Rituximab in IgG4-RD: A Phase 1-2 Trial

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety and effectiveness of rituximab in IgG4-RD.

Detailed Description
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This two-center trial will enroll at total of 30 patients with IgG4-RD. The two participating sites are the Massachusetts General Hospital (Boston, MA) and the Mayo Clinic (Rochester, MN). All patients will receive rituximab 1 gram intravenously times two doses, separated by approximately 15 days. The primary efficacy outcome - disease remission and successful completion of the glucocorticoid taper - will be assessed at six months. Patients will be followed on the protocol for an additional six months after measurement of the primary outcome.

Official Title
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Rituximab (RTX) for IgG4-related Disease (IgG4-RD): a Prospective,Open-label Trial

Conditions
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Retroperitoneal Fibrosis, Autoimmune Pancreatitis, Sialadenitis, Pseudotumor

Intervention / Treatment
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* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients will be included in the trial based on the following disease-specific criteria: Age 18 or older Diagnosis of IgG4-RD, based upon either pathological criteria* (for those who have undergone biopsies) or clinical criteria.** The criteria for pathological and clinical diagnoses are specified below. The subject can be either steroid-naive, in relapse, steroid dependent, or refractory to steroids. Subjects who are steroid dependent or refractory are eligible for enrollment if steroid dose has not been increased in the past 2 weeks, and their treating physician plans to withdraw steroids completely (by dose taper) within 8 weeks of starting rituximab. Pathological diagnosis: Histopathologic features consisting of a lymphoplasmacytic infiltrate and storiform fibrosis within involved organs. Other histopathologic features consistent with IgG4-RD (e.g., obliterative phlebitis) may be present but are not required. Either an IgG4/IgG plasma cell ratio of > 50% within the affected organs or more than 10 IgG4-bearing plasma cells per high-power field. All patients with pathologic diagnoses will have their specimens reviewed by pathology investigators. **Clinical diagnosis: • Organ involvement in a pattern consistent with IgG4-RD. This must include dysfunction of one of the following organs: pancreas (autoimmune pancreatitis); salivary glands (chronic sclerosing sialadenitis); lacrimal glands; orbital pseudotumor; kidneys; lungs; lymph nodes; meninges; aorta (including aortitis/periaortitis and/or retroperitoneal fibrosis); thyroid gland (Riedel's thyroiditis). If a patient is enrolled with a clinical diagnosis alone, the diagnosis must be accompanied by both an imaging finding compatible with IgG4-RD and a 1.5-fold elevation in the serum IgG4 concentration. Exclusion Criteria: Patients will be excluded from the study based on the following criteria: Disease-Specific Concerns: Excessive fibrosis within organs, such that a disease response to rituximab would not be expected. General Medical Concerns: Pregnancy (a negative serum pregnancy test should be performed for all women of childbearing potential within 7 days of treatment), or lactating. Inability to comply with study and/or follow-up procedures. Rituximab-Specific Concerns: History of HIV. Presence of active infection. New York Heart Association Classification III or IV heart disease (See Appendix D). Concomitant malignancies or previous malignancies within the last five years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix. At the Investigator's discretion, receipt of a live vaccine within 4 weeks prior to randomization. Positive hepatitis B or C serology is considered a potential exclusion criterion. Hepatitis B screening should include hepatitis B antibody and surface antigen for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add core antibodies and e-antigen. Allergies: History of severe allergic reactions to human or chimeric monoclonal antibodies or murine protein. Uncontrolled disease: They show evidence of other uncontrolled disease, including drug and alcohol abuse, which that could interfere with participation in the trial according to the protocol. History of anti-human anti-chimeric antibody formation.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br> | Drug: Rituximab<br>* Rituximab 1000 mg IV times two doses, separated by approximately 15 days.<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IgG4-RD RI Score at Baseline and Six Months After Rituxan Treatment | The IgG4-RD RI is then calculated by adding the individual organ scores.At each assessment, the physician enters a 0-4 score after the organ/site listed with: 0 = Normal or resolved = Improved but still present = Persistent (still active; unchanged from previous visit) = New or recurrent disease activity while patient is off treatment = Worsened or new disease despite treatment Definitions Organ/Site score: The overall level of IgG4-RD activity within a specific organ system Symptomatic: Is the disease manifestation in a particular organ system symptomatic? (Y = yes; N = no) Urgent disease: Disease that requires treatment immediately to prevent serious organ dysfunction (Y = yes; N = no) (Presence of urgent disease within an organ leads to DOUBLING of that organ system score) Damage: Organ dysfunction that has occurred as a result of IgG4-RD and is considered permanent (Y = yes; N = no) The Responder Index ranges from 0-60. | 6 months | 
| Cumulative Glucocorticoid Use at Baseline and 6 Months | Cumulative glucocorticoid therapy between baseline and 6 months. | 6 months | 
| No Disease Flares During Rituximab Treatment Phase | Disease flare measured by responder Index score: At each assessment, the physician enters a 0-4 score after the organ/site listed with: 0 = Normal or resolved = Improved but still present = Persistent (still active; unchanged from previous visit) = New or recurrent disease activity while patient is off treatment = Worsened or new disease despite treatment Definitions Organ/Site score: The overall level of IgG4-RD activity within a specific organ system Symptomatic: Is the disease manifestation in a particular organ system symptomatic? (Y = yes; N = no) Urgent disease: Disease that requires treatment immediately to prevent serious organ dysfunction (Y = yes; N = no) (Presence of urgent disease within an organ leads to DOUBLING of that organ system score) Damage: Organ dysfunction that has occurred as a result of IgG4-RD and is considered permanent (Y = yes; N = no) | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retreatment With Rituximab for Disease Relapse | Number of subjects that relapsed during the course of the trial | 12 months | 
| Disease Response at 6 Months | Decline of IgG4-RD Responder Index by at least two points for at least 6 months | 6 months | 
| Sustained Disease Response | Decline of the IgG4-RD RI by at least two points and maintained for 12 months. | 12 months | 
| Complete Remission | IgG4-RD RI (including serum IgG4) of 0 at six months | 6 months | 
| Complete Remission IgG-RD RI (Exclusive of Serum IgG4) of 0 at 6 Months. | IgG-RD RI (exclusive of serum IgG4) of 0 at 6 months. | 6 months | 
| Complete Remission at Any Timepoint | IgG4-RD RI = 0 at any point in the trial | 12 months | 
| Complete Remission (Any Timepoint), Exclusive of Serum IgG4 | IgG4-RD RI = 0 (exclusive of serum IgG4) at any point in the trial | 12 months | 
| Time to Disease Response | Treatment phase up to 52 weeks (365 days) | Mean days +/- standard deviation | 
| Time to Relapse | Treatment phase up to 52 weeks (365 days) | Days | 
| Time to Complete Remission | Treatment phase up to 52 weeks (365 days) | Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aorta, Type 1 autoimmune pancreatitis, IgG4-related sclerosing cholangitis, Chronic sclerosing sialadenitis, Lacrimal glands, Orbital pseudotumor, IgG4-related tubulointerstitial nephritis, Lymphadenopathy, Pachymeningitis, Peri-aortitis, Retroperitoneal fibrosis, Riedel's thyroiditis