MabionCD20® Compared to MabThera® and Rituxan® in Patients With Rheumatoid Arthritis
- Conditions
- Rheumatoid Arthritis
- Interventions
- Biological: MabionCD20 (candidate biosimilar to rituximab)Biological: MabThera®Biological: Rituxan®
- Registration Number
- NCT04680962
- Lead Sponsor
- Mabion SA
- Brief Summary
Primary objective of the study is to establish a 3-way PK similarity bridge between MabionCD20 (candidate biosimilar to rituximab), MabThera® (EU-sourced rituximab) and Rituxan® (US-sourced rituximab) following the administration of these drugs to patients with moderate-to-severe rheumatoid arthritis. Main secondary objective is to confirm therapeutic similarity between MabionCD20 and the reference rituximab.
- Detailed Description
Patients with active moderate-to-severe rheumatoid arthritis diagnosed according to the 2010 ACR criteria will be randomized to receive a blinded treatment course of either MabionCD20, EU-Rituximab (MabThera®) or US-Rituximab (Rituxan®) on the top of a stable methotrexate therapy. Two infusions of investigational drug at a dose of 1000 mg will be given at Day 1 and 15. Patients will be then followed for a minimum of 24 weeks to establish PK and therapeutic similarity and to compare PD, safety and immunogenicity parameters between the three rituximab products (Main Phase). Patients may receive a second course of investigational therapy at Week 24, provided that they meet re-treatment eligibility criteria specified in the study protocol. Subjects in MabionCD20 and EU-Rituximab groups will be continued on their assigned treatments, while all subjects in US-Rituximab group will be switched to MabionCD20. All subjects (re-treated and not re-treated) will continue the follow-up until Week 48 to collect long-term safety, immunogenicity and efficacy data.
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description US-Rituximab / MabionCD20 Rituxan® Patients receive a single treatment course of Rituxan®, consisting of two 1000 mg i.v. infusions at Day 1 and Day 15. After 24 weeks of follow-up, all patients eligible for re-treatment, are switched to receive a single treatment course of MabionCD20, consisting of two 1000 mg i.v. infusions at Week 24 and Week 26. MabionCD20 / MabionCD20 MabionCD20 (candidate biosimilar to rituximab) Patients receive one or two treatment courses of MabionCD20, each consisting of two 1000 mg i.v. infusions at an interval of 14 days. Investigational drug will be administered at Day 1 and Day 15, and, if patient is eligible for re-treatment, also at Week 24 and Week 26. EU-Rituximab / EU-Rituximab MabThera® Patients receive one or two treatment courses of MabThera®, each consisting of two 1000 mg i.v. infusions at an interval of 14 days. Investigational drug will be administered at Day 1 and Day 15, and, if patient is eligible for re-treatment, also at Week 24 and Week 26. US-Rituximab / MabionCD20 MabionCD20 (candidate biosimilar to rituximab) Patients receive a single treatment course of Rituxan®, consisting of two 1000 mg i.v. infusions at Day 1 and Day 15. After 24 weeks of follow-up, all patients eligible for re-treatment, are switched to receive a single treatment course of MabionCD20, consisting of two 1000 mg i.v. infusions at Week 24 and Week 26.
- Primary Outcome Measures
Name Time Method Area Under the Serum Concentration-time Curve from Day 1 to Week 24, with extrapolation to infinity [AUC 0-inf (D1-W24)] Day 1 to Week 24 Concentration of rituximab in serum over the entire PK study duration, with extrapolation to infinity. Outcome based on all PK samples collected in the study - from Day 1 (first infusion) to Week 24 (before administration of the 2nd treatment course).
Area Under the Serum Concentration-time Curve from Day 1 to Day 15 [AUC 0-t (D1-D15)] Day 1 to Day 15 Concentration of rituximab in serum measured from Day 1 (before the 1st drug infusion) to Day 15 (before the 2nd drug infusion).
- Secondary Outcome Measures
Name Time Method Maximum drug concentration in serum after the 1st infusion (Cmax1) Day 1 Maximum drug concentration measured after the 1st study drug infusion at Day 1
Percentage of patients with low disease activity (DAS28-ESR <3.2) Baseline to Week 48 DAS28 scale ranges from 0 to approximately 10 points, with a score higher than 5.1 indicating high disease activity, a score less than 3.2 indicating low disease activity, and a score less than 2.6 indicating clinical remission of RA.
Percentage of patients with a good response on EULAR scale Baseline to Week 48 There are three categories of EULAR response (good, moderate and non-responders) which include not only the individual's amount of change in the DAS but also the attainment of a particular DAS value (low, moderate or high) at the endpoint.
To be classified as having a good EULAR response, the patient must demonstrate a significant change from baseline (\> 1.2) as well as reach low disease activity (DAS-28 ≤ 3.2).Percentage of patients with a moderate response on EULAR scale Baseline to Week 48 There are three categories of EULAR response (good, moderate and non-responders) which include not only the individual's amount of change in the DAS but also the attainment of a particular DAS value (low, moderate or high) at the endpoint.
To be classified as having a moderate EULAR response, the patient must demonstrate a minimum change from baseline on DAS28-ESR of \> 0.6 to \< 1.2, as well as the endpoint achievement of a DAS-28 ≤ 5.1.Simplified Disease Activity Index (SDAI) Baseline to Week 48 SDAI is composed of the following clinical and laboratory variables:
* tender joint count (up to 28 joints);
* swollen joint count (up to 28 joints);
* patient's assessment of global disease activity;
* physician's assessment of global disease activity;
* CRP (C-reactive protein).
Summation of all above variables produces a SDAI score (maximum 86.0 points). High disease activity is defined on SDAI as a score higher than 26.0 points, while a cut-off for remission is set at 3.3 points.Clinical Disease Activity Index (CDAI) Baseline to Week 48 CDAI is calculated in the same way as SDAI, except that only clinical parameters of disease level are taken into account (without CRP). Maximum score is 76.0 points. High disease activity is defined above 22.0 points and remission as ≤ 2.8 points
Area Under the Serum Concentration-time Curve from Day 1 to Week 24 [AUC 0-t (D1-W24)] Baseline to Week 24 Concentration of rituximab in serum over the entire PK study duration, without extrapolation to infinity. Outcome based on all PK samples collected in the study - from Day 1 (first infusion) to Week 24 (before administration of the 2nd treatment course).
Area Under the Serum Concentration-time Curve from Day 15 to Week 24 [AUC 0-t (D15-W24)] Day 15 to Week 24 Concentration of rituximab in serum measured from Day 15 (before the 2nd drug infusion) to Week 24 (before the 2nd treatment course)
Maximum drug concentration in serum after the 2nd infusion (Cmax2) Day 15 Maximum drug concentration measured after the 2nd study drug infusion at Day 15
Time to achieve maximum drug concentration in serum after the 2nd infusion (Tmax2) Day 15 Time to achieve maximum drug concentration in serum after the 2nd infusion at Day 15
Trough drug concentration in serum (Ctrough) Day 15 Drug concentration measured shortly before the 2nd study drug infusion at Day 15
Time to achieve maximum drug concentration in serum after the 1st infusion (Tmax1) Day 1 Time to achieve maximum drug concentration in serum after the 1st infusion at Day 1
Mean Change from Baseline in DAS28-ESR score Baseline to Week 48 DAS28-ESR is a disease activity index calculated from the following variables:
* Tender joint count (28 joints);
* Swollen joint count (28 joints);
* Erythrocyte sedimentation rate (ESR);
* Patient's assessment of global disease activity.
The score ranges from 0 to ca. 10 points, with \> 5.1 indicating high disease activity, \< 3.2 indicating low disease activity, and \< 2.6 indicating clinical remission. Change from baseline to Week 24 will be used for the confirmation of therapeutic similarity.
For the US submission, therapeutic similarity will be confirmed if 90% CI of the difference between MabionCD20 and the combined EU- plus US-Rituximab group is contained within (-0.6; +0.5) equivalence margin. For the EU submission, therapeutic similarity will be declared if 95% CI of the difference is contained within (-0.6; +0.6) margin. In an additional analysis, MabionCD20 group will be compared against EU-Rituximab group alone using the above EU criteria.Mean Change from Baseline in DAS28-CRP score Baseline to Week 48 DAS28-CRP is a disease activity index calculated from the following variables:
* Tender joint count (28 joints);
* Swollen joint count (28 joints);
* C-reactive protein (CRP);
* Patient's assessment of global disease activity.
It ranges from 0 to ca. 10 points, with a score \> 5.1 indicating high disease activity, a score \< 3.2 indicating low disease activity, and a score \< 2.6 indicating clinical remission of RA.Percentage of patients with disease remission (DAS28-ESR <2.6) Baseline to Week 48 DAS28 scale ranges from 0 to approximately 10 points, with a score higher than 5.1 indicating high disease activity, a score less than 3.2 indicating low disease activity, and a score less than 2.6 indicating clinical remission of RA.
Percentage of patients achieving an ACR20/50/70 response Baseline to Week 48 A positive ACR20/50/70 response is achieved, when all of the following improvement criteria are met:
1. ≥ 20%/50%/70%\* improvement in tender joint count.
2. ≥ 20%/50%/70%\* improvement in swollen joint count.
3. ≥ 20%/50%/70%\* improvement in minimum 3 of the following 5 parameters:
* Patient's assessment of pain;
* Patient's global assessment of disease activity;
* Physician's global assessment of disease activity;
* Patient's assessment of physical function (HAQ-DI);
* Laboratory evaluation of acute phase reactant (ESR)
* 20%, 50% and 70% improvement apply to ACR20, ACR50 and ACR70 response, respectivelyAbsolute CD19+ B cell counts by visit Day 1 to Week 24 Evolution of CD19+ B cell counts from the 1st study drug infusion at Day 1 to Week 24
Percentage of patients with undetectable levels of CD19+ B-cells Day 3 and Week 24 Percentage of patients who achieve a complete depletion of CD19+ B-cells two days after the 1st infusion (Day 3) and percentage of patients who remain depleted of CD19+ B-cells on Week 24
Percentage of patients with Adverse Events (AEs) Day 1 to Week 48 Patients with AEs, which occurred after signing the Informed Consent Form (ICF) until the study end at Week 48. Several categories of AEs will be evaluated:
* Treatment-emergent adverse events (TEAEs, AEs occurring after the initiation of study treatment);
* Related TEAEs (classified as at least possibly related to the study drug by Investigators);
* Severe TEAEs;
* TEAEs leading to permanent/temporary discontinuation of the study drug or reduction in infusion rate;
* Treatment-emergent serious adverse events (TESAEs);
* Related TESAEs;
* TESAEs leading to permanent/temporary discontinuation or reduction in infusion rate;
* TEAEs leading to death;
* Adverse events of special interest (AESI), which include: Infusion-related reactions (IRRs), Hypersensitivity and allergic reactions, Infusion-associated cardiovascular events, Serious infection events, SARS-CoV-2 infections and Progressive multifocal leukoencephalopathy (PML).Percentage of patients with a positive anti-drug antibody (ADA) response Day 1 to Week 48 Positive ADA response is a composite of treatment-induced and treatment-boosted ADAs. Patients with persistent response will be distinguished from patients with transient ADAs. Patients with positive samples will be additionally analyzed for ADA titer and for the presence of drug neutralizing antibodies (percentage of patients with nAb).