There are a number of wetting agents and sprays that by pqhJNdjb

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									                                                                HHT TREATMENT

                                                                     Table of Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .     2

Recommendations for Physicians Treating HHT Epistaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .                                    3

Medical Information for patients scheduled for submucosal Bevacizumab . . . . . . . . . . . . . . . . .                                            6

Epistaxis Severity Score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .           7

Sample OR Report for submucosal injection of Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . .                                     8

Prescription for topical Bevacizumab with patient letter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .                             9

Patient Letter for Topical Avastin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .                10

Sample authorization letter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .           11

IRB Project #090666: Topical Bevacizumab for the Management of Recurrent Epistaxis in
patients with Hereditary Hemorrhagic Telangiectasia (HHT) . . . . . . . . . . . . . . . . . . . . . . . . . . . .                                12-16
        Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    17-20

IRB Project #100295: Submucosal Bevacizumab for the Management of Recurrent Epistaxis
in patients with Hereditary Hemorrhagic Telangiectasia (HHT) . . . . . . . . . . . . . . . . . . . . . . . . . . .                               21-25
        Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    26-29

Data Collection Forms
      Topical Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .            30-31
      Submucosal Bevacizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .                 32-34
      Application Journal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .            35

Publications
   Simonds J, Miller F, Mandel J, and Davidson TM.: The Effect of Bevacizumab (Avastin) Treatment on
   Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT). Laryngoscope 119:988-992, 2009.

     Davidson TM, Olitsky SE, Wei JL.: Hereditary Hemorrhagic Telangiectasia/Avastin. Laryngoscope
     120:432-435, 2010.

     Chen S, Karnezis T and Davidson TM.: Safety of Intranasal Bevacizumab (Avastin) Treatment in
     Patients with HHT Associated Epistaxis. Laryngoscope 121:644-646, 2011.

     Karnezis T and Davidson TM.: Efficacy of Intranasal Bevacizumab (Avastin) treatment in patients with
     Hereditary Hemorrhagic Telangiectasia Associated Epistaxis. Laryngoscope 121(3):636-638, 2011.

     Guthrie CC, Bishop ML and Davidson TM: The Effect of Anterior Palatine Blocks on Bleeding in HHT
     Nasal Surgery. In preparation.



                                                                 1
                               INTRODUCTION TO HHT

The following summarizes information appropriate for Bevacizumab treatment for epistaxis in
patients with Hereditary Hemorrhagic Telangiectasias. It is hoped and intended that physicians
will use this information to treat their patients and whenever possible to conduct studies so that
there are multiple publications from multiple places documenting the value of Bevacizumab in
the treatment of HHT. Bevacizumab is now granted Orphan Drug status for the treatment of
Hereditary Hemorrhagic Telangiectasia, any dose and any means of administration.

We primarily use the Epistaxis Severity Score, which can be calculated off my website,
http://drdavidson.ucsd.edu, or from the HHT Foundation, http://hht.org. Mild epistaxis as
measured by an ESS of ≤2 is best treated by local measures. Epistaxis of moderate degree as
measured by an ESS of ≤5 is generally treated in a clean nose with topical Bevacizumab, typically
100 mg. This is repeated monthly until bleeding is controlled. This will often have to be repeated
quarterly. Topical Bevacizumab can be ordered by any physician.

Severe epistaxis with an ESS of ≥5 is best treated with submucosal injection under general
anesthesia. Currently we are injecting 200 mgs and have seen no complications. In certain cases
where the patient for one or another reason is too old to undergo a general anesthesia,
Bevacizumab is very effective when administered intravenously. Typically one uses a dose of 5
mg/kg, administered in an infusion lab every 2 weeks for ≤6 or less courses until bleeding is
controlled. This is most commonly used in individuals with other problems, such as liver
telangiectasias, where the Bevacizumab is intended to affect not only the nose, but other organs
as well. It is occasionally used for some patients who cannot get a hemoglobin of 10 or more to
make anesthesia safe.

Included in this packet is a DVD with a video of the submucosal injection. The DVD includes all
the written information. Also included is a CD with all the written information and we hope you
use whatever you need and find useful.

If ever there are questions or problems, please email me.

Sincerely,

Terence M. Davidson, MD
Professor of Surgery, Head and Neck Surgery
Associate Dean for Continuing Medical Education
University of California, San Diego, School of Medicine
Website: http://drdavidson.ucsd.edu
Email: tdavidson@ucsd.edu




                                          2
            Recommendations for Physicians Treating HHT Epistaxis

Therapy for difficult HHT epistaxis is challenging. I have found Bevacizumab (Avastin), a
VEGF inhibitor, to be effective. The following is my general approach. The patients are
evaluated at the UCSD Nasal Dysfunction Clinic or in the UCSD HHT Center Clinic. The
diagnosis of HHT is confirmed. An Epistaxis Severity Score is measured as are the
hemoglobin, hematocrit and serum ferritin levels.

To properly treat HHT epistaxis, the surgeon requires a clean nasal cavity. There are
numerous and different possibilities. Patients should irrigate their nose with hypertonic
pulsatile saline twice daily. All patients should determine whether alcohol worsens their
epistaxis and if it does, avoid alcoholic beverages. If blood clots are a problem, application
of a petroleum-based ointment such as Vaseline or Bacitracin 2-4 times daily will help soften
the clots and make it easier to irrigate them clean. There are a number of wetting agents and
sprays that patients have used, and if one prefers a specific lubricant, they are encouraged to
use them. Some have found benefit with Estradiol, an estrogen cream. Other centers have
found some success with tranexemic acid.

There are some patients, however, in whom recurrent bleeding is so problematic that they
can never clean their nose of bleeding and blood clot. The nose is a very active organ and is
responsible for filtering, humidifying and warming inspired air. This requires tremendous
blood flow. When airflow is obstructed, the nose no longer carries out these tasks and blood
flow is markedly reduced. The Young’s Procedure, namely the operation that surgically
closes the nasal cavity, achieves its success by permanently obstructing airflow. This can be
done on a temporary basis b y obstructing the nose with a nasal plug. The easiest and most
available plug is a piece of cotton saturated in Bacitracin ointment and placed just inside the
front of the nose. For cleanliness purposes, this should be changed 2-3 times daily. This only
works if the nose is obstructed 23 or more hours per day. Hence the recommendation is to
use the cotton plugs for the entire 24-hour day, removing them only at mealtime. Generally,
a two-week treatment will clean almost any nose, reduce the bleeding and provide a nasal
cavity in optimum condition for further treatment.

For patients with an ESS of two or less, this is all that is required.

For patients with an ESS of two to five, the following is recommended:

The treatment is to spray Bevacizumab, 100mg.1 This can be done by spraying 0.1cc into
each nostril, waiting 2-3 minutes and then repeating the application, completing the spraying
in clinic.

Alternatively one can place 100mg in a nasal squirt bottle that delivers 0.1cc per spray. One
then squirts 0.1cc into each nostril, twice each day until the medicine is gone.

There are many nasal sprayers calibrated to deliver 0.1cc. We use the sprayer distributed by
Wolfe Tory Medical. For repeat spraying we use the MADomizer Refillable Bottle
Atomizer. The Laryngo-Tracheal Atomizer is the best nozzle. 100mgs is 4cc. We use this

                                            3
without dilution. We repeat this treatment monthly until epistaxis is under good control and
then typically quarterly when bleeding first begins to recur.

Compounding pharmacies can provide Bevacizumab in a spray bottle, either the Wolfe Tory
Medical or another squirt bottle. Alternatively any physician can phone in a prescription to
O’Brien Pharmacy in Kansas City, URL: http://www.obrienrx.com, telephone
#913.322.0001. They then ship it in a cooled container by overnight mail. Spraying 100mg
of Bevacizumab can be repeated monthly.

For those with an ESS greater than 5, we recommend Bevacizumab submucosal injection.
After the patient is anesthetized 1cc of local anesthesia with adrenaline is injected into each
sphenopalatine fossa via the greater palatine nerve canals. The anterior palatine vessels are
then injected sublabially (see last paper). The nose is then vasoconstricted topically and
then injected with local anesthesia with adrenaline as one does for endoscopic sinus surgery.
The nasal cavity is no longer lasered as has been described in prior publication. The details
are noted in the attached sample OR report.

Next, 200mg of Avastin, typically delivered in 8cc’s, is then injected with 100mg per side.
The injection is not unlike sinus surgery anesthesia. The lateral wall is injected in numerous
spots. The posterior septum and lateral wall in the area of the sphenopalatine are injected.
The middle turbinate is injected, the lateral wall and the nasal floor, especially towards the
inferior meatus, are injected. The inferior turbinate is also injected. Care is taken not to inject
Avastin on or near the cartilaginous septum for septal perforation is the one real risk of this
procedure. Other procedures in or around the nose or elsewhere on the body are not
undertaken at the same time for fear that the VEGF inhibitor will interfere with wound
healing.

At the completion of the injection, the nose is sprayed with 2cc of a fibrin sealant.
Immediately after spraying, a #28 or #30 nasal trumpet is passed along the floor of the nose.
This is left in place for 3 or more minutes so that the patient will have a nasal airway during
the healing period. The nose is left alone for 7 days at which time nasal irrigation is begun to
wash out the remaining sealant. Patients are encouraged to keep their nose clean with twice
daily irrigation. The above generally lasts for a period of 6-24 months. If and when the nose
begins bleeding, as long as the patient presents early, the cavity can now be sprayed with
Bevacizumab as described above.

On October 21, 2010, The FDA Office of Orphan Products Development (OOPD)
designated Bevacizumab as an orphan-drug for the treatment of hereditary hemorrhagic
telangiectasia (request # 10-3175). This provides support for our IRB applications and fully
supports our insurance coverage requests.

