A randomized, double-blind, controlled study to evaluate pharmacokinetics, pharmacodynamics, safety and efficacy of GP2013 and rituximab in patients with rheumatoid arthritis refractory or intolerant to standard DMARDs and one or two anti- TNF therapies
- Conditions
- Refractory rheumatoid arthritisMedDRA version: 12.1Level: LLTClassification code 10039073Term: Rheumatoid arthritis
- Registration Number
- EUCTR2010-021184-32-FR
- Lead Sponsor
- Hexal AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 164
1. Patients must give written informed consent before any study-related assessment is performed.
2. Patients must be =18 years of age.
3. Patients must have a diagnosis of Rheumatoid Arthritis, based on the ACR 1987 criteria. At least 4 of the following 7 criteria must be fulfilled to confirm the diagnosis of RA:
• joint morning stiffness of at least one hour
• swelling of joints in at least in three joint areas, diagnosed by a doctor
• swelling of MCP and wrist joints, diagnosed by a doctor
• bilateral, symmetric swelling of joints in the same joint areas, diagnosed by a doctor
• rheumatoid nodule
• rheumatoid factor seropositivity
• positive findings in hand radiographs.
4. Patients must have had the diagnosis of RA for at least 6 months.
5. Patients must have active RA at baseline:
• = 6 swollen joints (of 66 joints assessed)
• = 6 tender joints (of 68 joints assessed)
• CRP = 10 mg/L
OR ESR = 28mm/1st hour
Note: If one of the criteria is not met at baseline, the patient is not eligible for randomization at this timepoint. Rescreening (i.e. a second baseline visit) is at the discretion of the investigator.
6. Patients must be seropositive for rheumatoid factor (RF) and/or have antibodies to cyclic citrullinated peptide (anti-CCP).
7. Patients must have inadequate response or intolerance to non-biologic DMARDs, including MTX, and one or two TNF antagonists:
• infliximab (= 3 mg/kg, = 4 infusions),
• adalimumab (40 mg biweekly = 3 months),
• etanercept (25 mg twice weekly or 50 mg weekly = 3 months),
• certolizumab pegol (400 mg every 2 weeks = 3 months),
• or golimumab (50 mg every 4 weeks = 4 months),
and discontinued the biological treatment due to lack of efficacy, or due to being intolerant to at least 1 administration of these agents.
8. Patients may have previously received hydroxychloroquine, chloroquine, steroids, sulfasalazine, leflunomide, gold, cyclosporin but NEITHER any alkylating agents or azathioprine, NOR rituximab, abatacept, tocilizumab, anakinra or other biological treatments, apart from TNF antagonists, for RA.
9. Patients must be on a stable dose of MTX (10-25 mg per week). They must have received MTX for at least 4 months with 25 mg/week as the maximal dose, and with a stable dose for 4 weeks prior to randomization.
10. Patients must be on a stable dose of folic acid or equivalent (= 5 mg per week). They must have received folic acid or equivalent for at least 4 months and with a stable dose for 4 weeks prior to randomization.
11. Patients must have stopped DMARDs for at least 4 weeks. In case of leflunomide it has to be discontinued for 8 weeks prior to randomization (unless a cholestyramine washout is performed, than randomization can happen 4 weeks after). Antimalarial drugs (hydroxychloroquine, chloroquine) or sulfasalazine which are permitted in combination with MTX should be taken at least for 4 months prior to randomization and at a stable dose for at least 4 weeks prior to randomization.
12. Patients must have stopped etanercept, certolizumab pegol and adalimumab for at least 4 weeks, infliximab and golimumab for at least 8 weeks before randomization.
13. If taking glucocorticoids, patients must be on stable dose of maximally 10 mg/day prednisone or equivalent over the past 2 weeks before randomization and continue this therapy during the trial.
14. Patients requiring vaccination should be vaccinated according to current local guidance or practice at least 4 weeks prior to administration of
1. RA patients with functional status class IV classified according to the ACR 1991 revised criteria.
2. Patients with levels of serum IgG, IgM and IgA below LLN.
3. Patients with systemic manifestations of RA, with the exception of Sjögren’s syndrome.
4. Patients taking high potency opioid analgesics (e.g. methadone, hydromorphone, morphine).
5. Female patients nursing (lactating / breast-feeding), pregnant or planning of pregnancy within 12 months after the last infusion of study drug, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
6. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives and intrauterine devices (IUDs)). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable.
7. Patients who have had any therapy with intra-articular injections (e. g. corticoid) required by a flare up to 4 weeks before randomization.
8. Patients with underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, infectious or gastrointestinal conditions, which in the opinion of the investigator immunocompromizes the patient and/or places the patient at unacceptable risk by receiving immunomodulatory therapy within the study – especially patients with clinical history of Felty’s Syndrome.
9. Patients with significant medical problems, including but not limited to the following: uncontrolled hypertension (= 160/95 mmHg), congestive heart failure (New York Heart Association status of class III or IV).
10. Patients with screening total WBC count < 3000/µL, platelets < 100,000/µL, neutrophils < 1,500/µL or hemoglobin < 8.5 g/dL.
11. History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests such as AST, ALT, or alkaline phosphatase. Any single parameter may not exceed 3 x upper limit of normal (ULN). A single parameter elevated up to and including 3 x ULN should be re-checked once more as soon as possible, and in all cases, at least prior to randomization.
12. Patients with history of renal trauma, glomerulonephritis, a single kidney or a creatinine level exceeding 1.5 mg/dL.
13. History of lymphoproliferative disease or any known malignancy or history of malignancy within the past 5 years (except non-melanoma skin cancer which has been treated with no evidence of recurrence in the past 3 months, carcinoma in situ of the cervix, polyps (removed) in the colon with non-invasive malignancy).
14. Patients who have lost or donated ? 400 mL blood in the 8 weeks prior to randomization.
15. Inability or unwillingness to undergo repeated venepuncture (poor tolerability or lack of access to veins).
16. Patients with plans to receive live vaccines during the study or 4 weeks prior to randomization.
17. Known infection with HIV according to patient history.
18. Active or latent hepatitis B (HBsAg positive) or hepatitis C at screening.
19. Patients with other inflammatory diseases which might confound the evaluation of the efficacy (e.g. Crohn’s disease, ulcerative colitis).
20. History of ongoing, chronic or recurrent infectious disease or evidence of tub
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method