Safety, Tolerability, PK and PD of Biosimilar Drug Ritumax® Compared to Original Drug MabThera®

Multicenter Double-blind Randomized Clinical Study of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Biosimilar Drug Ritumax® Compared to Original Drug MabThera® in Patients With Rheumatoid Arthritis

This is a multicenter, double-blind, randomized clinical study of safety, tolerability, pharmacokinetics and pharmacodynamics of biosimilar drug Ritumax® compared to original drug MabThera® in patients with rheumatoid arthritis, receiving stable doses of Methotrexate.

At Week -2, after signing the Patient Information Sheet and Informed Consent Form, patients with rheumatoid arthritis receiving stable doses of Methotrexate (10-25 mg per week orally or parenterally) will pass screening procedures.

Patients meeting all the inclusion/exclusion criteria will be invited to the investigational site for Visit 2 (Week 0) to be randomized into one of two treatment arms:

• Ritumax® 1000 mg х 2 intravenous infusions
• MabThera® 1000 mg х 2 intravenous infusions After being assigned to the treatment arm patients will receive a course of study treatment, including two i/v infusions at 14-day interval: at Week 0 and Week 2.

After that, patients will be followed up for the next 22 weeks. Safety, pharmacokinetic and pharmacodynamic parameters will be monitored at this visits.

Study Overview

• Status: Terminated
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: MabThera®; Drug: Ritumax®

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 115522
    • Federal State Budgetary Institution "Scientific Research Institution of Rheumatology" Russian Academy of Medical Sciences (FSBI "SRIR" RAMS)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed Patient Information Sheet and Informed Consent Form to participate in the study.
2. Men and women aged 18 years and older.
3. Patient diagnosed with rheumatoid arthritis of at least 6-month duration, determined according to classification criteria of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) (ACR-EULAR 2010) or the American College of Rheumatology (ACR1987) (in case if the diagnosis of rheumatoid arthritis was determined till 2010).

4. Active phase of the disease confirmed due to the combination of the following parameters:

   • DAS28 > 3,2
   • 5 (of 28) of tender and 5 (of 28) of swollen joints
   • CRP level ≥1,5 mg/dL and/or ESR > 28 mm/h
   • positive test for rheumatoid factor and/or CCP antibodies
5. Patients with negative response to or intolerability to the DMARD therapy.

6. Current outpatient therapy of rheumatoid arthritis:

   • continuous therapy with Methotrexate for at least 12 weeks prior to screening
   • stable doses of Methotrexate (10-25 mg per week) within 4 weeks prior to screening
   • when currently under the corticosteroids therapy, the dose should be stable within the last 4 weeks prior to screening and be less than 10 mg of Prednisolone or its equivalent
   • when currently under the NSAID therapy, the dose should be stable within the last 4 weeks prior to screening

Exclusion Criteria:

The patient will be deemed ineligible for the study meeting any of the following criteria:

1. Other inflammatory arthropathies apart from rheumatoid arthritis (e.g. gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme desease) or other system autoimmune diseases (e.g. systemic lupus erythematosus, inflammatory bowel disease, pneumosclerosis or Felly's syndrome, sclerodermia, inflammatory myopathy, mixed collagenosis or other crossed syndrome). Patients with secondary Sjorgen's syndrome or secondary limited cutaneous vasculitis with a rheumatoid arthritis background may participate in the study.
2. Chronic heart failure Class III or IV in New York Heart Association (NYHA) classification and clinically significant ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation).
3. Serious chronic pulmonary diseases (COPD, bronchial asthma); functional dyspnea of severity level III and higher (due to the Medical Science Research Council scale for dyspnea).
4. Signs of significant uncontrolled concomitant disease, e.g. renal, hepatic, gastrointestinal, endocrine system and nervous system disorders, which, according to the Investigator's opinion, could prevent the patient's participation in the study.
5. Any surgical procedure, including bone and joint surgeries, or synovectomy (including arthrodesis or endoprosthesis replacement), performed within 12 weeks prior to screening or planned to be performed within 24 weeks after (except for small surgical procedures, requiring a local anesthesia or no anesthesia).
6. Infectious diseases.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: MabThera®; 2 intravenous infusions on Week 0 and Week 2 (14-day interval).	Drug: MabThera®; 1000 mg intravenously; Other Names: Rituximab
EXPERIMENTAL: Ritumax®; 2 intravenous infusions on Week 0 and Week 2 (14-day interval).	Drug: Ritumax®; 1000 mg intravenously

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration versus time curve (AUC)	Comparative assessment of pharmacokinetic parameters of Ritumax® and MabThera	within a 24-week period
Peak Plasma Concentration (Cmax)	Comparative assessment of pharmacokinetic parameters of Ritumax® and MabThera	within a 24-week period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD19+ B- lymphocytes	Comparative assessment of pharmacodynamic parameters of Ritumax® and MabThera®	within a 24-week period
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability).	The number of patients with treatment-related AEs	within a 24-week period

Collaborators and Investigators

• Sponsor: Biointegrator LLC

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 27, 2016
• Primary Completion (ACTUAL): March 14, 2018
• Study Completion (ACTUAL): March 14, 2018

Study Registration Dates

• First Submitted: February 20, 2017
• First Submitted That Met QC Criteria: February 20, 2017
• First Posted (ACTUAL): February 23, 2017

Study Record Updates

• Last Update Posted (ACTUAL): July 19, 2019
• Last Update Submitted That Met QC Criteria: July 17, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: ONCRA-RXM-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No