CTRI/2014/07/004742 [Registered on: 16/07/2014] Trial Registered Retrospectively
Last Modified On:
24/01/2018
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug Biological
Study Design
Randomized, Parallel Group, Active Controlled Trial
Public Title of Study
Phase III clinical trial comparing efficacy and safety of BCD-020 (CJSC BIOCAD, Russia) and MabThera® (F. Hoffmann-La Roche Ltd., Switzerland) in patients with rheumatoid arthritis.
Scientific Title of Study
International multicentre double blind randomized clinical study evaluating the efficacy and safety of BCD-020 (CJSC BIOCAD, Russia) and MabThera® (F. Hoffmann-La Roche Ltd., Switzerland) in patients with rheumatoid arthritis who had an inadequate response or intolerance to other DMARDs including one or more TNF inhibitor therapies
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
BCD-020-02 version 2.2 dated 6 September 2013
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Mrutyunjaya Ganiger
Designation
Sr. Clinical Research Associate - Clinical Trials,
Affiliation
BIOCAD INDIA PVT LTD,
Address
BIOCAD INDIA PVT LTD, 163/C, 3rd Cross, 3rd Phase,
J.P.Nagar,Bangalore
KARNATAKA 560078
India
Bangalore KARNATAKA 560078 India
Phone
8123000277
Fax
8041699773
Email
mrutyunjaya.g@biocadindia.com
Details of Contact Person Scientific Query
Name
Dr Mrutyunjaya Ganiger
Designation
Sr. Clinical Research Associate - Clinical Trials,
Affiliation
BIOCAD INDIA PVT LTD,
Address
BIOCAD INDIA PVT LTD, 163/C, 3rd Cross, 3rd Phase,
J.P.Nagar,Bangalore
KARNATAKA 560078
India
KARNATAKA 560078 India
Phone
8123000277
Fax
8041699773
Email
mrutyunjaya.g@biocadindia.com
Details of Contact Person Public Query
Name
Dr Mrutyunjaya Ganiger
Designation
Sr. Clinical Research Associate - Clinical Trials,
Affiliation
BIOCAD INDIA PVT LTD,
Address
BIOCAD INDIA PVT LTD, 163/C, 3rd Cross, 3rd Phase,
J.P.Nagar,Bangalore
KARNATAKA 560078
India
KARNATAKA 560078 India
Phone
8123000277
Fax
8041699773
Email
mrutyunjaya.g@biocadindia.com
Source of Monetary or Material Support
BIOCAD INDIA PVT LTD
Primary Sponsor
Name
BIOCAD INDIA PVT LTD
Address
BIOCAD INDIA PVT LTD, 163/C, 3rd Cross, 3rd Phase, J.P.Nagar, Bangalore KARNATAKA 560078 India
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
India
Sites of Study
No of Sites = 18
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr K V Puttakempa Raju
Victoria Hospital, Bangalore Medical College & Research institute
Victoria Hospital, Bangalore Medical College & Research institute,Dept of Orthopaedics. Bangalore - 560002, Karnataka Bangalore KARNATAKA
9845172978
kvpkr@hotmail.com
Dr Jesalpura
AMC MET Medical College and Sheth L G general Hospital
AMC MET Medical College and Sheth L G general Hospital,Dept of Orthopaedics. Maninagar, Ahmadabad Ahmadabad GUJARAT
919033023000
bjesalpura@yahoo.com
Dr Ajay Chandanwale
 B J Medical College & Sasoon General Hospitals
B J Medical College & Sasoon General Hospitals,Dept of Orthopaedics. Pune - 411001 Pune MAHARASHTRA
9420697474
drasc62@rediffmail.com
Dr Anil Dhule
 Govt. Medical College and Hospital
Govt. Medical College and Hospital,Dept of Orthopaedics. Panchakki Road, GHATI Campus,Aurangabad – 431001 Maharashtra Aurangabad MAHARASHTRA
919422204998
dranildhule5@gmail.com
Dr VS Negi
 Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER)
Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), dept of Immunology.
