To evaluate endoscopic healing in a substudy of the ustekinumab (UST) induction (UNITI-1&2) and maintenance (IM-UNITI) Phase 3 studies and to explore the relationship between induction clinical outcomes and baseline endoscopic ulceration.Methods:
Substudy patients had colonoscopies at baseline (UNITI Wk 0), then 8 & 52 weeks later (IM-UNITI Wk 44). The endoscopy analysis population (EAP) was the subset of the total substudy evaluable population (EVP) who had ulceration in ≥1 segment (i.e., baseline SES-CD ≥3). A single central reader blindly scored all video endoscopies for ulcerations and SES-CD. At Wk 0, patients received a single IV dose of PBO or UST (130 mg or ∼6 mg/kg). At Wk 8, patients with clinical response (CR) (CDAI decrease ≥100) to IV UST induction were re-randomized to subcutaneous (SC) PBO or UST 90 mg (q12w or q8w). For the non-randomized maintenance groups: (1) UST induction non-responders received SC UST 90 mg, then continued SC UST 90 mg q8w if in CR 8 wks later; (2) PBO induction nonresponders received UST IV 130 mg, then continued SC UST 90 mg q12w if in CR after 8 wks; (3) PBO induction responders received PBO throughout. The substudy primary endpoint was change in SES-CD at Wk 8 (for combined UST doses in both induction studies versus PBO) in the EAP. Pre-specified analyses also included >3 pt SES-CD decrease, 50% SES-CD decrease, SES-CD <2 and mucosal healing (absence of ulcers) in the EAP. The same endoscopic endpoints in maintenance were evaluated in the primary randomized maintenance EAP and the combined randomized & nonrandomized maintenance EAP. Induction clinical remission and response were also analyzed in the EVP and EAP populations.Results:
Of the EVP (n = 289), 87% of subjects had SES-CD ≥3 and constituted the EAP (n = 252). Reduction in SES-CD was significantly greater with UST (mean: −2.8) versus PBO (−0.7) at Wk 8 (P = 0.01). Other endoscopic endpoints at week 8 consistently favored UST versus PBO, including a significantly greater proportion of pts achieving >3 pt SES-CD reduction (47.7% versus 29.9%, respectively; P < 0.01). Rates of clinical response and remission (and treatment differences) were generally comparable between patients demonstrating ulceration at baseline (i.e., EAP) and the total substudy evaluable population (EVP). In the primary randomized maintenance population, trends for greater efficacy were seen at wk 52 with UST (especially UST 90 mg q8w) versus PBO maintenance across endpoints, but small sample sizes (UST n = 46; PBO n = 24) precluded definitive conclusions. In the combined randomized and non-randomized maintenance population (UST n = 121; PBO n = 51), similar differences in outcomes as were seen in the randomized population were observed across endoscopic endpoints at wk 52, (e.g., 50% response in 13.7% PBO versus 17.0% q12w & 33.8% q8w; P = 0.01).Conclusions:
Almost 90% of the UNITI substudy population demonstrated endoscopic inflammation/ulceration at baseline and rates of clinical response and remission were similar in this subset compared to the overall substudy population. IV UST induced significantly greater reduction in endoscopic disease activity versus PBO at Wk 8, achieving the substudy primary endpoint. Greater proportions of pts receiving UST maintenance, most notably UST 90 mg q8w, achieved maintenance endoscopic endpoints versus PBO. Together, these data support UST efficacy in achieving endoscopic healing in CD.