Retrograde Cricopharyngeus Dysfunction, a New Motility Disorder: Single Center Case Series and Treatment Results.

Background/Aims: Retrograde cricopharyngeus dysfunction (R-CPD) is a new clinical entity characterized by inability to belch and associated symptoms of loud gurgling noises, chest and/or abdominal pressure, abdominal bloating, and excessive flatulence. R-CPD can be treated with botulinum toxin (BT) injection in the upper esophageal sphincter. We hereby report patient demographics, symptomatology, and treatment results of a series of consecutive patients who presented at our center. Methods: Data on 50 consecutive patients presenting with R-CPD were prospectively collected using a standardized questionnaire prior to, 1 month after treatment and at the end of follow-up. All patients were diagnosed using a set of clinical symptoms. Results: Fifty patients (26 females) were included, median age was 27.5 years (range, 17-65). Median body mass index was 22.7 kg/m2 (range, 16.6-37.5). Inability to belch was present in all patients, > 90% of patients experienced gurgling noises and abdominal/chest discomfort as result of their condition. One month after injection of BT, 40.8% of patients experienced complete relief of symptoms, 24.5% good symptom improvement, 24.5% some symptom improvement and 10.2% no improvement. At median follow-up of 29 months (range, 3-50) post-treatment, 51.3% (n = 20/39) of patients reported persistent complete relief of symptoms, 12.8% good improvement of symptoms (n = 5/39), in 15.4% some improvement (6/39) and 20.5% loss of or no response (n = 8/39). Only minor and transient side effects were reported. Conclusions: Our case series of 50 patients with R-CPD shows very good short-term and good long-term improvement of symptoms after injection of BT. These results are in line with previous studies.

Efficacy of vedolizumab during intravenous induction therapy in ulcerative colitis and Crohn's disease: post hoc analysis of patient-reported outcomes from the VISIBLE 1 and 2 studies.

BACKGROUND: Vedolizumab is an anti-α4ß7 integrin antibody used to treat moderate to severe ulcerative colitis (UC) and Crohn's disease (CD). This post hoc analysis of patient-reported outcomes (PROs) from the VISIBLE 1 (NCT02611830) and 2 (NCT02611817) phase 3 studies evaluated onset of treatment effect on patient-reported symptoms during 6-week vedolizumab induction. METHODS: Patient-reported stool frequency (SF) and rectal bleeding (RB) (UC Mayo score), and SF and abdominal pain (AP) in CD were collected via electronic diary from VISIBLE patients receiving one or more open-label intravenous (IV) vedolizumab induction doses (weeks 0 and 2). PRO data were analyzed using descriptive statistics. RESULTS: Data from 994 patients (UC 383, CD 611) showed mean ratings for all PROs declined consistently week-on-week from baseline through week 6, with early onset of improvement. By week 2, 22% of patients with UC reported RB improvement (≥1-point reduction in RB subscore, 7-day mean), rising to 45% by week 6. By week 6, 18% of patients with UC achieved SF improvement (SF subscore 0; 21% antitumor necrosis factor alpha [anti-TNFα] naive, 13% anti-TNFα experienced). SF improvement in patients with CD (reduction of ≥3 stools, 7-day mean) was achieved by 32% at week 6 (34% anti-TNFα naive, 30% anti-TNFα experienced). Fewer patients with CD reported severe/moderate AP at week 6 (5.1%/28.5%) than baseline (14.6%/61.5%). SF decline appeared greater and faster for anti-TNFα-naive vs. anti-TNFα-experienced patients (UC and CD). CONCLUSION: Results indicate early onset of patient-reported UC and CD symptom improvement during vedolizumab IV induction in VISIBLE 1 and 2.

Prophylactic versus endoscopy-driven treatment of Crohn's postoperative recurrence: A retrospective, multicentric European study (PORCSE study).