Thoughts, feedback and experiences are greatly appreciated.




                                            4
References:
   1. Simonds J, Miller F, Mandel J, and Davidson TM. The Effect of Bevacizumab
      (Avastin) Treatment on Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT).
      Laryngoscope 119(5):988-992, 2009.
      http://www.ncbi.nlm.nih.gov/pubmed/19194865.
   2. Davidson TM, Olitsky SE, Wei, JL. Hereditary Hemorrhagic Telangiectasia/Avastin.
      Laryngoscope. 120(2):432-5, 2010.
      http://www.ncbi.nlm.nih.gov/pubmed/19998344.
   3. Chen S, Karnezis T and Davidson TM.: Safety of Intranasal Bevacizumab (Avastin)
      Treatment in Patients with HHT Associated Epistaxis. Laryngoscope 121:644-646,
      2011.

   4. Karnezis T and Davidson TM.: Efficacy of Intranasal Bevacizumab (Avastin)
      treatment in patients with Hereditary Hemorrhagic Telangiectasia Associated
      Epistaxis. Laryngoscope 121(3):636-638, 2011.

   5. Guthrie CC, Bishop ML and Davidson TM: The Effect of Anterior Palatine Blocks
      on Bleeding in HHT Nasal Surgery. In preparation.




                                       5
Dear Patient,

RE:    Avastin Injection

You are scheduled to come for injection of Avastin to control your nosebleeds. It is critically
important that by one means or another you raise your hemoglobin to 10 or hematocrit to
30; otherwise, the surgery is not safe from an anesthesia perspective. It is also important that
you have as clean a nose as possible, for the cleaner your nose, the easier and better the
surgery.

The single most important thing that you can do is to place cotton balls saturated in
Bacitracin or another antibiotic ointment in your nose 24 hours a day, 7 days a week, for a
minimum of 2 weeks prior to surgery. You can change the cotton plugs as often as you like.
This puts the nose at rest, decreases blood flow and quickly terminates all bleeding for this
period of time. After surgery your nose will have been sprayed with a fibrin sealant which
will protect the mucosa for 5 to 7 days. Hopefully, we will have established an air passage so
that you can breathe normally.

Beginning on post-operative day 7, you should begin irrigating your nose twice daily with
hypertonic pulsatile nasal saline. Any of the commercially available irrigators will work. You
can read about this on Dr. Davidson’s website at URL http://drdavidson.ucsd.edu. The
irrigators are described under the “Handbook of Nasal Disease,” and the treatments for HHT
under the HHT link. You may also be given a prescription for Estrace cream. This is an
estrogen containing cream and it is probably the best of the available creams to use as a
moisturizer, 2 or 3 times a day. The prescription is refillable or you can obtain a second
prescription from your treating physicians at home.

As you know, we are trying to learn more regarding VEGF inhibitors and HHT Epistaxis. It
is therefore critically important that you stay in contact. If you can email your ESS score
monthly, it will make life easier and our work more accurate.




                                           6
                                      Epistaxis Severity Score (ESS) for
                                    Hereditary Hemorrhagic Telangiectasia
The purpose of these questions is to calculate a severity score of epistaxis (nose bleeding) for patients with
Hereditary Hemorrhagic Telangiectasia. Treatment for epistaxis should be determined by a care provider with
experience in treating patients with HHT, and using the calculation found on the Epistaxis Severity Score form should
serve as an adjunct to clinical evaluation. For more information regarding the meaning of this score, please discuss with
your health care provider.

Please answer each of the following questions as they pertain to your TYPICAL symptoms since your last
treatment for nose bleeding. Please answer all questions.

1.      How often do you TYPICALLY have nose bleeding?
          Less than monthly
          Once per month
          Once per week
          Several per week
          Once per day
          Several per day

2. How long do your TYPICAL nose bleeding episodes last?
          < 1 minute
          1-5 minutes
          6-15 minutes
          16-30 minutes
          > 30 minutes

3. How would you describe your TYPICAL nose bleeding intensity?
         Not Typically Gushing or Pouring
         Typically Gushing or Pouring

4. Have you sought medical attention for your nose bleeding?
          No
          Yes

5. Are you anemic (low blood counts) currently?
           No
           Yes

6. Have you received a red blood cell transfusion SPECIFICALLY for nose bleeding?
          No
          Yes
               Raw Epistaxis Severity Score
               Normalized Epistaxis Severity Score



0         1          2          3          4          5          6          7         8          9          10
Note: The HHT-ESS was developed by Jeffrey B. Hoag, M.D., M.S. from Drexel University College of Medicine in conjunction
with Christian A. Merlo, M.D., M.P.H. and members of The Johns Hopkins University HHT Center of Excellence.




                                                 7
                                    Sample OR Report
Submucosal Bevacizumab for the Management of HHT Epistaxis

Preoperative Diagnosis: Anterior/posterior HHT Epistaxis
Postoperative Diagnosis: Same.

Operation: Nasal Endoscopy, control of anterior and posterior epistaxis, submucosal
injection of Bevacizumab 200mg.

Procedure: The patient is an adult male or non-pregnant female, who is suffering disabling
epistaxis as a result of Hereditary Hemorrhagic Telangiectasia. The patient’s hematocrit is 30
or more. The patient is brought to the operating room and general anesthesia is induced.
Care is taken to be certain that the patient does not experience a surge in blood pressure
during induction; this will cause the nose to bleed. Therefore intubation does not occur until
the patient is quite deep. Afrin is spayed into each nasal cavity. 1% lidocaine with 1:100,000
adrenaline is then injected into the right and the left greater palatine canals. The needle is
generally inserted 1 to 1.5 cm, thereby gaining some vasoconstriction to the posterior nasal
cavity. Next, the upper lip is retracted superiorly and lidocaine with adrenaline is injected
into the base of the columella and the floor of the nose, thereby vasoconstricting anterior
palatine vessels.

The patient is draped. A mixture of 1:10,000 adrenaline is placed on 1x6 cottonoids and
these are gently placed in the nasal cavity and allowed to sit and take effect for 5 minutes.
Using the above technique, we rarely have any bleeding at the beginning of the surgery. The
entire nasal cavity is next injected with the lidocaine and adrenaline solution. If minor
bleeding is encountered, additional adrenaline packs are placed; more recalcitrant bleeding is
generally controlled with suction cautery. With the nose fully vasoconstricted, 200mg of
Bevacizumab (8cc) is injected submucosally, 100mg (4cc) into the submucosa on each side of
the nose being very careful to spare the septal cartilage. The floor of the nose is injected, the
lateral wall of the nose is injected, the inferior turbinate is injected, the middle turbinate is
injected, and the lateral wall of the nose in the region of the anterior ethmoid artery is
injected. The posterior septum is injected and the area in the vicinity of the sphenopalatine
artery is injected. The same is performed on both sides.

2cc of a fibrin sealant such as Evicel are sprayed into the nasal cavity. A #28 or a #30 nasal
trumpet is then passed along the floor of the nose to preserve a nasal passage during healing.
These can be removed after 3 minutes, or can be left and removed later in the PACU. The
patient is now awakened and returned to the recovery room. The patient is discharged to
home. Antibiotics are optional. The patient will begin twice daily hypertonic pulsatile nasal
saline irrigations 6 to 7 days after surgery.




                                           8
                      Prescription for Topical Bevacizumab


Rx
Avastin 100 mg / 4cc

Dispense in Wolfe Tory Medical MADomizer refillable bottle with a Laryngo-
Tracheal Atomizer

Sig. 1 squirt (0.1cc) per nostril b.i.d. until gone

Refill p.r.n. monthly




                                       9
                             Patient Letter for Topical Avastin


Dear ______,

We are now planning to treat your HHT epistaxis with a prescription nasal spray of Avastin that
will be administered at home by yourself. Before starting to use the prescription spray it is
important that you know the following:

   1. Women must not be pregnant.
   2. You must not have surgery 30 days before or 30 days after this treatment.
   3. Included with this letter is a current consent form for the prescription spray, it is important
      that you sign and return it promptly. You can fax it back to (619) 471-0656 or mail it
      back. Copies of this consent form and the patient’s bill of rights can be found on the
      website at drdavidson.ucsd.edu.
   4. We will need an ESS Score from you prior to your first treatment and monthly thereafter.
      Please communicate these to Anna Vacchi at avacchi@ucsd.edu or let her know the best
      time to call you each month.
   5. We will also need quarterly blood work, specifically for hemoglobin (Hgb), hematocrit
      (Hct) and serum ferritin. The order for this is included in with this letter and the results
      can be sent to Ms. Vacchi.
   6. To get started you can use the spray once a month for up to 4-5 months. If after this point
      you should be able to only need to spray about once every 3 months.
   7. If your bleeding does not improve, gets worse, or your ESS score is still above a 5 please
      get in touch with us to consider coming in for the submucosal Avastin injection.
   8. Also included is a letter that you can provide to your insurance company if they request
      prior authorization for the prescription.

Please do not hesitate to email us if you have any questions or concerns.




                                          10
              Authorization Letter for Bevacizumab to treat HHT epistaxis

Dear Sir or Madam,

_______________ suffers from severe HHT epistaxis. The disease is related to genetic defects in
vascular endothelial growth factor (VEGF) function. 95% of HHT patients suffer nose bleeds and
in the more advanced stages require frequent emergency department visits, iron transfusions,
blood transfusions and multiple surgeries. Bevacizumab (Avastin) is a VEGF inhibitor which has
been found to successfully treat the epistaxis as well as other AV malformations. There are now
4 papers, listed below, describing the safety and efficacy in treating HHT epistaxis. Use is off-
label, but so is the use of Avastin in treating millions of patients with ophthalmologic neovascular
diseases. In 2010 Bevacizumab was granted orphan-drug status to treat HHT, epistaxis included.
The Orphan Designation is 2010-3175. Bevacizumab can be injected submucosally in the
operating room or can also be sprayed intranasally in the clinic or at home.

