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  • A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis

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Clinical and epidemiological research
Concise report
A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis
  1. Josef S Smolen1,
  2. Stanley B Cohen2,
  3. Hans-Peter Tony3,
  4. Morton Scheinberg4,
  5. Alan Kivitz5,
  6. Andra Balanescu6,
  7. Juan Gomez-Reino7,
  8. Liyi Cen8,
  9. Peijuan Zhu9,
  10. Tamas Shisha10
  1. 1 Department of Rheumatology, Medical University of Vienna, Vienna, Austria
  2. 2 Metroplex Clinical Research, Dallas, Texas, USA
  3. 3 Department of Internal Medicine, Rheumatology/Clinical Immunology, University of Wuerzburg, Wuerzburg, Germany
  4. 4 Department of Rheumatology, Hospital Israelite Albert Einstein, Sao Paulo, Brazil
  5. 5 Altoona Center for Clinical Research, Duncansville, Pennsylvania, USA
  6. 6 Research Center of Rheumatic Diseases, St Mary Hospital, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
  7. 7 University Clinic of Santiago, Santiago, Spain
  8. 8 Department of Statistics, Sandoz, a Novartis Division, Princeton, New Jersey, USA
  9. 9 Sandoz, a Novartis Division, Clinical Pharmacology, Princeton, New Jersey, USA
  10. 10 Sandoz, a Novartis Division, Hexal AG, Clinical Development, Holzkirchen, Germany
  1. Correspondence to Dr Tamas Shisha, Sandoz, a Novartis Division, Clinical Development, Industriestrasse 25, 83607 Holzkirchen, Germany; tamas.shisha{at}sandoz.com

Abstract

Objectives The aim of this report is to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence as well as similar efficacy, safety and immunogenicity between GP2013, a biosimilar rituximab, and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitor (TNFi) treatment.

Methods In this multinational, randomised, double-blind, parallel-group study, 312 patients with active disease despite prior TNFi therapy were randomised to receive GP2013 or either the EU (RTX-EU) or the US (RTX-US) reference product, along with methotrexate (MTX) and folic acid. The primary endpoint was the area under the serum concentration–time curve from study drug infusion to infinity (AUC0-inf). Additional PK and PD parameters, along with efficacy, immunogenicity and safety outcomes were also assessed up to week 24.

Results The 90% CI of the geometric mean ratio of the AUCs were within the bioequivalence limits of 80% to 125% for all three comparisons; GP2013 versus RTX-EU: 1.106 (90% CI 1.010 to 1.210); GP2013 versus RTX-US: 1.012 (90% CI 0.925 to 1.108); and RTX-EU versus RTX-US: 1.093 (90% CI 0.989 to 1.208). Three-way PD equivalence of B cell depletion was also demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX.

Conclusions Three-way PK/PD equivalence of GP2013, RTX-EU and RTX-US was demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX.

Trial registration number NCT01274182; Results.

  • Rheumatoid arthritis
  • DMARDs (biologic)
  • B cells

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/annrheumdis-2017-211281

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    Footnotes

    • Contributors Josef S Smolen: Principle investigator, author, reviewer. Stanley B Cohen: Expert, reviewer. Hans-Peter Tony: study investigator, reviewer. Morton Scheinberg: study investigator, reviewer. Alan Kivitz: study investigator, reviewer. Andra Balanecsu: study investigator, reviewer. Juan Gomez-Reino: study investigator, reviewer. Liyi Cen: study statistician, reviewer. Peijuan Zhu: study clinical pharmacologist, reviewer. Tamas Shisha: study medical expert, author, reviewer.

    • Funding The study reported in the current submission was funded by Hexal, a Sandoz Company for all countries expect the USA and by Sandoz for USA. Sandoz is a Novartis Division.

    • Competing interests PZ, LC and TS are employees of Sandoz/Hexal. JSS, HPT, AK, AB, JG-R and MS received investigator fees from Sandoz, a Novartis Division.

    • Patient consent Obtained.

    • Ethics approval The study involved human subjects. Ethics Committee/Institutional Review Board approval was obtained. The following bodies approved the study: National Ethics Committees/Institutional Review Boards.

    • Provenance and peer review Not commissioned; externally peer reviewed.