Abatacept in the Treatment and Prevention of Active Systemic Lupus Erythematosus (SLE) Flares in Combination With Prednisone

Study Overview
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Brief Summary
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The purpose of this clinical research study is to learn whether Abatacept can treat and prevent lupus flares; specifically, in patients with active lupus flares in at least one of three organ systems: skin (discoid lesions); inflammation of the lining of the heart (pericarditis), or inflammation of the lining of the lung (pleuritis/pleurisy); or inflammation of more than 4 joints (arthritis). All participants will receive prednisone or prednisone-equivalent treatment in combination with study medication. The safety of this treatment will also be studied.

Official Title
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A Phase IIB, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Abatacept vs Placebo on a Background of Oral Glucocorticosteroids in the Treatment of Subjects With Systemic Lupus Erythematosus and the Prevention of Subsequent Lupus Flares

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: Abatacept
* Drug: Placebo
* Drug: Prednisone
* Drug: Abatacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: participants must be diagnosed with SLE and be experiencing an active lupus flare in at least one of three organ systems: skin (discoid lesions), inflammation of the lining of the heart (pericarditis), or inflammation of the lining of the lung (pleuritis/pleurisy); or inflammation of more than 4 joints within 14 days of a screening visit (arthritis) Stable dose of prednisone (<30mg) for at least one month Exclusion Criteria: participants experiencing an active lupus flare in the kidney or central nervous systems Treatment with a stable dose of azathioprine, mycophenolate mofetil, hydroxychloroquine, chloroquine, or methotrexate for less than three months prior to the study participants with active viral or bacterial infections participants with any other autoimmune disease as a main diagnosis Prior 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: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Abatacept + Prednisone<br>Double Blind Period | Drug: Abatacept<br>* Injectable, intravenous, 10 mg/kg, abatacept every 28 days, 12 months<br>* Other names: Orencia;Drug: Prednisone<br>* Tablets, oral, 30 mg, daily for 28 days then taper off, 12 months<br>|
| Placebo Comparator: Placebo + Prednisone<br>Double Blind Period | Drug: Placebo<br>* Injectable, intravenous, 0 mg, every 28 days, 12 months<br>Drug: Prednisone<br>* Tablets, oral, 30 mg, daily for 28 days then taper off, 12 months<br>|
| Experimental: Abatacept<br>Open Label | Drug: Abatacept<br>* Injectable, intravenous, 10 mg/kg, every 28 days<br>* Other names: Orencia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double Blind Period (DB); Number of Participants Experiencing a New SLE Flare | SLE flares scored using BILAG:A:presence of =>1 serious;B:more moderate;C:mild symptomatic;D:prior activity,no current symptoms;E:organ that has never been involved. Calculated based on change during previous 4 weeks (1=improving,2=staying same,3=worsening,4=new).New SLE flare:first BILAG 'A' or 'B' event adjudicated to be flare following resolution of entry flare and start of prednisone/prednisone-equivalent taper.Inception treatment failure included (entry flare did not subside by Day 57/participant discontinued double-blind period before Day 29). | From start of corticosteroid taper to Day 365 | 
| Open Label Period (OL); Number of Participants Who Died, Experienced Adverse Events (AEs), Serious AEs, Drug Related AEs or SAEs and Discontinued Due to AEs | AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Participants who discontinued the study due to an AE were recorded. Drug-related AEs or SAEs: events with a relationship to the study therapy of certain; probable; possible; or missing. | From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period | 