The current recommendation for mild to moderate HHT epistaxis (ICD/9:448.0) is
Bevacizumab, 100 mg sprayed as a topical medication. The medication is typically dispensed by
a compounding pharmacy in a nasal vial delivering 0.1cc’s per spray. The normal
recommendation is 0.1cc sprayed in each nostril twice daily for a period of 10 days. If done in
the clinic, repeat spraying can be done every 3 to 5 minutes. Many do this with their own
spraying, reporting that they find it more effective. This can be repeated monthly until the
epistaxis is under good control, at which time repeat sprayings are generally required on a
quarterly basis.

Once under treatment most of these individuals no longer require ER visits for management of
epistaxis, nor do they require intravenous iron treatments or blood transfusions. For those who
require Bevacizumab injection, a trip to the operating room is expensive. However, these
procedures are working far better than those in the past such as laser without Bevacizumab
injection, recurrent cauterizations, lasers, arterial ligations, embolizations and septal dermoplasty.
A typical dose of Bevacizumab is 100mg; the expense for this is $650.00 and is substantially less
than the other required treatments. Furthermore quality of life for these individuals is
significantly improved.

The ICD/9 code for HHT epistaxis is 448.0.

References:
        Simonds J, Miller F, Mandel J, and Davidson TM.: The Effect of Bevacizumab (Avastin) Treatment on
        Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT). Laryngoscope 119:988-992, 2009.

       Davidson TM, Olitsky SE, Wei JL.: Hereditary Hemorrhagic Telangiectasia/Avastin. Laryngoscope
       120:432-435, 2010.

       Chen S, Karnezis T and Davidson TM.: Safety of Intranasal Bevacizumab (Avastin) Treatment in Patients
       with HHT Associated Epistaxis. Laryngoscope 121:644-646, 2011.

       Karnezis T and Davidson TM.: Efficacy of Intranasal Bevacizumab (Avastin) treatment in patients with
       Hereditary Hemorrhagic Telangiectasia Associated Epistaxis. Laryngoscope 121(3):636-638, 2011.

       Guthrie CC, Bishop ML and Davidson TM: The Effect of Anterior Palatine Blocks on Bleeding in HHT
       Nasal Surgery. In preparation.

                                             11
                                              UCSD Human Research Protections Program
                                                    New Biomedical Application
                                                        RESEARCH PLAN
                                                                 Version Date 3/30/2004
     (Enter text in the white space areas below each numbered heading bar. Expand the size of table cells as needed – to multiple pages if needed.
                                 See accompanying Instructions for explanation of headings and information to be provided)
1. PROJECT TITLE
Project # 090666
Topical Bevacizumab for the Management of Recurrent Epistaxis in patients with Hereditary Hemorrhagic
Telangiectasia (HHT)
2. PRINCIPAL INVESTIGATOR
Terence Davidson, M.D. (PI)
Professor of Surgery
Division Of Head and Neck Surgery
Director of Clinical Operations
UCSD Nasal Dysfunction Clinic
3. FACILITIES
UCSD Nasal Dysfunction Clinic
4. ESTIMATED DURATION OF THE STUDY
1-2 years
5. SPECIFIC AIMS
To determine if a VEGF inhibitor, Bevacizumab, topically applied will diminish epistaxis in patients with HHT as
measured by the HHT foundation Epistaxis Severity Score, hematocrit, hemoglobin and serum ferritin levels.
6. BACKGROUND AND SIGNIFICANCE
Hereditary hemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu syndrome is inherited as an autosomal dominant
trait and has a general prevalence of 1/10,000 in Caucasians and as high as 1/400 in the Dutch Antilles people.(1) HHT
is diagnosed by the presence of epistaxis, telangiectasias on the lips, oral cavity, fingers or nose, visceral lesions such
as gastrointestinal telangiectasia, pulmonary arterio-venous malformations (AVM), hepatic or cerebral AVMs, family
history of HHT in first-degree relatives and genetic testing. The presence of any 3 of these findings is required to fulfill
the Curacao criteria. Recurrent and severe epistaxis is the most common presentation of HHT frequently leading to
severe anemia requiring intravenous iron and blood transfusions. In the management of HHT epistaxis multiple
approaches have been tried including electrocautery, laser, septodermoplasty, embolization, arterial ligation, and
sprayable fibrin sealant. (2, 3) Except for nasal closure (Young’s procedure) all of these approaches are largely palliative
with variable results, many requiring repeated interventions.(4) Most recently we have reported treating 50 HHT
epistaxis patients with topical or submucosal injection of 100mgs of Bevacizumab, a recombinant humanized
monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor
(VEGF).

Antineoplastic doses are 5-10mg/kg IV every 2 weeks until tumor regresses. A 70 kg person at the 5mg/kg dose would
be using 350 per injection, 700mgs per month and 350 x 26=9,100 mgs/year. Cancer treatment often continues for up
to 2 years. The 100 mgs used in this study is less than 30% of this individual dose and is not repeated at weekly
intervals as in cancer therapy. Our recent experience with Bevacizumab is by far the best HHT epistaxis control so far
reported. Unfortunately, this requires general anesthesia. There remains a great need for a better treatment.

Recently, angiogenesis has been implicated in the pathogenesis of HHT. Circulating concentrations of both
transcriptional growth factor beta (TGF-ß) and vascular endothelial growth factor (VEGF) are significantly elevated in
HHT.(5) Therefore, inhibition of angiogenic factors might be a plausible way of interfering with the disease process.
Bevacizumab is a recombinant, humanized, monoclonal antibody that binds to and inhibits the biological activity of
VEGF in vivo and in vitro. Bevacizumab, by binding VEGF, prevents endothelial cell proliferation and angiogenesis.
                                                      12
It was approved by the Food and Drug Administration (FDA) in 2004 for the treatment of metastatic colorectal cancer
in combination with 5-fluorouracil.

Bevacizumab has been used off label extensively in ophthalmology since 2005 to treat various neovascular diseases in
which underlying pathologic new vessel growth is seen in association with increased levels of VEGF(6). Diseases that
were studied include idiopathic perifoveal telangiectasia (7), idiopathic macular telangiectasia(8), bilateral acquired
juxtafoveal retinal telangiectasia(9), retinal vein occlusion and neovascular glaucoma. Recent review of over 3500
patients treated with Bevacizumab in uncontrolled, open-label, case series studies reported short-term benefits
measured by various means, such as significant improvement in vision, blood leaks and decreases in
neovascularization. The overall rate of complications was 0.21%(10). Bevacizumab has also been used topically in the
treatment for corneoneovascularization (11). In patients with HHT the mucosal membranes of the nose have
disorganized vascular lesions which lack elastic and muscular tissues. A recent experience by Davidson et al injecting
100mgs of Bevacizumab after KTP lasering has dramatically decreased epistaxis as measured by frequency, intensity,
ED visits and the need for intravenous iron or blood transfusion 12. A topical medication to control intranasal
telangiectasias would be ideal. Topical Bevacizumab is a new, effective VEGF inhibitor and when applied to the nasal
mucosa has the potential to dramatically decrease epistaxis and improve the health and quality of life of patients with
HHT. Bevacizumab was granted orphan-drug status for the treatment of hereditary hemorrhagic telangiectasia October
21, 2010.

7. PROGRESS REPORT/PRELIMINARY STUDIES
A pediatric ophthalmologist from the Midwest brought his father with advanced HHT to the UCSD Nasal Dysfunction
Clinic then for treatment with laser and Bevacizumab. The son, a 40-year old male, pediatric ophthalmologist, also had
HHT and daily nose bleeds, albeit not as severe as his father. While waiting for his father’s surgery and recovery, the
son asked me if I would inject his nose in the clinic. 100 mgs of the Bevacizumab were injected. The patient had no
difficulties and within a week all nasal bleeding on account of HHT stopped. The patient experienced no nasal
bleeding due to HHT for the ensuing 4 months and during this time, successfully climbed Mount Kilimanjaro.
However, at the end of 4 months the bleeding resumed. He and I talked by phone and discussed the idea of applying
the Bevacizumab topically. We agreed to do this and began treating around April 1, 2009. Within a week, (25mgs) the
frequency and severity of bleeding diminished. Three weeks into the study, he has sprayed 50mgs and all bleeding
stopped (14). At 3 months all nasal bleeding due to HHT is stopped and there have been no adverse effects. Based on
one case example it appears that topical Bevacizumab maybe a successful treatment.
8. RESEARCH DESIGN AND METHODS
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 a prepublication PDF (and now the official publication) have been circulated around the
world. There is no paucity of potential patients. Those who come for our evaluation and are deemed appropriate for
topical Bevacizumab without laser will be recruited for this study. Those agreeing to participate will sign a consent
form.

Pharmacy will provide 4cc (100mgs) of undiluted Bevacizumab. The Bevacizumab will then be sprayed by the treating
physician in the clinic, under direct observation. Spray will be achieved by administering the Bevacizumab through a
mucosal atomization device (Wolfe Tory Inc.) This is a device commonly used in our clinic to spray a fine mist of
normal saline to soften blood clots or crust. The syringe is placed in the anterior nose. It is then directed slightly
superiorly and slightly laterally typically towards the ipsilateral ear. This is the same orientation used for applying
nasal steroids. This orientation minimizes spraying medication into the posterior nose and into the pharynx. It also
minimizes spraying against the nasal septum. 0.1cc will be sprayed in such a fashion into both nares. Patients will then
sit for 5 minutes; the application will be repeated for a total of 40 applications, thereby administering 50mgs into each
nostril, a total of 100mgs into each patient. The 5 minute spacing has been arbitrarily chosen as sufficient time for
0.1cc of solution to be absorbed by the nasal mucosa. That will complete the treatment.


