IgG4-related Disease
Conditions
Brief summary
This is a Phase 2, single center, proof of concept clinical trial in subjects with active IgG4-Related Disease (IgG4-RD). Approximately 10 subjects with active IgG4-RD will be enrolled into this study. Subjects will receive weekly subcutaneous doses of abatacept (125mg) for 24 doses (24 weeks).
Detailed description
After obtaining informed consent, all screening procedures and tests establishing eligibility will be performed on the initial screening visit. Subjects determined to be eligible at screening will receive an initial subcutaneous dose of abatacept (125mg), which will be continued weekly for a total of up to 24 doses (24 weeks). Steroid therapy must be tapered off and discontinued over a 4 week period (taper must be completed no later than week 4). Should patients be deemed to have worsening disease or failing therapy at 4 weeks then a trial of steroids can be considered. Subjects will return on weeks 1, 2, 4, 8, 12, 16, 20, and 24 while on treatment for their injections, and for the scheduled safety and disease response assessments. Subjects will be allowed to self-administer their injections at home. The full treatment period is 24 doses given weekly for 24 weeks. Subjects who are not able to be tapered off corticosteroids or who require reinstitution of corticosteroid therapy at any time during the study will be counted as treatment failures, but may continue on study. Should the IgG4-RD responder index fail to improve by 8 weeks or should there be development of new organ failure at 4 weeks, patient's will be deemed treatment failure and can begin corticosteroid or alternative immunosuppressive therapy at the Investigator's discretion. Those who require rituximab or who require addition of other oral immunosuppressives will be counted as treatment failures and will terminate the study. All subjects completing the treatment period will have follow up visits off protocolized treatment at 28 and 36 weeks. All adverse events (including serious adverse events (AEs) and deaths) and use of concomitant medication information will be collected throughout the study from screening through study termination. Subjects developing treatment-emergent adverse events or clinically significant safety lab abnormalities will be followed until resolution or until stabilization of the adverse events/abnormalities.
Interventions
DRUGAbatacept
Subjects will receive weekly subcutaneous doses of abatacept (125mg) for 24 doses (24 weeks)
Sponsors
Bristol-Myers Squibb
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
1. Are male or female 18 years of age or older 2. Meet the American College of Rheumatology (ACR)/EULAR 2018 Classification Criteria for IgG4-RD 3. Have active disease based on an IgG4-RD Responder Index (RI) ≥2 at screening with disease manifestation in at least one organ system excluding lymph nodes at screening 4. May or may not have received prior IgG4-RD therapy 5. Must be willing to taper off any systemic corticosteroid therapy within 4 weeks of first dose of trial drug. 6. Must be able and willing to discontinue any immunosuppressive agent at screening (e.g. methotrexate, mycophenolate mofetil, 6-mercaptopurine, tacrolimus, cyclophosphamide or azathioprine). 7. No history of severe allergic reactions to monoclonal antibodies. 8. Are able and willing to complete the entire study according to the study schedule. 9. Are willing to forego other forms of experimental treatment during the study. 10. Are able to provide written informed consent.
Exclusion criteria
1. History or evidence of a clinically unstable/uncontrolled disorder, condition or disease (including but not limited to cardiopulmonary, oncologic, renal, hepatic, metabolic, hematologic or psychiatric) other than IgG4-RD that, in the opinion of the Investigator, would pose a risk to patient safety or interfere with the study evaluation, procedures or completion. 2. Malignancy within 5 years (except successfully treated in situ cervical cancer, resected squamous cell or basal cell carcinoma of the skin, or prostate cancer with no recurrence ≥3 years following prostatectomy). 3. Liver disease: Acute or chronic non-IgG4-related liver disease deemed sufficiently severe to impair their ability to participate in the trial. 4. Uncontrolled disease: evidence of another uncontrolled condition, including drug and alcohol abuse, which could interfere with participation in the trial according to the protocol. 5. Presence of recurrent or chronic infections, defined as ≥3 infections requiring antimicrobials over the past 6 months prior to screening. 6. Active infection requiring hospitalization or treatment with parenteral antimicrobials within the 30 days prior to randomization. 7. Prior use of rituximab (or other B cell depleting agents) within 6 months of enrollment unless B cells have been demonstrated to have repopulated. 8. Use of any investigational agent within 5 half-lives of the agent (or 6 months if the half-life is unknown) prior to enrollment. 