| OL; Number of Participants With Significant AEs of Special Interest | An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition (even if not caused by the study drug). For this study, it was decided that AEs of particular importance were associated with the use of immunomodulatory agents. Number of participants with infections, malignant Neoplasms, pre-specified autoimmune disorders, acute-infusional AEs and peri-infusional AEs were recorded. | From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period | 
| OL; Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Erythrocytes and Platelet Count | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Hemoglobin: >3 g/dL decrease from pre-treatment (pre-Rx) value; hematocrit: <0.75* pre-Rx value; erythrocyte count: <0.75* pre-Rx value; platelet count: <0.67* lower limit of normal (LLN) or >1.5* upper limit of normal (ULN) (or, if pre-Rx value <LLN, then <0.5* pre-Rx value or <100000/mm^3). | From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period | 
| OL; Number of Participants With MAs in Hematology: Leukocytes, Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | MMAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Leukocytes: <0.75* LLN or >1.25* ULN (or, if pre-Rx value <LLN, then <0.8* pre-Rx or >ULN. If pre-Rx value >ULN, then >1.2* pre-Rx or <LLN; Neutrophils+bands (absolute): <1.00* 10^3 cells/microliter (c/uL); Lymphocytes (absolute): <0.75* 10^3 c/uL or >7.50* 10^3 c/uL; Monocytes (absolute): >2000/mm^3; Basophils (absolute): >0.40* 10^3 c/uL; Eosinophils (absolute): >0.75* 10^3 c/uL. | From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period | 
| OL; Number of Participants With MAs in Serum Chemistry: Alkaline Phosphatase (ALP), Aspartate-aminotransferase (AST), Alanine-aminotransferase (ALT), Gamma-glutamyl Transferase (GGT), Bilirubin(Total), Blood Urea Nitrogen (BUN), Creatinine | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. ALP, GGT: >2* ULN (if pre-Rx >ULN, then >3* pre-Rx); AST, ALT: >3* ULN (if pre-Rx >ULN, then >4* pre-Rx). Bilirubin (total): >2* ULN (if pre-Rx >ULN, then >4* pre-Rx), BUN:>2* pre-Rx; Creatinine:>1.5* pre-Rx. | From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period | 
| OL; Number of Participants With MAs in Serum Chemistry: Sodium (Serum), Potassium (Serum), Chloride (Serum), Calcium (Total), Protein (Total) | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria, Sodium (serum): <0.95x LLN or >1.05x ULN (if pre-Rx<LLN, then <0.95x pre-Rx or >ULN. If pre-Rx >ULN, then >1.05x pre-Rx or <LLN); Potassium (serum), Chloride (serum), protein (total): <0.9x LLN or >1.1xULN (if pre-Rx <LLN, then <0.9xpre-Rx or >ULN. If pre-Rx >ULN, then >1.1xpre-Rx or <LLN; Calcium (total): <0.8xLLN or >1.2xULN (if pre-Rx <LLN, then <0.75x pre-Rx or >ULN. If pre-Rx >ULN, then >1.25x pre-Rx or <LLN. | From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period | 
| OL; Number of Participants With MAs in Serum Chemistry: Glucose (Serum), Glucose (Fasting Serum), Albumin, Cholesterol (Total), Triglycerides, Fasting Triglycerides | MAs are laboratory measurements marked as abnormal, as per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria, Glucose: <65 mg/dL or >220 mg/dL; Glucose (fasting serum): <0.8* LLN or >1.5 ULN (if pre-Rx <LLN, then <0.8* pre-Rx or >ULN. If pre-Rx >ULN, then >2.0* pre-Rx or <LLN; Albumin: <0.9* LLN (if pre-Rx <LLN, then <0.75 * pre-Rx); cholesterol (total): >2* pre-Rx; triglycerides: >=2.5* ULN, or if pre Rx>ULN then use >2.5* pre Rx; fasting triglycerides: >=2.0* ULN, or if pre Rx>ULN then use >2.0* pre Rx. | From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period | 
| OL; Number of Participants With MAs in Urinalysis | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following definitions specify the criteria for MAs in urinalysis, Protein, glucose, blood, Leukocyte esterase, red blood cells (RBC), white blood cells (WBC): >=2+ (or, if value >=4, or if pre-Rx value = 0 or 0.5, then >= 2* or if pre-Rx value =1, then >=3, or if pre-Rx = 2 or 3, then >=4); protein (24 hour urine): >1000 mg/24 hrs and >=2* pre-Rx; Glomerular filtration rate (GFR): <=60 mL/min/1.73m^2 or > 15% change from baseline; Protein/creatinine ratio: > 100 mg/mmol. | From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DB; Number of