| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Active Rheumatoid Arthritis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Active Rheumatoid Arthritis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| 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 |
|
| 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 demonstrate biosimilarity between Test Product: MabionCD20® and the Reference Product: MabThera® (rituximab) in patients with active rheumatoid arthritis (RA), based on the percentage of patients in each treatment group achieving the primary efficacy endpoint of a ³ 20% improvement on the American College of Rheumatology score (ACR20) at Week 24 |
|
| E.2.2 | Secondary objectives of the trial |
1.To assess biosimilarity between Test Product: MabionCD20 and the Reference Product: rituximab.
2. To demonstrate comparative safety and tolerability of a single course of treatment (two infusions spaced two
weeks apart) of MabionCD20 and rituximab in patients with moderate to severe active RA.
3. To demonstrate bioequivalence in pharmacokinetic (PK) characteristics between MabionCD20 and rituximab.
4. To demonstrate safety of MabionCD20 as second cycle treatment after initial rituximab treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient/subject must meet all of the following inclusion criteria to be enrolled in the study:
1. Able to provide written informed consent after receiving information about benefits and potential risks of the trial, as
well as details of the insurance covering the subjects participating in the study
2. Caucasian males and females ³ 18 up to 80 years old
3. Body Surface Area (BSA) between 1.5 – 2.2 m2 calculated according to the DuBois & DuBois formula : BSA in m2 =
(Weight (kg) 0.425 x Height (cm) 0.725) x 0.007184
4. Patients with Rheumatoid Arthritis diagnosed according to revised 1987 American Rheumatism Association (ARA)
criteria [Appendix 3] with disease duration minimum 6 months prior to screening visit, who are naive to tumor necrosis
factor (TNF) antagonists or any other biological agents and who have had an inadequate response to an adequate
regimen of methotrexate or/and other disease modifying anti-rheumatic drugs (DMARDs)
5. Patients with moderate to severe active RA defined as the presence of the following:
· ³ 8 swollen joints and ³ 8 tender joints, observed by a physician at the screening
· radiographic evidence of ³ 1 joint with define erosion attributable to RA and 2 or more of the following:
· serum C-reactive protein (CRP) ³ 6 mg/L
· erythrocyte sedimentation rate (ESR) ³ 28 mm/hr
· morning stiffness in and around joints lasting longer than 45 minutes
6. Patients on methotrexate treatment receiving 10-25 mg /week for at least 12 weeks, with the last 4 weeks at a stable
dose
7. Negative serum pregnancy test for women of childbearing potential
8. Female and male (or her/his partner) of childbearing potential willing to use acceptable forms of contraception (e.g.,
hormonal contraceptive, contraceptive patch, intrauterine device, double- barrier method (condom or diaphragm with
spermicide, surgical sterilization, partner’s vasectomy) starting from screening and until 12 months following the last
infusion.
9. Ability and willingness to comply with the requirements of the study protocol |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following exclusion criteria [12] are not to be enrolled:
1. History of or current rheumatic autoimmune disease other than RA eg. Juvenile Idiopathic Arthritis (except concurrent Sjogren’s
syndrome)
2. History of or current inflammatory joint disease other than RA
3. American College for Rheumatology functional Class IV disease
4. History of significant systemic involvement secondary to RA (systemic lupus erythematosus [SLE], scleroderma, inflammatory bowel
disease, severe vasculitis, pulmonary fibrosis, Felty’s syndrome)
5. Inability to understand the written and verbal instructions, in particular the risks connected with the study
6. History of psychiatric disorder that would interfere with normal participation in this protocol
7. Subject has known positive tests for HIV, hepatitis B surface antigen (HBsAg), hepatitis C antibody
8. Serious and uncontrolled coexisting diseases which, in the Investigator's opinion, would preclude subject participation. These may
include but are not limited to:
· Known cardiopulmonary disease, e.g. coronary artery disease, significant cardiac arrhythmias or severe congestive heart failure,
i.e. satisfying criteria for the New York Heart Association [NYHA] classes III or IV
· Serious and uncontrolled pulmonary diseases (chronic, latent and acute infections of the lung, obstructive pulmonary disease)
· History of or currently treated serious central nervous system/neurological disorders
· Any neurological (congenital or acquired), vascular or systemic disorder that might affect any of the efficacy assessments, in
particular, joint pain and swelling (e.g., neuropathies and neurovasculopathies, Parkinson’s disease, cerebral palsy, diabetic
neuropathy
· Serious disorders of the renal, hepatic, endocrine, or gastrointestinal system
· Active bacterial, viral, fungal, mycobacterial, or other infection (including tuberculosis, sepsis, opportunistic infections) but
excluding fungal infections of nail beds
· History of recurrent clinically significant infection
· History of tuberculosis or latent tuberculosis tested and confirmed according to the local standards and regulations and/or
positive result of Chest X-ray for tuberculosis at screening or within last 6 months prior to screening.
