Table 4.

Studies of biologic and small molecule therapies using novel IBD outcomes in CD

Study	Treatment	Key study details and findings
Histological remission/healing
VERSIFY—Phase 3b, prospective, open-label, single-group study109	Vedolizumab	Histologic remission = no neutrophils in the epithelium in patients with neutrophils in the epithelium at baseline (exploratory endpoint)Primary study population (n = 101) patients with inadequate/loss of response/intolerance to standard CD treatments (CS, immunosuppressants or anti-TNFα agents) treated with vedolizumab for up to 26 weeksSubstudy population comprised 56 patients treated with vedolizumab for up to 52 weeksHistological remission with vedolizumab treatment Week 26 in 14/92 (15.2% [95% CI, 8.6-24.2]) patients in the primary study Week 52 in 11 of 55 patients (20% [95% CI, 10.4-33.0]) in the substudy
LOVE-CD—Prospective study at tertiary centers in Belgium and The Netherlands110	Vedolizumab	Histological remission = GS < 3.1 (absence of neutrophils in the epithelium) or RHI ≤ 6 (absence of granulocyte in mucosal biopsies)Study population included both anti-TNFα-experienced and -naïve patients with CD and ulcerations at baseline endoscopy, analysis of paired biopsies from all segments at baseline and week 26 where active inflammation (GS ≥ 3 or RHI > 7) was present at baselineHistological remission with vedolizumab treatment Week 26 in 64% (43/67) of patients based on GS and 66% (37/56) of patients based on RHI scores
EXTEND—Multicenter, randomized, double-blind, placebo-controlled clinicaltrial111	Adalimumab	Histological healing = GHAS ≤ 2 assessed in the ileum and colonAmong patients with CD receiving maintenance adalimumab treatment and who had a colon/ileum GHAS score ≥ 3 at baseline,Histological remission with adalimumab Week 52 histological remission in the colon (n = 53) achieved by 28.3% of patients and in the ileum (n = 33) by 21.2%
Post hoc analysis of Phase 2 SERENITY trial112	Mirikizumab	Histologic remission = absence of mucosal neutrophils or epithelial damage3 histology scoring systems employed: RHI, modified GHAS, and active GHASAt week 12, rates of histological remission in all intestinal segments were greater in mirikizumab-treated patients 26% (13/50) than placebo-treated patients 6% (3/49); P < .01At week 52, 13%-31% of mirikizumab-treated patients achieved histological remission in all intestinal segments
Transmural remission/healing
VERSIFY—Phase 3b, open-label, single-group study using MRE (MaRIA)—exploratory endpoint109	Vedolizumab	Radiologic remission = MaRIA scores < 7 in all segments, or MaRIA scores < 11 in all bowel segments in those patients with scores of ≥7 or ≥11 in at least 1 segment at baseline, respectively (exploratory endpoint)MRE evaluations performed in 32 patients (primary study) treated with vedolizumab for up to 26 weeks and 21 patients (substudy) treated with vedolizumab for up to 52 weeksMaRIA-7 radiologic remissionWeek 26 in 7/32 patients (21.9%; 95% CI, 9.3-40.0)Week 52 in 8/21 patients (38.1%; 95% CI, 18.1-61.6)MaRIA-11 radiologic remissionWeek 26 in 11/32 (34.4%; 95% CI, 18.6-53.2)Week 52 in 9/21 (42.9%; 95% CI, 21.8-66.0)
Real-world prospective observational study using MRI or intestinal US113	Ustekinumab	Transmural healing = complete healing of all layers of the bowel as assessed by MRI or normal US examination with a decrease in BWT to values ≤ 3 mmStudy included 92 ustekinumab-treated patients. Transmural healing at week 52 assessed by MRI in 40 patients and intestinal US in 35 patients as a secondary endpoint.Transmural healing in ustekinumab-treated patients Week 52 transmural healing (MRI) in 15/40 (37.5%) patients Week 52 transmural healing (intestinal US) in 11/35 (31.4%) patients
Retrospective observational single-center study using MRE (MaRIA)114	Ustekinumab	Transmural healing on MRE = BWT ≤ 3 mm without any signs of inflammation (ie, ulceration, edema, diffusion-weighted hyperintensity, and increased contrast enhancement)Study included 37 ustekinumab-treated patients. The primary outcome was transmural healing at week 26 evaluated using MRE, baseline predictors of transmural healing at week 26 analyzed as a secondary outcomeTransmural healing in ustekinumab-treated patients Week 26, transmural healing in 7/37 patients (18.9%) Week 26, decreased baseline BWT (OR 0.29 [95% CI, 0.1-0.9]; P = .035) and increased apparent diffusion coefficient (OR 3.0 [95% CI, 1.0-8.9]; P = .048) were independent predictors for transmural healing (multivariate analysis)
