|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|Rheumatoid Arthritis, Nos
|E.1.3||Condition being studied is a rare disease || No
|E.2 Objective of the trial
|E.2.1||Main objective of the trial ||
|The co-primary objectives for this study will compare the clinical efficacy of abatacept
used in combination with methotrexate versus methotrexate alone on the following:
1) The proportion of subjects who achieve remission in 12 months of treatment
(Day 365), as defined by a DAS 28 score less than 2.6 and
2) Joint damage progression measured by radiographic evaluation using the
Genant-Modified Sharp total score at 12 months of treatment (Day 365).
|E.2.2||Secondary objectives of the trial ||
|1) Compare proportion of subjects with an ACR50 response at month 12 (Day 365).
2) Compare proportion of subjects achieving major clinical response defined by
6 months of consecutive ACR 70 response at month 12 (Day 365).
3) Compare disease activity as measured by DAS 28 score at month 12 (Day 365).
4) Compare improvement in physical function using the HAQ disability index at
month 12 (Day 365) and assess improvement in physical function at month 24
5) Compare inhibition of joint damage progression measured by radiographic
evaluation using the Genant-modified Sharp erosion, and joint space narrowing at
month 12 (Day 365).
6) Assess inhibition of joint damage progression measured by radiographic
evaluation using the Genant-modified Sharp erosion, joint space narrowing and total
score at month 24 (Day 729).
7) Determine safety and tolerability of abatacept in this subject population, including evaluation of immunogenicity of abatacept.
|E.2.3||Trial contains a sub-study || Yes
|E.2.3.1||Full title, date and version of each sub-study and their related objectives||
|* MRI Exploratory Research Sub-Study Amendment 3 - Site specific, Version 3.0, dated 28-Dec-2005.
The primary objective of this amendment is to assess the change in structural joint damage measured by Magnetic Resonance Images from Day 1 to month 12 between abatacept/methotrexate versus methotrexate alone.
* dose reduction/long term extension sub-study Amendment 07 - Site Specific, version 2.0, dated 27-Jul-2007.
The primary objective of this sub-study is to assess the time to disease relapse for the abatacept 10 mg/kg and 5 mg/kg doses in subjects with early RA in remission (DAS 28 ESR < 2.6) who have received treatment with abatacept 10 mg/kg for at least one year. A relapse will be defined as follows:
• Additional DMARD therapy given
• Two or more course of high dose steroids given
• Return to abatacept 10 mg/kg (rescue medication given)
• DAS28 CRP score ≥ 3.2 at 2 consecutive visits
* RNA Exploratory Research Sub-Study Amendment 4 - Site specific, version 2.0, dated 28-Dec-2005.
The primary objective of this amendment is to analyze RNA expression patterns as a potential biomarker in RA and to confirm the presence of distinct RNA expression patterns in RA subjects.
|E.3||Principal inclusion criteria ||
|1) Subject is willing to participate in the study and has signed the informed consent.
2) Males or females (not nursing and not pregnant) ≥ 18 years of age. Males and
women of child-bearing potential are eligible if they are practicing effective
3) Subjects must meet the criteria of the American Rheumatism Association (1987) for
the diagnosis of rheumatoid arthritis.
4) Subjects must have a diagnosis of RA less than or equal to 2 years.
5) Subjects must have high disease activity as defined by a tender joint count of at least 12, swollen joint count of at least 10, and a CRP of ≥ .45 mg/dL or ≥ 4.5 mg/L.
6) Subjects that are RF or anti-CCP positive.
7) Subjects must have evidence of erosion of the hands, wrists or feet on the screening radiograph. (To be read centrally)
8) Subjects must be methotrexate naive or their prior exposure must have been ≤10mg a week for not more than 3 weeks and no dose for 3 months prior to signing the informed consent.
9) Men and women (not nursing and not pregnant) ≥ 18 years of age. Men and Women of childbearing potential are eligible if they are practicing effective contraceptive measures.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity
25 IU/L or equivalent units of HCG) within 48 hours prior to the start of study
Male subjects must be using an adequate method of contraception throughout the study including up to 10 weeks after the last infusion of abatacept so that the risk of pregnancy to their partner is minimized.
|E.4||Principal exclusion criteria||
|1) WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period and for up to 10 weeks after the last infusion of abatacept.
2) Subjects who are impaired, incapacitated, or incapable of completing study related
3) Subjects who meet diagnostic criteria for any other rheumatic disease (e.g., lupus
4) Subjects who have previously received treatment with an approved or investigational biologic RA therapy (infliximab, etanercept, anakinra, adalimumab).
5) Subjects with active vasculitis of a major organ system with the exception of
6) Subjects with current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral disease, or other medical conditions that, in the opinion of the investigator, might place the subject at unacceptable risk for participation in this study.
7) Female subjects, who have not had age and/or risk factor appropriate breast cancer screening or who have had a breast cancer screening study that is suspicious for malignancy, and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations (Please refer to Section 7.3.2).
8) Subjects with a history of cancer within the last five years (other than non-melanoma skin cell cancers cured by local resection). Existing non-melanoma skin cell cancers must be removed prior to dosing.
