| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid Arthritis (RA) |
|
| 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 |
To investigate the effect of TCZ on markers of atherogenic risk in
patients with RA.
Primary objectives:
• To investigate the effect of 12 weeks of treatment with
TCZ on small LDL-L1 particle number
• To investigate the effect of 12 weeks of treatment with
TCZ on arterial stiffness as assessed by pulse-wave
velocity (PWV) |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objective:
• To investigate the effect of 24 weeks of treatment with
TCZ on small LDL-L1 particle number
• To investigate the effect of 24 weeks of treatment with
TCZ on arterial stiffness as assessed by pulse-wave
velocity (PWV) |
|
| 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 >6 months duration diagnosed according to the
revised 1987 American College of Rheumatology criteria.
3. Able to receive treatment on an outpatient basis
4. Have received MTX for at least 12 weeks immediately prior to baseline, of which
the last 8 weeks prior to baseline must have been at a stable dose of between 7.5
and 25 mg/week (oral or parenteral). Patients who have partially responded MTX,
but discontinued treatment for surgery or pregnancy may reinitiate treatment at least
8 weeks prior to baseline with a stable dose for at least 4 weeks.
5. All DMARDs, other than MTX will be withdrawn prior to baseline (see Inclusion
#7 and Exclusion #12)
6. 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
4 weeks prior to baseline
7. Prior to randomization, will have discontinued etanercept for ≥ 2 weeks, infliximab
or adalimumab for ≥ 8 weeks, anakinra for ≥ 1 week, or abatacept for ≥ 8 weeks
(see exclusion #9); discontinuation of leflunomide for ≥12 weeks (or ≥4 weeks after
11 days of standard cholestyramine washout).
8. Swollen joint count (SJC) ≥ 6 (66 joint count) and tender joint count (TJC) ≥ 6 (68
joint count) at screening (Week -3) and baseline
9. At screening HS-CRP ≥ 1.0 mg/dL (10 mg/L) or ESR ≥ 28 mm/hr
10. Palpable carotid and femoral pulse at screening
11. 18 years ≤ Age ≤ 75 years
12. Must be willing to receive oral folate at a minimum dose of 5 mg/week
13. Females of child-bearing potential and males with female partners of child-bearing 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)
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 |
1. Major surgery (including joint surgery) within eight weeks prior to screening or
surgery planned to occur during the first 24 weeks of the study
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
RA
4. Prior history of or current inflammatory joint disease other than RA (e.g., gout,
reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme
disease)
5. Patients weighing >150 kg
6. Patients with uncontrolled co-morbidities, such as diabetes (insulin-dependent),
hypertension (systolic blood pressure > 150 mm Hg or diastolic blood pressure >
100 mm Hg), CAD or CHF, or current atrial fibrillation and cardiac conditions
precluding accurate evaluation of PWV and/or safety
7. Secondary causes of hyperlipidemia, such as uncontrolled primary hypothyroidism
or nephrotic syndrome
8. Intra-articular or parenteral corticosteroids within 6 weeks prior to baseline
9. Inadequate response to an anti-TNF agent during the 6 months prior to baseline
10. Inadequate response to more than 2 anti-TNF agents
11. Initiation of treatment with lipid-lowering agents within 12 weeks prior to baseline; treatment with lipid lowering agents must be at a stable dose within this period
12. Initiation of oral anti-diabetes or anti-hypertensive medication dose within 12
weeks prior to baseline; treatment with anti-hypertensive agents must be at a stable dose within this period
13. Treatment with any investigational agent within 6 weeks of baseline
14. Previous treatment with any cell depleting therapies within 6 months of baseline,
including investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3,
anti-CD19, anti-CD20, and anti-BLys)
15. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba ™ column within 6 months of baseline
16. Immunization with a live/attenuated vaccine within four weeks prior to baseline
17. Previous treatment with TCZ
18. Any previous treatment with alkylating agents within 1 year of baseline such as
cyclophosphamide or chlorambucil, or with total lymphoid irradiation
19. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies
20. 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
21. Evidence of serious uncontrolled concomitant cardiovascular, nervous system,
pulmonary (incl. obstructive pulmonary disease), renal, hepatic, endocrine (incl.
uncontrolled diabetes mellitus) or gastrointestinal disease
22. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel
disease where flares are commonly treated with oral or parenteral corticosteroids
23. Current liver disease as determined by principal investigator.
24. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial
or other infections or any major episode of infection requiring hospitalization or completion of treatment with IV antibiotics within four weeks of screening or completion of treatment with oral antibiotics within two weeks prior to screening
25. Primary or secondary immunodeficiency (history of or currently active)
26. 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
27. Pregnant or nursing (breast feeding) women
28. History of alcohol, drug or chemical abuse within the 6 months prior to screening
29. Patients with lack of peripheral venous access
30. Serum creatinine > 1.4 mg/dL (123 μM) in female patients and > 1.6 mg/dL (140
μM) in male patients
31. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times
upper limit of normal (ULN). (If initial sample yields ALT or AST > 2 times the
ULN, a second sample may be taken and tested during the screening period)
32. Platelet count < 100,000/mm3
33. Hemoglobin < 8.5 g/dL
34. White Blood Cells < 3000/mm3
35. Absolute Neutrophil Count < 2000/mm3
36. Absolute Lymphocyte Count < 500/mm3
37. Positive Hepatitis BsAg, or Hepatitis C antibody with a positive qualitative HCV
PCR test
38. Total Bilirubin > ULN. (If initial sample yields Bilirubin > ULN, a second sample
may be taken and tested during the screening period)
39. Triglycerides > 10 mmol/L (> 900 mg/dL) (non-fasted)
40. TSH > 1.5x ULN
41. Proteinuria > 3+ on spot urine unless 24 hour urine protein < 500 mg |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• To investigate the change from baseline in small LDL particle numbers at Week
12 and,
• To investigate the change from baseline in Pulse Wave Velocity 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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
|
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 8 |
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