Comparative Pharmacokinetic, Pharmacodynamic, Safety and Efficacy Study of Three Anti-CD20 Monoclonal Antibodies in Patients With Moderate to Severe Rheumatoid Arthritis
- Conditions
- Rheumatoid Arthritis
- Interventions
- Biological: RituxanBiological: DRL_RIBiological: MabThera
- Registration Number
- NCT02296775
- Lead Sponsor
- Dr. Reddy's Laboratories Limited
- 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
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 276
- 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
-
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
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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)
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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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Rituxan Rituxan - DRL_RI DRL_RI - MabThera MabThera -
- Primary Outcome Measures
Name Time Method 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 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.
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 Outcome Measures
Name Time Method 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).
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).
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).
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).
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.
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 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.
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.
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.
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 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).
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 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.
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.
Trial Locations
- Locations (28)
Maulana Azad Medical College & Associated Lok Nayak Hospitals
🇮🇳New Delhi, Delhi, India
lndraprastha Apollo Hospitals
🇮🇳New Delhi, Delhi, India
Sushruta Multispeciality Hospital & Research Centre Pvt. Ltd
🇮🇳Hubli, Karnataka, India
Oyster & Pearl Hospital
🇮🇳Pune, Maharashtra, India
S. R. Kalla Memorial Gastro & General Hospital
🇮🇳Jaipur, Rajasthan, India
Shri Nidaan Hospital & Hope Fertility Centre
🇮🇳Jaipur, Rajasthan, India
King George's Medical University
🇮🇳Lucknow, Uttar Pradesh, India
Apollo Specialty Hosptials
🇮🇳Madurai, Tamil Nadu, India
Communal Healthcare Institution Kharkiv City Clinical Hospital #8
🇺🇦Kharkiv, Ukraine
State Institution National Scientific Center Acad. Strazhesko Institute of Cardiology of National Academy of Medical Science
🇺🇦Kyiv, Ukraine
Medical Clinical Investigational Center MC LLC Health Clinic
🇺🇦Vinnytsia, Ukraine
Vinnytsia M.I. Pyrogov Regional Clinical Hospital
🇺🇦Vinnytsia, Ukraine
Care Hospitals
🇮🇳Hyderabad, Andhra Pradesh, India
Communal Institution Zaporzhzhia Regional Clinical Hospital of Zaporizhzhia Regional Council
🇺🇦Zaporizhzhia, Ukraine
Yashoda Hospital
🇮🇳Secunderabad, Andhra Predesh, India
Chanre Rheumatology & Immunology Center & Research
🇮🇳Bangalore, Karnataka, India
Government Medical College & New Civil Hospital
🇮🇳Surat, Gujarat, India
Gurunank Care Hospital
🇮🇳Hyderabad, Andhra Pradesh, India
Krishna Institute of Medical Sciences Ltd.
🇮🇳Secunderabad, Andhra Pradesh, India
Jagadguru Sri Shivarathreeshwara Hospital
🇮🇳Mysore, Karnataka, India
Shalby Hospitals
🇮🇳Ahmedabad, Gujarat, India
Deennath Mangeshkar Hospital and Research Centre
🇮🇳Pune, Maharashtra, India
Dayanand Medical College & Hosptial
🇮🇳Ludhiana, Punjab, India
Kokilaben Dhirubhai Ambani Hospital & Medical Research Institute
🇮🇳Mumbai, Maharashtra, India
Jehangir Clinical Development Centre Pvt. Ltd.
🇮🇳Pune, Maharashtra, India
M.V. Sklifosovskyi Poltava Regional Clinical Hospital
🇺🇦Poltava, Ukraine
lnamdar Multispeciality Hospital
🇮🇳Pune, Maharashtra, India
State Institution D.F. Chebotariov Institute of Gerontology of NAMS of Ukraine
🇺🇦Kyiv, Ukraine