The rationale for conducting the PARADIGM study is to evaluate the safety and effectiveness of the AVP III for closure of PVLs. Until recently, current treatment in the US and OUS included off-label use of various occluder devices. The study will…
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Source
Brief title
Condition
- Cardiac valve disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is a composite of safety and effectiveness measures
evaluating the percent of patients successfully treated with an AVP III for the
reduction of PVL, where success is defined as:
• Transcatheter placement of the AVP III in the intended location without
interfering with the surgical valve function on exit from procedure,
• Reduction in PVL by greater than or equal to two grades (defined in appendix
II of the protocol) on exit from procedure,
• Freedom from intra-procedural death, and
• Freedom from unplanned surgical procedure or transcatheter reintervention
related to the AVP III through 30 days
Secondary outcome
The descriptive safety endpoints will be the incidence of the following adverse
events:
o Early events (occurring <= 30 days post-implant):
o Life-threatening, disabling or major bleeding, or other major cardiac
complications (BARC type 3a and above)
o Major and minor vascular complications (access-site and access-related)
o Complications due to septal crossing (for trans-septal access)
o Device dislodgement, migration or embolization
o Coronary obstruction (peri-procedure)
o Unplanned surgical or interventional procedures (such as cardiopulmonary
bypass or hemodynamic support response, and conversion to
emergency surgery)
o Heart block requiring permanent pacemaker insertion
o Early (<=30 days) and late events (31 days to 1 year):
o Mortality (all-cause and cardiac-related)
o Endocarditis (related to the device)
o Valve dehiscence
o Hemolytic anemia (newly developed or worsening)
o Device-related hemolytic anemia (newly developed or worsening)
o Device or valve thrombosis
o Interference of AVP III with surgical valve function
o Heart failure hospitalizations
o Systemic Embolism
o Device Related Embolism
o Stroke and TIA
o Blood transfusions for treatment of hemolytic anemia
The descriptive efficacy endpoints are as follows:
o NYHA functional class at 30 days, 6 months, and 1 year, and change or no
change in NYHA functional class observed between Baseline and
30 days, between Baseline and 6 months, and between Baseline and 1 year
o Improvement in Quality of life measures (Kansas City Cardiomyopathy
Questionnaire (KCCQ) and EuroQol 5D (EQ-5D)) observed between
Baseline and 30 days and between Baseline and 1 year
o Type and severity of PVL or freedom from residual PVL as assessed by
echocardiography at Baseline, Discharge, 30 days, 6 months, and 1
year
o Transvalvular regurgitation (whether present, and severity if present)
assessed by echocardiography at Baseline, Discharge, 30 days, 6
months and 1 year.
o Transvalvular mean and peak gradients assessed by echocardiography at
Baseline, Discharge, 30 days, 6 months and 1 year
o Left ventricular ejection fraction assessed by echocardiography, at Baseline
, Discharge, 30 days, 6 months and 1 year
Background summary
Paravalvular leak (PVL) is the presence of a regurgitant flow around a
prosthetic valve when there is an incomplete seal between the prosthesis and
the native valve tissue. PVL is a known potential complication after valve
replacement by either a surgical or a transcatheter approach. Predisposing
factors to PVL may be patient-related, such as calcification, fibrosis or
infection; but may also be related technical factors such as valve debridement,
valve sizing, valve suturing, and valve positioning; or even precipitated by
endocarditis or generalized frail tissue.
PVLs are primarily detected by echocardiography and are graded as mild, mild to
moderate, moderate, moderate to severe or severe based on echocardiographic
measurements, as described by Ruiz et al.1 PVLs may be asymptomatic if small
with mild severity but can be moderate or severe and cause symptoms of heart
failure (breathlessness, edema) and/or anemia due to hemolysis. A clinically
significant PVL occurs with a higher severity grade of PVL (moderate or severe)
and typically involves the aortic or mitral valves since both valves are on the
left side of the heart where there is greater blood pressure and a higher
likelihood for producing symptoms of heart failure and/or hemolysis. PVL with a
severity grade of moderate or higher is considered to be representative of the
target patient population who may be treated with the AVP III. Asymptomatic
patients or patients with a clinically insignificant PVL with a severity grade
of mild or lower are typically monitored with periodic echocardiographic
evaluation and functional assessment and do not undergo surgical or
transcatheter intervention to treat the PVL. Repeat open-heart surgery for
moderate or severe PVL is often necessary to relieve symptoms and avoid
worsening clinical outcomes, and medical therapy is considered palliative.
However, repeat surgery is known to be associated with a high morbidity and
mortality rates, as well as a high risk of PVL recurrence.2-4
The overall PVL incidence rate (all grades included) is cited as 7-17% in
surgical mitral valve replacement (SMVR) and 2-10% in surgical aortic valve
replacement (SAVR), and most occur within the first year after valve
replacement.1,5,6 Based on a review of recently published literature the
highest reported rate of moderate to severe PVL for a surgical valve implanted
in the mitral position is 5.4% and in the aortic position is 3%.7,8
Transcatheter (percutaneous) PVL closure (TPVLC) emerged as an alternative to
open cardiac surgical repair of PVL in the early 1990*s. Hourihan et al.
