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| General |
| Study Status |
Terminated |
Application Number /
Requirement Number |
P060038 S017/ PAS001 |
| Date Original Protocol Accepted |
07/15/2014
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| Date Current Protocol Accepted |
11/25/2014
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| Study Name |
NEMO PAS
|
| Device Name |
MITROFLOW AORTIC PERICARDIAL HEART VALVE WITH PHOSPHOLIPID REDUCTION TREATMENT, MODEL DL
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| General Study Protocol Parameters |
| Study Design |
Prospective Cohort Study
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| Data Source |
Sponsor Registry
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| Comparison Group |
Objective Performance Criterion
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| Analysis Type |
Analytical
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| Study Population |
Neonate: 1-28 days,
Infant: 29 days-2 yrs,
Child: 2-12 yrs,
Adolescent: 13-18 yrs,
Adult: >21
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| Detailed Study Protocol Parameters |
| Study Objectives |
This study is a prospective, non-randomized, multicenter post-
approval study (PAS)
Primary effectiveness:
*To evaluate the hemodynamic performance of the Mitroflow DL valve as compared to other stented aortic bioprostheses in the current literature; and
*To evaluate the overall improvements in patient condition by comparison of pre- operative and post-operative New York Heart Association (NYHA) functional classification.
Secondary safety objective:
*To determine early (day 1-30) and late (>30 days) valve-related adverse event rates (including valve thrombosis, thromboembolism, paravalvular leak (all and major), bleeding (all and major) and endocarditis for Mitroflow DL are comparable to appropriate historical controls manifested as Objective Performance Criteria (OPC) in the FDA¿s Heart Valve Guidance4 and the ISO 5840 guidelines.
* Additional safety endpoints to be included are rates of the
following adverse events: hemolysis, non-structural dysfunction, valve-related embolism, reoperation, explant, and death (all- cause and valve-related).
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| Study Population |
Patients who were implanted with Mitroflow, Model DL,
implantation according to the Instructions for Use (IFU).
Historical controls specified as objective performance criteria (OPCs) in the FDA Draft Replacement Heart Valve Guidance (where applicable).
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| Sample Size |
Assuming a 32% mortality and 20% attrition rate into account, the PAS will include a minimum of 15 U.S. sites and 185 patients implanted with the Mitroflow DL valve in a commercial environment. A minimum of one-hundred (100) patients followed for at least eight (8) years will be necessary to comply with the
800 patient/year requirement outlined in the FDA Heart Valve
Guidance.
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| Key Study Endpoints |
Occurrence of early and late structural valve deterioration (SVD) and valve-related complications (early and late), including valve thrombosis, thromboembolism, bleeding, anticoagulation-related bleeding, paravalvular leak, endocarditis, clinically significant hemolysis, non-structural dysfunction, reoperation, explant and death.
The primary hemodynamic effectiveness endpoints for hemodynamic performance of the valve to be evaluated are
trans-valvular peak and mean pressure gradients, effective orifice area (EOA) and EOA index (EOAI), performance index (PI), cardiac output (CO), cardiac index (CI), the location and severity of regurgitation, and LV mass regression.
|
| Follow-up Visits and Length of Follow-up |
8 years
¿Pre-implant
¿Implant
¿Post-operative (within 30 days of implant)
¿Annual clinical and echocardiographic follow-up
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| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
A total of 186 patients were enrolled in the study and implanted with a valve.
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| Actual Number of Sites Enrolled |
12
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| Patient Follow-up Rate |
Follow-up was conducted for n=184 patients with a cumulative 469.65 patient-years of follow-up overall. A mean follow-up of 2.52 years was achieved before the study was terminated early on November 21, 2019, and no further follow-up was conducted after December 2019.
• Year 1 Follow-Up Rate: 91.7%
• Year 2 Follow-Up Rate: 85.1%
• Year 3 Follow-Up Rate: 82.8%
• Year 4 Follow-Up Rate: 16.8% (low follow-up primarily due to early termination of study and patient withdrawal prior to 4Y f
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| Final Safety Findings |
The safety endpoints were evaluated based on events reported by sites per the Valve Academic Research Consortium-2 (VARC-2) definitions, and were stratified by early (less than or equal to 30 days) and late (>30 days) post-operative events for 186 patients with 455.24 late patient-years. A total of 33 deaths (17.7%) were observed during the follow-up period.
