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Trial record 2 of 137 for:    "Connective Tissue Disease" | "Abatacept"

Clarification of Abatacept Effects in SLE With Integrated Biologic and Clinical Approaches (ABC)

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ClinicalTrials.gov Identifier: NCT02270957
Recruitment Status : Recruiting
First Posted : October 22, 2014
Last Update Posted : December 7, 2017
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Oklahoma Medical Research Foundation

Tracking Information
First Submitted Date  ICMJE October 13, 2014
First Posted Date  ICMJE October 22, 2014
Last Update Posted Date December 7, 2017
Study Start Date  ICMJE January 2014
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 19, 2014)
BILAG-based Combined Lupus Assessment (BICLA) [ Time Frame: 6 months ]
All baseline severe features (BILAG A) improving to moderate (BILAG B) or better and all baseline BILAG B features improving to mild or resolved (C or D) without increase in any other feature on BILAG or SLEDAI (SLE Disease Activity Index), increase in Physician's Global Assessment or rescue medications after the month 2 visit
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02270957 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 19, 2014)
  • BICLA and SRI at each month [ Time Frame: 6 months ]
    BICLA as defined in primary endpoint. SRI is SLE Responder Index defined as decrease of SLEDAI of at least 4 (or 5) points with no increased BILAG or PGA
  • Mean SLEDAI at baseline vs 6 months [ Time Frame: 6 months ]
    SLEDAI is defined as the SLE Disease Activity Index score
  • Mean BILAG at baseline vs 6 months [ Time Frame: 6 months ]
    BILAG is defined above. A cumulative score is given for additive severity in each active organ
  • Mean CLASI score at baseline vs 6 months [ Time Frame: 6 months ]
    CLASI is a Cutaneous Lupus scoring system which also results in a cumulative score
  • LFA REAL scoring at baseline vs 6 months [ Time Frame: 6 months ]
    LFA REAL stands for Lupus Foundation of America Rapid Evaluation of Activity in Lupus
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 19, 2014)
  • Exploratory Biologic Endpoints [ Time Frame: 6 months ]
    Patients with or without increased ratio of TH17/Treg signals or activated B signals (e.g. ErK phosphorylation) at baseline will be compared for response rates
  • Safety Data [ Time Frame: 6 months ]
    Descriptive analysis of SAEs, AEs and AEs of special interest
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Clarification of Abatacept Effects in SLE With Integrated Biologic and Clinical Approaches
Official Title  ICMJE Clarification of Abatacept Effects in SLE With Integrated Biologic and Clinical Approaches (The ABC Study)
Brief Summary This is a randomized, double blind, placebo controlled trial of abatacept for the treatment of lupus arthritis and other manifestations of lupus. Patients with lupus and at least 3 tender and 3 swollen joints and </= 20 mg prednisone have other background immune suppressants withdrawn at entry. They can elect to receive up to a total of 320 mg depomedrol (in two or more injections) between the screening visit and the visit 2 months after dosing begins. Abatacept (125 mg) or placebo is administered in weekly subcutaneous doses. After 3 months of treatment patients who are not responding may elect to receive open label abatacept with or without additional standard of care therapies. Such patients are considered non responders. The primary endpoint is the British Isles Lupus Assessment Group Index (BILAG)-linked Combined Lupus Assessment (BICLA) which will require a clinically significant improvement in arthritis and other active features of lupus
Detailed Description

Research Hypothesis: Abatacept is effective in lupus arthritis and this will be discernible in a small trial with robust endpoints which incorporates withdrawal of background immune suppressants

Study Schematic: Abatacept 125 mg or placebo will be given in a 1:1 randomization subcutaneously each week for six months. All patients may elect to continue six more months on open label Abatacept. Background Immune Suppressants will be withdrawn at any time between screening and the first dosing visit. At or after screening, patients may elect 40-160 mg depomedrol shots prn not to exceed 320 mg total up to and including the Month 2 Visit (two months after the first dosing visit) After that, additional steroids or immune suppressants, if necessary, will be allowed but the patient will be considered a non-responder in the primary endpoint at six months on that basis. At of after the 3 month visit patients with significant clinical flare may also elect to receive open label Abatacept but will be considered non-responders in the primary endpoint at six months.

