Heart Failure, Mitral Valve Insufficiency
Conditions
Keywords
Functional mitral regurgitation, Secondary mitral regurgitation, Percutaneous mitral repair
Brief summary
The objective of this prospective, multi-center, randomized, double-blind trial is to assess the safety and efficacy of the Carillon Mitral Contour System in treating functional mitral regurgitation (FMR) associated with heart failure, compared to a randomized Control group which is medically managed according to heart failure guidelines.
Detailed description
The American Heart Association (AHA) estimates that there are more than 22 million people worldwide with heart failure. Functional mitral regurgitation, defined as the leakage of the mitral valve caused by global or regional changes in left ventricular geometry as well as mitral annular dilation, occurs as a consequence of heart failure. Cardiac Dimensions has developed proprietary technology designed to address functional mitral regurgitation in a minimally invasive manner. Cardiac Dimensions plans to conduct a clinical trial of the Carillon Mitral Contour System in study subjects with functional mitral regurgitation. This study is a prospective, randomized parallel-group, double-blind, multi-center clinical trial designed to examine the safety and efficacy of the Carillon Mitral Contour System in study subjects with functional mitral regurgitation. The study will consent up to 180 subjects in order to randomize up to 120 subjects at 25 investigational sites in Europe and Australia/New Zealand. Subjects will be randomized into one of two study groups using a 3:1 (Treatment group : Control group) ratio. Study subjects who are eligible for this clinical study and have consented to participating in the study will undergo multiple assessments prior to randomization to evaluate the eligibility (inclusion/exclusion) criteria. Subjects who meet all eligibility criteria will be randomized into one of two study groups (Treatment or Control). Study subjects randomized to the Treatment group will undergo a venous angiogram to assess the suitability of the coronary sinus/great cardiac vein (CS/GCV) for placement of the Carillon implant. If the subject meets the anatomic requirements for device placement, the Carillon implant procedure begins. With the distal aspect of the device anchored, incremental tension will be applied to plicate the peri-annular tissue. A transesophageal or transthoracic echocardiogram will be obtained during the procedure to evaluate the effect on functional mitral regurgitation and to evaluate left ventricular function. After the proximal anchor of the implant is locked in place, safety (including assessment of coronary arterial flow) and efficacy will be reconfirmed prior to releasing the Carillon implant from the delivery system. Subjects randomized to the Control group will experience an index procedure similar to the Treatment group, however, without device placement. To ensure that subjects randomized to the Control group will not be able to deduce the treatment assignment based on the type of intervention or time associated with the procedure, minimal interventional procedures, such as femoral arterial pressure monitoring and a jugular venous drip. If a recent (within the last 3 months for ischemic cardiomyopathy or 12 months for non-ischemic cardiomyopathy) coronary angiogram is available, this assessment may be precluded. After the study subjects are discharged, the subjects' primary care specialists (cardiologist/heart failure physician) and clinical investigation site staff will coordinate follow-up evaluations. Subjects will be evaluated at one (1), six (6), and twelve (12) months post-implant, to assess long-term safety, and functional and clinical status. (Reference Section 3.8-Study Follow-up Evaluations) This study will provide for an independent Clinical Events Committee (CEC) and an independent Data Safety Monitoring Board (DSMB). The CEC will be responsible for adjudicating complications reported during the study that are related to study endpoints (objectives), the procedure or the device. The DSMB will review the safety data against the established criteria and in the context of other safety data accumulated to date and the continued validity of the study.
