E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rheumatoid Arthritis, Nos |
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MedDRA Classification |
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 score less than 1.6 and 2) Joint damage progression measured by radiographic evaluation using the Genant-Modified Sharp total score at 12 months of treatment (Day 365). |
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E.2.2 | Secondary objectives of the trial |
1) Compare the proportion of subjects with an ACR50 response at month 12 (Day 365). 2) Compare the proportion of subjects achieving major clinical response defined by 6 months of consecutive ACR 70 response at month 12 (Day 365). 3) Compare the disease activity as measured by Disease Activity Score (DAS) at month 12 (Day 365). 4) Compare the improvement in physical function using the HAQ disability index at month 12 (Day 365) and assess the improvement in physical function at month 24 (Day 729). 5) Compare the 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 the 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 the safety and tolerability of abatacept, including evaluation of immunogenicity of abatacept. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
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) at least 18 years of age. Males and women of child-bearing potential are eligible if they are practicing effective contraceptive measures. 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 10, swollen joint count of 12, and a CRP of .8 dg/L or 8.0 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 have minimal exposure to methotrexate described as not more than 10mg a week for not more than 3 weeks and no dose for three months prior to enrollment. 9) Men and women, ages 18 - 75 years old. 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 medication. 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. |
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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 assessments. 3) Subjects who meet diagnostic criteria for any other rheumatic disease (e.g., lupus erythematous). 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 rheumatoid nodules. 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) Subjects with active tuberculosis (TB) requiring treatment within the previous 3 years. A PPD response that is equal to or greater than 10 mm should be considered a positive test, although a lower threshold (5 mm) may be applied as determined by the clinical circumstance and investigator according to published guidelines and/or local standards endorsed by the medical society. (Section 7.3.2) 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 (abatacept). 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy 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 (defined using the DAS definition of remission) by 12 months (Day 365) and total Sharp scores using the Genant-modified Sharp method at 12 months (Day 365). The DAS is a continuous variable which is a composite of 4 variables: the Ritchie Articular index, the number of swollen joints out of 44 joints, CRP and subject assessment of disease activity measure on a visual analogue scale. Safety: 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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.7.1.3 | Other | No |
E.7.1.3.1 | 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 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
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.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
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 |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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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 | |
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 |