Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study

Byong Duk Ye; Marina Pesegova; Olga Alexeeva; Marina Osipenko; Adi Lahat; Andriy Dorofeyev; Sigal Fishman; Olena Levchenko; Jae Hee Cheon; Maria Lia Scribano; Radu Bogdan Mateescu; Kang Moon Lee; Chang Soo Eun; Sang Joon Lee; Sung Young Lee; Ho Ung Kim; Stefan Schreiber; Heather Fowler; Raymond Cheung; Young Ho Kim

doi:10.1016/S0140-6736(18)32196-2

Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study

Byong Duk Ye, Marina Pesegova, Olga Alexeeva, Marina Osipenko, Adi Lahat, Andriy Dorofeyev, Sigal Fishman, Olena Levchenko, Jae Hee Cheon, Maria Lia Scribano, Radu Bogdan Mateescu, Kang Moon Lee, Chang Soo Eun, Sang Joon Lee, Sung Young Lee, Ho Ung Kim, Stefan Schreiber, Heather Fowler, Raymond Cheung, Young Ho Kim

Department of Internal Medicine

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129 Citations (Scopus)

Abstract

Background: The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis; however, concerns about such indication extrapolation have been expressed. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy. Methods: In this randomised, multicentre, double-blind, phase 3 non-inferiority study, we enrolled patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every 8 weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of −20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than −20). This trial is registered with ClinicalTrials.gov, number NCT02096861, and is completed. Findings: Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13–CT-P13 group and 55 to the CT-P13–infliximab group) and 109 to initiate infliximab (54 to the infliximab–infliximab group and 55 to the infliximab–CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69·4%, 95% CI 59·9 to 77·8] of 111) and infliximab (81 [74·3%, 95% CI 65·1 to 82·2] of 109; difference −4·9% [95% CI −16·9 to 7·3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13–CT-P13 group, 34 [62%] in the CT-P13–infliximab group, 37 [69%] in the infliximab–infliximab group, and 40 [73%] in the infliximab–CT-P13 group). Interpretation: This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn's disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn's disease. Funding: Celltrion, Pfizer.

Original language	English
Pages (from-to)	1699-1707
Number of pages	9
Journal	The Lancet
Volume	393
Issue number	10182
DOIs	https://doi.org/10.1016/S0140-6736(18)32196-2
Publication status	Published - 2019 Apr 27

Bibliographical note

Funding Information:
BDY reports personal fees and non-financial support from Celltrion during the conduct of the study and personal fees from Abbvie Korea, Cornerstones Health, Ferring Korea, IQVIA, Janssen Korea, Kangstem Biotech, Kuhnil Pharm, Robarts Clinical Trials, Shire Korea, and Takeda Korea outside the submitted work. AL reports consultancy and lecture fees from Takeda and lecture fees from Abbvie, Celltrion, and Janssen outside the submitted work. MLS reports advisory board fees from Janssen, Mundipharma, and Pfizer and advisory board and speaker fees from Abbvie and Takeda outside the submitted work. R-BM reports personal fees from Amgen outside the submitted work; personal fees and non-financial support from Abbvie, Alfa Sigma, Alvogen, Dr Reddys, Egis Pharmaceutical, MSD, and Takeda outside the submitted work; and grants from Abbvie outside the submitted work. K-ML reports consultancy and lecture fees from Takeda and consultancy fees from Celltrion outside the submitted work. CSE reports consultancy and lecture fees from Celltrion outside the submitted work. SJL is an employee of, and has stock options for, Celltrion. SYL and HUK are employees of Celltrion. SS reports consulting (advisory board) fees from AbbVie, Biogen/Samsung, Boehringer Ingelheim, Celltrion, Merck, Pfizer, Sandoz, Shire, and UCB outside the submitted work. HF reports consultancy fees from Pfizer UK Limited during the conduct of the study and consultancy fees from Pfizer UK Limited outside the submitted work. RC is an employee of Pfizer. Y-HK reports personal fees from Celltrion during the conduct of the study and personal fees from Chong Kun Dang Pharm, Eisai Korea, Ferring Korea, Janssen Korea, Shire Korea, and Takeda Korea outside the submitted work. MP, OA, MO, AD, SF, OL, and JHC declare no competing interests.

Funding Information:
The authors thank all patients, staff, and investigators involved in this study. The study was funded by Celltrion (Incheon, South Korea) and Pfizer (New York, NY, USA). Medical writing support, including development of a draft outline and subsequent drafts in consultation with the authors, assembling tables and figures, collating author comments, copyediting, fact checking, and referencing, was provided by Emma Prest, at Aspire Scientific Limited (Bollington, UK), and was funded by Celltrion.

Publisher Copyright:
© 2019 Elsevier Ltd

All Science Journal Classification (ASJC) codes

Medicine(all)

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10.1016/S0140-6736(18)32196-2

Cite this

Ye, B. D., Pesegova, M., Alexeeva, O., Osipenko, M., Lahat, A., Dorofeyev, A., Fishman, S., Levchenko, O., Cheon, J. H., Scribano, M. L., Mateescu, R. B., Lee, K. M., Eun, C. S., Lee, S. J., Lee, S. Y., Kim, H. U., Schreiber, S., Fowler, H., Cheung, R., & Kim, Y. H. (2019). Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study. The Lancet, 393(10182), 1699-1707. https://doi.org/10.1016/S0140-6736(18)32196-2

@article{ad94aeffdc524bd1bdc87ad888121ecb,

title = "Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study",

abstract = "Background: The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis; however, concerns about such indication extrapolation have been expressed. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy. Methods: In this randomised, multicentre, double-blind, phase 3 non-inferiority study, we enrolled patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every 8 weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of −20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than −20). This trial is registered with ClinicalTrials.gov, number NCT02096861, and is completed. Findings: Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13–CT-P13 group and 55 to the CT-P13–infliximab group) and 109 to initiate infliximab (54 to the infliximab–infliximab group and 55 to the infliximab–CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69·4%, 95% CI 59·9 to 77·8] of 111) and infliximab (81 [74·3%, 95% CI 65·1 to 82·2] of 109; difference −4·9% [95% CI −16·9 to 7·3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13–CT-P13 group, 34 [62%] in the CT-P13–infliximab group, 37 [69%] in the infliximab–infliximab group, and 40 [73%] in the infliximab–CT-P13 group). Interpretation: This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn's disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn's disease. Funding: Celltrion, Pfizer.",

author = "Ye, {Byong Duk} and Marina Pesegova and Olga Alexeeva and Marina Osipenko and Adi Lahat and Andriy Dorofeyev and Sigal Fishman and Olena Levchenko and Cheon, {Jae Hee} and Scribano, {Maria Lia} and Mateescu, {Radu Bogdan} and Lee, {Kang Moon} and Eun, {Chang Soo} and Lee, {Sang Joon} and Lee, {Sung Young} and Kim, {Ho Ung} and Stefan Schreiber and Heather Fowler and Raymond Cheung and Kim, {Young Ho}",

