E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rheumatoid Arthritis |
Rheumatoider Arthritis |
|
E.1.1.1 | Medical condition in easily understood language |
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation and deformity of the joints. Other problems may also develop, including inflammation in various parts of the body. |
Rheumatoide Arthritis(RA) ist eine chronische Autoimmunerkrankung,die Entzündung und Deformierung der Gelenke verursacht.Es könnte sich auch Entzündung an verschiedenen Teilen des Körpers entwickeln. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10039075 |
E.1.2 | Term | Rheumatoid arthritis and associated conditions |
E.1.2 | System Organ Class | 100000004870 |
|
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 |
The study objective is to identify potential safety risk of the transition from the originator product (US-licensed Rituxan® or EU-approved MabThera®) to GP2013 (proposed biosimilar product) as compared to continuous treatment with the originator product in terms of general safety and immunogenicity.
|
|
E.2.2 | Secondary objectives of the trial |
Is no secondary objectives |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or non-pregnant, non-lactating female patients at least 18 years of age at screening, who give written informed consent before any assessment is performed. 2. Patients must have the diagnosis of RA (according to American College of Rheumatology 2010 criteria). 3. Patients must have received at least one full treatment course of rituximab for the therapy of RA (i.e. 2 complete i. v. infusions of 1000 mg of Rituxan® in the USA or MabThera® in the EU) six to eighteen months prior to randomization. 4. Patients must be eligible for the subsequent treatment course with Rituxan® or MabThera® according to the clinical judgment of the Investigator. 5. Patients must be on a stable dose of methotrexate (MTX) (7.5 to 25 mg per week) for at least 4 weeks prior to randomization. If patients receive a combination of DMARDs (MTX + hydroxychloroquine or MTX+ chloroquine or MTX+ sulfasalazine) these DMARDs must be also on a stable dose for at least 4 weeks prior to randomization. 6. Patients must be on a stable dose of folic acid or folinic acid (≥ 5 mg per week) for at least 4 weeks prior to randomization.
|
|
E.4 | Principal exclusion criteria |
1. RA of functional status class IV classified according to the ACR 1991 revised criteria. 2. Systemic manifestation of RA, with the exception of Sjögren’s syndrome. 3. Use of any other investigational drugs within 30 days prior to screening (or within 5 half-lives or until the expected PD effect has returned to baseline, whichever is longer). 4. Requiring treatment with any biological medicinal product during the study other than the study medication. 5. Treatment with any biologics for any indication since the start of last treatment with either Rituxan®/MabThera®. 6. History of severe hypersensitivity to either Rituxan®/MabThera® or any of its excipients, requiring drug discontinuation. 7. Any contraindication to Rituxan®/MabThera® or MTX. 8. Therapy with any DMARDs (including tofacitinib) other than MTX or combination of MTX with hydroxychloroquine or MTX with chloroquine or MTX with sulfasalazine within 4 weeks prior to randomization. In case of leflunomide it has to be discontinued 8 weeks prior to randomization (if a cholestyramine washout is performed, leflunomide has to be discontinued 4 weeks prior to randomization). 9. Previous treatment with any cell depleting therapies, including investigational agents. 10. Current treatment or need for treatment with any prohibited medications. 11. Any serious illness or uncontrolled medical condition, including but not limited to severe infections, significant hepatic or renal disease, uncontrolled hypertension (defined as ≥160/95), congestive heart failure (NYHA class III or IV), or other severe, uncontrolled cardiac disease. 12. Any medical condition which, in the investigator’s opinion, would preclude the patient from completing all protocol requirements. 13. Any of the following laboratory values at screening: WBC < 3000/μL; Platelets < 100.000/μL; Neutrophils < 1.500/μL; Hemoglobin < 85 g/L; aspartate aminotransferase (AST) > 3 × ULN (upper limit of normal); alanine aminotransferase (ALT) > 3 × ULN; gamma-glutamyl transferase (GGT) > 3 × ULN; alkaline phosphatase (AP) > 3 × ULN; glomerular filtration rate (GFR) < 60 mL/min/1.73m2 (GFR calculated as per 4-variable MDRD formula); immunoglobulin G (IgG) and/or IgM and/or IgA below LLN. 14. Positive serology to hepatitis C infection. 15. Positive serology to hepatitis B infection. 15a. In case a patient is HBsAg negative but positive for hepatitis B core antibody [anti-HBc], this patient can only be included after consultation with a hepatitis expert to clarify the potential risk of Hepatitis B reactivation, required Hepatitis B monitoring and antiviral therapy. 16. History of serious recurrent or chronic infectious disease (excluding fungal infections of the nail beds) or active systemic infection within 2 weeks prior to screening or during the screening period, except for common cold. 17. Severely immunocompromised state, including but not limited to Felty’s syndrome and known (HIV) infection. 18. Any malignancy prior to screening, with exception of adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer, or non-invasive malign colon polyps that have been removed with no evidence of recurrence. 19. Active tuberculosis. If a QuantiFERON®- Tuberculosis (TB) Gold test at screening is positive, further work-up, according to local guidelines/practices needs to be performed to conclusively establish that that the patient has no evidence of active tuberculosis. 20. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum hCG laboratory test (> 5 mIU/mL). 21. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they agree to use highly effective methods of contraception during the study and up to 12 months after last infusion of study medication. Women are considered not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. 22. History of vaccination with live vaccines within 4 weeks prior to randomization or known to require live vaccines during the 6 month after the randomization visit. 23. History or evidence of ongoing drug or alcohol abuse within the last 6 months. 24. Blood donation or blood loss of >400 mL in the 8 weeks prior to randomization. 25. Inability or unwillingness to undergo repeated venipuncture (poor tolerability or lack of access to veins).
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The following safety variables will be evaluated: • Hypersensitivity reactions • Anaphylactic reactions • Infusion-related reactions • Immunogenicity (development of anti-drug-antibodies (ADA)) • Adverse events and serious adverse events • Other safety variables (vital signs, laboratory variables, body weight) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
All safety parameters will be analyzed on the safety analysis set (SAF). |
|
E.5.2 | Secondary end point(s) |
Is no secondary endpoints |
Keine sekundäre Endpunkte |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Is no secondary endpoints |
Keine sekundäre Endpunkte |
|
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 | No |
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 | 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) | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 | No |
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 |
Germany |
Hungary |
Poland |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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 | 0 |
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 | 0 |