Puducheery – 605006, India Pondicherry PONDICHERRY
04132297358
negi.v@jipmer.edu.in
Dr P V Vijayaraghavan
 Sri Ramachandra Medical Centre
 Sri Ramachandra Medical Centre, Dept of Orthopaedics.
Ramchandra Nagar, Porur, Chennai-600116, Tamil Nadu Chennai TAMIL NADU
Hi-Tech Medical College & Hospital,Dept of Orthopaedics.
Pandra, Rasulgarh,Bhubaneswar, 751025 Cuttack ORISSA
919437094747
Bipinkumar.mohapatra@yahoo.in
Dr SK Das
King Georges Medical University
King Georges Medical University,Dept of Rheumatology.
Lal Bahadur Shastri Bhawan, RALC Campus, Lucknow - 226018 Lucknow UTTAR PRADESH
0522-2624275
rheumatologykgmu@gmail.com
Dr Arvind Gorengaonkar
Lokamanya Tilak General Hospital
 Lokamanya Tilak General Hospital, Dept of Orthopaedics.
1105, Sidhivinayak Tower, N S Mankikar Road, Chuna Bhatti (W), Mumbai- 400022 Mumbai MAHARASHTRA
9821351787
abgortho@hotmail.com
Dr Rajeev Gupta
Medanta - The Medicity
Medanta - The Medicity,Dept of Orthopaedics.
Sector 38, Gurgaon, Haryana - 122001, India Gurgaon HARYANA
9829068150
rajeevgg@gmail.com
Dr R N Sarkar
Medical College, Kolkata, Department of Medicine
Medical College, Kolkata, Department of Rheumatology, #88, College Street Kolkata - 700073 Kolkata WEST BENGAL
91332212-3741
prin_kmch@wbhealth.gov.in
Dr Sushil Mankar
NKPSIMS, Dept. of Orthopaedic
NKPSIMS, Dept. of Orthopaedic, Digdoh Hills, Hingana Road, Nagpur Nagpur MAHARASHTRA
919422108284
drshmankar@rediffmail.com
Dr Ajit Nalawade
Ruby Hall Clinic
Ruby Hall Clinic.Dept of Consultant Rheumatology.
40, Sasoon Road, Pune – 411001
Pune MAHARASHTRA
919822746248
dr.ajitnalawade@gmail.com
Dr Vishwanath Yaligod
Sapthagiri Institute of Medical Sciences & Research Centre
Sapthagiri Institute of Medical Sciences & Research Centre,Dept of Orthopaedics. No 15, Chikkasandra, Hesaraghatta Main Road, Bangalore - 560090 Bangalore KARNATAKA
080-22791638
hospitalssapthagiri@gmail.com
Details of Ethics Committee
No of Ethics Committees= 18
Name of Committee
Approval Status
AMC MET Ethics Committee
Submittted/Under Review
 Ethical Committee of B.J. Medical, Govt. Medical College.
Submittted/Under Review
 Ethics Committee,JIPMER, Puducheery
Submittted/Under Review
 Hi-Tech Medical College & Hospital
Approved
 Institutional Ethics Committee, Gandhi Hospital
Submittted/Under Review
 Institutional Ethics CommitteeNKPSIMS and LMH, Nagpur
Approved
Ethics Committee of Bangalore Medical College and Research institute
Approved
hatia Hospital, Medical Research Society Ethics Committee
Submittted/Under Review
Institutional Ethics Committee of Human Research, Kolkata Medical College
Submittted/Under Review
Institutional Ethics Committee, CMC
Submittted/Under Review
Institutional Ethics Committee, King Georges Medical University
Institutional Ethics Committee, Poona Medical research Foundation.