Primary Objective: To compare response rates between Abatacept-Treated and Placebo-Treated Patients with active lupus arthritis in a trial designed with background immune suppressant withdrawal, limited steroid rescue, and a robust, discriminatory endpoint. The trial design and primary endpoint of response by BICLA (defined below) have been pre-tested by us for safety and ability to ensure placebo group non-response, underscoring our powering of the study. This will support a rational decision about further development of abatacept for SLE at minimal cost.

Secondary clinical outcome measures used as endpoints will include: SRI 4/5, changes in joint counts, SLEDAI, BILAG, CLASI, PGA, and LFA REAL measures.

The definitions of the clinical outcome measures are as follows: BICLA: BILAG-based Combined Lupus Assessment, This is defined as British Isles Lupus Assessment Group (BILAG) index scores that were severe at entry (BILAG A scores) improving to a moderate (BILAG B) level (or better) and all features that were moderate at entry improving to a mild level (BILAG C scores) or resolved (BILAG D scores) without increase in any other BILAG feature or SLEDAI scoring (see SLEDAI definition below), as well as no more than 10% worsening in a Physician's Global Assessment or any additional treatments after the protocolized baseline rescue (e.g. no new SLE treatments after the two month visit). SLEDAI stands for the Systemic Lupus Erythematosis Disease Activity Index. SRI 4/5 is defined as SLEDAI improvement by at least 4 points (or 5 points respectively), no increase in BILAG-measured disease activity and no more than 10% worsening in a Physician's Global Assessment (PGA). CLASI stands for the Cutaneous Lupus Erythematosus Disease Area and Severity Index. PGA stands for Physician's Global Assessment. LFA REAL stands for the Lupus Foundation of America Rapid Evaluation of the Activity of Lupus. This instrument is in a pilot phase but will be tested in the ABC study.

PK and immunogenicity studies will also be performed to help in interpretation of outcomes. Novel biologic discovery will be integrated into the clinical trial to support both pre-specified and exploratory biomarker discovery. Data will be generated that might be used to help select more appropriate patient subsets for future trials and, along with PK data, help to guide optimal dosing strategies. Optimizing patient selection and dosing are important goals for further increasing demonstrable effect size in trials by increasing the response rates in the treatment group.

This study will be performed as a double blind, randomized, placebo-controlled clinical trial with 1:1 randomization of patients to abatacept 125 mg weekly subcutaneous dose or placebo, with the withdrawal of background immune suppressants. Limited steroid rescue is allowed between the screening visit and the Month 2 visit per protocol. Additional standard of care rescue medications may be used after that as needed but will define non-response at the primary endpoint date of six months. Flaring patients may elect to receive open label abatacept at Month 3 but will also be defined as non-responders in the primary endpoint. All patients may elect to receive open label abatacept for an additional six months after the primary endpoint date, with two follow up visits (2 and 4 months post medication withdrawal) to assess withdrawal effects and to complete the safety assessments.

Accrual Goal: This study will continue to recruit until we achieve the goal of 60 patients who complete study visits through the 6 month endpoint.

Correlative Studies: Extensive exploratory protocol-specific and ancillary immune pharmacodynamic studies, focusing first on changes in IFN alpha, BLyS and other B Cell pathways. A major focus will also be on T Cell pathways with a focus on T suppressor/TH17 dichotomy after treatment with abatacept. A responder analysis will be performed in order to generate hypotheses useful for selecting appropriate patients for this treatment and optimizing dosing strategies.