                                           13
A new Epistaxis severity score sheet (ESS) has been developed and tested by the HHT foundation. This will be
incorporated into our data collection. This will be completed by the patient prior to treatment and at 1 month intervals
following treatment. The follow-up can be completed by a clinic visit, by telephone or by mail. The patients will be
contact each month and have an ESS calculated. At the 3 and 6 month visit, the patient will be asked to have another
10cc of blood drawn at their doctor’s office or at UCSD and analyzed for hemoglobin hematocrit and serum ferritin
levels. Prior to treatment, patients will have a hematocrit, hemoglobin and serum ferritin level drawn. To avoid
applying Bevacizumab in a pregnant female, the urine test for pregnancy, as is used in surgery, will be required for
women of child bearing ages. The laboratory tests namely the hemoglobin, hematocrit and serum ferritin will be
repeated at 3 and 6 months.

If at some time prior to the 6 months study completion, patients resume nasal bleeding due to HHT, they can elect to
drop out of the study and proceed to a surgical therapy or they can elect to have a repeat Bevacizumab application, not
to exceed 100mgs/month.

My experience is that Bevacizumab by injection or by spray significantly decreases epistaxis severity in the majority of
HHT patients. The total benefit seems to last for a period of 3-4 months at which time nasal bleeding due to HHT will
resume albeit, less frequently and substantially less voluminously. If the nasal bleeding due to HHT is not severe, a
decision to be made by the patient, not by the doctor, they will be encouraged to not initiate repeat spraying until the 6
month time period. However if they request they will be sprayed and they will continue to be monitored in the study.

The minimum sample size is 10 patients, the hoped for sample size is 30 patients. Based on prior referral patterns this
is a number which can be achieved in 4-6 months. Data will be reported by means and standard deviations. Patients
will be compared individually (de-identified) and collectively to their pretreatment data specifically hematocrit,
hemoglobin, serum ferritin and epistaxis severity score.

Safety monitoring will be conducted by the PI, Dr. Davidson. The drug safety officer is Dr. Deborah Watson. Any
adverse event will be reported to the IRB.

9. HUMAN SUBJECTS
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.
10. RECRUITMENT
Patients will be recruited from those presenting to the UCSD Nasal Dysfunction Clinic with a diagnosis of HHT
requesting treatment for their epistaxis.
11. INFORMED CONSENT (Note: provide information in Section 28 on Surrogate Consent and Decisional Capacity Assessment, if applicable)
Patients will be required to review and sign an informed consent form.
12. THERAPEUTIC ALTERNATIVES (therapeutic studies only)
The alternatives are all surgical and include lasering or direct injection of a VEGF inhibitor.
13. POTENTIAL RISKS
The 100 mgs dose is relatively low compared to the large FDA approved anti neoplastic doses. 100 mgs has been used
as a single injection in approximately 50 patients injected submucosally. Eye complications have not been seen. Renal
and hepatic complications have not been seen. The only significant complication is septal perforation. This occurred
in some patients who were lasered and injected. This is a complication of wound healing. A VEGF inhibitor inhibits
wound healing. Therefore elective surgery should not be performed for 30 days after completion of Bevacizumab
treatment. Patients will be counseled regarding this. The other risks are failure to achieve benefit and loss of
confidentiality.


                                                  14
Bevacizumab has been used extensively in ophthalmology, albeit with lower dosage, but with virtually no significant
complications. A summary report of 3500 cases supports this statement.
14. RISK MANAGEMENT PROCEDURES
The nasal sprays will be directed away from the cartilaginous septum. Records will be kept in the patient’s medical file
which will soon be electronic. The paper file will be kept in a locked cabinet.
15. POTENTIAL BENEFITS
Decreased epistaxis and improved quality of life.
16. RISK/BENEFIT RATIO
 Favorable. It is the author’s opinion that the risk of spraying the Bevacizumab is less than that of injection. The
benefit is hopefully equal to injection.
17. EXPENSE TO SUBJECT
Patient will have to pay for the treatments from their medical insurance or by themselves.
18. PAYMENT FOR PARTICIPATION
None
19. PRIVILEGES/CERTIFICATIONS AND LICENSES
The PI of the study, Dr. Davidson, is a physician, board certified in Otolaryngology-Head and Neck Surgery and
licensed to practice medicine in the state of California. The evaluation and treatment of epistaxis is included in the
scope of practice of otolaryngology and covered by the privileges of licensed physicians in the state of California.
20. BIBLIOGRAPHY
     1.    Guttmacher AE, Marchuk, DA, White RI Jr. Hereditary Hemorrhagic Telangiectasia. The New England Journal of Medicine. 1955;
           333(14):918-924.
     2.    Richmon JD, Tian Y, Husseman J, Davidson, TM. Use of a Sprayed Fibrin Hemostatic Sealant after Laser Therapy for Hereditary
           Hemorrhagic Telangiectasia Epistaxis. American Journal of Rhinology. 2007; 21(2):187-191.
     3.    Harvey RJ, Kanagalingam MA and Lund VJ. The impact of Septodermoplasty and Potassium-Titanyl-Phosphate (KTP) Laser
           Therapy in the Treatment of Hereditary Hemorrhagic Telangiectasia-Related Epistaxis. American Journal of Rhinology. 2008;
           22(2);182-187.
     4.    Lund VJ, Howard DJ. Closure of the Nasal Cavities in the Treatment of Refractory Hereditary Haemorrhagic Telangiectasia. The
           Journal of Laryngology and Otolaryngology. 1997;111(1):30-33.
     5.    Sadick H, Riedel F, Naim R, Goessles U, Hormann K, Hafner M, Lux A. Paatients with Hereditary Hemorrhagic Telangiectasia Have
           Increased Plasma Levels of Vascular Endothelial Growth Factor and Transforming Growth Factor-beta1 As Well As High ALK1
           Tissue Expression. Haematologica. 2005; 90(6):818-828.
     6.    Andreoli CM, Miller JW. Anti-Vascular Endothelial Growth Factor Therapy for Ocular Neovascular Disease. Current Opinions in
           Ophthalmology. 2007; 18(6):502-508.
     7.    Maia OO Jr, Bonanomi MT, Takahashi WY, Nascimento VP, Tahakashi BS. Intravitreal Bevacizumab for Foveal Detatchment in
           Idiopathic Perifoveal Telangiectasia. American Journal of Ophthalmology. 2007; 144(2):296-299.
     8.    Charbel IP, Holz FG, Scholl HP. Findings in Fluorescein Angiography and Optical Coherence Tomography after Intravitreal
           Bevacizumab in Type 2 Idiopathic Macular Telangiectasia. Ophthalmology. 2007; 114(9):1736-1742.
     9.    Kim JH, Hwang JM. Intravitreal Bevacizumab (Avastin) for Treatment of Bilateral Acquired Juxtafoveal Retinal Telangiectasis
           Associated with Choroidal Neovascular Membrane. Eye. 2007; 21:1431-1433; doi:10.1038/sj.eye.6702945; published online 3
           August 2007.
     10.   Lynch SS, Cheng CM. Bevacizumab for Neovascular Ocular Diseases. The Annals of Pharmacotherapy. 2007; 41(4):614-625.
     11.   DeStafeno J and Kim T. topical Bevacizumab Therapy for Corneal Neovascularization. Archives of Ophthalmology. 2007;125:834-
           836.
     12.   Simonds J, Miller F, Mandel J, Davidson T. The Effect of Bevacizumab (Avastin) Treatment on Epistaxis in Hereditary Hemorrhagic
           Telangiectasia (HHT). Laryngoscope. 119:988-992, 2009.
     13.   Flieger D, Hainke S, Fischbach W. Dramatic Improvement in Hereditary Hemorrhagic Telagiectasia after Treatment with the
           Vascular Endothelial Growth Factor (VEGF) Antagonist Bevacizumab. Annals of Hematology. 2006; 85(9):631-632.
     14.   Personal communication, Scott Olitsky M.D.

21. INDUSTRY STUDIES
NA
22. FUNDING SUPPORT FOR THIS STUDY
None available
                                                   15
23. BIOLOGICAL MATERIALS TRANSFER AGREEMENT
NA
24. INVESTIGATIONAL DRUG FACT SHEET
NA
25. IMPACT ON NURSING STAFF
NA

26. CONFLICT OF INTEREST
NA
27. CANCER-RELATED STUDIES
NA
28. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT
NA

                                                                                             Version date 3-30-2004
References:
       Simonds J, Miller F, Mandel J, and Davidson TM.: The Effect of Bevacizumab (Avastin) Treatment on
       Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT). Laryngoscope 119:988-992, 2009.

      Davidson TM, Olitsky SE, Wei JL.: Hereditary Hemorrhagic Telangiectasia/Avastin. Laryngoscope
      120:432-435, 2010.

      Chen S, Karnezis T and Davidson TM.: Safety of Intranasal Bevacizumab (Avastin) Treatment in Patients
      with HHT Associated Epistaxis. Laryngoscope 121:644-646, 2011.

      Karnezis T and Davidson TM.: Efficacy of Intranasal Bevacizumab (Avastin) treatment in patients
      with Hereditary Hemorrhagic Telangiectasia Associated Epistaxis. Laryngoscope 121(3):636-638, 2011.




                                        16
                              University of California, San Diego
                              Consent to Act as a Research Subject

          Topical Avastin (Bevacizumab) for the Management of Recurrent Epistaxis
               in patients with Hereditary Hemorrhagic Telangiectasia (HHT)

Terence M. Davidson, MD is conducting a research study to find out more about the topical
application of Avastin (proper chemical name is Bevacizumab) in the treatment of epistaxis
(nose bleeding) in patients with Hereditary Hemorrhagic Telangiectasia (HHT). You have been
asked to take part because you and your physicians are concerned that nose bleeding due to
HHT is medically unsafe or socially disabling.

