Clinical trial NCT00533897: Phase IIIB Subcutaneous Missed Dose Study
Official title: A Phase IIIb, Multi-Center, Randomized, Withdrawal Study to Evaluate the Immunogenicity and Safety of Subcutaneous Administered Abatacept in Adults With Active Rheumatoid Arthritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis (RA)
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2007-09-24
Enrollment: 270
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to determine whether subcutaneous abatacept administered to patients with rheumatoid arthritis is associated with increased immunogenicity or increased safety events upon withdrawal and reintroduction.


Eligibility criteria: Inclusion Criteria:

* Clinical diagnosis of Rheumatoid Arthritis
* Disease Activity Score (DAS)28-C-Reactive Protein (CRP) score ≥ 3.2 and ≤5.1
* On background methotrexate at least 3 months (≥10mg weekly)
* Must be able to self injection or allow a care giver to do it for them
* Discontinue all Biologics and Disease-Modifying Anti-rheumatic Drugs (DMARDs) except for methotrexate

Exclusion Criteria:

* Participants who had prior exposure to abatacept or CTLA-4 Ig
* Received treatment with rituximab.
* Participants who have received treatment with leflunomide within 1 year of screening
* Participants who have received treatment with immunoadsorption columns (such as Prosorba columns), mycophenolate mofetil (Cellcept®), cyclosporine A or other calcineurin inhibitors, or D-Penicillamine.

Primary outcomes:
measure: Double-blind Withdrawal (DBW) Period; Percentage of Participants With Positive Anti-Abatacept or Anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Antibody Responses by Enzyme-Linked Immunosorbent Assay (ELISA) at Day 169
timeFrame: Day 169
measure: Re-introduction (RI) Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA at Day 253, by DBW Period Groups
timeFrame: Day 253 (short term)
Secondary outcomes:
measure: RI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA at Day 253, by DBW Period Placebo Group
timeFrame: Day 253 (short term)
measure: Lead-in (LI) Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA Over Time
timeFrame: For on-treatment visits: Day 1-Day 85, includes ≤21 Days after last dose or up to 1st dose of DBW Period. For follow-up post visits for participants who discontinued drug in LI: Day 22 after last dose of drug to Day 85 after last dose of drug
measure: LI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by Electrochemiluminescence (ECL) Over Time
timeFrame: For on-treatment visits: Day 1-Day 85, includes ≤21 Days after last dose or up to 1st dose of DBW Period. For follow-up post visits for participants who discontinued drug in LI: Day 22 after last dose of drug to Day 85 after last dose of drug
measure: DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA Over Time
timeFrame: Days 86-169, includes ≤21 Days after last dose or up to 1st dose of RI Period
measure: DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA at Post Visits
timeFrame: Day 22 after last dose of drug to Day 85 after last dose of drug
measure: DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ECL Over Time
timeFrame: Days 86-169, includes ≤21 Days after last dose or up to 1st dose of RI Period
measure: DBW Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ECL At Post Visits
timeFrame: Day 22 after last dose of drug to Day 85 after last dose of drug
measure: RI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ELISA Over Time by DBW Treatment Group
timeFrame: For on-treatment visits: Days 170-253, includes ≤21 Days after last dose or up to 1st dose of LTE Period. For follow-up post visits for participants who discontinued drug in RI: Day 22 after last dose of drug to Day 85 after last dose of drug
measure: RI Period; Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses by ECL Over Time by DBW Treatment Group
timeFrame: For on-treatment visits: Days 170-253, includes ≤21 Days after last dose or up to 1st dose of LTE Period. For follow-up post visits for participants who discontinued drug in RI: Day 22 after last dose of drug to Day 85 after last dose of drug
measure: Short Term (ST); Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 ELISA Antibody Responses by DBW Treatment Groups
timeFrame: For on-TRT visits: Days 1-253 (ST). For follow-up post visits for participants who discontinued drug in the ST: Day 22 after last dose of ST drug to Day 85 after last dose of ST drug
measure: Short Term: Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 ECL Antibody Responses by DBW Treatment Groups
timeFrame: For on-TRT visits: Days 1-253 (ST). For follow-up post visits for participants who discontinued drug in the ST: Day 22 after last dose of ST drug to Day 85 after last dose of ST drug
