Leflunomide for Maintenance of Remission in IgG4 Related Disease

Study Overview
=================
Brief Summary
-----------------
The study has been designed as a 12-month, open-label, randomized, controlled study comparing the use of prednisone mono-therapy and prednisone and leflunomide combination therapy in treating patients with IgG4-related disease.

Detailed Description
-----------------
The aim of this clinical trial is to determine the safety and efficacy of Leflunomide in treating patients with IgG4-related disease by comparing the outcomes of prednisone and leflunomide combination therapy with prednisone mono-therapy. The follow-up period will be 12 months. During the follow-up period, results of laboratory tests and image examinations, IgG4-RD RI and other parameters which can reflect treatment response as well as adverse effect events will be recorded.

Official Title
-----------------
A Study of Safety and Efficacy of Leflunomide for Maintenance of Remission in IgG4 Related Disease

Conditions
-----------------
Immunoglobulin G4 Related Sclerosing Disease

Intervention / Treatment
-----------------
* Drug: Prednisone
* Drug: Leflunomide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age between 18 and 80 years. Diagnosis of IgG4-RD according to either Consensus statement on the pathology of IgG4-related disease (for those who have undergone biopsies) or 2011 Comprehensive diagnostic criteria for IgG4-related disease. Both of the two criteria for diagnosis are specified below. (1)Consensus statement on the pathology of IgG4-related disease Histopathologic features consisting of dense lymphoplasmacytic infiltrate, fibrosis(usually storiform in character)and/or obliterative phlebitis within involved organs. Either an elevated IgG4+/IgG+cell ratio of >40% within the affected organs or elevated IgG4-bearing plasma cells per high-power field is necessary. The cut-off number of IgG4-bearing plasma cells per high-power field is different depending upon the types of affected organs and specimens(through surgery or needle puncture biopsy). (2)2011 Comprehensive diagnostic criteria for IgG4-related disease Clinical examination showing characteristic diffuse/localized swelling or masses in single or multiple organs. Hematological examination shows elevated serum IgG4 concentrations(135 mg/dl). Histopathologic examination shows marked lymphocyte and plasmacyte infiltration and fibrosis or Infiltration of IgG4+ plasma cells(ratio of IgG4+/IgG+ cells > 40% and >10 IgG4+ plasma cells/HPF). Definite: a + b + c,Probable: a + c,Possible: a + b Excluded from malignant tumors of each organ (e.g. cancer, lymphoma) and similar diseases (e.g. Sjögren's syndrome, primary sclerosing cholangitis, Castleman's disease, secondary retroperitoneal fibrosis, Wegener's granulomatosis, sarcoidosis, Churg-Strauss syndrome) by additional histopathological examination. Even when patients cannot be diagnosed using the Comprehensive diagnostic criteria, they may be diagnosed using organ-specific diagnostic criteria for IgG4-RD, such as Diagnostic criteria for IgG4-Mikulicz's disease. Exclusion Criteria: Subjects having received steroids or immunosuppressants in recent 3 months will be excluded. Subjects who were hypersensitive to leflunomide will be excluded. ALT and/or AST is more than two folds of the upper limit of relevant reference value at baseline. WBC is less than 3×10*9/L at baseline. Female patients who are pregnant or breastfeeding. Known significant concurrent medical disease.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prednisone<br>Prednisone mono-therapy | Drug: Prednisone<br>* Prednisone:A starting dose of 0. 5-0. 8mg/(kg*d) will be given. Following four-week period, the dose will be tapered gradually to 5mg/d until the end of 12 months of follow-up period.<br>* Other names: Prednisolone;|
| Experimental: Prednisone and Leflunomide<br>Prednisone and Leflunomide combination therapy | Drug: Prednisone<br>* Prednisone:A starting dose of 0. 5-0. 8mg/(kg*d) will be given. Following four-week period, the dose will be tapered gradually to 5mg/d until the end of 12 months of follow-up period.<br>* Other names: Prednisolone;Drug: Leflunomide<br>* Leflunomide:A starting dose of 20 mg/day will be given. This dose may be decreased to 10 mg/day at the discretion of the treating physician if minor adverse effects occur(e.g., liver enzyme elevations).<br>* Other names: ARAVA®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse rate at 12 months. | Relapse referred to the recurrence of previous clinical manifestations or abnormality of organ-specific imaging findings or serology tests after remission. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse rate at 6 months. | Relapse referred to the recurrence of previous clinical manifestations or abnormality of organ-specific imaging findings or serology tests after remission. | 6 months | 
| Complete response assessed by IgG4-RD Responder Index (IgG4-RD RI) at 1, 3, 6 and 12 months. | Complete response (CR) is defined as IgG4-RD RI <3 at 1, 3, 6 and 12 months. | Up to 12 months | 
| Partial response assessed by IgG4-RD RI at 1, 3, 6 and 12 months. | Partial response (PR) is defined as IgG4-RD RI remaining ≥3 at 1, 3, 6 and 12 months. | Up to 12 months | 
| Serum IgG4 concentrations (mg/dL) measured by immunonephelometry at 1, 3, 6 and 12 months. |  | Up to 12 months | 
| Number of circulating plasmablasts (cell number/mL) assessed by flow cytometry by gating peripheral blood at 1, 3, 6 and 12 months. |  | Up to 12 months | 
| Adverse effect events | Treatment-related adverse effect, including abnormal liver function and leukopenia. | Up to 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
IgG4-related disease, IgG4-related sclerosing cholangitis, Mikulicz disease, Pancreatitis, Retroperitoneal fibrosis, Lymphadenopathy