Efficacy of the COronary SInus Reducer in Patients With Refractory Angina II

Study Overview
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Brief Summary
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To demonstrate the safety and effectiveness of the Reducer system for treatment of patients with refractory angina pectoris treated with maximally tolerated guideline-directed medical therapy who demonstrate objective evidence of reversible myocardial ischemia in the distribution of the left coronary artery and who are deemed unsuitable for revascularization. A non-randomized single-arm will further assess the safety and effectiveness of the Neovasc Reducer System in selected subjects with reversible myocardial ischemia in the distribution of the right coronary artery and who are deemed unsuitable for revascularization, subjects with reversible myocardial ischemia without documented obstructive coronary disease and subjects who cannot complete an exercise tolerance test due to an above-the-ankle amputation.

Detailed Description
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The COSIRA-II study is a multicenter, randomized (1:1 ratio), double-blinded, sham-controlled clinical trial.

Official Title
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Efficacy of the COronary SInus Reducer in Patients With Refractory Angina II

Conditions
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Refractory Angina

Intervention / Treatment
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* Device: Arm 1: treatment with Neovasc Reducer
* Other: Arm 2 (control): Implantation procedure with no device implanted
* Device: Arm 3 (unblinded, non-randomized): Single arm registry


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is older than 18 years of age Symptomatic coronary artery disease (CAD) with greater than or equal to 90 days of persistent refractory angina pectoris classified as CCS Grade III or IV despite maximally tolerated guideline directed medical therapy as determined by the local heart team and confirmed by a Central Screening Eligibility Committee. Note: subjects may also have exertional dyspnea, but the symptoms that limit activity must be anginal in nature (including chest pain, pressure, heaviness, discomfort, with or without radiation to the neck, jaw, shoulders, arms, or other location) and not dyspnea Must have attempted treatment with the maximally tolerated dose of at least three of the four (preferably all four) approved classes of anti-anginal agents: long-acting nitrates, calcium channel blockers (either a dihydropyridine or a non-dihydropyridine), beta blockers, and ranolazine. The regimen must be stable for at least 60 days prior to enrollment, must remain stable from enrollment to randomization, and there must be no intent to change the medical regimen for at least 12 months after randomization Note: If the dose of a medication was increased or decreased for a temporary period and then returned to the original dose, which will then be continued for at least 12 months after randomization, the subject may be immediately enrolled without needing to otherwise requalify. Subject has either no treatment options for revascularization by coronary artery bypass grafting or by percutaneous coronary intervention, or is otherwise unsuitable or high risk for revascularization as determined by the local heart team, and confirmed by a Central Screening Eligibility Committee Evidence of either exercise or pharmacologically induced reversible ischemia severity by stress echo, nuclear study, PET, perfusion MRI, CT perfusion, FFRCT, FFR, iFR, or other non-hyperemic FDA approved tests in the distribution of the left coronary artery (LCA), performed within 12 months prior to enrollment and while the patient is maintained on their stable regimen of maximally tolerated doses of anti-anginal medications. Note: If the subject has evidence of ischemia in both the LCA and RCA distributions, the extent of ischemia must be greater in the LCA distribution. Note: The qualifying assessment must be performed after any myocardial infarction, CABG, or successful PCI within the prior 12 months. If the anti-anginal medication regimen is permanently changed after the assessment of ischemia, the test must be repeated. For subjects with multiple assessments, the one performed closest to enrollment will serve as the qualifying study. Functional limitation due to refractory angina as defined by a modified Bruce exercise tolerance test duration of greater than or equal to 2 minutes but less than or equal to 8 minutes, performed while the subject is maintained on their stable regimen of maximally tolerated doses of anti-anginal medications. Note: The ETT variability must be less than 20% between last two ETTs performed. Left ventricular ejection fraction (LVEF) greater than or equal to 30% within the 12-months prior to enrollment Note: The LVEF must be reassessed after any intervening myocardial infarction. For subjects with multiple assessments, the most recent LVEF assessment is used as the qualifying test. Subject is willing and able to sign informed consent Subject is willing to comply with the specified follow-up evaluations Angiographic Inclusion Criteria: 1) Three-vessel coronary angiography performed within 12 months prior to enrollment demonstrating