measure: Short Term: Mean Change in Disease Activity Score (DAS) 28 (Using C-Reactive Protein [CRP]) From Baseline Over Time by DBW Treatment Groups
timeFrame: Days 1 (Baseline),15, 29, 57, 78, 85, 113, 141, 169, 197, 225, and 253 (short term)
measure: Short Term: Percentage of Participants Achieving Clinically Meaningful Improvement (CMI) in DAS 28 (CRP), Low Disease Activity (LDAS), or Clinical Remission Over Time by DBW Treatment Groups
timeFrame: Days 85, 169, and 253 (short term)
measure: Short Term; Mean Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Baseline Over Time by DBW Treatment Groups
timeFrame: Days 1 (Baseline),15, 29, 57, 78, 85, 113, 141, 169, 197, 225, and 253 (short term)
measure: Short Term; Percentage of Participants With HAQ-DI Response Over Time by DBW Treatment Groups
timeFrame: Days 1 (Baseline),15, 29, 57, 78, 85, 113, 141, 169, 197, 225, and 253 (short term)
measure: LI; Mean Change in DAS 28 (CRP) From Baseline Over Time
timeFrame: Days 1 (Baseline), 15, 29, 57, 78, 85
measure: LI; Percentage of Participants With Clinically Meaningful Improvement in DAS (CRP) Over Time
timeFrame: Days 15, 29, 57, 78, 85
measure: DBW Period; Mean Change in DAS 28 (CRP) From DBW Period Baseline (Day 85) Over Time
timeFrame: Days 85 (Period 2 Baseline), 113, 141, and 169
measure: DBW Period; Percentage of Participants With Rheumatoid Arthritis (RA) Flare Over Time
timeFrame: Days 85, 113, 141, and 169
measure: RI Period; Mean Change in DAS 28 (CRP) From RI Period Baseline (Day 169) Over Time
timeFrame: Days 169 (Period III Baseline), 197, 225, and 253
measure: LI; Number of Participants With Deaths, Serious Adverse Events (SAEs), SAEs Leading to Discontinuation, Adverse Events (AEs), Related AEs, or AEs Leading to Discontinuation
timeFrame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier
measure: LI Period; Number of Participants With AEs of Special Interest
timeFrame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier
measure: LI; Number of Participants With Hematology Values Meeting the Marked Abnormality (MA) Criteria
timeFrame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier
measure: LI; Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria
timeFrame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier
measure: LI; Number of Participants With Electrolyte Values Meeting the Marked Abnormality Criteria
timeFrame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier
measure: LI; Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria
timeFrame: From Day 1 through Day 85, up to 56 days post last dose in Lead-in Period or up to first dose in next period, whichever occurred earlier
measure: LI Period; Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Days 1, 15, 29, 57, 78, and 85
measure: LI Period; Mean Heart Rate (HR)
timeFrame: Days 1, 15, 29, 57, 78, and 85
measure: LI Period; Mean Temperature (T)
timeFrame: Days 1, 15, 29, 57, 78, and 85
measure: DBW; Number of Participants With Death, Serious SAEs, Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, or AEs Leading to Discontinuation
timeFrame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier
measure: DBW; Number of Participants With AEs of Special Interest
timeFrame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier
measure: DBW; Number of Participants With Hematology Values Meeting the Marked Abnormality Criteria
timeFrame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier
measure: DBW; Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria
timeFrame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier
measure: DBW; Number of Participants With Electrolytes Values Meeting the Marked Abnormality Criteria
timeFrame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier
measure: DBW; Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria
timeFrame: From Day 85 through Day 169, up to 56 days post last dose in DBW Period or up to first dose in RI Period, whichever occurred earlier
measure: DBW; Mean Seated Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) During Double Blind Period
timeFrame: Days 113, 141, and 169
measure: DBW Period; Mean Heart Rate (HR) During Period 2
timeFrame: Days 113, 141, and 169
measure: DBW Period; Mean Temperature (T) During Period II
timeFrame: Days 113, 141, and 169
measure: RI; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, or AEs Leading to Discontinuation
timeFrame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier.
measure: RI; Number of Participants With AEs of Special Interest
timeFrame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier.
