Comparative Pharmacokinetic, Pharmacodynamic, Safety and Efficacy Study of Three Anti-CD20 Monoclonal Antibodies in Patients With Moderate to Severe Rheumatoid Arthritis

Study Overview
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Brief Summary
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This study will compare the plasma pharmacokinetic profile and the change in disease activity score in patients with active rheumatoid arthritis following treatment with two 1000 mg doses of DRL_RI or one of two sources of rituximab (Rituxan® or MabThera®). Patients will also be monitored for safety, B cell depletion and recovery, and for the development of immune responses to the administered study drugs

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: DRL_RI
* Biological: Rituxan
* Biological: MabThera


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients, 18 to 65 years of age Diagnosis of RA, according to ACR criteria (1987), of at least 6 months duration At randomization, tender joint count ≥ 6 and swollen joint count ≥ 6 Evidence of at least moderate disease activity Patients receiving oral or parenteral MTX with a dose of 15 to 25 mg per week when given alone or 10 to 25 mg per week in combination with additional non-biologic DMARD(s) for at least 6 months and on stable dose for at least 3 months Patients must be on a stable dose of folic acid or equivalent (≥5 mg per week) Chest X-ray not suggestive of any lung infections including pulmonary tuberculosis (TB) Contraception required per protocol Exclusion Criteria: Prior therapy with Rituximab, abatacept, tocilizumab, anakinra or an agent/antibody targeting CD20, CD19 or B cells Tumor necrosis factor (TNF) alfa antagonists or other biologic DMARDs Other prior or concurrent therapies may also be excluded Any clinically relevant abnormality detected on screening history, physical examination, clinical laboratory, chest X-ray, or electrocardiogram (ECG), other than values consistent with RA Evidence of active, suspected or inadequately treated TB Positive serological test for hepatitis C virus antibodies, hepatitis B surface antigen, hepatitis B core antibody, or human immunodeficiency virus History of cardiovascular disease, history of stroke, or uncontrolled hypertension History of lymphoproliferative disease or organ allograft History of cancer (except for in situ cancer, excised, or limited stage, curatively treated cancer with no sign of disease for >5 years) History of allergy (medication history) to any of the compounds used in the study Pregnant or lactating women or women planning to become pregnant during the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DRL_RI<br> | Biological: DRL_RI<br>* Two 1000 mg intravenous infusions, one each on Day 1 and Day 15<br>|
| Active Comparator: Rituxan<br> | Biological: Rituxan<br>* Two 1000 mg intravenous infusions, one each on Day 1 and Day 15<br>* Other names: Rituximab;|
| Active Comparator: MabThera<br> | Biological: MabThera<br>* Two 1000 mg intravenous infusions, one each on Day 1 and Day 15<br>* Other names: Rituximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve From Time 0 to 336 Hours (AUC0-336) Post First Dose | PK samples were collected pre-infusion; 3 hours post infusion; EOI; and at 1, 6, 24, 48, 168 hours post End of Infusion. A PK sample at 336 hours post EOI were also to be collected after the second dose. | 2 weeks | 
| AUC0-∞ Over the Entire Course of Therapy (2 Doses) From Day 1 Through Week 16. | PK samples were collected pre-infusion; 3 hours post infusion; EOI; and at 1, 6, 24, 48, 168 hours post End of Infusion. A PK sample at 336 hours post EOI were also to be collected after the second dose. | 16 weeks | 
| Area Under Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t) (Second Dose). | PK samples were collected pre-infusion; 3 hours post infusion; EOI; and at 1, 6, 24, 48, 168 hours post End of Infusion. A PK sample at 336 hours post EOI were also to be collected after the second dose | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) After First Dose | Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) ,and 168 hours (post-EOI). | 2 weeks | 
| Maximum Plasma Concentration (Cmax) After Second Dose | Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI),6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , 168 (post-EOI), and 336 hours post EOI. | 2 weeks | 
| Time to Cmax (Tmax) After First Dose. | Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , and 168 hours (post-EOI). | 2 weeks | 
| Time to Cmax (Tmax) After Second Dose | Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , and 168 hours (post-EOI). | 2 weeks | 
| Volume of Distribution (Vz) | Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , 168 (post-EOI), 336 hours (post-EOI), 4 weeks, 6 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, and 22 weeks relative to infusion. | 24 weeks | 
| Systemic Clearance (CL) | Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , 168 (post-EOI), 336 hours (post-EOI), 4 weeks, 6 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, and 22 weeks relative to infusion. | 24 weeks | 
| Terminal Half-life (t1/2) | Plasma concentration was measured at 0, 3, 4.25 (End of infusion (EOI)) ,1 (post- EOI), 6 (post-EOI) , 24 (post-EOI) , 48 (post-EOI) , 168 (post-EOI), 336 hours (post-EOI), 4 weeks, 6 weeks, 8 weeks, 10 weeks, 14 weeks, 18 weeks, and 22 weeks relative to infusion. | 24 weeks | 
| Mean Change in Disease Activity Score-C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Weeks 4 | In clinical studies, Disease Activity Score (DAS) is used to assess improvement in disease activity in RA patients over time. The assessment involved an examination of 28 joints for swelling, tenderness, blood C-reactive protein (CRP), and a one on one consultation between the patient and healthcare professional. The results were combined to produce a score which indicated how active the RA was at that particular time. The disease activity is interpreted as low (DAS <2.6), mild (2.6 to <3.2), moderate (3.2 to <5.1), and severe with DAS > 5.1. A DAS score between 0 and 2.6 corresponds to remission. The analysis of DAS28-CRP was based on a generalized estimating equation model in RA patients with DAS28 score > 3.2. The mean change was calculated from two time points (Value at 4 weeks minus baseline value). | Baseline and 4 weeks | 
