Study of Safety and Efficacy of BCD-020 Comparing to MabThera in Patients With Rheumatoid Arthritis (BIORA)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Biocad
ClinicalTrials.gov Identifier:
NCT01759030
First received: December 20, 2012
Last updated: January 30, 2015
Last verified: January 2015
  Purpose

The purpose of this study is to prove that efficacy, safety and immunogenicity of BCD-020 is equivalent to MabThera when used in combination with methotrexate for the treatment of patient with rheumatoid arthritis


Condition Intervention Phase
Rheumatoid Arthritis
Drug: Rituximab
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Double Blind Randomized Clinical Study Evaluating Efficacy and Safety of BCD-020 and MabThera in Patients With Rheumatoid Arthritis Who Had an Inadequate Response or Intolerance to Other DMARDs Including One or More TNF Inhibitor Therapies

Resource links provided by NLM:


Further study details as provided by Biocad:

Primary Outcome Measures:
  • Number of patients who have reached ACR20 within 24 weeks after the treatment initiation [ Time Frame: week 24 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Frequency of adverse events (AE) and serious adverse events (SAE) that is related, in Investigator's opinion, to rheumatoid arthritis therapy [ Time Frame: during all time of participation in the study ] [ Designated as safety issue: Yes ]
  • Frequency of AE and SAE grade 3-4 that is related, in Investigator's opinion, to rheumatoid arthritis therapy [ Time Frame: during all time of participation in the study ] [ Designated as safety issue: Yes ]
  • Number of cases of early withdrawal from the study caused by AE or SAE [ Time Frame: during all time of participation in the study ] [ Designated as safety issue: Yes ]
  • Level of binding and neutralizing antibodies to rituximab in patients from both groups [ Time Frame: at screening, week 12, week 24 ] [ Designated as safety issue: Yes ]
  • CD19+ and CD20+ lymphocyte counts [ Time Frame: before infusion, after the 1st and the 2nd infusion of rituximab, on day 3,17,29 after the 1st infusion, at week 12,24,48 ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • CD3+ lymphocyte count [ Time Frame: before infusion, after the 1st and the 2nd infusion of rituximab, on day 3,17,29, at week 12,24,48 ] [ Designated as safety issue: No ]
  • Number of patients in each group who have reached ACR20 [ Time Frame: week 48 ] [ Designated as safety issue: No ]
  • Number of patients in each group that have reached ACR50/70 [ Time Frame: week 24, week 48 ] [ Designated as safety issue: No ]
  • Number of patients in each group with low RA activity according to DAS28 [ Time Frame: week 24, week 48 ] [ Designated as safety issue: No ]
  • Number of patients in each group with RA remission according to DAS28 [ Time Frame: week 24, week 48 ] [ Designated as safety issue: No ]
  • Number of patients in each group with RA remission according to ACR/EULAR [ Time Frame: week 24, week 48 ] [ Designated as safety issue: No ]
  • X-ray characteristic of the involved joints [ Time Frame: week 24, week 48 ] [ Designated as safety issue: No ]
    1. Rate of progression in structural joint damage in Total Modified Sharp Score (erosion score, joint space narrowing score);
    2. Percentage of patients without radiologic progression (by Steinbrocker).