Interventions
Percutaneous mitral valve repair
Sponsors
Menzies Institute for Medical Research
Cardiac Dimensions Pty Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
With crossover for sham procedure patients who are eligible at time of 12 month follow up.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of dilated ischemic or non-ischemic cardiomyopathy * Functional Mitral Regurgitation: 2+ (Moderate), 3+ (Moderate/Severe), or 4+ (Severe) * New York Heart Association (NYHA) II, III, or IV * Six Minute Walk distance of at least 150 meters and no farther than 450 meters * Left Ventricular Ejection Fraction ≤ 50 % * LV end diastolic dimension (LVEDD) \>55mm or LVEDD/Body Surface Area (BSA) \> 3.0cm/m2 * Stable heart failure medication regimen for at least three (3) months prior to index procedure
Exclusion criteria
* Hospitalization in past three (3) months due to myocardial infarction, coronary artery bypass graft surgery, and/or unstable angina * Hospitalization in the past 30 days for coronary angioplasty or stent placement * Subjects expected to require any cardiac surgery within one (1) year * Subjects expected to require any percutaneous coronary intervention within 30 days of enrollment * Pre-existing device (e.g., pacing lead) in coronary sinus (CS) / great cardiac vein (GCV), or anticipated need for CRT within twelve (12) months * Presence of a coronary artery stent under the CS / GCV in the implant target zone * Presence of left atrial appendage (LAA) clot. * Presence of primary renal dysfunction or significantly compromised renal function as reflected by a serum creatinine \> 2.2 mg/dL OR eGFR \< 30 ml/min * Inability to undertake a six-minute walk test due to physical restrictions/limitations * Chronic severe pathology limiting survival to less than 12-months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Baseline Regurgitant Volume Associated With the Carillon Device Relative to the Control Population at 12 Months | Baseline and 12 months | The primary echocardiographic index and primary endpoint of the REDUCE FMR study was Regurgitant Volume (RV) in the ITT population (N=120). RV was analyzed for the ITT patient population calculated as the mean change per randomization group among subjects with evaluable data. Between group comparisons were performed using the Students' t-test. |
| Difference in the Rate of Major Adverse Events Between Treatment (Carillon) and Control Groups | Baseline and 12 months | Cumulative number of events for Death, Myocardial Infarction, Cardiac Perforation, Device embolization, and surgical or percutaneous intervention related to device. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Heart Failure Hospitalizations Between Treatment (Carillon) and Control Groups | Baseline and 12 months | A diagnosis of acute decompensated heart failure hospitalization (ADHF) requires an in-hospital stay that includes at least one calendar date change and requires intravenous or mechanical heart failure treatment. The length of hospital stay will be calculated from admission to discharge to home or other disposition. The diagnosis of ADHF will be based on: * Symptoms of worsening heart failure such as increased shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, fatigue, decreased exercise tolerance or history of weight gain; * Physical examination evidence such as neck vein distention, the presence of a third heart sound, bilateral pulmonary rales, worsening ascites or pedal edema, hypotension or signs of worsening end-organ perfusion; and/or * Laboratory evidence, which may include pulmonary congestion on chest x-ray, elevated natriuretic peptide level, worsening oxygenation or respiratory acidosis. |
| Change in Six-minute Walk Distance Between Treatment (Carillon) and Control Groups | Baseline and 12 Months | Subjects had 6-MWT conducted at baseline and each follow-up visit. The subject walked as far as they could within a 6-minute period. They were allowed to rest. The distance (in whole meters) was captured at each visit. |
| Change in Left Ventricular Volumes Between Treatment (Carillon) and Control Groups | Baseline and 12 Months | The volume of the left ventricle will be measured by a blinded echosonographer ajdn submitted to the core lab for blinded analysis. The ventricle will be measured as systole and diastole. |
Countries
Australia, Czechia, France, Germany, Netherlands, New Zealand, Poland, United Kingdom
Participant flow
Recruitment details
163 subjects consented to randomize 120. 28 Screen Failed prior to procedure 15 Excluded at the procedure due to angiographic results
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group CARILLON Mitral Contour System: Percutaneous mitral valve repair | 87 |
| Control Group Optimized stable medical therapy | 33 |
| Total | 120 |
Baseline characteristics
| Characteristic | Control Group | Total | Treatment Group |
|---|---|---|---|
| Age, Continuous | 69.1 years STANDARD_DEVIATION 8.9 | 69.8 years STANDARD_DEVIATION 9.5 | 70.1 years STANDARD_DEVIATION 9.7 |
| NYHA NYHA III Marked limitation | 17 Participants | 63 Participants | 46 Participants |
| NYHA NYHA II Mild symptoms | 16 Participants | 55 Participants | 39 Participants |
| NYHA NYHA IV Severe limitations | 0 Participants | 2 Participants | 2 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Sex: Female, Male Female | 9 Participants | 33 Participants | 24 Participants |
| Sex: Female, Male Male | 24 Participants | 87 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 87 | 5 / 33 |
| other Total, other adverse events | 0 / 87 | 0 / 33 |
| serious Total, serious adverse events | 46 / 87 | 19 / 33 |
Outcome results
Primary
Change in Baseline Regurgitant Volume Associated With the Carillon Device Relative to the Control Population at 12 Months
The primary echocardiographic index and primary endpoint of the REDUCE FMR study was Regurgitant Volume (RV) in the ITT population (N=120). RV was analyzed for the ITT patient population calculated as the mean change per randomization group among subjects with evaluable data. Between group comparisons were performed using the Students' t-test.