The purpose of this study is to determine whether the topical application of 100 mg of Avastin,
both a chemical known to inhibit blood vessel growth and a drug which has been shown to
inhibit HHT telangiectasias when injected into a vein or into the nasal tissues, will have the
same or similar benefit when applied topically, meaning sprayed, into your nose and onto the
nasal mucosa. There will be approximately 20-50 patients in this study. We plan to observe you
for 6 months, assessing your nosebleeds every month using the Epistaxis Severity Score (ESS)
developed by the HHT foundation and checking your blood count prior to treatment and at 3
and 6 months. If the treatment does not work you can drop out of the study and have alternative
treatment at any time. You may also choose to repeat the Avastin treatment by spray or
injection. If this is required, we will continue to check on you through the 6-month study end or
with repeat treatments up to 2 years.

Your name or your personnel identification data will not be revealed or published. Rather the
details of your evaluation are entered into a large database. The findings are evaluated by
averages and means and then appropriate scientific analysis made. Therefore all of the
publications deal with collective data and not with individual data. You and your medical
information remain confidential.

If you agree to be in this study, Dr. Davidson and his associates will take a medical history about
you, your HHT and your nose bleeding. Specific information will be asked about the frequency,
severity and duration of nose bleeding and recorded on the new HHT foundation Epistaxis
Severity Score sheet (ESS). A standard Ear, Neck & Throat (ENT) examination, with particular
attention to your nose, will also be conducted. A standard ENT exam includes an examination
of your ears with a lighted tool called an otoscope. The patient’s nose will also be inspected
using a hand-held light or a light placed on the physician’s forehead. The front of the nose may
sometimes be expanded using a nasal speculum which is a delicate surgical tool inserted gently
into the front of the patient’s nose, and when spread open, allow the physician better visibility to
examine the interior of the nose. In many cases, nasal medicines may be sprayed into the nose.
This might include a decongestant such as Afrin and Neo-synephrine or an anesthetic such as
Lidocaine and Tetracaine. The volume and the doses will be small and adverse reactions are not
common. A lighted endoscope can then be placed inside the nose, this should not damage the
mucosa or cause any discomfort. The endoscope allows the physician to peer further into the
patient’s nose, examining the blood vessels and the nasal telangiectasias associated. The lips are
examined for telangiectasias as well as the tongue and the interior of the mouth. Finally, the

                                          17
neck is palpated to ensure no tumors or other abnormalities are present. Laboratory tests will
also be
required and will include hemoglobin, hematocrit, standard red cell indices and a serum ferritin
level (a measure of your body’s iron storage).

If you are of childbearing age you will be asked to provide a urine sample to be certain you are
not pregnant, and a pregnancy test will be administered as a preliminary measure to ensure that
those who become involved are not at risk.

At this time there are no funds to cover the cost of the evaluation or the medications. Therefore,
you will be expected to pay for this either with your insurance or with your own money. There
will be no payment to patients for their participation in this study.

The cost of 100 mgs of Avastin is currently around $800.00. Your insurance company will be
billed for the clinic visit, the blood and urine tests and the Avastin. You are responsible for co-
pays and if uninsured, for all expenses. It is your responsibility to determine how this will be
paid.

To be included in the study you must complete the ESS once a month via email, letter,
telephone, or in person. While the pretreatment and 3 and 6-month post-treatment blood tests
can be completed by your own physicians and mailed to Dr. Davidson, we prefer if you live in
San Diego to perform these at a UCSD facility.

Participation in this study may involve several risks. The most concerning is septal perforation.
This is a risk of epistaxis with repeated cautery. It appears to be a risk of Avastin injection and it
maybe a risk of Avastin sprays. Avastin may impair wound healing so you are advised not to
have any elective surgeries during and up to 30 days after Avastin spray nasal treatment.

The topical use of Avastin for the treatment of nosebleeds caused by HHT is off label and has
currently been granted Orphan drug status by the FDA. Avastin is FDA approved for colon
cancer in much higher doses than used in this study. Genentech, the manufacturer of this drug
notes potential complications that are listed below:
    Hypertension
    Heart attack
    Stroke
    Protein/blood in urine
    Headache
    Runny nose
    Taste alteration
    Dry skin
    Lacrimation disorder
    Back pain
    Exfoliative dermatitis

These are thought to be unlikely by the investigators when using 200mgs of Avastin in a single
application. As blood measurements are part of the study, you will have blood drawn prior to
                                           18
spraying Avastin and at three and six months following treatment. The risks to blood drawing
include:
     Black and blue discoloration under the skin
     Feeling faint

While there is early evidence that Avastin, a vascular endothelial growth factor, abbreviated
VEGF inhibitor, temporarily decreases telangiectasias and bleeding in HHT patients, most of the
treatments have been administered with large dose intravenous injections or 200 mgs intranasal
injections. We are not certain that Avastin is absorbed by nasal spray administration, but
believe this is the case because the spray was effective in treating epistaxis in one HHT patient
and because many medicines, likes nasal decongestants such as Afrin, or nasal steroids are
effectively administered by topical nasal spray.

The first report of Avastin treatment for HHT was published in 2006. No adverse events have
been reported. Nonetheless some unknown long-term complication could occur.

In summary we are not certain that sprayed Avastin will be absorbed by the nasal mucosa
(lining) or that it will effectively treat your nasal bleeding. In fact, that is what this study hopes
to discover. Since this is an investigational study there may be some unknown risks that are
currently unforeseeable and you will be informed of any new findings.

Avastin may be harmful to an unborn baby. We will not treat anyone who is pregnant and we
strongly advise anyone who is being treated to not become pregnant for at least 6 to 12 weeks
after Avastin treatment. Pregnancy tests will be administered to all women of childbearing age,
who wish to participate in the study.

The potential benefit of Avastin spray is that nasal bleeding may decrease or disappear for
several months or longer.

Alternatives to this study include the same treatment, having 100 mgs of Avastin sprayed into
the nasal tissues in clinic or 200 mgs injected under anesthesia in the operating room or having a
surgical procedure such as cauterization, septal dermoplasty or nasal closure.

Participation in this study may also involve breach of confidentiality, meaning your name and
your data somehow are disclosed to someone you would not have wanted access to your health
information. This risk is called a breach of confidentiality. This is a potential albeit unlikely risk
of this study.

There may be no benefit to your participation in this study, meaning that your nasal bleeding is
not favorably changed. If this happens you may wish to withdraw from the study or Dr.
Davidson may chose to withdraw you from the study and you may consider proceeding to other
treatments.

The last alternative to participation in this study is to not participate. At this time this study
does not protect data contained in your medical records. This is separately protected by the
University of California and the UCSD Medical Center. This only applies to the data that we
extract from your evaluation and maintained in our separate records, computer and analysis.
                                            19
Research records will be kept confidential to the extent allowed by law.

Dr. ________________and his associates has explained this to you and answered your questions.
If you have other questions or research related problems, you may reach Dr. Davidson at (619)
543-6737.

If you are injured as a result of participation in this research, the University of California will
provide any medical care you need to treat those injuries. The University will not provide any
other form of compensation if you are injured. You may call the UCSD Human Research
Protections Program at (858) 455-5050 for more information about this, to inquire about your
rights as a research subject or to report research-related problems.

If you no longer wish to continue in this study, you will be required to advise Dr. Davidson that
you wish to be terminated, and in such case he will remove your data from the study. This will
not in any way change, alter or adversely affect your ongoing evaluation and treatment. You
will be informed if any new information is found during the course of this study, particularly if it
would benefit your ongoing evaluation and treatment.

The Institutional Review Board and Dr. Davidson have the right to review the research records
of this study.

You have received a copy of this consent document and a copy of the “Experimental
Subject's Bill of Rights” to keep.

You agree to participate.


_______________________              _______________________ _______________
Subject's Signature                  Witness                 Date




                                           20
                                              UCSD Human Research Protections Program
                                                    New Biomedical Application
                                                        RESEARCH PLAN
                                                                 Version Date 3/30/2004
     (Enter text in the white space areas below each numbered heading bar. Expand the size of table cells as needed – to multiple pages if needed.
                                 See accompanying Instructions for explanation of headings and information to be provided)
2. PROJECT TITLE
Project # 100295
Submucosal Bevacizumab for the Management of Recurrent Epistaxis in patients with Hereditary Hemorrhagic
Telangiectasia (HHT)
2. PRINCIPAL INVESTIGATOR
Terence Davidson, M.D. (PI)
Professor of Surgery,
Division Of Head and Neck Surgery
Director of Clinical Operations
UCSD Nasal Dysfunction Clinic
3. FACILITIES
UCSD Nasal Dysfunction Clinic
4. ESTIMATED DURATION OF THE STUDY
1-2 years
5. SPECIFIC AIMS
To determine if a VEGF inhibitor, Bevacizumab, injected into the nasal mucosa will diminish epistaxis in patients with
HHT as measured by the HHT foundation Epistaxis Severity Score, hematocrit, hemoglobin and serum ferritin levels.
6. BACKGROUND AND SIGNIFICANCE
Hereditary hemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu syndrome is inherited as an autosomal dominant
trait and has a general prevalence of 1/10,000 in Caucasians and as high as 1/400 in the Dutch Antilles people.(1) HHT
is diagnosed by the presence of epistaxis, telangiectasias on the lips, oral cavity, fingers or nose, visceral lesions such
as gastrointestinal telangiectasia, pulmonary arterio-venous malformations (AVM), hepatic or cerebral AVMs, family
history of HHT in first-degree relatives and genetic testing. The presence of any 3 of these findings is required to fulfill
the Curacao criteria. Recurrent and severe epistaxis is the most common presentation of HHT frequently leading to
severe anemia requiring intravenous iron and blood transfusions. In the management of HHT epistaxis multiple
approaches have been tried including electrocautery, laser, septodermoplasty, embolization, arterial ligation, and
sprayable fibrin sealant. (2, 3) Except for nasal closure (Young’s procedure) all of these approaches are largely palliative
with variable results, many requiring repeated interventions.(4) Most recently we have reported treating 10 HHT
epistaxis patients with by lasering and submucosal injection of 200mgs of Bevacizumab, a recombinant humanized
monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor
(VEGF).

