any FDA comments or conditions have been addressed, unless the amendment is necessary to protect the safety of enrolled subjects.
The Principal Investigator may implement a deviation from the Protocol without prior Sponsor or IRB approval only when necessary to eliminate an immediate hazard to a study subject. In such cases, the Principal Investigator will notify the Sponsor and the HUMC IRB as promptly as possible, but in no event later than 5 business days after the deviation, and will submit a written report documenting the deviation, the rationale, and any corrective actions taken.
All protocol amendments will be documented using a formal Protocol Amendment form, assigned a sequential amendment number, and incorporated into the regulatory files maintained at the study site and by the Sponsor. Updated versions of the Protocol will be distributed to all relevant parties, including the CRO, the DSMB, and the CEC, as applicable.
23. References to Agreement Exhibits and Related Documents
This Protocol Synopsis is attached as Exhibit B to, and is incorporated by reference into, the Clinical Trial Agreement by and between Thornwick Medical Research Institute, Inc. and Hargrove University Medical Center, Inc., dated March 2, 2026 (the "Agreement"). All capitalized terms used but not defined in this Protocol Synopsis shall have the meanings ascribed to them in the Agreement.
The following additional exhibits and related documents are referenced herein:
•  Exhibit A (Study Budget): Sets forth the financial terms supporting the Cadence-3 Trial, including a per-subject payment of $95,000 per enrolled and evaluable subject (payable in three installments: an initial installment upon enrollment and completion of the index procedure, a second installment of $28,500 upon completion of the 12-month follow-up visit, and a third installment of $28,500 upon completion of the 24-month follow-up visit) and a complete study budget allocation of $6,000,000, encompassing per-subject payments, institutional overhead, investigator time and effort, laboratory and imaging costs, and other study-related expenses.
•  Full Protocol (Version 3.0): The complete Cadence-3 Trial Protocol, including detailed study procedures, visit schedules, data collection requirements, and statistical analysis methodology, is maintained on file with the Sponsor and will be provided to the Institution and the HUMC IRB as part of the regulatory document package. In the event of any inconsistency between this Protocol Synopsis and the full Protocol, the full Protocol shall control.
•  Investigator's Brochure: The current version of the Investigator's Brochure for the ThornValve MV-200 System, containing all available nonclinical and clinical data, device description, and risk analysis, is maintained on file with the Sponsor and has been provided to the Principal Investigator and the HUMC IRB.
This Protocol Synopsis, together with the full Protocol and the other exhibits and schedules to the Clinical Trial Agreement, constitutes the complete description of the Cadence-3 Trial as agreed upon by the Sponsor and the Institution.
Exhibit B — Protocol Synopsis — Cadence-3 (NCT06198234)
CONFIDENTIAL — This document contains confidential and proprietary information of Thornwick Medical Research Institute, Inc. and Hargrove University Medical Center, Inc. Unauthorized disclosure, reproduction, or distribution is strictly prohibited.
Identifier Type | Number / Date
ClinicalTrials.gov Identifier | NCT06198234
FDA Investigational Device Exemption (IDE) Number | G260012
IRB Protocol Number | HUMC-IRB-2025-0847
IRB Approval Date | December 18, 2025 (Hargrove University Medical Center Institutional Review Board)
Sponsor Internal Grant Award Number | TMRI-CV-2025-018
Design Element | Description
Study Type | Interventional (clinical trial)
Study Phase | Feasibility (pre-pivotal)
Design | Prospective, single-arm, open-label
Control | None (single-arm study; no concurrent control group)
Blinding | Open-label (no blinding of subjects, investigators, or assessors)
Number of Sites | One (single-site study at Hargrove University Medical Center)
Allocation | Non-randomized
Milestone | Estimated Date
IRB Approval | December 18, 2025 (completed)
Clinical Trial Agreement Execution | March 2, 2026
IDE Supplement Filing | March 15, 2026
First Patient Enrollment | April 7, 2026
Last Patient Enrollment | June 30, 2027
Last Patient, Last Visit (Study Completion) | June 30, 2029
Total Estimated Study Duration | Approximately 36 months from first patient enrollment