Ritter, Timothy E.

ImportanceA safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence.ObjectivesTo evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks.Design, Setting, and ParticipantsThis phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry.InterventionsSER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI.Main Outcomes and MeasuresThe main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population.ResultsOf 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]).Conclusions and RelevanceIn this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI.Trial RegistrationClinicalTrials.gov identifier: NCT03183141

INTRODUCTION: Patients with ulcerative colitis (UC) regard rapid onset of action among the most important aspects of their treatment. We used the partial Mayo Clinic Score (pMCS) and component patient-reported subscores to assess the rapidity and sustainability of response to filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, in adults with moderately to severely active UC in the phase 2b/3 SELECTION trial. The association between early symptomatic improvements and health-related quality of life (HRQoL) outcomes was also assessed. METHODS: In these post hoc analyses of the double-blinded, randomized, placebo-controlled 58-week SELECTION trial (NCT02914522), rectal bleeding and stool frequency diary data on days 1–15 and pMCS remission and response at multiple time points including weeks 10 and 58 were evaluated. HRQoL was assessed using the Inflammatory Bowel Disease Questionnaire at weeks 10 and 58. RESULTS: Filgotinib 200 mg relative to placebo improved rectal bleeding and stool frequency within 7 days ( P < 0.05). By week 2, greater proportions of filgotinib 200 mg-treated patients than placebo-treated patients achieved pMCS remission (biologic-naive, 15.1% vs 8.0%, P = 0.0410; biologic-experienced, 10.3% vs 4.2%, P = 0.0274). A similar treatment effect was observed at week 58 ( P < 0.0001). Day 7 rectal bleeding and stool frequency subscores were associated with the Mayo Clinic Score response at weeks 10 and 58. Patients in pMCS remission at weeks 10 and 58 had greater improvements in the Inflammatory Bowel Disease Questionnaire score than those not in pMCS remission. DISCUSSION: Filgotinib 200 mg daily resulted in rapid and sustained improvements in both UC symptoms and HRQoL.

Abstract Background Filgotinib (FIL) is a preferential Janus kinase 1 inhibitor in development for the treatment of inflammatory bowel disease. SELECTION was a phase 2b/3 randomized, double-blind, placebo (PBO)-controlled trial to evaluate FIL for the treatment of moderately to severely active ulcerative colitis (UC) (NCT02914522). The aim of this post hoc analysis was to assess the speed of improvement in patient-reported outcomes (PROs) during FIL treatment. Methods Eligible patients who were biologic-naïve or -experienced were enrolled in induction study A or induction study B, respectively. In each study, patients were randomized 2:2:1 to receive FIL 100 mg, FIL 200 mg or PBO once daily orally for 10 weeks. In this post hoc analysis, data from daily patient diaries up to day 15 of induction, including Mayo stool frequency subscores (SF; range, 0 [normal] to 3 [≥5 stools/day more than normal]) and rectal bleeding subscores (RB; range, 0 [no blood] to 3 [passing blood alone]), were used to evaluate the proportion of patients achieving predefined subscores or subscore reductions. Results Induction studies A and B comprised 659 and 689 patients, respectively. Baseline characteristics were similar across treatment groups within induction study A and within induction study B. In induction study A, more patients treated with FIL 200 mg vs PBO reported a reduction in SF of ≥1 from baseline as early as day 6 (FIL 200 mg, 35.8%; PBO, 20.6%, p&lt;0.01) and every day from day 10 (Figure 1), and a reduction in RB of ≥1 from baseline as early as day 4 (FIL 200 mg, 36.9%; PBO, 23.7%; p&lt;0.01) and every day from day 7 (Figure 2). In induction study B, more patients treated with FIL 200 mg vs PBO reported a reduction in SF of ≥1 from baseline as early as day 2 (FIL 200 mg, 21.6%; PBO, 12.1%; p&lt;0.05) (Figure 3) and a reduction in RB of ≥1 from baseline as early as day 3 (FIL 200 mg, 29.5%; PBO, 17.6%; p&lt;0.01) (Figure 4). More patients receiving FIL 200 mg vs PBO achieved the composite score of RB=0 and SF≤1 as early as day 9 in induction study A (FIL 200 mg, 18.8%; PBO, 9.5%, p&lt;0.05). More patients receiving FIL 200 mg vs PBO achieved the composite score of RB=0 and SF≤1 as early as day 7 in induction study B (FIL 200 mg, 10.7%; PBO, 4.2%, p&lt;0.05). Conclusion In this post hoc analysis of induction study data from SELECTION, improvements in SF and RB were observed within the first week of therapy with FIL 200 mg, compared with PBO, in patients with moderately to severely active UC. These data demonstrate that FIL 200 mg has rapid onset of action, as assessed by PROs, in both biologic-naïve and biologic-experienced patients.

Abstract Electronic medical records (EMRs) have gained widespread use in clinical practice and by default serve as a large patient database with potential for use in clinical research. Although there remains significant interest in leveraging EMRs for research purposes, extraction of data has proven to be complex and with insufficient accuracy. We describe the limitations of an EMR in our attempt to conduct a seemingly simple study aimed at validating variables identified in the PRECiSE 3, a 7-year open label safety and efficacy study of certolizumab pegol in Crohn’s disease that identified clinical factors that predicted both short- and long-term efficacy. A multicenter, retrospective cohort study from 8 academic and large community practices was performed, and data were collected from each respective EMR. Significant challenges with reliable capture of key data elements were encountered, and overall a screen fail rate of 91.8% across all sites was seen. We describe these challenges and potential future directions to work together to advance accuracy and implementation of the use of EMRs in inflammatory bowel disease.