Objective To evaluate the efficacy, biological activity and safety of tregalizumab in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).
Methods 321 patients were randomised (1:1:1:1) to placebo or tregalizumab 25, 100 or 200 mg once-weekly subcutaneously in addition to MTX treatment. Responders at week 12 continued the same treatment, and non-responders at week 12 were escalated to the next higher tregalizumab dose level or re-randomised from placebo to active treatment. After 24 weeks, patients could continue treatment with tregalizumab for 24 weeks (extension phase). The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Safety and biological activity were monitored through week 48.
Results At week 12, ACR20 response rates were not statistically significantly different between placebo and any of the tregalizumab doses. Tregalizumab injections were well tolerated; most adverse events were mild to moderate and comparable among treatment and placebo groups. Biological activity was shown by dose-dependent CD4 downmodulation.
Conclusion Treatment with tregalizumab did not show significant clinical efficacy in patients with active RA compared with placebo but resulted in the expected biological effect on CD4 modulation. Tregalizumab was generally well tolerated, and no new safety findings were identified.
Trial registration number NCT01999192; Results.
- rheumatoid arthritis
- t cells
- autoimmune diseases
- Dmards (biologic)
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Handling editor Josef S Smolen
Contributors RFvV, ECK, VS, FB, RS, SA, BD and AW-D were involved in the design of the study; CP-T, JV, FB, AR, DZ, FR, RW, LK and XZ performed research; CP-T, JV, FB and AR collected data; RFvV, ECK, VS, FB, DZ, FR, RW, LK, RS, XZ, SA, BD and AW-D analysed and interpreted data; RFvV wrote the manuscript; all authors reviewed and approved the manuscript’s content before submission.
Funding This study was sponsored by Biotest AG. AbbVie provided financial support to Biotest for scientific and clinical evaluation of tregalizumab (BT-061) including this work from June 2011 to June 2015.
Competing interests RFvV has received research support and grants from AbbVie, BMS, GSK, Pfizer and UCB and has been a consultant and received honoraria from AbbVie, AstraZeneca, Biotest, BMS, Celgene, Crescendo, GSK, Janssen, Lilly, Novartis, Pfizer, Roche and UCB. ECK has received research funding from Abbott Laboratories, Amgen, AstraZeneca, BMS, Roche, Janssen, Lilly, Novartis, Pfizer, Sanofi-Aventis and UCB; has served as a consultant/advisory board member for Abbott Laboratories, AstraZeneca, Biotest, BMS, Crescendo, Roche, Genentech, Janssen, Lilly, Merck, Pfizer, and UCB; and has received speaker honoraria from Amgen, Abbott Laboratories, Astrazeneca, BMS Canada, Roche, Janssen, Pfizer, Sanofi Genzyme, and UCB. VS has been a consultant for Biotest. CP-T has received support from Abbvie, BMS, Roche, UCB, Janssen, Amgen, AstraZeneca, Pfizer, GSK, Ely Lilly, Sanofi, Celltrion, Vertex and Novo-Nordisk. FB has received research grants/support from Roche, Pfizer and Chugai and has been a consultant for AbbVie, Biotest, BMS, Janssen, Lilly, Pfizer, UCB, Novartis, Genzyme, AstraZeneca, MSD/Merck. DZ, FR, RW, LK, RS, XZ, SA, BD and AW-D are or were employees of Biotest.
Ethics approval Ethics Committee for Multicenter Trials, Veritas IRB, Multicentricka Eticka komise, Eticka komise Revmatologicky ustav, Tallinn Medical Research Ethics Committee, Ethik-Kommission der Medizinischen, Fakultaet der LMU Muenchen, Egeszsegugyi Tudomanyos Tanacs Klinikai Farmakologiai Etikai Bizottsaga, Lithuanian Bioethics Committee, CEI Hospital Dalinde, Comite Bioetico para la Investigacion Clinica, Comite de Etica de la Fac de Med de la UANL y Hospital Universitario Dr. Jose Eleuterio Gonzalez, Comite de Etica e Investigacion Christus Muguerza del Parque SA de CV, Comite de Etica en Investigacion de Comite Mexicano para la Prevencion de la Osteoporosis, A.C., Comité Independiente de Ética e Investigación del Centro de Estudios de Inv. Básica y Clínica S.C., Comite Institucional de Revision (Comite de Etica e Investigacion) Hospital Aranda de la Parra, Comite para la Asesoria en Etica Medica COMET, Komisja Bioetyczna przy Okregowej Izbie Lekarskiej w Krakowie.
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators Jacob Aelion, Jorge Aguilar Arreola, Maria Araujo Arias, Johan Back, Asta Baranauskaite, Frank Behrens, Ralph Bennett, Arthur Bookman, Jan Brzezicki, Irena Butrimiene, Melvin Churchill, Svetlana Djacenko, Eva Dokoupilova, Edit Drescher, Anna Dudek, William Edwards, Larisa Eliseeva, Olga Ershova, Isabelle Fortin, Dagmar Galatikova, Ignacio Garcia de la Torre, Olena Garmish, Yuriy Gasanov, Andriy Gnylorybov, Marc Goldberg, Oleksandr Golovchenko, Ivan Gordeev, Falk Hiepe, Gabriela Huerta Sil, Viola Husarova, Oleg Iaremenko, Slawomir Jeka, Daniela Kamburova, Arthur Kavanaugh, Peter Keszthelyi, Edward Keystone, Larisa Knyazeva, Diana Krechikova, Stefka Kuzmanova, Angelika Lapcikova, Dennis Levinson, Jesus Alberto Lopez Garcia, Iurii Lymar, Natalia Marinova, Sergey Moiseev, Lucie Musilova, Magdolna Nagy, Sabeen Najam, Jovan Nedovic, Eleonora Nemeth, Libor Novosad, Luis Ochoa-Ortega, Boycho Oparanov, Cesar Pacheco Tena, Dimitar Penev, Yves Pesant, Lucie Podrazilova, Grazyna Pulka, Artur Racewicz, Tatiana Raskina, Dmytro Rekalov, Olga Reshetko, Janett Carmen Riega Torres, Andrea Rubbert-Roth, Anna Rychlewska-Hanczewska, Ludmila Savina, Hendrik Schulze-Koops, Mirjana Sefik Bukilica, Sergii Shevchuk, Eszter Simoncsics, Lubomira Simova, Karina Sitek-Ziolkowska, Andrea Skublova, Beata Sliwowska, Svetlana Smakotina, Wolfgang Spieler, Mykola Stanislavchuk, Dusan Stefanovic, Zuzana Stejfova, Rumen Stoilov, Maria Strapkova, Raisa Stryuk, Gabriella Sulyok, Anna Sylwestrzak, Istvan Szombati, Jan Theander, Sona Tomkova, Robert Trapp, Vira Tseluyko, Jaak Tälli, Jiri Vencovsky, Petr Vitek, Stoyanka Vladeva, Jacqueline Vo, Ronald van Vollenhoven, Nada Vujasinovic-Stupar, Siegfried Wassenberg, Juergen Wollenhaupt, Agnieszka Zielinska.
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