| Mean Change in DAS28-CRP From Baseline Per Unit Time at 8 Weeks. | In clinical studies, Disease Activity Score (DAS) is used to assess improvement in disease activity in RA patients over time. The assessment involved an examination of 28 joints for swelling, tenderness, blood C-reactive protein (CRP), and a one on one consultation between the patient and healthcare professional. The results were combined to produce a score which indicated how active the RA was at that particular time. The disease activity is interpreted as low (DAS <2.6), mild (2.6 to <3.2), moderate (3.2 to <5.1), and severe with DAS > 5.1. A DAS score between 0 and 2.6 corresponds to remission. The analysis of DAS28-CRP was based on a generalized estimating equation model in RA patients with DAS28 score > 3.2. The mean change was calculated from two time points (Value at 8 weeks minus baseline value). | Baseline and 8 weeks | 
| Mean Change in DAS28-CRP From Baseline Per Unit Time at Week 12. | In clinical studies, Disease Activity Score (DAS) is used to assess improvement in disease activity in RA patients over time. The assessment involved an examination of 28 joints for swelling, tenderness, blood C-reactive protein (CRP), and a one on one consultation between the patient and healthcare professional. The results were combined to produce a score which indicated how active the RA was at that particular time. The disease activity is interpreted as low (DAS <2.6), mild (2.6 to <3.2), moderate (3.2 to <5.1), and severe with DAS > 5.1. A DAS score between 0 and 2.6 corresponds to remission. The analysis of DAS28-CRP was based on a generalized estimating equation model in RA patients with DAS28 score > 3.2. The mean change was calculated from two time points (Value at 12 weeks minus baseline value). | Baseline and 12 weeks | 
| Mean Change in Disease Activity Score- C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Week 16. | In clinical studies, Disease Activity Score (DAS) is used to assess improvement in disease activity in RA patients over time. The assessment involved an examination of 28 joints for swelling, tenderness, blood C-reactive protein (CRP), and a one on one consultation between the patient and healthcare professional. The results were combined to produce a score which indicated how active the RA was at that particular time. The disease activity is interpreted as low (DAS <2.6), mild (2.6 to <3.2), moderate (3.2 to <5.1), and severe with DAS > 5.1. A DAS score between 0 and 2.6 corresponds to remission. The analysis of DAS28-CRP was based on a generalized estimating equation model in RA patients with DAS28 score > 3.2. The mean change was calculated from two time points (Value at 16 weeks minus baseline value). | Baseline and 16 weeks | 
| Percentage of Patients With B-cell Counts 20% Below the Lower Limit of Normal | The time to depletion and repletion of peripheral blood cell counts (determined by CD19+ cell counts) as well as the B-cell counts at selected time points (taking into consideration the patient baseline count) were used to assess the PD of the study drugs. | 48 hours | 
| Percentage of Patients With Peripheral B-cell Counts Depletion at Week 16. | Analysis of the PD parameter peripheral B-Cell count was performed by evaluating the 95% CI for the difference between treatment arms in the percentage of patients with B-cell depletion at 48 hours after dose 1, Week 16, and at Week 24. Percentage of patients with B-cell repletion at each evaluation time is also reported and descriptively compared. | 16 weeks | 
| Percentage of Patients With Peripheral B-cell Counts Depletion at Week 24. | Analysis of the PD parameter peripheral B-Cell count was performed by evaluating the 95% CI for the difference between treatment arms in the percentage of patients with B-cell depletion at 48 hours after dose 1, Week 16, and at Week 24. Percentage of patients with B-cell repletion at each evaluation time is also reported and descriptively compared. | 24 weeks | 
| Percentage of Patients With ACR20 at Week 24 | Percentage of the patients with at least 20% improvement in counts of tender, swollen joints and in 3 of the following: patient's assessment of pain, patient's global assessment of disease activity, patient's assessment of physical function, the physician's global assessment of disease activity, and acute phase reactant. Adjusted response rates for the treatment arms using the logistic regression analysis including treatment, gender and region as fixed effects and patients as random effect in the model. | 24 weeks | 
| Percentage of Patients With ACR50 at Week 24 | Percentage of the patients with at least 50% improvement in counts of tender, swollen joints and in 3 of the following: patient's assessment of pain, patient's global assessment of disease activity, patient's assessment of physical function, the physician's global assessment of disease activity, and acute phase reactant. Adjusted Response rates for the treatment arms using the logistic regression analysis including treatment, gender and region as fixed effects and patients as random effect in the model. | 24 weeks | 
| Percentage of Patients With ACR70 Response at Week 24 | Percentage of the patients with at least 70% improvement in counts of tender, swollen joints and in 3 of the following: patient's assessment of pain, patient's global assessment of disease activity, patient's assessment of physical function, the physician's global assessment of disease activity, and acute phase reactant. Adjusted Response rates for the treatment arms using the logistic regression analysis including treatment, gender and region as fixed effects and patients as random effect in the model. | 24 weeks | 
| Change From Baseline in HAQ-DI at Week 24. | The health assessment questionnaire disability index (HAQ-DI) was assessed at Week 24. The disability assessment component of the HAQ, the HAQ-DI, assessed a patient's level of functional ability and included questions about fine movements of the upper extremities, locomotor activities of the lower extremities, and activities that involved both upper and lower extremities. There were 20 questions in 8 categories of functioning which represented a comprehensive set of functional activities-dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. The stem of each item asked over the past week Were you able to perform a particular task. The patient's responses were made on a scale from 0 (no disability) to 3 (completely disabled). Each category contained at least 2 specific component questions. Physical function was measured using the HAQ-DI Scores, which range from 0-3, with lower scores reflecting better physical function and thus, less disability. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid arthritis, Rituximab, Pharmacokinetics