Topical Bevacizumab for the Management of Recurrent Epistaxis in Patients With Hereditary Hemorrhagic Telangiectasia (HHT)

Plans are to recruit patients with HHT from the UCSD Nasal Dysfunction Clinic. The HHT world
is connected through the HHT Foundation. The Foundation is interested in VEGF inhibitors.
They have carefully watched our work at UCSD for a long time and our two papers on Avastin
have been circulated around the world. Those who come for our evaluation and are deemed
appropriate for Bevacizumab injection will be recruited for this study. Those agreeing to
participate will sign a consent form.

The treatment, regardless of participation in the proposed research, is to bring the
patients to the operating room where under general anesthesia the nose is suctioned clean of
blood clot, crust and secretion. The mucosa is then injected with a local anesthetic with
adrenaline to reduce discomfort and to reduce bleeding. The nasal mucosa is treated with a
KTP laser in our standard fashion. A 100mg of Avastin delivered in 4cc is then diluted with
4cc of normal saline to a total volume of 8cc. The dilution is made not for any known
difference in treatment but rather it normally takes a minimum of 8cc to properly inject the
nasal mucosa. The 1% Bevacizumab is then injected submucosally throughout the nasal cavity
sparing the mucosa of the cartilage and the septum. The nasal cavity is then sprayed with
2cc of a fibrin sealant (EVICEL) this reduces postoperative bleeding and facilitates healing
from the laser therapy. It has nothing to do with the Bevacizumab injection. The patient is
then awakened and returned to the recovery room and discharged home. Beginning in
approximately one week the patient is instructed to begin their hypertonic pulsatile nasal
irrigations. They will follow-up in the clinic at 1 month. The data collection form is
attached. Prior to treatment patient completes the HHT epistaxis severity score, blood is
drawn for hematocrit, hemoglobin and serum feritin levels. Women of childbearing age all
have a urine pregnancy test, required both by anesthesia and for the Bevacizumab study as
well. Patients are followed monthly for the first 6 months. At 3 and 6 months the blood
tests are repeated. For those living in San Diego they can be performed at UCSD. For those
living outside the San Diego area they can be repeated by their primary care physician. For
the ensuing 18 months patients are followed monthly either electronically or by telephone.
ESS scores are calculated. Laboratory tests are not repeated. Patients are followed-up until
such time as they begin re-bleeding and their ESS scores increase either above 2 or by 1
point above their 1 month post-op evaluation. Experience to date with 20 or 30 patients is
that bleeding ceases within 1 to 2 weeks. Hence the 1 month score should be their optimum
result. Adverse events will be recorded and appropriately reported to the IRB.

A new epistaxis severity score (ESS) has been developed and tested by the HHT Foundation. We
have used this for the past several months and found it to be an excellent measure of HHT
epistaxis. A copy is attached.

The minimum sample size is 10 patients. Study duration is planned for 24 months and if more
patients are recruited they will be included. If fewer patients are recruited the study may
be extended. Data will be reported by means and standard deviations. Patients will be
compared individually and collectively to their pretreatment data specifically hematocrit,
hemoglobin, serum ferritin and epistaxis severity score. All medical information collected
at UCSD will be included in their EPIC electronic medical record. All data will be
maintained on a de-identified spreadsheet. Patients will be numbered 1-99. A separate
database correlating patient number with name and medical record number will be kept
separately. Both of these data sheets are maintained on a password protected computer and
backed-up on a thumb drive. These are maintained within the University Medical Center and a
locked office.

Inclusion Criteria:

- Adults over the age of 18

- Both male and non-pregnant females adults capable of making informed consent who have
HHT by Curacao criteria and whose nasal bleeding due to HHT is of such a magnitude
that it requires medical care

- Additionally, females of childbearing age will be given a pregnancy test as a
preliminary measure to ensure that those who become involved are not at risk.