Lenalidomide in the Treatment of Mucosal Behçet's Syndrome

The study is to evaluate the efficacy and safety of lenalidomide in the treatment of oral ulcers in adult patients with refractory mucosal Behcet's syndrome.

Behçet's Syndrome (BS) is a systemic vasculitis involving blood vessels of all sizes. It is characterised by recurrent oral and genital ulcers, skin lesions, musculoskeletal, ophthalmic, large vessel and intestinal involvements. Mucosal BS is the most common phenotype of BS, commonly treated with thalidomide and colchicine, yet some patients respond poorly or had limited use due to side effects.

Lenalidomide, a second-generation derivative of thalidomide, has a role as an angiogenesis inhibitor, an antineoplastic agent and an immunomodulator.

Its neurotoxicity and reproductive toxicity are significantly reduced, and the ability of TNF-alpha inhibition is significantly increased.

Reports on lenalidomide for refractory mucosal BS have been mostly case reports and preliminary studies, clinical trials are lacking.

This is a single-centre, prospective, open-label, single-arm study to evaluate the efficacy and safety of lenalidomide in the treatment of refractory mucosal BS; with the rate of complete remission of oral ulcers in subjects at 12 weeks as the primary endpoint; partial remission of oral and genital ulcers, non-response rate and BS disease activity as secondary endpoints; and adverse events and newly-developed BS-related symptoms as safety endpoints.

This study aims to enroll adult patients with refractory mucosal BS with a stable dosage of low-dose glucocorticoids and/or other conventional immunomodulators. All subjects will be treated with lenalidomide 10mg/day with regular follow-up, those having adverse effects will be evaluated by investigators and adjusted to 5mg/day if necessary, with glucocorticoids and immunosuppressive agents adjusted as needed. Each subject will complete a 12-week treatment period, followed by 4 weeks of observation after cessation of lenalidomide.

Eligibility Criteria:
Inclusion Criteria:

* Patients that can understand and voluntarily sign an informed consent document prior to the study;
* Male and female subjects ≥ 18 years and ≤ 65 years of age at the time of signing the informed consent document.
* Fulfilling the ICBD (International Conference on Behcet's Disease) criteria(2013);
* Presented with active mucosal lesions: Subjects must have at least 1 oral ulcer within 4 weeks after the screening visit and at least 2 oral ulcers on the day of enrollment; subjects may be with or without genital ulcers and (or) skin lesions.
* Refractory mucosal lesions: Subjects must experience at least 2 relapses of oral ulcers during 3 consecutive months of conventional treatment with corticosteroids and(or) immunosuppressants.
* Without major organ involvement, including active gastrointestinal, ocular, nervous system, and major vessel involvement; previous major organ involvement is allowed if it occurred at least 1 year prior to the screening visit and is not active at the time of enrollment.; subjects with arthritis are permitted.

Exclusion Criteria: The presence of any of the following will exclude a subject from the study enrollment.

Exclusion Criteria:

* Pregnant women or breastfeeding mothers, Male and female patients with recent fertility requirements.
* Skin and mucosal lesions should exclude erythema multiforme, syphilis, Sweet disease, Stevens-Johnson syndrome, acne vulgaris, herpes simplex infection, periodic granulocytopenia, and acquired immunodeficiency.
* Subjects with Behçet's syndrome-related active major organ involvement that requires aggressive immunosuppressive therapy, including active gastrointestinal, ocular, nervous system, and major vessel involvement.
* Severe Concomitant disease: including heart failure(≥level Ⅲ, NYHA), respiratory failure, renal insufficiency (Serum creatinine ≥ 1.5 mg/dL ), hepatic insufficiency(Aspartate transaminase (AST) and alanine transaminase (ALT) ≥ 2 X ULN.), myelosuppression(WBC\<3.0×109/L or N\<1.5×109/L, HGB≤85g/L, PLT\<100×109/L), peripheral neuropathy.
* Acute severe infections such as sepsis and cellulitis, active hepatitis B or C virus infection, active tuberculosis, and history of a positive test for, or any clinical suspicion of, human immunodeficiency virus (HIV).
* Patients with malignancy, or any history of malignancy within the 5 years prior to the screening phase, risk factors for myocardial infarction (including a history of thrombosis), or hypercoagulability.
* History of use of lenalidomide or thalidomide within 1 month before enrollment.
* Patients with allergies or contraindications to lenalidomide or thalidomide.
* Having received concomitant immune-modulating therapy or small molecule drugs. At least 5 terminal half-lives for all biologics, including, but not limited to, those listed below; within:

Ten days prior to the day of enrollment for tofacitinib and baricitinib Four weeks prior to the day of enrollment for etanercept Eight weeks prior to the day of enrollment for infliximab Ten weeks prior to the day of enrollment for adalimumab, golimumab, certolizumab, abatacept, and tocilizumab Six months prior to the day of enrollment for secukinumab