measure: RI; Number of Participants With Hematology Values Meeting the Marked Abnormality Criteria
timeFrame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier.
measure: RI; Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria
timeFrame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier.
measure: RI; Number of Participants With Electrolytes Values Meeting the Marked Abnormality Criteria
timeFrame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier.
measure: RI; Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria
timeFrame: From Day 169 through Day 253, up to 56 days post last dose in RI Period or up to first dose in LTE, whichever occurred earlier.
measure: RI Period; Mean Seated Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) During Period III
timeFrame: Days 169, 197, 225, and 253
measure: RI Period; Mean Heart Rate (HR) During Period III
timeFrame: Days 169, 197, 225, and 253
measure: RI Period; Mean Temperature (T) During Period III
timeFrame: Days 169, 197, 225, and 253
measure: Short Term; Abatacept Serum Concentration by Immunogenicity Status as Measured by ELISA by RI Treatment Groups
timeFrame: Day 197 through Day 253
measure: Short Term; Abatacept Serum Concentration by Immunogenicity Status as Measured by ECL by RI Treatment Groups
timeFrame: Day 197 through Day 253
measure: ST; Number of Participants Positive for Anti-nuclear Antibody (ANA), Anti-double Stranded DNA Antibody (dsDNA), or Rheumatoid Factor (RF) at Day 253 According to Baseline Status (Negative at Baseline or Positive at Baseline) by DBW Treatment Groups
timeFrame: Baseline, Day 253
measure: LTE: DAS28-CRP Mean Change From Baseline (Day 1) Over Time - All Participants Treated in LTE
timeFrame: For Period 1 non-responders: as of Study Day 85 and up to Day 1821. For ST completers: as of Study Day 253 and up to Day 1821.
measure: LTE: Percent of Participants Who Achieved Clinical Remission in the Long Term Extension - All Participants Treated in LTE
timeFrame: For Period I non-responders: as of Study Day 85 and up to Study Day 1821. For ST completers: as of Study Day 253 and up to Study Day 1821
measure: LTE: Percent of Participants With Low Disease Activity in Long Term Extension: All Participants Treated in LTE
timeFrame: For Period 1 non-responders: as of Study Day 85 and up to Day 1821. For ST completers: as of Study Day 253 and up to Day 1821.
measure: LTE: Percent of Participants With HAQ Response Over Time - All Participants Treated in LTE
timeFrame: Study Days 1 (Baseline),15, 29, 57, 78, 85, 253, 337, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1177, 1261, 1345, 1457, 1541,1625,1709,1821,1905,1989, 2073
measure: LTE: Overall Percentage of Participants With Positive Anti-Abatacept or Anti-CTLA4 Antibody Responses (ECL Method) for On-Treatment Visits, Post Last Dose Visits, and Overall Study - All Participants Treated in LTE
timeFrame: Days 337, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1177, 1261, 1457, 1625, 1821, 1989 and 28, 56, 85, 168 days post last dose in LTE
measure: LTE: Number of Participants With Death, Related SAEs, SAEs Leading to Discontinuation, Related AEs, or AEs Leading to Discontinuation During Long Term Extension (LTE)
timeFrame: For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014), up to 56 days post last dose. For ST completers: as of Day 253 and up to completion of LTE (FEB 2014) up to 56 days post last dose.
measure: LTE: Number of Participants With AEs of Special Interest During LTE
timeFrame: For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014) up to 56 days post last dose. For ST completers: as of Day 253 and up to completion of LTE (FEB 2014) up to 56 days post last dose.
measure: LTE: Number of Participants With Hematology Values Meeting the Marked Abnormality Criteria During LTE
timeFrame: For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014). For ST completers: as of Day 253 and up to completion of LTE (FEB 2014). Data included up to 56 days post last dose.
measure: LTE: Number of Participants With Liver and Kidney Function Values Meeting the Marked Abnormality Criteria During LTE
timeFrame: For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014). For ST completers: as of Day 253 and up to completion of LTE (FEB 2014). Data included up to 56 days post last dose.
measure: LTE: Number of Participants With Electrolyte Values Meeting the Marked Abnormality Criteria During LTE
timeFrame: For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014). For ST completers: as of Day 253 and up to completion of LTE (FEB 2014). Data included up to 56 days post last dose.
