| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 |
Primary Objectives:
To assess the efficacy of treatment with MRA versus placebo, in
combination with methotrexate (MTX), with regard to the
following three primary endpoints in patients with moderate to
severe active rheumatoid arthritis (RA) who have had an
inadequate response to MTX:
Reduction in signs and symptoms over 6 months,
Prevention of structural joint damage over 12 months
(with confirmation at 24 months), and
Improvement in physical function over 12 months (with
confirmation at 24 months).
To assess the safety of MRA versus placebo, in combination with
Methotrexate (MTX), with regard to adverse events and
laboratory assessments. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
To explore the pharmacokinetics, immunogenicity and
pharmacodynamic parameters of MRA in this patient
population
To assess long-term safety and efficacy of MRA
administration in the defined patient population |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able and willing to give written informed consent and comply with the
requirements of the study protocol.
2. Patients with rheumatoid arthritis of ≥6 months duration, diagnosed according to
the revised 1987 American College of Rheumatology (ACR; formerly American
Rheumatism Association) criteria
3. Receiving treatment on an outpatient basis.
4. Prior to randomization, will have discontinued etanercept for ≥2 weeks, infliximab
or adalimumab for ≥8 weeks (see exclusion #5), anakinra for ≥1 week,
leflunomide for ≥12 weeks (or ≥4 weeks after 11 days of standard cholestyramine
washout).
5. Have received methotrexate for at least 12 weeks immediately prior to baseline, of
which the last 8 weeks must have been at a stable dose of between 10 and
25 mg/week (p.o. or parenteral).
6. All DMARDs, other than MTX, withdrawn prior to baseline.
7. Swollen joint count (SJC) ≥6 (66 joint count) and tender joint count (TJC) ≥8 (68
joint count) at screening and baseline.
8. At screening either CRP ≥1 mg/dL (10 mg/L) or ESR ≥28 mm/hr
9. Radiographic evidence of at least one joint with a definite erosion attributable to
rheumatoid arthritis, as determined by the central reading site. Any joint of the
hands, wrist, or feet can be considered with the exception of the DIP joints of the
hands.
10. Age ≥18 years.
11. Oral corticosteroids (≤10 mg/day prednisone or equivalent) and NSAIDs (up to
the maximum recommended dose) are permitted if the dose has been stable for at
least 6 weeks prior to baseline.
12. Females of child-bearing potential and males with female partners of childbearing
potential may participate in this trial only if using a reliable means of
contraception (e.g. physical barrier (patient and partner), contraceptive pill or
patch, spermicide and barrier, or IUD).
13. Must be willing to receive oral folate.
14. If female and of childbearing potential, the patient must have a negative urine
pregnancy test within three weeks prior to baseline. |
|
| E.4 | Principal exclusion criteria |
General:
1. Major surgery (including joint surgery) within eight weeks prior to screening or
planned major surgery within six months following randomization.
2. Rheumatic autoimmune disease other than RA, including SLE, MCTD,
scleroderma, polymyositis or significant systemic involvement secondary to RA
(e.g., vasculitis, pulmonary fibrosis or Felty’s syndrome). Sjögren’s Syndrome
with RA is allowable.
3. Functional class IV as defined by the ACR Classification of Functional Status in
Rheumatoid Arthritis.
4. Prior history of or current inflammatory joint disease other than RA (e.g., gout,
reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme
disease).
Excluded Previous or Concomitant Therapy
5. Unsuccessful treatment with an anti-TNF agent (i.e. significant safety issues or
lack of efficacy. Patients who terminated previous anti-TNF treatment due to cost
or discomfort with the subcutaneous injections, may participate in this study) (see
Inclusion #4 for anti-TNF agent washouts).
6. Treatment with any investigational agent within four weeks (or five half-lives of
the investigational drug, whichever is longer) of screening.
7. Previous treatment with any cell depleting therapies, including investigational
agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-
CD20).
8. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba ™
column within six months of baseline.
9. Intra-articular or parenteral corticosteroids within six weeks prior to baseline.
10. Immunization with a live/attenuated vaccine within four weeks prior to baseline.
11. Previous treatment with MRA. (An exemption to this exclusion may be granted
for single dose exposure upon application to the sponsor on a case by case basis.)
12. Any previous treatment with alkylating agents such as cyclophosphamide or
chlorambucil or with total lymphoid irradiation.
Exclusions for General Safety
13. History of severe allergic or anaphylactic reactions to human, humanized or
murine monoclonal antibodies.
14. Evidence of serious uncontrolled concomitant cardiovascular, nervous system,
pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine
(including uncontrolled diabetes mellitus) or gastrointestinal disease.
15. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel
disease, where flares are commonly treated with oral or parenteral corticosteroids.
15a History of diverticulitis, diverticulosis requiring antibiotic treatment or chronic
ulcerative lower GI disease such as Crohn’s disease, ulcerative colitis or other
symptomatic lower GI conditions that might predispose to perforations.
16. Current liver disease as determined by principal investigator. (Patients with prior
history of ALT elevation will not be excluded.)
17. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial
or other infections (including but not limited to tuberculosis and atypical
mycobacterial disease, clinically significant abnormalities on chest X-ray as
determined by the investigator, Hepatitis B and C, and herpes zoster, but
excluding fungal infections of nail beds) or any major episode of infection
requiring hospitalization or treatment with IV antibiotics within four weeks of
screening or oral antibiotics within two weeks prior to screening.
18. Primary or secondary immunodeficiency (history of or currently active).
19. Evidence of active malignant disease, malignancies diagnosed within the previous
10 years (including hematologic malignancies and solid tumors, except basal cell carcinoma of the skin that has been excised and cured), or breast cancer diagnosed
within the previous 20 years.
20. Pregnant women or nursing (breast feeding) mothers.
21. History of alcohol, drug or chemical abuse within the six months prior to
screening.
22. Neuropathies or other painful conditions that might interfere with pain evaluation.
23. Patients with lack of peripheral venous access.
24. Body weight >150 kg.
For Laboratory Exclusion criteria (at screening) please refer to section 4.3 of the Protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary:
1. At Week 24 (6 months):
Proportion of patients with ACR20 response
2. At Week 52 (12 months):
(a) Change from baseline* in modified Sharp total
radiographic score
(b) Change in physical function as measured by the area
under the curve for the change from baseline in the Health
Assessment Questionnaire (HAQ) Disability Index
3. At Week 104 (24 months):
(a) Change from baseline* in modified (Genant) Sharp total
radiographic score (confirmation of week 52 result)
(b) Change in physical function as measured by the area
under the curve for the change from baseline in the Health
Assessment Questionnaire (HAQ) Disability Index
* assessment taken prior to receiving first dose of study
medication is considered baseline |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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 |
|
| 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 | 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.8.4.1 | 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 | 56 |
| 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 |
|
| 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
|
The end of trial will occur when the last participating patient completes the last scheduled visit of the extension period, or when the sponsor decides to discontinue the development program.
All patients, including those who withdraw from the study, must return for a follow-up assessment 4, 8 and 12 weeks after last dose of study medication. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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