Participants With a New SLE Flare During the Initial 6 Months | SLE flares scored using BILAG:A:presence of =>1 serious;B:more moderate;C:mild symptomatic;D:prior activity,no current symptoms;E:organ that has never been involved.Calculated based on change during previous 4 weeks (1=improving,2=staying same,3=worsening,4=new).New SLE flare:first BILAG 'A' or 'B' event adjudicated to be flare following resolution of entry flare and/or start of prednisone/prednisone-equivalent taper.Inception treatment failure included (entry flare did not subside by Day 57/participant discontinued double-blind period before Day 29). | From start of corticosteroid taper to 6 months. | 
| DB; Total Number of New SLE Flares Each Participant Experienced | SLE flares scored using BILAG:A:presence of =>1 serious;B:more moderate;C:mild symptomatic;D:prior activity,no current symptoms;E:organ that has never been involved.Calculated based on change during previous 4 weeks (1=improving,2=staying same,3=worsening,4=new).New SLE flare:BILAG 'A' or 'B' event adjudicated to be flare following resolution of entry flare and/or start of prednisone/prednisone-equivalent taper.Inception treatment failure included (entry flare did not subside by Day 57/participant discontinued double-blind period before Day 29). | From start of corticosteroid taper to Day 365 | 
| DB; Median Number of Days to the First Occurrence of a New SLE Flare | Elapsed days between start of corticosteroid taper & first day of flare.Scored using BILAG:A:presence of =>1 serious;B:more moderate;C:mild symptomatic;D:prior activity,no current symptoms;E:organ that has never been involved.Calculated based on change during previous 4 weeks (1=improving,2=staying same,3=worsening,4=new).New SLE flare:first BILAG 'A' or 'B' event adjudicated to be flare following resolution of entry flare and/or start of corticosteroid taper.Inception treatment failure included (entry flare did not subside by Day 57/participant discontinued double-blind period before Day 29). | From start of corticosteroid taper to confirmation of disease flare or the end of double-blind period | 
| DB; Number of Participants With a Change in the SLICC/ACR Damage Index at 1 Year Compared to Baseline | SLICC/ACR score or damage index is a measure of cumulative damage due to Systemic Lupus Erythematosus (SLE). Damage is defined as non-reversible change (not related to active inflammation) occurring since onset of lupus, ascertained by clinical assessment and present for at least 6 months. A score of 0=no damage, early damage is defined as ≥1. The total maximum score is 48, and increasing score indicates increasing disease severity. | From start of study drug treatment to Day 365 | 
| DB; Number of Participants Who Died, Experienced AEs, Other SAEs or Discontinuations Due to AEs, Drug Related AEs | AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose. Drug-related AEs: events with a certain; probable; possible; or missing relationship to the study therapy. Participants who discontinued the study due to an AE were recorded. | Events recorded at each participant encounter, from start of study drug therapy up to Day 337, including up to 56 days after the last dose or up to the first dose of open-label, whichever occurred earlier | 
| DB; Number of Participants With Significant AEs of Special Interest | An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition (even if not caused by the study drug). For this study, AEs of special interest were associated with the use of immunomodulatory agents. Number of participants with infections, malignant neoplasms, pre-specified autoimmune disorders, acute infusional AEs and peri-infusional AEs were recorded. | Events recorded at each participant encounter, from start of study drug therapy up to Day 337, including up to 56 days after the last dose or up to the first dose of open-label, whichever occurred earlier | 
| DB; Number of Participants With MAs in Hematology: Hemoglobin, Hematocrit, Erythrocytes and Platelet Count | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Hemoglobin: >3 g/dL decrease from pre-treatment (pre-Rx) value; hematocrit: <0.75* pre-Rx value; erythrocyte count: <0.75* pre-Rx value; platelet count: <0.67* LLN or >1.5* ULN (or, if pre-Rx value <LLN, then <0.5* pre-Rx value or <100000/mm^3). | Events recorded at each participant encounter, from start of study drug therapy up to Day 337, including up to 56 days after the last dose or up to the first dose of open-label, whichever occurred earlier | 
| DB; Number of Participants With MAs in Hematology: Leukocytes, Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Leukocytes: <0.75* LLN or >1.25* ULN (or, if pre-Rx value <LLN, then <0.8* pre-Rx or >ULN. If pre-Rx value >ULN, then >1.2* pre-Rx or <LLN; Neutrophils+bands (absolute): <1.00* 10^3 cells/microliter (c/uL); Lymphocytes (absolute): <0.75* 10^3 c/uL or >7.50* 10^3 c/uL; Monocytes (absolute): >2000/mm^3; Basophils (absolute): >0.40* 10^3 c/uL; Eosinophils (absolute): >0.75* 10^3 c/uL. | Events recorded at each participant encounter, from start of study drug therapy up to Day 337, including up to 56 days after the last dose or up to the first dose of open-label, whichever occurred earlier | 
| DB: Number of Participants With MAs in Serum Chemistry: ALP, AST, ALT, GGT, Bilirubin (Total), BUN and Creatinine | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. ALP, GGT: >2* ULN (if pre-Rx >ULN, then >3* pre-Rx); AST, ALT: >3* ULN (if pre-Rx >ULN, then >4* pre-Rx). Bilirubin (total): >2* ULN (if pre-Rx >ULN, then >4* pre-Rx), BUN:>2* pre-Rx; Creatinine:>1.5* pre-Rx. | Events recorded at each participant encounter, from start of study drug therapy up to Day 337, including up to 56 days after the last dose or up to the first dose of open-label, whichever occurred earlier | 
| DB; Number of Participants With MAs in Serum Chemistry: Sodium (Serum), Potassium (Serum), Chloride (Serum), Calcium (Total),Protein (Total) | MAs are laboratory measurements marked as abnormal as per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria, Sodium (serum): <0.95* LLN or >1.05* ULN (if pre-Rx <LLN, then <0.95* pre-Rx or >ULN. If pre-Rx >ULN, then >1.05* pre-Rx or <LLN); Potassium (serum), Chloride (serum), protein (total): <0.9* LLN or >1.1* ULN (if pre-Rx <LLN, then <0.9* pre-Rx or >ULN. If pre-Rx >ULN, then >1.1* pre-Rx or <LLN; Calcium (total): <0.8* LLN or >1.2* ULN (if pre-Rx <LLN, then <0.75* pre-Rx or >ULN. If pre-Rx >ULN, then >1.25* pre-Rx or <LLN. | Events recorded at each participant encounter, from start of study drug therapy up to Day 337, including up to 56 days after the last dose or up to the first dose of open-label, whichever occurred earlier | 
| DB; Number of Participants With MAs in Serum Chemistry: Glucose (Serum), Glucose (Fasting Serum), Albumin, Cholesterol (Total), Triglycerides, Fasting Triglycerides | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria, Glucose: <65 mg/dl or >220 mg/dl; Glucose (fasting serum): <0.8* LLN or >1.5 ULN (if pre-Rx <LLN, then <0.8* pre-Rx or >ULN. If pre-Rx >ULN, then >2.0* pre-Rx or <LLN; Albumin: <0.9* LLN (if pre-Rx <LLN, then <0.75 * pre-Rx); cholesterol (total): >2* pre-Rx; triglycerides: >=2.5* ULN, or if pre Rx>ULN then use >2.5* pre Rx; fasting triglycerides: >=2.0* ULN, or if pre Rx>ULN then use >2.0* pre Rx. | Events recorded at each participant encounter, from start of study drug therapy up to Day 337, including up to 56 days after the last dose or up to the first dose of open-label, whichever occurred earlier | 
| DB; Number of Participants With MAs in Urinalysis | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following definitions specify the criteria for MAs in urinalysis, Protein, glucose, blood, Leukocyte esterase, RBC, WBC: >=2+ (or, if value >=4, or if pre-Rx value = 0 or 0.5, then >= 2* pre-Rx, or if pre-Rx value =1, then >=3, or if pre-Rx = 2 or 3, then >=4); protein (24 hour urine): >1000 mg/24 hrs and >=2* pre-Rx; GFR: <=60 mL/min/1.73m^2 or > 15% change from baseline; Protein/creatinine ratio: > 100 mg/mmol. | Events recorded at each participant encounter, from start of study drug therapy up to Day 337, including up to 56 days after the last dose or up to the first dose of open-label, whichever occurred earlier | 
