Safety Study of Octreotide Injection to Prevent GI Bleeding in Patients With Left Ventricular Assist Device (LVAD)

The primary specific aim is to determine the safety of octreotide LAR in patients with a
LVAD.

Patient experience of the following will be assessed throughout the study (list obtained
from up-to-date.com)

Cardiovascular:

Sinus bradycardia (19% to 25%) Hypertension (≤13%) conduction abnormalities (9% to 10%)

Central nervous system:

Fatigue (1% to 32%) headache (6% to 30%) malaise (16% to 20%) fever (16% to 20%) dizziness
(5% to 20%) Pain (4% to 15%)

Dermatologic:

Pruritus (≤18%) Rash (15%; depot formulation) alopecia (≤13%)

Endocrine & metabolic:

Hyperglycemia (2% to 27%)

Gastrointestinal:

Abdominal pain (5% to 61%) loose stools (5% to 61%) nausea (5% to 61%) diarrhea (34% to 58%)
flatulence (≤38%) cholelithiasis (13% to 38%; length of therapy dependent) constipation (9%
to 21%) vomiting (4% to 21%)

Hematologic Anemia (5-15%)

Local:

Injection site pain (2% to 50%; dose and formulation related)

Neuromuscular & skeletal:

Back pain (1% to 27%) arthropathy (8% to 19%) myalgia (≤18%)

Renal Kidney Stones (5-15%)

Respiratory:

Upper respiratory infection (10% to 23%)

Miscellaneous:

flu symptoms (1% to 20%)

Our key secondary outcomes will focus on study drug efficacy. Patient experience of the
following will be assessed:

Need for Blood Transfusion Hospital Admission for GI Bleed

Heart disease is a leading cause of death and disability, according to the American Heart
Association. Current therapies include lifestyle modification, medical management and
revascularization via Percutaneous Coronary Intervention (PCI) or Coronary Artery Bypass
Surgery (CABG). However, a large portion of patients develop cardiomyopathy which is
refractory to the above interventions. They are treated with chronic inotropes,
resynchronization and other forms of medical management.

Many of these patients eventually worsen and need consideration for cardiac transplantation.
The Thoratec Heartmate II, which is the primary left ventricular assist device (LVAD)
implanted at our institution, has been used as a bridge-to-transplantation. More recently it
has been approved as destination therapy for patients who are not candidates for
transplantation. Over 6000 of these devices have been implanted worldwide since their
introduction. We have implanted over 70 here at the VCU Health System and the McGuire VA
Medical Center.

The early LVAD devices provided physiologic pulsatility, but were large in size and required
large catheters for external venting. The newer continuous flow LVAD devices, such as the
Heartmate II, offer the benefit of being smaller and easier to implant as well as improving
mobility and thus quality of life. However, this benefit comes with a complication of an
increased incidence of GI bleeding, thought to be related to the loss of pulsatility and the
nature of these smaller devices.

Approximately 10-30% of patients experience at least one episode GI bleeding which is likely
multifactorial. It has already been demonstrated that an acquired von Willebrand Syndrome
(vWS) develops due to destruction of multimeric vWF. Additionally, it has been shown that
these patients have a higher than normal percentage of gastrointestinal angiodysplasia.
Whether these are preexisting or develop as a result of de novo angiogenesis from the gut
mucosa is unknown. It is thought that the loss of pulsatility and potential hypoxia result
in secretion of angiogenic mediators and contribute to the development of angiodysplasia.

Current treatment for LVAD associated GI bleeding is aimed at identifying the location of
bleeding and treatment with blood product transfusion, cryoprecipitate for vWS, Desmopressin
for platelet dysfunction, and interventions through Interventional Radiology (IR) and
surgery. In addition to the obvious costs and increase in morbidity and mortality associated
with the above therapies, patients who receive multiple transfusions develop antibodies and
thus become more difficult to transplant. Thus a vicious cycle develops.

We need to strive for a proactive stance in these patients and attack the problem at the
source. There is a considerable amount of experience using octreotide in idiopathic chronic
GI bleeding. This is likely due to its ability to decrease splanchnic blood flow and its
potential ability to inhibit angiogenesis. Octreotide has been thoroughly studied and has a
known safety profile. Off label use of octreotide LAR for the purpose of attenuating LVAD
associated GI bleeding is currently practiced by some physicians at VCU with no adverse side
effects encountered. It is time to formally study the safety and efficacy of octreotide LAR
for this purpose. We propose an open-label safety study for 10 subjects to be followed for a
total of 24 weeks. Should the safety study be favorably completed, a multi-center trial with
randomization to octreotide LAR or placebo with endpoints of GI bleeding and transfusion
will be pursued.

Inclusion Criteria:

- LVAD insertion as bridge to transplant or destination

- 18 years of age or older

Exclusion Criteria:

- Poorly controlled diabetes, A1C greater than 8%

- Poorly controlled hypothyroidism, TSH > upper limit of normal (5.5)

- End Stage Renal Disease (ESRD) requiring dialysis

- Cirrhosis

- Anemia (Hgb < 8)

- Acromegaly

- Hx of chronic diarrhea - as determined by history of loose stool lasting longer than
2-4 weeks

- Pregnancy or breastfeeding

- Inability to provide informed consent

- Incarceration or otherwise a ward of the state

- Non-English speaking