Antineoplastic doses are 5-10mg/kg IV every 2 weeks until tumor regresses. A 70 kg person at the 5mg/kg dose would
be using 350 per injection, 700mgs per month and 350 x 26=9,100 mgs/year. Cancer treatment often continues for up
to 2 years. Our recent experience with Bevacizumab is by far the best HHT epistaxis control so far reported.
Unfortunately, this requires general anesthesia. Laser treatment under general anesthesia is the standard of care for
HHT epistaxis. There remains a great need for a better treatment.

Recently, angiogenesis has been implicated in the pathogenesis of HHT. Circulating concentrations of both
transcriptional growth factor beta (TGF-ß) and vascular endothelial growth factor (VEGF) are significantly elevated in
HHT.(5) Therefore, inhibition of angiogenic factors might be a plausible way of interfering with the disease process.
Bevacizumab is a recombinant, humanized, monoclonal antibody that binds to and inhibits the biological activity of
VEGF in vivo and in vitro. Bevacizumab, by binding VEGF, prevents endothelial cell proliferation and angiogenesis.

                                                      21
It was approved by the Food and Drug Administration (FDA) in 2004 for the treatment of metastatic colorectal cancer
in combination with 5-fluorouracil.

Bevacizumab has been used off label extensively in ophthalmology since 2005 to treat various neovascular diseases in
which underlying pathologic new vessel growth is seen in association with increased levels of VEGF(6). Diseases that
were studied include idiopathic perifoveal telangiectasia (7), idiopathic macular telangiectasia (8), bilateral acquired
juxtafoveal retinal telangiectasia (9), retinal vein occlusion and neovascular glaucoma. Recent review of over 3500
patients treated with Bevacizumab in uncontrolled, open-label, case series studies reported short-term benefits
measured by various means, such as significant improvement in vision, blood leaks and decreases in
neovascularization. The overall rate of complications was 0.21%(10). A recent experience by Davidson et al injecting
200mgs of Bevacizumab after KTP lasering has dramatically decreased epistaxis as measured by frequency, intensity,
ED visits and the need for intravenous iron or blood transfusion 12.

The above study was only conducted for one year. Many of these patients have returned reporting that in fact they had
no significant nose bleeds for periods of up to two years. Furthermore we are concurrently conducting a study of
sprayable Bevacizumab but with increasing experience more advanced patients have difficulty keeping a sufficiently
clean nose to do well with the sprayable Bevacizumab hence in these patients a trip to the operating room with some
lasering and the submucosal injection of Bevacizumab seem warranted. It may even come to pass that patients are best
treated initially with the injection and then once controlled maintained with a sprayable Bevacizumab.
7. PROGRESS REPORT/PRELIMINARY STUDIES
The original study published by Dr. Simonds basically closed the PI’s particular interest in those patients. It was not
until some months later that many of these patients reappeared now a full 2 years following their original injections and
only recently having begun to once again bleed. Furthermore as we were looking to spray patients with Bevacizumab
many were simply too far advanced in their disease to ever get their nose clean and be good candidates for spraying.
Therefore it became obvious that injection was going to continue to be important and play a major role in the
management of HHT epistaxis. Based on this certain preliminary ideas were developed and are attached as the
document, “Recommendations for ENT Physicians treating HHT epistaxis”.
8. RESEARCH DESIGN AND METHODS
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. Next, 200mg of Avastin, typically delivered in 8cc’s, is then injected with 100mg
per side. The injection is not unlike sinus surgery anesthesia. The lateral wall is injected in numerous spots. The
posterior septum and lateral wall in the area of the sphenopalatine are injected. The middle turbinate is injected, the
lateral wall and the nasal floor, especially towards the inferior meatus, are injected. The inferior turbinate is also
injected. Care is taken not to inject Avastin on or near the cartilaginous septum for septal perforation is the one real risk
of this procedure. Other procedures in or around the nose or elsewhere on the body are not undertaken at the same time
for fear that the VEGF inhibitor will interfere with wound healing.

At the completion of the injection, the nose is sprayed with 2cc of a fibrin sealant. Immediately after spraying, a #28 or
#30 nasal trumpet is passed along the floor of the nose. This is left in place for 3 or more minutes so that the patient
will have a nasal airway during the healing period. The nose is left alone for 7 days at which time nasal irrigation is
begun to wash out the remaining sealant. Patients are encouraged to keep their nose clean with twice daily irrigation.
The above generally lasts for a period of 6-24 months. If and when the nose begins bleeding, as long as the patient

                                             22
presents early, the cavity can now be sprayed with Bevacizumab as described above.

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 ferritin 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.

Safety monitoring will be conducted by the PI, Dr. Davidson. The drug safety monitoring committee will be comprised
of Drs Davidson, Mandel and Kinney. Meetings will be convened if and when any adverse event is reported. Should
such occur the same would be reported to the IRB.

9. HUMAN SUBJECTS
Adults over the age of 18, both male and non-pregnant females 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. 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. Generally these patients will have an ESS score of 5 or greater. However on occasion an individual with a
score between 2 and 5 but not capable of cleansing their nose adequately to be involved in a Bevacizumab spray
treatment may be included.
10. RECRUITMENT
Patients will be recruited from those presenting to the UCSD Nasal Dysfunction Clinic with a diagnosis of HHT
requesting treatment for their epistaxis.
11. INFORMED CONSENT (Note: provide information in Section 28 on Surrogate Consent and Decisional Capacity Assessment, if applicable)
Patients will be required to review and sign an informed consent form.
12. THERAPEUTIC ALTERNATIVES (therapeutic studies only)
This is the first and only VEGF inhibitor injection treatment in the world. The alternatives are surgical or no treatment.
13. POTENTIAL RISKS
All complications have been reported with anti-neoplastic doses of Bevacizumab namely 5 to 10mg per kg infused
intravenously every 2 weeks for a period of 1 to 2 years. Complications from lower doses of Bevacizumab used in
ophthalmology have not been reported. The only complication we have seen in our patient is septal perforation. These

                                                  23
occurred exclusively in individuals early in our experience who had their septum lasered and injected at the time of
treatment. Since avoiding any septal lasering and all cartilaginous septal injections, septal perforations have not been
seen.

14. RISK MANAGEMENT PROCEDURES
Avoiding injection in pregnant females; avoiding injection in individuals requiring surgeries other than the lasering in
the next 6 weeks as wound healing is theoretically compromised. Records will be kept in the patient’s medical file and
in a separate paper file and database maintained in a locked room in the UCSD Head & Neck Surgery Clinic.
15. POTENTIAL BENEFITS
The morbidity of HHT epistaxis is substantial. Patients bleed daily; this affects their personal and professional lives.
When advanced patients often require visits to the Emergency Department, intravenous iron and blood transfusions.
These can all be improved with proper management of their epistaxis. Hence the benefits are decreased epistaxis and
improved quality of life.
16. RISK/BENEFIT RATIO
Favorable

17. EXPENSE TO SUBJECT
There is no industry or other support for his study. Patient will therefore have to pay for the treatments from their
medical insurance or by themselves. This has not been problematic in the past.
18. PAYMENT FOR PARTICIPATION
None
19. PRIVILEGES/CERTIFICATIONS AND LICENSES
The PI of the study, Dr. Davidson, is a physician, board certified in Otolaryngology-Head and Neck Surgery and
licensed to practice medicine in the state of California. The evaluation and treatment of epistaxis is included in the
scope of practice of otolaryngology and covered by the privileges of licensed physicians in the state of California.

