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

Refractory Angina Clinical Trial

— COSIRA-II  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05102019
• Other study ID #: 022-REDUCLN-002
• Status: Recruiting
• Phase: N/A
• Start date: January 4, 2022
• Est. completion date: December 2028

Study information

• Verified date: January 2024
• Source: Neovasc Inc.
• Contact: COSIRA-II Study Team
• Phone: 877-775-4846
• Email: ReducerIDE[@]neovasc.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 380
• Est. completion date: December 2028
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Subject is older than 18 years of age

2. 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

3. 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.

4. 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

5. 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.

6. 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.

7. 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.

8. Subject is willing and able to sign informed consent

9. 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, PCI, 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:

1. 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

2. 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

3. Recent unsuccessful PCI (e.g., failed attempt to open a chronic total occlusion) within 30 days prior to enrollment

4. 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)

5. 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).

6. NYHA Class III or IV heart failure (HF), decompensated HF or hospitalization due to HF during the 90 days prior to enrollment

7. Life threatening rhythm disorders or any rhythm disorders that would require future placement of an internal defibrillator and/or pacemaker

8. 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

9. Severe valvular heart disease (any valve)

10. Moderate or severe RV dysfunction by echocardiography

11. Pacemaker electrode/lead is present in the coronary sinus

12. A Class I indication is present for an implantable defibrillator or cardiac resynchronization therapy according to ACCF/AHA/HRS guidelines

13. Recent implantation of a new pacemaker or defibrillator lead with electrode in the right atrium within 90 days of enrollment

14. Chronic severe renal failure (estimated eGFR less than 30 mL/min/1.73m2 by the MDRD formula) or subjects on chronic dialysis

15. Known allergy to stainless steel or nickel

16. 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.)

17. 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

18. 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)

19. 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.

20. 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

21. Comorbidities limiting life expectancy to less than one year

22. Subject is currently hospitalized for definite or suspected COVID-19

23. 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

24. 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:

1. Mean right atrial pressure greater than 15 mmHg assessed during the final screening procedure for eligibility assessment and potential randomization

2. Anomalous or abnormal CS anatomy (e.g., tortuosity, aberrant branch, persistent left superior vena cava [SVC]) as demonstrated by angiogram

3. 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 may meet more than one of the following criteria but must meet at least one):

1. 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

2. 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%)

3. 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

1. 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.

2. 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.

Related Conditions & MeSH terms

• Angina Pectoris
• Refractory Angina

Intervention

Device:
• Arm 1: treatment with Neovasc Reducer
Neovasc reducer is an implantable device being evaluated for the alleviation of refractory angina symptoms

Other:
• Arm 2 (control): Implantation procedure with no device implanted
No device is implanted

Device:
• Arm 3 (unblinded, non-randomized): Single arm registry
Neovasc reducer is an implantable device being evaluated for the alleviation of refractory angina symptoms

Locations

Country	Name	City	State
Canada	CHUM	Montréal	Quebec
Canada	IUCPQ-Ulaval	Québec	Quebec
United States	University of Michigan	Ann Arbor	Michigan
United States	Northside Hospital	Atlanta	Georgia
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	The Christ Hospital	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	Medical City Fort Worth	Fort Worth	Texas
United States	The Cardiac and Vascular Institute	Gainesville	Florida
United States	HCA Houston Healthcare Medical Center	Houston	Texas
United States	University of Texas Health Science Center at Houston	Houston	Texas
United States	Saint Luke's Hospital	Kansas City	Missouri
United States	Cedars-Sinai	Los Angeles	California
United States	TriStar Centennial Medical Center	Nashville	Tennessee
United States	Vanderbilt Heart	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Columbia University Medical Center/NYPH	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	Sentara Norfolk General Hospital	Norfolk	Virginia
United States	Mayo Clinic	Phoenix	Arizona
United States	Providence Heart Institute	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	St. Francis Hospital	Roslyn	New York
United States	Methodist Hospital of San Antonio	San Antonio	Texas
United States	UCSD	San Diego	California
United States	HonorHealth Research Institute	Scottsdale	Arizona
United States	Ascension Providence Hospital	Southfield	Michigan
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Tallahassee Research Institute	Tallahassee	Florida
United States	Los Robles Hospital and Medical Center	Thousand Oaks	California
United States	University of Arizona Sarver Heart Center	Tucson	Arizona
United States	MedStar Cardiovascular Research Network	Washington	District of Columbia
United States	Cardiovascular Research Institute of Kansas	Wichita	Kansas

Sponsors (2)

Lead Sponsor	Collaborator
Neovasc Inc.	Shockwave Medical, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Verheye S, Jolicoeur EM, Behan MW, Pettersson T, Sainsbury P, Hill J, Vrolix M, Agostoni P, Engstrom T, Labinaz M, de Silva R, Schwartz M, Meyten N, Uren NG, Doucet S, Tanguay JF, Lindsay S, Henry TD, White CJ, Edelman ER, Banai S. Efficacy of a device to narrow the coronary sinus in refractory angina. N Engl J Med. 2015 Feb 5;372(6):519-27. doi: 10.1056/NEJMoa1402556. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Canadian Cardiovascular Society (CCS) Angina Score	Improvement by greater than or equal to 1 and greater than or equal to 2 CCS angina grades compared to baseline. 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).	12 months, 2 years, 3 years, 4 years, and 5 years
Other	Angina Burden	Angina frequency and burden compared to baseline	6 and 12 months
Other	Activity	Measure of activity assessed by actigraphy compared to baseline	6 and 12 months
Other	Exercise Tolerance Testing	Change in ETT parameters compared to baseline	6 and 12 months
Other	Exercise Tolerance Testing	Change in total exercise duration compared to baseline	12 months
Other	Doctor Visits	Number of unplanned office visits due for angina, and any hospitalizations or emergency department visits compared to baseline	6 months, 12 months, 2 years, 3 years, 4 years, and 5 years
Other	Exercise Tolerance Testing	Total exercise duration	6 and 12 months
Other	Seattle Angina Questionnaire (SAQ) Score	Change in other Seattle Angina Questionnaire (SAQ) domain scores compared to baseline. 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 month, 12 month, 2 years, 3 years, 4 years, and 5 years
Other	Adverse Events	Number of deaths, myocardial infarctions, strokes, unplanned revascularization procedures in-hospital, at 30 days, 3 months, 6 months, 12 months and annually post procedure (all and ischemia-relate) and composite major adverse cardiac events (cardiac death, myocardial infarction, stroke, or unplanned revascularization for ischemia) in-hospital	30 day, 6 month, 12 month, 2 years, 3 years, 4 years, and 5 years
Primary	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
Primary	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	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
Secondary	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
Secondary	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