A phase III randomized study to evaluate the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results from the PLANETRA study

Abstract

Background: CT-P13 (Remsima®, Inflectra®) is a biosimilar of the infliximab reference product (RP; Remicade®). The aim of this study was to compare the 54-week efficacy, immunogenicity, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of CT-P13 and RP in patients with active rheumatoid arthritis (RA).

Methods: In this multinational phase III double-blind study, patients with active RA and an inadequate response to methotrexate (MTX) were randomized (1:1) to receive CT-P13 (3 mg/kg) or RP (3 mg/kg) at weeks 0, 2, 6 and then every 8 weeks to week 54 in combination with MTX (12.5-25 mg/week). Efficacy endpoints included American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates, Disease Activity Score in 28 joints (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), European League Against Rheumatism (EULAR) response rates, patient-reported outcomes and joint damage progression. Immunogenicity, safety and PK/PD outcomes were also assessed.

Results: Of 606 randomized patients, 455 (CT-P13 233, RP 222) were treated up to week 54. At week 54, ACR20 response rate was highly similar between groups (CT-P13 74.7 %, RP 71.3 %). ACR50 and ACR70 response rates were also comparable between groups (CT-P13 43.6 % and 21.3 %, respectively; RP 43.1 % and 19.9 %, respectively). DAS28, SDAI and CDAI decreased from baseline to week 54 to a similar extent with CT-P13 and RP. Radiographic progression measured by Sharp scores as modified by van der Heijde was also comparable. With both treatments, patient assessments of pain, disease activity and physical ability, as well as mean scores on the Medical Outcomes Study Short Form Health Survey (SF-36), improved markedly at week 14 and remained stable thereafter up to week 54. The proportion of patients positive for antidrug antibodies at week 54 was similar between the two groups: 41.1 % and 36.0 % with CT-P13 and RP, respectively. CT-P13 was well tolerated and had a similar safety profile to RP. PK/PD results were also comparable between CT-P13 and RP.

Conclusions: CT-P13 and RP were comparable in terms of efficacy (including radiographic progression), immunogenicity and PK/PD up to week 54. The safety profile of CT-P13 was also similar to that of RP.

Trial registration: ClinicalTrials.gov identifier: NCT01217086 . Registered 4 Oct 2010.

Keywords: ACR20; Biosimilar; CT-P13; Efficacy; Immunogenicity; Infliximab; Pharmacokinetics; Rheumatoid arthritis; Safety; Sharp score.

Fig. 1

Patient disposition. A total of 606 patients were randomized into either the CT-P13 group (n = 302) or the RP group (n = 304). A total of 151 patients were withdrawn for the stated reasons. The first patient was screened in November 2010, and the last patient visit was in July 2012. RP reference product (i.e., reference infliximab)

Fig. 2

American College of Rheumatology (ACR) response rates over time in the per-protocol population, with nonresponder imputation approach. To estimate the difference in proportions between the two treatment groups, we used the exact binomial test. ACR20, ACR50 and ACR70 denote the ACR 20 %, 50 % and 70 % improvement criteria, respectively. CI confidence interval, RP reference product (i.e., reference infliximab)

Fig. 3

Changes in efficacy parameters over time with CT-P13 and RP in the per-protocol population. a Disease activity based on DAS28-ESR. b Disease activity based on DAS28-CRP. c Disease activity based on SDAI. d Disease activity based on CDAI. e EULAR response criteria based on DAS28-ESR score. f EULAR response criteria based on DAS28-CRP score. *Proportional odds model with EULAR as response, treatment as a fixed effect, and region and CRP category as covariates. An odds ratio >1 implied that a patient who received CT-P13 had a higher likelihood of EULAR response than a patient who received RP. The proportional odds assumption implied that the relationship between each pair of outcome responses was the same. CDAI Clinical Disease Activity Index, CI confidence interval, CRP C-reactive protein, DAS28 Disease Activity Score in 28 joints, ESR erythrocyte sedimentation rate, EULAR European League Against Rheumatism, RP reference product (i.e., reference infliximab), SD standard deviation, SDAI Simplified Disease Activity Index

Fig. 4

Proportion of patients with ACR/EULAR remission in the intent-to-treat population, with nonresponder imputation approach. a ACR/EULAR remission by Boolean-based criterion. b ACR/EULAR remission by index-based criterion (SDAI). p value was calculated using Fisher’s exact test. ACR American College of Rheumatology, EULAR European League Against Rheumatism, RP reference product (i.e., reference infliximab), SDAI Simplified Disease Activity Index

Fig. 5

Serum concentrations of infliximab (mean ± SD) versus time in the CT-P13 and RP treatment groups in the pharmacokinetic population. RP reference product (i.e., reference infliximab), SD standard deviation