measure: LTE: Number of Participants With Other Chemistry and Urinalysis Values Meeting the Marked Abnormality Criteria During LTE
timeFrame: For Period I non-responders: as of Day 85 and up to completion of LTE (FEB 2014). For ST completers: as of Day 253 and up to completion of LTE (FEB 2014). Data included up to 56 days post last dose.
measure: LTE: Mean Seated Systolic Blood Pressure (SBP) During LTE
timeFrame: Days 337, 365, 449, 533, 617, 729,813, 897,981, 1093, 1177,1261,1345, 1457,1541,1625,1709,1821,1905,1989,2073
measure: LTE: Mean Seated Diastolic Blood Pressure (DBP) During LTE
timeFrame: Days 337, 365, 449, 533, 617, 729,813, 897,981, 1093, 1177,1261, 1345, 1457,1541,1625,1709,1821,1905,1989,2073
measure: LTE: Mean Heart Rate (HR) During LTE
timeFrame: Days 337, 365, 449, 533, 617, 729,813, 897,981, 1093, 1177,1261, 1345, 1457,1541,1625,1709,1821,1905,1989,2073
measure: LTE: Mean Temperature (T) During LTE
timeFrame: Days 337, 365, 449,533, 617, 729,813, 897,981, 1093, 1177,1261, 1345, 1457,1541,1625,1709,1821,1905,1989,2073
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Wallace Rheumatic Study Center
state: California
city: Trumbull
country: United States
facility: New England Research Associates, Llc
state: Connecticut
city: Sarasota
country: United States
facility: Sarasota Arthritis Research Center
state: Florida
city: Indianapolis
country: United States
facility: Diagnostic Rheumatology And Research,Pc
state: Indiana
city: Cumberland
country: United States
facility: Klein And Associates, M.D., Pa
state: Maryland
city: Worcester
country: United States
facility: Clinical Pharmacology Study Group
state: Massachusetts
city: Eagan
country: United States
facility: St. Paul Rheumatology, P.A.
state: Minnesota
city: Albuquerque
country: United States
facility: Albuquerque Clinical Trials, Inc.
state: New Mexico
city: Bethlehem
country: United States
facility: East Penn Rheumatology Associates
state: Pennsylvania
city: Duncansville
country: United States
facility: Altoona Center For Clinical Research
state: Pennsylvania
city: Erie
country: United States
facility: Center For Assessment And Research Of Erie
state: Pennsylvania
city: Columbia
country: United States
facility: Columbia Arthritis Center
state: South Carolina
city: Clarksburg
country: United States
facility: Mountain State Clinical Research
state: West Virginia
city: Capital Federal
country: Argentina
facility: Local Institution
state: Buenos Aires
city: Rosario
country: Argentina
facility: Local Institution
state: Santa Fe
city: Cordoba
country: Argentina
facility: Local Institution
city: Santa Fe
country: Argentina
facility: Local Institution
city: Trois-Rivieres
country: Canada
facility: Local Institution
state: Quebec
city: Mexico City
country: Mexico
facility: Local Institution
state: Distrito Federal
city: Metepec
country: Mexico
facility: Local Institution
state: Estado De Mexico
city: Leon
country: Mexico
facility: Local Institution
state: Guanajuato
city: Merida
country: Mexico
facility: Local Institution
state: Yucatan
city: Bloemfontein
country: South Africa
facility: Local Institution
state: Free State
city: Muckleneuk
country: South Africa
facility: Local Institution
state: Gauteng
city: Pretoria
country: South Africa
facility: Local Institution
state: Gauteng
city: Berea
country: South Africa
facility: Local Institution
state: Kwa Zulu Natal
city: Panorama
country: South Africa
facility: Local Institution
state: Western Cape
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Kaine J, Gladstein G, Strusberg I, Robles M, Louw I, Gujrathi S, Pappu R, Delaet I, Pans M, Ludivico C. Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of withdrawal and reintroduction on immunogenicity, efficacy and safety (phase Iiib ALLOW study). Ann Rheum Dis. 2012 Jan;71(1):38-44. doi: 10.1136/annrheumdis-2011-200344. Epub 2011 Sep 13.