described TPVLC in 1992 via arterial and venous femoral access using occluders
originally designed for patent ductus arteriosus, septal defects and patent
foramen ovale closure.9 The transapical route for TPVLC was later described by
Lim in 2008 using Amplatzer occluders.10 Since its first description two
decades ago, TPVLC has further been developed as a completely transvascular
approach and is now an accepted less invasive alternative to surgery for
high-risk patients and for patients who refuse additional surgery. As an
increasing number of reports have been published on TPVLC, the 2017 EACTS/ESC
guidelines for the management of valvular heart disease state that TPVLC may be
considered for PVL with clinically significant regurgitation in surgical
high-risk patients11, and the AHA/ACC guideline for management of patients with
valvular heart disease grants a IIa level recommendation, suggesting TPVLC is
beneficial to treat high-risk symptomatic patients who have PVL, and anatomic
features suitable for TVPLC at experienced surgical centers.12 Finally, in
recognition of the increasing adoption of TPVLC as an alternative therapeutic
approach to address a clinically significant PVL, the PVL Academic Research
Consortium (PVL-ARC) published in 2017 the first guideline document describing
the clinical incidence and impact of PVL. The guideline document also provides
definitions and methodology for assessing PVL and suggests endpoints for
clinical trials of PVL closure devices.1
Despite the increasing off-label utilization of commercially available
occluders that are approved for other indications for TPVLC, there is limited
availability of approved transcatheter occluders indicated for PVL. No device
is approved for this indication in the United States (US). Some physicians have
adopted off-label use of transcatheter vascular occlusion devices for TPVLC. In
particular, use of the Abbott nitinol occluders in the AMPLATZER family of
devices for TPVLC has been documented in the literature.13-16 According to
published data, the AVP III is a favored occlusion device for TPVLC in
geographies where it is available.14 The AVP III is oblong rather than circular
in cross-section design, relatively short, with a low profile, and extended
rims, and is thought to better fit the common semilunar shape of a defect
causing PVL than circular devices.15
Study objective
The rationale for conducting the PARADIGM study is to evaluate the safety and
effectiveness of the AVP III for closure of PVLs. Until recently, current
treatment in the US and OUS included off-label use of various occluder devices.
The study will collect safety and effectiveness data to support FDA approval
and post market clinical follow-up (PMCF) requirements in Europe as a condition
for CE Mark approval.
Study design
This is a prospective, multi-center, single arm study to demonstrate the safety
and effectiveness of the AVP III for closure of PVL following surgical valve
replacement in either the mitral or the aortic position.
Study burden and risks
Most risks associated with participation in this trial are similar to the risks
associated with commercially available AVP procedures. Study specific
assessments contain the following risks:
TTE : TTE does not have additional risks for the subject, only a burden in
time.
Physical exam: (weight, blood pressure, heart rate measurement) does not
provide additional risks, only a burden in time
Bloodwithdrawal: There is a minor risk associated with collection of blood
required per the protocol and include discomfort from needle stick, a small
risk of infection, bruising, swelling and bleeding or fainting. These risks are
minimized by cleaning the site carefully prior to obtaining blood by a
qualified person.
Questionnaires: No risks, only a burden in time
TEE: For subjects who have multiple plugs implanted during the procedure, a TEE
will be requested at the 6-month follow-up visit for the study. The TEE can be
experienced as unpleasant by the subject because it requires a sedation or a
full anesthesia. Discomfort can also be experienced when making a
trans-oesophageal ultrasound. The most common discomforts are gagging and sore
throat. Less common discomforts include vomiting and pain when swallowing. Rare
discomforts include bleeding, difficulty breathing, heart problems, tooth
injuries, and damage to the esophagus.
Standaardruiter 13
VEENENDAAL 3905 PT
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Standaardruiter 13
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Listed location countries
Age
Inclusion criteria
1. Subject is implanted with a mechanical or biological surgical valve in the
aortic or mitral position. Note: Subjects in European countries can only be
implanted with a mechanical valve in the aortic or mitral position
2. Subject has a clinically significant paravalvular leak with a severity grade
of moderate or higher, associated with signs of heart failure and/or hemolysis
necessitating recurring blood transfusions.
3. Subject has one PVL defect that can be closed with a single AVP III as
assessed pre-procedurally
4. Subject has provided written informed consent
5. Subject is >=18 years old
Exclusion criteria
1. Subject has a rocking valve or extreme dehiscence of the prosthetic valve
involving more than 40% of the sewing ring.
2. Subject*s PVL(s) originates from a transcatheter aortic or mitral valve
replacement, or from rapid deployment or sutureless surgical replacement valves
3. Subject has multiple clinically significant PVL defects adjacent to a single
prosthetic valve, or a prosthetic aortic valve and prosthetic mitral valve
which both have a clinically significant paravalvular leak.
4. Subject who is hemodynamically unstable or who cannot undergo an elective
procedure
5. Subject with known or suspected active endocarditis or other active
infection
6. Subject has within the last 6 months a previously documented intracardiac
mass, vegetation, tumor, or thrombus which would interfere with placement of
the AVP III
7. Subject has inadequate vasculature for delivery of the AVP III
8. Subject has unsuitable anatomy for PVL closure using the AVP III (such as a
PVL associated with an abscess cavity or a pseudoaneurysmal sac) or anatomy
where the AVP III would interfere with other intracardiac or intravascular
structures (such coronary ostia)
9. Subjects who are unable to receive intraprocedural anticoagulant therapy
10. Pregnant or nursing subjects or subjects who plan pregnancy during the
clinical investigation follow-up period.
11. Presence of other anatomic or comorbid conditions, or other medical,
social, or psychological conditions that, in the investigator*s opinion, could
limit the subject*s ability to participate in the clinical investigation or to
comply with follow-up requirements, or impact the scientific soundness of the
clinical investigation results.
12. Life expectancy is less than 1 year in the opinion of the Investigator
13. Incapacitated individuals, defined as persons with mental illnesses or
handicaps that impair their ability to provide informed consent, or individuals
without legal authority to provide informed consent.
14. Individuals who are currently participating in an investigational drug or
device study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT04489823 |
| CCMO | NL75026.100.20 |