• Early period (less than or equal to 30 days) safety findings:
o All-cause death: 6 (3.2%)
¿ Cardiovascular Mortality: 4 (2.2%)
¿ Non-Cardiovascular Mortality: 2 (1.1%)
o Reintervention: 3 (1.6%)
o Valve Thrombosis: 1 (0.6%)
o Bleeding Events: 5 (2.7%), and 1 case (0.6%) of arterial hemorrhage
o Non-structural Valve Dysfunction: 1 (0.6%)
o Not observed: Structural valve deterioration, hemolysis, clinically significant paravalvular leak
• Late period (>30 days) safety findings:
o All-cause death: 27 (14.7%; linearized-rate on 455.2 pts-year (LR) of 5.9%)
¿ Cardiovascular Mortality: 11 (6.0%; LR of 2.4%)
¿ Non-Cardiovascular Mortality: 16 (8.7%; LR of 3.3%)
o Stroke and/or Transient Ischemic Attack: 5 (2.7%; LR of 1.1%)
o Reintervention: 4 (2.2%)
o Structural Valve Deterioration: 3 (1.6%; LR of 0.7%) and 1 (0.6%, LR of 0.2%) additional case of structural valve deterioration requiring intervention.
o Peripheral Thromboembolic Events: 3 (1.6%; LR of 0.7%), which included pulmonary embolism,
thrombectomy, and deep vein thrombosis.
o Endocarditis: 1 (0.5%; LR of 0.2%)
o Non-structural Valve Dysfunction: 2 (1.1%; LR of 0.4%)
o Paravalvular Leak: 1 (0.5%: LR of 0.2%)
o Cerebral Hemorrhage: 2 (1.1%; LR of 0.4%)
o Not observed: Hemolysis, valve thrombosis
o 52 (28.3%) subjects reported 125 serious adverse events
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| Final Effect Findings |
As very few patients were included at the 4-Year Follow-Up due to study termination, 3-Year Follow-Up findings are presented.
• NYHA Classification: There was improvement in NYHA classification that was sustained to 3Y
o Baseline (n=186): patients were primarily NYHA Class II (n=68, 41.4%) and Class III (n=31, 31.2%)
o 1 Year (n=155): Patients were primarily Class I (n=104, 69.7%) and Class II (n=29, 18.7%), with no Class IV classification.
o 3 Year (n=125): Patients were primarily Class I (n=100, 80%) and Class II (n=15, 12%)
• Mean Pressure Gradient (MPG): There was improvement in MPG that was sustained to 3Y
o Baseline (n=147): 42.6 ± 16.5 mm Hg.
o Discharge (n=165): 12.1 ± 5.0 mmHg
o 1 Year (n=147): 12.1 ± 5.0 mmHg
o 3 Year (n=52): 13.5 ± 5.7 mmHg
• Effective Orifice Area (EOA): There was improvement in EOA that was sustained to 3Y
o Baseline (n=84): 0.8 ± 0.3 cm2
o Discharge (n=150): 1.7 ± 0.4 cm2
o 1 Year (n=141): 1.5 ± 0.4 cm2
o 3 Year (n=51): 1.4 ± 0.4 cm2
• Regurgitation
o Discharge (n=172 patients/echoes performed): 114 patients had no aortic regurgitation (66.3%) and 58 patients exhibited regurgitation. Of the 58 patients that did have regurgitation, 36 had central regurgitation, 9 had paravalvular regurgitation, and 2 had both forms of regurgitation. The severity of regurgitation was trace (n=31), mild (n=26), or moderate (n=1).
o 1 Year (n=149): 105 patients had no aortic regurgitation (70.5%), and of the 44 patients that did have regurgitation, 36 had central regurgitation, and 6 had paravalvular regurgitation (2 patients were not evaluable). The severity of regurgitation was trace (n=27) or mild (n=17).
o 2 Year (n=129): 91 patients had no aortic regurgitation (70.5%) and of the 38 patients that did have regurgitation, 22 had central regurgitation and 10 had perivalvular regurgitation (6 patients were not evaluable). The severity of the regurgitation was trace (n=20), mild (n=17), or moderate (n=1).
o 3 Year (n=54): 38 patients had no aortic regurgitation (70.4%), and of the 16 patients that did have regurgitation, 12 patients had central regurgitation, and 4 had paravalvular regurgitation. The severity of regurgitation was trace (n=13) or mild (n=3).
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| Study Strengths & Weaknesses |
This study was terminated early due to discontinued marketing of the device in the US; thus, the study did not meet the target 800 patient years follow-up, and instead only achieved a cumulative follow-up of 469.65 patient-years with <16.8% of subjects completing their 4-year follow-up visit. Due to study termination and significant missing data/echo measurements for the intended outcomes, the conclusions that can be derived from this study are limited.
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| Recommendations for Labeling Changes |
No labeling change is recommended as the device has been discontinued.
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