Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results of the UNIFI Long-Term Maintenance Study

Abstract

Introduction: Ulcerative colitis (UC) is a chronic condition that may require long-term treatment. We report the final efficacy and safety results of the UNIFI long-term extension study of ustekinumab in patients with UC through 4 years.

Methods: Ustekinumab induction responders who completed 44 weeks of maintenance treatment and agreed to enter the long-term extension continued their subcutaneous maintenance therapy (90 mg ustekinumab every 8 or 12 weeks [q8w or q12w] or placebo). Starting at week 56, randomized patients could receive dose adjustment to 90 mg q8w. Symptoms and adverse events were assessed through the study; endoscopic assessment was conducted at week 200.

Results: Of the 348 patients randomized to subcutaneous ustekinumab at maintenance baseline (q8w and q12w combined), 55.2% were in symptomatic remission at week 200. A greater proportion of biologic-naive patients (67.2% [117/174]) were in symptomatic remission than those with a history of biologic failure (41.6% [67/161]). Among patients in symptomatic remission at week 200, 96.4% were corticosteroid-free. Of the 171 patients with endoscopic evaluation at week 200, 81.6% (71/87) in the q12w group and 79.8% (67/84) in the q8w group had endoscopic improvement. From weeks 156 to the final safety visit (up to week 220), no deaths, major adverse cardiovascular events, or tuberculosis occurred in patients receiving ustekinumab. Nasopharyngitis, UC worsening, and upper respiratory tract infections were the most frequently reported adverse events.

Discussion: The long-term efficacy of ustekinumab maintenance in patients with UC was confirmed through 4 years. No new safety signals were observed. ClinicalTrials.gov number NCT02407236.

Graphical abstract

Figure 1.

Symptomatic remission^a and corticosteroid-free symptomatic remission^a from maintenance baseline through week 200 for all ustekinumab IV induction responders randomized in the maintenance study (ITT analysis).^b,c,d,e Symptomatic remission for the (a) overall population, (b) biologic-naive patients, and (c) patients with a history of biologic failure. Corticosteroid-free symptomatic remission for the (d) overall population, (e) biologic-naive patients, and (f) patients with a history of biologic failure. ^aSymptomatic remission was defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0. ^bData are shown by randomized treatment group at maintenance week 0, regardless of whether patients received dose adjustment during the long-term extension. ^cPatients who had both stool frequency and rectal bleeding subscores missing at a visit were considered not to be in symptomatic remission for that visit. ^dPatients who had a prohibited change in UC medication, an ostomy or colectomy, or used a rescue medication after clinical flare, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC before week 44 were considered not to be in symptomatic remission at every visit thereafter up to week 44. ^ePatients who had an ostomy or colectomy or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC after week 44 were considered not to be in symptomatic remission at every visit thereafter. AE, adverse event; ITT, intent-to-treat; LTE, long-term extension; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous, UC, ulcerative colitis.

Figure 2.

Symptomatic remission^a from week 44 to week 200 among patients randomized to ustekinumab at maintenance baseline and treated in the LTE using (a-c) nonresponder imputation analysis,^b,c,d or (d-f) observed case analysis^e for the overall population, biologic-naive patients, and patients with a history of biologic failure. ^aSymptomatic remission was defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0. ^bData are shown by randomized treatment group at maintenance week 0, regardless of whether patients received dose adjustment during the LTE. ^cPatients who had both stool frequency and rectal bleeding subscores missing at a visit were considered not to be in symptomatic remission for that visit. ^dPatients who had an ostomy or colectomy or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC after week 44 were considered not to be in symptomatic remission at every visit thereafter. ^eDenominator is number of patients with available data at each visit. AE, adverse event, LTE, long-term extension; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous; UC, ulcerative colitis.

Figure 3.

Full Mayo clinical remission, full Mayo clinical response, modified Mayo score response, and endoscopic improvement among patients with endoscopic evaluations at week 200 using (a) observed case analysis and (b) modified observed case analysis. Data are shown by randomized treatment group at maintenance week 0, regardless of whether patients received dose adjustment during the LTE. Full Mayo clinical remission was defined as a Mayo score ≤2 points, with no individual subscore >1. Full Mayo clinical response was defined as a decrease from induction baseline in the total Mayo score by ≥ 30% and ≥3 points, with either a decrease from induction baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. Modified Mayo score response was defined as a decrease from induction baseline in the modified Mayo score by ≥ 30% and ≥2 points, with either a decrease from induction baseline in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. Endoscopic improvement was defined as an endoscopy subscore of 0 or 1. ^aIncludes data for patients who had endoscopic subscores at week 200. No imputation for missing data or treatment failure. ^bIncludes data for patients who had endoscopic subscores at week 200 or those who met treatment failure criteria. Patients who met treatment failure criteria (i.e., had an ostomy or colectomy or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC before week 200) were not considered to have achieved the end point. AE, adverse event; LTE, long-term extension; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous; UC, ulcerative colitis.

Figure 4.

Key safety events per 100 patient-years of follow-up for the first, second, third, and fourth years of ustekinumab maintenance therapy. ^aNumber of adverse events per 100 patient-years of follow-up and 95% CI (rates by each year of follow-up) in the combined ustekinumab ulcerative colitis safety cohort. CI were based on an exact method assuming that the observed number of events follows a Poisson distribution. ^bInfection as assessed by the investigator. ^c1st year includes the following: (i) patients who received ustekinumab SC (q8w or q12w) in the maintenance study with data from maintenance weeks 0 through 44; (ii) patients who were in full Mayo clinical response to ustekinumab IV induction dosing and received placebo SC on entry into this maintenance study with data from maintenance weeks 0 through 8. d2nd, 3rd, and 4th years include the following: (i) patients who were in full Mayo clinical response to ustekinumab IV induction dosing and were randomized to ustekinumab 90 mg SC q12w or q8w on entry into the maintenance study; (ii) patients who were in full Mayo clinical response to ustekinumab IV induction dosing, randomized to receive placebo SC on entry into the maintenance study, and had a dose adjustment to ustekinumab 90 mg SC q8w, with data from the time of dose adjustment onward; and (iii) patients who were not in full Mayo clinical response to ustekinumab IV at induction week 8 but were in full Mayo clinical response at induction week 16 after an SC administration of ustekinumab at induction week 8 and received ustekinumab 90 mg SC q8w on entry into the maintenance study. The 2nd year included data from week 44 through week 96, the 3rd year included data from week 96 through week 156, and the 4th year included data from week 156 through the final safety visit up to week 220. CI, confidence interval; IV, intravenous; LTE, long-term extension; q8w, every 8 weeks; q12w, every 12 weeks; SC, subcutaneous.