Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid arthritis, Rituximab, Pharmacokinetics
Brief summary
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
Interventions
BIOLOGICALDRL_RI
Two 1000 mg intravenous infusions, one each on Day 1 and Day 15
BIOLOGICALRituxan
Two 1000 mg intravenous infusions, one each on Day 1 and Day 15
BIOLOGICALMabThera
Two 1000 mg intravenous infusions, one each on Day 1 and Day 15
Sponsors
Dr. Reddy's Laboratories Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female patients, 18 to 65 years of age 2. Diagnosis of RA, according to ACR criteria (1987), of at least 6 months duration 3. At randomization, tender joint count ≥ 6 and swollen joint count ≥ 6 4. Evidence of at least moderate disease activity 5. 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 6. Patients must be on a stable dose of folic acid or equivalent (≥5 mg per week) 7. Chest X-ray not suggestive of any lung infections including pulmonary tuberculosis (TB) 8. Contraception required per protocol
Exclusion criteria
1. 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 2. Any clinically relevant abnormality detected on screening history, physical examination, clinical laboratory, chest X-ray, or electrocardiogram (ECG), other than values consistent with RA 3. Evidence of active, suspected or inadequately treated TB 4. Positive serological test for hepatitis C virus antibodies, hepatitis B surface antigen, hepatitis B core antibody, or human immunodeficiency virus 5. History of cardiovascular disease, history of stroke, or uncontrolled hypertension 6. History of lymphoproliferative disease or organ allograft 7. History of cancer (except for in situ cancer, excised, or limited stage, curatively treated cancer with no sign of disease for \>5 years) 8. History of allergy (medication history) to any of the compounds used in the study 9. Pregnant or lactating women or women planning to become pregnant during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-Time Curve From Time 0 to 336 Hours (AUC0-336) Post First Dose | 2 weeks | 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. |
| AUC0-∞ Over the Entire Course of Therapy (2 Doses) From Day 1 Through Week 16. | 16 weeks | 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. |
| Area Under Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t) (Second Dose). | 16 weeks | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Cmax (Tmax) After Second Dose | 2 weeks | 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). |
| Volume of Distribution (Vz) | 24 weeks | 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. |
| Systemic Clearance (CL) | 24 weeks | 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. |
| Terminal Half-life (t1/2) | 24 weeks | 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. |
| Mean Change in Disease Activity Score-C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Weeks 4 | Baseline and 4 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 4 weeks minus baseline value). |
| Mean Change in DAS28-CRP From Baseline Per Unit Time at 8 Weeks. | Baseline and 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). |
| Mean Change in DAS28-CRP From Baseline Per Unit Time at Week 12. | Baseline and 12 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 12 weeks minus baseline value). |
| Maximum Plasma Concentration (Cmax) After First Dose | 2 weeks | 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). |
| Percentage of Patients With B-cell Counts 20% Below the Lower Limit of Normal | 48 hours | 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. |
| Percentage of Patients With Peripheral B-cell Counts Depletion at Week 16. | 16 weeks | 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. |
| Percentage of Patients With Peripheral B-cell Counts Depletion at Week 24. | 24 weeks | 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. |
| Percentage of Patients With ACR20 at Week 24 | 24 weeks | 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. |
| Percentage of Patients With ACR50 at Week 24 | 24 weeks | 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. |
| Percentage of Patients With ACR70 Response at Week 24 | 24 weeks | 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. |
| Change From Baseline in HAQ-DI at Week 24. | 24 weeks | 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. |
| Mean Change in Disease Activity Score- C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Week 16. | Baseline and 16 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 16 weeks minus baseline value). |
| Maximum Plasma Concentration (Cmax) After Second Dose | 2 weeks | 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. |
| Time to Cmax (Tmax) After First Dose. | 2 weeks | 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). |
Countries
India, Ukraine
Participant flow
Recruitment details
The study was conducted in 2 parts, a treatment and evaluation period (Part 1) and a recovery and follow-up period (Part 2). Study period was between November 2014 to June 2017 in a total of 29 sites across India and Ukraine.
Pre-assignment details
The study was having 6 weeks screening period to accommodate 4 weeks washout/run-in stabilization and screening procedures.
