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Leflunomide for Maintenance of Remission in IgG4 Related Disease

Primary Purpose

Immunoglobulin G4 Related Sclerosing Disease

Status

Completed

Phase

Phase 4

Locations

China

Study Type

Interventional

Intervention

Prednisone

Leflunomide

About this trial

This is an interventional treatment trial for Immunoglobulin G4 Related Sclerosing Disease focused on measuring IgG4-related disease, IgG4-related sclerosing cholangitis, Mikulicz disease, Pancreatitis, Retroperitoneal fibrosis, Lymphadenopathy

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Chinese PLA General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Prednisone

Prednisone and Leflunomide

Arm Description

Prednisone mono-therapy

Prednisone and Leflunomide combination therapy

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

Serum IgG4 concentrations (mg/dL) measured by immunonephelometry at 1, 3, 6 and 12 months.

Number of circulating plasmablasts (cell number/mL) assessed by flow cytometry by gating peripheral blood at 1, 3, 6 and 12 months.

Adverse effect events

Treatment-related adverse effect, including abnormal liver function and leukopenia.

Full Information

NCT ID

NCT02703194

First Posted

February 27, 2016

Last Updated

March 4, 2019

Sponsor

Chinese PLA General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02703194

Brief Title

Leflunomide for Maintenance of Remission in IgG4 Related Disease

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2019

Overall Recruitment Status

Completed

Study Start Date

March 2016 (Actual)

Primary Completion Date

January 2019 (Actual)

Study Completion Date

January 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Chinese PLA General Hospital

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Immunoglobulin G4 Related Sclerosing Disease

Keywords

IgG4-related disease, IgG4-related sclerosing cholangitis, Mikulicz disease, Pancreatitis, Retroperitoneal fibrosis, Lymphadenopathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

68 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Prednisone

Arm Type

Experimental

Arm Description

Prednisone mono-therapy

Arm Title

Prednisone and Leflunomide

Arm Type

Experimental

Arm Description

Prednisone and Leflunomide combination therapy

Intervention Type

Drug

Intervention Name(s)

Prednisone

Other Intervention Name(s)

Prednisolone

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Leflunomide

Other Intervention Name(s)

ARAVA®

Intervention Description

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).

Primary Outcome Measure Information:

Title

Relapse rate at 12 months.

Description

Relapse referred to the recurrence of previous clinical manifestations or abnormality of organ-specific imaging findings or serology tests after remission.

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Relapse rate at 6 months.

Description

Relapse referred to the recurrence of previous clinical manifestations or abnormality of organ-specific imaging findings or serology tests after remission.

Time Frame

6 months

Title

Complete response assessed by IgG4-RD Responder Index (IgG4-RD RI) at 1, 3, 6 and 12 months.

Description

Complete response (CR) is defined as IgG4-RD RI <3 at 1, 3, 6 and 12 months.

Time Frame

Up to 12 months

Title

Partial response assessed by IgG4-RD RI at 1, 3, 6 and 12 months.

Description

Partial response (PR) is defined as IgG4-RD RI remaining ≥3 at 1, 3, 6 and 12 months.

Time Frame

Up to 12 months

Title

Serum IgG4 concentrations (mg/dL) measured by immunonephelometry at 1, 3, 6 and 12 months.

Time Frame

Up to 12 months

Title

Number of circulating plasmablasts (cell number/mL) assessed by flow cytometry by gating peripheral blood at 1, 3, 6 and 12 months.

Time Frame

Up to 12 months

Title

Adverse effect events

Description

Treatment-related adverse effect, including abnormal liver function and leukopenia.

Time Frame

Up to 12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jian Zhu

Organizational Affiliation

Chinese PLA General Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Chinese PLA General Hospital

City

Beijing

ZIP/Postal Code

100000

Country

China

12. IPD Sharing Statement

Citations:

PubMed Identifier

32113839

Citation

Wang Y, Zhao Z, Gao D, Wang H, Liao S, Dong C, Luo G, Ji X, Li Y, Wang X, Zhao Y, Li K, Zhang J, Jin J, Zhang Y, Zhu J, Zhang J, Huang F. Additive effect of leflunomide and glucocorticoids compared with glucocorticoids monotherapy in preventing relapse of IgG4-related disease: A randomized clinical trial. Semin Arthritis Rheum. 2020 Dec;50(6):1513-1520. doi: 10.1016/j.semarthrit.2020.01.010. Epub 2020 Feb 3.

Results Reference

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Leflunomide for Maintenance of Remission in IgG4 Related Disease

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