Time frame: Baseline and 12 months
Population: Image quality from sites reduced ultimate number of images able to be analyze by central review committee for RV values.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group | Change in Baseline Regurgitant Volume Associated With the Carillon Device Relative to the Control Population at 12 Months | -7.07 ml/beat |
| Control Group | Change in Baseline Regurgitant Volume Associated With the Carillon Device Relative to the Control Population at 12 Months | 3.32 ml/beat |
Primary
Difference in the Rate of Major Adverse Events Between Treatment (Carillon) and Control Groups
Cumulative number of events for Death, Myocardial Infarction, Cardiac Perforation, Device embolization, and surgical or percutaneous intervention related to device.
Time frame: Baseline and 12 months
Population: 120 randomized subjects, regardless of follow-up period.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group | Difference in the Rate of Major Adverse Events Between Treatment (Carillon) and Control Groups | -7.07 Mitral Regurgitant Volume (mL) |
| Control Group | Difference in the Rate of Major Adverse Events Between Treatment (Carillon) and Control Groups | 3.32 Mitral Regurgitant Volume (mL) |
Secondary
Change in Left Ventricular Volumes Between Treatment (Carillon) and Control Groups
The volume of the left ventricle will be measured by a blinded echosonographer ajdn submitted to the core lab for blinded analysis. The ventricle will be measured as systole and diastole.
Time frame: Baseline and 12 Months
Population: Randomized population with paired images from baseline to 12-month only.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment Group | Change in Left Ventricular Volumes Between Treatment (Carillon) and Control Groups | LVEDV | -10.42 mL |
| Treatment Group | Change in Left Ventricular Volumes Between Treatment (Carillon) and Control Groups | LVESV | -6.19 mL |
| Control Group | Change in Left Ventricular Volumes Between Treatment (Carillon) and Control Groups | LVEDV | 6.54 mL |
| Control Group | Change in Left Ventricular Volumes Between Treatment (Carillon) and Control Groups | LVESV | 6.1 mL |
Secondary
Change in Six-minute Walk Distance Between Treatment (Carillon) and Control Groups
Subjects had 6-MWT conducted at baseline and each follow-up visit. The subject walked as far as they could within a 6-minute period. They were allowed to rest. The distance (in whole meters) was captured at each visit.
Time frame: Baseline and 12 Months
Population: Randomized subjects
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group | Change in Six-minute Walk Distance Between Treatment (Carillon) and Control Groups | 32.0 Meters |
| Control Group | Change in Six-minute Walk Distance Between Treatment (Carillon) and Control Groups | 17.5 Meters |
Secondary
Rate of Heart Failure Hospitalizations Between Treatment (Carillon) and Control Groups
A diagnosis of acute decompensated heart failure hospitalization (ADHF) requires an in-hospital stay that includes at least one calendar date change and requires intravenous or mechanical heart failure treatment. The length of hospital stay will be calculated from admission to discharge to home or other disposition. The diagnosis of ADHF will be based on: * Symptoms of worsening heart failure such as increased shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, fatigue, decreased exercise tolerance or history of weight gain; * Physical examination evidence such as neck vein distention, the presence of a third heart sound, bilateral pulmonary rales, worsening ascites or pedal edema, hypotension or signs of worsening end-organ perfusion; and/or * Laboratory evidence, which may include pulmonary congestion on chest x-ray, elevated natriuretic peptide level, worsening oxygenation or respiratory acidosis.
Time frame: Baseline and 12 months
Population: Randomized subjects, per treatment arm
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group | Rate of Heart Failure Hospitalizations Between Treatment (Carillon) and Control Groups | 0.57 Rate of HFH per patient-year |
| Control Group | Rate of Heart Failure Hospitalizations Between Treatment (Carillon) and Control Groups | 0.73 Rate of HFH per patient-year |