Impact of Baseline Corticosteroid Use on the Efficacy and Safety of Upadacitinib in Patients with Ulcerative Colitis: A Post Hoc Analysis of the Phase 3 Clinical Trial Programme

Abstract

Background and aims: This post hoc analysis assessed the efficacy and safety of upadacitinib in patients with moderately to severely active ulcerative colitis stratified by corticosteroid use from the ulcerative colitis Phase 3 clinical trial programme.

Methods: Patients were randomised [1:2] to 8 weeks' placebo or upadacitinib 45 mg once daily; Week 8 responders were re-randomised [1:1:1] to 52 weeks' placebo or upadacitinib 15 or 30 mg daily. Corticosteroid dose was kept stable during induction but tapered according to a protocol-defined schedule [or investigator discretion] during maintenance Weeks 0-8. Efficacy outcomes and exposure-adjusted, treatment-emergent adverse event [TEAE] rates were assessed for induction and maintenance stratified by corticosteroid use at induction baseline.

Results: Overall, 377/988 [38%] patients were receiving corticosteroids at induction baseline [placebo, n = 133; upadacitinib 45 mg, n = 244] and 252 [37%] of the 681 clinical responders who entered maintenance were on corticosteroids at induction baseline [n = 84 for each treatment]. Similar proportions of patients receiving upadacitinib achieved clinical remission per Adapted Mayo Score with and without baseline corticosteroids at Weeks 8 and 52. The total proportion of patients re-initiating corticosteroids was higher with placebo [24/84;29%] vs upadacitinib 15 mg [16/81; 20%)] and 30 mg [11/81; 14%]. During induction, patients receiving corticosteroids at baseline had higher rates of TEAEs, serious TEAEs, and serious infections vs those not receiving corticosteroids; however, TEAE rates were similar during maintenance after corticosteroid withdrawal.

Conclusions: Upadacitinib is an effective steroid-sparing treatment in patients with moderately to severely active ulcerative colitis. Clinicaltrials.gov identifiers: NCT02819635; NCT03653026.

Keywords: Clinical trials.

Figure 1.

Study designs. Data are for the ITT population, pooled for the U-ACCOMPLISH and U-ACHIEVE Induction studies, and defined as patients who were randomised and received at least one dose of study drug [PBO or UPA 45 mg QD] during the 8-week induction period. For maintenance, this was defined as UPA 45 mg QD 8-week induction responders who were enrolled per protocol for the 52-week maintenance treatment period and received at least one dose of study drug [PBO, UPA 15 mg QD, or UPA 30 mg QD]. ^aInitial randomisation was stratified by baseline bio-IR status [yes or no], corticosteroid use [yes or no], and Adapted Mayo Score [≤7 or >7]. Baseline was defined as the last non-missing value collected on or before the first dose in the two induction studies. ^bClinical response was defined as a decrease in Adapted Mayo Score of ≥2 points and ≥30% from baseline, plus a decrease in rectal bleeding sub-score of ≥1 or an absolute rectal bleeding sub-score of ≤1. ^c21 patients entered from the Phase 2b study.^dRR was stratified by bio-IR status [bio-IR or non-bio-IR], CS use at Week 0 of maintenance [yes or no], and clinical remission status at Week 0 of maintenance [yes or no]. ^eAll CS use was stopped by maintenance Week 8 and tapered according to the protocol-defined schedule shown in the table [except at the discretion of the investigator]; however, if a patient had worsening of UC during or after the initial CS taper, CS could be re-initiated, or the dose increased, at the investigator’s discretion. ^fOral budesonide-MMX [eg, Cortiment, eUceris] and oral beclomethasone were discontinued. Bio-IR, biologic inadequate response [defined as inadequate response, loss of response, or intolerance to one or more biologic]; CS, corticosteroids; ITT, intention to treat; MMX, multimatrix; PBO, placebo; QD, once daily; RR, re-randomisation; UC, ulcerative colitis; UPA, upadacitinib; Wk, Week.

