Efficacy and Safety Study of Abatacept Subcutaneous Plus Methotrexate in Inducing Remission in Adults With Very Early Rheumatoid Arthritis

Rheumatoid Arthritis Clinical Trial

Official title:

A Phase 3b, Randomized, Active Controlled Trial to Evaluate the Efficacy and Safety of Abatacept SC in Combination With Methotrexate in Inducing Clinical Remission Compared to Methotrexate Monotherapy in Adults With Very Early RA

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01142726
• Other study ID #: IM101-226
• Secondary ID: 2010-018674-20
• Status: Completed
• Phase: Phase 3
• First received: June 3, 2010
• Last updated: December 9, 2015
• Start date: December 2010
• Est. completion date: October 2014

Study information

• Verified date: December 2015
• Source: Bristol-Myers Squibb
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustralia: National Health and Medical Research CouncilBelgium: The Federal Public Service (FPS) Health, Food Chain Safety and EnvironmentCanada: Health CanadaMexico: Federal Commission for Sanitary Risks ProtectionGermany: Federal Institute for Drugs and Medical DevicesGermany: Ministry of HealthKorea: Food and Drug AdministrationFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)South Africa: Medicines Control CouncilDenmark: Danish Dataprotection AgencyDenmark: Danish Medicines AgencyDenmark: The Danish National Committee on Biomedical Research EthicsFinland: Finnish Medicines AgencyFinland: Data Protection BoardFinland: National Advisory Board on Health Care EthicsSweden: Medical Products AgencySweden: The National Board of Health and WelfareSweden: The Swedish Data Inspection BoardSweden: Central Ethics BoardItaly: Ministry of HealthItaly: National Bioethics CommitteeItaly: National Institute of HealthItaly: National Monitoring Centre for Clinical Trials - Ministry of HealthItaly: The Italian Medicines AgencyPoland: National Institute of MedicinesPoland: Ministry of HealthPoland: Ministry of Science and Higher EducationPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
• Study type: Interventional

Clinical Trial Summary

The primary purpose of the protocol is to demonstrate the ability of abatacept plus methotrexate to induce remission in patients with very early rheumatoid arthritis after 12 months of treatment and to maintain remission following 6 months of drug withdrawal.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 511
• Est. completion date: October 2014
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Presence of active clinical synovitis in at least 2 joints, 1 of which must have been a small joint, for a minimum of 8 weeks prior to screening

• Onset of persistent symptoms = 2 years prior to screening

• Positive test result for anticyclic citrullinated peptides 2

• Methotrexate naive or with minimum exposure to methotrexate, defined as no more than 10 mg/week for =4 weeks and no methotrexate dose for 1 month prior to screening visit

• Biologic naive, including no treatment with an investigational biologic prior to screening

• Disease Activity Score 28 based on C-reactive protein score =3.2 at screening

• Withdrawal from any treatment with chloroquine, hydroxychloroquine, and/or sulfasalazine (wash-out) for a minimum of 28 days prior to randomization

• If receiving oral corticosteroids, on a stable low dose (= 10 mg/day prednisone equivalent) for at least 4 weeks

• Able to undergo magnetic resonance imaging

Key Exclusion Criteria:

• Meeting diagnostic criteria for other rheumatic disease (eg, lupus erythematosus)

• Treatment with an intravenous, intramuscular, or intraarticular corticosteroid within 4 weeks prior to randomization

• Scheduled for or anticipating joint replacement surgery

• Presence of concomitant illness likely to require systemic glucocorticosteroid therapy during the study, in the opinion of the investigator

• History of malignancy in the last 5 years

• Any serious bacterial infection within the last 3 months not treated or resolved with antibiotics, or any chronic or recurrent bacterial infection

• At risk for tuberculosis

• Evidence of active or latent bacterial or viral infection at the time of potential enrollment, including human immunodeficiency or herpes zoster virus or cytomegalovirus that resolved less than 2 months prior to enrollment

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Abatacept
Injection, subcutaneous, 125 mg by syringe, once weekly, 12 months
• Methotrexate
Tablets, oral, 2.5 mg, once weekly, 12 months
• Abatacept placebo
Injection, subcutaneous, to match 125 mg by syringe, once weekly, 12 months
• Methotrexate placebo
Tablets, oral, to match 2.5-mg tablet, once weekly, 12 months