9) Subjects who have clinically significant drug or alcohol abuse.
10) Subjects with any serious acute bacterial infection (such as pneumonia or
pyelonephritis) unless treated and completely resolved with antibiotics.
11) Subjects with severe chronic or recurrent bacterial infections (such as recurrent
pneumonia, chronic bronchiectasis).
12) The following subjects are excluded from this study:
- Subjects with current clinical or laboratory evidence of active or latent
- Subjects with a history of active TB that was treated within the last 3 years.
- Subjects with a history of active TB greater than 3 years ago unless there is
documentation that the prior anti-TB treatment was appropriate in duration and
13) Subjects with herpes zoster that resolved less than 2 months prior to enrollment.
14) Subjects with evidence (as assessed by the investigator) of active or latent bacterial or viral infections at the time of potential enrollment, including subjects with evidence of Human Immunodeficiency Virus (HIV) infection.
15) Subjects with Hepatitis B surface antigen.
16) Subjects with Hepatitis C antibody-positive subjects who are also RIBA-positive or PCR-positive.
17) Subjects with any of the following laboratory values:
- Hgb < 8.5 g/dL.
- WBC < 3,000/mm3 (3 x 109/L)
- Platelets < 100,000/mm3 (100 x 109/L).
- Serum creatinine > 2 times upper limit of normal.
- Serum ALT or AST > 2 times upper limit of normal.
- Any other laboratory test results that, in the opinion of the investigator, might place
the subject at unacceptable risk for participation in this study.
18) Subjects with a history of intolerance to methotrexate.
19) Subjects who have at any time received treatment with CTLA4Ig, BMS-188667
20) Subjects who have received treatment with any investigational drug within 28 days (or less than 5 terminal half-lives of elimination) of the Day 1 dose.
21) Subjects currently receiving treatment with leflunomide, mycophenolate mofetil
(CellCept), cyclosporine, and tacrolimus, D-Penicillamine, Cytoxan, or immunoadsorption columns (such as Prosorba columns).
22) No approved or investigational biologics
23) Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.
|E.5 End points
|E.5.1||Primary end point(s)||
Co-primary efficacy analysis include, in the order of sequential testing, comparisons
between abatacept in combination with methotrexate and a placebo control of
methotrexate alone in remission rate (EULAR defined DAS 28 remission) by 12 months (Day 365) and total Sharp scores using the Genant-modified Sharp method at 12 months (Day 365).
The co-primary efficacy analysis will be performed with the intent-to-treat (ITT) analysis population including all subjects randomized and treated. All subjects who prematurely discontinue the trial after receiving study medication will have missing data imputed as a DAS 28 remission non-responder at all scheduled protocol visits subsequent to the point of discontinuation. Missing annual radiographic data will be imputed with linear extrapolation for discontinued subjects having baseline radiographs and at least one of either Day 169 radiographs or discontinuation radiographs. Subjects with missing baseline radiographic data will be excluded from the primary radiographic analyses.
The DAS 28 is a continuous variable which is a composite of 4 variables: the number of tender joints out of 28 joints, the number of swollen joints out of 28 joints, CRP and subject assessment of disease activity measure on a visual analog scale.
The evaluation of drug safety is based on clinical AEs, vital signs and laboratory
abnormalities reported during the study. All safety presentations will include subjects
who received at least one dose of study medication and will group subjects by treatment received.
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| No
|E.6.13.1||Other scope of the trial description||
|E.7||Trial type and phase
|E.7.1||Human pharmacology (Phase I)|| No
|E.7.1.1||First administration to humans|| No
|E.7.1.2||Bioequivalence study|| No
|E.126.96.36.199||Other trial type description||
|E.7.2||Therapeutic exploratory (Phase II)|| No
|E.7.3||Therapeutic confirmatory (Phase III)|| Yes
|E.7.4||Therapeutic use (Phase IV)|| No
|E.8 Design of the trial
|E.8.1.3||Single blind|| No
|E.8.1.4||Double blind || Yes
|E.8.1.5||Parallel group|| No
|E.8.1.6||Cross over || No
|E.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| No
|E.8.2.2||Placebo || Yes
The trial involves single site in the Member State concerned
|E.8.4|| The trial involves multiple sites in the Member State concerned || Yes
|E.8.4.1||Number of sites anticipated in Member State concerned||2
|E.8.5||The trial involves multiple Member States|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||43
|E.8.6 Trial involving sites outside the EEA
|E.8.6.1||Trial being conducted both within and outside the EEA|| Yes
|E.8.6.2||Trial being conducted completely outside of the EEA|| Information not present in EudraCT
|E.8.6.3||If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned||
|E.8.7||Trial has a data monitoring committee|| No
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|E.8.9.1||In the Member State concerned years||3
|E.8.9.1||In the Member State concerned months||0
|E.8.9.1||In the Member State concerned days||0
|E.8.9.2||In all countries concerned by the trial years||3
|E.8.9.2||In all countries concerned by the trial months||0
|E.8.9.2||In all countries concerned by the trial days||0