Efficacy and Safety of Low-dose IL-2 in Patients With SLE: a Multicenter, Randomised, Placebo-controlled Trial

Study Overview
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Brief Summary
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The management of active systemic lupus erythematosus (SLE) is challenging due to the heterogeneous nature of the disease and lack of specific treatment. Current treatment regimens mainly rely on corticosteroids and immunosuppressive agents which are associated with substantial adverse effects including various infections. Therefore, there is an unmet need for new therapies with better efficacy and less adverse effects. Defective IL-2 production contributes to the unbalanced immune system in SLE. Previous short term open-labelled trials showed that low-dose IL-2 was efficient and tolerated in active SLE. It was suggested that low-dose IL-2 treatment promoted regulatory T cells (Treg) and inhibited T helper 17 cells (Th17) and follicular helper T cells (Tfh). The immunological rebalancing was associated with the induction of remission in SLE patients. To establish that which low doses of IL-2 would be more efficacious and safe in active SLE, we carried out a multi-center, randomized, double-blind, placebo-controlled trial of three doses of IL2 (0.2 MIU, 0.5 MIU or 1 MIU) versus placebo.

Detailed Description
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Active SLE patients at 18 to 75 years of age were enrolled. Patients were randomly assigned (in a 1:1:1:1 ratio) to one of the four arms (placebo or IL-2 at 0.2 MIU, 0.5 MIU or 1 MIU) in the study. IL-2 (0.2 MIU, 0.5 MIU or 1 MIU) or placebo was administered subcutaneously every other day for the first 12 weeks , and then was adjusted to once a week for the second 12 weeks. Follow-up visits occurred on weeks 4, 8,12,16,20 and 24. The end points were safety and clinical and immunologic response.

Official Title
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Efficacy and Safety of Low-dose Interleukin-2 in Patients With Systemic Lupus Erythematosus: a Multicenter, Randomised, Placebo-controlled Trial

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: Interleukin-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet the 1997 revised classification criteria of the American College of Rheumatology SLE disease activity index(SLEDAI) ≥ 8 age:18 to 75 years, weight 45-80Kg Patients had an inadequate response to standard treatment for ≥ 3 months. The background treatment included corticosteroids (≤1.0 mg/kg), hydroxychloroquine, cyclophosphamide , mycophenolate mofetil or other immunosuppressants. Negative urine pregnancy test Written informed consent form Exclusion Criteria: allergic to IL-2, corticosteroids, hydroxychloroquine, cyclophosphamide or mycophenolate mofetil active severe neuropsychiatric manifestations of SLE; hepatic insufficiency (alanine aminotransferase or aspartate aminotransferase ≥ 2 times of the upper limit of the normal range); pregnancy or lactation in females. Cancer or history of cancer cured for less than five years (except in situ carcinoma of the cervix or Basocellular carcinoma); Serious infection such as bacteremia, sepsis;history of chronic infection; active infection (hepatitis B or C virus, Epstein-Barr virus, human immunodeficiency virus or Mycobacterium tuberculosis); history vision and visual field disorders, cataract； severe comorbidities including heart failure (≥ grade III NYHA) active peptic ulcers； complicated with other autoimmune diseases; History of administration of rituximab or other biologics within 6 months; therapy with other immunosuppressors; participate in other clinical trial within 4 weeks;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>placebo s.c. injection every other day for the first 12 weeks and then once a week for the second 12 weeks | Drug: Interleukin-2<br>* IL2 (0.2 MIU, 0.5 MIU or 1 MIU) : placebo = 1:1:1:1<br>* Other names: Human recombinant IL-2;|
| Active Comparator: IL-2 at 0.2MIU<br>0.2 MIU doses of IL-2 s.c. injection every other day for the first 12 weeks and then once a week for the second 12 weeks | Drug: Interleukin-2<br>* IL2 (0.2 MIU, 0.5 MIU or 1 MIU) : placebo = 1:1:1:1<br>* Other names: Human recombinant IL-2;|
| Active Comparator: IL-2 at 0.5MIU<br>0.5 MIU doses of IL-2 s.c. injection every other day for the first 12 weeks and then once a week for the second 12 weeks | Drug: Interleukin-2<br>* IL2 (0.2 MIU, 0.5 MIU or 1 MIU) : placebo = 1:1:1:1<br>* Other names: Human recombinant IL-2;|
| Active Comparator: IL-2 at 1.0MIU<br>1.0 MIU doses of IL-2 s.c. injection every other day for the first 12 weeks and then once a week for the second 12 weeks | Drug: Interleukin-2<br>* IL2 (0.2 MIU, 0.5 MIU or 1 MIU) : placebo = 1:1:1:1<br>* Other names: Human recombinant IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the response measured by the SLE Responder Index-4 (SRI-4) | SRI response was defined as (1) a ≥ 4-point reduction in SELENA-SLEDAI score, (2) no new BILAG A score or ≤ 1 new BILAG B score, and (3) no deterioration from baseline in the physician's global assessment by ≥ 0.3 points. | week 12 |