  • Functional ability index according to HAQ [ Time Frame: week 12, week 24, week 48 ] [ Designated as safety issue: No ]
  • Quality of life assessment by SF-36 questionnaire [ Time Frame: week 12, week 24, week 48 ] [ Designated as safety issue: No ]
  • Level of hsCRP and ESR by Westergren [ Time Frame: Day 29, weeks 8,12,16,20,24,32,40,48 ] [ Designated as safety issue: No ]
  • Serum levels of IgA, IgG, IgM [ Time Frame: Day 17,29, 46 weeks 24,48 ] [ Designated as safety issue: No ]
  • Serum level of rituximab [ Time Frame: 0 h, 3 h, 6 h after infusion, on day 3 (48 h after the 1st infusion), day 17 (48 hours after the 2nd infusion), day 29 (after 336 hours after the 2nd infusion) and day 46 (744 hours after the 2nd infusion) ] [ Designated as safety issue: No ]
  • Hazard ratio for the absence of remission according to DAS28 after 24 weeks from the switching from MabThera to BCD-020, comparing to the patients, which were retreated with MabThera without the switching to BCD-020 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Hazard ratio for the absence of remission according to DAS28 after 24 weeks from the switching from BCD-020 to MabThera, comparing to the patients, which were retreated with BCD-020 without the switching to MabThera [ Time Frame: 48 ] [ Designated as safety issue: No ]
  • Percentage of patients in each group that have reached ACR20/50/70 within 24 weeks after the retreatment initiation [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Percentage of patients in each group with low RA activity according to DAS28 (2.6-3.2) in 24 weeks after the retreatment initiation [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Percentage of patients in each group with RA remission according to DAS28 (<2.6) in 24 weeks after the retreatment initiation [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Percentage of patients in each group with RA remission according to ACR/EULAR 2011 in 24 weeks after the retreatment initiation [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Radiography characteristic of the involved joints after 24 weeks from the retreatment initiation including [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Functional disability index according to HAQ-DI after 24 weeks from the start of retreatment [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Quality of life assessment by SF-36 questionnaire after 24 weeks from the start of retreatment [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Percentage of patients in each group withf binding and neutralizing antibodies to rituximab at screening, at week 12 an week 24 after the first infusion during the first cycle of therapy and after 24 weeks from the start of retreatment [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Mean titre of binding and neutralizing antibodies to rituximab at screening, at week 12 and week 24 after the first infusion during the first cycle of therapy and after 24 weeks from the start of retreatment [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Hazard ratio of any AE, that is related, in Investigator's opinion, to the use of rituximab and which has occurred after the switching from MabThera to BCD-020, in comparison with patients who were retreated with MabThera without switching to BCD-020 [ Time Frame: 48 weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 160
Study Start Date: December 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: MabThera (F. Hoffmann-La Roche Ltd.)

Stage 1 (week 1 - week 24) MabThera will be administered at a dose of 1000 mg, IV (on day 1 and day 15).

Stage 2 (week 24 - 48) If the disease activity remains on Week 24 the patient will undergo the second randomization (1:1 ratio): if he/she randomised into group A then he/she recieves BCD-020 at a dose f 1000 mg, IV, once in 2 weeks, 2 infusions per course (on day 1 and day 15); if he/she if he/she randomised into group B then he/she continues to recieve MabThera at a dose f 1000 mg, IV, once in 2 weeks, 2 infusions per course (on day 1 and day 15).

MabThera/BCD-020 will be used in combination with methotrexate (irrespectively to study stage).

Drug: Rituximab
Patients will will receive rituximab a dose of 1000 mg , intravenously, slowly, once in 2 weeks, with 2 infusions per course (on day 1 and day 15).
Other Name: MabThera, Rituxan, BCD-020
Experimental: BCD-020 (CJSC BIOCAD)

Stage 1 (week 1-week 24) BCD-020 will be administered at a dose of 1000 mg, IV (on day 1 and day 15).

Stage 2 (week 24-48) If the disease activity remains on Week 24 the patient will undergo the second randomization (1:1 ratio): if he/she randomised into group A then he/she recieves MabThera at a dose f 1000 mg, IV, on day 1 and day 15; if he/she if he/she randomised into group B then he/she continues to recieve BCD-020 at a dose f 1000 mg, IV, on day 1 and day 15.

MabThera/BCD-020 will be used in combination with methotrexate (irrespectively to study stage).

Drug: Rituximab
Patients will will receive rituximab a dose of 1000 mg , intravenously, slowly, once in 2 weeks, with 2 infusions per course (on day 1 and day 15).
Other Name: MabThera, Rituxan, BCD-020

Detailed Description:

This is an international multicenter double-blind randomized clinical study of the efficacy and safety (Phase III) with an active comparator; the study provides the additional evaluation of the interchangeability of rituximab biosimilar and original product MabThera.

The study will include 308 subjects with active seropositive rheumatoid arthritis who had intolerance or inadequate response to current therapy regimens including one or more TNF inhibitors, or who had contraindications to TNF inhibitors.

The first 24-week stage includes one course of rituximab therapy. The first study stage proposes central randomization into 2 large groups (1:1): patients from the first group will recieve BCD-020 (rituximab manufactured by CJSC BIOCAD) at a dose 1000 mg in a drop-wise manner on day 1 and day 15; patients from the second group will recieve MabThera at a same regimen.

On the final visit of Stage 1 (visit 11 at week 24) all efficacy parameters must be evaluated. If the disease activity remains (DAS28 score ≥2.6 or increased by 0.6 points or more compared to the last measurement) the patient will recieve another course of rituximab treatment. In this case a partial crossover (Stage 2) will take place (by means of the second randomization): one half of patients with active RA, previously treated with BCD-020, will receive MabThera at a dose 1000 mg on day 1 and day 15; and one half of patients with active RA, previously treated with MabThera, will receive BCD-020 at a dose 1000 mg ion day 1 and day 15. After the first rituximab infusion performed for retreatment, the patient will undergo 24-week follow-up (counted starting from the date of retreatment initiation). Thus, effects of the switch from BCD-020 to MabThera and vice versa will be assessed in 24 weeks after the crossover (Stage 2 of the study).

