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 | 21.0 |
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 |
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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. Have a body weight of <100 kg at screening. 3. 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. 4. 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. b. Radiographic evidence of ≥1 joint with a definite erosion attributable to rheumatoid arthritis at screening. The radiographic evidence of joint erosion should be no older than 6 months. c. C-reactive protein ≥1 mg/dL (≥10 mg/L) and/or erythrocyte sedimentation rate ≥28 mm/hour at screening. 5. 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. Note: Oral and/or subcutaneous administration of methotrexate is allowed. 6. Must be willing to receive at least 5 mg/week or equivalent of folic acid. 7. Have had previous inadequate clinical response to at least one modifying anti rheumatic drug. 8. Have withdrawn all disease-modifying anti-rheumatic drugs other than methotrexate at least 8 weeks prior to randomization with the exception of leflunomide which must have been discontinued for ≥12 weeks prior to randomization (or ≥4 weeks after 11 days of standard cholestyramine washout). 9. Had discontinued biologic treatment for ≥12 weeks prior to randomization. 10. Must be able and willing to self-administer subcutaneous injections or have a qualified/trained person(s) available to administer subcutaneous injections. 11. 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. Women of childbearing potential whose preferred lifestyle is total abstinence from intercourse may participate in the study. Withdrawal and rhythm methods are not considered to be highly effective methods of contraception and are not permitted as the sole method of contraception in this study. 12. Women who are postmenopausal (i.e., age-related amenorrhea ≥12 consecutive months and increased follicle-stimulating hormone >40 mIU/mL), or women who have undergone documented hysterectomy, bilateral oophorectomy, or bilateral salpingectomy are exempt from pregnancy testing. If necessary to confirm postmenopausal status, a follicle-stimulating hormone sample will be tested at screening. Females on hormone replacement therapy and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their hormone replacement therapy during the study. Otherwise, they must discontinue hormone replacement therapy to allow confirmation of postmenopausal status before study enrollment. Women who were taking hormone replacement therapy prior to study entry are allowed to participate in the study if they have a negative pregnancy test at screening and prior to randomization. Initiating hormone replacement therapy during the study is not permitted. 13. Men must either be surgically sterile (vasectomy with documented confirmation of aspermia) or must agree to use a condom (with spermicide) and to have their female partners agree to use a highly effective contraception (i.e., methods with a failure rate of less than 1% per year, unless their partners are infertile or surgically sterile, from the time of the first administration of study drug and for at least 3 months after the study drug administration and refrain from donating sperm during this period. 14. Must voluntarily give written informed consent before any study-related activities are performed. Patients must read and fully understand the ICF and the requirements of the study. Patients must be willing to comply with all study visits and assessments. Patients must be willing to complete each study procedure. 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. 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. 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 (whichever is longer) 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 a dose of ≤325 mg daily for cardiac prophylaxis. Use of paracetamol is allowed in the study. 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 such as but not limited to poorly controlled diabetes, unstable ischemic heart disease, uncontrolled hypertension (systolic ≥160 mmHg and/or diastolic ≥95 mmHg) or other cardiovascular, cerebrovascular, gastrointestinal, hepatic, renal, hematological (including pancytopenia, aplastic anemia, or blood dyscrasia), endocrine, nervous system or pulmonary disease or other relevant medical condition or a history of clinically significant disease or any other 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 gastrointestinal 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. Curatively treated basal or squamous cell carcinoma of the skin is not excluded, unless it occurred within 12 months of randomization. Curatively treated localized in situ carcinoma of the cervix within 5 years of randomization is also not excluded, if there is no evidence of recurrence prior to randomization. 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, such as multiple sclerosis or optic neuritis, or symptoms suggestive of such a disorder as per Investigator’ 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 specific infections. 27. Medical evidence of active or latent tuberculosis, chest X-ray and/or clinical examination 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 that were considered clinically significant by the Investigator OR any of the following at screening. |
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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) (i.e., at Weeks 2, 4, 8, 12, 16, 30, 42 and 52) other than Week 24. - ACR20 (20% improvement in ACR Core Set Measurements) response rate at Week 24. Safety: - Occurrence of treatment-emergent adverse events up to Week 24, Week 30, Week 55 and Week 63. - Occurrence of serious adverse events up to Week 24, Week 30, Week 55 and Week 63. Immunogenicity: - 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.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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 |
Bulgaria |
Czech Republic |
Georgia |
Hungary |
Moldova, Republic of |
Poland |
Russian Federation |
Serbia |
Slovakia |
Spain |
United States |
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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 | |
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 |