Safety and Efficacy of Abatacept in IgG4-Related Disease

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT03669861
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 10
• Location: 1
• Arm: 1
• Actual Duration (Months): 23.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
IgG4-related Disease	Drug: Abatacept	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Open-label, Single Center Abatacept in IgG4-Related Disease 10-patient Proof-of-concept Study
• Actual Study Start Date: Nov 13, 2018
• Actual Primary Completion Date: Apr 10, 2020
• Actual Study Completion Date: Nov 10, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Abatacept To assess the effect of weekly subcutaneous (SC) administration of abatacept on complete remission of IgG4-RD	Drug: Abatacept; Subjects will receive weekly subcutaneous doses of abatacept (125mg) for 24 doses (24 weeks); Other Names: Orencia

Outcome Measures

Primary Outcome Measures

1. Treatment Response [24 weeks]

   Effect of weekly subcutaneous (SC) administration of abatacept on complete remission

Secondary Outcome Measures

1. Disease Response [12 weeks]

   Assess the effect of abatacept on disease response at week 12

2. Disease Response at Week 24 [disease response at 24 weeks]

   Percentage of patients achieving disease response at week 24

3. Disease Remission: Flares Over Time Per Subject [24 weeks]

   number of disease flares per subject

4. Decline in Serum IgG4 Concentration of Responders [24 Weeks]

   Serum IgG4 measured at baseline and week 24

5. Decline in Serum IgE Concentration of Responders [24 weeks]

   Serum IgE concentration was measured at baseline and Week 24

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• Bristol-Myers Squibb

Investigators

• Principal Investigator: John H Stone, MD, Massachusetts General Hospital and Harvard Medical School

Study Documents (Full-Text)

• Study Protocol - Oct 28, 2018

More Information

Publications

None provided.

• Responsible Party: Stone, John H, M.D., M.P.H, Director, Division of Rheumatology, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT03669861
• Other Study ID Numbers: IM101-744
• First Posted: Sep 13, 2018
• Last Update Posted: Aug 24, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Immunoglobulin G4-Related Disease; Abatacept

Study Results

Participant Flow

Pre-assignment Detail	Concurrent glucocorticoid treatment was permitted but was required to be discontinued by week 4.

Arm/Group Title	Abatacept
Arm/Group Description	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)
Period Title: Overall Study
STARTED	10
COMPLETED	3
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Abatacept
Arm/Group Description	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
Overall Participants	10
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	4 40%
>=65 years	6 60%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	64.8
Sex: Female, Male (Count of Participants)
Female	3 30%
Male	7 70%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 10%
Not Hispanic or Latino	9 90%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 10%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	9 90%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%
Baseline Serum IgG4 (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	597
Baseline Serum IgE (IU) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [IU]	480.5
Disease activity: IgG4-RD Responder Index score (points range 0-75) [Mean (Full Range) ]
Mean (Full Range) [points range 0-75]	7.2
BAS-Duration of IgG4-RD (months) (months) [Mean (Full Range) ]
Mean (Full Range) [months]	54.4
Number of active organs affected (count of number of organs involved) [Mean (Full Range) ]
Mean (Full Range) [count of number of organs involved]	3.4

Outcome Measures

1. Primary Outcome

Title	Treatment Response
Description	Effect of weekly subcutaneous (SC) administration of abatacept on complete remission
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

The primary outcome, complete remission at week 24

Arm/Group Title	Abatacept
Arm/Group Description	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)
Measure Participants	10
Count of Participants [Participants]	3 30%

2. Secondary Outcome

Title	Disease Response
Description	Assess the effect of abatacept on disease response at week 12
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

All 10 patients were treated initially with abatacept

Arm/Group Title	Abatacept
Arm/Group Description	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)
Measure Participants	10
Count of Participants [Participants]	6 60%

3. Secondary Outcome

Title	Disease Response at Week 24
Description	Percentage of patients achieving disease response at week 24
Time Frame	disease response at 24 weeks

Outcome Measure Data

Analysis Population Description

disease response at week 24

Arm/Group Title	Abatacept
Arm/Group Description	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)
Measure Participants	10
Count of Participants [Participants]	5 50%

4. Secondary Outcome

Title	Disease Remission: Flares Over Time Per Subject
Description	number of disease flares per subject
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	Abatacept
Arm/Group Description	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)
Measure Participants	10
Mean (Full Range) [units on a scale]	0.2

5. Secondary Outcome

Title	Decline in Serum IgG4 Concentration of Responders
Description	Serum IgG4 measured at baseline and week 24
Time Frame	24 Weeks

Outcome Measure Data

Analysis Population Description

serum IgG4 concentration can be used as a surrogate marker for disease activity

Arm/Group Title	Abatacept
Arm/Group Description	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)
Measure Participants	6
Count of Participants [Participants]	3 30%

6. Secondary Outcome

Title	Decline in Serum IgE Concentration of Responders
Description	Serum IgE concentration was measured at baseline and Week 24
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Serum IgE concentrations declined in all 6 patients (100%) who demonstrated a disease response with abatacept

Arm/Group Title	Abatacept
Arm/Group Description	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)
Measure Participants	6
Count of Participants [Participants]	6 60%

Adverse Events

Time Frame	Adverse Event monitoring (from time of study drug administration) to end of study (visit 10 (week 36) or safety follow up visit, if needed). Ten subjects were enrolled in the study between December 2018 and August 2019. Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study drug a nd that does not necessarily have a causal relationship with this treatment.
Adverse Event Reporting Description	A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalization or causes prolongation of existing hospitalization; results in persistent or significant disability/incapacity/congenital anomaly. All Serious Adverse Events (SAEs) that occur following the subject's written consent to participate in the study through 30 days of discontinuation of dosing must be reported.
Arm/Group Title	Abatacept
Arm/Group Description	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)
All Cause Mortality
	Abatacept
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Serious Adverse Events
	Abatacept
	Affected / at Risk (%)	# Events
Total	1/10 (10%)
Cardiac disorders
Myocardial Infarction	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Abatacept
	Affected / at Risk (%)	# Events
Total	3/10 (30%)
Blood and lymphatic system disorders
thrombocytopenia	1/10 (10%)	1
Eye disorders
episcleritis	1/10 (10%)	1
Gastrointestinal disorders
abdominal pain	1/10 (10%)	1

Limitations/Caveats

The trial also comes with additional limitations, specifically the small number of patients, the lack of a comparator group, and the open-label design.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.