BACKGROUND AND AIMS: No consensus exists on optimal strategy to prevent postoperative recurrence (POR) after ileocecal resection (ICR) for Crohn's disease (CD).We compared early medical prophylaxis versus expectant management with treatment driven by findings at elective endoscopy 6-12 months after ICR. METHODS: A retrospective, multicentric, observational study was performed. CD-patients undergoing first ICR were assigned to cohort1 if a biologic or immunomodulator was (re)started prophylactically after ICR, or to cohort2 if no postoperative prophylaxis was given and treatment was started as reaction to elective endoscopic findings. Primary endpoint was rate of endoscopic POR (Rutgeerts>i1). Secondary endpoints were severe endoscopic POR (Rutgeerts i3/i4), clinical POR, surgical POR and treatment burden during follow-up. RESULTS: Of 346 included patients, 47.4% received prophylactic postoperative treatment (proactive/cohort1) and 52.6% did not (reactive/cohort2).Endoscopic POR (Rutgeerts>i1) rate was significantly higher in cohort2 (41.5% vs 53.8%, OR1.81, P=0.039) at endoscopy 6-12 months after surgery. No significant difference in severe endoscopic POR was found (OR1.29, P=0.517). Cohort2 had significantly higher clinical POR rates (17.7% vs 35.7%, OR3.05, P=0.002) and numerically higher surgical recurrence rates (6.7% vs 13.2%, OR2.59, P=0.051). Cox proportional hazards regression analysis showed no significant difference in time to surgical POR of proactive versus expectant/reactive approach (HR2.50, P=0.057). Quasi-Poisson regression revealed a significantly lower treatment burden for immunomodulator use in cohort2 (mean ratio 0.53, P=0.002), but no difference in burden of biologics or combination treatment. CONCLUSIONS: The PORCSE study showed lower rates of endoscopic POR with early postoperative medical treatment compared to expectant management after first ileocecal resection for Crohn's disease.

Baseline Data and Measurement Instruments Reported In Observational Studies In Inflammatory Bowel Disease: Results From A Systematic Review.

BACKGROUND: Heterogeneity in demographic and outcomes data with corresponding measurement instruments (MI) creates barriers for data pooling and analysis. Several core outcome sets developed in inflammatory bowel disease (IBD) homogenise outcomes data. A parallel Minimum Data Set (MDS) for baseline characteristics is lacking. We conducted a systematic review to develop the first MDS. METHODS: A systematic review of observational studies from 3 databases (2000 to 2021). Titles and abstracts were screened; full-text articles reviewed, and data extracted by two reviewers. Baseline data were grouped into 10 domains: demographics, clinical features, disease behaviour/complications, biomarkers, endoscopy, histology, radiology, healthcare utilisation and patient-reported data. Frequency of baseline data and MI within respective domains are reported. RESULTS: From 315 included studies (600,552 subjects), most originated from Europe (196; 62%), and North America (59; 19%), and were published between 2011 and 2021 (251; 80%). The most frequent domains were demographics (311; 98.7%) and clinical (289; 91.7%); 224 (71.1%) studies reported on the triad of sex (306; 97.1%), age (289; 91.7%) and disease phenotype (231; 73.3%). Few included baseline data for radiology 19; 6%), healthcare utilisation (19; 6%) and histology (17; 5.4%). Ethnicity (19; 6%), race (17; 5.4%) and alcohol/drug consumption (6; 1.9%) were least reported demographics. From 25 MI for clinical disease activity, Harvey Bradshaw Index (n=53) and Mayo score (n=37) were most frequently used. CONCLUSIONS: Substantial variability exists in baseline population data reporting. These findings will inform a future consensus for MDS in IBD to enhance data harmonisation and credibility of real-world evidence.

Outcome of Biological Therapies and Small Molecules in Ulcerative Proctitis: A Belgian Multicenter Cohort Study.

BACKGROUND & AIMS: Several advanced therapies (biologic therapies and small molecules) have been approved for the treatment of moderate-to-severe ulcerative colitis. The registration trials for these agents typically excluded patients with isolated proctitis, leaving an evidence gap. We evaluated efficacy and safety of advanced therapies in patients with ulcerative proctitis (UP). METHODS: This multicenter retrospective cohort study included consecutive patients with active UP (Mayo endoscopy subscore of ≥2, rectal inflammation up to 15 cm) initiating advanced therapy, after failing conventional therapy. The primary end point was short-term steroid-free clinical remission (total Mayo score ≤2 with no individual subscore >1). In addition, drug persistence and relapse-free and colectomy-free survival were assessed. Both binary logistic and Cox regression analyses were performed. RESULTS: In total, 167 consecutive patients (52.0% female; median age 41.0 years; 82.0% bionaive) underwent 223 courses of therapy for UP (38 adalimumab, 14 golimumab, 54 infliximab, 9 ustekinumab, 99 vedolizumab, 9 tofacitinib). The primary end point was achieved with 36.3% of the treatment courses, and based on multivariate analysis, more commonly attained in bionaive patients (P = .001), patients treated with vedolizumab (P = .001), patients with moderate endoscopic disease activity (P = .002), and a body mass index <25 kg/m2 (P = .018). Drug persistence was significantly higher in patients treated with vedolizumab (P < .001) and patients with a shorter disease duration (P = .006). No new safety signals were observed. CONCLUSIONS: Advanced therapies are also efficacious and safe in patients with ulcerative colitis limited to the rectum. Therefore, the inclusion of patients with UP in future randomized-controlled trials should be considered.

Early versus Late Use of Vedolizumab in Ulcerative Colitis: Clinical, Endoscopic, and Histological Outcomes.

BACKGROUND AND AIMS: We explored the potential for differential efficacy of vedolizumab between "early" and "late" ulcerative colitis (UC) with evaluation of clinical, endoscopic, and histological endpoints. METHODS: This was a multicentre, multinational open-label study in patients with moderately-to-severely active UC, defining "early" UC by a disease duration <4 years and bio-naïve and "late" UC by a disease duration >4 years and additional exposure to tumour necrosis factor antagonists. Patients received standard treatment with intravenous vedolizumab for 52 weeks (300 mg weeks 0-2-6, every 8 weeks thereafter without escalation). The primary endpoint was corticosteroid-free clinical remission with endoscopic improvement (total Mayo score ≤2 with no subscore >1) at both week 26 and 52. RESULTS: A total of 121 patients were included: in the "early" group 25/59 (42.4%) achieved the primary endpoint versus 19/62 (30.6%) in the "late" group (P = 0.18). There were no significant differences between the two groups in endoscopic improvement (week 26: "early" 32/59 [54.2%] vs. "late" 29/62 [46.8%]; P = 0.412; week 52: 27/59 [45.8%] vs. 25/62 [40.3%]; P = 0.546) or histological remission (Robarts Histopathology Index <3 without neutrophils in the epithelium and lamina propria) (week 26: 24/59 [40.7%] vs. 21/62 [33.9%]; P = 0.439; week 52: 22/59 [37.3%] vs. 22/62 [35.5%]; P = 0.837). CONCLUSIONS: No significant differences in clinical, endoscopic, and histological outcomes were observed between "early" and "late" disease.

Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies.

BACKGROUND: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. INTERPRETATION: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. FUNDING: Arena Pharmaceuticals.

Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.

BACKGROUND: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. METHODS: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. FINDINGS: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. INTERPRETATION: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. FUNDING: European Union's Horizon 2020.

The Impact of COVID-19 on Patients with IBD in a Prospective European Cohort Study.

BACKGROUND AND AIMS: There are concerns regarding the potential impact of the COVID-19 outbreak on patients with inflammatory bowel disease [IBD]. We report on the impact of the COVID-19 outbreak in a European prospective cohort study of patients with IBD. PATIENTS AND METHODS: We prospectively collected data from 5457 patients with IBD nested in the ongoing I-CARE project and still followed up in April 2020, with monthly online monitoring of clinical activity, treatment, imaging and endoscopy. Investigators were also contacted to report incidental cases. RESULTS: In total, 233 [4.3%] reported COVID-19 and 12 [0.2%] severe COVID-19, with no COVID-19 deaths. The risk of COVID-19 in patients with IBD was not increased compared to the general population (standardized incidence ratio [SIR]: 1.18, 95% confidence interval [CI] [1.03-1.34], p = 0.009), as well as the risk of severe COVID-19 (SIR: 0.69, 95% CI [0.35-1.20], p = 0.93). We did not observe any negative impact of the different IBD-related medication on the risk of either COVID-19 or severe COVID-19. In 2020, the COVID-19 outbreak resulted in a drastic decrease in endoscopic and imaging procedures from March to May 2020 compared to 2018 and 2019. No impacts on clinical IBD disease activity as well as ongoing treatment were noted. CONCLUSION: No increases in either COVID-19 or severe COVID-19 incidences were observed in patients with IBD. There was no impact of COVID-19 on IBD-related medication and clinical activity. Access to endoscopy and imaging was restricted during the first months of the first COVID-19 outbreak.

I-CARE, a European Prospective Cohort Study Assessing Safety and Effectiveness of Biologics in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators. METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment. RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia. CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Development of a Core Outcome Set for Real-world Data in Inflammatory Bowel Disease: A European Crohn's and Colitis Organisation [ECCO] Position Paper.

BACKGROUND AND AIMS: The utility of real-world data is dependent on the quality and homogeneity of reporting. We aimed to develop a core outcome set for real-world studies in adult patients with inflammatory bowel disease [IBD]. METHODS: Candidate outcomes and outcome measures were identified and categorised in a systematic review. An international panel including patients, dietitians, epidemiologists, gastroenterologists, nurses, pathologists, radiologists, and surgeons participated in a modified Delphi consensus process. A consensus meeting was held to ratify the final core outcome set. RESULTS: A total of 26 panellists from 13 countries participated in the consensus process. A total of 271 items [130 outcomes, 141 outcome measures] in nine study domains were included in the first-round survey. Panellists agreed that real-world studies on disease activity should report clinical, endoscopic, and biomarker disease activity. A disease-specific clinical index [Harvey-Bradshaw Index, Partial Mayo Score, Simple Clinical Colitis Activity Index] should be used, rather than physician global assessment. In ulcerative colitis [UC], either the UC Endoscopic Index of Severity or the Mayo Endoscopic Score can be used, but there was no consensus on an endoscopic index for Crohn's disease, nor was there consensus on the use of the presence of ulcers. There was consensus on using faecal calprotectin and C-reactive protein. There was no consensus on the use of histology in real-world studies. CONCLUSIONS: A core outcome set for real-world studies in IBD has been developed based on international multidisciplinary consensus. Its adoption will facilitate synthesis in the generation of real-world evidence.

Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial.

BACKGROUND: There is a great unmet need for new therapeutics with novel mechanisms of action for patients with Crohn's disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was efficacious and well tolerated as induction therapy. Here, we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy. METHODS: FORTIFY is a phase 3, multicentre, randomised, double-blind, placebo-controlled, maintenance withdrawal study across 273 clinical centres in 44 countries across North and South America, Europe, Oceania, Africa, and the Asia-Pacific region that enrolled participants with clinical response to risankizumab in the ADVANCE or MOTIVATE induction studies. Patients in ADVANCE or MOTIVATE were aged 16-80 years with moderately to severely active Crohn's disease. Patients in the FORTIFY substudy 1 were randomly assigned again (1:1:1) to receive either subcutaneous risankizumab 180 mg, subcutaneous risankizumab 360 mg, or withdrawal from risankizumab to receive subcutaneous placebo (herein referred to as withdrawal [subcutaneous placebo]). Treatment was given every 8 weeks. Patients were stratified by induction dose, post-induction endoscopic response, and clinical remission status. Patients, investigators, and study personnel were masked to treatment assignments. Week 52 co-primary endpoints were clinical remission (Crohn's disease activity index [CDAI] in the US protocol, or stool frequency and abdominal pain score in the non-US protocol) and endoscopic response in patients who received at least one dose of study drug during the 52-week maintenance period. Safety was assessed in patients receiving at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03105102. FINDINGS: 712 patients were initially assessed and, between April 9, 2018, and April 24, 2020, 542 patients were randomly assigned to either the risankizumab 180 mg group (n=179), the risankizumab 360 mg group (n=179), or the placebo group (n=184). Greater clinical remission and endoscopic response rates were reached with 360 mg risankizumab versus placebo (CDAI clinical remission was reached in 74 (52%) of 141 patients vs 67 (41%) of 164 patients, adjusted difference 15% [95% CI 5-24]; stool frequency and abdominal pain score clinical remission was reached in 73 (52%) of 141 vs 65 (40%) of 164, adjusted difference 15% [5-25]; endoscopic response 66 (47%) of 141 patients vs 36 (22%) of 164 patients, adjusted difference 28% [19-37]). Higher rates of CDAI clinical remission and endoscopic response (but not stool frequency and abdominal pain score clinical remission [p=0·124]) were also reached with risankizumab 180 mg versus withdrawal (subcutaneous placebo; CDAI clinical remission reached in 87 [55%] of 157 patients, adjusted difference 15% [95% CI 5-24]; endoscopic response 74 [47%] of 157, adjusted difference 26% [17-35]). Results for more stringent endoscopic and composite endpoints and inflammatory biomarkers were consistent with a dose-response relationship. Maintenance treatment was well tolerated. Adverse event rates were similar among groups, and the most frequently reported adverse events in all treatment groups were worsening Crohn's disease, arthralgia, and headache. INTERPRETATION: Subcutaneous risankizumab is a safe and efficacious treatment for maintenance of remission in patients with moderately to severely active Crohn's disease and offers a new therapeutic option for a broad range of patients by meeting endpoints that might change the future course of disease. FUNDING: AbbVie.

Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.

BACKGROUND: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease. METHODS: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete. FINDINGS: Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. INTERPRETATION: Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease. FUNDING: AbbVie.

A Narrative Systematic Review and Categorisation of Outcomes in Inflammatory Bowel Disease to Inform a Core Outcome Set for Real-world Evidence.

BACKGROUND: Heterogeneity exists in reported outcomes and outcome measurement instruments [OMI] from observational studies. A core outcome set [COS] for observational and real-world evidence [RWE] in inflammatory bowel disease [IBD] will facilitate pooling large datasets. This systematic review describes and classifies clinical and patient-reported outcomes, for COS development. METHODS: The systematic review of MEDLINE, EMBASE, and CINAHL databases identified observational studies published between 2000 and 2021 using the population exposure outcome [PEO] framework. Studies meeting eligibility criteria were included. After titles and abstracts screening, full-text articles were extracted by two independent reviewers. Primary and secondary outcomes with corresponding OMI were extracted and categorised in accordance with OMERACT Filter 2.1 framework. The frequency of outcomes and OMIs are described. RESULTS: From 5854 studies, 315 were included: 129 [41%] Crohn's disease [CD], 60 [19%] ulcerative colitis [UC], and 126 [40%] inflammatory bowel disease [IBD] studies with 600 552 participants. Totals of 1632 outcomes and 1929 OMI were extracted mainly from medical therapy [181; 72%], surgical [34; 11%], and endoscopic [6; 2%] studies. Clinical and medical therapy-related safety were frequent outcome domains recorded in 194 and 100 studies. Medical therapy-related adverse events [n = 74] and need for surgery [n = 71] were the commonest outcomes. The most frequently reported OMI were patient or event numbers [n = 914], Harvey-Bradshaw Index [n = 45], and Montreal classification [n = 42]. CONCLUSIONS: There is substantial variability in outcomes reporting and OMI types. Categorised outcomes and OMI from this review will inform a Delphi consensus on a COS for future RWE in IBD. Data collection standardisation may enhance the quality of RWE applied to decision-making.

Higher vs Standard Adalimumab Induction Dosing Regimens and Two Maintenance Strategies: Randomized SERENE CD Trial Results.

BACKGROUND & AIMS: Dose-optimization strategies for biologic therapies in Crohn's disease (CD) are not well established. The SERENE CD (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Crohn's Disease) trial evaluated higher vs standard adalimumab induction dosing and clinically adjusted (CA) vs therapeutic drug monitoring (TDM) maintenance strategies in patients with moderately to severely active CD. METHODS: In this phase 3, randomized, double-blind, multicenter trial, eligible adults (Crohn's Disease Activity Index score of 220-450, endoscopic evidence of mucosal inflammation, and previous failure of standard therapies) were randomized to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3; n = 308) or standard induction regimen (adalimumab 160 mg at week 0 and 80 mg at week 2; n = 206) followed by 40 mg every other week from week 4 onward. Co-primary end points included clinical remission at week 4 and endoscopic response at week 12. At week 12, patients were re-randomized to maintenance therapy optimized by Crohn's Disease Activity Index and C-reactive protein (CA; n = 92) or serum adalimumab concentrations and/or clinical criteria (TDM; n = 92); exploratory end points were evaluated at week 56. RESULTS: Similar proportions of patients receiving higher induction regimen and standard induction regimen achieved clinical remission at week 4 (44% in both; P = .939) and endoscopic response at week 12 (43% vs 39%, respectively, P = .462). Week 56 efficacy was similar between CA and TDM. Safety profiles were comparable between dosing regimens. CONCLUSIONS: Higher induction regimen was not superior to standard induction regimen, and CA and TDM maintenance strategies were similarly efficacious. Adalimumab therapy was well tolerated, and no new safety concerns were identified. (ClinicalTrials.gov, Number: NCT02065570).

Review article: randomised controlled trials in inflammatory bowel disease-common challenges and potential solutions.

BACKGROUND: Recruitment rates for Crohn's disease and ulcerative colitis clinical trials continue to decrease annually. The inability to reach recruitment targets and complete trials has serious implications for stakeholders in the inflammatory bowel disease (IBD) community. Action is required to ensure patients with an unmet medical need have access to new therapies to improve the management of their IBD. AIMS: Identify challenges contributing to recruitment decline in IBD clinical trials and propose potential solutions. METHODS: PubMed and Google were used to identify literature, regulatory guidelines and conference proceedings related to IBD clinical trials and related concepts. Data on IBD clinical trials conducted between 1989 and 2020 were extracted from the Trialtrove database. RESULTS: Key aspects that may improve recruitment rates were identified. An increasingly patient-centric approach should be taken to study design including improvements to the readability of key trial documentation and inclusion of patient representatives in trial planning. Placebo is unappealing to patients; approaches including platform trials should be explored to minimise placebo exposure. Non-invasive imaging, biomarkers and novel digital endpoints should continue to be examined to reduce the burden on patients. Reducing the administrative burden associated with trials via the use of electronic signatures, for example, may benefit study sites and investigators. Changes implemented to IBD trials during the COVID-19 pandemic provided examples of how trial conduct can be rapidly and constructively adapted. CONCLUSIONS: To improve recruitment in Crohn's disease and ulcerative colitis trials, the IBD community should address a broad range of issues related to clinical trial conduct.

Steroid-Free Deep Remission at One Year Does Not Prevent Crohn's Disease Progression: Long-Term Data From the TAILORIX Trial.

BACKGROUND & AIMS: Crohn's disease (CD) patients included in the Tailored Treatment With Infliximab for Active Crohn's Disease (TAILORIX) trial started infliximab in combination with an immunosuppressant for 1 year. The aim of the present study was to determine the long-term disease course beyond the study period. METHODS: We compared the outcomes of patients who did or did not reach the primary end point of the TAILORIX trial, defined as sustained corticosteroid-free clinical remission from weeks 22 through 54, with no ulcers on ileocolonoscopy at week 54. The primary outcome of this follow-up study was the progression-free survival of CD defined by anal or major abdominal surgery, CD-related hospitalization, or the need for a new systemic CD treatment. RESULTS: The 95 patients (median disease duration, 4.5 mo; interquartile range, 1.0-56.6 mo) analyzed, including 45 (47%) who achieved the primary end point, were followed up for a median duration of 64.2 months (interquartile range, 57.6-69.9 mo) after the end of the study period. There was no significant difference in CD progression-free survival at 1, 3, and 5 years between patients who achieved the TAILORIX primary end point and patients who did not (P = .64). No difference was observed between both groups for each component of CD progression: anal surgery, major abdominal surgery, CD-related hospitalization, or the need for a new systemic CD treatment. CONCLUSIONS: Achieving a sustained clinical remission off steroids with complete endoscopic remission in this cohort of 95 patients with early CD was not associated with less disease progression. Prospective trials to define the therapeutic goals that change the natural history of CD and prevent complications are needed.

Efficacy and Safety of Subcutaneous Vedolizumab in Patients With Moderately to Severely Active Crohn's Disease: Results From the VISIBLE 2 Randomised Trial.

BACKGROUND AND AIMS: To report results from VISIBLE 2, a randomised, double-blind, placebo-controlled, phase 3 trial evaluating a new subcutaneous [SC] vedolizumab formulation as maintenance treatment in adults with moderately to severely active Crohn's disease [CD]. METHODS: Following open-label vedolizumab 300 mg intravenous induction therapy at Weeks 0 and 2, Week 6 clinical responders (≥70-point decrease in CD Activity Index [CDAI] score from baseline) were randomised 2:1 to receive double-blind maintenance vedolizumab 108 mg SC or placebo every 2 weeks until Week 50. Assessments at Week 52 included clinical remission [primary endpoint; CDAI ≤150], enhanced clinical response [≥100-point decrease in CDAI from baseline], corticosteroid-free clinical remission among patients using a corticosteroid at baseline, clinical remission in anti-tumour necrosis factor [anti-TNF]-naïve patients, and safety. RESULTS: Following vedolizumab intravenous induction, 275 patients were randomised to vedolizumab SC and 135 to placebo maintenance. At Week 52, 48.0% of patients receiving vedolizumab SC versus 34.3% receiving placebo were in clinical remission [p = 0.008]. Enhanced clinical response at Week 52 was achieved by 52.0% versus 44.8% of patients receiving vedolizumab SC versus placebo, respectively [p = 0.167]. At Week 52, 45.3% and 18.2% of patients receiving vedolizumab SC and placebo, respectively, were in corticosteroid-free clinical remission, and 48.6% of anti-TNF-naïve patients receiving vedolizumab SC and 42.9% receiving placebo were in clinical remission. Injection site reaction was the only new safety finding observed for vedolizumab SC [2.9%]. CONCLUSIONS: Vedolizumab SC is an effective and safe maintenance therapy in patients with CD who responded to two infusions of vedolizumab intravenous induction therapy.