GP2013 in the Treatment of RA Patients Refractory to or Intolerant of Standard Therapy

A Randomized, Double-blind, Controlled Study to Evaluate PK, PD, Safety and Efficacy of GP2013 and Rituximab in Patients With Rheumatoid Arthritis Refractory or Intolerant to Standard DMARDs and up to Three Anti-TNF Therapies.

The purpose of this study is to determine the PK/PD, efficacy and safety of GP2013 in patients with severe rheumatoid arthritis.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Biological: GP2013; Biological: MabThera; Biological: Rituxan

• Study Type: Interventional
• Enrollment (Actual): 312
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires#1, Argentina
    • Investigative Site
  • Buenos Aires#2, Argentina
    • Investigative Site
• Austria
  • Innsbruck, Austria
    • Investigative Site
  • Vienna#1, Austria
    • Investigative Site
• Belgium
  • Kortrijk, Belgium
    • Investigative Site
  • Merksem, Belgium
    • Investigative Site
• Brazil
  • Curitiba, Brazil
    • Investigative Site
  • Goiânia, Brazil
    • Investigative Site
  • Sao Paulo#1, Brazil
    • Investigative Site
  • Sao Paulo#2, Brazil
    • Investigative Site
• Estonia
  • Tallinn, Estonia
    • North Estonia Medical Centre Foundation
• France
  • Amiens Cedex, France
    • Investigative Site
  • Cahors, France
    • Investigative Site
  • Corbeil Essonnes, France
    • Investigative Site
  • La Gaillarde, France
    • Investigative Site
  • Orleans, France
    • Investigative Site
• Germany
  • Frankfurt, Germany
    • Investigative Site
  • Freiburg, Germany
    • Investigative Site
  • Göttingen, Germany
    • Investigative Site
  • Hildesheim, Germany
    • Investigative Site
  • Jena, Germany
    • Investigative Site
  • München, Germany
    • Investigative Site
  • Nürnberg, Germany
    • Investigative Site
  • Ratingen, Germany
    • Investigative Site
  • Regensburg, Germany
    • Investigative Site
  • Würzburg, Germany
    • Investigative Site
• Hungary
  • Kistarcsa, Hungary, 2143
    • Pest Megyei Flór Ferenc
  • Veszprem, Hungary, H-2800
    • Megyei Csolnoky Ferenc Kórház Nonprofit Zrt.
• India
  • Ajmer, India
    • Investigative Site
  • Bangalore, India
    • Investigative Site
  • Hyderabad, India
    • Investigative Site
  • Jaipur, India
    • Investigative Site
  • New Delhi, India
    • Investigative Site
  • Secunderabad, India
    • Investigative Site
• Italy
  • Milano, Italy
    • Investigative Site
• Romania
  • Bucharest#1, Romania
    • Investigative Site
  • Bucharest#2, Romania
    • Investigative Site
  • Cluj, Romania
    • Investigative Site
• Spain
  • Madrid, Spain
    • Investigative Site
  • Mérida, Spain
    • Investigative Site
  • Santiago de Compostela, Spain
    • Investigative Site
  • Sevilla, Spain
    • Investigative Site
• Turkey
  • Istanbul, Turkey
    • Investigative Site
  • Izmir, Turkey
    • Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90057
      • Miller Clinical Research
  • Kentucky
    • Lexington, Kentucky, United States, 40504
      • Bluegrass Community Research, Inc.
  • Maryland
    • Cumberland, Maryland, United States, 21502
      • Klein & Associates
    • Hagerstown, Maryland, United States, 21740
      • Klein & Associates
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
      • Clinical Pharmacology Study Group
  • Nebraska
    • Lincoln, Nebraska, United States, 68516
      • Physician Research Collaboration, LLC
  • Nevada
    • Las Vegas, Nevada, United States, 89128
      • Innovative Health Research
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • DJL Clinical Research PLLC
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • Health Research of Oklahoma
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center For Clinical Research
    • Wyomissing, Pennsylvania, United States, 19610
      • Clinical Research Center of Reading LLC
  • South Carolina
    • Charleston, South Carolina, United States, 29406
      • Low Country Rheumatology, PA
  • South Dakota
    • Rapid City, South Dakota, United States
      • Regional Health Clinical Research
  • Tennessee
    • Jackson, Tennessee, United States, 38305
      • West Tennessee Research Institute
  • Texas
    • San Antonio, Texas, United States, 78232
      • Arthritis & Osteoporosis Center of South Texas
  • Washington
    • Seattle, Washington, United States, 98133
      • The Seattle Arthritis Center

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:

• Rheumatoid arthritis as defined by the 1987 ACR classification
• Severe active seropositive disease
• Inadequate response or intolerance to other DMARDs and anti-TNFs
• Treatment with Methotrexate

Exclusion Criteria:

• Patients with systemic manifestations of rheumatoid arthritis
• Female patients nursing
• Women of childbearing potential unless using birth control
• Active infection
• Known immunodeficiency syndrome
• Positive Hepatitis B surface antigen or antibodies to Hepatitis C
• History of cancer

