E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately to severely active Rheumatoid Arthritis |
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E.1.1.1 | Medical condition in easily understood language |
Moderately to severely active Rheumatoid Arthritis |
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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 | 23.1 |
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 |
The primary objective of the study is to demonstrate equivalent efficacy of proposed biosimilar tocilizumab MSB11456 and EU-approved RoActemra both administered subcutaneously to patients with moderately to severely active rheumatoid arthritis. |
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E.2.2 | Secondary objectives of the trial |
To compare the safety, immunogenicity and long-term efficacy of MSB11456 to EU-approved RoActemra. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetics Sub-study (as detailed in the main study protocol) During the population pharmacokinetic sub-study additional blood samples will be taken for the measurement of tocilizumab concentrations in order to characterize pharmacokinetics of both products. The sample size for the population PK sub-study is approximately 30 patients per group, for a total of up to 60 patients. |
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E.3 | Principal inclusion criteria |
1. Are ≥18 years of age. 2. Diagnosis of rheumatoid arthritis according to the revised 1987 ACR/EULAR Classification 2010 criteria with disease duration of ≥6 months prior to the Screening Visit. 3. Have moderately to severely active rheumatoid arthritis as defined by: a.Swollen Joint Count ≥6 (66 joint count) and Tender Joint Count ≥6 (68 joint count) at screening and randomization. 4. Must have been treated with methotrexate for at least 12 consecutive weeks immediately prior to randomization and are on a stable dose between 10 and 25 mg/week methotrexate for the last 8 weeks prior to screening. 5. Have had previous inadequate clinical response to at least one modifying anti rheumatic drug. 6. Women of childbearing potential (i.e., considered fertile following menarche and until becoming postmenopausal unless permanently sterile) can participate only if they have a negative serum pregnancy test at screening and a negative urine pregnancy test at Day -1 before randomization. Women of childbearing potential must have used and agree to use a highly effective contraception (i.e., methods with a failure rate of less than 1% per year), for 4 weeks before randomization and must agree to continue to practice adequate contraception for 3 months after the last study drug administration. Note: A separate ICF will be provided to and signed by each patient to provide information on the general risks of study participation related to COVID-19 and to document that it is understood by the patient. Another separate Informed Consent Form will be required to be understood and signed by partners of male participating patients who become pregnant during the study or within 10 weeks after the participating patient's last dose of study drug |
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E.4 | Principal exclusion criteria |
1. American College of Rheumatology functional class IV as defined by the ACR classification of functional status or wheelchair/bedbound. 2. Rheumatic autoimmune disease or history of/current inflammatory joint disease other than rheumatoid arthritis or significant systemic involvement secondary to rheumatoid arthritis. Sjögren's syndrome secondary to rheumatoid arthritis is allowed. 3. Previously received tocilizumab, an investigational or licensed biosimilar of tocilizumab or any interleukin-6 acting drugs (approved or investigational). 4. Prior use of targeted synthetic disease-modifying anti-rheumatic drugs like janus kinase inhibitors 5. Prior use of any biological agent for a condition other than rheumatoid arthritis (e.g., ranibizumab, denosumab). 6. Prior use of more than two biologic treatments for rheumatoid arthritis. 7. Prior use of biologic investigational drugs (excluding biosimilars) for the treatment of rheumatoid arthritis. 8. Received any investigational drugs within 12 weeks or five drug half lives prior to screening or planned intake of an investigational drug during the course of this trial including the Follow-Up Period. 9. Previous treatment with any alkylating agents or cell-depleting therapies including investigational drugs or approved biosimilars, or has previously undergone total lymphoid irradiation. 10. Use of non-steroidal anti-inflammatory drugs not at a stable dose for at least 4 weeks prior to randomization or exceeding the maximum recommended dose. Note: Patients are permitted to take aspirin at dose of ≤325 mg daily for cardiac prophylaxis. 