Locations

Country	Name	City	State
Australia	Local Institution	Cairns	Queensland
Australia	Local Institution	Heidelberg	Victoria
Australia	Local Institution	Malvern	Victoria
Australia	Local Institution	Maroochydore	Queensland
Australia	Local Institution	Victoria Park	Western Australia
Australia	Local Institution	Woodville	South Australia
Belgium	Local Institution	Bruxelles
Belgium	Local Institution	Kortrijk
Belgium	Local Institution	Merksem
Canada	Local Institution	Calgary	Alberta
Canada	Local Institution	Laval	Quebec
Denmark	Local Institution	Hjorring
Finland	Local Institution	Helsinki
Finland	Local Institution	Tampere
France	Local Institution	Chambray Les Tours
France	Local Institution	Montpellier
France	Local Institution	Paris Cedex 14
France	Local Institution	Poitiers
Germany	Local Institution	Berlin
Germany	Local Institution	Berlin
Germany	Local Institution	Hildesheim
Germany	Local Institution	Muenchen
Germany	Local Institution	Muenchen
Germany	Local Institution	Muenchen
Italy	Local Institution	Ancona
Italy	Local Institution	Siena
Korea, Republic of	Local Institution	Daegu
Korea, Republic of	Local Institution	Daejeon
Korea, Republic of	Local Institution	Seoul
Korea, Republic of	Local Institution	Seoul
Mexico	Local Institution	Chihuahua
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Merida	Yucatan
Mexico	Local Institution	Metepec	Estado De Mexico
Mexico	Local Institution	Monterrey	Nuevo Leon
Mexico	Local Institution	Queretaro
Mexico	Local Institution	San Luis Potosi
Poland	Local Institution	Lublin
Poland	Local Institution	Poznan
Poland	Local Institution	Torun
Poland	Local Institution	Warszawa
Poland	Local Institution	Warszawa
Poland	Local Institution	Wroc#aw
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Tver
South Africa	Local Institution	Durban	Kwa Zulu Natal
South Africa	Local Institution	Kempton Park	Gauteng
South Africa	Local Institution	Panorama	Western Cape
South Africa	Local Institution	Pretoria	Gauteng
South Africa	Local Institution	Pretoria	Gauteng
South Africa	Local Institution	Pretoria	Gauteng
Sweden	Local Institution	Goteborg
Sweden	Local Institution	Linkoping
Sweden	Local Institution	Malmo
Sweden	Local Institution	Stockholm
Sweden	Local Institution	Uppsala
United States	Johns Hopkins University Division Of Rheumatology	Baltimore	Maryland
United States	Metrohealth Medical Center	Cleveland	Ohio
United States	Coeur D'Alene Arthrit Clin	Coeur D Alene	Idaho
United States	Alan J. Kivitz, Md, Cpi	Duncansville	Pennsylvania
United States	Kurt Oelke, Md	Glendale	Wisconsin
United States	Piedmont Rheumatology, Pa	Hickory	North Carolina
United States	St. Joseph'S Mercy Clinic	Hot Springs	Arkansas
United States	Rheumatology Associates Of North Alabama, P.C.	Huntsville	Alabama
United States	Arthritis Associates Of Mississippi	Jackson	Mississippi
United States	Physician Research Collaboration, Llc	Lincoln	Nebraska
United States	Isam A. Diab, Md	Middleburg	Ohio
United States	Mitchell C. Feinman, Md	Orangeburg	South Carolina
United States	Sarasota Arthritis Research Center	Sarasota	Florida
United States	Carolina Arthritis Associates	Wilmington	North Carolina
United States	Clinical Pharmacology Study Group	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Denmark,  Finland,  France,  Germany,  Italy,  Korea, Republic of,  Mexico,  Poland,  Russian Federation,  South Africa,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Who Achieved Remission by Disease Activity Score 28 Based on C-reactive Protein (DAS28-CRP) Criteria at Month 12 and at Both Months 12 and 18	DAS28-CRP remission defined as <2.6; TP=treatment phase; WP=withdrawal phase. The DAS 28-CRP is a measure of disease activity in rheumatoid arthritis (RA) that assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). These measures are then fed into a complex mathematical formula to produce the overall DAS (a score greater than 5.1 implies active disease; less than 3.2, well controlled disease; and less than 2.6, remission.)	Randomization to Months 12 and 18	No
Secondary	Percentage of Participants Who Received Monotherapy and Achieved Remission by Disease Activity Score 28 Based on C-reactive Protein (DAS28-CRP) Criteria at Month 12 and at Both Months 12 and 18	TP=treatment period; WP=withdrawal period. Remission defined as DAS28-CRP<2.6. The DAS 28-CRP is a measure of disease activity in rheumatoid arthritis (RA) that assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). DAS-CRP scores range from 0 to 10, with higher values indicating greater disease activity. Individual measures are fed into a complex mathematical formula to produce the overall DAS (a score greater than 5.1 implies active disease; less than 3.2, well controlled disease; and less than 2.6, remission.)	Randomization to Months 12 and 18	No