obstructive CAD (visually estimated diameter stenosis of ≥70% or ≥50% - <70% with fractional flow reserve (FFR) value of ≤0.80 or an iFR or other FDA-approved/cleared non-hyperemic physiological assessment of ≤0.89 in one or more lesions) in the left coronary artery (main epicardial vessels or branches) that is not suitable for and will not be treated with PCI or CABG as determined by the local heart team. Note: The qualifying 3-vessel angiogram must be performed after any myocardial infarction or CABG within the 12 months prior to enrollment. For patients with multiple 3-vessel angiograms, the one performed closest to enrollment will serve as the qualifying study. Exclusion Criteria: Recent (within 30 days prior to enrollment) troponin or CKMB positive acute coronary syndrome (NSTEMI or STEMI). Note: subjects with an elevated troponin or CKMB without acute coronary syndrome may still be enrolled Recent successful revascularization by either CABG or PCI within six months prior to enrollment Note: Successful revascularization is defined as any CABG procedure, or any PCI procedure with a reduction of one or more lesions to <50% diameter stenosis Recent unsuccessful PCI (e.g., failed attempt to open a chronic total occlusion) within 30 days prior to enrollment The predominant manifestation of angina is dyspnea. Note: some dyspnea may be present with exertion, but the predominant symptom that limits activity must be angina (i.e., chest pain, pressure, tightness, heaviness, or discomfort, with or without radiation to the neck, jaw, shoulders, arms, or other location) Has extra-coronary contributory causes of angina - e.g., untreated hyperthyroidism, anemia (hgb <10 g/dL), uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg despite medications), atrial fibrillation with rapid ventricular response (consistently >100 bpm despite medications) or other tachyarrhythmia, severe aortic stenosis, hypertrophic cardiomyopathy with left ventricular outflow tract obstruction or asymmetric septal hypertrophy (concentric left ventricular hypertrophy is not an exclusion criterion). NYHA Class III or IV heart failure (HF), decompensated HF or hospitalization due to HF during the 90 days prior to enrollment Life threatening rhythm disorders or any rhythm disorders that would require future placement of an internal defibrillator and/or pacemaker Severe chronic obstructive pulmonary disease (COPD) as indicated by a forced expiratory volume in one second (FEV1) that is less than 55% of the predicted value, or need for home daytime oxygen or oral steroids Severe valvular heart disease (any valve) Moderate or severe RV dysfunction by echocardiography Pacemaker electrode/lead is present in the coronary sinus A Class I indication is present for an implantable defibrillator or cardiac resynchronization therapy according to ACCF/AHA/HRS guidelines Recent implantation of a new pacemaker or defibrillator lead with electrode in the right atrium within 90 days of enrollment Chronic severe renal failure (estimated eGFR less than 30 mL/min/1.73m2 by the MDRD formula) or subjects on chronic dialysis Known allergy to stainless steel or nickel Any clinical condition that might interfere with the trial protocol or the subject's ability to be compliant with the trial protocol (e.g., active alcohol or drug abuse, dementia, magnetic resonances imaging (MRI) planned within 8 weeks of randomization.) Currently enrolled in another investigational device or drug trial that has not reached its primary endpoint or that might clinically interfere with the current trial endpoints or procedures Pregnant or planning pregnancy within the next 12 months (women of reproductive potential must have a negative pregnancy test within 7 days of the randomization procedure) Subject is part of a vulnerable population who, in the judgment of the investigator, is unable to give Informed Consent for reasons of incapacity, immaturity, adverse personal circumstances or lack of autonomy. This may include individuals with mental disability, persons in nursing homes, children, impoverished persons, persons in emergency situations, homeless persons, nomads, refugees, and those incapable of giving informed consent. Vulnerable populations also may include members of a group with a hierarchical structure such as university students, subordinate hospital and laboratory personnel, employees of the Sponsor, members of the armed forces, and persons kept in detention. Inability to tolerate dual antiplatelet therapy for 6 months if not on a chronic oral anticoagulant, or inability to tolerate a P2Y12 inhibitor for at least 6 months if on a chronic oral anticoagulant Comorbidities limiting life expectancy to less than one year Subject is currently hospitalized for definite or suspected COVID-19 Subject has previously been symptomatic with or hospitalized for COVID-19 and has been asymptomatic for <8 weeks prior to enrollment or has not returned to his or her prior baseline (pre-COVID-19) clinical condition Subject is asymptomatic but has had a positive PCR or antigen test for COVID-19 within the past 4 weeks prior to enrollment Angiographic/Hemodynamic Exclusion Criteria: 1) Coronary anatomy amenable to revascularization of ischemic myocardial territory by either PCI or CABG with at least moderate likelihood of long-term