E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rheumatoid Arthritis (RA) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 assess the early efficacy of TCZ at week 16 defined as DAS28 remission (<2.6), after 4 courses of 8mg/kg TCZ treatment. |
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E.2.2 | Secondary objectives of the trial |
To assess: - the efficacy of RTX treatment in terms of improvement in commonly used RA outcome measures (DAS28 remission (<2.6), EULAR responses, ACR responses) at week 32 in patients not having responded to 4 courses of TCZ. The efficacy of TCZ treatment (EULAR responses especially late clinical remission, ACR responses) at week 32 in DMARD-IR patients.The effects of TCZ and RTX treatment on patient-reported outcomes.
?Safety will be assessed via reporting of incidences of adverse events and serious adverse events and the number and percentage of patients who discontinue study treatment due to AEs and SAEs.
?To correlate DAS28 response with B-cell panels.
Due to character limitation - details see protocol |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients at baseline with active rheumatoid arthritis (RA) and a DAS28 (ESR) of >3.2 and of ≥6 months duration, diagnosed according to the ACR (American College of Rheumatology) criteria of 1987.
2. Patients able and willing to give written informed consent to participate and comply with the requirements of the study; in addition, written consent for data protection (legal requirement in Germany: Datenschutz-rechtliche Einwilligung) must be provided.
3. Receiving treatment on an outpatient basis.
4. Age ≥18 years.
5. At screening and/or baseline either ESR ≥28mm/h or CRP ≥0.7mg/dL (SI: ≥7mg/L).
6. Receiving permitted DMARDs, one or more; current DMARD therapy must have been at a stable dose for at least 4 weeks prior to baseline.
7. Oral corticosteroids (≤10mg/day prednisone or equivalent) are permitted if dose was stable for at least 4 weeks prior to baseline.
8. Women of child-bearing potential are allowed to participate in this trial only if using reliable, highly effective contraceptives (allowed methods of birth control, i.e. with a failure rate of less than 1 % per year, are implants, injectables, combined oral contraceptives, IUSs (only hormonal contraceptive coil), sexual abstinence or vasectomized partner.
9. Women of childbearing potential or less than one year after menopause (unless surgically steril) must have a negative pregnancy test (urine β-HCG) at screening. Pregnancy test has to be repeated at baseline in case of ab-sence of menstruation or irregular menstrual cycle. |
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E.4 | Principal exclusion criteria |
Exclusion criteria related to general health
1. Major surgery (including joint surgery) within eight weeks prior to baseline or planned major surgery within the study duration (a maximum of 32 weeks following baseline)
2. Functional class IV as identified by the ACR classification of Functional Status in Rheumatoid Arthritis.
3. Rheumatic autoimmune disease other than RA, including SLE, mixed connective tissue disease, 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.
4. Prior history of or current inflammatory joint disease other than RA (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, active Lyme disease).
Exclusion criteria related to medications
5. Patients currently participating in another clinical trial or patients who have participated in another clinical trial within 30 days prior to screening (or five half-lifes of the IMP, whichever is longer) or patients who participated in this trial before.
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. Treatment with intravenous gamma globulin plasmapheresis or immunosorbent column (e.g. Prosorba®) within six months of base-line.
8. Intra-articular or parenteral corticosteroids within four weeks prior to baseline. Injection of intra-articular steroids while on study medication is discouraged, but may be used in a limited fashion.
9. Immunization with a live/attenuated vaccine within four weeks prior to baseline.
10. Previous treatment with TCZ, RTX, or other biologic DMARDs such as TNF-blockers.
11. Combination therapy with methotrexate (MTX) and leflunomide within 4 weeks prior to baseline.
12. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation.
Exclusion criteria related to general safety
13. Severe heart failure (NYHA class IV) or severe, uncontrolled cardiac diseases.
14. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
15. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (incl. obstructive pulmonary disease), renal, hepatic, endocrine (incl. uncontrolled diabetes mellitus) or gastrointestinal disease.
16. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids.
17. History of diverticulitis, diverticulosis requir-ing 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 or evidence of serious uncontrolled concomitant gastrointestinal disease.
18. Current liver disease as determined by principal investigator (patients with prior history of ALT elevation will not be excluded.)
19. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, granulomatous disease on chest X-ray (X-ray should not be older than 90 days related to treatment start), 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.
20. Active tuberculosis (TB) requiring treatment
within the previous 3 years. Quantiferon testing
(IGRA) should be used in preference to protein derivative tuberculin skin (PPD) or ELISPOT testing and must be negative. Patients also must have a negative CXR.
20. Exception: If a PPD test was performed and the test result is positive, treatment for latent TB must be completed and
patients must have a negative CXR. In addition, retesting with IGRA or ELISPOT must be performed and the result must be negative.
21. Primary or secondary immunodeficiency (history of or currently active).
22. History of malignancy, including solid tumors and hematologic malignancies (except basal cell carcinoma of the skin that has been excised and cured).
23. Pregnant or nursing (breast feeding) women.
24. History of alcohol, drug or chemical abuse within the six months prior to screening.
25. Neuropathies or other painful conditions (only referred to joint status) that might interfere with pain evaluation.
26. Any severe neurological diseases and any history of or actual demyelinating diseases
27. Patients with lack of peripheral venous access.
28. Body weight of >130 kg.
Exclusion criteria related to lab findings and Exclusion criteria related to formal aspects ->due to character limitation -> please refer to protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the rate of patients achieving DAS28 remission (<2.6) at week 16. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 80 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |