A Phase IIIB Multicenter, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Abatacept Administered Subcutaneously and Intravenously in Subjects with Rheumatoid Arthritis, Receiving Background Methotrexate, and Experiencing an Inadequate Response to Methotrexate. (Short title: MTX-IR Study) Revised Protocol 02 incorporating Protocol amendment 02 (v2.0 date 19-dec-2007), Protocol amendment 03 (v1.0, date 25-Apr-2008), and Protocol Amendment 06 (v1.0, date 25-Sep-2008). And Anti-TNF failure Substudy Protocol Amendment 05-Site Specific (v2.0, date 02-Oct-2008). - MTX-IR Study

• Register: EUCTR
• Last refreshed on: 6 January 2015
• Main ID: EUCTR2007-005434-37-AT
• Date of registration: 20/06/2008
• Prospective Registration: Yes
• Primary sponsor: Bristol Myers Squibb International Corporation
• Public title: A Phase IIIB Multicenter, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Abatacept Administered Subcutaneously and Intravenously in Subjects with Rheumatoid Arthritis, Receiving Background Methotrexate, and Experiencing an Inadequate Response to Methotrexate. (Short title: MTX-IR Study) Revised Protocol 02 incorporating Protocol amendment 02 (v2.0 date 19-dec-2007), Protocol amendment 03 (v1.0, date 25-Apr-2008), and Protocol Amendment 06 (v1.0, date 25-Sep-2008). And Anti-TNF failure Substudy Protocol Amendment 05-Site Specific (v2.0, date 02-Oct-2008). - MTX-IR Study
• Scientific title: A Phase IIIB Multicenter, Randomized, Double-Blind, Double-Dummy Study to Compare the Efficacy and Safety of Abatacept Administered Subcutaneously and Intravenously in Subjects with Rheumatoid Arthritis, Receiving Background Methotrexate, and Experiencing an Inadequate Response to Methotrexate. (Short title: MTX-IR Study) Revised Protocol 02 incorporating Protocol amendment 02 (v2.0 date 19-dec-2007), Protocol amendment 03 (v1.0, date 25-Apr-2008), and Protocol Amendment 06 (v1.0, date 25-Sep-2008). And Anti-TNF failure Substudy Protocol Amendment 05-Site Specific (v2.0, date 02-Oct-2008). - MTX-IR Study
• Date of first enrolment: 30/07/2008
• Target sample size: 2400
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-005434-37
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: yes Other specify the comparator: comparison of 2 different administration routes of Abatacept

Countries of recruitment

Austria, Belgium, France, Germany, Greece, Hungary, Ireland, Italy, Netherlands, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1) Signed Written Informed Consent
a) Subject is willing to participate in the study and signed the informed consent.

2) Target Population
a) Subjects must meet the criteria of the American Rheumatism Association (1987)
for the diagnosis of rheumatoid arthritis and the American College of Rheumatology (1991) functional Classes I, II, or III. (Protocol Appendices 3 and 4).
b) Subjects must have had rheumatoid arthritis for more than 1 year from the initial
diagnosis. Not Applicable per Amendment 03.
c) Subjects with stable renal, endocrine, hepatic, hematological, gastrointestinal,
pulmonary, cardiac, neurological or cerebral disease(s) (eg, diabetes mellitus,
congestive heart failure, chronic obstructive pulmonary disease) will be allowed
to participate in this study.
d) Subjects who are considered methotrexate inadequate responders by a treating
physician or investigator. Subjects must have been taking methotrexate for at least
3 months at a minimal weekly dose of 15 mg, and at a stable dose for 28 days
prior to randomization (Day 1). A methotrexate weekly dose as low as 10 mg is
permitted for subjects who can not tolerate higher doses. In this circumstance, the
10 mg weekly dose will be permitted if there is verifiable documentation in the
medical record prior to entry into the study that the subject could not tolerate
higher doses. Use of parenteral methotrexate is acceptable as clinically indicated.

3) Age and Sex
a) Men and women, ages = 18
Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 10 weeks weeks (and for 14 weeks in the European countries in which the European SmPC for Orencia® IV is applicable) after the last dose of abatacept in such a manner that the risk of pregnancy is minimized.

4) Concomitant medication
Informed consent must be signed before making any changes in RA therapy, if those
are solely for the purpose of this study.
a) Drug stabilization requirements:
Oral corticosteriod treatment must have been reduced to the equivalent of = 10 mg
prednisone daily for 28 days and stabilized for at least 25 out of 28 days prior to treatment (Day 1). No intra-articular or IM injections of corticosteriods are permitted
within 28 days prior to treatment (Day 1).
b) Washout requirements:
Subjects receiving methotrexate monotherapy will not require a washout. Subjects
receiving combination RA therapy should discontinue their DMARDs (other than methotrexate) at least 28 days prior to treatment (Day 1).
Required washout periods (prior to Day 1):
At least 4 weeks for
- Gold
- Azathioprine
- Cyclosporin A and other Calcineurin inhibitors
- D-Penicillamine
- mycophenylate mofetil (CellCept®)
- Immunoadsorption columns
At least 8 weeks for
- Leflunomide (or perform active wash-out with cholestyramine according to
the manufacturer’s recommendations).