Figure 2.

Population flow diagram. ITT, intention to treat; QD, once daily; UPA, upadacitinib.

Figure 3.

Proportion of patients in clinical remission per Adapted Mayo Score at the end of induction [Week 8], by CS use at induction baseline. Data are for the ITT population, pooled for U-ACCOMPLISH and U-ACHIEVE Induction studies, and defined as patients who were randomised and received at least one dose of study drug [placebo or UPA 45 mg QD] during the 8-week induction period. Clinical remission per Adapted Mayo Score was defined as Adapted Mayo Score ≤2, stool frequency score ≤1 and not greater than baseline, rectal bleeding sub-score = 0, and endoscopic sub-score ≤1. ***Nominal p <0.001 vs placebo. CI, confidence interval; CS, corticosteroids; ITT, intention to treat; QD, once daily; UPA, upadacitinib.

Figure 4.

Proportion of patients in clinical remission per Adapted Mayo Score at the end of maintenance [Week 52], by CS use at induction baseline. Data are for the ITT population. For maintenance, this was defined as UPA 45 mg QD 8-week induction responders who were enrolled per protocol for the 52-week maintenance treatment period and received at least one dose of study drug. Clinical remission per Adapted Mayo Score was defined as Adapted Mayo Score ≤2, stool frequency score ≤1 and not greater than baseline, rectal bleeding sub-score = 0, and endoscopic sub-score ≤1. ***Nominal p <0.001 vs placebo. CI, confidence interval; CS, corticosteroids; ITT, intention to treat; QD, once daily; UPA, upadacitinib.

Figure 5.

Partial Mayo Score from Week 0 to Week 52 of maintenance in patients with or without CS use at induction baseline. Data are for the ITT population. For maintenance, this was defined as UPA 45 mg QD 8-week induction responders who were enrolled per protocol for the 52-week maintenance treatment period and received at least one dose of study drug [placebo, UPA 15 mg QD, or UPA 30 mg QD]. CS, corticosteroids; ITT, intention to treat; LS, least squares; QD, once daily; UPA, upadacitinib.

Figure 6.

Proportion of patients achieving clinical remission per Adapted Mayo Score and who were CS-free for 90 or 183 days immediately before Week 52, among patients with CS use at induction baseline. Data are for the ITT population. For maintenance, this was defined as UPA 45 mg QD 8-week induction responders who were enrolled per protocol for the 52-week maintenance treatment period and received at least one dose of study drug [placebo, UPA 15 mg QD, or UPA 30 mg QD]. CS-free clinical remission was defined as clinical remission per Adapted Mayo Score [defined as Adapted Mayo Score ≤2, stool frequency score ≤1 and not greater than baseline, rectal bleeding sub-score = 0, and endoscopic sub-score ≤1] at Week 52 and CS-free for ≥90 or ≥183 consecutive days immediately preceding Week 52 among patients taking CS at baseline in the induction study. ***Nominal p <0.001 vs placebo. CI, confidence interval; CS, corticosteroids; ITT, intention to treat; QD, once daily; UPA, upadacitinib.

Figure 7.

Proportions of patients who were CS-free at each time point during maintenance after the CS taper among patients with CS use at baseline. Data are for the ITT population. For maintenance, this was defined as UPA 45 mg QD 8-week induction responders who were enrolled per protocol for the 52-week maintenance treatment period and received at least one dose of study drug. CS-free clinical remission was defined as clinical remission per Adapted Mayo Score [defined as Adapted Mayo Score ≤2, stool frequency score ≤1 and not greater than baseline, rectal bleeding sub-score = 0, and endoscopic sub-score ≤1] at Week 52 and CS-free for ≥90 or ≥183 consecutive days immediately preceding Week 52 among patients taking CS at baseline in the induction study. **Nominal p <0.01 vs placebo. ***Nominal p <0.001 vs placebo. CS, corticosteroids; ITT, intention to treat; QD, once daily; UPA, upadacitinib.