Intranasal Bevacizumab for HHT-Related Epistaxis

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder
characterized by systemic vascular malformations that result from mutations of the ENG gene,
which encodes for factors in the vascular endothelial growth factor (VEGF) pathway. HHT is
diagnosed by the Curacao Criteria including the presence of epistaxis; telangiectasias or
vascular malformations in the lungs, liver, or nervous system; and a positive family history
involving a first-degree relative. One of the most common presentations of this disease is
recurrent and profound epistaxis, with many patients reporting more than 4 epistaxis episodes
in a day, many lasting up to an hour. HHT-related epistaxis often results in severe anemia
requiring intravenous iron and repeated blood transfusions, and also carries significant
psychosocial disability relating to impaired quality of life and work absenteeism. Multiple
approaches to treatment have been described, including electrocautery, laser treatment,
embolization, septodermoplasty, and as a last resort, Young's procedure, involving closure of
the nasal vestibule. These approaches are largely palliative, with variable effectiveness,
and almost always require repeated procedures for chronic management of bleeding. There is a
great need for the development of new treatment options for reducing the medical morbidity
and quality of life impairment associated with refractory epistaxis in HHT.

Recently there has been promising data suggesting that inhibition of angiogenesis may be an
effective strategy for managing HHT-related bleeding. Circulating concentrations of VEGF are
significantly elevated in HHT, making VEGF an attractive therapeutic target. Preliminary
studies suggest that bevacizumab, a recombinant monoclonal antibody that inhibits the
biologic activity of VEGF, can significantly improve epistaxis severity when topically
applied, locally injected, or intravenously administered. However, these early pilot studies
of bevacizumab have been limited exclusively to retrospective case series. As yet, there has
been no prospective double-blind placebo controlled trial with serial follow up time points
to establish the role of bevacizumab in the treatment of HHT-related epistaxis.

Based on existing level 4 evidence that suggests that bevacizumab injection is beneficial in
the management of HHT-related epistaxis, we hypothesize that patients who receive intranasal
injection with bevacizumab at the time of electrocautery treatment will have an improvement
in the frequency and severity of epistaxis compared to patients who receive injection of
saline control.

Inclusion Criteria:

1. The patient carries a diagnosis of hereditary hemorrhagic telangiectasia (HHT)

2. The patient is to undergo treatment with electrocautery in the operating room under
endoscopic visualization

3. The patient is able to give informed consent

4. The patient is at least 18 years old

Exclusion Criteria:

1. The patient has had prior treatment with systemic or nasal bevacizumab within the past
year

2. The patient has undergone electrocautery for epistaxis within the 6 months prior to
study enrollment

3. The patient is a minor

4. The patient is pregnant

5. The patient is incapable of understanding the consent process

6. The patient has a history of HIV or another known cause of immunosuppression, or is
actively taking immunosuppressive medications due to organ transplantation, rheumatoid
disease, or other medical conditions.