SynCardia 70cc TAH-t for Destination Therapy (DT)

On 15 October 2004, the SynCardia temporary Total Artificial Heart (TAH-t) received Food and
Drug Administration (FDA) approval (Premarket Approval Application [PMA] #P030011) for
in-hospital use as a bridge to transplant (BTT) in cardiac transplant-eligible candidates at
risk of imminent death from biventricular failure.

On 2 March 2012, FDA granted a Humanitarian Use Designation (HUD) to the 70cc TAH-t System
for use as Destination Therapy (DT) in patients at risk of imminent death from irreversible
biventricular heart failure who are not eligible for transplant and have a body surface area
(BSA) >1.7m. This clinical study is intended to determine the safety and probable benefit of
the 70cc TAH-t for use in DT and support a Humanitarian Device Exemption (HDE) application
for this new indication for the TAH-t System.

The SynCardia TAH-t System is a pulsatile biventricular device that replaces a patient's
native ventricles and valves by pumping blood to both the pulmonary and systemic circulation.

The TAH-t System for DT consists of the implantable TAH-t with SynHall Valves, powered by
PMA-approved external pneumatic drivers [the Circulatory Support System (CSS) Console, the
Companion 2 Driver System and the Freedom Driver System]. The TAH-t System is intended to be
implanted in the operating room by a qualified surgeon and is capable of supporting the
patients both inside and outside the hospital.

The SynCardia TAH-t for DT is indicated for refractory advanced heart failure patients with
biventricular failure who are not candidates for cardiac transplant because of the presence
of contraindications to transplant, including cancer, advanced age, obesity, end-stage
diabetes mellitus, high panel reactive antibodies (PRAs), non-cardiac congenital defects,
contraindications to immunosuppression, lack of social support, poor medical compliance,
neurological impairment or other co-morbidities with a poor prognosis for survival. Patients
with life-threatening, irreversible biventricular failure who are not eligible for transplant
currently have no alternative but death.

The rationale for conducting this study is based on the results of clinical studies in the
bridge-to-transplant (BTT) patient population, together with the in vitro design verification
and validation testing, in vitro reliability testing, and clinical reliability experience of
more than thirty years.

The study design is a prospective, non-randomized, two-treatment arm, multi-center study.
Nineteen (19) patients will be enrolled in the Primary Arm at up to 30 investigational sites
to support an HDE for the use of the TAH-t as DT. Up to an additional 19 patients may be
enrolled in the Secondary Arm to futher characterize the use of the TAH-t for DT in a broader
patient population.

Patients treated with the 70cc TAH-t System for DT under the Primary Arm will be adult male
and female patients between the ages of 19 and 75 years old with a BSA ≥1.7m2 with
life-threatening irreversible biventricular failure who are not eligible for a heart
transplant (as determined by the implanting center at the time of implant assessment) and who
meet the enrollment criteria defined in the clinical protocol. Patients treated with the 70cc
TAH-t System for DT under the Secondary Arm will be adult male and female patients who are at
least 19 years old, are not eligible for a heart transplant (as determined by the implanting
center at the time of implant assessment), and who meet the less restrictive enrollment
criteria defined in the clinical protocol.

The risks to which the TAH-t subjects will be exposed in this clinical investigation are
expected to be no more than the well-characterized risks of the PMA-approved TAH-t System
when used for the bridge-to-transplant population and have been mitigated by the design and
testing of the TAH-t System.

The primary objective of the SynCardia temporary Total Artificial Heart (TAH-t) for DT Study
is to evaluate whether the TAH-t can support patients with life-threatening irreversible
biventricular heart failure who are ineligible for cardiac transplantation (as determined by
the implanting center at time of implant screening assessment), without experiencing
permanent disabling stroke-related deficits (as evidenced by a Modified Rankin Scale score of
0 - 2). The other primary objective of the study is to evaluate whether the safety profile of
the device, when used for DT, is acceptable.