5) Disease Activity Requirements
The disease activity requirements will depend on whether the subject requires a
washout period (see Inclusion Criteria #4).
a) For subjects receiving methotrexate monotherapy (no washout):
At randomization (Day 1), subjects must have the following disease activity:
i) 10 or more swollen joints (66 joint count) and
ii) 12 or more tender joints (68 joint count) and
iii) C reactive protein (hsCRP) = 0.8 mg/dL (result used from screening visit).
b) For subjects receiving methotrexate plus other DMARDs (washout):
At screening visit, subjects must have the
Exclusion criteria:
1)Sex & Reproductive Status
a)WOCBP unwilling or unable to use acceptable method to avoid pregnancy for entire study & up to 10 weeks after last dose of IMP
b)pregnant or breastfeeding Women
c)Women with + pregnancy test on enrollment or prior to IMP administration

2)Target Disease Exceptions
a)Subjects who meet diagnostic criteria for any other rheumatic disease (eg, lupus
erythematous)
b)Subjects with active vasculitis of a major organ system (except for SC rheumatoid nodules)

3)Medical History & Concurrent Diseases
a)Subjects who are impaired, incapacitated, or incapable of completing study
related assessments
b)Current symptoms of severe, progressive, or uncontrolled renal, hepatic,
hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral
disease. Concomitant medical conditions that, in opinion of investigator,
might place subject at unacceptable risk for participation in study
c)Female subjects who have had breast cancer screening study that is suspicious
for malignancy & in whom possibility of malignancy cannot be reasonably
excluded following additional clinical, laboratory or other diagnostic evaluations
(Protocol Section 6.3.6)
d)Subjects with history of cancer within the last 5 years (other than nonmelanoma skin cell cancers cured by local resection). Existing NMSC cancers must be removed prior to dosing. Subjects with carcinoma in situ, treated with definitive surgical intervention prior to study entry, are allowed
e)Subjects who have clinically significant drug or alcohol abuse
f)Subjects with serious acute bacterial infection (such as pneumonia or
pyelonephritis unless treated & completely resolved with antibiotics)
g)Subjects with severe chronic or recurrent bacterial infections (such as recurrent
pneumonia, chronic bronchiectasis)
h)Subjects at risk for TB. Specifically subjects with:
i)Current clinical, radiographic or laboratory evidence of active or latent TB
ii)history of active TB within last 3 years even if it was treated.
iii)history of active TB > 3 years ago unless there is documentation
that prior anti-TB treatment was appropriate in duration & type
iv)Latent TB not successfully treated. Subjects with a positive TB
screening test indicative of latent TB will not be eligible for the study unless
active TB infection has been ruled out & they have initiated treatment for
latent TB with isoniazid (INH) for at least 4 weeks prior to dosing of study
drug & they have a negative chest X-ray at enrollment. Such subjects should
complete 9 months of INH treatment
i)Subjects with herpes zoster resolved <2 months prior to enrollment
j)Subjects with evidence of active or latent bacterial or viral infections at time of potential enrollment, incl. subjects with evidence of HIV infection

4)Physical & Laboratory Test Findings
a)Hepatitis B surface antigen + subjects
b)Hepatitis C antibody + subjects who are also RIBA + or PCR +
c)Subjects with any of following laboratory values:
i)Hgb <8.5 g/dL
ii)WBC <3,000/mm³
iii)Platelets <100,000/mm³
iv)Serum creatinine >2 x ULN
v)Serum ALT or AST >2 x ULN
vi)Any other laboratory test results that might place subject at unacceptable risk
for participation in study

5)Allergies & Adverse Drug Reactions
None

6)Prohibited Treatments &/or Therapies
a)Subjects who have received treatment with rituximab
b)Subjects who have had prior exposure to abatacept (CTLA4-Ig)
c)Subjects exposed to any investigational drug within 4 weeks or 5 half-lives, whicheve

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

RHEUMATOID ARTHRITIS, NOS
MedDRA version: 9.1 Level: LLT Classification code 10039073 Term: Rheumatoid arthritis

Intervention(s)

Trade Name: Orencia
Product Name: Abatacept (IV)
Product Code: BMS-188667
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: Abatacept
CAS Number: 332348-12-6
Current Sponsor code: BMS-188667
Other descriptive name: CTLA4Ig
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 250-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Product Name: Abatacept (SC)
Product Code: BMS-188667
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Abatacept
CAS Number: 332348-12-6
Current Sponsor code: BMS-188667
Other descriptive name: CTLA4Ig
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 125-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Main Objective: The primary objective for this study is to demonstrate that subcutaneous (SC)
injections of abatacept are non-inferior to intravenous (IV) infusions of abatacept in ACR 20 responses after 6 months of treatment in subjects who have active RA, are receiving methotrexate and experiencing an inadequate response to methotrexate.

Primary end point(s): The primary analysis will assess the proportion of subjects meeting the ACR criteria of 20% improvement (ACR 20) after 6 months (Day 169). The ACR 50, ACR 70 and HAQ will also be assessed.

Secondary Objective: 1) Assess the proportion of subjects with ACR 50 response at month 6 (Day 169).
2) Assess the proportion of subjects with ACR 70 response at month 6 (Day 169).
3) Assess the pharmacokinetics of SC injections of abatacept.
4) Assess the immunogenicity of abatacept.
5) Assess the change in physical function as measured by the HAQ disability index at
Month 6 (Day 169).
6) Assess the proportion of subjects with a HAQ response as measured by a reduction of at least 0.3 unit from baseline in the HAQ disability index at Month 6 (Day 169)
7) Assess the safety and tolerability of SC injections of abatacept.

Subjects receiving SC injections of abatacept will be assessed relative to subjects
receiving IV infusions of abatacept.

Secondary ID(s)

2007-005434-37-FR

IM101-174