| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 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 |
|
| 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 immunogenicity of transitioning subjects with RA to DRL_RI (biosimilar rituximab) from US rituximab/EU rituximab to continued treatment with US rituximab/EU rituximab.
To assess the safety of transitioning subjects with RA to DRL_RI from US rituximab/EU rituximab to continued treatment with US rituximab/EU rituximab. |
|
| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects aged 18 years or older who have provided valid written informed consent.
2. Subjects with a diagnosis of active RA who are eligible for the subsequent treatment course with US rituximab or EU rituximab according to the clinical judgment of the investigator.
3. Documented evidence that subject has received at least 1 full course comprising two 1000 mg infusions of either US rituximab at least 16 weeks prior to the randomization visit or EU rituximab at least 24 weeks prior to the day of randomization visit.
Note: Subjects are only eligible if they have received the prior US or EU-rituximab course within the 15 months prior to the date of randomization.
4. Subjects receiving a stable dose of weekly MTX for at least 4 weeks prior to randomization (between 7.5 mg and 25 mg) and folic acid (at least 5 mg per week). |
|
| E.4 | Principal exclusion criteria |
1. Subjects with RA in functional Class IV.
2. Subjects with human immunodeficiency virus (positive HIV1Ab or HIV2Ab), hepatitis B virus and/or hepatitis C virus infection, including those with positive results in the viral disease screening.
3. Subjects with active tuberculosis (TB). Subjects with evidence of latent TB or a history of TB must have completed treatment or have initiated treatment for at least 1 month before the first dose of study treatment (Day 1). TB testing is required only if it is required by local regulations or practice.
4. Active systemic infection.
5. Severely immunocompromised.
6. History of severe hypersensitivity to either US rituximab or EU rituximab or any of its excipients requiring drug discontinuation.
7. Any serious illness or uncontrolled medical condition, including but not limited to severe infections, significant hepatic or renal disease, uncontrolled hypertension despite treatment (defined as blood pressure [BP] ≥160/95 mmHg), congestive heart failure, or other severe, uncontrolled cardiac disease or uncontrolled diabetes with immediate risk of acute complications.
8. Any condition that in the opinion of the investigator represents an obstacle for study conduct and/or represents a potential unacceptable risk for subjects.
9. Requires treatment with any biological medicinal product during the study other than the study treatment.
10. Previous treatment with B-cell modulating or cell depleting biologic therapy except US rituximab or EU rituximab.
11. Prior participation in this clinical trial or prior participation in any clinical trial with any monoclonal antibody within 12 months of screening or prior participation in any clinical trial within 3 months of screening or within 5 half-lives of the investigational drug or until the expected PD effect has returned to baseline, whichever is longer.
12. Treatment with other biologic DMARDs, or Janus kinase (JAK) inhibitors administered within 12 weeks before the first dose of rituximab of the prior treatment course onwards till the date of randomization.
13. Subjects with the following laboratory abnormalities:
• Subjects with screening total white blood cell count <3000/μL, platelets <100,000/μL, neutrophils <1,500/μL, or hemoglobin <8.5 g/dL
• Abnormal liver function tests such as aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase >2 × ULN. A single parameter >2 × ULN can be re-checked as soon as possible, at least prior to randomization, if required as per the investigator’s discretion.
• Creatinine clearance (Cockcroft & Gault formula) of less than 50 mL/min.
14. History of vaccination with live vaccines within 4 weeks of the first dose of study treatment (Day 1) or known to require live vaccines during the study.
15. Lactating or pregnant female.
16. Women of childbearing potential who do not consent to use highly effective methods of birth control (e.g., barrier contraceptives, oral contraceptives, intrauterine devices, true abstinence if it allowed as per the country specific regulatory requirement [periodic abstinence {e.g., calendar ovulation, symptothermal, post ovulation methods} and withdrawal are not acceptable methods of contraception], or sterilization) during treatment and for at least 12 months after the last administration of study treatment.
17. For men involved in any sexual intercourse that could lead to pregnancy, subjects must agree to use 1 of the highly effective methods of birth control listed in Exclusion Criterion #16 during treatment and for at least 12 months after the last administration of study treatment.
18. Subject with serum IgG <LLN |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The immunogenicity endpoint is:
• The incidence of anti-drug antibodies (ADA), including titer and neutralizing antibodies (NAb).
The primary safety endpoints are:
• Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).
• Incidence of anaphylactic reactions, hypersensitivity reactions, and IRRs.
Other safety endpoints are:
• Clinical laboratory parameters
• Vital signs
• Twelve-lead electrocardiogram (ECG)
• Physical examination |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Samples for detection of ADA will be collected at Weeks 4, 8, and 12 (EOS/ET visit).
• Samples for detection of NAB will be collected at Weeks 4, 8, and 12 (EOS/ET visit).
• Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) - on occurrence.
• Incidence of anaphylactic reactions, hypersensitivity reactions, and IRRs - on occurrence.
• Clinical laboratory assessments, vital signs measurement and Physical examination will be performed at the screening, on Day 1, Day 15, and at Weeks 4, 8, and 12 (EOS/ET) visits.
• Twelve-lead electrocardiogram (ECG) - at the screening and End of Treatment. |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 |
| Estonia |
| Germany |
| Hungary |
| Lithuania |
| Poland |
| United States |
|
| 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
|
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 20 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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