| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
|
| 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 primary objective of this study in subjects with active RA and inadequate response to MTX is to assess changes in wrist synovitis as measured by gadolinium-enhanced Magnetic Resonance Imaging (MRI) and using the OMERACT 6 RA MRI score after 4 months of treatment with Abatacept or placebo, on a background therapy with MTX. |
|
| E.2.2 | Secondary objectives of the trial |
1) To assess in subjects with active RA and inadequate response to MTX changes in
bone lesions (i.e. bone edema, bone erosions) in hands/wrists (measured by
gadolinium-enhanced MRI, using the OMERACT 6 RA MRI score) after 4 months of treatment with Abatacept or placebo, on a background therapy with MTX).
2) To assess in subjects with active RA and inadequate response to MTX changes in
biochemical markers of bone, cartilage and synovial tissue metabolism at Days 15, 29 and 113 (4 months) after 4 months of treatment with Abatacept or placebo, on a background therapy with MTX.
3) To assess the safety and tolerability of Abatacept versus placebo in subjects with
active RA and inadequate response to MTX, on a background therapy with MTX over 4 months. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed written informed consent
2) Subjects must meet the criteria of the American Rheumatism Association (1987)
for the diagnosis of rheumatoid arthritis (Protocol Appendix 1).
3) Subjects must have a diagnosis of RA greater than 6 months and no longer than 5
years from the time of initial diagnosis of RA.
4) Subjects must have a disease activity as defined by a tender joint count of >= 6,
swollen joint count of >= 6, and a CRP of at least 1.5 times the upper limit of normal
5) Subjects must have clinically detectable synovitis (i.e. “synovial swelling”) of at
least one wrist at screening and baseline visit (D1, prior to infusion).
6) Subjects must have at least one erosion present in the hands/wrists and /or feet
(documented by previous plain radiography) or be anti-CCP positive or have a
rheumatoid factor (RF) titer >1:160.
7) Subjects must have been treated with MTX, on a stable dose of at least 15 mg or a maximum tolerated dose (i.e. 10 mg weekly) for at least 3 months before screening
8) Subjects must be biologic DMARDs naive (i.e. anti-TNFα, anakinra, rituximab or
other investigational biologics).
9) Subjects who consented to have a knee/ankle arthroscopy with tissue and synovial biopsy must have clinically detectable synovitis (i.e. “synovial swelling”) of at
least one knee/ankle at screening and baseline visit (D1).
10) At randomization (Day 1), subjects must have the following disease activity :
a) 6 or more swollen joints (66 joint count) and
b) 6 or more tender joints (68 joint count) and
c) CRP of at least 1.5 times the upper limit of normal at screening and baseline
visit (D1, prior to infusion). (result used from screening visit sample collection).
11) Drug stabilization requirements (except MTX): Informed consent must be
signed before making any changes in RA therapy if those changes are solely for
the purpose of this study.
a) All DMARDs (except MTX) should be discontinued at least 28 days prior to
treatment (Day 1).
-MTX monotherapy: Subjects who are treated only with MTX will not
require washout.
-Combination DMARD therapy: Subjects who are treated with MTX in
combination with another anti-rheumatic treatment (DMARD) will
require washout.
b) In the case of leflunomide, the subject can be washed-out with cholestyramine
according to manufacturer recommendations.
c) Oral corticosteroid treatment must have been reduced to a maximum equivalent dose of 10 mg prednisone daily for 28 days and stabilized for at least 25 out of 28 days, prior to treatment (Baseline i.e. Day 1).
12) Osteoporosis treatment:
Subjects taking treatments for the prevention of glucocorticoid-induced osteoporosis
(Calcium, vitamin D, Bisphosphonates) will be enrolled as long as their dose has been
stable for at least 3 months prior to randomization and remains stable during the entire double-blind period. Other concomitant osteoporosis treatments will not be permitted at randomization.
13) Men and women (not nursing and not pregnant) >= 18 years of age. Women of
childbearing potential are eligible if they are practicing effective contraceptive
measures.
