| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| 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 2 co-primary objectives for this study will compare the clinical efficacy of
abatacept in combination with methotrexate to methotrexate alone on the following:
1) The proportion of randomized and treated subjects with DAS28-CRP < 2.6 at
Month 12.
2) The proportion of randomized and treated subjects with DAS28-CRP < 2.6 at
both Month 12 and Month 18. |
|
| E.2.2 | Secondary objectives of the trial |
1) Assess physical function and health-related quality of life using HAQ and SF-36
(V2.0) in the abatacept/MTX combination, abatacept monotherapy, and MTX
monotherapy arms
2) Assess joint damage progression by MRI scoring at Months 6, 12, 18, and 24 in the abatacept/MTX combination, abatacept monotherapy, and MTX monotherapy arms
3) Assess safety and tolerability including immunogenicity in the abatacept/MTX
combination, abatacept monotherapy, and MTX monotherapy arms.
4) Assess the proportion of randomized and treated subjects in the abatacept
monotherapy arm with a) DAS28-CRP < 2.6 at Month 12 and b) subjects with
DAS28-CRP < 2.6 at both Month 12 and Month 18.
5) Assess the proportion of randomized and treated subjects achieving
Simplified Disease Activity Index (SDAI) defined remission criteria of
3.3 in the abatacept/MTX combination, abatacept monotherapy, and MTX
monotherapy arms at
a) Month 12 and b) Month 18 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 have active clinical synovitis of at least 2 joints, 1 of which must be a
small joint, for at least 8 weeks at the Screening Visit. Distal interphalangeal
joints (DIP)s do not count toward this requirement
b) Subjects have had the onset of persistent symptoms for ≤ 2 years prior to the
Screening Visit.
c) Subjects have a DAS28-CRP ≥ 3.2 at the Screening Visit
d) Subjects are positive for anti-CCP2.
e) Subjects are MTX naive or have minimum exposure to MTX defined as no more
than 10 mg/wk for no more than 4 weeks and no dose for 1 month prior to the
Screening Visit.
f) Subjects are biologic naive and have not received treatment with an approved or
investigational biologic RA therapy (for ex, infliximab, etanercept, anakinra,
adalimumab, rituximab, tocilizumab, golimumab, and certolizumab) prior to screening.
.g) Subjects receiving chloroquin, hydroxychloroquine and sulfasalazine
must stop
treatment (wash-out) for a minumum of 28 days prior to randomization.
h) Subjects receiving oral corticosteroids must be on a stable dose and
at theequivalent of ≤ 10 mg prednisone daily for ≥ 4 weeks or may have
received an IM, IV or IA administration of a corticosteroid ≥ 4 weeks
prior to randomization
3/ Age and Reproductive Status
a) Men and women, ages ≥ 18
b) Men and women of childbearing potential (WOCBP) must be using an acceptable
method of contraception to avoid pregnancy throughout the study for up to
10 weeks (14 weeks for EU) after the last dose of abatacept in such a manner that
the risk of pregnancy is minimized. See Protocol Section 3.3.4 for the definition of WOCBP.
c) Women 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 investigational product.
d) Women must not be breastfeeding
e) Investigators should follow the manufacturer’s recommendations for MTX.
f) Subjects must be able to receive an MRI. See Protocol Section 3.3.4 for contraindications. |
|
| E.4 | Principal exclusion criteria |
1/ Target Disease Exceptions
a) Subjects who meet diagnostic criteria for other rheumatic disease (eg, lupus
erythematosus).
2/ Medical History and 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 the opinion of the investigator,
might place the subject at unacceptable risk for participation in this study.
c) Female subjects who 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
d) Subjects with a history of cancer within the last 5 years (other than non-melanoma skin cell cancers cured by local resection). Existing non-melanoma skin cell
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 any serious acute bacterial infection (such as pneumonia or
pyelonephritis unless treated and completely resolved with antibiotics).
g) Subjects with severe chronic or recurrent bacterial infections (such as recurrent
pneumonia, chronic bronchiectasis).
h) Subjects at risk for tuberculosis (TB). Specifically, subjects with:
i) Current clinical, radiographic or laboratory evidence of active TB.
ii) A history of active TB within the last 3 years even if it was treated.
iii) 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 type.
iv) Latent TB which was 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 and they have initiated treatment for
latent TB with isoniazid (INH) for at least 4 weeks prior to dosing of study
drug and they have a negative chest x-ray at enrollment. Such subjects should
complete 9 months of INH treatment.
i) Subjects with herpes zoster that resolved less than 2 months prior to enrollment.
j) 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
3/ Physical and Laboratory Test Findings
a) Hepatitis B surface antigen-positive subjects.
b) Hepatitis C antibody-positive subjects who are also RIBA-positive or PCR positive.
c) Subjects with any of the following laboratory values:
i) Hgb < 8.5 g/dL.
ii) WBC < 3,000/mm3 (3 x 109/L)
iii) Platelets < 100,000/mm3 (100 x 109/L).
iv) Serum creatinine > 2 times upper limit of normal.
v) Serum ALT or AST > 2 times upper limit of normal.
vi) Any other laboratory test results that, in the opinion of the investigator, might
place the subject at unacceptable risk for participation in this study.
4/ Allergies and Adverse Drug Reaction
a) None
5/ Prohibited Treatments and/or Therapies
a) Subjects who have had prior exposure to abatacept (CTLA4-Ig)
b) Subjects who have been exposed to any investigational drug within 4 weeks or
5 half-lives, whichever is longer.
c) Subjects currently (or in the last 3 months) receiving treatment with azathioprine,
gold, leflunomide, immunoadsorption columns (such as Prosorba columns),
mycophenylate mofetil (CellCept®), cyclosporin, other calcineurin inhibitors or
D-Penicillamine.
d) Subjects who have received any live vaccines within 3 months of study drug
administration or are scheduled to receive live vaccines.
e) Subject who have received an IM, IV or IA administration of a
corticosteroid <= 4
6/ Sex and Reproductive Status
a) Sexually active fertile men not using effective birth control if their partners are
WOCBP.
7/ Other
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
c) Subjects who are illiterate. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The co-primary endpoints are:
1) The proportion of randomized and treated subjects in remission (DAS28-CRP < 2.6) at Month 12 in the Treatment Period
2) The proportion of randomized and treated subjects in remission at both Month 12 and Month 18. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) at Month 12 in the treatment period
2) at both Month 12 and Month 18 |
|
| E.5.2 | Secondary end point(s) |
a) Physical function (HAQ) and SF 36
b) Joint damage progression (MRI)
c) Adverse Event rates
d) Proportion of subjects in the Abatacept monotherapy arm in remission
as defined by the Disease Activity Score (DAS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| 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.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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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.8.4.1 | 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 | 38 |
| 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 | No |
| 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 |
| Australia |
| Canada |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| South Africa |
| United States |
|
| 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 | 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 |
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