Patients in whom remission of RA (DAS28 < 2.6) is reported on week 24 counting from the initial randomization will undergo the follow up for the next 24 weeks. During this period they will attend 3 visits (weeks 32, 40 and 48) in order to monitor the disease. If the exacerbation occurs within the time period not corresponding to week 32 or week 40, the patient will be invited to the study site for an out-of-schedule visit. If disease exacerbation is confirmed, he/she undergoes the second randomization, second rituximab treatment course and further follow up for 6 months (as described above).

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Having signed a written informed consent form.
  • Patients must be from 18 to 80 years of age (both ages inclusive)
  • Rheumatoid arthritis confirmed according to ACR 1987 criteria.
  • Seropositive rheumatoid arthritis.
  • Active rheumatoid arthritis during the last 3 months.
  • Disease score according to DAS28 of 3.2 or more, TJC≥8 (68), SJC≥8 (66), hsCRP≥6 mg/l, ESR≥28 mm/hr (by Westergren) at the moment of screening.
  • Patient's functional status - class I-III according to ACR classification
  • Inadequate response to DMARDs that include one or more TNF inhibitors, intolerance or contraindications to TNF inhibitors.
  • Necessity of methotrexate treatment during the last 4 weeks prior to screening period with stable/consistent dosage of 7.5 - 20 mg per week.
  • Patient's ability (in Investigator's opinion) to follow the protocol procedures;
  • Willingness to use contraception during all study period.

Exclusion Criteria:

  • Patients with Felty's syndrome (irrespectively to clinical form).
  • Patient's functional status - class IV according to ACR classification .
  • Rheumatoid arthritis low activity (less than 3.2 according to DAS28).
  • Concomitant therapy:

    • Previous treatment with any biological drug products causing CD20+ lymphocyte depletion, including biological investigational drugs.
    • Treatment with azathioprine within 28 days before the study initiation and with leflunomide within 8 weeks before the study's principal phase (treatment with rituximab).
    • Intra-articular glucocorticosteroids within 4 weeks before the study's principal phase (treatment with rituximab).
    • Necessity for prednisone or its equivalent administration at dose more than 10 mg per day.
    • Necessity for prednisone or its equivalent administration at dose ≤10 mg per day in cases when this dose wasn't stable/consistent during last 4 weeks.
    • Necessity for administration of non-steroidal anti-inflammatory drugs for arthritis treatment in cases when its doses were not stable/consistent during last 4 weeks.
  • Pregnancy and breast-feeding.
  • Changes of laboratory values:

    • Hemoglobin level is less than 100 g/l;
    • Leucocyte level is less than 3,0×10e9/l;
    • Absolute neutrophil count is less than 1,5×10e9/l;
    • Thrombocyte level is less than 100×10e9/l.
  • Confirmed chicken pox within 30 days before inclusion to the screening.
  • Confirmed herpes zoster infection.
  • Acute forms of any infectious diseases, history of chronic infections with severe clinical manifestations.
  • Active tuberculosis, history of latent tuberculosis.
  • Inflammatory disease of the joints (present or in anamnesis) not related to rheumatoid arthritis (including gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease and others) or other systemic autoimmune disease (including systemic lupus erythematosus, Crohn's disease, ulcerative colitis, systemic scleroderma, inflammatory myopathy, mixed forms of connective tissue inflammatory diseases, cross-syndrome and others).
  • Juvenile idiopathic arthritis or juvenile rheumatoid arthritis and/or rheumatoid arthritis developed before the age of 16.
  • Any determined immunodeficiency.
  • Pernicious anemia.
  • Confirmed cobalamine deficiency.
  • Other somatic diseases (apart from rheumatoid arthritis) that can increase the probability of adverse events during the study or can influence the estimation of symptom manifestation of RA ; mask, enhance or alter the symptoms of RA or cause clinical or laboratory symptoms similar to that of RA;
  • Positive results of serological test of Hepatitis B surface antigen (HbsAg) or presence of Hbc IgM together with positive results of HBV PCR test, presence of antibodies to Hepatitis C virus, syphilis or HIV.
  • Major surgery within 28 days prior to the trial principal phase (treatment with rituximab).
  • Any mental disorder, including major depression and/or suicidal thoughts in anamnesis that can, in Investigator's opinion, create a risk for the patient or influence the patient's ability to follow the study protocol.
  • Unstable angina pectoris.
  • Myocardial infarction within less than 1 year prior to participation in the study.
  • Severe central or peripheral nervous system diseases.
  • Drug addiction, alcoholism.
  • Known hypersensitivity to murine proteins or any other components of the medications used in the treatment, methotrexate, folic acid and any drugs used in premedication.
  • Presence of malignant neoplasm, with the exception of adequately treated basal cell carcinoma and cervical carcinoma in situ and any malignancy with complete remission of more than 5 years;
  • Simultaneous participation in any other clinical trial, as well as former participation in other clinical trials within 3 months before this study initiation; previous participation in this study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01759030

