Efficacy, pharmacokinetics and safety of subcutaneous versus intravenous CT-P13 in rheumatoid arthritis: a randomized phase I/III trial

Abstract

Objective: To assess non-inferiority of s.c. to i.v. CT-P13 in RA.

Methods: Patients with active RA and inadequate response to MTX participated in this phase I/III double-blind study at 76 sites. Patients received CT-P13 i.v. 3 mg/kg [week (W) 0 and W2] before randomization (1:1) at W6 to CT-P13 s.c. via pre-filled syringe (PFS) 120 mg biweekly until W28, or CT-P13 i.v. 3 mg/kg every 8 weeks until W22. Randomization was stratified by country, W2 serum CRP and W6 body weight. From W30, all patients received CT-P13 s.c. In a usability sub-study, patients received CT-P13 s.c. via auto-injector (W46-54) then PFS (W56-64). The primary endpoint was change (decrease) from baseline in disease activity score in 28 joints (DAS28)-CRP at W22 (non-inferiority margin: -0.6).

Results: Of 357 patients enrolled, 343 were randomized to CT-P13 s.c. (n = 167) or CT-P13 i.v. (n = 176) at W6. The least-squares mean change (decrease) from baseline (standard error) in DAS28-CRP at W22 was 2.21 (0.22) for CT-P13 s.c. (n = 162) and 1.94 (0.21) for CT-P13 i.v. [n = 168; difference 0.27 (95% CI: 0.02, 0.52)], establishing non-inferiority. Efficacy findings were similar between arms at W54. Safety was similar between arms throughout: 92 (54.8%; CT-P13 s.c.) and 117 (66.9%; CT-P13 i.v.) patients experienced treatment-emergent adverse events (from W6). There were no treatment-related deaths or new safety findings. Usability was similar for CT-P13 s.c. via auto-injector or PFS.

Conclusion: CT-P13 s.c. was non-inferior to CT-P13 i.v. in active RA. The convenience of s.c. administration could benefit patients.

Trial registration: ClinicalTrials.gov, https://ichgcp.net/clinical-trials-registry/NCT03147248.

Keywords: CT-P13; biosimilar; immunogenicity; infliximab; non-inferiority; pharmacokinetics; rheumatoid arthritis; subcutaneous; switching.

© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.

Figures

Fig. 1

Patient disposition aFive patients were excluded from all analysis populations because of significant Good Clinical Practice non-compliance of the study centre. bThree patients (1 in the CT-P13 s.c. arm and 2 in the i.v. arm) with at least one major protocol deviation and 1 patient (in the CT-P13 s.c. arm) with no efficacy assessment after week 6 were excluded from the efficacy population. cOne patient randomized to the CT-P13 i.v. arm received CT-P13 s.c. treatment instead of placebo s.c. treatment at week 14, thus receiving both CT-P13 i.v. 3 mg/kg and CT-P13 s.c. 120 mg at week 14. This patient was included in the CT-P13 s.c. arm for the PD and safety populations and excluded from the efficacy and PK populations. dOne patient with a major protocol deviation (CT-P13 i.v. arm) and 2 patients without PK concentration data (1 in each of the CT-P13 s.c. and i.v. arms) were excluded from the PK population. eAll 168 patients eligible for usability assessment (patients in Bulgaria, Poland and Russian Federation continuing the study at week 46) were included in the usability population. PD, pharmacodynamics; PK, pharmacokinetics.

Fig. 2

ANCOVA analysis of change (decrease) from baseline of DAS28-CRP at W22a (A) L.S.M. (s.e.) change from baseline in DAS28-CRP at W22 (efficacy populationb). (B) L.S.M. (s.e.) change from baseline in DAS28-CRP at W22 (all-randomized populationc). (C) Estimate of treatment difference (95% CI) in L.S.M. change from baseline in DAS28-CRP at W22 for efficacyb and all-randomizedc populations. aChange (decrease) from baseline for this primary analysis was defined as decrease from baseline and calculated as (DAS28-CRP at baseline − DAS28-CRP at W22). bAnalysed according to actual treatment received. cAnalysed according to randomized treatment at W6. dCriteria for non-inferiority met. ANCOVA, analysis of covariance; DAS28, disease activity score in 28 joints; L.S.M., least-squares mean; W, week.

Fig. 3

Response (efficacy populationa) (A) Proportion of patients achieving clinical response according to ACR20, ACR50 and ACR70 criteria. (B) Proportion of patients with good/moderate response according to EULAR (CRP) and EULAR (ESR). aFrom W30 to W54, all patients received CT-P13 s.c. and are analysed according to treatment received prior to W30. bAt W6, patients were randomized to treatment; efficacy results up to W6 represent the efficacy of CT-P13 i.v. loading dose, regardless of randomized arm. ACR20, 20% improvement in ACR criteria; ACR50, 50% improvement in ACR criteria; ACR70, 70% improvement in ACR criteria; W, week.