| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RHEUMATOID ARTHRITIS, NOS |
|
| E.1.1.1 | Medical condition in easily understood language |
| Rheumatoid Arthritis (RA) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| 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 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.
The primary objective of the LT phase of the study is to assess the safety and long-term tolerability of SC injections of abatacept in subjects who have completed the initial 6-month treatment period. |
|
| E.2.2 | Secondary objectives of the trial |
*ST phase
Assess:
1 & 2) proportion of subjects with ACR 50 and ACR 70 response at Day 169
3)PK of SC injections of abatacept
4)immunogenicity of abatacept
5)change in physical function as measured by HAQ disability index at Day 169
6)proportion of subjects with a HAQ response as measured by reduction of at least 0.3 unit from baseline in the HAQ disability index at Day 169
7)safety & tolerability of SC injections of abatacept
Subjects receiving SC injections of abatacept will be assessed relative to subjects
receiving IV infusions of abatacept.
*LT Phase
Assess:
1)proportion of subjects with ACR 20, ACR 50 and ACR 70 responses throughout LT
2)PK of SC injections of abatacept throughout LT
3)immunogenicity of abatacept
4)change in physical function as measured by HAQ disability index throughout LT
5)proportion of subjects with a HAQ response as measured by a reduction of at least 0.3 units from baseline in the HAQ disability index throughout LT
|
|
| 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 |
Anti-TNF failure Substudy Protocol Amendment 05 - Site Specific (v2.0, date 02-Oct-2008) & Amendment 08 - Site Specific (v1.0, date 11-May-2009).
*Primary Objective:
Assess immunogenicity and safety of SC abatacept in the anti-TNF failure population.
*Secondary Objectives:
Assess PK of SC abatacept in the anti-TNF failure population
Assess ACR 20 response with SC and IV abatacept treatment at Month 6 in the anti-TNF failure population
Assess physical function (as measured by HAQ disability index) with SC and IV abatacept treatment at Month 6 in the anti-TNF failure population
Assess disease activity (as measured by DAS28-CRP) with SC and IV abatacept treatment at Month 6 in the anti-TNF failure population. |
|
| 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 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 following disease activity:
i) 6 or more swollen joints (66 joint count) and
ii) 8 or more tender joints (68 joint count) and
iii) no restriction on hsCRP
After 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) Creactive protein (hsCRP) ≥ 0.8 mg/dL (result used from screening or Day -3
visit).
6) Subjects must be willing to self-inject or allow a caregiver to do it for them.
7) Subjects must be able to adhere to the study visit schedule, understand, and comply with other protocol requirements.
|
|
| E.4 | Principal 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, whichever is longer
d)Subjects currently (or in last 3 months) receiving treatment with azathioprine,
gold, leflunomide, immunoadsorption columns (such as Prosorba columns),
mycophenylate mofetil (CellCept®), cyclosporin A, other calcineurin inhibitors or
D-Penicillamine. Not applicable per Amendment 03
e)Subjects who have received any live vaccines within 3 months of study drug
administration or are scheduled to receive live vaccines
f)Subjects currently (at time of informed consent) treated with anti-TNF
therapy, such as Adalimumab & Infliximab (within 8 weeks of last dose), or
Etanercept (within 4 weeks of last dose). Not applicable in Amendment 05
g)Subjects having discontinued an anti-TNF therapy due to lack of efficacy in the
past. Not applicable in Amendment 05
h)Subjects exposed to multiple anti-TNF therapies
i)Subjects currently treated with anakinra unless a minimum 4-week wash-out
period has been completed before Day 1
j)Subjects that received prior treatment with any investigational biologic not
currently approved
k)Subjects who have been exposed to any approved biologic (not listed in inclusion criterion 4b, wash-out requirements) within 4 weeks or 5
half-lives, whichever is longer
7)Other
a)Involuntarily incarcerated subjects or prisoners
b)Subjects who are compulsorily detained for treatment of psychiatric or physical (eg infectious disease) illness
c)Illiterate Subjects |
|
| E.5 End points |
| E.5.1 | 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.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Number of Participants Achieving ACR 50 and ACR 70 Responses at Day 169
2) Mean Baseline Health Assessment Questionnaire Disability Index (HAQ-DI) for Participants With Assessments at Day 169
3) Adjusted Mean Change From Baseline to Day 169 in HAQ-DI
4) Number of Participants Achieving Clinically Meaningful HAQ-DI Response at Day 169
5) Number of Participants With Death As Outcome, Serious Adverse Events (SAEs), Treatment-related SAEs, SAEs Leading to Discontinuation, Adverse Events (AEs), Treatment-related AEs, or AEs Leading to Discontinuation
6) Number of Participants With AEs of Special Interest
7) Number of Participants With Clinically Significant Abnormalities in Vital Sign Measurements
8) Number of Participants With Hematology Laboratory Test Results Meeting the Criteria for Marked Abnormality
9) Number of Participants With Liver Function Laboratory Test Results Meeting the Criteria for Marked Abnormality
10) Number of Participants With Electrolyte Laboratory Test Results Meeting the Criteria for Marked Abnormality
11) Minimum Observed Serum Concentration of Abatacept
12) Maximum Observed Serum Concentration of Abatacept
13) Area Under The Curve In A Dose Interval (AUC TAU) of Abatacept
14) Total Body Clearance of Abatacept
15) Apparent Clearance of Abatacept
16) Number of Participants With Positive Anti-abatacept or Anti-Cytotoxic T Lymphocyte Antigen 4-T Cell (CTLA4-T) Responses Over Time by Enzyme Linked Immunoabsorbant Assay (ELISA)
17) Number of Participants With Positive Anti-abatacept Responses Over Time by Electrochemiluminescence Immunoassay Among the First 10% of Participants Randomized
18) Time-matched Median Percent Change From Baseline in Levels of Serum C-reactive Protein Over the Short-term Period
19) Number of Participants Seroconverting by Day 169 According to Status (Negative or Positive) at Baseline. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) & 2) Day 169
3) Baseline to Day 169
4) Day 169
5) and 6) Day 1 to 56 days after last dose in short-term or first dose in the long-term, whichever occurs first.
7) 8) 9) and 10) Day 1 through end of short-term period (Day 169)
11) Days 57, 85, 113, 120, 127, 134, 141, and 169
12) End of infusion on Days 1 and 113 for IV infusion and in the dosing interval of Days 113 to 120 for subcutaneous
13) 14) and 15) Dosing interval between Days 113 and 141 (TAU=28 days)
16) and 17) Days 1, 85, and 169 and postvisits on Days 28, 56, and 85
18) Baseline to Days 15, 29, 57, 85, 113, 141, and 169
19) Baseline to Day 169 |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| comparison of 2 different administration routes of Abatacept |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 |
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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