Dr. Deborah Watson will be the Safety Monitor for this study.
20. BIBLIOGRAPHY
   15. Guttmacher AE, Marchuk, DA, White RI Jr. Hereditary Hemorrhagic Telangiectasia. The New England Journal of Medicine. 1955;
       333(14):918-924.
   16. Richmon JD, Tian Y, Husseman J, Davidson, TM. Use of a Sprayed Fibrin Hemostatic Sealant after Laser Therapy for Hereditary
       Hemorrhagic Telangiectasia Epistaxis. American Journal of Rhinology. 2007; 21(2):187-191.
   17. Harvey RJ, Kanagalingam MA and Lund VJ. The impact of Septodermoplasty and Potassium-Titanyl-Phosphate (KTP) Laser
       Therapy in the Treatment of Hereditary Hemorrhagic Telangiectasia-Related Epistaxis. American Journal of Rhinology. 2008;
       22(2);182-187.
   18. Lund VJ, Howard DJ. Closure of the Nasal Cavities in the Treatment of Refractory Hereditary Haemorrhagic Telangiectasia. The
       Journal of Laryngology and Otolaryngology. 1997;111(1):30-33.
   19. Sadick H, Riedel F, Naim R, Goessles U, Hormann K, Hafner M, Lux A. Paatients with Hereditary Hemorrhagic Telangiectasia Have
       Increased Plasma Levels of Vascular Endothelial Growth Factor and Transforming Growth Factor-beta1 As Well As High ALK1
       Tissue Expression. Haematologica. 2005; 90(6):818-828.
   20. Andreoli CM, Miller JW. Anti-Vascular Endothelial Growth Factor Therapy for Ocular Neovascular Disease. Current Opinions in
       Ophthalmology. 2007; 18(6):502-508.
   21. Maia OO Jr, Bonanomi MT, Takahashi WY, Nascimento VP, Tahakashi BS. Intravitreal Bevacizumab for Foveal Detatchment in
       Idiopathic Perifoveal Telangiectasia. American Journal of Ophthalmology. 2007; 144(2):296-299.
   22. Charbel IP, Holz FG, Scholl HP. Findings in Fluorescein Angiography and Optical Coherence Tomography after Intravitreal
       Bevacizumab in Type 2 Idiopathic Macular Telangiectasia. Ophthalmology. 2007; 114(9):1736-1742.
   23. Kim JH, Hwang JM. Intravitreal Bevacizumab (Avastin) for Treatment of Bilateral Acquired Juxtafoveal Retinal Telangiectasis
       Associated with Choroidal Neovascular Membrane. Eye. 2007; 21:1431-1433; doi:10.1038/sj.eye.6702945; published online 3
       August 2007.
   24. Lynch SS, Cheng CM. Bevacizumab for Neovascular Ocular Diseases. The Annals of Pharmacotherapy. 2007; 41(4):614-625.
   25. DeStafeno J and Kim T. topical Bevacizumab Therapy for Corneal Neovascularization. Archives of Ophthalmology. 2007;125:834-
       836.
   26. Simonds J, Miller F, Mandel J, Davidson T. The Effect of Bevacizumab (Avastin) Treatment on Epistaxis in Hereditary Hemorrhagic
                                               24
         Telangiectasia (HHT). Laryngoscope. 119:988-992, 2009.
     27. Flieger D, Hainke S, Fischbach W. Dramatic Improvement in Hereditary Hemorrhagic Telagiectasia after Treatment with the
         Vascular Endothelial Growth Factor (VEGF) Antagonist Bevacizumab. Annals of Hematology. 2006; 85(9):631-632.
     28. Personal communication, Scott Olitsky M.D.

21. INDUSTRY STUDIES
NA
22. FUNDING SUPPORT FOR THIS STUDY
None available
23. BIOLOGICAL MATERIALS TRANSFER AGREEMENT
NA
24. INVESTIGATIONAL DRUG FACT SHEET
NA
25. IMPACT ON NURSING STAFF
NA
26. CONFLICT OF INTEREST
NA
27. CANCER-RELATED STUDIES
NA

28. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT
NA



References:
       Simonds J, Miller F, Mandel J, and Davidson TM.: The Effect of Bevacizumab (Avastin) Treatment on
       Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT). Laryngoscope 119:988-992, 2009.

         Davidson TM, Olitsky SE, Wei JL.: Hereditary Hemorrhagic Telangiectasia/Avastin. Laryngoscope
         120:432-435, 2010.

         Chen S, Karnezis T and Davidson TM.: Safety of Intranasal Bevacizumab (Avastin) Treatment
         in Patients with HHT Associated Epistaxis. Laryngoscope 121:644-646, 2011.

         Karnezis T and Davidson TM.: Efficacy of Intranasal Bevacizumab (Avastin) treatment in patients
         with Hereditary Hemorrhagic Telangiectasia Associated Epistaxis. Laryngoscope 121(3):636-638, 2011.




                                                  25
                                University of California, San Diego
                                Consent to Act as a Research Subject

  Submucosal Injection of Avastin (Bevacizumab) for the Management of Recurrent Epistaxis in
                 patients with Hereditary Hemorrhagic Telangiectasia (HHT)

Terence M. Davidson, MD, is conducting a research study to find out more about the use of
Avastin (proper chemical name is Bevacizumab) in the treatment of epistaxis (nose bleeding) in
patients with Hereditary Hemorrhagic Telangiectasia (HHT). You have been asked to take part
because you and your physicians are concerned that nose bleeding due to HHT is medically unsafe
or socially disabling.

The purpose of this study is to determine whether the application of Avastin, a chemical known to
inhibit blood vessel growth and a drug which has been shown to inhibit HHT telangiectasias when
injected into a vein or into the nasal tissues, will have the same or similar benefit when injected into
your nasal tissues. There will be approximately 15 - 30 patients in this study. We plan to observe
you for 2 years, assessing your nosebleeds every month using the Epistaxis Severity Score (ESS)
developed by the HHT foundation and checking your blood count prior to treatment every 3
months when possible. If the treatment does not work you can drop out of the study and have
alternative treatment at any time. You may also choose to repeat the Avastin treatment by repeat
injection or by spray. If this is required, we will still continue to check on you through the 2-year
study end.

Your name and your personnel identification data will not be revealed or published. Rather the
details of your evaluation are entered into a large database. The findings are evaluated by averages
and means and then appropriate scientific analysis made. Therefore all of the publications deal
with collective data and not with individual data. You and your medical information remain
confidential.

If you agree to be in this study, Dr. Davidson will take a medical history about you, your HHT and
your nose bleeding. You will be asked to complete an epistaxis severity score as part of the history.
The surgical procedure, anesthesia and attendant risks for the general anesthesia and the laser
surgery will be discussed, and a separate UCSD medical center consent for surgery will be required.
All of this is our usual and customary treatment for moderate to severe HHT epistaxis.
Laboratory tests will also be required and will include hemoglobin, hematocrit, standard red cell
indices and a serum ferritin level (a measure of your body’s iron storage).

The surgical procedure, anesthesia and attendant risks for the general anesthesia and the laser
surgery will be discussed, and a separate UCSD medical center consent for surgery will be required.
All of this is our usual and customary treatment for moderate to severe HHT epistaxis.

The investigative portion will involve the submucosal injection of 200 mg of Avastin into your
nose; 100 mgs per side. This is done while you are asleep. Dr. Davidson has been performing these
injections for approximately 5 years, and to date, the results are excellent. With 80-90% of patients
achieving a 1-2 year decrease in their nasal bleeding.


                                           26
If you are female and capable of child-bearing, a sample of urine will be collected before the study
is begun in order to be as sure as possible that you are not pregnant. It is important to be as sure as
possible that you are not pregnant since drug being tested may cause harm to an unborn child.

At this time there are no funds to cover the cost of the evaluation, the medications and treatment.
You or your insurance will be expected to cover all expenses. There will be no payment to patients
for their participation in this study.

Participation in this study may involve several risks. Avastin may impair wound healing so you are
advised not to have any elective surgeries during and up to 30 days after Avastin injection nasal
treatment. Local infection at the injection site is another possible risk. Nasal bleeding is also a
possible risk of Avastin treatment albeit, difficult to distinguish from HHT nasal bleeding.
Blindness occurred in one patient secondary to the nasal injection of local anesthesia with
epinephrine.

The use of Avastin for the treatment of nosebleeds caused by HHT is off label and is not currently
approved by the FDA; however, Avastin is FDA approved for colon cancer in much higher doses
than used in this study. Genentech, the manufacturer of this drug, notes potential complications
that are listed below:
     Hypertension
     Heart attack
     Stroke
     Protein/blood in urine
     Headache
     Runny nose
     Taste alteration
     Dry skin
     Lacrimation disorder
     Back pain
     Exfoliative dermatitis
     Septal perforation

These are thought to be unlikely by the investigator when using 200 mgs of Avastin in a single
application. The only complication seen with the nasal injections occurred very early in Dr.
Davidson’s experience when the nasal septum was lasered and then injected with Avastin. In some
of these cases where repeated cautery was performed, a septal perforation occurred. Since stopping
the septal lasering and injection, but lasering all other portions of the nasal mucosa followed by the
Avastin injections, epistaxis control has been the same and septal perforations have not occurred.

The first report of Avastin as a treatment for HHT was back in 2009. Other than the septal
perforation, no adverse events have been reported. Nonetheless, some long-term complications
could occur.

Blood measurements are required all throughout the study. You will have blood drawn prior to the
Avastin injection and at follow-up months 3, 6, 12, 15, 18, 21 and 24 of the treatment. The risks of
blood drawing include black and blue skin discoloration under the skin.
                                           27
In summary we are not certain that Avastin will effectively treat your nasal bleeding. In fact, that
is the motivation behind completing this study. Since this is an investigational study, there are
some unknown risks but you will be informed of any new findings.

Avastin may be harmful to an unborn baby. We will not treat anyone who is pregnant and we
strongly advise anyone who is being treated to not become pregnant for at least 6 to 12 weeks after
Avastin treatment. Pregnancy tests will be administered to all women of childbearing age, who
wish to participate in the study.

The potential benefit of Avastin submucosal injection is that nasal bleeding may decrease or
disappear for several months or longer.

Alternatives to this study include the same treatment, other medical or nasal surgeries or this
treatment without study participation.

Participation in this study may also involve breach of confidentiality, meaning your name and your
data somehow are disclosed to someone you would not have wanted access to your health
information. This risk is called a breach of confidentiality. This is a potential albeit unlikely risk of
this study.

There may be no benefit to your participation in this study, meaning your nasal bleeding is not
favorably changed. If this happens you may wish to withdraw from the study or Dr. Davidson
may chose to withdraw you from the study and you may consider proceeding to other treatments.

The last alternative to participation in this study is to not participate. At this time this study does
not protect data contained in your medical records. This is separately protected by the University
of California and the UCSD Medical Center. This only applies to the data that we extract from
your evaluation and maintained in our separate records, computer and analysis.

Research records will be kept confidential to the extent allowed by law.

Dr. ________________and his associates has explained this to you and answered your questions. If
you have other questions or research related problems, you may reach Dr. Davidson at (619) 543-
6737.

