Phase 2 Study of PEG-Intron in Hereditary Hemorrhagic Telangiectasia
Condition: Anemia; Liver Disease; Hypoxemia
MeSH terms: Liver Diseases; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Anemia; Hypoxia
Intervention: Pegylated Interferon Alpha2b; Standard care
Intervention description: Weekly subcutaneous injection of 1 microgram/kg/week; Standard care
Intervention MeSH terms: Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2b
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: anemia; HHT; Liver disease; Hypoxemia; Iron deficiency anemia; Liver disease with high cardiac output; Diffuse pulmonary AVMs with hypoxemia

Summary:

      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)
    

Eligibility criteria:

        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.