North American Study of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)

140 patients with moderate to severe epistaxis secondary to HHT will be randomized to receive
one of four intranasal sprays for a period of 12 weeks and then followed for an additional 12
weeks off therapy. Enrollment will occur over a period of 18-36 months. The primary endpoint
will be the frequency of epistaxis. Secondary endpoints will include duration of epistaxis,
the Hoag Epistaxis Severity Score (ESS), a quality of life survey, satisfaction with
treatment, hemoglobin and ferritin levels, transfusion requirements, and treatment failure.
The sprays will be: saline spray (Placebo); estriol 0.1% in methylcellulose suspension (EST);
tranexamic acid 10% in saline (TA), and bevacizumab 1% in saline (BEV). All sprays will be
applied to the nasal mucosa by an identical spray bottle at a dose of 0.1 ml per nostril
twice daily (total dose of 0.4 ml daily). Thus, the delivered doses will be: EST, 0.4 mg/day;
TA, 40 mg/day; BEV, 4 mg/day.

Inclusion Criteria:

1. A diagnosis of definite or possible HHT by the Curacao criteria (Shovlin 2000) or a
positive DNA test for HHT (as characterized by a disease causing mutation in the gene
coding for endoglin, activin like kinase 1, or SMAD-4). According to the Curacao
criteria, a definite diagnosis of HHT is defined as having at least 3 of the following
criteria while a possible diagnosis is defined as 2 criteria:

1. Spontaneous and recurrent epistaxis.

2. Multiple telangiectasias at characteristic sites (lips, oral cavity, fingers,
nose).

3. Visceral lesions such as gastrointestinal telangiectasias and arteriovenous
malformations (AVM) in lung, brain, spine and liver.

4. A history of definite HHT in a first degree relative using these same criteria.

2. Epistaxis of at least 1 minute (on average) and which occurs at least once weekly when
averaged during the preceding 8 weeks.

3. Epistaxis severity score (ESS) of at least 3.0.

4. Age of at least 18 years.

5. Written and informed consent obtained prior to study entry.

6. Subject is able and willing to return for outpatient visits.

7. The epistaxis is considered to be clinically stable during the past 8 weeks in the
clinical judgment of the investigator (i.e. no major changes in frequency or duration
of epistaxis or in transfusion requirements).

8. Negative pregnancy test at enrollment.

Exclusion Criteria:

1. Allergy to any of the active treatment agents or their spray additives.

2. Estimated life expectancy less than 1 year.

3. A psychiatric or substance abuse problem that is expected to interfere with study
compliance.

4. History of deep venous thrombosis (DVT), pulmonary embolism (PE), acute myocardial
infarction (MI), arterial thromboembolism, or ischemic stroke in the past 6 months.6.
History of receiving more than 12 units of red blood cells in the past 12 weeks.

7. Presence of an untreated coagulopathy that is felt to be contributing to the 5. History
of estrogen receptor positive breast cancer. epistaxis. 8. Presence of active disseminated
intravascular coagulation. 9. Uncontrolled hypertension (systolic BP >160 and/or diastolic
BP >100). 10. Presence of untreated brain AVM. 11. Presence of active malignancy in the
brain, lung, or colon. 12. Presence of symptomatic heart failure. 13. Use of estrogens,
epsilon aminocaproic acid, tranexamic acid, or thalidomide by any route for more than 1
week in the past 12 weeks. Any use of a VEGF inhibitor by any route in the past 24 weeks.

14. Baseline use of the following anticoagulants is not allowed: warfarin or other vitamin
K antagonists at any dose; unfractionated or low molecular weight heparins at standard
doses for treatment of venous thromboembolism (VTE); or aspirin at >325 mg/day. Baseline
use of the following anticoagulants is allowed: heparins at standard doses for VTE
prophylaxis; clopidogrel; or aspirin at ≤325 mg/day.

15. Addition of new treatments for epistaxis in the past 12 weeks (including laser ablation
of nasal telangiectasias and over the counter medications).

16. Presence of another overt cause (e.g. overt gastrointestinal bleeding) that is felt to
be significantly contributing to anemia.

17. Lactating women.