Phase 2 Study of PEG-Intron in Hereditary Hemorrhagic Telangiectasia
Phase 2 Study of PEG-Intron in Hereditary Hemorrhagic Telangiectasia
The purpose of the study is to evaluate the safety and tolerability of pegylated interferon
 alpha-2b (PEG-Intron) in patients with severe complications related to Hereditary hemorrhagic
 telangiectasia (HHT).

 Funding Source - FDA Office of Orphan Products Development (OOPD)
The objective of this study is to evaluate the safety and tolerability of pegylated
 interferon alpha-2b (PEG-Intron) in patients with severe complications related to Hereditary
 Hemorrhagic Telangiectasia (HHT). Participants will be randomized to the treatment arm or
 control arm and then crossed over to the alternate arm at 6 months for the remainder of the
 12-month study. Study treatment will consist of weekly subcutaneous injections of pegylated
 interferon alpha-2b (PEG-Intron), 1 microgram/kilogram/week. Adverse events as well as
 monitoring and treatment of toxicities will be followed as stated in the protocol. Adverse
 events will be graded according to the Modified NCI Common Toxicity Criteria. After every
 five participants have completed one month of treatment, an independent data safety
 monitoring board will review any adverse events.
Inclusion Criteria:

 1. Definite diagnosis of HHT by clinical criteria or genetic diagnosis. For the clinical
 diagnosis, 3 of the 4 following criteria1 must be present:

 1. Epistaxis: spontaneous, recurrent

 2. Telangiectases: multiple at characteristic sites

 3. Visceral lesions including telangiectases and/or arteriovenous malformations
 (AVM) (pulmonary, hepatic, gastrointestinal, cerebral, spinal)

 4. Family history of a first degree relative with HHT

 2. Transfusion-dependent anemia from HHT-related bleeding (epistaxis from nasal mucosal
 telangiectases or gastrointestinal bleeding from gastrointestinal telangiectases)
 defined as a hemoglobin (Hb) < 9g/dL with transfusion of at least one unit of packed
 red blood cells within the past 6 months or Hb < 11g/dL in females or < 13g/dL in
 males with transfusion of at least 5 units of blood within the past 6 months. Patients
 must be on a stable dose of iron or intolerant of iron. Patients must have failed
 traditional treatment options.

 3. Clinically stable outpatient

 4. Able and willing to return for outpatient visits

 5. Ability to perform subcutaneous injections

 6. Adult (Age 18 - 70 years)

 7. Presence of the following laboratory results at entry:

 1. White blood cell count ≥ 2000/mm^3

 2. Neutrophil count ≥ 1000/mm^3

 3. Platelet count ≥ 80,000/mm^3

 4. Thyroid stimulating hormone within normal limits (Minimal abnormalities of the
 sensitive thyroid stimulating hormone may be allowed provided that the free
 thyroxin is normal and the patient is clinically euthyroid)

 8. Negative pregnancy test at enrollment, if applicable

 9. If the participant is a sexually active woman of childbearing potential, evidence that
 she is practicing adequate contraception during the treatment period. Adequate
 contraception includes use of an intrauterine device, oral contraceptives,
 progesterone implanted rods, medroxyprogesterone acetate, surgical sterilization,
 barrier method (diaphragm + spermicide), a monogamous relationship with a male partner
 who has had a vasectomy or is using a condom + spermicide or a birth control method
 acceptable to the study physicians. Participants and/or their partners must agree to
 continue the use of adequate contraception for at least 6 months following completion
 of treatment.

 10. Written informed consent specific for this protocol obtained prior to entry

 11. Patients agree to take study medication as directed and follow all study related
 procedures until the conclusion of their protocol participation

 12. Hepatic involvement by HHT characterized by high output heart failure due to hepatic
 vascular malformations (symptoms of heart failure including edema, ascites, S3 gallop,
 orthopnea, or jugular venous pressure > 10 cm H_2O) plus cardiac index (CI) measured
 at right heart catheterization > 4.4 L/min/m^2. Patients must have failed traditional
 treatment options.

 13. Computed tomography scanning (CT) of the liver documenting vascular abnormalities
 consistent with HHT

 14. Child-Pugh category A

 15. Diffuse pulmonary telangiectases or AVMs documented by pulmonary angiography not
 amenable to treatment with embolization techniques. Patients must have failed
 traditional treatment options.

 16. Positive contrast echocardiography documenting right to left intrapulmonary shunt

 17. Resting or exercise-induced hypoxemia defined as a partial pressure of oxygen (PaO_2)
 < 70 mmHg at rest or an oxygen saturation (SpO_2) < 85% with exercise.

 Exclusion Criteria:

 1. Anemia from any other cause than that due to HHT-related bleeding

 2. Hypersensitivity to PEG-Intron or any other component of the product

 3. Decompensated liver disease

 1. Chronic active Hepatitis B infection

 2. Child-Pugh category B or C

 4. History of severe psychiatric disease

 1. Prior suicide attempt

 2. Hospitalization for psychiatric disease

 3. Period of disability due to a psychiatric disease

 4. Current episode of moderate to severe depression not responsive to treatment

 5. History of immunologically mediated disease

 1. Inflammatory bowel disease

 2. Idiopathic thrombocytopenic purpura

 3. Systemic lupus erythematosus

 4. Autoimmune hemolytic anemia

 5. Scleroderma

 6. Sarcoidosis

 7. Multiple sclerosis

 8. Severe psoriasis

 9. Clinical evidence of rheumatoid arthritis

 10. Autoimmune hepatitis

 6. History of clinically significant cardiovascular disease

 1. Positive stress test

 2. Clinically significant arrhythmia

 3. Congestive heart failure

 4. Uncontrolled hypertension

 5. Coronary artery bypass surgery within 24 weeks prior to entry

 6. Angina pectoris or myocardial infarction within 1 year prior to entry

 7. Seizure disorder uncontrolled by anticonvulsants (within the last 12 months)

 8. History of thyroid disease poorly controlled on prescribed medications

 9. History or evidence of retinopathy

 10. Patients on chronic anticoagulation

 11. History of chronic renal insufficiency (creatinine > 2.5 mg/dL)

 12. Patients who have received an investigational drug within 24 weeks of treatment
 assignment

 13. History or other evidence of severe illness or other comorbid condition which would
 make the patient unsuitable for participation in a research protocol

 14. Liver dysfunction from any other cause than that due to HHT (chronic active hepatitis
 B infection, hepatitis C infection, alcoholic cirrhosis, etc.)

 15. Cardiac index < 4.4 L/min/m^2

 16. Pulmonary AVMs with feeding arteries > 3 mm in diameter amenable to embolization
 techniques

 17. Other pulmonary diseases causing hypoxemia.