| 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 | Classification code | 10039073 |
|
| 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 |
1. To determine the efficacy of RO0506997 (a dual α4 integrin [VCAM1] antagonist) in combination with methotrexate, in adult patients with rheumatoid arthritis (RA) who currently exhibit a partial clinical response to their existing methotrexate therapy.
2. To determine the safety of RO0506997 (a dual α4 integrin [VCAM1] antagonist) in combination with methotrexate, in adult patients with rheumatoid arthritis (RA).
3. To explore the pharmacokinetics (PK) of RO0506997 (in combination with methotrexate) in this population of patients, utilising a population pharmacometric approach.
4. To explore the pharmacodynamics (PD) of RO0506997 (in combination with methotrexate) in this population of patients. |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Patients with RA diagnosed according to the revised 1987 American Rheumatism Association (ACR) criteria.
2. Having RA for a minimum of 6 months.
3. Receiving treatment on an outpatient basis.
4. Have failed no more than 5 DMARDs.
5. Have received oral methotrexate (not necessarily at constant dose) for at least 24 weeks, with a stable dose for at least 8 weeks prior to their baseline visit. The dose of methotrexate at the baseline visit must be at least 10 mg/week and no greater than 25 mg/week.
6. Swollen joint count (SJC) ≥ 6 (66 joint count) at baseline.
7. Tender joint count (TJC) ≥ 8 (68 joint count) at baseline.
8. At least 1 of the following 3 parameters at screening:
- CRP ≥ 1.5 mg/dL as determined by sensitive CRP assay
- ESR ≥ 28 mm/h
- Morning stiffness > 45 minutes
9. Age ≥ 18 years.
10. Corticosteroids (≤ 10 mg/d prednisolone or equivalent) or NSAIDs are permitted if stable for at least 4 weeks prior to baseline. These must remain stable for the duration of the study.
11. Able and willing to receive a stable dose of greater than or equal to 5 mg/week folic acid or the equivalent, given as either a single dose or as divided daily doses.
12. Able and willing to give written informed consent and comply with the requirements of the study protocol.
13. Women who are not either surgically sterile (tubal ligation or removal or ovaries or uterus) or post-menopausal (no spontaneous menstrual periods for at least 1 year) must commit to use a barrier form of contraception in addition to either an intrauterine device or hormonal contraception until at least 1 month after the end of treatment. (Abstinence or sterile partner acceptable).
14. Men who are not surgically sterile must commit to use a condom for contraception until 1 month after the end of treatment. (Abstinence or sterile partner acceptable). |
|
| E.4 | Principal exclusion criteria |
1. Elevation of hepatic transaminases (AST or ALT) > 2x the upper limit of normal during previous treatment with methotrexate or leflunomide, or >1.5x the upper limit of normal at screening.
2. Baseline QTc > 450 msec.
3. Bone/joint surgery within 6 months prior to screening (including joint fusion).
4. Rheumatic autoimmune disease other than RA (Sjögren’s Syndrome with RA is allowable).
5. Felty’s syndrome.
6. ARA functional class IV disease.
7. Active or history of rheumatoid vasculitis.
8. Prior history of gout.
9. Prior history of systemic diseases associated with arthritis, such as inflammatory bowel disease or infectious diseases associated with arthritis, such as Lyme disease or reactive arthritis.
10. Chronic fatigue syndrome or fibromyalgia.
11. Concomitant diseases or conditions that could interfere with clinical evaluations. This includes, but is not limited to, cancer, alcoholism, drug dependency or abuse, psychiatric diseases and active infections.
12. Any condition that would interfere with absorption of oral medicine.
Excluded Previous/concomitant medications
1. Concurrent treatment with any DMARD (DMARDS, including sulphasalazine (SSA) and hydroxychloroquine, must be washed out for 28 days prior to baseline).
2. Previous therapy with anti-TNF or IL-1 antagonist, or other biologic therapy at any time, including previous treatment with any cell depleting therapies (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD20).
3. Treatment with any investigational agent within 4 weeks or 5 half lives of screening, whichever the longer, or 3 months if the experimental agent is a DMARD
4. Patients receiving leflunomide within 6 months of screening, unless an eleven day standard cholestyramine washout is completed 28 days before screening.
5. Previous treatment within 6 months with immunosuppressive agents, for example azathioprine, mycophenolate mofetil, FK506 or cyclosporin A.
6. Previous treatment with alkylating agents within 6 months of the screening visit, such as cyclophosphamide or chlorambucil.
7. Greater than 10 mg/day of prednisolone (or equivalent) within 4 weeks prior to screening visit.
8. Intraarticular or parenteral corticosteroids within 4 weeks prior to the screening visit
9. Immunization with a live or attenuated vaccine (e.g. certain formulations of influenza vaccine) is specifically prohibited during the study, as well as patients, who have had recent (within 4 weeks) immunization with live or attenuated virus.
Exclusions for General Safety
1. Evidence of serious uncontrolled concomitant diseases such as cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders.
2. Subjects susceptible to, or with a history of biliary obstruction or with either an autoimmune or a clinically significant concomitant disease that predisposes to such.
3. Uncontrolled disease states, such as, but not limited to asthma, where flares are commonly treated with oral or parenteral corticosteroids.
4. Active infection, with the exception of fungal infections of nail beds.
5. History of recurrent significant infection or history of recurrent bacterial infections (e.g. Neisseria, Pneumococcal infections).
6. Lymphopenia, defined as total lymphocyte count < 1 x 103/μL for more than 3 months duration immediately (within 6 months) prior to screening.
7. Primary or secondary immunodeficiency (history of or currently active).
8. Prior history of cancer, including solid tumors and hematologic malignancies, excluding basal cell carcinoma of the skin with surgical cure.
9. Required dosing with any medications that are contraindicated with simultaneous MTX dosing (including, but not limited to trimethoprim, probenecid, sulphonamides, etc).
10. Pregnant women or nursing (breast feeding) mothers.
11. History of alcohol, drug or chemical abuse within the previous year.
12. Neuropathies and neurovasculopathies which might interfere with pain evaluation.
13. Patients with lack of peripheral venous access.
Laboratory Exclusion criteria (at screening)
1. Serum creatinine > 2.0 mg/dl.
2. Proteinuria > 2+ on dipstick test and > 2+ on repeated dipstick test. (If 24 hour urine protein is normal, patient need not be excluded)
3. AST or ALT > 1.5 times upper limit of normal.
4. Alkaline phosphatase > 2 times upper limit of normal.
5. Total bilirubin >2 times upper limit of normal.
6. Platelet count < 100,000/μl.
7. Hemoglobin < 9.0 g/dl.
8. Neutrophil count < 1.5 x 103/μl. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the proportion of patients with an ACR20 response at week 12. |
|
| 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 | Information not present in EudraCT |
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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