Locations
Belarus
Gomel Regional Clinical Hospital
Gomel, Belarus
City Clinical Hospital №1
Minsk, Belarus
City Clinical Hospital №9
Minsk, Belarus
Vitebsk Regional Clinical Hospital
Vitebsk, Belarus
India
Satellite Orthopaedic Hospital & Research Centre Pvt Ltd
Ahmadabad, India
Smt NHL Medical College and SethVS General Hospital
Ahmadabad, India
Government Medical College and Hospital Panchakki Road
Aurangabad, India
Bangalore Medical College and Research Institute, Victoria Hospital
Bangalore, India
Pristine Hospital and Research Center Pvt. Ltd
Bangalore, India
Sapthagiri Institute of Medical Sciences and Research Centre#15
Bangalore, India
Sri Venkateshwara Hospital
Bangalore, India
Sri Ramachandra Medical Centre, No.1
Chennai, India
Swami Vivekananda National Institrute of Rehabilitation Training and research
Cuttack, India
Sri Sri Holistic Hospitals
Hyderabad, India
Gandhi Hospital, Department of Orthopedics
Hyderabad, India
Sumana Hospitals, Research Department
Hyderabad, India
Yashoda Hospital
Hyderabad, India
Jaipur Hospital, Lal Kothi, Near SMS Stadium
Jaipur, India
SMS Medical College & Hospital
Jaipur, India
Calcutta national medical college, Kolkata
Kolkata, India
Bhatia Hospital, Medical Research Society
Mumbai, India
Government Medical College and Hospital
Nagpur, India
Jawarlal Institute of Postgraduation Medical Education and Research
Puducherry, India
B.J Medical college Sassoon General Hospital, Near Pune Railway Station
Pune, India
Medipoint Hospitals Pvt Ltd
Pune, India
Ruby Hall Clinic
Pune, India
Christian Medical College
Vellore, India
Russian Federation
Chelyabinsk Regional Clinical hospital
Chelyabinsk, Russian Federation
Clinical Hospital at Chelyabinsk Railway Station
Chelyabinsk, Russian Federation
Kursk regional hospital
Kursk, Russian Federation
Research Institute of Rheumotology
Moscow, Russian Federation
Nizhegorodskaya Regional Clinical Hospital named after N.A. Semashko
N.Novgorod, Russian Federation
Limited liability company Consultation and Diagnostic Center "Zdorovyye sustavy"
Novosibirsk, Russian Federation
Local hospital at the station Smolensk OAO RZD
Smolensk, Russian Federation
Smolensk State Medical Academy
Smolensk, Russian Federation
North-Western State Medical University n.a. I.I.Mechnikov
St.Petersburg, Russian Federation
Novgorod regional clinical hospital
Velikiy Novgorod, Russian Federation
Ukraine
Kharkiv City Clinical Emergency Hospital n.a. O.I.Meschaninov
Kharkiv, Ukraine
National Research Center "Cardiology Institute n.a. M.D.Strazheska"
Kyiv, Ukraine
Odessa Regional Cardiology Dispensary
Odessa, Ukraine
Sponsors and Collaborators
Biocad
  More Information

No publications provided

Responsible Party: Biocad
ClinicalTrials.gov Identifier: NCT01759030     History of Changes
Other Study ID Numbers: BIORA (BCD-020-2)
Study First Received: December 20, 2012
Last Updated: January 30, 2015
Health Authority: Russia: Ministry of Health of the Russian Federation
Ukraine: Ministry of Health
Belarus: Ministry of Health
India: Ministry of Health

Keywords provided by Biocad:
rheumatoid arthritis, DMARDs
rituximab
biosimilar
interchangeability

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on May 25, 2015