Approved
Institutional Ethics Committee,Sapthagiri Institute of Medical Sciences & Research Centre
Approved
Institutional Ethics Committee Govt. Medical College and Hospital,Aurangabad
Submittted/Under Review
Medanta Institutional Ethics Committee, Medanta - The Medicity, Sector 38, Gurgaon, Haryana - 122001, India
Approved
Sri Ramachandra Institutional Ethics Committee,
Approved
Yashoda Academy of Medical Education & Research
Submittted/Under Review
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
Patients with rheumatoid arthritis who had an inadequate response or intolerance to other DMARDs including one or more TNF inhibitor therapies,
Intervention / Comparator Agent
Type
Name
Details
Intervention
BCD-020 – Rituximab (INN: rituximab), concentrate for solution for infusion
This study is designed to be double blind, therefore neither the patient nor the study doctor should know which rituximab drug product the patient receives.
after completing the screening period and obtaining the Investigator’s positive decision on participation in the study, each patient should be stratified according to age (younger than 40 years of age, 40 years of age or over), ACPA-positive or negative, necessity of taking oral glucocorticosteroids. After stratification, patients will be centrally randomized into one of the two study groups.Patients from the first group (154 patients) will receive BCD-020 as 1000 mg single dose, intravenously, slowly, once in 2 weeks, with 2 infusions per course (on day 1 and day 15).
Patients from the second group (154 patients) will receive MabThera® as 1000 mg single dose, intravenously, slowly, once in 2 weeks, with 2 infusions per course (on day 1 and day 15).
Comparator Agent
MabThera® (INN: rituximab, F. Hoffmann-La Roche Ltd., Switzerland), concentrate for solution for infusion
This study is designed to be double blind, therefore neither the patient nor the study doctor should know which rituximab drug product the patient receives.
after completing the screening period and obtaining the Investigator’s positive decision on participation in the study, each patient should be stratified according to age (younger than 40 years of age, 40 years of age or over), ACPA-positive or negative, necessity of taking oral glucocorticosteroids. After stratification, patients will be centrally randomized into one of the two study groups.Patients from the first group (154 patients) will receive BCD-020 as 1000 mg single dose, intravenously, slowly, once in 2 weeks, with 2 infusions per course (on day 1 and day 15).
Patients from the second group (154 patients) will receive MabThera® as 1000 mg single dose, intravenously, slowly, once in 2 weeks, with 2 infusions per course (on day 1 and day 15).
Inclusion Criteria
Age From
18.00 Year(s)
Age To
80.00 Year(s)
Gender
Both
Details
1. Having signed a written informed consent form.
2. Patients must be from 18 to 80 years of age (both ages inclusive)
3. Rheumatoid arthritis confirmed according to ACR 1987 criteria.
4. Seropositive rheumatoid arthritis .
5. Active rheumatoid arthritis during the last 3 months.
6. 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.
7. Patient’s functional status – class I-III according to ACR classification
8. Inadequate response to DMARDs that include one or more TNF inhibitors, intolerance or contraindications to TNF inhibitors.
9. Necessity of methotrexate treatment during the last 4 weeks prior to screening period with stable/consistent dosage of 7.5 – 20 mg per week.
10. Patient’s ability (in Investigator’s opinion) to follow the protocol procedures;
11. Male and female patients with normal reproductive function and their sexual partners are aware and willing to use voluntarily reliable methods of contraception during the whole period of the study including the screening period. This requirement does not apply to patients who underwent operative sterilization or those defined as post-menopausal (documentally confirmed) within last 2 years. Reliable methods of contraception suggest using 1 barrier method in combination with 1 of the following methods: spermicides, intra-uterine device etc
ExclusionCriteria
Details
1. Patients with Felty’s syndrome complicated by severe skin vasculitis (ulcerative-necrotic form).
2. Patient’s functional status – class IV according to ACR classification .
3. Rheumatoid arthritis low activity (less than 3.2 according to DAS28).
4. Taking medications :
• 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.
5. Pregnancy and breast-feeding.
6. Changes of laboratory values:
 Hemoglobin level is less than 100 g/l;
 Leucocyte level is less than 3,0×109/l;
 Absolute neutrophil count is less than 1,5×109/l;
 Thrombocyte level is less than 100×109/l.
7. Confirmed chicken pox within 30 days before inclusion to the screening.
8. Confirmed herpes zoster infection.
9. Acute forms of any infectious diseases, history of chronic infections with severe clinical manifestations.
10. Active tuberculosis, history of latent tuberculosis.
11. 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).
