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://clinicaltrials.gov/ct2/show/NCT03147248.

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

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 W22^a (A) L.S.M. (s.e.) change from baseline in DAS28-CRP at W22 (efficacy population^b). (B) L.S.M. (s.e.) change from baseline in DAS28-CRP at W22 (all-randomized population^c). (C) Estimate of treatment difference (95% CI) in L.S.M. change from baseline in DAS28-CRP at W22 for efficacy^b and all-randomized^c 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 population^a) (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.