Prospective, controlled, single-arm clinical investigation for the treatment of subjects with severe symptomatic aortic valve stenosis using Valvosoft® Pulsed Cavitational Ultrasound Therapy (PCUT) - First-In-Man.

Calcific Aortic Stenosis (CAS) affects 2 13% of the population aged 65 and
over. It has become a major public health concern because of the ageing western
population (by 2030 one person in three will be over the age of 65 in Europe).
The mean survival rate is 2 3 years for patients diagnosed with severe
symptomatic CAS: about 1.3 million patients in Europe are affected at present.
The only medical response to CAS is currently invasive: Surgical Aortic Valve
Replacement (SAVR) and Transcatheter Aortic Valve Replacement (TAVR). The
morbidity associated with both procedures remains high: 2 5% of patients die
during surgery or after 30 days, 17% die within 1 year, 35% within 3 years.
These surgeries also cause numerous complications (strokes, infections and
infarctions). The cost to the community is ultimately extremely high: e.g. more
than 100,000$ per patient in the United States. In Europe and in the US, direct
and indirect costs associated with aortic valve disease were over 50 billion$
in 2012.
Moreover, not all patients are eligible for open-heart surgery or TAVR or they
refuse surgery (about 10 to 15% of patients).
CARDIAWAVE has developed a new non-invasive, real-time image-guided,
therapeutic approach to treat patients suffering from Calcific Aortic Stenosis.
CARDIAWAVE*s Valvosoft device is a new ultrasound therapy based on a disruptive
technology involving delivering an extremely precise and focused ultrasound
beam to perform a reparative effect on the aortic valve leaflets, softening the
valve*s tissues, restoring leaflet mobility, and therefore improving the
overall clinical status related to the aortic valve stenosis.

Primary Study Objectives:
Safety objective: assessment of procedure related mortality up to 30 days
post-procedure.
Performance objective: demonstration of the ability of Valvosoft to modify the
structure of the calcified valve leaflets to improve their mobility immediately
post-procedure compared to baseline.

Secondary Study Objectives:
Safety assessment of:
1. All-cause mortality and Major Adverse Events (MAEs) peri and post-procedure
up to 30 days and then 3, 6, 12 and 24 months post operatively.
MAE defined as:
• Disabling stroke,
• Myocardial infarction or any clinically significant changes in biomarkers
(CK, Troponin I - T) that would indicate damage to the heart structure, and,
• Clinically significant conduction disturbances requiring pacemaker
implantation or persistent arrhythmias.
2. Non-disabling stroke at 1, 3, 6, 12 and 24 months.
3. Damage to surrounding body structure caused during the procedure.
4. All adverse events (non-device/procedure related; serious and non-serious)
throughout the study.
Performance assessment of:
1. Demonstration of the ability of Valvosoft to modify the structure of the
calcified valve leaflets to improve their mobility at 1, 3, 6, 12 and 24 months.
2. User handling (questionnaire for operator + procedure duration).
Effectiveness assessment of:
1. NYHA classification, presyncope/syncope and angina at 1, 3, 6, 12 and 24
months.
2. Kansas City Cardiomyopathy Questionnaire (KCCQ) at 1, 3, 6, 12 and 24
months.

Prospective, controlled, multicenter, single arm clinical investigation,
conducted in up to three clinical investigation sites.
Up to thirty (30) subjects can be enrolled and screened simultaneously but will
be treated in a consecutive manner: a subsequent subject can only be treated if
the previous subject did not experience any SAE after at least 24 hours after
the treatment or, in case of an SAE, an independent data safety monitoring
board (DSMB) after review of the event has given its approval.
Close proctoring by specialists appointed by Cardiawave will be done for each
new investigator starting with the treatment.

This is an exploratory pilot study, and no formal justification of the sample
size will be made. A total of up to thirty (30) subjects will be enrolled.

Valvosoft PCUT consists in delivering trans-thoracically precisely focused and
controlled short ultrasound pulses (<20µsec) at an extremely high acoustic
intensity measured in watts per square centimeter (W/cm2), to produce
non-thermal mechanical tissue softening of the stiffened calcified aortic valve
which is targeted. Echocardiographic live imaging enables to follow valve
movements in real-time and thus target the therapeutic ultrasound on the
calcified valve with great precision.
Cardiawave's Valvosoft is intended for non-invasive treatment of subjects with
severe symptomatic aortic valve stenosis.

Animal studies did not show any serious risks. However, since this is a first
human study, there are unforeseen risks associated with this study. Valvosoft
therapy refers to patients with severe aortic valve stenosis for whom valve
replacement is not an option. By means of this non-invasive therapy, these
patients may still be able to achieve an improvement in their clinical
condition.

Study Duration:
Enrollment: 24 months.
Follow up: discharge, 1, 3, 6, 12 and 24 months.

Study Assessments:
Baseline:
- Demographics, medical history, clinical and neuropsychological assessment,
concomitant medication.
- TTE/TEE to determine eligibility and centralized assessment of baseline
status of aortic valve, mitral and tricuspid valve.
- Cardiac CT-scan.
- Blood test: CBC, renal function (creatinine), Troponin T, Haptoglobin, LDH,
CK.
- NYHA classification.
- KCCQ.
- Concomitant medication.
During procedure:
- TTE/TEE.
- Adverse events and device deficiencies.
- Concomitant medication.
Post-operative/at discharge
- Blood test for safety (CBC and renal function) including Troponin T, CK; to
be repeated over the next 4 days if elevated.
- Clinical assessment.
- Neuropsychological assessment.
- TTE/TEE.
- Adverse events and device deficiencies.
- Operator feedback.
- Concomitant medication.
1, 3, 6, 12 and 24 months follow up:
- Clinical assessment.
- Neuropsychological assessment (at 1 month only).
- TTE/TEE.
- NYHA classification.
- KCCQ.
- Adverse events.
- Concomitant medication.