Clinical trial NCT01441076: Anakinra for Behcet s Disease
Official title: A Pilot Study of Anakinra in Behcet's Disease (BD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Autoimmune Connective Tissue Disorder
Immune System Diseases
Keywords: Behcet's Disease
Aphthous Ulcer
Uveitis
IL-1
Autoinflammation
BD
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-09-27
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

- Behcet's disease (BD) is an autoimmune disease where the immune system attacks the body. People with BD may develop oral or genital ulcers, skin problems, and eye disease. Most drugs used to treat BD suppress the immune system, but they are not always helpful and may have side effects. A new drug, anakinra, may be able to treat BD with fewer side effects. Because it has not been studied in people with BD, anakinra is considered an experimental treatment.

Objectives:

- To test whether anakinra can be a safe and effective treatment for Behcet s disease.

Eligibility:

- People who have Behcet's disease with ongoing oral or genital ulcers for at least one month, or three or more flares of eye disease in the past 6 months.

Design:

* Participants will be screened with a physical exam and medical history. They will also have blood and urine tests. They will be divided into two groups: those with oral or genital ulcers and those with eye disease.
* All participants will keep a diary of symptoms for a month before starting the study drug.
* Participants with oral or genital ulcers will receive daily injections of anakinra for 3 to 6 months. Treatment will be monitored with frequent blood draws and daily diaries. Those who improve but do not have a full response to the drug may receive a higher dose. Those who improve after 6 months may have an extra 6 months on either anakinra or placebo to study the differences in response.
* Participants with eye disease will receive anakinra for up to 12 months. Treatment will be monitored with frequent blood draws, daily diaries, and regular eye exams.
* All participants will have a final study visit 1 month after stopping the study drug.

Detailed description: Autoinflammatory diseases are illnesses characterized by episodes of inflammation that, unlike autoimmune disorders, lack the production of high titer autoantibodies or antigen-specific T cells. There is growing genetic and clinical evidence that Interleukin-1 (IL-1) plays a pathogenic role in several of these diseases. This exploratory study aims to examine the utility of anakinra in the treatment of adult subjects with Behcet s Disease (BD), a disease which shows similarities to the known anakinra-responsive autoinflammatory disorders, familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells Syndrome (MWS). Anakinra is a recombinant form of the human interleukin-1 receptor antagonist that has been studied in rheumatoid arthritis (RA) and the autoinflammatory disorders. It has a half life of 4 to 6 hours with a FDA approved recommended dose of 100 mg/day subcutaneously for the treatment of rheumatoid arthritis.

This pilot study is designed to address: 1) the utility of anakinra in the treatment of BD; 2) the effect of anakinra on laboratory biomarkers in BD; and 3) an exploratory assessment of the safety of anakinra in individuals with Behcet's Disease.

Subjects with oral or genital ulcers will receive anakinra for three to six months. If five of the initial seven patients have a positive response, up to 20 patients with oral or genital ulcers will then be randomized to withdrawal or continuation of drug for six months once placebo is available. Patients with eye disease will be treated with anakinra for a total of twelve months without randomization to withdrawal. Clinical and biochemical correlates of inflammation will be measured at appropriate intervals to assess response and to further understand disease mechanisms.

Eligibility criteria: * INCLUSION CRITERIA:

  1. Male or female subjects with BD associated inflammatory disease greater than or equal 18 years of age
  2. Participation in NIH study #03-AR-0173 ( Studies of the Natural History, Pathogenesis, and Outcome of Autoinflammatory Diseases )
  3. Diagnosis of Behcet s disease as determined by the International Study Group Criteria \[17\] or by complete Japanese Criteria \[18\].
  4. Active mucocutaneous disease as defined by at least one oral or genital ulcer within the past month.
  5. Stable dose of steroids, NSAIDs, DMARDs, or colchicine for four weeks prior to enrollment visit.
  6. For patients with ocular disease, no active intermediate or posterior disease at enrolment but history of an ocular flare (greater than or equal to 3 in the last 6 months) in the presence of any systemic anti-inflammatory therapy such as prednisone, azathioprine, Mycophenolate, methotrexate, cyclosporine, a tumor necrosis factor (TNF) inhibitor, or a combination of these medications. Patients must have developed active disease in the presence of at treatment with at least one of the following medications for at least six months: azathioprine, cyclosporine, or a TNF inhibitor.
  7. Females of childbearing potential (young women who have had at least one menstrual period regardless of age) must have a negative urine pregnancy test at screening and a negative serum pregnancy test at baseline prior to performance of any radiologic procedure or administration of study medication. Female patients will be screened for pregnancy at all NIH visits.
  8. Women of childbearing age and men able to father a child, who are sexually active, who agree to use a form of effective birth control, including abstinence.
  9. Either (1) a negative PPD test using 5 T.U. intradermal testing per Center for Disease Control and Prevention guidelines and no evidence of active tuberculosis (TB) on chest X-ray at the time of enrollment or (2) a positive PPD with no evidence of active TB by history or on chest X-ray at the time of enrollment and either past or present treatment with adequate therapy for at least one month prior to first dose of study medication. Full prophylaxis regimens will be completed. Subjects who have been Bacillus Calmette-Guerin (BCG)-vaccinated will also be skin-tested.
  10. Able to understand, and complete study-related questionnaires.
  11. Able and willing to give informed consent and abide with the study procedures.