Probable benefit is defined as survival to six months on TAH-t System support with the same
implanted TAH-t, without experiencing permanent disabling stroke-related deficits. This
patient population, without treatment, has a poor prognosis of survival. Per M.L.A. Haeck,
"Patients with drug refractory end-stage HF [heart failure] receiving support with inotropic
drugs [have] a 3-, 6-, and 12-month survival of 51%, 26%, and 6%, respectively, with a mean
survival of only 3.4 months."1

The study success criteria are: alive on the original TAH-t and free from permanent disabling
stroke-related deficits (as evidenced by Modified Rankin Scale score of 0 - 2) at six months
post-implant (or transplanted prior to six months post-implant). For the study to be
considered a success, eight of the 19 subjects either must be alive at six months on the
original TAH-t implant, without experiencing a permanent disabling stroke deficit, or have
become transplant eligible (or have been transplanted).

The safety endpoints will be captured according to the Intermacs Registry AE definitions and
will be assessed according to the same data collection schedule followed under the Intermacs
Registry protocol. Secondary safety endpoints will be the incidences of major infection
(sepsis), neurological events (ischemic or hemorrhagic cardiovascular accident [CVA]),
chronic renal dysfunction, and the rate of major device failures/malfunctions, each defined
per the Intermacs definitions. A performance goal for each has been established based on the
previous experience of TAH-t patients who were waiting for a heart transplant.

All subjects will be followed in the study from the date of TAH-t implant until six months
post-implant, cardiac transplantation, death, or withdrawal from study, whichever occurs
first. Data from the six month post-TAH-t implant period will be used to support an HDE
application. After the six month follow-up visit, patients will continue to be followed under
the study for up to five (5) years post-TAH-t implant [every six months for up to two years
while supported with the TAH-t implant and then annually for another three years].

1 Neth Heart J (2012) 20:167-175 15 November 2011

Primary Arm

Inclusion Criteria:

1. Patients with ife-threatening, irreversible biventricular heart failure (Intermacs
Patient Profile Classifications 1 - 4)

2. Ineligible for cardiac transplantation (e.g., contraindication to immunosuppression,
cancer, elevated panel reactive antibodies [PRAs]) as determined by the implanting
center at time of implant screening assessment.

3. On optimal medical management and failing to respond or failing DT VAD therapy
(continuing to decline)

4. Ambulatory without assistance

5. Patients between 19 and 75 years of age

6. Patients with Body Surface Area (BSA) of ≥ 1.7m2

7. Sternum to T10 distance > 10cm OR adequate room in chest as determined by 3-D imaging
assessment or by other standard clinical assessments

Exclusion Criteria:

1. Cardiac transplant-eligible patients

2. Patients who cannot be adequately anticoagulated on the TAH-t

3. Patients with insufficient space in the chest

4. Patients on ECMO support

5. Patients with Cirrhosis (evidenced by ultrasound, CT scan, or positive biopsy)

6. Patients with Acute or Chronic Renal dysfunction (per Intermacs AE Definitions)

7. Patients with cardiac cachexia (e.g., pre-albumin <17, fragility, and
catabolic/anabolic imbalance)

8. Patients with a comorbidity that has a poor prognosis of survival beyond six months

9. Patients with insufficient social support or who have demonstrated non-compliance with
medical instructions (as determined by the Principal Investigator)

Secondary Arm

Inclusion Criteria:

1. Patients who are NOT eligible to participate in the Primary Arm

2. Patients with life-threatening, irreversible biventricular heart failure (Intermacs
Patient Profile Classifications 1 - 7)

3. Ineligible for cardiac transplantation (as determined by the implanting center at time
of implant screening assessment).

4. On optimal medical management and failing to respond or failing DT VAD therapy
(continuing to decline)

5. Patients 19 years of age or older

6. Sternum to T10 distance > 10cm OR adequate room in chest as determined by 3-D imaging
assessment or by other standard clinical assessments

Exclusion Criteria:

1. Patients who are less than 19 years old

2. Cardiac transplant-eligible patients

3. Patients with Cirrhosis (evidenced by ultrasound, CT scan, or positive biopsy)

4. Patients with Chronic Renal dysfunction (per Intermacs AE Definitions)

5. Patients with insufficient space in the chest

6. Patients who cannot be adequately anticoagulated on the TAH-t

7. Patients with insufficient social support or who have demonstrated non-compliance with
medical instructions (as determined by the Principal Investigator)