11. Use of oral corticosteroids >10 mg/day prednisone or equivalent if the dose has not been stable for at least 6 weeks prior to randomization. 12. Intra-articular or parenteral corticosteroids within 4 weeks prior to randomization. 13. Use of high potency opioid analgesics; 14. Has been treated with intravenous gamma globulin or plasmapheresis within 6 months of randomization. 15. Received a live or attenuated vaccine within 4 weeks prior to randomization. 16. History of hypersensitivity or severe allergic reactions to monoclonal antibodies, any components of the study drug formulations, comparable drugs, or latex. 17. Patient is considered by the Investigator, for any reason, to be an unsuitable candidate for the study. Investigator should specifically evaluate the patient's eligibility taking into consideration COVID-19 risk factors and situation. 18. Has a serious and/or unstable and/or poorly controlled medical condition that, in the opinion of the Investigator, would put the patient at risk by participation in the study. 19. History of diverticulosis requiring antibiotic treatment or any other GI condition that might predispose the patient to gastrointestinal perforations. 20. Uncontrolled medical conditions for which flares are commonly treated with corticosteroids or systemic corticosteroid treatment for these conditions within the last 12 months prior to randomization. 21. Major surgery within 8 weeks prior to screening or planned major surgery during the study. 22. History of, or current myeloproliferative or lymphoproliferative disease or malignancy. 23. Medical evidence of current or history of primary or secondary immunodeficiency as per Investigator's judgment. 24. Pre-existing or recent-onset central or peripheral nervous system demyelinating disorder, or symptoms suggestive of such a disorder as per Investigator's judgment. 25. Confirmed or, based on the signs and symptoms observed at the time of assessment, suspected active COVID-19 infection at the time of screening and/or randomization. 26. Has had any infection as follows: a. Herpes zoster or any opportunistic invasive infection within 6 months of screening. b. Frequent chronic or recurrent infections c. A positive test for human immunodeficiency virus subtype 1 or 2, hepatitis C antibody, hepatitis B surface antigen and/or core antibody for immunoglobulin G and/or immunoglobulin M or total immunoglobulin at screening. d. A serious infection within 8 weeks prior to randomization. e. Treatment with oral antibiotics and/or anti-fungal drugs within 14 days prior to randomization. 27. Medical evidence of active or latent tuberculosis or has had active or latent tuberculosis disease at any time in the past. 28. History of clinically significant drug or alcohol abuse within the last year prior to randomization. 29. Laboratory abnormalities (excluding erythrocyte sedimentation and C reactive protein values) that were considered clinically significant by the Investigator 30. Received a COVID 19 vaccine within 4 weeks prior to randomization, are receiving ongoing COVID-19 vaccination at the time of screening or plan to receive COVID-19 vaccination before the completion of the Week 30 visit of the study. COVID-19 vaccination is considered ongoing if a multidose regimen has been started but has not been completed. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the mean absolute change from baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to Week 24. |
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E.5.2 | Secondary end point(s) |
Efficacy: - DAS28-ESR mean absolute change from baseline at all assessment visits (except Week 1). - ACR20 (20% improvement in ACR Core Set Measurements) response rate at Week 24. Safety: - Occurrence of treatment-emergent adverse events - Occurrence of serious adverse events Immunogenicity: - Antidrug antibody incidence - Antidrug antibody titer - Neutralizing antibody incidence |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
DAS28-ESR mean absolute change from baseline at all assessment visits excl. Week 1 and 24. ACR20 response rate at Week 24.
Occurrence of treatment-emergent AEs up to Week 24, Week 30, Week 55 and Week 63. Occurrence of SAEs up to Week 24, Week 30, Week 55 and Week 63.
Antidrug antibody incidence at Weeks 2, 12, 24, 30, 52 and 55. Antidrug antibody titer at Weeks 2, 12, 24, 30, 52 and 55. Neutralizing antibody incidence at Weeks 2, 12, 24, 30, 52 and 55. |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 64 |
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 |
Moldova, Republic of |
Russian Federation |
Serbia |
Bulgaria |
Germany |
Hungary |
Poland |
Slovakia |
Czechia |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |