Phase 2 Study of PEG-Intron in Hereditary Hemorrhagic Telangiectasia

• Sponsor: Mayo Clinic (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00588146
• Collaborator: Augusta University (Other), Unity Health Toronto (Other), Schering-Plough (Industry)
• Enrollment: 10
• Location: 1
• Arms: 2
• Duration (Months): 56
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief 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)

Condition or Disease	Intervention/Treatment	Phase
Anemia; Liver Disease; Hypoxemia	Drug: Pegylated Interferon Alpha2b; Other: Standard care	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of PEG-Intron in Hereditary Hemorrhagic Telangiectasia
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pegylated Interferon Alpha2b, then Standard Care Weekly subcutaneous injection of pegylated interferon alpha2b 1 microgram/kg/week for 6 months, then standard care for 6 months.	Drug: Pegylated Interferon Alpha2b; Weekly subcutaneous injection of 1 microgram/kg/week; Other Names: PEG-Intron ; Other: Standard care; Standard care
Experimental: Standard Care, then Pegylated Interferon Alpha2b Standard care for 6 months, then weekly subcutaneous injection of pegylated interferon alpha2b 1 microgram/kg/week for 6 months.	Drug: Pegylated Interferon Alpha2b; Weekly subcutaneous injection of 1 microgram/kg/week; Other Names: PEG-Intron ; Other: Standard care; Standard care

Outcome Measures

Primary Outcome Measures

1. Change in Hemoglobin [baseline, one year]

   The hemoglobin level is expressed as the amount of hemoglobin in grams (gm) per deciliter (dL) of whole blood.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

2. Epistaxis: spontaneous, recurrent

3. Telangiectases: multiple at characteristic sites

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

5. Family history of a first degree relative with HHT

6. 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.

7. Clinically stable outpatient

8. Able and willing to return for outpatient visits

9. Ability to perform subcutaneous injections

10. Adult (Age 18 - 70 years)

11. Presence of the following laboratory results at entry:

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

13. Neutrophil count ≥ 1000/mm^3

14. Platelet count ≥ 80,000/mm^3

15. 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)

16. Negative pregnancy test at enrollment, if applicable

17. 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.

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

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

20. 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.

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

22. Child-Pugh category A

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

24. Positive contrast echocardiography documenting right to left intrapulmonary shunt

25. 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

4. Chronic active Hepatitis B infection

5. Child-Pugh category B or C

6. History of severe psychiatric disease

7. Prior suicide attempt

8. Hospitalization for psychiatric disease

9. Period of disability due to a psychiatric disease

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

11. History of immunologically mediated disease

12. Inflammatory bowel disease

13. Idiopathic thrombocytopenic purpura

14. Systemic lupus erythematosus

15. Autoimmune hemolytic anemia

16. Scleroderma

17. Sarcoidosis

18. Multiple sclerosis

19. Severe psoriasis

20. Clinical evidence of rheumatoid arthritis

21. Autoimmune hepatitis

22. History of clinically significant cardiovascular disease

23. Positive stress test

24. Clinically significant arrhythmia

25. Congestive heart failure

26. Uncontrolled hypertension

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

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

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

30. History of thyroid disease poorly controlled on prescribed medications

31. History or evidence of retinopathy

32. Patients on chronic anticoagulation

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

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

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

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

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

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

39. Other pulmonary diseases causing hypoxemia.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• Augusta University
• Unity Health Toronto
• Schering-Plough

Investigators

• Principal Investigator: Karen L Swanson, DO, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00588146
• Other Study ID Numbers: 2400-05; R01FD003076-01
• First Posted: Jan 8, 2008
• Last Update Posted: Feb 22, 2013
• Last Verified: Feb 1, 2013

• Keywords provided by , ,: anemia; HHT; Liver disease; Hypoxemia; Iron deficiency anemia; Liver disease with high cardiac output; Diffuse pulmonary AVMs with hypoxemia
• Additional relevant MeSH terms: Liver Diseases; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Anemia; Hypoxia; Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2b

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from Mayo Clinic, Rochester, Minnesota from January 2007 through September 2010.

Arm/Group Title	Pegylated Interferon Alpha2b, Then Standard Care	Standard Care, Then Pegylated Interferon Alpha2b
Arm/Group Description	Weekly subcutaneous injection of pegylated interferon alpha2b 1 microgram/kg/week for 6 months, then standard care for 6 months.	Standard care for 6 months, then weekly subcutaneous injection of pegylated interferon alpha2b 1 microgram/kg/week for 6 months.
Period Title: First Intervention (Baseline to 6 mo)
STARTED	5	5
COMPLETED	1	2
NOT COMPLETED	4	3
Period Title: First Intervention (Baseline to 6 mo)
STARTED	1	2
COMPLETED	1	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes groups randomized to pegylated interferon alpha-2b first and standard care first.
Overall Participants	10
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	6 60%
>=65 years	4 40%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56 (15.8)
Sex: Female, Male (Count of Participants)
Female	8 80%
Male	2 20%
Region of Enrollment (participants) [Number]
United States	10 100%

Outcome Measures

1. Primary Outcome

Title	Change in Hemoglobin
Description	The hemoglobin level is expressed as the amount of hemoglobin in grams (gm) per deciliter (dL) of whole blood.
Time Frame	baseline, one year

Outcome Measure Data

Analysis Population Description

Only 3 subjects completed the study, so the numbers were too low to analyze the study.

Arm/Group Title	Pegylated Interferon Alpha2b, Then Standard Care	Standard Care, Then Pegylated Interferon Alpha2b
Arm/Group Description	Weekly subcutaneous injection of pegylated interferon alpha2b 1 microgram/kg/week for 6 months, then standard care for 6 months.	Standard care for 6 months, then weekly subcutaneous injection of pegylated interferon alpha2b 1 microgram/kg/week for 6 months.
Measure Participants	0	0

Adverse Events

Time Frame	Adverse events were collected over the 1-year study by telephone or direct interview. Adverse events were graded according to Modified NCI Common Toxicity Criteria. If a subject discontinued for an adverse event, they were observed for 12 weeks.
Arm/Group Title	Pegylated Interferon Alpha-2b		Standard Care
Arm/Group Description	Weekly subcutaneous injection of pegylated interferon alpha2b 1 microgram/kg/week		Subjects received standard care for hereditary hemorrhagic telangiectasia.
All Cause Mortality
	Pegylated Interferon Alpha-2b		Standard Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pegylated Interferon Alpha-2b		Standard Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/10 (30%)		0/10 (0%)
Blood and lymphatic system disorders
Neutropenia	3/10 (30%)	3	0/10 (0%)	0
Other (Not Including Serious) Adverse Events
	Pegylated Interferon Alpha-2b		Standard Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/10 (20%)		2/10 (20%)
General disorders
Seizure	0/10 (0%)	0	1/10 (10%)	1
Musculoskeletal and connective tissue disorders
Myalgias	1/10 (10%)	1	1/10 (10%)	1
Arthralgias	1/10 (10%)	1	1/10 (10%)	1
Right flank pain	1/10 (10%)	1	0/10 (0%)	0
Psychiatric disorders
Depression	0/10 (0%)	0	1/10 (10%)	2

Limitations/Caveats

The study was terminated early because Schering-Plough discontinued supplying study drug.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.