Subcutaneous infliximab (CT-P13 SC) as maintenance therapy for Crohn's disease and ulcerative colitis: 2-year results from open-label extensions of two randomized controlled trials (LIBERTY)

Abstract

Background and aims: In the LIBERTY phase 3 studies in Crohn's disease (CD) or ulcerative colitis (UC), maintenance CT-P13 subcutaneous (SC) 120 mg was more effective than placebo after 1 year. Here we report 2-year data from the LIBERTY open-label extensions.

Methods: Two randomized, placebo-controlled, double-blind studies evaluated the efficacy and safety of CT-P13 SC maintenance in moderate-to-severe CD or UC. Responders to CT-P13 intravenous induction were randomized at week (W) 10 to CT-P13 SC 120 mg or placebo biweekly, until W54. From W22, dose adjustment to CT-P13 SC 240 mg was permitted for loss of response. At W56, patients could enter an open-label extension, receiving CT-P13 SC 120 mg (or 240 mg if dose-adjusted), biweekly, until W102.

Results: The extension comprised 278/343 (81.0%) and 348/438 (79.5%) patients in the CD and UC studies, respectively. In those continuing on-study, efficacy (non-responder imputation) was well maintained in the CT-P13 SC group at W102: 63.5% (as-observed: 70.5%) and 49.0% (as-observed: 58.8%) of CD patients (N = 192) achieved clinical remission and endoscopic response, respectively; 45.1% (as-observed: 60.1%) and 41.4% (as-observed: 52.4%) of UC patients (N = 237) achieved clinical remission and endoscopic-histologic mucosal improvement, respectively. No new safety signals were identified from longer-term CT-P13 SC treatment or starting CT-P13 SC 120 mg after placebo, with similar adverse event rates for patients undergoing dose adjustment to CT-P13 SC 240 mg from CT-P13 SC 120 mg or placebo.

Conclusion: CT-P13 SC is an effective and well-tolerated long-term maintenance treatment in moderate-to-severe CD and UC.

Clinicaltrials.gov identifiers: NCT03945019 (CD) and NCT04205643 (UC).

Keywords: CT-P13 SC; LIBERTY; inflammatory bowel disease.

Graphical Abstract

Figure 1.

Study design overview. 1. CD: CDAI-100 responder, defined as a decrease in CDAI score of 100 points or more from baseline. UC: Clinical response by modified Mayo score: a decrease in modified Mayo score from baseline of ≥ 2 points and ≥ 30%, with an accompanying decrease in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0 or 1 point. 2. From W22 through W102, dose adjustment was allowed. Patients who received CT-P13 SC 120 mg could increase the dose to CT-P13 SC 240 mg, and patients who received placebo SC could receive CT-P13 SC 240 mg, if they initially responded but then lost response according to the loss of response criteria. The adjusted dose was maintained for the remainder of the study (up to W102). 3. In the extension phase, all patients who completed the maintenance phase up to W54 and could benefit from continued treatment, in the opinion of the investigator, received active treatment with CT-P13 SC 120 mg via PFS (UC), or via PFS or AI (CD) from W56. AI, auto-injector; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; IV, intravenous; PFS, pre-filled syringe; UC, ulcerative colitis; SC, subcutaneous; W, week.

Figure 2.

Summary of patient disposition in the CD study (A) and the UC study (B). ¹One patient from the CD study in the CT-P13 SC 120 mg group was excluded from all analysis populations due to significant good clinical practice non-compliance of the study center. CD, Crohn’s disease; SC, subcutaneous; UC, ulcerative colitis; W, week.

Figure 3.

Proportion of patients in the CD study who achieved efficacy endpoints at W54 and W102 in the CT-P13 SC group (all-randomized population treated in the extension phase), showing NRI (A) and as-observed (B) analyses, as well as analyses regardless of dose adjustment (C). (A) Denominator = number of patients who were treated in the extension phase; patients with missing data or those who underwent dose adjustment were considered as non-responders/non-remitters for all subsequent visits up to W54 and W102. (B) Denominator = number of patients who were treated in the extension phase and had data available for the specified endpoint; patients with dose adjustment were considered non-responders/non-remitters for all subsequent visits up to W54 and W102. (C) Denominator = number of patients who were treated in the extension phase; remitters/responders were determined based on whether observed data met remission/response criteria regardless of dose adjustment and patients with missing data were considered non-responders/non-remitters. Clinical remission: CDAI score < 150; CDAI-100 response: decrease of ≥ 100 points from baseline in CDAI score; endoscopic remission: SES-CD score of ≥ 4 (≥ 2 point decrease from baseline [all subscores ≤ 1]); endoscopic response: 50% decrease in SES-CD score from baseline; clinical remission based on AP and SF: average worst daily AP score of ≤ 1 (using 4-point scale) and an average daily loose/watery SF score of ≤ 3 (of type 6 or type 7 on BSFS) with no worsening in either average score compared with the baseline value; corticosteroid-free remission: clinical remission (CDAI score < 150) and not receiving corticosteroids for ≥ 8 weeks prior to scheduled visit of interest among patients who were using corticosteroids at baseline; deep remission: meeting both clinical and endoscopic remission criteria. AP, abdominal pain; BSFS, Bristol Stool Form Scale; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; NRI, non-responder imputation; SES-CD, Simple Endoscopic Score for Crohn’s Disease; SC, subcutaneous; SF, stool frequency; W, week.

Figure 4.

Proportion of patients in the UC study who achieved efficacy endpoints at W54 and W102 in the CT-P13 SC group (all-randomized population treated in the extension phase), showing NRI (A) and as-observed (B) analyses, as well as analyses regardless of dose adjustment (C). (A) Denominator = number of patients who were treated in the extension phase; patients with missing data or those who underwent dose adjustment were considered non-responders/non-remitters for all subsequent visits up to W54 and W102. (B) Denominator = number of patients who were treated in the extension phase and had data available for the specified endpoint; patients with dose adjustment were considered non-responders/non-remitters for all subsequent visits up to W54 and W102. (C) Denominator = number of patients who were treated in the extension phase; remitters/responders are determined based on whether observed data met remission/response criteria regardless of dose adjustment and patients with missing data were considered non-responders/non-remitters. Clinical remission: based on modified Mayo score (stool frequency and endoscopic subscores of 0 or 1, rectal bleeding subscore of 0); clinical response: decrease of ≥ 2 points and ≥ 30% from baseline in modified Mayo score (with rectal bleeding subscore of 0 or 1 or decrease of ≥ 1 point); endoscopic-histologic mucosal improvement: endoscopic subscore of 0 or 1 (modified Mayo score) and RHI score of ≤ 3 points (with lamina propria neutrophils and neutrophils in epithelium subscore of 0); corticosteroid-free remission: clinical remission (based on modified Mayo score) and not receiving corticosteroids for ≥ 8 weeks prior to scheduled visit of interest among patients who were using corticosteroids at baseline. NRI, non-responder imputation; RHI, Roberts Histopathology Index; UC, ulcerative colitis; W, week.

Figure 5.

Kaplan–Meier plots of drug persistence (all-randomized population) in the CD study (A) and the UC study (B). Patients in the CT-P13 SC 120 mg group who received at least one administration of study drug after randomization are included in this figure. Time (weeks) to drug persistence is derived as the last study drug administration visit for patients with early discontinuation of study drug administration. Patients who completed study drug administration at W102 are considered censored at W102. Patients were considered to be receiving study drug regardless of dose adjustment. CD, Crohn’s disease; SC, subcutaneous; UC, ulcerative colitis; W, week.