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

Rheumatoid Arthritis Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02296775
• Other study ID #: RI-01-003
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 2014
• Est. completion date: October 5, 2017

Study information

• Verified date: December 2019
• Source: Dr. Reddy's Laboratories Limited
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 276
• Est. completion date: October 5, 2017
• Est. primary completion date: November 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Biological:
• DRL_RI
Two 1000 mg intravenous infusions, one each on Day 1 and Day 15
• Rituxan
Two 1000 mg intravenous infusions, one each on Day 1 and Day 15
• MabThera
Two 1000 mg intravenous infusions, one each on Day 1 and Day 15

Locations

Country	Name	City	State
India	Shalby Hospitals	Ahmedabad	Gujarat
India	Chanre Rheumatology & Immunology Center & Research	Bangalore	Karnataka
India	Sushruta Multispeciality Hospital & Research Centre Pvt. Ltd	Hubli	Karnataka
India	Care Hospitals	Hyderabad	Andhra Pradesh
India	Gurunank Care Hospital	Hyderabad	Andhra Pradesh
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	Dayanand Medical College & Hosptial	Ludhiana	Punjab
India	Apollo Specialty Hosptials	Madurai	Tamil Nadu
India	Kokilaben Dhirubhai Ambani Hospital & Medical Research Institute	Mumbai	Maharashtra
India	Jagadguru Sri Shivarathreeshwara Hospital	Mysore	Karnataka
India	lndraprastha Apollo Hospitals	New Delhi	Delhi
India	Maulana Azad Medical College & Associated Lok Nayak Hospitals	New Delhi	Delhi
India	Deennath Mangeshkar Hospital and Research Centre	Pune	Maharashtra
India	Jehangir Clinical Development Centre Pvt. Ltd.	Pune	Maharashtra
India	lnamdar Multispeciality Hospital	Pune	Maharashtra
India	Oyster & Pearl Hospital	Pune	Maharashtra
India	Krishna Institute of Medical Sciences Ltd.	Secunderabad	Andhra Pradesh
India	Yashoda Hospital	Secunderabad	Andhra Predesh
India	Government Medical College & New Civil Hospital	Surat	Gujarat
Ukraine	Communal Healthcare Institution Kharkiv City Clinical Hospital #8	Kharkiv
Ukraine	State Institution D.F. Chebotariov Institute of Gerontology of NAMS of Ukraine	Kyiv
Ukraine	State Institution National Scientific Center Acad. Strazhesko Institute of Cardiology of National Academy of Medical Science	Kyiv
Ukraine	M.V. Sklifosovskyi Poltava Regional Clinical Hospital	Poltava
Ukraine	Medical Clinical Investigational Center MC LLC Health Clinic	Vinnytsia
Ukraine	Vinnytsia M.I. Pyrogov Regional Clinical Hospital	Vinnytsia
Ukraine	Communal Institution Zaporzhzhia Regional Clinical Hospital of Zaporizhzhia Regional Council	Zaporizhzhia

Sponsors (1)

Lead Sponsor	Collaborator
Dr. Reddy's Laboratories Limited

Countries where clinical trial is conducted

India,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	2 weeks
Primary	AUC0-8 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
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	16 weeks
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).	2 weeks
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.	2 weeks
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).	2 weeks
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).	2 weeks
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.	24 weeks
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.	24 weeks
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.	24 weeks
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).	Baseline and 4 weeks
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).	Baseline and 8 weeks
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).	Baseline and 12 weeks
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).	Baseline and 16 weeks
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.	48 hours
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.	16 weeks
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.	24 weeks
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.	24 weeks
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.	24 weeks
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.	24 weeks
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.	24 weeks