Participants by arm
| Arm | Count |
|---|---|
| DRL- Rituximab-DRL_RI On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen. | 91 |
| Rituxan® (US Licensed Reference Product): RP On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen. | 92 |
| MabThera® (EU Approved Reference Medicinal Product): RMP On successful completion of the screening period, patients were randomized to 1 of the 3 treatment arms (DRL\_RI, Rituxan®, or MabThera®) and administered 1000 mg of the study drug, one each on Day 1 and Day 15, while continuing their individual background stabilized DMARD regimen. | 93 |
| Total | 276 |
Baseline characteristics
| Characteristic | DRL- Rituximab-DRL_RI | Rituxan® (US Licensed Reference Product): RP | MabThera® (EU Approved Reference Medicinal Product): RMP | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 91 Participants | 92 Participants | 93 Participants | 276 Participants |
| Age, Continuous | 44.1 years STANDARD_DEVIATION 10.96 | 44.0 years STANDARD_DEVIATION 10.36 | 45.5 years STANDARD_DEVIATION 10.41 | 44.5 years STANDARD_DEVIATION 10.56 |
| Disease Activity Score-C Reactive Protein (DAS28-CRP) | 6.031 Score on a scale STANDARD_DEVIATION 0.6702 | 5.719 Score on a scale STANDARD_DEVIATION 0.7603 | 5.831 Score on a scale STANDARD_DEVIATION 0.7024 | 5.786 Score on a scale STANDARD_DEVIATION 0.7233 |
| Region of Enrollment India | 78 Participants | 78 Participants | 78 Participants | 234 Participants |
| Region of Enrollment Ukraine | 13 Participants | 14 Participants | 15 Participants | 42 Participants |
| Sex: Female, Male Female | 81 Participants | 81 Participants | 81 Participants | 243 Participants |
| Sex: Female, Male Male | 10 Participants | 11 Participants | 12 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 91 | 0 / 92 | 0 / 93 |
| other Total, other adverse events | 60 / 91 | 58 / 92 | 66 / 93 |
| serious Total, serious adverse events | 3 / 91 | 5 / 92 | 10 / 93 |
Outcome results
Primary
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
Time frame: 16 weeks
Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=220
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Area Under Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t) (Second Dose). | 139000 ug*h/ml | Geometric Coefficient of Variation 37.3 |
| Rituxan® (US Licensed Reference Product): RP | Area Under Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t) (Second Dose). | 137000 ug*h/ml | Geometric Coefficient of Variation 37.2 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Area Under Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-t) (Second Dose). | 146000 ug*h/ml | Geometric Coefficient of Variation 33.5 |
Primary
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.
Time frame: 2 weeks
Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=218
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Area Under the Concentration-Time Curve From Time 0 to 336 Hours (AUC0-336) Post First Dose | 49000 ug*h/ml | Geometric Coefficient of Variation 27.1 |
| Rituxan® (US Licensed Reference Product): RP | Area Under the Concentration-Time Curve From Time 0 to 336 Hours (AUC0-336) Post First Dose | 49000 ug*h/ml | Geometric Coefficient of Variation 25.4 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Area Under the Concentration-Time Curve From Time 0 to 336 Hours (AUC0-336) Post First Dose | 51400 ug*h/ml | Geometric Coefficient of Variation 24.1 |
Primary
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.
Time frame: 16 weeks
Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=212
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | AUC0-∞ Over the Entire Course of Therapy (2 Doses) From Day 1 Through Week 16. | 189000 ug*h/ml | Geometric Coefficient of Variation 33.2 |
| Rituxan® (US Licensed Reference Product): RP | AUC0-∞ Over the Entire Course of Therapy (2 Doses) From Day 1 Through Week 16. | 189000 ug*h/ml | Geometric Coefficient of Variation 34 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | AUC0-∞ Over the Entire Course of Therapy (2 Doses) From Day 1 Through Week 16. | 201000 ug*h/ml | Geometric Coefficient of Variation 30.1 |
Secondary
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.
