Methotrexate - Inadequate Response Device Sub-Study

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and acceptability of a device used in place of traditional syringes for abatacept self-injection.

Official Title
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Sub-study-A Phase IIIB Multicenter, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Abatacept Administered Subcutaneously and Intravenously in Subjects With Rheumatoid Arthritis, Receiving Background Methotrexate, and Experiencing an Inadequate Response to Methotrexate

Conditions
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Rheumatoid Arthritis (RA)

Intervention / Treatment
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* Device: Abatacept combination product (ACP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, ages ≥ 18 Participants who are considered methotrexate inadequate responders (MTX-IR) 10 or more swollen joints (66 joint count) and 12 or more tender joints (68 joint count) Participants were to have been enrolled in the main MTX-IR study and been treated with open label abatacept for at least 3 months in the long term period Exclusion Criteria: Participants who failed one or multiple anti-tumor necrosis factor (TNF) therapies Participants who meet diagnostic criteria for any other rheumatic disease (e.g., lupus erythematosus) Participants with active vasculitis of a major organ system (except for subcutaneous rheumatoid nodules) Participants with severe chronic or recurrent bacterial infections Participants who have received treatment with rituximab

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: Abatacept Combination Product (ACP)<br>Participants from the long-term period of study NCT00559585 who enrolled in the ACP substudy switched to administration of subcutaneous (SC) abatacept via the ACP for the duration of the substudy. Abatacept was administered SC using the ACP by the participant or caregiver on Substudy Day 1 and at weekly intervals thereafter. The ACP was a pre-filled liquid product device delivering 125 mg abatacept/device (125 mg/mL). | Device: Abatacept combination product (ACP)<br>* Abatacept Solution, Subcutaneous, 125 mg/device, Weekly, 3 months<br>* Other names: BMS-188667;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Death, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, and AEs Leading to Discontinuation | An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=possibly, probably, or certainly related to and of unknown relationship to study treatment. | ACP substudy Day 1 to last substudy assessment occurring prior to the 1st dose of non-ACP subcutaneous (SC) abatacept, assessed up to 12 months | 
| Number of Participants With AEs of Special Interest in the ACP Device Substudy | AE=any new untoward medical occurrence or worsening of a preexisting medical condition which does not necessarily have a causal relationship with this treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs including all infections, local injection reactions (prespecified), and systemic injection reactions (within 24 hours of dosing). | ACP substudy Day 1 to last substudy assessment occurring prior to 1st dose of non-ACP SC abatacept (administered once participants switched back to main study). For participants discontinuing both studies: Day 1 of ACP dosing to 56 days post last ACP dose | 
| Number of Participants With Laboratory Test Results in Hematology Meeting the Criteria for Marked Abnormality in the ACP Device Substudy | BL=baseline; LLN lower limit of normal; ULN=upper limit of normal. Marked abnormality criteria: Hemoglobin: >3 g/dL decrease from BL; Hematocrit: <0.75*BL; Erythrocytes: <0.75*BL; Platelets: <0.67*LLN/>1.5*ULN, or if BL <LLN, use 0.5*BL/<100,000 mm^3; Leukocytes: <0.75*LLN/ >1.25*ULN, or if BL<LLN, use <0.8*BL/>ULN, or if BL>ULN, use >1.2*BL/<LLN; neutrophils+bands: <1.0*10^3 c/uL; eosinophils: >0.750*10^3 c/uL; basophils: >400 mm^3; monocytes: >2000 mm^3; lymphocytes: <0.750*10^3 c/uL/ >7.50*10^3 c/uL. | ACP substudy Day 1 to last substudy assessment occurring prior to 1st dose of non-ACP SC abatacept (administered once participants switched back to main study). For participants discontinuing both studies: Day 1 of ACP dosing to 7 days post last ACP dose. | 
| Number of Participants With Liver Function Laboratories Meeting MA Criteria in the ACP Device Substudy | Marked abnormality criteria: Alkaline phosphatase (ALP): >2* ULN, or if BL>ULN then use >3* BL; aspartate aminotransferase (AST): >3* ULN, or if BL>ULN then use >4* BL; alanine aminotransferase (ALT): >3* ULN, or if BL>ULN then use >4* BL; G-Glutamyl transferase (GGT): >2* ULN, or if BL>ULN then use >3* BL; Bilirubin: >2* ULN, or if BL>ULN then use >4* BL; blood urea nitrogen (BUN): >2* BL; creatinine: >1.5* BL | ACP substudy Day 1 to last substudy assessment occurring prior to 1st dose of non-ACP SC abatacept (administered once participants switched back to main study). For participants discontinuing both studies: Day 1 of ACP dosing to 7 days post last ACP dose. | 