Real-world prospective single-center study using MRE (sMaRIA)115	Infliximab, adalimumab, ustekinumab, and vedolizumab	Transmural remission = sMaRIA score of the most affected segment < 2 on MREStudy included 134 patients treated with biologic agents (induction and 1 year of maintenance); outcomes were compared between patients achieving or not achieving transmural remissionTransmural remission rate at 1 year was 40% (54/134 patients)After a median of 30 months, 43 (32%) patients were hospitalized Patients with transmural remission had a lower risk of hospitalization than those without remission (P < .01) Hospitalization-free rates were 96%, 94%, and 91% after 12, 24, and 36 months follow-up, respectively. Adjusted HR of transmural remission for predicting hospitalization was 0.11 (95% CI, 0.04-0.32); P < .01 Patients with transmural remission had a lower risk of surgery than those without (P < .01) Adjusted HR of transmural remission for predicting surgery was 0.02 (95% CI, 0.00-0.92); P = .04
Observational multicenter study in France using MRE (MaRIA)116	Anti-TNFα	Transmural response = ≥25% improvement in MaRIA scoreAnalysis of 46 infliximab-treated patients with MRI data at baseline, and weeks 12 and 52 following anti-TNFα treatmentTransmural response at week 12 (OR 4.2 95% CI, 1.3-13.3; P = .015) was predictive of corticosteroid-free remission at week 52
Real-world prospective observational single center study using intestinal US117	Anti-TNFα	Transmural healing = BWT ≤ 3 mm measured using intestinal US1-year clinical outcomes evaluated in 218 patients treated with anti-TNFα therapies (infliximab or adalimumab) for 2 years compared in patients achieving vs not achieving transmural healingTransmural healing in 68/218 patients (31.2%) after 2 years of anti‐TNFα treatment At 1-year follow-up, transmural healing associated with a higher rate of steroid-free clinical remission than mucosal healing alone and no healing, 95.58%, 75%, and 41.11%, respectively (P < .001) Hospitalization during 1-year follow‐up was significantly lower in the transmural healing group (8.8%) than the mucosal healing group (28.3%) and no healing group (66.6%; P < .001) and occurred later than in patients with mucosal healing (HR 0.88 [95% CI, 0.69-0.95]; P = .007) or no healing (HR 0.58 [95% CI, 0.44-0.75]; P = .008) Need for surgery during 1-year follow-up was significantly lower in patients with transmural healing vs and those with mucosal healing or no healing (P = .007) and occurred later than patients with mucosal healing (HR 0.94 [95% CI, 0.84-0.98]; P = .009) or no healing (HR 0.79 [95% CI, 0.62-0.84]; P = .006) At 1-year follow-up, transmural healing was an independent risk factor for steroid-free clinical remission, and reduced need for hospitalization and surgery
Real-world prospective multicenter study using intestinal US118	Adalimumab, infliximab, vedolizumab, and ustekinumab	Transmural healing = normalization of intestinal US parametersAnalysis included 188 patients with CD treated with a biologic (adalimumab n = 103, infliximab n = 31, vedolizumab n = 24, and ustekinumab n = 30) and followed up for 1 year, intestinal US was performed at baseline and months 3, 6, and 12`Transmural healing rate at Months 3, 6, and 12 was 16.4%, 24.5%, and 27.5% Transmural healing at 12 months: 37% infliximab-treated patients, 27.2% vedolizumab-treated, 26.5% adalimumab-treated, and 20% ustekinumab-treated
MORE—Prospective multicenter study in China, using intestinal US119	Infliximab	Transmural healing = BWT ≤ 3.0 mm, preserved BWS, DCS 0-1, and the absence of i-fat in the most affected segment identified by intestinal USStudy included 129 patients who received infliximab for ≥44-52 weeks. Intestinal US performed at baseline, weeks 14-26, and post-maintenance weeks 44-56.Weeks 44-56 49/129 (38.0%) of infliximab-treated patients achieved transmural healing Multivariate analysis of baseline intestinal US factors identified the presence of i-fat at baseline as the best independent negative predictor for transmural healing (adjusted OR 0.57 95% CI, 0.38-0.87; P = .008) High BWT after induction was the best independent post-induction negative predictor for transmural healing (OR 0.24 95% CI, 0.14-0.42; P < .001)
STARDUST—multicenter, phase 3b randomized study, with intestinal US substudy120	Ustekinumab	Transmural remission = ≥25% BWT reduction from baseline and normalization of all intestinal US parametersSubstudy evaluated intestinal US parameters for 77 ustekinumab-treated patients with intestinal US assessments for exploratory analysisWeek 48 Transmural remission achieved in 24.1% of ustekinumab-treated patients (n = 54)
Deep remission
Exploratory analysis of data from randomized, double-blind controlled study EXTEND73	Adalimumab	Deep remission = absence of mucosal ulceration plus clinical remission (CDAI < 150)Rates of deep remission (secondary study outcome) compared between the continuous adalimumab and adalimumab induction/placebo treatment groups at weeks 12 and 52Deep remission rates for continuous adalimumab vs adalimumab induction/placebo Week 12: 10/62 (16%) vs 6/61 (10%) (P = .34) Week 52: 12/62 (19%) vs 0/61 (0%) (P < .001) Patients with early deep remission by week 12 (n = 11) vs without early deep remission (n = 53) Fewer hospitalizations 0/11(0%) vs 9/53 (17%) Fewer CD-related surgeries 0/11 (0%) vs 5/53 (9%)
Real-world multicenter retrospective cohort study conducted in Scotland121	Ustekinumab	Deep remission = complete resolution of CD-related symptoms on PGA in the absence of CS + absence of mucosal ulceration/erosions on ileocolonoscopyAnalysis of deep remission (secondary endpoint) included 123 ustekinumab-treated patientsCumulative rates of deep remission 6 months 8.5% (n = 68) 12 months: 19.3% (n = 19)
Propensity matched retrospective analysis of data from 2 referral centers in France122	Ustekinumab and vedolizumab	Deep remission = CS-free clinical remission + deep biological remission of fecal calprotectin < 100 μg/g) at week 14 and week 24Analysis of deep remission (secondary endpoint) included 87 ustekinumab-treated and 45 vedolizumab-treated patients. Propensity score matching and inverse probability weighting (IPTW) were applied to minimize baseline group differencesDeep remission after IPTW ustekinumab vs vedolizumab Week 14: 17.9% vs 5.7% (P = .047) Week 24: 26.6% vs 16.1% (P = .58)
Patient-reported outcomes
Post hoc analysis Phase 2b trials123	Tofacitanib	PRO2-75 clinical remission = the sum of SF score and AP score < 75PRO3-80 clinical remission = the sum of SF score, AP score, and general well-being score < 80Post hoc analyses of PRO endpoints at week 8 with non-responder imputation included 180 patients treated with tofacitinib 5 mg (n = 85), 10 mg (n = 86), or placebo (n = 90)Clinical remission at week 8 for tofacitinib 5 mg, 10 mg and placebo treatment groups PRO2-75: 50/85 (58.8%), 48/86 (55.8%), and 36/90 (40.0%) (P < .05 for tofacitinib 5 mg and 10 mg vs placebo) PRO3-80: 33/85 (38.8%), 31/86 (36.1%), and 22/90 (24.4%) (P < .05 for tofacitinib 5 mg vs placebo)
CELEST Phase 2 dose-ranging study124	Upadac itinib	PRO2 clinical remission = average daily SF of ≤1.5 and AP score of ≤1.0, with neither worse than the baseline value, was a week 16 PRO2 clinical remission was evaluated as co-primary endpoint with endoscopic remission. Study included 220 patients randomized to receive placebo (n = 37), or upadacitinib 3 mg BID (n = 39), 6 mg BID (n = 37), 12 mg BID (n = 36), or 24 mg BID (n = 36) or 24 mg QD (n = 35)Week 16 PRO2 clinical remission rates were 13%, 27%, 11%, 22%, and 14% for upadacitinib 3 mg BID, 6 mg BID and 12 mg BID, 24 mg BID, 24 mg QD, 11% for placebo.

Abbreviations: aHR, adjusted hazard ratio; AP, abdominal pain; BID, twice daily; BWS, bowel wall stratification; BWT, bowel wall thickness; CD, Crohn’s disease; CDAI, Crohn’s disease activity index; DCS, color Doppler signal; CI, confidence interval; CS, corticosteroid; GHAS, global histologic disease activity score; GS, Goebes Score; IBD, inflammatory bowel disease; i-fat, inflammatory mesenteric fat; QD, once daily; MaRIA, Magnetic Resonance Index of Activity for CD; MRE, magnetic resonance enterography; MRI, magnetic resonance imaging; PGA, Physicians Global Assessment; PRO, patient-reported outcome; RHI, Robarts Histology Index; SF, stool frequency; sMaRIA, simplified Magnetic Resonance Index of Activity for CD; TNFα, tumor necrosis factor alpha; US, ultrasound.