Time frame: 24 weeks
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Change From Baseline in HAQ-DI at Week 24. | 0.742 score on a scale | Standard Deviation 0.60603 |
| Rituxan® (US Licensed Reference Product): RP | Change From Baseline in HAQ-DI at Week 24. | 0.691 score on a scale | Standard Deviation 0.62598 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Change From Baseline in HAQ-DI at Week 24. | 0.726 score on a scale | Standard Deviation 0.5659 |
Secondary
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).
Time frame: 2 weeks
Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=218.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Maximum Plasma Concentration (Cmax) After First Dose | 405.452 ug/ml | Geometric Coefficient of Variation 24.5 |
| Rituxan® (US Licensed Reference Product): RP | Maximum Plasma Concentration (Cmax) After First Dose | 388.017 ug/ml | Geometric Coefficient of Variation 24.4 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Maximum Plasma Concentration (Cmax) After First Dose | 405.200 ug/ml | Geometric Coefficient of Variation 30.1 |
Secondary
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.
Time frame: 2 weeks
Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=224
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Maximum Plasma Concentration (Cmax) After Second Dose | 490.182 ug/ml | Geometric Coefficient of Variation 28.1 |
| Rituxan® (US Licensed Reference Product): RP | Maximum Plasma Concentration (Cmax) After Second Dose | 470.237 ug/ml | Geometric Coefficient of Variation 26.8 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Maximum Plasma Concentration (Cmax) After Second Dose | 478.149 ug/ml | Geometric Coefficient of Variation 24.7 |
Secondary
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).
Time frame: Baseline and 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Mean Change in DAS28-CRP From Baseline Per Unit Time at 8 Weeks. | -1.379 units on a scale | Standard Deviation 1.0274 |
| Rituxan® (US Licensed Reference Product): RP | Mean Change in DAS28-CRP From Baseline Per Unit Time at 8 Weeks. | -1.192 units on a scale | Standard Deviation 0.8635 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Mean Change in DAS28-CRP From Baseline Per Unit Time at 8 Weeks. | -1.424 units on a scale | Standard Deviation 1.1764 |
Secondary
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).
Time frame: Baseline and 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Mean Change in DAS28-CRP From Baseline Per Unit Time at Week 12. | -1.652 units on a scale | Standard Deviation 1.1405 |
| Rituxan® (US Licensed Reference Product): RP | Mean Change in DAS28-CRP From Baseline Per Unit Time at Week 12. | 1.443 units on a scale | Standard Deviation 0.9648 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Mean Change in DAS28-CRP From Baseline Per Unit Time at Week 12. | -1.718 units on a scale | Standard Deviation 1.153 |
Secondary
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).
Time frame: Baseline and 16 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Mean Change in Disease Activity Score- C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Week 16. | -1.892 units on a scale | Standard Deviation 1.1257 |
| Rituxan® (US Licensed Reference Product): RP | Mean Change in Disease Activity Score- C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Week 16. | -1.49 units on a scale | Standard Deviation 1.0222 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Mean Change in Disease Activity Score- C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Week 16. | -1.814 units on a scale | Standard Deviation 1.2105 |
Secondary
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).
Time frame: Baseline and 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Mean Change in Disease Activity Score-C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Weeks 4 | -1.004 units on a scale | Standard Deviation 0.9955 |
| Rituxan® (US Licensed Reference Product): RP | Mean Change in Disease Activity Score-C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Weeks 4 | -0.871 units on a scale | Standard Deviation 0.7918 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Mean Change in Disease Activity Score-C Reactive Protein (DAS28-CRP) From Baseline Per Unit Time at Weeks 4 | -0.96 units on a scale | Standard Deviation 0.9125 |
Secondary
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.
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DRL- Rituximab-DRL_RI | Percentage of Patients With ACR20 at Week 24 | 72 Percentage of participants |
| Rituxan® (US Licensed Reference Product): RP | Percentage of Patients With ACR20 at Week 24 | 69.1 Percentage of participants |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Percentage of Patients With ACR20 at Week 24 | 68.4 Percentage of participants |
Secondary
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.
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DRL- Rituximab-DRL_RI | Percentage of Patients With ACR50 at Week 24 | 43.9 Percentage of participants |
| Rituxan® (US Licensed Reference Product): RP | Percentage of Patients With ACR50 at Week 24 | 39.5 Percentage of participants |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Percentage of Patients With ACR50 at Week 24 | 43.0 Percentage of participants |
Secondary
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.