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GP2013	Biological: GP2013; 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15)
Active Comparator: MabThera	Biological: MabThera; 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15); Other Names: EU-Rituximab
Active Comparator: Rituxan	Biological: Rituxan; 1000 mg iv infusion on two separate occasions, two weeks apart (i.e. on Day 1 and on Day 15); Other Names: US-Rituximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC(0-inf) of GP2013, MabThera and Rituxan Following IV Infusion in Patients With RA	Area under the curve AUC(0-inf) calculated based on serum samples, collected from baseline up to 24 weeks: Day 1, 4, 8, 15, 18, 29, 57, 85,113 and 169	From baseline to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Serum Concentration (Cmax) of GP2013, MabThera and Rituxan Following IV Infusion in Patients With RA	Maximum serum concentration (Cmax) after the first infusion of GP2013, MabThera and Rituxan in patients with RA. Samples collected from baseline up to 24 weeks: Day 1, 4, 8, 15, 18, 29, 57, 85,113 and 169.	From baseline to week 24
Area Under the Effect Curve From Baseline to Day 14 (AUEC(0-14d)) of Percent B-cells of GP2013, MabThera and Rituxan in Patients With RA	Area under the effect curve of percent change of peripheral B-cell count from baseline to Day 14 (AUEC(0-14d)) of GP2013, MabThera and Rituxan in patients with RA	14 days
Change From Baseline in DAS28(CRP) at Week 24	Change from baseline in Disease Activity Score 28 joint count - C-reactive proteine DAS28(CRP) at Week 24. In order to calculate the DAS28(CRP) the number of tender joints and swollen joints were assessed using 28-joint count (tender28 and swollen28).The patient's global assessment of disease activity (GH) measured on a Visual Analogue Scale (VAS from 0mm - best to 100mm - worst) was obtained. DAS28(CRP) = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * GH + 0.96 The DAS28(CRP) provides a number on a scale from 0 to 10 indicating the current activity of the RA, while lower values correspond with less disease activity. A decrease in DAS28 signifies a clinical improvement.	24 weeks
Number of Patients With ACR20 (CRP) Response	A patient will be considered as improved according the ACR20 criteria; at least 20 % improvement from baseline in tender joint count, using the 68-joint count; at least 20 % improvement from baseline in swollen joint count, using the 66-joint count; and at least 20% improvement from baseline in a least 3 of the following 5 measures:; Patient's assessment of RA pain (VAS 100 mm); Patient's global assessment of disease activity (VAS 100 mm); Physician's global assessment of disease activity (VAS 100 mm); Patient self-assessed disability (Health Assessment Questionnaire disability index); Acute phase reactant (C-reactive protein or erythrocyte sedimentation rate)	24 weeks
Summary of Disease Activity According to CDAI	In order to calculate the Clinical Disease Activity Index (CDAI) the number of tender and swollen joints were assessed using the 28 -joint count (tender28 and swollen28). The patient's global assessment of disease activity and the physician's global assessment of disease activity were measured using a Visual Analogue Scale (VAS) of 10 cm (from 0=best to 10=worst). CDAI = tender28 + swollen28 + patient's global assessment (in cm) + physician's global assessment (in cm)	At week 24
Summary of Disease Activity According to SDAI	In order to calculate the Simplified Disease Activity Index (SDAI) the number of tender and swollen joints were assessed using the 28 -joint count (tender28 and swollen28). The patient's global assessment of disease activity and the physician's global assessment of disease activity were measured using a Visual Analogue Scale (VAS) of 10 cm (from 0=best to 10=worst). SDAI = CDAI + CRP (in mg/dL) (CDAI = tender28 + swollen28 + patient's global assessment (in cm) + physician's global assessment (in cm))	At week 24
Participant Response as Assessed by EULAR Response Criteria	Present DAS28 ≤ 3.2 (low): good response (if improvement > 1.2), moderate response (if improvement >0.6 and ≤ 1.2), no response (if improvement ≤ 0.6). Present DAS28 > 3.2 to ≤ 5.1 (moderate): moderate response (if improvement > 1.2), moderate response (if improvement >0.6 and ≤ 1.2), no response (if improvement ≤ 0.6). Present DAS28 > 5.1 (high): moderate response (if improvement > 1.2), no response (if improvement >0.6 and ≤ 1.2), no response (if improvement ≤ 0.6).	At week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With at Least One Anti-Drug-Antibody (ADA) Positive Serum Sample	Number of patients with at least one post-baseline Anti-Drug-Antibody (ADA) positive serum sample until the last study visit. Sampling was at Day 1, 29, 113, 169, 267, 365, optional visit 1 (could be at any time between day 169 - week 24 and day 365 - week 52 for patients, who received a 2nd treatment course) and optional visit 2 (only applicable for patients, who received a 2nd treatment course, 26 weeks thereafter, if this was after day 365 - week 52).	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Sandoz
• Collaborators: Novartis Pharmaceuticals
• Investigators: Study Director: Sandoz Biopharmaceuticals, Sandoz

Publications and helpful links

General Publications

• Smolen JS, Cohen SB, Tony HP, Scheinberg M, Kivitz A, Balanescu A, Gomez-Reino J, Cen L, Zhu P, Shisha T. A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis. Ann Rheum Dis. 2017 Sep;76(9):1598-1602. doi: 10.1136/annrheumdis-2017-211281. Epub 2017 Jun 21.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: January 10, 2011
• First Submitted That Met QC Criteria: January 10, 2011
• First Posted (Estimate): January 11, 2011

Study Record Updates

• Last Update Posted (Actual): January 24, 2018
• Last Update Submitted That Met QC Criteria: January 23, 2018
• Last Verified: January 1, 2018

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: GP13-201; 2010-021184-32 (EudraCT Number); GPN013A2301 (Other Identifier: Novartis)