STRUCTURED ABSTRACT

Question: Is biologic monotherapy with ustekinumab, an anti-interleukin-12/23 monoclonal antibody, superior to adalimumab, an anti-tumor necrosis factor (anti-TNF) monoclonal antibody, for clinical remission in biologic-naïve patients with moderately to severely active Crohn’s disease?

Design: The SEAVUE study is a 56-week, randomized, double-blind, double dummy, parallel-group, active comparator, phase 3b trial, the first randomized controlled trial (RCT) to directly compare 2 biologic agents for the treatment of Crohn’s disease (CD).

Setting: Patients were recruited from 121 practices in 18 countries.

Patients: Inclusion criteria included: (a) age ≥18 years; (b) confirmed diagnosis of Crohn’s disease; (c) no previous biologic therapy; (d) non-response or intolerance to “conventional therapy” OR corticosteroid dependence; (e) moderately to severely active disease, Crohn’s disease activity index (CDAI) of  220-450, for at least 3 months; and, (f) at least 1 ulcer of any size on ileocolonoscopy (Simple Endoscopy Score for Crohn’s Disease [SES-CD] ≥3). Exclusion criteria included, but were not limited to: (a) pregnancy; (b) abscess in prior 3-8 weeks; (c) bowel resection in prior 6 months; (d) ongoing infection or malignancy. [CDAI includes assessment of frequency of liquid stools, use of anti-diarrheals, severity of abdominal discomfort, general well-being, presence of extra-intestinal symptoms, hematocrit, weight loss, presence/absence of abdominal mass, anal fissure, fistulae, or fever.]

Prior to study enrollment, eligible patients completed a 3 week wash out period for thiopurines, methotrexate and intravenous (IV) corticosteroids and a 4 week wash out period for other immunosuppression such as Janus kinase inhibitors and cyclosporine. If patients were using oral corticosteroids, they required that the dose be stable and ≤40mg of prednisone-equivalents or ≤9mg of budesonide equivalents for at least 3 weeks prior to randomization.

Intervention: Ustekinumab 6mg/kg IV dose at day zero and then 90mg subcutaneous (subq)  every 8 weeks through week 56 vs adalimumab 160 mg subq on   day  0, 80mg subq on week 2, and 40mg subq every 2 weeks without dose optimization due to double-blind, double-dummy protocol and without additional use of immunomodulators.

Outcomes: The primary outcome was clinical remission at week 52, defined as CDAI score <150. Major secondary endpoints included: (a) corticosteroid-free remission: CDAI <150 + no corticosteroids at week 52; (b) clinical response: CDAI decrease at least 100 points from baseline at week 52; (c) PRO-2 symptom remission: mean daily abdominal pain score ≤1 with mean daily stool frequency score ≤3 at week 52; (d) clinical remission at week 16; and, (e) endoscopic remission, SES-CD ≤3 (or SES-CD 0 for patients who were 3 at baseline) at week 52. If study patients had Crohn’s disease related surgery, treatment discontinuation due to an adverse event or prohibited change in concomitant medications during the 52 week study period, then this was also considered failure to achieve primary outcome of clinical remission.

Data Analysis: The analysis was powered (80%) to detect superiority of ustekinumab over adalimumab by 15% for the primary outcome of clinical remission at week 52. Sample size was calculated using data from Phase 3/3b studies for each group, assuming response rates of 56% and 41%, respectively, for ustekinumab and adalimumab. Modified intention-to-treat analysis defined as patients who were randomized and received at least one dose of study medication was performed for the primary endpoint with Cochran-Mantel-Haenszel chi-square test. Continuous variables were assessed with analysis of covariance. A hierarchical testing procedure was used for analysis, starting with the primary endpoint to control the inflation of type I error rate for multiple efficacy outcomes. If the primary endpoint did not demonstrate a significant difference, then all major secondary outcomes were considered not statistically significant and p values were nominal.

Funding: Janssen Biotech, the manufacturer of ustekinumab, had a role in study design and employed study statisticians.

Results: Between June 2018 and December 2019, 633 patients were screened. Of the 386 patients who enrolled, 191 were randomly assigned to the ustekinumab arm and 195 to the adalimumab arm. Baseline characteristics were similar in both arms with a mean age of 37; 51%-53% female; 86%-93% White; mean disease duration of 5 years; and, mean CDAI score was 300-301. Over 50% of patients in both arms had ileocolonic involvement, 9%-16% had upper GI involvement and 9%-10% patients had fistulae. At baseline, 22%-24% of patients were treated with systemic corticosteroids.

There was no significant difference in clinical remission at week 52 between ustekinumab and adalimumab: 65% vs 61%, respectively, and no significant differences in the treatment arms for the major secondary endpoints (Figure 1), including endoscopic remission (29% vs 31%, respectively). Time to treatment discontinuation was significantly shorter in the adalimumab arm (P=0.047), and treatment discontinuation prior to week 52 was numerically higher with adalimumab (24% vs 15%).

Adverse event data reported infection with adalimumab (41%) and ustekinumab (34%), and serious infection occurred with adalimumab (3%) and ustekinumab (2%). Only abdominal pain (13% vs 8%) and headaches (12% vs 7%) occurred more frequently in the ustekinumab arm than in the adalimumab. Notably, they included a category of “Crohn’s disease events” which occurred more frequently in the adalimumab arm (16% vs 12%).

Figure 1. Primary and secondary study endpoints.

In patients with moderate to severe Crohn’s disease who have not been treated previously with a biologic agent, both ustekinumab and adalimumab have similar efficacy at achieving clinical remission at 52 weeks (65% vs 61%) without significant differences in clinical remission at 16 weeks, corticosteroid-free remission and improvement in patient-reported outcomes at 52 weeks.