Secondary	Percentage of Participants With Remission by Disease Activity Score 28 Based on C-reactive Protein (DAS28-CRP) Criteria Over Time - Intent to Treat Population	TP=treatment period; WP=withdrawal period. Remission defined as DAS28-CRP<2.6. The DAS 28-CRP is a measure of disease activity in rheumatoid arthritis (RA) and assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). DAS-CRP scores range from 0 to 10, with higher values indicating greater disease activity. Individual measures are fed into a complex mathematical formula to produce the overall DAS (a score greater than 5.1 implies active disease; less than 3.2, well controlled disease; and less than 2.6, remission.)	Randomization to Month 24	No
Secondary	Adjusted Mean Change From Baseline in Disease Activity Score 28 Based on C-reactive Protein (DAS28-CRP) at Months 6, 12, and 18	TP=treatment period; WP=withdrawal period. The DAS 28-CRP is a measure of disease activity in rheumatoid arthritis (RA) that assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). DAS-CRP scores range from 0 to 10, with higher values indicating greater disease activity. Individual measures are fed into a complex mathematical formula to produce the overall DAS (a score greater than 5.1 implies active disease; less than 3.2, well controlled disease; and less than 2.6, remission.)	Baseline to Month 18	No
Secondary	Percentage of Participants Who Achieved Remission by Criteria of the Simplified Disease Activity Index (SDAI) at Months 12 and 18	TP=treatment period; WP=withdrawal period. SDAI-defined remission= =3.3. The SDAI is the simple linear sum of 5 outcome parameters: tender joint count (TJC) and swollen joint count (SJC) (based on a 28-joint assessment); patient's and physician's global assessments of disease activity (assessed on 0-10 cm visual analog scale, on which higher scores=greater affection due to disease activity); and C-reactive protein level (mg/dL). SDAI total score=0-86. SDAI <=3.3 indicates disease remission, >3.4 to 11=low disease activity, >11 to 26=moderate disease activity, and >26=high disease activity. TJC is assessed and recorded at each visit, with no swelling=0, swelling=1. SJC is assessed through identification of joints that are painful under pressure or to passive motion. TJC is recorded on the joint assessment form at each visit, with no tenderness =0, tenderness = 1. Higher score indicates greater affection due to disease activity.	Randomization to Month 18	No
Secondary	Adjusted Mean Change From Baseline in Scores on Simplified Disease Activity Index (SDAI) Over Time	TP=treatment period; WP=withdrawal period. The SDAI is the simple linear sum of 5 outcome parameters: swollen joint count (SJC) and tender joint count (TJC) (based on a 28-joint assessment); patient's and physician's global assessments of disease activity (assessed on 0-10 cm visual analog scale, on which higher scores=greater affection due to disease activity); and C-reactive protein level (mg/dL). SDAI total score=0-86. SJC is assessed and recorded at each visit, with no swelling=0, swelling=1 (higher score indicates greater swelling). TJC is assessed at each visit through identification of joints that are painful under pressure or to passive motion, with no tenderness=0, tenderness=1 (higher score indicates greater affection due to disease activity)..	Randomization to Month 18	No
Secondary	Percentage of Participants Achieving a Health Assessment Questionnaire (HAQ) Response Over Time	HAQ response defined as a reduction of at least 0.3 units from baseline in score on the Health Assessment Questionnaire Disability Index (HAQ-DI), which assesses patients' functional ability by rating their abilities over the previous week. The HAQ-DI includes at least 2 questions from each of 8 categories: dressing and grooming, hygiene, arising, reach, eating, grip, walking, and common daily activities. Patients rate difficulty performing specific tasks: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The sum of the categories score (the highest scored item in the category) is divided by the number of categories answered, yielding a score from 0-3. When aids, devices, or help is indicated by the patient, the score for the category item is raised from a 0 or a 1 to a 2, but if the patient's highest score for a subcategory is a 3, it stays a 3.	Randomization to Month 24	No
