A Phase III Transition Study of DRL Rituximab to Reference Medicinal Products

Study Overview
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Brief Summary
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The objective of the current study is to assess the immunogenicity and safety of transitioning subjects with RA to DRL_RI from US-rituximab/EU-rituximab to continued treatment with US-rituximab/EU-rituximab. The primary objective of this study is 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.

Detailed Description
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This is a randomized, double-blind, parallel group, multicenter, Phase 3 transition study in subjects with active RA who are eligible for the subsequent treatment course with US-rituximab or EU-rituximab according to the clinical judgment of the investigator. Subjects will then be randomized by interactive web response system (IWRS) to receive either two 1000 mg infusions of DRL_RI (Arm A) or US-rituximab/EU-rituximab (Arm B) on Day 1 and Day 15. Subjects randomized to Arm A will receive DRL_RI and subjects randomized to Arm B will continue to receive either US-rituximab or EU-rituximab. The study will consist of a screening period (Days -14 to 0) and a double-blind period (Day 1 to Week 12). Subjects will attend a screening visit followed by a visit at Weeks 0 (Day 1), 2, 4, 8, and 12 after randomization It is planned that approximately 50 sites will be initiated for this study in up to 7 countries (including but not restricted to United States). There has been no randomization of patients till date for this study. The study endpoints include: 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.

Official Title
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A Randomized, Double-blind, Parallel Group, Multicenter Study to Assess the Immunogenicity and Safety of Transitioning Subjects With Rheumatoid Arthritis to Biosimilar Rituximab (DRL_RI) or Continued Treatment With Rituxan® or MabThera®