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DRL- Rituximab-DRL_RI | Percentage of Patients With ACR70 Response at Week 24 | 17.1 Percentage of participants |
| Rituxan® (US Licensed Reference Product): RP | Percentage of Patients With ACR70 Response at Week 24 | 14.8 Percentage of participants |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Percentage of Patients With ACR70 Response at Week 24 | 15.2 Percentage of participants |
Secondary
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.
Time frame: 48 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DRL- Rituximab-DRL_RI | Percentage of Patients With B-cell Counts 20% Below the Lower Limit of Normal | 98.8 Percentage of participants |
| Rituxan® (US Licensed Reference Product): RP | Percentage of Patients With B-cell Counts 20% Below the Lower Limit of Normal | 100 Percentage of participants |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Percentage of Patients With B-cell Counts 20% Below the Lower Limit of Normal | 100 Percentage of participants |
Secondary
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.
Time frame: 16 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DRL- Rituximab-DRL_RI | Percentage of Patients With Peripheral B-cell Counts Depletion at Week 16. | 10.0 percentage of participants |
| Rituxan® (US Licensed Reference Product): RP | Percentage of Patients With Peripheral B-cell Counts Depletion at Week 16. | 4.9 percentage of participants |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Percentage of Patients With Peripheral B-cell Counts Depletion at Week 16. | 10.1 percentage of participants |
Secondary
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.
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DRL- Rituximab-DRL_RI | Percentage of Patients With Peripheral B-cell Counts Depletion at Week 24. | 0.0 percentage of participants |
| Rituxan® (US Licensed Reference Product): RP | Percentage of Patients With Peripheral B-cell Counts Depletion at Week 24. | 3.7 percentage of participants |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Percentage of Patients With Peripheral B-cell Counts Depletion at Week 24. | 1.3 percentage of participants |
Secondary
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.
Time frame: 24 weeks
Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=230
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Systemic Clearance (CL) | 0.254 L/day | Geometric Coefficient of Variation 33.2 |
| Rituxan® (US Licensed Reference Product): RP | Systemic Clearance (CL) | 0.254 L/day | Geometric Coefficient of Variation 33.9 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Systemic Clearance (CL) | 0.238 L/day | Geometric Coefficient of Variation 30 |
Secondary
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.
Time frame: 24 weeks
Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=230
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Terminal Half-life (t1/2) | 374 h | Geometric Coefficient of Variation 30.1 |
| Rituxan® (US Licensed Reference Product): RP | Terminal Half-life (t1/2) | 378 h | Geometric Coefficient of Variation 25 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Terminal Half-life (t1/2) | 391 h | Geometric Coefficient of Variation 23.9 |
Secondary
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).
Time frame: 2 weeks
Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=218
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DRL- Rituximab-DRL_RI | Time to Cmax (Tmax) After First Dose. | 5.25 Hours |
| Rituxan® (US Licensed Reference Product): RP | Time to Cmax (Tmax) After First Dose. | 5.25 Hours |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Time to Cmax (Tmax) After First Dose. | 5.25 Hours |
Secondary
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).
Time frame: 2 weeks
Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=224
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| DRL- Rituximab-DRL_RI | Time to Cmax (Tmax) After Second Dose | 5.25 Hours |
| Rituxan® (US Licensed Reference Product): RP | Time to Cmax (Tmax) After Second Dose | 5.25 Hours |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Time to Cmax (Tmax) After Second Dose | 5.25 Hours |
Secondary
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.
Time frame: 24 weeks
Population: Population numbers exclude ADA positive individuals and the total number analyzed is updated to n=230
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| DRL- Rituximab-DRL_RI | Volume of Distribution (Vz) | 5.69 L | Geometric Coefficient of Variation 26.3 |
| Rituxan® (US Licensed Reference Product): RP | Volume of Distribution (Vz) | 5.76 L | Geometric Coefficient of Variation 23.1 |
| MabThera® (EU Approved Reference Medicinal Product): RMP | Volume of Distribution (Vz) | 5.55 L | Geometric Coefficient of Variation 26.4 |