A Clinical Trial to study the Safety, Tolerability and Effect of Tocilizumab in Patients with Active Rheumatoid Arthritis taking Background Non-biologic DMARDs and having an Inadequate Response to Current Non-biologic DMARD and/or Anti-TNF Therapy
Multi-National Open-Label Study to Evaluate the Safety, Tolerability and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis on Background Non-biologic DMARDs who have an Inadequate Response to Current Non-biologic DMARD and/or Anti-TNF Therapy
1. Male or non-pregnant, non-nursing female
2. Greater or equal to 18 years of age
3. Diagnosis of RA of Greater or equal to 6 months duration and moderate to severe disease activity
defined as a DAS28 greater 3.2 at screening
4. Receiving treatment on an outpatient basis
5. Patients on greater or equal to 1 non-biologic DMARDs and/or anti-TNF therapy (see section 6.1) at a
stable dose for a period greater or equal to 8 weeks at any time prior to treatment (baseline)
6. Patients with inadequate clinical response to a stable dose of non-biologic DMARD
or anti-TNF therapy
7. If patients are receiving an oral corticosteroid, the dose must have been stable for at
least 25 out of 28 days prior to treatment (baseline)
8. Able and willing to give written informed consent and comply with the requirements
of the study protocol
ExclusionCriteria
Details
Disease
1. Major surgery (including joint surgery) within 8 weeks prior to screening or planned
major surgery within 6 months following enrollment
2. Rheumatic autoimmune disease other than RA, including systemic lupus
erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma,
polymyositis, or significant systemic involvement secondary to RA (e.g. vasculitis,
pulmonary fibrosis or Felty?s syndrome)
Patient with interstitial pulmonary fibrosis and still able to tolerate MTX therapy are
permitted
Sjögren?s Syndrome with RA is permitted
3. Functional class IV as defined by the ACR Classification of Functional Status in RA
(largely or wholly incapacitated with patient bedridden or confined to wheel chair,
permitting little or no self-care)
4. Prior history of or current inflammatory joint disease other than RA (e.g. gout,
reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease)
Drug-specific
5. Treatment with any investigational agent or with anakinra, calcineurin inhibitors (e.g.
tacrolimus or cyclosporine) , mycophenolate mofetil or mycophenolic acid sodium
within 4 weeks (or 5 half-lives of investigational agent, whichever is longer) before
screening
6. Previous treatment with any cell-depleting therapies, including investigational agents
(e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20)
7. Previous treatment with abatacept
8. Treatment with leflunomide in combination with MTX
9. Treatment with IV gamma globulin, plasmapheresis or Prosorba® column within 6
months before baseline
10. Intraarticular or parenteral corticosteroids within 6 weeks prior to baseline
11. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline
12. Previous treatment with TCZ (an exception to this criterion may be granted for
single-dose exposure upon application to the sponsor on a case by case basis)
13. Any previous treatment with alkylating agents, such as cyclophosphamide or
chlorambucil, or with total lymphoid irradiation
Laboratory analyses (at screening)
14. Serum creatinine > 142 μmol/L (1.6 mg/dL) in female patients and > 168 μmol/L (1.9
mg/dL) in male patients and no active renal disease.