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: Experimental: Arm A: DRL_RI
* Biological: Arm B: Rituxan®/Mabthera®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged 18 years or older who have provided valid written informed consent. 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. 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. Subjects receiving a stable dose of weekly methotrexate (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. EXCLUSION CRITERIA; Subjects with RA in functional Class IV 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. Subjects with active tuberculosis. 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. Active systemic infection. Severely immunocompromised. History of severe hypersensitivity to either US-rituximab or EU-rituximab or any of its excipients requiring drug discontinuation. 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 ≥160/95 mmHg), congestive heart failure (New York Heart Association [NYHA] Class III or IV), or other severe, uncontrolled cardiac disease or uncontrolled diabetes with immediate risk of acute complications. Any condition that in the opinion of the investigator represents an obstacle for study conduct and/or represents a potential unacceptable risk for subjects. Requires treatment with any biological medicinal product during the study other than the study treatment. Previous treatment with B-cell modulating or cell depleting biologic therapy except US-rituximab or EU-rituximab. 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. Treatment with other biologic disease-modifying anti-rheumatic drugs, 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. 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 × upper limit of normal (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. 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. Lactating or pregnant female. 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. 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. Subject with serum IgG < lower limit of normal.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized, double-blind, parallel group, multicenter study to assess the immunogenicity and safety of transitioning subjects with rheumatoid arthritis to biosimilar rituximab (DRL_RI) or continued treatment with Rituxan® or MabThera®
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: DRL_RI<br>Subjects who have already received at least 1 full course comprising two 1000 mg infusions of either US-rituximab or EU-rituximab and are candidates for re-treatment with Rituximab, will be enrolled. DRL_RI will be administrated in combination with MTX as two 1000 mg infusions on Day 1 and Day 15 | Biological: Experimental: Arm A: DRL_RI<br>* Proposed rituximab biosimilar, 100mg or 500mg, concentrate for solution for infusion<br>|
| Active Comparator: Arm B: US-Rituximab or EU-Rituximab<br>Subjects who have already received at least 1 full course comprising two 1000 mg infusions of either US-rituximab or EU-rituximab and are candidates for re-treatment with rituximab, will be enrolled. Patients enrolled in Arm -B will continue to receive US-rituximab or EU-rituximab. The rituximab reference product used (US-licensed rituximab [Rituxan] or EU-approved rituximab [MabThera]) should be the same in the prior and the randomized treatment course, respectively. | Biological: Arm B: Rituxan®/Mabthera®<br>* Reference product US- rituximab (Rituxan®) or EU-rituximab (MabThera®), 100mg or 500mg, concentrate for solution for infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Positive Anti-Drug Antibodies (ADA) on Day 1 | For Immunogenicity: Number of subjects with positive Anti-Drug Antibodies (ADA) on Day 1 was reported | ADA will be obtained before the administration of study treatment on Day 1 | 
| Number of Subjects With Positive Anti-Drug Antibodies (ADA) on Day 15 | For Immunogenicity: Number of subjects with positive Anti-Drug Antibodies (ADA) on Day 15 was reported | ADA will be obtained before the administration of study treatment on Day 15 | 
| Number of Subjects With Positive Anti-Drug Antibodies (ADA) at Week 4 | For Immunogenicity: Number of subjects with positive Anti-Drug Antibodies (ADA) at Week 4 was reported | ADA will be obtained before the administration of study treatment at Week 4 | 
| Number of Subjects With Positive Anti-Drug Antibodies (ADA) at Week 8 | For Immunogenicity: Number of subjects with positive Anti-Drug Antibodies (ADA) at Week 8 was reported | ADA will be obtained before the administration of study treatment at Week 8 | 
| Number of Subjects With Positive Anti-Drug Antibodies (ADA) at Week 12 Visits | For Immunogenicity: Number of subjects with positive Anti-Drug Antibodies (ADA) at Week 12 visits was reported | ADA will be obtained at Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting Anaphylactic Reactions at Dosing Time Points (Either at Week 1 or Week 3) | Number of Subjects reporting anaphylactic reactions during the study drug administration either at Week 1 or Week 3 was reported | Assessments of Anaphylactic reactions will be carried out at either Week 1 or Week 3 | 
| Number of Subjects Reporting TEAEs (Treatment Emergent Adverse Events) That Led to Study Drug Discontinuation at Either Week 1 or Week 3 Dosing Timepoint | TEAEs (Treatment emergent adverse events) which lead to study subjects discontinuation from the study drug administration at either week 1 or week 3 dosing timepoint | Assessment of AE's (Adverse Events) that led to study drug discontinuation were carried out at either week 1 or week 3 dosing timepoint | 
| Number of Subjects Reporting SAEs (Serious Adverse Events) From Baseline (Week 1) to End of Study (Week 26) | Incidence of SAEs: SAE is defined as Results in death, is life-threatening, Requires in-subject hospitalization or prolongs existing hospitalization, Results in persistent or significant disability/incapacity. The measure here is only subjects reporting SAE. | Assessment of SAE's was carried out from baseline (week 1) to end of study (week 26) | 
| Number of TEAEs Reported From Baseline (Week 1) to End of Study (Week 26) | Number of TEAEs: Treatment-emergent AE are defined as any AE occurring or worsening on or after the first dose of study medication. | Assessment of AE's will be carried out from baseline (week 1) to end of study (week 26) | 
| Number of Subjects Reporting AE From Baseline (Week 1) to End of Study (Week 26) | number of subjects reporting AE in the overall study are defined as any AE occurring or worsening after the ICF signed in the study | Assessment of AE's will be carried out from baseline (week 1) to end of study (week 26) | 
| Number of Subjects Reporting TEAEs From Baseline (Week 1) to End of Study (Week 26) | Number of subjects reporting Treatment-emergent AE (TEAEs) are defined as any AE occurring or worsening on or after the first dose of study medication. | Assessment of AE's will be carried out from baseline (week 1) to end of study (week 26) | 
| Number of Subjects Reporting Hypersensitivity Reactions at Dosing Time Points (Either at Week 1 or Week 3) | Safety assessment will be done by measuring hypersensitivity reactions at Dosing Time Points (Either at Week 1 or Week 3) | Assessments of hypersensitivity reactions either at Week 1 or Week 3 | 
| Number of Subjects Reporting Infusion-related Reactions (IRRs) at Dosing Time Points (Either at Week 1 or Week 3) | Safety assessment: Number of Subjects Reporting Infusion-related reactions (IRRs) at Dosing Time Points (Either at Week 1 or Week 3) was reported | Assessments of IRRs were carried out at either Week 1 or Week 3 |