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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01584388
First Posted: April 25, 2012
Last Update Posted: July 2, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
John H. Stone, MD, Massachusetts General Hospital
  Purpose
The primary objective of this study is to evaluate the safety and effectiveness of rituximab in IgG4-RD.

Condition Intervention Phase
Retroperitoneal Fibrosis Autoimmune Pancreatitis Sialadenitis Pseudotumor Drug: Rituximab Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Rituximab (RTX) for IgG4-related Disease (IgG4-RD): a Prospective,Open-label Trial

Resource links provided by NLM:


Further study details as provided by John H. Stone, MD, Massachusetts General Hospital:

Primary Outcome Measures:
  • IgG4-RD RI Score at Baseline and Six Months After Rituxan Treatment [ Time Frame: 6 months ]

    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

    1. = Improved but still present
    2. = Persistent (still active; unchanged from previous visit)
    3. = New or recurrent disease activity while patient is off treatment
    4. = 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.


  • Cumulative Glucocorticoid Use at Baseline and 6 Months [ Time Frame: 6 months ]
    Cumulative glucocorticoid therapy between baseline and 6 months.

  • No Disease Flares During Rituximab Treatment Phase [ Time Frame: Month 6 ]

    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

    1. = Improved but still present
    2. = Persistent (still active; unchanged from previous visit)
    3. = New or recurrent disease activity while patient is off treatment
    4. = 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)


Secondary Outcome Measures:
  • Retreatment With Rituximab for Disease Relapse [ Time Frame: 12 months ]
    Number of subjects that relapsed during the course of the trial

  • Disease Response at 6 Months [ Time Frame: 6 months ]
    Decline of IgG4-RD Responder Index by at least two points for at least 6 months

  • Sustained Disease Response [ Time Frame: 12 months ]
    Decline of the IgG4-RD RI by at least two points and maintained for 12 months.

  • Complete Remission [ Time Frame: 6 months ]
    IgG4-RD RI (including serum IgG4) of 0 at six months

  • Complete Remission IgG-RD RI (Exclusive of Serum IgG4) of 0 at 6 Months. [ Time Frame: 6 months ]
    IgG-RD RI (exclusive of serum IgG4) of 0 at 6 months.

  • Complete Remission at Any Timepoint [ Time Frame: 12 months ]
    IgG4-RD RI = 0 at any point in the trial

  • Complete Remission (Any Timepoint), Exclusive of Serum IgG4 [ Time Frame: 12 months ]
    IgG4-RD RI = 0 (exclusive of serum IgG4) at any point in the trial

  • Time to Disease Response [ Time Frame: Mean days +/- standard deviation ]
    Treatment phase up to 52 weeks (365 days)

  • Time to Relapse [ Time Frame: Days ]
    Treatment phase up to 52 weeks (365 days)

  • Time to Complete Remission [ Time Frame: Days ]
    Treatment phase up to 52 weeks (365 days)


Enrollment: 30
Study Start Date: April 2012
Study Completion Date: January 2015
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rituximab Drug: Rituximab
Rituximab 1000 mg IV times two doses, separated by approximately 15 days.
Other Name: Rituxan

Detailed Description:
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.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01584388


Sponsors and Collaborators
Massachusetts General Hospital
Genentech, Inc.
Investigators
Study Chair: John H Stone, MD, MPH Massachusetts General Hospital (Rheumatology Unit)
Study Director: Arezou Khosroshahi, MD Massachusetts General Hospital (Rheumatology Unit)
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: John H. Stone, MD, Director, Clinical Rheumatology, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01584388     History of Changes
Other Study ID Numbers: 2011p002414
First Submitted: April 22, 2012
First Posted: April 25, 2012
Results First Submitted: December 14, 2015
Results First Posted: July 2, 2017
Last Update Posted: July 2, 2017
Last Verified: May 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by John H. Stone, MD, Massachusetts General Hospital:
Retroperitoneal fibrosis
Type 1 autoimmune pancreatitis
IgG4-related sclerosing cholangitis
Chronic sclerosing sialadenitis
Lacrimal glands
Orbital pseudotumor
IgG4-related tubulointerstitial nephritis
Lymphadenopathy
Pachymeningitis
Aorta
Peri-aortitis
Riedel's thyroiditis

Additional relevant MeSH terms:
Retroperitoneal Fibrosis
Fibrosis
Pancreatitis
Sialadenitis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Salivary Gland Diseases
Mouth Diseases
Stomatognathic Diseases
Rituximab
Immunoglobulin G
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents