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

Systemic Lupus Erythematosus Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00119678
• Other study ID #: IM101-042
• Status: Completed
• Phase: Phase 2
• First received: June 30, 2005
• Last updated: September 11, 2014
• Start date: September 2005
• Est. completion date: November 2008

Study information

• Verified date: September 2014
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 183
• Est. completion date: November 2008
• Est. primary completion date: November 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Systemic Lupus Erythematosus

Intervention

Drug:
• Abatacept
Injectable, intravenous, 10 mg/kg, abatacept every 28 days, 12 months
• Placebo
Injectable, intravenous, 0 mg, every 28 days, 12 months
• Prednisone
Tablets, oral, 30 mg, daily for 28 days then taper off, 12 months
• Abatacept
Injectable, intravenous, 10 mg/kg, every 28 days

Locations

Country	Name	City	State
Australia	Local Institution	Cairns	Queensland
Australia	Local Institution	Clayton	Victoria
Australia	Local Institution	Heidelberg	Victoria
Australia	Local Institution	Malvern	Victoria
Australia	Local Institution	Maroochydore	Queensland
Austria	Local Institution	Graz
Belgium	Local Institution	Bruxelles
Belgium	Local Institution	Leuven
Brazil	Local Institution	Campinas	Sao Paulo
Brazil	Local Institution	Curitiba	Parana
Brazil	Local Institution	Goiania	Goias
Brazil	Local Institution	Rio De Janeiro - Rj	Rio De Janeiro
Brazil	Local Institution	Sao Paulo
Brazil	Local Institution	Sao Paulo
Brazil	Local Institution	Sao Paulo
Brazil	Local Institution	São Paulo	Sao Paulo
Canada	Local Institution	Vancouver	British Columbia
Canada	Local Institution	Winnipeg	Manitoba
France	Local Institution	Bordeaux Cedex
France	Local Institution	Montpellier Cedex 5
France	Local Institution	Paris Cedex 14
Germany	Local Institution	Berlin
Germany	Local Institution	Duesseldorf
Germany	Local Institution	Freiburg
Italy	Local Institution	Ferrara
Korea, Republic of	Local Institution	Seoul	Sungdong-Gu
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Mexico	Local Institution	Aguascalientes
Mexico	Local Institution	Mexico City	Distrito Federal
Mexico	Local Institution	Morelia	Michioacan
Puerto Rico	Local Institution	Ponce
South Africa	Local Institution	Berea	Kwa Zulu Natal
South Africa	Local Institution	Panorama	Western Cape
Taiwan	Local Institution	Kaohsiung
Taiwan	Local Institution	Taichung
Taiwan	Local Institution	Taipei
Taiwan	Local Institution	Taipei
United Kingdom	Local Institution	London	Greater London
United States	Suny Downstate Medical Center	Brooklyn	New York
United States	The University Of Chicago	Chicago	Illinois
United States	Denver Arthritis Clinic	Denver	Colorado
United States	Cria Research	Ft. Lauderdale	Florida
United States	Kelly, Timothy	Las Vegas	Nevada
United States	Office Of Geoffrey S. Dolan, Md	Long Beach	California
United States	8737 Beverly Blvd.	Los Angeles	California
United States	Kentuckiana Center For Better Bone And Joint Health	Louisville	Kentucky
United States	Columbia University Medical Center	New York	New York
United States	Ok Medical Research Foundations	Oklahoma City	Oklahoma
United States	Texas Research Center	Sugarland	Texas
United States	University Of Arizona Arthritis Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  Canada,  France,  Germany,  Italy,  Korea, Republic of,  Mexico,  Puerto Rico,  South Africa,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	Yes
Primary	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	Yes
Primary	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	From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period	Yes
Primary	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	From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period	Yes
Primary	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	Yes
Primary	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	From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period	Yes
Primary	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	From start of study drug therapy in open-label period (Day 365) up to 56 days after the last dose of open-label period	Yes
Primary	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	Yes
Secondary	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.	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	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	Yes
Secondary	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	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	Yes
Secondary	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	Yes
Secondary	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	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	Yes
Secondary	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	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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	Yes
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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	Yes

External Links

•   BMS Clinical Trials Disclosure
•   For FDA Safety Alerts and Recalls refer to the following link www.fda.gov/MEDWATCH/safety.htm