Autoimmune Pancreatitis, Pseudotumor, Retroperitoneal Fibrosis, Sialadenitis
Conditions
Keywords
Type 1 autoimmune pancreatitis, IgG4-related sclerosing cholangitis, Chronic sclerosing sialadenitis, Lacrimal glands, Orbital pseudotumor, IgG4-related tubulointerstitial nephritis, Lymphadenopathy, Pachymeningitis, Aorta, Peri-aortitis, Retroperitoneal fibrosis, Riedel's thyroiditis
Brief summary
The primary objective of this study is to evaluate the safety and effectiveness of rituximab in IgG4-RD.
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.
Interventions
DRUGRituximab
Rituximab 1000 mg IV times two doses, separated by approximately 15 days.
Sponsors
Genentech, Inc.
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| IgG4-RD RI Score at Baseline and Six Months After Rituxan Treatment | 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 | 6 months | Cumulative glucocorticoid therapy between baseline and 6 months. |
| No Disease Flares During Rituximab Treatment Phase | 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
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission | 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. | 6 months | IgG-RD RI (exclusive of serum IgG4) of 0 at 6 months. |
| Complete Remission at Any Timepoint | 12 months | IgG4-RD RI = 0 at any point in the trial |
| Retreatment With Rituximab for Disease Relapse | 12 months | Number of subjects that relapsed during the course of the trial |
| Time to Disease Response | Mean days +/- standard deviation | Treatment phase up to 52 weeks (365 days) |
| Time to Relapse | Days | Treatment phase up to 52 weeks (365 days) |
| Time to Complete Remission | Days | Treatment phase up to 52 weeks (365 days) |
| Complete Remission (Any Timepoint), Exclusive of Serum IgG4 | 12 months | IgG4-RD RI = 0 (exclusive of serum IgG4) at any point in the trial |
| Disease Response at 6 Months | 6 months | Decline of IgG4-RD Responder Index by at least two points for at least 6 months |
| Sustained Disease Response | 12 months | Decline of the IgG4-RD RI by at least two points and maintained for 12 months. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab Rituximab: Rituximab 1000 mg IV times two doses, separated by approximately 15 days. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Rituximab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Age, Continuous | 48 Years STANDARD_DEVIATION 17 |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 30 |
| serious Total, serious adverse events | 5 / 30 |
Outcome results
Primary
Cumulative Glucocorticoid Use at Baseline and 6 Months
Cumulative glucocorticoid therapy between baseline and 6 months.
Time frame: 6 months
Population: cumulative glucocorticoid use at 6 and compare them to baseline using paired T tests.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| IgG4-RD Responder Index | Cumulative Glucocorticoid Use at Baseline and 6 Months | 42 mg |
| 6 Months | Cumulative Glucocorticoid Use at Baseline and 6 Months | 15 mg |
Primary
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 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.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IgG4-RD Responder Index | IgG4-RD RI Score at Baseline and Six Months After Rituxan Treatment | 11 units on a scale | Standard Deviation 7 |
| 6 Months | IgG4-RD RI Score at Baseline and Six Months After Rituxan Treatment | 1 units on a scale | Standard Deviation 2 |
Primary
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 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)
Time frame: Month 6
Population: number of subjects without disease flares during baseline to 6 month of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IgG4-RD Responder Index | No Disease Flares During Rituximab Treatment Phase | 23 Participants |
Secondary
Complete Remission
IgG4-RD RI (including serum IgG4) of 0 at six months
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IgG4-RD Responder Index | Complete Remission | 14 Participants |
Secondary
Complete Remission (Any Timepoint), Exclusive of Serum IgG4
IgG4-RD RI = 0 (exclusive of serum IgG4) at any point in the trial
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IgG4-RD Responder Index | Complete Remission (Any Timepoint), Exclusive of Serum IgG4 | 20 Participants |
Secondary
Complete Remission at Any Timepoint
IgG4-RD RI = 0 at any point in the trial
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IgG4-RD Responder Index | Complete Remission at Any Timepoint | 18 Participants |
Secondary
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.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IgG4-RD Responder Index | Complete Remission IgG-RD RI (Exclusive of Serum IgG4) of 0 at 6 Months. | 18 Participants |
Secondary
Disease Response at 6 Months
Decline of IgG4-RD Responder Index by at least two points for at least 6 months
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IgG4-RD Responder Index | Disease Response at 6 Months | 29 Participants |
Secondary
Retreatment With Rituximab for Disease Relapse
Number of subjects that relapsed during the course of the trial
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IgG4-RD Responder Index | Retreatment With Rituximab for Disease Relapse | 4 Participants |
Secondary
Sustained Disease Response
Decline of the IgG4-RD RI by at least two points and maintained for 12 months.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IgG4-RD Responder Index | Sustained Disease Response | 22 Participants |
Secondary
Time to Complete Remission
Treatment phase up to 52 weeks (365 days)
Time frame: Days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IgG4-RD Responder Index | Time to Complete Remission | 198 Days | Standard Deviation 87 |
Secondary
Time to Disease Response
Treatment phase up to 52 weeks (365 days)
Time frame: Mean days +/- standard deviation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IgG4-RD Responder Index | Time to Disease Response | 43 Days | Standard Deviation 37 |
Secondary
Time to Relapse
Treatment phase up to 52 weeks (365 days)
Time frame: Days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IgG4-RD Responder Index | Time to Relapse | 210 Days | Standard Deviation 105 |