If you are injured as a direct result of participation in this research, the University of California will
provide any medical care you need to treat those injuries. However, because the therapy in this
study is designed to benefit you directly as a treatment for your Hereditary Hemorrhagic
Telangiectasia (HHT) epistaxis, the cost of treating complications of your HHT epistaxis will be
billed to you or your insurer for medical care. The University will not provide any other form of
compensation to you if you are injured. You may call the Human Research Protections Program
office at (858) 455-5050 for more information about this or to report research-related problem.
If you no longer wish to continue in this study, you will be required to advise Dr. Davidson that
you wish to be terminated, and in such case he will remove your data from the study. This will not
in any way change, alter or adversely affect your ongoing evaluation and treatment. You will be

                                            28
informed if any new information is found during the course of this study, particularly if it would
benefit your ongoing evaluation and treatment.

The Institutional Review Board Dr. Davidson and Dr. Mandel have the right to review the
research records of this study.

You have received a copy of this consent document and a copy of the “Experimental
Subject's Bill of Rights” to keep.

You agree to participate.


_______________________             _______________________ _______________
Subject's Signature                 Witness                 Date




                                          29
                           Patient Data Form: Topical Bevacizumab
Name: _____________________           MR#: ________________             Study Patient ID: _________

DOB __________             Gender: _______      Ethnicity: ___________

Curacao criteria: (√ positives)                     Epistaxis history
□ Epistaxis                                         # Nosebleeds per week: _______
□ Telangiectasias                                   # Blood transfusions last year: _____
    □ Lips      □ Nose      □ Tongue                # ED visits last year: _______
    □ Mouth □ Finger □ Other: _________             □ Oral iron                 □ IV iron
□ Visceral lesions                                  Prior surgeries (include date)
    □ GI        □ Pulmonary                         □ Septoplasty ______________
    □ CNS       □ Other: ______________             □ Rhinoplasty ______________
□ Family history HHT (list information below)       □ Office cautery ______________
  ____________________________________              □ OR cautery ______________
  ____________________________________              □ Septal dermoplasty ______________
□ + Genetic testing                                 □ Endoscopic sinus surgery ______________

PMH: (√ positives)
□ Snoring                     □ Night time mouth breather □ Coagulopthy
□ OSA                         □ Allergic rhinitis         □ Other: _________________
□ Daytime mouth breather      □ Chronic sinusitis         _________________________
Current Medication (name, indication, and date started)
____________________________________________________________________________________
____________________________________________________________________________________
_______________________________________________________________
Screening Visit Examination                                             Date _______________
Ht _____ in    Wt ______ lb        BMI ______        BP ____/___      Pulse _____     Temp _____
Septum:         □ straight         □ deviated        □ perforated nasal septum
Nasal Cavity:   □ patent                 □ filled with clotted blood: □ partially     □ totally
Labs:    HgB ______        HCT______         MCV______           Ferritin ______

Epistaxis Severity Score   ________
Treatment
Date ______________

Bevacizumab 100mgs/4cc sprayed in 0.1cc aliquots into right and left nares, 50mg/side
Comments:____________________________________________________________________
_______________________________________________________________________________
_______________________________________________________________________________

Follow Up:
One Month                  Date ______________       Two Months              Date ______________

Epistaxis Severity Score______________               Epistaxis Severity Score______________

Adverse Events __________________                    Adverse Events _________________

                                             30
Three Months            Date ______________
                                                  Notes: ________________________________
Epistaxis Severity Score______________            ______________________________________
Adverse Events ____________________               ______________________________________
                                                  ______________________________________
Labs:
        HgB ______       HCT______        Ferritin Level ____



Four Months               Date ______________     Five Months           Date ______________
Epistaxis Severity Score______________
Adverse Events ____________________               Epistaxis Severity Score______________
                                                  Adverse Events ____________________

Six Months                Date ______________
Epistaxis Severity Score______________            Notes: ________________________________
                                                  ______________________________________
Adverse Events ____________________               ______________________________________
                                                  ______________________________________
Labs:   HgB ______       HCT______        Ferritin ______




                                          31
                       Patient Data Form: Submucosal Bevacizumab
Name: _____________________         MR#: ________________               Study Patient ID: _________

DOB __________           Gender: _______        Ethnicity: ___________

Curacao criteria: (√ positives)                     Epistaxis history
□ Epistaxis                                         # Nosebleeds per week: _______
□ Telangiectasias                                   # Blood transfusions last year: _____
    □ Lips      □ Nose      □ Tongue                # ED visits last year: _______
    □ Mouth □ Finger □ Other: _________             □ Oral iron                 □ IV iron
□ Visceral lesions                                  Prior surgeries (include date)
    □ GI        □ Pulmonary                         □ Septoplasty ______________
    □ CNS       □ Other: ______________             □ Rhinoplasty ______________
□ Family history HHT (list information below)       □ Office cautery ______________
  ____________________________________              □ OR cautery ______________
  ____________________________________              □ Septal dermoplasty ______________
□ + Genetic testing                                 □ Endoscopic sinus surgery ______________

PMH: (√ positives)
□ Snoring                     □ Night time mouth breather □ Coagulopthy
□ OSA                         □ Allergic rhinitis         □ Other: _________________
□ Daytime mouth breather      □ Chronic sinusitis         _________________________
Current Medication (name, indication, and date started)
____________________________________________________________________________________
____________________________________________________________________________________
_______________________________________________________________
Screening Visit Examination                                            Date _______________
Ht _____ in    Wt ______ lb       BMI ______        BP ____/___      Pulse _____     Temp _____
Septum:         □ straight        □ deviated        □ perforated nasal septum
Nasal Cavity:   □ patent                □ filled with clotted blood: □ partially     □ totally
Labs:    HgB ______     HCT______      Ferritin ______        If female, Urine Pregnancy Test ______


Treatment:
Bevacizumab: 200mgs                                  Notes:




Follow Up:
One Month – Date ______________                      Two Months – Date ______________
Epistaxis Severity Score (ESS): _______              Epistaxis Severity Score (ESS): _______
Adverse Events: ___________________________          Adverse Events: ___________________________
_________________________________________            _________________________________________
_________________________________________            _________________________________________




                                           32
Three Months – Date ______________

Epistaxis Severity Score (ESS): _______       Notes:________________________________
Adverse Events: ___________________________   ______________________________________
_________________________________________     ______________________________________
_________________________________________
Labs:
        HgB ______     HCT______       Ferritin ______



Four Months – Date ______________
Epistaxis Severity Score (ESS): _______       Five Months – Date ______________
Adverse Events: ___________________________   Epistaxis Severity Score (ESS): _______
_________________________________________     Adverse Events: ___________________________
_________________________________________
                                              _________________________________________
                                              _________________________________________
Six Months – Date ______________
Epistaxis Severity Score (ESS): _______       Notes:________________________________
Adverse Events: ___________________________   ______________________________________
_________________________________________     ______________________________________
_________________________________________
Labs:
        HgB ______     HCT______       Ferritin ______




Seven Months – Date ______________            Eight Months – Date ______________
Epistaxis Severity Score (ESS): _______       Epistaxis Severity Score (ESS): _______
Adverse Events: ___________________________   Adverse Events: ___________________________
_________________________________________     _________________________________________
_________________________________________     _________________________________________

Nine Months – Date ______________             Ten Months – Date ______________
Epistaxis Severity Score (ESS): _______       Epistaxis Severity Score (ESS): _______
Adverse Events: ___________________________   Adverse Events: ___________________________
_________________________________________     _________________________________________
_________________________________________     _________________________________________

Eleven Months – Date ______________
Epistaxis Severity Score (ESS): _______
Adverse Events: ___________________________
_________________________________________
_________________________________________




                                       33
Twelve Months - Date ______________           Notes:________________________________
Epistaxis Severity Score (ESS): _______       ______________________________________
Adverse Events: ___________________________   ______________________________________
_________________________________________
_________________________________________
Labs:   HgB ______     HCT______       Ferritin ______



Fifteen Months - Date ______________          Notes:________________________________
Epistaxis Severity Score (ESS): _______       ______________________________________
Adverse Events: ___________________________   ______________________________________
_________________________________________
_________________________________________
Labs:   HgB ______     HCT______       Ferritin ______



Eighteen Months - Date ______________         Notes:________________________________
Epistaxis Severity Score (ESS): _______       ______________________________________
Adverse Events: ___________________________   ______________________________________
_________________________________________
_________________________________________
Labs:   HgB ______     HCT______       Ferritin ______



Twenty-One Months - Date ______________       Notes:________________________________
Epistaxis Severity Score (ESS): _______       ______________________________________
Adverse Events: ___________________________   ______________________________________
_________________________________________
_________________________________________
Labs:   HgB ______     HCT______       Ferritin ______



Twenty-Four Months - Date ______________      Notes:________________________________
Epistaxis Severity Score (ESS): _______       ______________________________________
Adverse Events: ___________________________   ______________________________________
_________________________________________
_________________________________________
Labs:   HgB ______     HCT______       Ferritin ______




                                       34
APPLICATIONS (Injections + Sprays)
                      1st Application         2nd Application        3rd Application        4th Application        5th Application       6th Application

   Inj or Spray


   Dose


   Date

   Side Effect (if
   so, specify)



EPISTAXIS SEVERITY SCORE (To be calculated monthly after the first injection… if patient reinjected plea
               Original ESS @      Month 1          Month 2             Month 3            Month 4            Month 5         Month 6          Month 7
               1st Application

   ESS

   Date


QUARTERLY BLOOD LEVELS
             Blood Levels at 1st Application                1nd Quarter                          2rd Quarter                         3th Quarter
                                                       (Quarterly= q3 months)
                     Hct      Hgb       Ferritin   Hct       Hgb        Ferritin         Hct         Hgb        Ferritin     Hct        Hgb        Ferritin
   Results

   Date




                                                   35

								
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