Secondary	Adjusted Mean Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Over Time	The Health Assessment Questionnaire Disability Index (HAQ-DI) assesses patients' functional ability by rating their abilities over the previous week. The HAQ-DI includes at least 2 questions from each of 8 categories: dressing and grooming, hygiene, arising, reach, eating, grip, walking, and common daily activities. Patients rate difficulty performing specific tasks: 0=without difficulty, 1=with some difficulty, 2=with much difficulty, and 3=unable to do. The sum of the categories score (the highest scored item in the category) is divided by the number of categories answered, yielding a score from 0-3. When aids, devices, or help is indicated by the patient, the score for the category item is raised from a 0 or a 1 to a 2, but if the patient's highest score for a subcategory is a 3, it stays a 3.	Randomization to Month 18	No
Secondary	Adjusted Mean Change From Baseline at Months 6, 12, and 18 in Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores of Short Form-36 (SF-36)	TP=treatment period; WP=withdrawal period. The SF-36 is a 36-item self-administered questionnaire developed to assess health-related quality of life (QOL) and comprises 8 domains, including 4 physical (physical health, bodily pain, physical functioning and physical role limitations) and 4 mental (mental health, vitality, social functioning, and emotional role limitation) subscales. Responses are used to derive physical and mental component summary scores, ranging from 0 to 100, with higher scores indicating better QOL (0=Poorest Health; 100=Best Health). Mean change from baseline=postbaseline value-baseline value; a higher value signifies improvement.	Randomization to Months 6, 12, and 18	No
Secondary	Adjusted Mean Change From Baseline Over Time in Findings on Magnetic Resonance Imaging (MRI)	TP=treatment period; WP=withdrawal period. Change from Baseline=Postbaseline-baseline value. MRI was used to assess joint damage progression at Months 6, 12, and 18. If >20% of joints with a missing score for a parameter (erosion, osteitis, and synovitis), the MRI score of each parameter was considered missing. If =20% of joints had a missing score for a parameter, the MRI score for that parameter from the missing joints was carried forward from the previous MRI assessment, or carried backward from the next MRI assessment, if missing score occurred at baseline. MRI total score ranged from 0 (best outcome) to 4 (worst outcome). A gadolinium-enhanced MRI of the dominant hand-wrist was performed on all randomized patients at 5 points. The hand/wrist assessed to have more synovitis was selected initially and used for all subsequent evaluations. The MRI examination was standardized to ensure sufficient image quality for the evaluation of radiographic progression of rheumatoid arthritis.	Randomization to Month 18	No
Secondary	Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to SAEs, Related Adverse Events (AEs), and Discontinuations Due to AEs During the Treatment Period	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug.	Day 1 to up to 56 days following the last dosing day (Day 365); all deaths during study period, including those that occurred >56 days after last dose in Treatment Period	Yes
Secondary	Adverse Events (AEs) of Interest During the Treatment Period	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or unknown relationship to study drug. AEs of special interest are events potentially associated with the drug or disease under study.	Day 1 to 56 days following last dosing day (Day 365)	Yes
Secondary	Number of Participants With Results on Hematology and Clinical Laboratory Tests Meeting the Criteria for Marked Abnormality During Treatment Period	Lower limit of normal (LLN); Upper limit of normal (ULN); Pretreatment (preRX). Criteria for marked abnormality: Platelet count (*10^9 c/µL) <0.67*LLN or >1.5*ULN, or if preRX	Day 1 up to 56 days following the last dosing day in the Treatment Period (Day 365)	Yes
