Ustekinumab Is Effective and Safe for Ulcerative Colitis Through 2 Years of Maintenance Therapy

Remo Panaccione; Silvio Danese; William J. Sandborn; Christopher D. O'Brien; Yiying Zhou; Hongyan Zhang; Omoniyi J. Adedokun; Ilia Tikhonov; Stephan Targan; Maria T. Abreu; Tadakazu Hisamatsu; Ellen J. Scherl; Rupert W. Leong; David S. Rowbotham; Ramesh P. Arasaradnam; Bruce E. Sands; Colleen Marano


Aliment Pharmacol Ther. 2020;52(11-12):1658-1675. 

In This Article

Materials and Methods

Study Design

Detailed methods of the UNIFI induction and maintenance studies were previously reported.[2] Briefly, adult patients with moderately-to-severely active UC (Mayo total score of 6–12, Mayo total score range 0–12, higher scores indicate more severe disease) including Mayo endoscopy subscore ≥2 (Mayo endoscopy subscore, range 0–3; determined during central review of video-endoscopy) were enrolled.[3,4] Eligible patients had inadequate response or failed to tolerate TNF antagonists, vedolizumab or conventional (ie non-biologic) therapy. Stable doses of 5-aminosalicylates and immunosuppressants were maintained from induction baseline through maintenance Week 44. Oral corticosteroids were maintained at a stable dose during the induction study, but tapered during the maintenance study by 5 mg/week for patients receiving >20 mg/day prednisone or equivalent (p.eq.) or by 2.5 mg/week for patients receiving ≤20 mg/day p.eq until 0 mg/day. During the long-term extension concomitant UC medications could be changed at the discretion of the treating physician.

Eligible patients were randomly assigned to intravenous (IV) induction of placebo, or ustekinumab 130 mg or a weight-based dose approximating 6 mg/kg. Patients who responded in the induction study could enter the maintenance study and participate as randomised or non-randomised patients.

The randomised maintenance study patient population (Figure 1A) comprised patients who were in clinical response 8 weeks after ustekinumab IV induction and randomly assigned to SC maintenance treatment with placebo, or 90 mg ustekinumab every 12 weeks (q12w) or every 8 weeks (q8w).

Figure 1.

UNIFI maintenance and long-term extension study design: randomised (A) and non-randomised (B) patients

The non-randomised population of the maintenance study (Figure 1B) included Week-16 ustekinumab induction responders and Week-8 placebo IV induction responders. Week-16 ustekinumab induction responders were patients who were not in clinical response to IV ustekinumab induction therapy at Week 8, received a SC administration of 90 mg ustekinumab and were in clinical response 8 weeks later (ie induction Week 16). Week-16 ustekinumab induction responders continued to receive ustekinumab 90 mg SC q8w in the maintenance study. Week-8 placebo IV induction responders continued to receive SC placebo in the maintenance study.

All patients completing Week 44 of the maintenance study were eligible to enter the long-term extension and continue their same ustekinumab or placebo maintenance regimen if in the opinion of the investigator, the patients would benefit from continued treatment. Randomised and non-randomised patients who were still receiving placebo in the long-term extension were discontinued after unblinding of the study and analysis of the Week-44 data.

Based on the investigator's clinical judgement of their UC disease activity, randomised patients who entered the long-term extension were eligible to receive a dose adjustment starting at Week 56 as follows: placebo to ustekinumab q8w, ustekinumab q12w to q8w and ustekinumab q8w to q8w (sham adjustment). Dose adjustment was conducted in a blinded fashion until maintenance study unblinding, after which patients and investigators were aware of their ustekinumab maintenance regimen. Non-randomised Week-16 ustekinumab induction responders and Week-8 placebo IV induction responders were not eligible for dose adjustment.

Efficacy Endpoints

Through Week 92, efficacy data (ie partial Mayo scores and inflammatory biomarkers [serum C-reactive protein {CRP}, faecal calprotectin]) were collected every 12 weeks, and at each dosing visit after unblinding. Symptomatic remission, defined as a stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0, was evaluated every 12 weeks.

Pharmacokinetics and Immunogenicity

Serum blood samples for immunogenicity and ustekinumab concentration assessments were collected every 6 months. Serum ustekinumab concentrations were measured using a validated electrochemiluminescent immunoassay (ECLIA) on the MesoScale Discovery platform, in which ustekinumab was used to capture and detect induced immune responses to ustekinumab. This assay also detected anti-drug antibodies (ADAs) in the presence of up to 100 mg/mL of ustekinumab in the sample. Patients were classified as positive if antibodies were detected in their serum sample at any time.


Safety (concomitant medications, adverse events [AEs], serious AEs [SAEs] and laboratory assessments) was evaluated through Week 96.

Statistical Analysis

Demographic and baseline disease characteristic summaries, and safety analyses were based on all patients who received at least one SC study agent administration during the long-term extension.

Efficacy was evaluated in three patient populations: (a) all randomized patients in the maintenance study (intent-to-treat population), (b) randomised patients who were treated in the long-term extension, and (c) non-randomised patients who were treated in the long-term extension. Three analysis approaches were undertaken for dichotomous endpoints, non-responder imputation with treatment failure and missing data rules applied, observed case without treatment failure and missing data rules applied, and modified observed case analyses up to the time of dose adjustment with treatment failure rules applied but not missing data rules (see Table 1 for details, including specific treatment failure rules). Dose adjustment was considered to be part of the treatment regimen (ie not included in treatment failure rules) unless otherwise indicated for dichotomous endpoints. For continuous endpoints, patients with a treatment failure or dose adjustment had their induction baseline value carried forward from the time of the event onward (ie consistent with nonresponse for dichotomous endpoints).

Serum ustekinumab concentrations were summarised over time through Week 92. The incidence of anti-drug antibodies (ADAs) was summarised through Week 96 for all treated patients who entered the long-term extension, received at least one dose of ustekinumab (either in the induction or maintenance study), and had appropriate samples for detection of antibodies to ustekinumab (ie patients with at least 1 sample obtained after their first dose of ustekinumab). Patients were considered positive if antibodies were detected at any timepoint.

Safety was evaluated by calculating the number of AEs, SAEs, infections, serious infections, AEs leading to discontinuation of study agent, and malignancies per 100 PY of follow-up among all patients (randomized and nonrandomized) who were treated in the long-term extension. Events per 100 PY that occurred during the maintenance study (first year of the study) and those that occurred during the second year of the study (long-term extension Weeks 44 through 96) were compared.

Descriptive statistics (eg mean, median, standard deviation, interquartile range, minimum, and maximum) were used to summarise continuous variables. Counts and percentages were used to summarise categorical variables.