12. Juvenile idiopathic arthritis or juvenile rheumatoid arthritis and/or rheumatoid arthritis developed before the age of 16.
13. Any determined immunodeficiency.
14. Pernicious anemia.
15. Confirmed cobalamine deficiency.
16. 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;
ï€ Severe hypertonic disease resistant to treatment ;
ï€ Decompensated heart (CHF III, NYHA class IV), liver or kidney diseases (creatinine level >133 µM/l, AST, ALT and bilirubin levels 3 and more times higher than normal), except for the cases when the symptom is caused by rheumatoid arthritis;
ï€ Decompensated forms of respiratory insufficiency;
ï€ Severe diabetes mellitus resistant to treatment;
17. 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.
18. Major surgery within 28 days prior to the trial principal phase (treatment with rituximab).
19. 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.
20. Unstable angina pectoris.
21. Myocardial infarction within less than 1 year prior to participation in the study.
22. Severe central or peripheral nervous system diseases.
23. Drug addiction, alcoholism.
24. 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.
25. Presence of malignant neoplasm, with the exception of:
 Adequately treated basal cell carcinoma and cervical carcinoma in situ;
 Any malignancy with complete remission of more than 5 years;
26. 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.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Sequentially numbered, sealed, opaque envelopes
Blinding/Masking
Participant and Investigator Blinded
Primary Outcome
Outcome
TimePoints
•Percentage of patients in each group that have reached ACR20 within 24 weeks after the treatment initiation.
•Safety and efficacy evaluation.
Prior to first infusion, 3hr after the infusion initiation, immediately after infusion termination, 6 hr after the infusion initiation, 48 hr after Second infusion, prior to the second infusion,immediately after infusion termination, 6 hr after the infusion initiation, 48 hr after Second infusion,336 hrs after initiation of second infusion and 744 hrs after initiation of second infusion.
Secondary Outcome
Outcome
TimePoints
1. Assessment of Safety parameters after one dose of one of the investigational drugs during the study
• AEs and SAEs incidence
Secondary study endpoints for pharmacokinetics assessment
2. Secondary study endpoints for pharmacodynamic assessment:
3.Secondary study endpoints for efficacy assessment
As defined in protocol
Target Sample Size
Total Sample Size="308" Sample Size from India="60" Final Enrollment numbers achieved (Total)= "0" Final Enrollment numbers achieved (India)="0"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
This study is multicentre double blind randomized clinical study evaluating the efficacy and safety of BCD-020 (CJSC BIOCAD, Russia) and MabThera® (F. Hoffmann-La Roche Ltd., Switzerland) in patients with rheumatoid arthritis who had an inadequate response or intolerance to other DMARDs including one or more TNF inhibitor therapies.
The main objective of the study is to compare the efficacy, safety, pharmacokinetics and pharmacodynamics of the drug BCD-020 (CJSC BIOCAD, Russia) and MabThera® (F. Hoffmann-La Roche Ltd., Switzerland) when using in combination with methotrexate in patients with rheumatoid arthritis and also to evaluate the diversity, frequency, severity and duration of adverse events in patients.
The study will be conducted at 18 sites of India and 60 patients after completing the screening period and obtaining the Investigator’s positive decision on participation in the study, each patient should be stratified according to age (younger than 40 years of age, 40 years of age or over), ACPA-positive or negative, necessity of taking oral glucocorticosteroids. After stratification, patients will be centrally randomized into one of the two study groups.This study is designed to be double blind, therefore neither the patient nor the study doctor should know which rituximab drug product the patient receives.
he drug Rituximab based on monoclonal antibodies a surface receptor of pre-B and mature B-lymphocytes, rituximab, which is a biological equivalent (Biosimilar) of MabThera® (F. Hoffmann-La Roche Ltd., Switzerland) a drug that is well known and widely used in rheumatology and oncology. Rituximab manufactured by CJSC BIOCAD (BCD-020) had undergone a series of comparative physical-chemical and preclinical studies (including animal studies) that showed a complete equivalence of the biological effects of BCD-020 and MabThera®.