EXCLUSION CRITERIA:

1. Treatment with a live virus vaccine during 3 months prior to baseline visit. No live vaccines will be allowed throughout the course of this study.
2. Patients with ocular disease who received local treatments other than eye drops (i.e. periocular or intraocular steroids, implants or other anti-inflammatory agents within 4 weeks prior to enrolment)
3. Current treatment with TNF inhibitors or discontinuation of TNF inhibitors within 8 weeks.
4. Presence of active infections or a history of pulmonary TB infection. Patients with a history of exposure to TB (positive PPD) who have not been treated with a TB prophylaxis regimen for at least one month.
5. Chest x-ray read by a radiologist with pleural scarring and/or calcified granuloma consistent with prior TB.
6. Positive test for or prior history of HIV, Hepatitis B or C.
7. History or concomitant diagnosis of congestive heart failure.
8. History of malignancy. Subjects deemed cured of superficial malignancies such as cutaneous basal or squamous cell carcinomas, or in situ cervical cancer may be enrolled.
9. Known hypersensitivity to Chinese Hamster Ovary (CHO) cell derived biologicals or any components of anakinra.
10. Presence of any additional rheumatic disease or significant systemic disease. For example, major chronic infectious/ inflammatory/ immunologic disease (such as inflammatory bowel disease, psoriatic arthritis, spondyloarthropathy, systemic lupus erythematosus in addition to autoinflammatory disease).
11. Presence of any of the following laboratory abnormalities at enrollment visit: creatinine \> 1.5 times the upper limit of normal , white blood cell \< 3.6 times10(9)/mm(3); platelet count \< 75,000 mm(3); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.0 times the upper limit of normal
12. Lactating females or pregnant females.
13. Subjects with asthma not adequately controlled on current inhaled therapy for at least four weeks.
14. Enrollment in any other investigational treatment study or use of an investigational agent, or has not yet completed at least 4 weeks or 5 half-lives, whichever is longer, since ending another investigational device or drug trial.
15. Subjects for whom there is concern about compliance with the protocol procedures.
16. Presence of other severe acute or chronic medical or psychiatric condition, or significant laboratory abnormality requiring further investigation that may cause undue risk for the subject s safety, inhibit protocol participation, or interfere with interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study.
17. Treatment within the past 12 months with canakinumab
18. Active neurologic disease which would require cyclophosphamide treatment. Active neurologic disease is defined as either new evidence of parenchymal (meningoencephalitis) or non-parenchymal (vascular complications including thrombosis) disease.
19. Subjects who experience an end organ flare after discontinuation of a TNF inhibitor as part of this study.

Primary outcomes:
measure: Clinical Remission From Months 3-6
timeFrame: Monthly study visits from months 3-6 during the trial
Secondary outcomes:
measure: Behcet's Disease Related Quality of Life (BDRQOL) Assessment Score
timeFrame: Month 6 study visit
measure: Behcet's Syndrome Activity Scale (BSAS) Score
timeFrame: Month 6 study visit
measure: Behcets Disease Current Activity Form (BDCAF) Score
timeFrame: Month 6 study visit
measure: Number of Genital Ulcers by Physician Evaluation
timeFrame: Month 6 study visit
measure: Number of Oral Ulcers by Physician Evaluation
timeFrame: Month 6 study visit
measure: Patient Global Score
timeFrame: Month 6 study visit
measure: Physician Global Score
timeFrame: Month 6 study visit
measure: Behcet's Disease Related Quality of Life (BDRQOL) Assessment Score
timeFrame: Baseline
measure: Behcet's Syndrome Activity Scale (BSAS) Score
timeFrame: Baseline
measure: Behcets Disease Current Activity Form (BDCAF) Score
timeFrame: Baseline
measure: Number of Genital Ulcers by Physician Evaluation
timeFrame: Baseline
measure: Number of Oral Ulcers by Physician Evaluation
timeFrame: Baseline
measure: Patient Global Score
timeFrame: Baseline
measure: Physician Global Score
timeFrame: Baseline
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
name: Peter C Grayson, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aksentijevich I, Putnam CD, Remmers EF, Mueller JL, Le J, Kolodner RD, Moak Z, Chuang M, Austin F, Goldbach-Mansky R, Hoffman HM, Kastner DL. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007 Apr;56(4):1273-1285. doi: 10.1002/art.22491.
citation: Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P, Rosenberg HF, Austin F, Remmers EF, Balow JE Jr, Rosenzweig S, Komarow H, Shoham NG, Wood G, Jones J, Mangra N, Carrero H, Adams BS, Moore TL, Schikler K, Hoffman H, Lovell DJ, Lipnick R, Barron K, O'Shea JJ, Kastner DL, Goldbach-Mansky R. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002 Dec;46(12):3340-8. doi: 10.1002/art.10688.
citation: Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, Teillac-Hamel D, Fischer A, de Saint Basile G. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet. 2002 Jul;71(1):198-203. doi: 10.1086/341357. Epub 2002 May 24.
citation: Grayson PC, Yazici Y, Merideth M, Sen HN, Davis M, Novakovich E, Joyal E, Goldbach-Mansky R, Sibley CH. Treatment of mucocutaneous manifestations in Behcet's disease with anakinra: a pilot open-label study. Arthritis Res Ther. 2017 Mar 24;19(1):69. doi: 10.1186/s13075-017-1222-3.