Low-dose IL-2 Treatment on Behcet's Disease

Efficacy and Safety of Low-Dose Interleukin 2 for Behçet's Syndrome: a Phase 2, Randomised, Double-blind, Placebo-controlled Trial

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

Study Overview

• Status: Completed
• Conditions: Behcet's Disease
• Intervention / Treatment: Drug: Low-dose IL-2; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jiali Chen, MD; Phone Number: +8618801206400; Email: chenjiali0389@163.com

Study Locations

• China
  • Beijing, China
    • Department of Rheumatology and Immunology, Peking University People's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-dose IL-2; After a 4-week screening period, patients received IL-2 at a dose of 1 million IU 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 with a 12-week observational followed up.	Drug: Low-dose IL-2; After a 4-week screening period, patients received IL-2 at a dose of 1 million IU 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 with a 12-week observational followed up.
Placebo Comparator: placebo; After a 4-week screening period, patients received 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 with a 12-week observational followed up.	Drug: Placebo; After a 4-week screening period, patients received 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 with a 12-week observational followed up.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the number of oral ulcers at week 12	the number of oral ulcers at week 12	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the change in pain from oral ulcers from baseline to week 12	measured on a 100-mm visual-analogue scale (with 0 representing nopain and 100 the worst pain ever experienced),and the change in disease activity from baselineto week 12.	Week 12 and Week 24
Change from baseline in the Behçet's Syndrome Activity Score	a scaleon which scores range from 0 to 100, with higherscores indicating more active disease	Week 12 and Week 24
Change from baseline in simplified Behcet Disease Current Activity Form (BDCAF) Score	cores range from 0 to 12, withhigher scores indicating more active disease	Week 12 and Week 24
Change from baseline in Protocol-specific immunophenotypic analysis of peripheral blood lymphocyte subsets	Relative proportions of Treg, Tfh, Th1, Th2 and Th17 cell subsets were analyzed by flow cytometetry usingFACSAria III (BD) and FlowJo software (Tree Star). Treg cells were defined as CD3+ CD4+ CD25high CD127low, Tfh cells as CD3+ CD4+ CXCR5+ PD1high CCR7low6, Th1 cells as CD3+ CD4+ CXCR3+ CCR6- CCR4- CCR7low, Th2 cells as CD3+ CD4+ CXCR3+ CCR6- CCR4+ CCR7low and Th17 cells as CD3+ CD4+ CXCR3- CCR6+ CCR4+ CCR7low26.	Week 12 and Week 24
the number of genital ulcers at week 12 and Week 24	the number of genital ulcers at week 12 and Week 24	Week 12 and Week 24
the proportion of patients with a complete response to oral ulcers	the proportion of patients who had no oral ulcers at week 12	Week 12
the percentage of patients with genital ulcers at baseline who were ulcer-free at week 12	the percentage of patients with genital ulcers at baseline who were ulcer-free at week 12	Week 12

Collaborators and Investigators

• Sponsor: HeJing
• Investigators: Principal Investigator: Zhanguo Li, MD,PhD, Department of Rheumatology and Immunology, Peking University People's Hospital.

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Helpful Links

• Primary outcome for BD patients

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2021
• Primary Completion (Actual): April 20, 2023
• Study Completion (Actual): July 28, 2023

Study Registration Dates

• First Submitted: August 20, 2019
• First Submitted That Met QC Criteria: August 21, 2019
• First Posted (Actual): August 22, 2019

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Treg cells; Th17 cells; Behçet's syndrome; LD-IL-2 therapy; T follicular cells
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Eye Diseases; Genetic Diseases, Inborn; Stomatognathic Diseases; Mouth Diseases; Uveitis, Anterior; Panuveitis; Uveitis; Uveal Diseases; Vasculitis; Hereditary Autoinflammatory Diseases; Skin Diseases, Genetic; Skin Diseases, Vascular; Behcet Syndrome
• Other Study ID Numbers: 2019PHB089-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No