· History of cancer including solid tumors, haematologic malignancies, without recovery /remission within 5 years prior to
screening, except basal cell and squamous cell carcinoma of the skin that have been excised and cured and treated cervical
cancer in situ.
· History of significant cytopenia or other serious bone marrow disorders
· Primary or secondary immunodeficiency
· History of drug, alcohol, or chemical abuse within 2 years prior to screening
· Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable
suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of
the results or render the patient at high risk from treatment complications
9. Serious abnormal laboratory findings, specifically:
· Neutrophil count < 1.500 / μL
· Platelet count < 75.000 / μL
· Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times upper limit of normal
· Hemoglobin <8.0 g/dL
· IgG below 5.0 mg/mL or IgM below 0.4 mg/mL
· Any other serious laboratory abnormality
10. Prior treatment with rituximab, other anti-CD20 mAb or anti-TNF-a drug or any other biological agent
11. Use of systemic glucocorticoids at dose higher than 10mg prednisolone daily or equivalent, within 2 weeks prior to screening and
between screening and Day 1
12. Allergic reaction or intolerance to rituximab, MabionCD20, or any of their components
13. Severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or previous treatment of any lymphocytedepleting
therapies
14. Intolerance or contraindications to administration of IV glucocorticoids
15. Major surgery (including joint surgery) within 8 weeks prior to screening or planned surgery within 12 months after baseline
16. Recent vaccination, especially live viral vaccinations (< 4 weeks prior to study drug infusion on Day 1)
17. Blood donation or other blood loss of more than 500 mL within the last two months prior to screening visit
18. Pregnancy or lactation or women planning to get pregnant during the course of the study and/or within 12 months post last study drug
infusion.
19. Lack of peripheral venous access
20. Participation in a clinical trial during the two months prior to enrolment in the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary PK Endpoints:
· AUC(0-t): area under the plasma concentration-time curve from the first administration to final time point at Week 24. The area under the plasma concentration will be calculated by the linear trapezoidal method up to Cmax and by log-linear approximation after Cmax
· Cmax - second: maximum measured plasma concentration after the second infusion of the treatment cycle
Efficacy Endpoints:
- Percentage of patients who achieved an ACR20 at Week 24.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary PK Endpoints:
- Cmax - first: maximum measured plasma concentration after the first infusion of the treatment cycle.
- Ctrough: plasma concentration just before second study treatment infusion on Day 15
- AUC(0-∞): The area under the plasma concentration versus time curve from time 0 to infinity. AUC(0-∞) is calculated as the sum of AUC(0-t) plus the ratio of the last measurable plasma concentration to Kel
- t½ - after second infusion: apparent first-order terminal elimination half life will be calculated as ln(2)/ Kel
- Volume of distribution at steady state
- Plasma clearance
Efficacy secondary endpoints:
- Percentage of patients who achieved an ACR20
- Percentage of patients who achieved an ACR50
- Percentage of patients who achieved an ACR70
- Mean change from baseline in Disease Activity Score (DAS28 – ESR)
- Percent of patients with moderate response on the European League Against Rheumatism (EULAR) scale
- Percent of patients with good response on the European League Against Rheumatism (EULAR) scale |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 4, 8, 12, 16, 20, 24, 48 |
|
| 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 | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Georgia |
| Lithuania |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Ukraine |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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