note = "Funding Information: BDY reports personal fees and non-financial support from Celltrion during the conduct of the study and personal fees from Abbvie Korea, Cornerstones Health, Ferring Korea, IQVIA, Janssen Korea, Kangstem Biotech, Kuhnil Pharm, Robarts Clinical Trials, Shire Korea, and Takeda Korea outside the submitted work. AL reports consultancy and lecture fees from Takeda and lecture fees from Abbvie, Celltrion, and Janssen outside the submitted work. MLS reports advisory board fees from Janssen, Mundipharma, and Pfizer and advisory board and speaker fees from Abbvie and Takeda outside the submitted work. R-BM reports personal fees from Amgen outside the submitted work; personal fees and non-financial support from Abbvie, Alfa Sigma, Alvogen, Dr Reddys, Egis Pharmaceutical, MSD, and Takeda outside the submitted work; and grants from Abbvie outside the submitted work. K-ML reports consultancy and lecture fees from Takeda and consultancy fees from Celltrion outside the submitted work. CSE reports consultancy and lecture fees from Celltrion outside the submitted work. SJL is an employee of, and has stock options for, Celltrion. SYL and HUK are employees of Celltrion. SS reports consulting (advisory board) fees from AbbVie, Biogen/Samsung, Boehringer Ingelheim, Celltrion, Merck, Pfizer, Sandoz, Shire, and UCB outside the submitted work. HF reports consultancy fees from Pfizer UK Limited during the conduct of the study and consultancy fees from Pfizer UK Limited outside the submitted work. RC is an employee of Pfizer. Y-HK reports personal fees from Celltrion during the conduct of the study and personal fees from Chong Kun Dang Pharm, Eisai Korea, Ferring Korea, Janssen Korea, Shire Korea, and Takeda Korea outside the submitted work. MP, OA, MO, AD, SF, OL, and JHC declare no competing interests. Funding Information: The authors thank all patients, staff, and investigators involved in this study. The study was funded by Celltrion (Incheon, South Korea) and Pfizer (New York, NY, USA). Medical writing support, including development of a draft outline and subsequent drafts in consultation with the authors, assembling tables and figures, collating author comments, copyediting, fact checking, and referencing, was provided by Emma Prest, at Aspire Scientific Limited (Bollington, UK), and was funded by Celltrion. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

month = apr,

day = "27",

doi = "10.1016/S0140-6736(18)32196-2",

language = "English",

volume = "393",

pages = "1699--1707",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier Limited",

number = "10182",

}

Ye, BD, Pesegova, M, Alexeeva, O, Osipenko, M, Lahat, A, Dorofeyev, A, Fishman, S, Levchenko, O, Cheon, JH, Scribano, ML, Mateescu, RB, Lee, KM, Eun, CS, Lee, SJ, Lee, SY, Kim, HU, Schreiber, S, Fowler, H, Cheung, R & Kim, YH 2019, 'Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study', The Lancet, vol. 393, no. 10182, pp. 1699-1707. https://doi.org/10.1016/S0140-6736(18)32196-2

Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study. / Ye, Byong Duk; Pesegova, Marina; Alexeeva, Olga et al.
In: The Lancet, Vol. 393, No. 10182, 27.04.2019, p. 1699-1707.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease

T2 - an international, randomised, double-blind, phase 3 non-inferiority study

AU - Ye, Byong Duk

AU - Pesegova, Marina

AU - Alexeeva, Olga

AU - Osipenko, Marina

AU - Lahat, Adi

AU - Dorofeyev, Andriy

AU - Fishman, Sigal

AU - Levchenko, Olena

AU - Cheon, Jae Hee

AU - Scribano, Maria Lia

AU - Mateescu, Radu Bogdan

AU - Lee, Kang Moon

AU - Eun, Chang Soo

AU - Lee, Sang Joon

AU - Lee, Sung Young

AU - Kim, Ho Ung

AU - Schreiber, Stefan

AU - Fowler, Heather

AU - Cheung, Raymond

AU - Kim, Young Ho

N1 - Funding Information: BDY reports personal fees and non-financial support from Celltrion during the conduct of the study and personal fees from Abbvie Korea, Cornerstones Health, Ferring Korea, IQVIA, Janssen Korea, Kangstem Biotech, Kuhnil Pharm, Robarts Clinical Trials, Shire Korea, and Takeda Korea outside the submitted work. AL reports consultancy and lecture fees from Takeda and lecture fees from Abbvie, Celltrion, and Janssen outside the submitted work. MLS reports advisory board fees from Janssen, Mundipharma, and Pfizer and advisory board and speaker fees from Abbvie and Takeda outside the submitted work. R-BM reports personal fees from Amgen outside the submitted work; personal fees and non-financial support from Abbvie, Alfa Sigma, Alvogen, Dr Reddys, Egis Pharmaceutical, MSD, and Takeda outside the submitted work; and grants from Abbvie outside the submitted work. K-ML reports consultancy and lecture fees from Takeda and consultancy fees from Celltrion outside the submitted work. CSE reports consultancy and lecture fees from Celltrion outside the submitted work. SJL is an employee of, and has stock options for, Celltrion. SYL and HUK are employees of Celltrion. SS reports consulting (advisory board) fees from AbbVie, Biogen/Samsung, Boehringer Ingelheim, Celltrion, Merck, Pfizer, Sandoz, Shire, and UCB outside the submitted work. HF reports consultancy fees from Pfizer UK Limited during the conduct of the study and consultancy fees from Pfizer UK Limited outside the submitted work. RC is an employee of Pfizer. Y-HK reports personal fees from Celltrion during the conduct of the study and personal fees from Chong Kun Dang Pharm, Eisai Korea, Ferring Korea, Janssen Korea, Shire Korea, and Takeda Korea outside the submitted work. MP, OA, MO, AD, SF, OL, and JHC declare no competing interests. Funding Information: The authors thank all patients, staff, and investigators involved in this study. The study was funded by Celltrion (Incheon, South Korea) and Pfizer (New York, NY, USA). Medical writing support, including development of a draft outline and subsequent drafts in consultation with the authors, assembling tables and figures, collating author comments, copyediting, fact checking, and referencing, was provided by Emma Prest, at Aspire Scientific Limited (Bollington, UK), and was funded by Celltrion. Publisher Copyright: © 2019 Elsevier Ltd

PY - 2019/4/27

Y1 - 2019/4/27

N2 - Background: The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis; however, concerns about such indication extrapolation have been expressed. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy. Methods: In this randomised, multicentre, double-blind, phase 3 non-inferiority study, we enrolled patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every 8 weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of −20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than −20). This trial is registered with ClinicalTrials.gov, number NCT02096861, and is completed. Findings: Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13–CT-P13 group and 55 to the CT-P13–infliximab group) and 109 to initiate infliximab (54 to the infliximab–infliximab group and 55 to the infliximab–CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69·4%, 95% CI 59·9 to 77·8] of 111) and infliximab (81 [74·3%, 95% CI 65·1 to 82·2] of 109; difference −4·9% [95% CI −16·9 to 7·3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13–CT-P13 group, 34 [62%] in the CT-P13–infliximab group, 37 [69%] in the infliximab–infliximab group, and 40 [73%] in the infliximab–CT-P13 group). Interpretation: This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn's disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn's disease. Funding: Celltrion, Pfizer.

AB - Background: The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis; however, concerns about such indication extrapolation have been expressed. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy. Methods: In this randomised, multicentre, double-blind, phase 3 non-inferiority study, we enrolled patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every 8 weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of −20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than −20). This trial is registered with ClinicalTrials.gov, number NCT02096861, and is completed. Findings: Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13–CT-P13 group and 55 to the CT-P13–infliximab group) and 109 to initiate infliximab (54 to the infliximab–infliximab group and 55 to the infliximab–CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69·4%, 95% CI 59·9 to 77·8] of 111) and infliximab (81 [74·3%, 95% CI 65·1 to 82·2] of 109; difference −4·9% [95% CI −16·9 to 7·3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13–CT-P13 group, 34 [62%] in the CT-P13–infliximab group, 37 [69%] in the infliximab–infliximab group, and 40 [73%] in the infliximab–CT-P13 group). Interpretation: This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn's disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn's disease. Funding: Celltrion, Pfizer.

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DO - 10.1016/S0140-6736(18)32196-2

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Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study

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