15. ALT (SGPT) or AST (SGOT) > 1.5 ULN (If initial sample yields ALT [SGPT] or
AST [SGOT] > 1.5 ULN, a second sample may be taken and tested during the
screening period)
16. Platelet count < 100 x 109/L (100,000/mm3)
17. Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
18. WBC count < 1.0 x 109/L (1000/mm3), ANC < 1 x 109/L (1000/mm3)
19. ALC < 0.5 x 109/L (500/mm3)
20. Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody
21. Total bilirubin > ULN (If initial sample yields bilirubin > ULN, a second sample may
be taken and tested during the screening period)
22. Triglycerides > 10 mmol/L (> 900 mg/dL) at screening (non-fasted)
General medical
23. Pregnant women or nursing (breastfeeding) mothers
24. Females of child-bearing potential who are not using a reliable means of
contraception, e.g. physical barrier (patient and partner), contraceptive pill or patch,
spermicide and barrier, or IUD
25. History of severe allergic or anaphylactic reactions to human, humanized, or murine
monoclonal antibodies
26. CXR evidence of any clinically significant abnormality
27. Evidence of serious uncontrolled concomitant cardiovascular, nervous system,
pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine
(including uncontrolled diabetes mellitus) or GI disease
28. In patients with a history of diverticulitis or diverticulosis requiring antibiotic
treatment, the treating physician needs to consider the benefit-risk ratio
29. A history of chronic ulcerative lower GI disease such as Crohn?s disease, ulcerative
colitis or other symptomatic lower GI conditions that might predispose to perforations
30. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease
where flares are commonly treated with oral or parenteral corticosteroids
31. Current liver disease as determined by principal investigator. Patients with prior
history of ALT (SGPT) elevation are not excluded
32. 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 CXR 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 4 weeks of screening, or oral antibiotics within 2 weeks prior to
screening (does not apply to treatment of latent TB)
33. History of or currently active primary or secondary immunodeficiency
34. Evidence of active malignant disease, malignancies diagnosed within the previous 5
years (including hematological malignancies and solid tumors, except non-melanoma
skin cancer that has been excised and cured), or breast cancer diagnosed within the
previous 5 years
35. Active tuberculosis (TB) requiring treatment within the previous 3 years
36. Patients should be screened for latent TB, prior to biologics use, as per local
guidelines or good clinical practice in your country. Patients with latent tuberculosis
should be treated with standard antimycobacterial therapy (at least 4 weeks) before
initiating TCZ and have a negative CXR for active TB at screening.
37. HIV positive patient
38. History of alcohol, drug or chemical abuse within the 6 months prior to screening
39. Neuropathies or other painful conditions that might interfere with pain evaluation
40. Patients with lack of peripheral venous access
41. Body weight of > 150 kg
To assess the safety and tolerability of tocilizumab (TCZ)
monotherapy or in combination with non-biologic diseasemodifying
antirheumatic drugs (DMARDs) in patients with
moderate to severe active RA
Incidence of adverse events and serious adverse events
during 24 weeks of TCZ monotherapy or combined
treatment with TCZ and one or more of the background nonbiologic
disease modifying anti-rheumatic drugs (DMARDs)
approved for rheumatoid arthritis (RA) in patients with
moderate to severe active RA
Secondary Outcome
Outcome
TimePoints
To assess the efficacy of TCZ monotherapy or in combination with
non-biologic DMARDs
? Number and percentage of patients with AE- and SAErelated
discontinuation of TCZ at every visit
? Number and percentage of patients with all-cause
discontinuation of TCZ at every visit
? Incidence of AEs, SAEs and discontinuations in current and prior users of TNF antagonists at every visit
? Number and percentage of patients with ALT (SGPT) or
AST (SGOT) elevations > 1.5 ULN, > 3 ULN and > 5 ULN
at every visit
? Number and percentage of serious infections at each visit
? Change from baseline to highest values for ALT (SGPT) or
AST (SGOT), LDL and total cholesterol and to lowest value
for ANC
? Number and percentage of patients with elevations in lipids
according to the ATPIII guidelines at every visit
? Number and percentage of patients achieving a clinically
meaningful improvement in Disease Activity Score 28
(DAS28) (reduction of at least 1.2 units) at every visit and
time to clinically meaningful improvement in DAS28
? Number and percentage of patients achieving low disease
activity (DAS28 < 3.2) at every visit and time to low disease
activity
? Number and percentage of patients achieving remission
(DAS28 < 2.6) at every visit and time to DAS28 remission
? Disease activity as measured by DAS28 at every visit
? Number and percentage of patients achieving ACR20,
ACR50, ACR70 and ACR90 response at every visit
? CRP and ESR at every visit
? Mean change from baseline in individual parameters of ACR
core data set at every visit
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
India is participating with the recruitment target of 50 patients. India Recruitment started on 8-May-2009 , currently ongoing.All the 11 sites have been initiated and India Completed the recruitment of 50 patients in the study in AUG 2009 and all sites were closed in India in Aug 2010.