| Number of Participants With Electrolyte Laboratories Meeting MA Criteria in the ACP Device Substudy | Marked abnormality criteria: Sodium (Na): <0.95*LLN/ >1.05*ULN, or if BL<LLN then use <0.95* BL or >ULN, or if BL>ULN then use>1.05* BL or <LLN; potassium (K): <0.9* LLN/>1.1*ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; (Cl): <0.9* LLN/>1.1* ULN, or if BL<LLN then use <0.9* BL or >ULN, or if BL>ULN then use>1.1* BL or <LLN; calcium (Ca): <0.8* LLN/>1.2* ULN, or if BL<LLN then use <0.75* BL or >ULN, or if BL>ULN then use>1.25* BL or <LLN; phosphorous (P): <0.75* LLN/ >1.25* ULN, or if BL<LLN then use 0.67* BL or >ULN, or if BL>ULN then use>1.33* BL or <LLN | ACP substudy Day 1 to last substudy assessment occurring prior to 1st dose of non-ACP SC abatacept (administered once participants switched back to main study). For participants discontinuing both studies: Day 1 of ACP dosing to 7 days post last ACP dose. | 
| Number of Participants With Other Chemistry and Urinalysis Laboratories Meeting MA Criteria in the ACP Device Substudy | MA criteria: serum glucose (Glu): <65 mg/dL/>220 mg/dL;fasting serum Glu: <0.8* LLN/>1.5*ULN,or if BL<LLN then use 0.8*BL or >ULN,or if BL>ULN then use >2.0*BL or <LLN;total protein: <0.9*LLN/>1.1*ULN,or if BL<LLN then use <0.9*BL or >UNL,or if BL>UNL then use >1.1*BL or <LLN; albumin: <0.9*LLN,or if BL<LLN then use <0.75 BL;uric acid: >1.5*ULN,or if BL>ULN then use >2*BL. Urinalysis (Urine protein,urine Glu,urine blood,leukocyte esterase,Red Blood Cells [RBCs], White Blood Cells [WBCs]):Use ≥2 when BL value missing or when pre-dose=0 or 0.5; use ≥3 when pre-dose=1, use ≥4 when pre-dose=2 or 3 | ACP substudy Day 1 to last substudy assessment occurring prior to 1st dose of non-ACP SC abatacept (administered once participants switched back to main study). For participants discontinuing both studies: Day 1 of ACP dosing to 7 days post last ACP dose. | 
| Mean Systolic Blood Pressure (SBP) Over Time in the ACP Device Substudy |  | ACP substudy Day 1 to last substudy assessment occurring prior to 1st dose of non-ACP SC abatacept (administered once participants switched back to main study). For participants discontinuing both studies: Day 1 of ACP dosing to 7 days post last ACP dose. | 
| Mean Diastolic Blood Pressure (DBP) Over Time in the ACP Device Substudy |  | ACP substudy Day 1 to last substudy assessment occurring prior to 1st dose of non-ACP SC abatacept (administered once participants switched back to main study). For participants discontinuing both studies: Day 1 of ACP dosing to 7 days post last ACP dose. | 
| Mean Heart Rate Over Time in the ACP Device Substudy |  | ACP substudy Day 1 to last substudy assessment occurring prior to 1st dose of non-ACP SC abatacept (administered once participants switched back to main study). For participants discontinuing both studies: Day 1 of ACP dosing to 7 days post last ACP dose. | 
| Mean Temperature Over Time in the ACP Device Substudy |  | ACP substudy Day 1 to last substudy assessment occurring prior to 1st dose of non-ACP SC abatacept (administered once participants switched back to main study). For participants discontinuing both studies: Day 1 of ACP dosing to 7 days post last ACP dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum Observed Serum Concentration (Cmin) of Abatacept Over Time in the ACP Device Substudy | Trough levels of abatacept were evaluated based upon serum samples. Day 1 pharmacokinetics were based on exposure to the pre-filled syringes and did not reflect abatacept exposure via the ACP device. | Days 1, 29, 57, 85, 169, and 253 of ACP substudy | 
| Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Responses Over Time by Enzyme Linked Immunosorbant Assay (ELISA) in the ACP Device Substudy | Serum samples from all treated adult participants with active rheumatoid arthritis were screened for the presence of drug-specific antibodies using ELISA. Immunogenicity was defined as the presence of a positive anti-abatacept or anti-CTLA4 antibody. | ACP substudy Day 1 to last substudy assessment occurring prior to 1st dose of non-ACP SC abatacept (administered once participants switched back to main study). For participants discontinuing both studies: Day 1 of ACP dosing to 28 days post last ACP dose | 
| Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay in the ACP Device Substudy | An electrochemiluminescence immunoassay screened sera for drug-specific antibodies; immunocompetition was used to identify specific anti-Abatacept reactivity. CTLA4 and Possibly immunoglobulin (Ig) category=reactivity against extracellular domain of human CTLA4, constant regions of human IgG1, or both (CTLA4Ig; Abatacept molecule). Ig and/or Junction (JNCT)category=reactivity against constant regions and/or hinge region of human IgG1. Drug-induced seropositivity defined as a post-baseline titer higher than Baseline, or any post-baseline positivity if Baseline value was missing. TRT=treatment | ACP substudy Day 1 to last substudy assessment occurring prior to 1st dose of non-ACP SC abatacept (administered once participants switched back to main study). For participants discontinuing both studies: Day 1 of ACP dosing to 85 days post last ACP dose |