alleviation of angina or angina equivalent symptoms, as per the assessment of the local heart team. Note: If a pathway to coronary revascularization is present which, in the opinion of the local heart team, is reasonably low risk and reasonably likely to provide long-term symptom relief and the subject refuses the revascularization procedure, the patient is ineligible for randomization Procedural Angiographic/Hemodynamic Randomization Exclusion Criteria: Mean right atrial pressure greater than 15 mmHg assessed during the final screening procedure for eligibility assessment and potential randomization Anomalous or abnormal CS anatomy (e.g., tortuosity, aberrant branch, persistent left superior vena cava [SVC]) as demonstrated by angiogram The CS diameter at the most proximal end of the planned implant region (2-4 cm distal to the coronary sinus ostium) is less than 9.5 mm or greater than 13.0 mm Single Arm Registry Inclusion Criteria: The subject must meet all inclusion and exclusion criteria for the main randomized trial, except for three possible specific conditions as follows: Subjects with evidence of either exercise or pharmacologically induced reversible ischemia by stress echo, nuclear study, PET, perfusion MRI, CT perfusion, FFRCT, FFR, iFR, or other non-hyperemic FDA approved or cleared tests in the predominate (RCA > LCA ischemia) or sole distribution of the right coronary artery Subjects with evidence of either exercise or pharmacologically induced reversible ischemia by stress echo, nuclear study, PET, perfusion MRI, CT perfusion, CFR, or IMR without documented obstructive coronary disease (i.e. estimated diameter stenosis in all coronary lesions is <50%) Subjects who are unable to complete the required COSIRA-II exercise tolerance test due to lower limb amputation (above the ankle). Single-Arm Registry Angiographic Inclusion Criteria Obstructive CAD: Three-vessel coronary angiography performed within the 12 months prior to enrollment demonstrating obstructive CAD (visually assessed diameter stenosis of ≥70%) in the RCA if it is single vessel disease, or the ischemia in the territory of the RCA is greater than the ischemia in the territory of the LCA when it is >2 vessel coronary disease, or a fractional flow reserve (FFR) value of ≤0.80 or an iFR (or other FDA-approved/cleared non-hyperemic physiologic assessment) of ≤0.89 in an RCA lesion with a visually assessed diameter stenosis of ≥50% in single RCA coronary disease, that is not suitable for and will not be treated with PCI or CABG as determined by the local heart team. Non-obstructive CAD: Patients with non-obstructive CAD (coronary narrowing of <50%, and/or FFR ≥0.81) Note: The qualifying 3-vessel angiogram must be performed after any myocardial infarction or CABG within the 12 months prior to enrollment. For patients with multiple 3-vessel angiograms, the one performed closest to enrollment will serve as the qualifying study.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (treatment arm):Implantation of the Reducer device<br> | Device: Arm 1: treatment with Neovasc Reducer<br>* Neovasc reducer is an implantable device being evaluated for the alleviation of refractory angina symptoms<br>|
| Sham Comparator: Arm 2 (sham-control arm): Control (no device implantation)<br> | Other: Arm 2 (control): Implantation procedure with no device implanted<br>* No device is implanted<br>|
| Other: Arm 3 (unblinded, non-randomized): Single Arm Registry<br> | Device: Arm 3 (unblinded, non-randomized): Single arm registry<br>* Neovasc reducer is an implantable device being evaluated for the alleviation of refractory angina symptoms<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effectiveness | Change in total exercise duration in a modified Bruce treadmill exercise tolerance testing evaluation in the Treatment arm compared to Sham-control arm. | 6 months | 
| Safety Events | The rate of occurrence of a composite of death, myocardial infarction (MI), pericardial effusion requiring surgical or percutaneous intervention, device embolization, or BARC 3 or 5 bleeding evaluation in the Treatment arm compared to the Sham-control arm. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Canadian Cardiovascular Society (CCS) Angina Score | Improvement by greater than or equal to 1 CCS angina grade. The CCS grading system for angina is a clinical tool used by doctors to assess the degree of severity of a patient's angina. Possible scores range from Class 0 (asymptomatic angina) to Class IV (angina at rest). | 6 months | 
| Canadian Cardiovascular Society (CCS) Angina Score | Improvement by greater than or equal to 2 CCS angina grades. The CCS grading system for angina is a clinical tool used by doctors to assess the degree of severity of a patient's angina. Possible scores range from Class 0 (asymptomatic angina) to Class IV (angina at rest). | 6 months | 
| Seattle Angina Questionnaire (SAQ) Score | Change in Angina Stability domain score from the Seattle Angina Questionnaire (SAQ). The Seattle Angina Questionnaire (SAQ) is a disease-specific questionnaire used to quantify patients' symptoms of angina and the extent to which their angina affects their functioning and quality of life. Possible scores range from 0 (daily angina) to 100 (no angina). Lower scores indicate worse angina symptoms. | 6 months |