Secondary	Percentage of Participants With Remission by Disease Activity Score 28 Based on C-reactive Protein (DAS28-CRP) Criteria Over Time During Withdrawal Period- Treated Participants in Remission at Month 12	WP=withdrawal period. Remission defined as DAS28-CRP<2.6. The DAS 28-CRP is a measure of disease activity in rheumatoid arthritis (RA) and assesses the 28 joints RA commonly affects; the score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment of health (ranging from very good to very bad). DAS-CRP scores range from 0 to 10, with higher values indicating greater disease activity. Individual measures are fed into a complex mathematical formula to produce the overall DAS (a score greater than 5.1 implies active disease; less than 3.2, well controlled disease; and less than 2.6, remission.). Percentage= number of participants with remission divided by number of participants who were analyzed (all treated participants who were in remission at end of treatment period and entered the Withdrawal Period)	End of Treatment Period (Month 12) to End of Withdrawal Period (Month 24)	No
Secondary	Percentage of Participants Who Achieved Remission by Criteria of the Simplified Disease Activity Index (SDAI) Over Time in Treatment Period and Withdrawal Period	TP=treatment period; WP=withdrawal period. SDAI-defined remission= =3.3. The SDAI is the simple linear sum of 5 outcome parameters: tender joint count (TJC) and swollen joint count (SJC) (based on a 28-joint assessment); patient's and physician's global assessments of disease activity (assessed on 0-10 cm visual analog scale, on which higher scores=greater affection due to disease activity); and C-reactive protein level (mg/dL). SDAI total score=0-86. SDAI <=3.3 indicates disease remission, >3.4 to 11=low disease activity, >11 to 26=moderate disease activity, and >26=high disease activity. TJC is assessed and recorded at each visit, with no swelling=0, swelling=1. SJC is assessed through identification of joints that are painful under pressure or to passive motion. TJC is recorded on the joint assessment form at each visit, with no tenderness =0, tenderness = 1. Higher score indicates greater affection due to disease activity. Percent=number with remission/number evaluated (ITT)	Randomization to Month 24	No
Secondary	Number of Participants With Death as Outcome, Serious Adverse Events (SAEs) and Discontinuations Due to AEs During the Full Study (All Periods)	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Includes data up to last active dose date +56 days if the participant discontinued the Treatment Period or did not enter the Withdrawal Period, up to the day of discontinuation in the Withdrawal Period for participants discontinuing the Withdrawal Period without entering the Re-exposure Period (RP), up to Day 729 visit (Month 24) for participants who complete the Withdrawal Period, and up to 56 days post last active dose in Re-exposure Period for participants entering the Re-exposure Period.	Day 1 to 56 days post last dose in the study, up to Month 30	Yes
Secondary	Adverse Events (AEs) of Interest During the Withdrawal Period	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. AEs of special interest are events potentially associated with the drug or disease under study. Includes events with an onset date on or after 57 days post last dosing day (active abatacept or active MTX whichever is the later) in the Treatment Period and up to end of Withdrawal Period. Treatment groups represent treatment received during the Treatment Period.	Last dose in TP + 57 days, up to Month 24	Yes
Secondary	Adverse Events (AEs) of Interest During the Re-exposure Period	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. AEs of special interest are events potentially associated with the drug or disease under study. Includes data up to 56 days post the last dosing day (active abatacept or active MTX, whichever is the later) in the Re-exposure Period. Treatment groups represent Treatment received during Treatment Period.	First dose in Re-exposure period up to last dose of Re-exposure Period + 56 days	Yes
Secondary	Number of Participants With Results on Hematology and Clinical Laboratory Tests Meeting the Criteria for Marked Abnormality in Withdrawal Period	LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Criteria for marked abnormality on laboratory test results: Platelet count (*10^9 c/µL) <0.67*LLN or >1.5*ULN, or if preRX	Last dose in TP + 57 days, up to Month 24	Yes
Secondary	Number of Participants With Results on Hematology and Clinical Laboratory Tests Meeting the Criteria for Marked Abnormality in Re-exposure Period	LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Criteria for marked abnormality on laboratory test results: Platelet count (*10^9 c/µL) <0.67*LLN or >1.5*ULN, or if preRX	Start of re-exposure period to 56 days post last dose, up to Month 30	Yes

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