9. White blood cell count \< 2.5 x 103/µL. 10. Absolute neutrophil count (ANC) \< 1.0 x 103/µL. 11. IgG4-related renal disease with serum creatinine \>2.0 mg/dL. 12. Hemoglobin \< 10 g/dL. 13. Platelet count \< 75 x 109/L. 14. Known positive result for HIV I or II antibody, hepatitis B surface antigen, hepatitis B core antibody or hepatitis C antibody. 15. Has received live vaccines within 4 weeks of enrollment. 16. Inability to communicate reliably with the investigator. 17. Patient is pregnant or breast feeding, or planning to become pregnant while enrolled in the study, up to end of study (EOS) visit. 18. Positive pregnancy test at screening or during the study. 19. Subjects who do not agree to use medically acceptable methods of contraception. 20. Male patient with a pregnant partner who is not willing to use a condom during the treatment and up to end of study (EOS)visit. 21. Known or suspected sensitivity to mammalian cell-derived products or any components of the study drug. 22. History of alcohol and/or substance abuse within 12 months prior to screening. 23. Unable or unwilling to partake in follow-up assessments or required protocol procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Response | 24 weeks | Effect of weekly subcutaneous (SC) administration of abatacept on complete remission |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Response | 12 weeks | Assess the effect of abatacept on disease response at week 12 |
| Disease Response at Week 24 | disease response at 24 weeks | Percentage of patients achieving disease response at week 24 |
| Disease Remission: Flares Over Time Per Subject | 24 weeks | number of disease flares per subject |
| Decline in Serum IgG4 Concentration of Responders | 24 Weeks | Serum IgG4 measured at baseline and week 24 |
| Decline in Serum IgE Concentration of Responders | 24 weeks | Serum IgE concentration was measured at baseline and Week 24 |
Countries
United States
Participant flow
Pre-assignment details
Concurrent glucocorticoid treatment was permitted but was required to be discontinued by week 4.
Participants by arm
| Arm | Count |
|---|---|
| Abatacept To assess the effect of weekly subcutaneous (SC) administration of abatacept on complete remission of IgG4-RD. Abatacept: Subjects will receive weekly subcutaneous doses of abatacept (125mg) for 24 doses (24 weeks). The protocol called for a final study visit at 36 weeks, three months after the patients discontinued their active treatment, primarily for safety | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Disease Flare | 5 |
| Overall Study | Lack of Efficacy | 2 |
Baseline characteristics
| Characteristic | Abatacept |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 64.8 years |
| BAS-Duration of IgG4-RD (months) | 54.4 months |
| Baseline Serum IgE | 480.5 IU |
| Baseline Serum IgG4 | 597 units on a scale |
| Disease activity: IgG4-RD Responder Index score | 7.2 points range 0-75 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Number of active organs affected | 3.4 count of number of organs involved |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 3 / 10 |
| serious Total, serious adverse events | 1 / 10 |
Outcome results
Primary
Treatment Response
Effect of weekly subcutaneous (SC) administration of abatacept on complete remission
Time frame: 24 weeks
Population: The primary outcome, complete remission at week 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Abatacept | Treatment Response | 3 Participants |
Secondary
Decline in Serum IgE Concentration of Responders
Serum IgE concentration was measured at baseline and Week 24
Time frame: 24 weeks
Population: Serum IgE concentrations declined in all 6 patients (100%) who demonstrated a disease response with abatacept
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Abatacept | Decline in Serum IgE Concentration of Responders | 6 Participants |
Secondary
Decline in Serum IgG4 Concentration of Responders
Serum IgG4 measured at baseline and week 24
Time frame: 24 Weeks
Population: serum IgG4 concentration can be used as a surrogate marker for disease activity
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Abatacept | Decline in Serum IgG4 Concentration of Responders | 3 Participants |
Secondary
Disease Remission: Flares Over Time Per Subject
number of disease flares per subject
Time frame: 24 weeks
Population: Subjects with reported disease flare on treatment. Disease flare was defined as recurrence of disease activity or demonstration of a disease exacerbation such that additional therapy beyond the trial protocol was indicated
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Abatacept | Disease Remission: Flares Over Time Per Subject | 0.2 units on a scale |
Secondary
Disease Response
Assess the effect of abatacept on disease response at week 12
Time frame: 12 weeks
Population: All 10 patients were treated initially with abatacept
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Abatacept | Disease Response | 6 Participants |
Secondary
Disease Response at Week 24
Percentage of patients achieving disease response at week 24
Time frame: disease response at 24 weeks
Population: disease response at week 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Abatacept | Disease Response at Week 24 | 5 Participants |