|
|
| E.4 | Principal exclusion criteria |
1)WOCBP unwilling or unable to use acceptable method to avoid pregnancy for entire study period & up to 10 weeks after study
2)WOCBP using prohibited contraceptive method
3)Pregnant or breastfeeding women
4)Women with +pregnancy test on enrollment or prior to study drug administration
5)Contraception for male subjects treated with protocol-permitted concomitant
medications during study should follow manufacturer’s recommendation for need to use contraception & permissible/recommended method(s)
6)Subjects who are impaired,incapacitated,or incapable of completing study related assessments
7)Subjects meeting diagnostic criteria for any other rheumatic disease
8)previous treatment with approved/investigational biologic RA therapy (infliximab, etanercept,anakinra,adalimumab,rituximab,Abatacept)
9)Active vasculitis of a major organ system with exception of rheumatoid nodules
10)current symptoms of severe,progressive, or uncontrolled renal, hepatic,hematological,gastrointestinal,pulmonary,cardiac,neurological,or cerebral disease,or other medical conditions that,in opinion of the investigator,might place subject at unacceptable risk for participation
11)Female subjects who have had breast cancer screening suspicious for malignancy & in whom possibility of malignancy cannot be reasonably excluded following additional clinical,laboratory or other diagnostic evaluations (Protocol Section 7.3.2.3)
12)history of cancer within last 5 years (other than nonmelanoma skin cell (NMSC) cancers cured by local resection). Existing NMSC cancers must be removed prior to dosing
13)Known current metabolic bone disorders other than osteoporosis or low bone mass
14)Vitamin D deficiency
15)Clinically significant drug or alcohol abuse
16)Subjects with any serious bacterial infection within last 3 months, unless treated & resolved with antibiotics, or any chronic bacterial infection
17)Subjects at risk for TB. Specifically subjects with:
-History of active TB within last 3 years even if treated
-History of active TB >3 years ago unless there is documentation
that prior anti-TB treatment was appropriate in duration & type
-Current clinical, radiographic or laboratory evidence of active TB
-Latent TB which was not successfully treated
18)Subjects with herpes zoster or CMV that resolved less than 2 months prior to signing ICF
19)Subjects with evidence of active or latent bacterial/viral infections at time of potential enrollment, including subjects with evidence of HIV, HPB or HPC infection detected during screening
20)Subjects with conditions that preclude accurate DXA measurements
including:
-BMI >35 kg/m²
- Advanced scoliosis or spinal degenerative changes (osteoarthritis, sclerosis)
-Less than 3 lumbar vertebrae in range L1-L4 which are evaluable by DXA
interfering conditions include prevalent vertebral fracture, metal implants or spinal
surgery
-History of bilateral distal radius fracture
21)Subject who received live vaccines within 3 months of anticipated
1st dose of study medication or who will have need of live vaccine at any time
following Day 1 of study
22)History of severe or anaphylactic infusion reaction after receiving a biologic
agent, suspected to be associated with an immune response
23)Subjects who have at any time received treatment with Abatacept
24)Subjects who have at any time received treatment with biologic DMARD
(infliximab, etanercept, adalimumab, rituximab, or any investigational biologic)
25)Subjects that received treatment with any investigational drug within
28 days (or< 5 terminal half-lives of elimination) of Day 1 dose
26)Subjects receiving treatment with mycophenolate mofetil (CellCept®),
cyclosporine, tacrolimus, D-Penicillamine, Cytoxan, or immunoadsorption columns
27)Subjects receiving treatment with following bone active agents, or had previous treatment according to following guidelines:
-Oral bisphosphonate, vitamin D, or calcium treatments for prevention of
glucocorticoid-induced osteoporosis if taken for less than 3 months of randomization or bisphosphonate treatment for established osteoporosis
-Any of following treatments within 3 months of randomization: PTH or PTH
fragments (teriparatide), systemic hormone replacement therapy, selective
estrogen receptor modulators (raloxifene, lasofoxifene, bazedoxifene, etc),
tamoxifen,tibolone,calcitonin,anabolic steroids or testosterone,androgen &
once weekly dose of >50,000 IU of Vitamin D
-treatment with fluoride or strontium ranelate
28)Subjects who received intra-articular injection of steroids within 3 months prior to Screening if injected in >1 joint other than a small joint or in any small joint or within 6 months prior to Screening in the target knee/ ankle for subjects who consented to have a knee/ ankle arthroscopy
29)Subjects who have had radiosynovectomy of the knee/ankle selected for arthroscopy in the past
See Section 5.2 of Protocol for additional Exclusion Criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Imaging assessments:
• MRI assessment of the degree of inflammation and structural damage [i.e. synovitis of the most clinically inflamed wrists and bone edema and erosions of the target wrist and metacarpophalangeal (MCP) joints] at baseline (D1), 4 months (end of double-blind treatment period) and 1 year (end of open-label extension) by gadolinium-enhanced MRI, using a centralized reader blinded to sequence and treatment and using the OMERACT 6 RA MRI score.
|
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| The double-blind phase is followed by an open-label phase of 8 months. |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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