Clinical trial NCT01759030: Study of Safety and Efficacy of BCD-020 Comparing to MabThera in Patients With Rheumatoid Arthritis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Keywords: rheumatoid arthritis, DMARDs
rituximab
biosimilar
interchangeability
Lead sponsor: Biocad
Sponsor class: INDUSTRY
First posted: 2013-01-02
Enrollment: 181
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

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 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.

Primary outcomes:
measure: Number of patients who have reached ACR20 within 24 weeks after the treatment initiation
timeFrame: week 24
Secondary outcomes:
measure: Frequency of adverse events (AE) and serious adverse events (SAE) that is related, in Investigator's opinion, to rheumatoid arthritis therapy
timeFrame: during all time of participation in the study
measure: Frequency of AE and SAE grade 3-4 that is related, in Investigator's opinion, to rheumatoid arthritis therapy
timeFrame: during all time of participation in the study
measure: Number of cases of early withdrawal from the study caused by AE or SAE
timeFrame: during all time of participation in the study
measure: Level of binding and neutralizing antibodies to rituximab in patients from both groups
timeFrame: at screening, week 12, week 24
measure: CD19+ and CD20+ lymphocyte counts
timeFrame: 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
Other outcomes:
measure: CD3+ lymphocyte count
timeFrame: before infusion, after the 1st and the 2nd infusion of rituximab, on day 3,17,29, at week 12,24,48
measure: Number of patients in each group who have reached ACR20
timeFrame: week 48
measure: Number of patients in each group that have reached ACR50/70
timeFrame: week 24, week 48
measure: Number of patients in each group with low RA activity according to DAS28
timeFrame: week 24, week 48
measure: Number of patients in each group with RA remission according to DAS28
timeFrame: week 24, week 48
measure: Number of patients in each group with RA remission according to ACR/EULAR
timeFrame: week 24, week 48
measure: X-ray characteristic of the involved joints
timeFrame: week 24, week 48
measure: Functional ability index according to HAQ
timeFrame: week 12, week 24, week 48
measure: Quality of life assessment by SF-36 questionnaire
timeFrame: week 12, week 24, week 48
measure: Level of hsCRP and ESR by Westergren
timeFrame: Day 29, weeks 8,12,16,20,24,32,40,48
measure: Serum levels of IgA, IgG, IgM
timeFrame: Day 17,29, 46 weeks 24,48
measure: Serum level of rituximab
timeFrame: 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)
measure: 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
timeFrame: 48 weeks
measure: 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
timeFrame: 48
measure: Percentage of patients in each group that have reached ACR20/50/70 within 24 weeks after the retreatment initiation
timeFrame: 48 weeks
measure: Percentage of patients in each group with low RA activity according to DAS28 (2.6-3.2) in 24 weeks after the retreatment initiation
timeFrame: 48 weeks
measure: Percentage of patients in each group with RA remission according to DAS28 (<2.6) in 24 weeks after the retreatment initiation
timeFrame: 48 weeks
measure: Percentage of patients in each group with RA remission according to ACR/EULAR 2011 in 24 weeks after the retreatment initiation
timeFrame: 48 weeks
measure: Radiography characteristic of the involved joints after 24 weeks from the retreatment initiation including
timeFrame: 48 weeks
measure: Functional disability index according to HAQ-DI after 24 weeks from the start of retreatment
timeFrame: 48 weeks
measure: Quality of life assessment by SF-36 questionnaire after 24 weeks from the start of retreatment
timeFrame: 48 weeks
measure: 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
timeFrame: 48 weeks
measure: 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
timeFrame: 48 weeks
measure: 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
timeFrame: 48 weeks
Locations:
city: Gomel
country: Belarus
facility: Gomel Regional Clinical Hospital
city: Minsk
country: Belarus
facility: City Clinical Hospital №1
city: Minsk
country: Belarus
facility: City Clinical Hospital №9
city: Vitebsk
country: Belarus
facility: Vitebsk Regional Clinical Hospital
city: Ahmadabad
country: India
facility: Satellite Orthopaedic Hospital & Research Centre Pvt Ltd
city: Ahmadabad
country: India
facility: Smt NHL Medical College and SethVS General Hospital
city: Aurangabad
country: India
facility: Government Medical College and Hospital Panchakki Road
city: Bangalore
country: India
facility: Bangalore Medical College and Research Institute, Victoria Hospital
city: Bangalore
country: India
facility: Pristine Hospital and Research Center Pvt. Ltd
city: Bangalore
country: India
facility: Sapthagiri Institute of Medical Sciences and Research Centre#15
city: Bangalore
country: India
facility: Sri Venkateshwara Hospital
city: Chennai
country: India
facility: Sri Ramachandra Medical Centre, No.1
city: Cuttack
country: India
facility: Swami Vivekananda National Institrute of Rehabilitation Training and research
city: Hyderabad
country: India
facility: Gandhi Hospital, Department of Orthopedics
city: Hyderabad
country: India
facility: Sri Sri Holistic Hospitals
city: Hyderabad
country: India
facility: Sumana Hospitals, Research Department
city: Hyderabad
country: India
facility: Yashoda Hospital
city: Jaipur
country: India
facility: Jaipur Hospital, Lal Kothi, Near SMS Stadium
city: Jaipur
country: India
facility: SMS Medical College & Hospital
city: Kolkata
country: India
facility: Calcutta national medical college, Kolkata
city: Mumbai
country: India
facility: Bhatia Hospital, Medical Research Society
city: Nagpur
country: India
facility: Government Medical College and Hospital
city: Puducherry
country: India
facility: Jawarlal Institute of Postgraduation Medical Education and Research
city: Pune
country: India
facility: B.J Medical college Sassoon General Hospital, Near Pune Railway Station
city: Pune
country: India
facility: Medipoint Hospitals Pvt Ltd
city: Pune
country: India
facility: Ruby Hall Clinic
city: Vellore
country: India
facility: Christian Medical College
city: Chelyabinsk
country: Russian Federation
facility: Chelyabinsk Regional Clinical hospital
city: Chelyabinsk
country: Russian Federation
facility: Clinical Hospital at Chelyabinsk Railway Station
city: Kursk
country: Russian Federation
facility: Kursk regional hospital
city: Moscow
country: Russian Federation
facility: Research Institute of Rheumotology
city: N.Novgorod
country: Russian Federation
facility: Nizhegorodskaya Regional Clinical Hospital named after N.A. Semashko
city: Novosibirsk
country: Russian Federation
facility: Limited liability company Consultation and Diagnostic Center "Zdorovyye sustavy"
city: Smolensk
country: Russian Federation
facility: Local hospital at the station Smolensk OAO RZD
city: Smolensk
country: Russian Federation
facility: Smolensk State Medical Academy
city: St.Petersburg
country: Russian Federation
facility: North-Western State Medical University n.a. I.I.Mechnikov
city: Velikiy Novgorod
country: Russian Federation
facility: Novgorod regional clinical hospital
city: Kharkiv
country: Ukraine
facility: Kharkiv City Clinical Emergency Hospital n.a. O.I.Meschaninov
city: Kyiv
country: Ukraine
facility: National Research Center "Cardiology Institute n.a. M.D.Strazheska"
city: Odessa
country: Ukraine
facility: Odessa Regional Cardiology Dispensary
Study officials:
References: