Clinical trial NCT04065672: Low-dose IL-2 Treatment on Behcet's Disease
Official title: Efficacy and Safety of Low-Dose Interleukin 2 for Behçet's Syndrome: a Phase 2, Randomised, Double-blind, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Behcet's Disease
Keywords: Behçet's syndrome
LD-IL-2 therapy
Treg cells
T follicular cells
Th17 cells
Lead sponsor: Peking University People's Hospital
Sponsor class: OTHER
First posted: 2019-08-22
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study aims to explore the clinical and immunological efficacy of low-dose IL-2 on Behcet's Disease.

Detailed description: The investigators designed a single center, Phase 2, randomised, double-blind, placebo-controlled, parallel-group, superiority design study that routinely administered low-dose IL-2 therapy to monitor the improvement of clinical and laboratory parameters to explore its efficacy and to observe changes in immune cell subsets and cytokines. After a 4-week screening period, patients were randomly assigned in a 1:1 ratio to receive IL-2 at a dose of 1 million IU or placebo subcutaneously every other day. After the initiation of the therapy, patients could continue with concurrent medication but were prohibited from changing or adding immunosuppression therapy during the course of the study. After 12 weeks placebo-controlled treatment period, a 12-week observational followed up.

Eligibility criteria: Inclusion Criteria:

1. Male or female 18-70 years of age at time of screening.
2. Diagnosis of Behçet's Disease (according to the 1989 ICBD) for ≥3 months before screening.
3. Active oral ulcer at time of screening.
4. Patients on corticosteroids (≤1 mg/kg/d prednisone or equivalent), DMARDs (e.g. methotrexate, hydroxychloroquine, azathioprine, MMF, leflunomide, ciclosporin etc.), must have been on a stable dose for 4 weeks prior to receiving the first infusion of study medication and expected to remain on this dose throughout the study. If the registered doctor plans to quit using current DMARDs or glucocorticoids, the washout period needs to be followed before patients join the groups. Each drug needs to meet the following washout period

   * glucocorticoids - 2 weeks
   * DMARDs (including mmethotrexate, hydroxychloroquine, azathioprine, MMF, leflunomide, and ciclosporin ) - 4 weeks
   * IVIg or cyclophosphamide - 2 months
   * Rituximab - 6 months
   * other bDMARDs(e.g. Infliximab, Adalimumab, Enanercept etc.) - 12 weeks
5. Given their written informed consent to participate in the trial and expected to be able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

1. BD-related active major organ involvement requiring immunosuppressive therapy, e.g., pulmonary (e.g., pulmonary artery aneurysm), vascular (e.g., thrombophlebitis, recurrent malignant aneurysms), gastrointestinal (e.g., gastrointestinal ulcers), and central nervous system (e.g., meningoencephalitis).
2. High-dose glucocorticoid (\>1mg/kg/d) usage within 1 month.
3. Severe comorbidities: including Heart failure (≥ grade III NYHA); Renal insufficiency (creatinine clearance ≤30 ml/min); Hepatic insufficiency (serum ALT or AST \>3 times the ULN, or total bilirubin \>ULN for the central laboratory conducting the test).
4. Other severe, progressive or uncontrolled hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral disease (including demyelinating diseases such as multiple sclerosis).
5. Known allergies, hypersensitivity, or intolerance to IL-2 or its excipients.
6. History of severe allergic reaction to monoclonal antibodies or to murine, chimeric, or human proteins or their excipients.
7. Had a severe infection (including, but not limited to hepatitis, pneumonia, sepsis, or pyelonephritis); had been hospitalized for an infection; or had been treated with IV antibiotics for an infection, within 2 months prior to the first administration of study agent.
8. Chest radiograph within 3 months prior to the first administration of study agent that showed an abnormality suggestive of a malignancy or current active infection, including TB.
9. Infected with HIV (positive serology for HIV antibody) or hepatitis C (positive serology for Hep C antibody). If seropositive, consultation with a physician with expertise in the treatment of HIV or hepatitis C virus infection was recommended.
10. Infected with hepatitis B virus. For patients who were not eligible for this study due to hepatitis B virus test results, consultation with a physician with expertise in the treatment of hepatitis B virus infection was recommended.
11. Had any known malignancy or has a history of malignancy within the previous 5 years (with the exception of a nonmelanoma skin cancer that had been treated with no evidence of recurrence for ≥3 months before the first study agent administration or cervical neoplasia with surgical cure).
12. Had uncontrolled psychiatric or emotional disorder, including a history of drug and alcohol abuse within the past 3 years that might prevent the successful completion of the study.
13. Received, or was expected to receive, any live virus or bacterial vaccination within 3 months before the first administration of study agent, during the study, or within 4 months after the last administration of study agent. Had a BCG vaccination within 12 months of screening.
14. Pregnancy, lactation or women of child-bearing potential (WCBP) unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment has finished.
15. Men whose partners are of child-bearing potential but who are unwilling to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment has finished.

Primary outcomes:
measure: the number of oral ulcers at week 12
timeFrame: Week 12
Secondary outcomes:
measure: the change in pain from oral ulcers from baseline to week 12
timeFrame: Week 12 and Week 24
measure: Change from baseline in the Behçet's Syndrome Activity Score
timeFrame: Week 12 and Week 24
measure: Change from baseline in simplified Behcet Disease Current Activity Form (BDCAF) Score
timeFrame: Week 12 and Week 24
measure: Change from baseline in Protocol-specific immunophenotypic analysis of peripheral blood lymphocyte subsets
timeFrame: Week 12 and Week 24
measure: the number of genital ulcers at week 12 and Week 24
timeFrame: Week 12 and Week 24
measure: the proportion of patients with a complete response to oral ulcers
timeFrame: Week 12
measure: the percentage of patients with genital ulcers at baseline who were ulcer-free at week 12
timeFrame: Week 12
Other outcomes:
Locations:
city: Beijing
country: China
facility: Department of Rheumatology and Immunology, Peking University People's Hospital
Study officials:
affiliation: Department of Rheumatology and Immunology, Peking University People's Hospital.
name: Zhanguo Li, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gunduz E, Teke HU, Bilge NS, Cansu DU, Bal C, Korkmaz C, Gulbas Z. Regulatory T cells in Behcet's disease: is there a correlation with disease activity? Does regulatory T cell type matter? Rheumatol Int. 2013 Dec;33(12):3049-54. doi: 10.1007/s00296-013-2835-8. Epub 2013 Aug 3.
citation: Nanke Y, Kotake S, Goto M, Ujihara H, Matsubara M, Kamatani N. Decreased percentages of regulatory T cells in peripheral blood of patients with Behcet's disease before ocular attack: a possible predictive marker of ocular attack. Mod Rheumatol. 2008;18(4):354-8. doi: 10.1007/s10165-008-0064-x. Epub 2008 Apr 22.
citation: Mohammadi M, Shahram F, Shams H, Akhlaghi M, Ashofteh F, Davatchi F. High-dose intravenous steroid pulse therapy in ocular involvement of Behcet's disease: a pilot double-blind controlled study. Int J Rheum Dis. 2017 Sep;20(9):1269-1276. doi: 10.1111/1756-185X.13095. Epub 2017 May 19.
citation: Zou J, Ji DN, Shen Y, Guan JL, Zheng SB. Mucosal Healing at 14 Weeks Predicts better Outcome in Low-dose Infliximab Treatment for Chinese Patients with Active Intestinal Behcet's Disease. Ann Clin Lab Sci. 2017 Mar;47(2):171-177.