| DB; Number of Participants With Clinically Significant Abnormal Vital Signs and/or Physical Examination Findings | Vital signs assessments and physical examination were conducted throughout the study. Vital signs assessments included body temperature, respiratory rate, blood pressure (systolic and diastolic) and heart rate. The investigator used his/her clinical judgment to decide whether or not abnormalities in vital signs or physical examination were clinically meaningful. | Events recorded at each participant encounter, from start of study drug therapy up to Day 337, including up to 56 days after the last dose or up to the first dose of open-label, whichever occurred earlier | 
| DB; Number of Participants With Antibodies Specific for CTLA4-T and Abatacept, Following Abatacept Treatment | Electrochemiluminescence (ECL) immunoassay based on Meso Scale Discovery (MSD) technology was used to detect antibodies specific for CTLA4-T and for abatacept. | From Day 1 to Day 365 | 
| OL; Number of Participants With a New SLE Flare | SLE flares scored using BILAG:A:presence of =>1 serious lupus features;B:more moderate features;C:mild symptomatic features;D:prior activity with no current symptoms due to active lupus;E:an organ that has never been involved.BILAG scores based on degrees of change in clinical features (1=improving,2=staying the same,3=worsening,4=new).New SLE flare means new BILAG A/B features in any organ system.Based on the recommendation of the Data Monitoring Committee, open-label period terminated, as failed to meet primary outcome measure for double-blind period/increase in SAEs in abatacept group. | From start of study drug therapy in open-label period (Day 365), Day 393, 421, 449 and every 28 days thereafter till Day 729. | 
| OL; Number of Participants With a Change in the SLICC/ACR Damage Index at Year 2 Compared to Baseline | SLICC/ACR damage index:measure of cumulative damage due to SLE.Damage=non-reversible change occurring since onset of lupus,ascertained by clinical assessment & present for =>6 months.Scores of SLICC/ACR index:1:single episode;2:repeated episodes at least 6 months apart.Change in score from baseline to 1 year presented as:no change,increase 1 (an increase in score of 1),increase >1 (an increase in score of >1).Based on recommendation of Data Monitoring Committee, open-label period terminated, as failed to meet primary outcome measure for double-blind period/increase in SAEs in abatacept group. | From start of study drug therapy in open-label period (Day 365) and on Day 729. | 
| OL; Total Number of BILAG A Flares Each Participant Experienced | Total number of BILAG A flares in any organ system after steroid tapering = new BILAG A features in any organ system. Scores defined as follows: None: participants with no BILAG A flare; 1: participants with 1 BILAG A flare or participants who discontinued without a new BILAG A flare were imputed as having one event. 2: participants with 2 BILAG A flares; 3 or >3: participants with 3 or more BILAG A flares.Based on recommendation of Data Monitoring Committee, open-label period terminated, as failed to meet primary outcome measure for double-blind period/increase in SAEs in abatacept group. | From start of study drug therapy in open-label period (Day 365), Day 393, 421, 449 and every 28 days thereafter till Day 729. | 
| OL; Area Under the Curve (AUC) for Prednisone or Prednisone Equivalent | Total exposure to glucocorticosteroid was measured by the total prednisone or prednisone equivalent AUC. Based on the recommendation of the Data Monitoring Committee, the open-label, long-term extension period was terminated by the sponsor, for failure to meet the primary outcome measure for the double-blind period and because of an increase in SAEs in the abatacept treatment group. As such, these data were not analyzed. | From start of study drug therapy in open-label period (Day 365), Day 393, 421, 449 and every 28 days thereafter till Day 729. | 
| OL; Number of Participants With Antibodies Specific for CTLA4-T and Abatacept, Following Abatacept Treatment | MSD technology was used to detect antibodies specific for CTLA4-T and for abatacept. | After the first dose of open-label period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SLE