Adverse Events, Serious Adverse Events and Adverse Events of special interest (infusion reactions and infections) will be collected and described. Stopping Rules: Patients may be withdrawn by the investigator for non-compliance or safety. All patients terminating before six months will be considered non responders in the primary analysis. Use of off protocol immune suppressants will not necessarily dictate withdrawal but will determine non-responder status. A DSMB board of at least two physicians (four are currently participating) will review data and may stop the study if needed.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Systemic Lupus Erythematosus
Intervention  ICMJE
  • Biological: Abatacept
    Other Name: Orencia
  • Other: Placebo
Study Arms  ICMJE
  • Active Comparator: Abatacept
    Patients receive Abatacept 125 mg subcutaneously weekly for six months. An optional continuation up until 12 months is allowed. Background immune suppressants are withdrawn at the beginning of the study and the option of depomedrol up to 320 mg total (in divided doses) is allowed at any time up through the visit 2 months after study medication is started. After this additional rescue is allowed with any standard of care treatment and/or open label abatacept (since patients are blinded) but this additional rescue will define non-response in the primary endpoint at six months.
    Intervention: Biological: Abatacept
  • Placebo Comparator: Placebo
    Patients receive Abatacept 125 mg subcutaneously weekly for six months. An optional continuation up until 12 months is allowed. Background immune suppressants are withdrawn at the beginning of the study and the option of depomedrol up to 320 mg total (in divided doses) is allowed at any time up through the visit 2 months after study medication is started. After this additional rescue is allowed with any standard of care treatment and/or open label abatacept (since patients are blinded) but this additional rescue will define non-response in the primary endpoint at six months.
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 19, 2014)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Signed Written Informed Consent
  2. Four 1997 revised ACR Classification Criteria for SLE
  3. Active polyarticular arthritis meeting at minimum BILAG 2004 B definition with a minimum of 3 tender and 3 swollen joints observed at the screening visit
  4. Men and women 18 to 70 years of age.
  5. Women of childbearing potential and men with partners of childbearing potential must use an acceptable method of birth control throughout the study
  6. Women of childbearing potential must have a negative urine pregnancy test at screening and Study Day 1 (baseline visit) and may not be breast feeding

Exclusion Criteria:

  1. Current severe, organ-threatening disease (e.g. acute nephritis appropriate for induction therapy, CNS lupus (excepting chorea, cranial neuropathy, and resolving optic neuritis) or any lupus condition requiring cyclophosphamide, biologic therapy, or IV bolus steroids of >/= 500 mg.
  2. Subjects who are incapable of understanding or completing study-related assessments.
  3. Subjects with any condition, whether or not related to SLE, which, in the opinion of the investigator, might place a subject at unacceptable risk for participation in the study.
  4. Subjects with a history of cancer in the last 5 years, other than non-melanoma skin cell cancers cured by local resection or carcinoma in situ.
  5. Subjects who currently abuse drugs or alcohol.
  6. Subjects with acute herpes zoster or cytomegalovirus (CMV) within 2 months of screening.
  7. Subjects who have received any live vaccines within 3 months of first dose.
  8. Subjects with any serious bacterial infection within the last 3 months, unless treated and resolved with antibiotics, or any chronic bacterial infection (eg, chronic pyelonephritis, osteomyelitis, or bronchiectasis).
  9. Subjects at risk for tuberculosis (TB).
  10. Subjects known to be positive for hepatitis B surface antigen or hepatitis C unless negative by PCR or RIBA
  11. Acute hemolytic anemia with hemoglobin < 7.0 g/dL or known change in Hg by 2.0 g/dL within four months
  12. WBC < 2500/mm3 (< 3 x 109/L) unless due to chronic stable lupus activity
  13. Platelets < 40,000/mm3 (< 3 x 109/L) (If less than 100,000 must have been stable (within a range of 10,000/mm3 ) within two months of screening or in two tests during the screening period.
  14. Serum creatinine > 2 times the ULN
  15. Serum ALT or AST > 2.5 times the ULN
  16. Any other laboratory test results that, in the opinion of the investigator, might place a subject at unacceptable risk for participation in the study.
  17. Known allergy/sensitivity to the study agent or carrier.
  18. Treatment with investigational drug within 28 days (or 5 terminal half-lives) of the Day 1 dose.
  19. Cyclophosphamide within 3 months of Day 1 or bolus IV steroids >/=500 mg within 1 month
  20. Prednisone > 20 mg qd after the screening visit

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Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Aikaterini Thanou, M.D. 405 271 7805 ext 34434 aikaterini-thanou@omrf.org
Contact: Fredonna Carthen 405 271 7805 ext 5 fredonna-carthen@omrf.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02270957
Other Study ID Numbers  ICMJE OMRF 13-38
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Oklahoma Medical Research Foundation
Study Sponsor  ICMJE Oklahoma Medical Research Foundation
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Study Director: Joan T Merrill, MD Oklahoma Medical Research Foundation
PRS Account Oklahoma Medical Research Foundation
Verification Date December 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP