Society: DDW

Background: Gut dysbiosis is associated with persistent multi-system symptoms following SARS-CoV-2 infection, or post-acute COVID-19 syndrome (PACS). We performed a randomised controlled trial to assess the effects of gut microbiome modulation on alleviation of PACS symptoms.

Methods: This is a single-centre, triple-blind, randomised, placebo-controlled study in recovered COVID-19 patients who reported persistent PACS symptoms. Eligible subjects were randomly assigned at 1:1 ratio to receive either a novel oral microbiome immunity formula (SIM01, synbiotic) or placebo orally for 6 months. The primary outcome was the alleviation of PACS symptoms by month 6 as compared to baseline, assessed by a structured 14-item symptom questionnaire. Chi-squared test was used to evaluate the association between intervention and symptom alleviation. The secondary outcome was the reduction of gastrointestinal symptoms severity, evaluated by a self-report scale from 1 to 4 (1=none, 4=severe). Wilcoxon signed-rank test was used to compare the changes in severity scores between baseline and month 6. Bonferroni correction was applied to adjust for multiple comparisons of symptoms.

Results: A total of 463 subjects (mean age 49.4 ± 13.4 years, 65.4% female) were randomised at a median duration of 4 (IQR: 3-11) months since COVID-19 diagnosis. All subjects had at least one of 14 common symptoms of PACS at randomisation and were included in the intention-to-treat analysis. A significantly higher proportion of subjects who received SIM01 had improvements in fatigue (62.8% vs 42.6%, p<0.001), memory loss (42.0% vs 26.9%, p=0.002), difficulty in concentration (62.3% vs 38.5%, p<0.001), digestive problems (70.2% vs 54.1%, p=0.001), and general unwellness (77.3% vs 59.0%, p=0.001) by 6 months compared with the placebo group, after adjusting for multiple comparisons. Amongst 134 subjects who reported improvement in digestive problems after SIM01 intervention, we found significant reductions in severity score for 7 out of 8 gastrointestinal symptoms assessed, including diarrhoea (p<0.001), constipation (p<0.001), abdominal pain (p=0.003), epigastric pain (p<0.001), bloating (p<0.001), vomiting (p=0.005) and acid reflux (p<0.001), following Bonferroni correction.

Conclusion: This is the first randomised controlled trial showing that modulation of gut microbiome with a novel oral microbiome formula (SIM01) alleviates gastrointestinal and neuropsychiatric symptoms of PACS.

This study was funded by the Health and Medical Research Fund under the Food and Health Bureau of the Government of the Hong Kong Special Administrative Region, and Hui Hoy & Chow Sin Lan Charity Fund Limited. The authors are partially supported by InnoHK, the Government of the HKSAR.

INTRODUCTION
The QUASAR Phase 3 Induction Study (NCT04033445) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of guselkumab (GUS), an interleukin-23 p19 subunit antagonist, as induction therapy in patients with moderately to severely active ulcerative colitis (UC) who had an inadequate response or intolerance to conventional (i.e., thiopurines or corticosteroids) and/or advanced therapies (i.e., tumor necrosis factor alpha antagonists, vedolizumab, or tofacitinib).

METHODS
The primary analysis population included patients with a baseline modified Mayo score of 5 to 9, inclusive, a rectal bleeding subscore ≥ 1, and an endoscopy subscore ≥ 2 evaluated during central review of video endoscopy. Patients were randomized 3:2 to receive IV GUS 200mg or placebo (PBO) at Weeks (Wks) 0, 4, and 8.

The primary endpoint was clinical remission at Wk 12. Symptomatic remission, clinical response, endoscopic improvement, histo-endoscopic mucosal improvement, endoscopic normalization, and safety were also assessed.

RESULTS
Seven hundred one patients were randomized and included in the primary analysis population (mean age, 40.5yrs; female, 43.1%; mean UC duration, 7.5yrs; mean modified Mayo score, 6.9; Mayo endoscopy subscore of 3 indicating severe disease, 67.9%; median fecal calprotectin, 1641.0mg/kg; median C-reactive protein, 4.2mg/L; baseline oral corticosteroid use, 43.1%). Baseline demographic and disease characteristics were balanced across the two treatment groups. Approximately 50% had a prior failure to advanced therapies for UC, and nearly half (47.4%) of these patients failed two or more advanced therapy classes.

A significantly greater proportion of patients treated with GUS compared with PBO achieved clinical remission at Wk 12 (22.6% vs 7.9%, adjusted Δ=14.9%, p<0.001). Relative to PBO, GUS induction treatment resulted in significantly greater proportions of patients achieving symptomatic remission, clinical response, endoscopic improvement, and histo-endoscopic mucosal improvement at Wk 12 and symptomatic remission at Wk 4 (Figure 1).

The frequencies of treatment-emergent adverse events (AEs) in the GUS group were generally similar to PBO (Table 1). There were numerically fewer serious AEs (2.9% vs 7.1%) and AEs leading to discontinuation (1.7% vs 3.9%) in GUS-treated patients compared to PBO. No AEs within 1 hour of infusion were considered serious or resulted in treatment discontinuation.

CONCLUSIONS
In this Phase 3 study, GUS 200mg IV induction was safe and effective in the treatment of patients with moderately to severely active UC compared to PBO with clinically meaningful improvements demonstrated across symptomatic and histo-endoscopic outcome measures. Overall, safety results through Wk 12 were consistent with the known and favorable safety profile of GUS in approved indications.

Figure 1. Primary and key secondary endpoints

Figure 1. Primary and key secondary endpoints

Table 1. Overall summary of treatment-emergent adverse events through Wk 12

Table 1. Overall summary of treatment-emergent adverse events through Wk 12

Background: Endoscopic treatment is the preferred approach for management of infected necrotizing pancreatitis. While transluminal stent placement followed by performance of direct endoscopic necrosectomy when there is no clinical improvement is a commonly practiced interventional strategy, the optimal timing to perform endoscopic debridement is unclear. We compared outcomes between direct endoscopic necrosectomy at index session vs. step-up approach for patients with infected necrotizing pancreatitis.
Methods: We conducted a multicenter, randomized trial of 70 patients with confirmed or suspected infected necrotizing pancreatitis who required intervention from November 2019 to October 2022. Patients were randomly assigned to groups that received direct endoscopic necrosectomy at index treatment session after lumen-apposing metal stent placement (n=37) or a step-up approach whereby necrosectomy was performed only if there was no clinical improvement after stent placement (n=33). The primary endpoint was number of reinterventions performed to achieve treatment success, which was defined as symptom relief in conjunction with disease resolution on computed tomography at 6 months.
Results: The mean number of reinterventions required was significantly lower in patients who received direct endoscopic necrosectomy at index session at 0.9 (SD 0.9), compared to 2.5 (SD 2.6) in patients who received step-up treatment approach (p=0.001). While overall length of hospital stay was significantly shorter in the direct endoscopic necrosectomy group (median 9 days [IQR 7-20] vs. 19 days [IQR 9-33], p=0.048), there was no significant difference in treatment success (94.6 vs. 90.9%, p=0.66), mortality (0 vs. 6.1%, p=0.22), adverse events (45.9 vs. 60.6%, p=0.22) and mean number of readmissions (0.8 [SD 1.0] vs. 0.8 [SD 0.9], p=0.93), between patients who received direct endoscopic necrosectomy at index session and the step-up treatment group, respectively.
Conclusions: Direct endoscopic necrosectomy at index session for infected necrotizing pancreatitis, compared with step-up approach, significantly reduced number of reinterventions to achieve treatment success and decreased length of hospital stay.

Introduction: Colorectal cancer (CRC) incidence and mortality have increased in young adults in the United States, prompting several new guidelines that promote screening individuals starting at age 45. Effective population health strategies to screen these individuals have not yet been established. Thus, we aimed to determine effective outreach strategies to maximize screening participation among patients aged 45-49 in a diverse health system.
Methods: The study setting is a large, urban, tertiary academic health system with >3.5 million annual outpatient clinic visits. All health system patients between the ages 45-49, at average risk for CRC, and assigned to a primary care provider were included. Patients were randomized to one of four screening strategies: 1) fecal immunochemical test (FIT) invitation (option to request mailed FIT); 2) colonoscopy invitation (option to request colonoscopy); 3) choice between FIT and colonoscopy; or 4) mailed FIT outreach (standard of care). All invitations were sent to patients via the electronic patient portal (activated for 83% of patients aged 45-75) and via USPS mail. All patients received one initial text message and one reminder text message two weeks later. The primary outcome was completion of any CRC screening at 26 weeks.
Results: There were 20,509 patients randomized; 53.9% were female, 50.8% were non-Hispanic White, and mean age was 47.8 yrs (SD:1.5 yrs) (Table). The overall screening completion rate was 18.6%. Screening completion was significantly higher in the mailed FIT outreach group (26.2%) than in the other three groups in which patients were required to opt into a screening modality (Figure; p<0.001). Participation was lowest in the colonoscopy invitation group (14.5%) (Figure). Patients offered a choice between FIT and colonoscopy (group 3) were more likely to complete screening of any kind, compared to patients who were offered only one screening modality (group 1 or group 2) (17.4% v. 15.4%; p=0.002). Overall, colonoscopy was more common than FIT (11.1% v. 8.1%; p<0.001). In fact, patients given a choice between FIT and colonoscopy (group 3) were more likely to complete colonoscopy than FIT (12.1% v. 5.6%; p<0.001). Among patients randomized to FIT invitation (group 1) or mailed FIT outreach (group 4), there was also notable conversion to colonoscopy (10.0% and 10.2%).
Conclusion: We conducted a large, randomized trial to determine the most effective population health approach to screen patients aged 45-49 for CRC. Mailing patients a FIT kit resulted in higher screening participation than offering a choice between FIT and colonoscopy, offering FIT alone, or offering colonoscopy alone. Requiring patients to opt into a screening modality appeared to decrease participation. These findings provide important insight for future population health strategies for young adults at average-risk for CRC.

<b>* </b>indicates p<0.01 compared to FIT in group 4<br /> <b>‡</b> indicates p<0.01 compared to colonoscopy in group 4<br /> <b>§</b> indicates p<0.01 compared to any screening modality in group 4

* indicates p<0.01 compared to FIT in group 4
‡ indicates p<0.01 compared to colonoscopy in group 4
§ indicates p<0.01 compared to any screening modality in group 4

Background: Colorectal cancer (CRC) screening rates for average-risk individuals remain sub-optimal due to poor adherence with the currently available strategies. A blood-based test with performance comparable to available options may dramatically improve screening adherence. We evaluated the performance of a cell-free DNA (cfDNA) blood-based CRC screening test in an average-risk population.

Methods: ECLIPSE (NCT#04136002) recruited individuals at average-risk for CRC, > 45 years old, presenting for screening colonoscopy, from 265 U.S. clinical sites between October 2019–September 2022. Consented individuals provided a whole blood sample prior to initiation of colonoscopy bowel preparation. Colonoscopy outcomes were classified based on the most advanced lesion: CRC, advanced precancerous lesion (APL; including sessile serrated lesions > 10mm and conventional advanced adenomas), non-APL, negative/no precancerous lesion, or incomplete procedure. Blood samples were analyzed (Shield, Guardant Health, USA) blinded to the patient outcomes. Co-primary objectives were sensitivity for CRC detection and specificity for the absence of CRC or APL, as compared to the reference colonoscopy. The secondary objective included APL sensitivity.

Results: The clinical validation cohort included 10,258 unique individuals. 7,861 individuals met all eligibility criteria and were evaluable; mean age 60 years (range 45-84); 54% female; 7% Asian, 12% Black/African-American, 79% white, 2% other; 12% Hispanic/Latino. Sensitivity for CRC detection was 83% (54/65, 95% CI 72–90%) meeting the co-primary sensitivity endpoint (lower bound of 95% CI > 65%). Sensitivity for cancers with full staging information available was 92% (48/52). Sensitivity in Stage I – III CRC was 90% (38/42) and was 100% in Stage IV CRC (10/10). Specificity for the absence of CRC or APL was 90% (5,982/6,680; 95% CI 89–90%) meeting the co-primary specificity endpoint (lower bound of 95% CI > 85%). Specificity for negative/no precancerous lesions was 90% (4,057/4,514; 95% CI 89–91%). Sensitivity for detection of APL was 13% (147/1,116; 95% CI 11-15%).

Conclusions: This blood-based test demonstrated 83% sensitivity for the detection of CRC and 90% specificity in an average risk screening population, performance metrics which are comparable to those of currently available non-invasive screening options. Adherence adjusted sensitivity (effective sensitivity) for a blood-based testing strategy is predicted to be much higher than current CRC screening strategies (Table 1), indicating the potential for this test to significantly improve adherence to CRC screening.

Table 1: Adherence adjusted sensitivity (effective sensitivity) for CRC screening strategies

Table 1: Adherence adjusted sensitivity (effective sensitivity) for CRC screening strategies

Frank Sinicrope

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