Contemporary Clinical Trials Communications

Background. Anaerostipes caccae CLB101TM is a next-generation probiotic that directly produces butyrate and is hypothesized to reduce gastrointestinal symptoms by strengthening intestinal barrier integrity. Clinical evidence for A. caccae in symptomatic adult populations remains limited. Methods. Ninety-three adults were randomized 1:1 to CLB101TM ( n=47) or placebo (n=46) for 28 days. The primary outcome was safety and tolerability as assessed by the number, frequency, and severity of adverse events. Secondary outcomes were focused on exploring signals of efficacy, and included change in the Gastrointestinal Symptom Rating Scale (GSRS) composite score from baseline to Week 4. Five GSRS subcategories were additionally evaluated. Exploratory endpoints included daily self-reported GI symptoms, as well as stool and blood measures of intestinal barrier function. Results. 71 participants were evaluated for the GSRS (77.5% female, aged 42.1 SD 12 years, BMI mean 31.3 SD 3.6). No adverse events were reported in the placebo arm, while three self-limiting adverse events were associated with CLB101TM administration. CLB101TM reduced GI symptom burden versus placebo on the primary GSRS composite at Week 4 (mean change: -1.60 vs -0.90; MWU p=0.040). Two secondary subscales reached significance after FDR-BH correction: Reflux (mean change: -1.26 vs -0.30; FDR-adjusted p=0.024) and Abdominal Pain (mean change: -1.86 vs -0.83; FDR-adjusted p=0.024). Daily symptom diaries showed trends toward greater reductions in abdominal discomfort, bloating, and flatulence in the active arm at the end of study. This study population did not demonstrate signs of intestinal barrier dysfunction. Product adherence averaged 97.7%. Conclusions. CLB101TM was safe and tolerable and significantly improved overall GI symptom burden, reflux, and abdominal pain after four weeks of daily supplementation in overweight symptomatic adults. Trial Registration. The trial was approved by Sterling IRB (14583-NACraft) and registered with ClinicalTrials.gov (NCT07336615).

Background Optimal timing for resuming direct oral anticoagulants (DOACs) after high-risk endoscopic procedures remains uncertain, and existing recommendations derive largely from expert opinion. The objective of this study was to characterize practice patterns and perceptions among endoscopists and outcome prioritization among patients with atrial fibrillation, in order to inform the design of the planned RESUME randomized trial. Methods We conducted parallel, cross-sectional surveys of practicing endoscopists and patients with atrial fibrillation using electronic questionnaires administered via Qualtrics. The endoscopist survey, distributed through the American Society for Gastrointestinal Endoscopy, assessed practice patterns, acceptability of early (postoperative day [POD] +1), intermediate (POD +3), and late (POD +5) resumption strategies, and perceptions of clinical equipoise. The patient survey, distributed through two advocacy organizations, assessed perceived confidence in existing guidance and prioritization of bleeding versus thromboembolic risk. Results A total of 201 endoscopists and 477 patients (92.5% taking a DOAC) provided evaluable responses. Endoscopists demonstrated wide variability in preferred timing of DOAC resumption after a standardized high-risk mucosal resection vignette, ranging from same-day resumption to delays beyond five days. POD +2 was the most commonly selected strategy, and most respondents rated more than one proposed RESUME trial arm as acceptable. Nearly all endoscopists (98.9%) rated a randomized trial to determine optimal timing as important. Patient preferences regarding bleeding versus stroke risk were heterogeneous and symmetrically distributed around the neutral response on a five-point ordinal scale. Preferences did not differ by prior stroke or transient ischemic attack, prior major bleeding, age, sex, or geographic region. More than half of patients (54.6%) reported being very or somewhat confident that clear guidance exists regarding DOAC resumption, despite the absence of high-quality randomized evidence informing this question. Conclusions Endoscopists demonstrate substantial practice variability and clinical equipoise, and patients demonstrate heterogeneous and balanced outcome preferences, regarding the timing of DOAC resumption after high-risk endoscopy. These findings support the ethical justification and relevance of the planned RESUME trial.

Background: Functional dyspepsia (FD) is among the most common gastrointestinal disorders worldwide and is characterized by symptoms including epigastric pain, early satiety, postprandial fullness, bloating, and upper abdominal discomfort. Itopride hydrochloride is commonly administered as 50 mg three times daily (TID). To improve convenience and potentially enhance adherence, a once-daily (OD) 150 mg extended-release formulation was developed. Phase 1 studies demonstrated bioequivalent overall exposure between the OD and TID regimens, with sustained-release characteristics and no evidence of dose dumping, supporting advancement to Phase 3. This pivotal clinical study evaluated whether itopride hydrochloride 150 mg OD is non-inferior to the established 50 mg TID regimen in improving FD symptoms over 8 weeks. Methods: This Phase 3, randomized, open-label, multicenter, active-controlled study enrolled 564 participants with FD (or chronic gastritis) to compare the efficacy and safety of itopride hydrochloride 150 mg OD versus 50 mg TID over 8 weeks. The primary endpoint was change in overall FD severity from baseline to Week 8, assessed using the Leeds Dyspepsia Questionnaire (LDQ) severity score. Secondary endpoints included symptom-specific severity, disease-specific quality of life, responder rates, treatment acceptance, and safety. Results: Clinical non-inferiority in terms of overall FD severity was demonstrated with OD treatment compared to TID. LDQ severity improved by -9.60 (95% CI -10.15, -9.05) with TID and -9.76 (95% CI -10.32, -9.19) with OD, with a between-group difference of 0.16 (95% CI -0.42, 0.74). Improvements across symptom domains and quality of life measures were comparable. Treatment acceptance favored OD (mean 4.22 vs 3.83; p < 0.001). Both regimens were well tolerated, with predominantly mild adverse events. This clinical evaluation of OD was supported by the Phase 1 results confirming that both single-dose and multiple-dose administration of itopride hydrochloride 150 mg OD provided a comparable extent of exposure to the 50 mg TID regimen, demonstrated by area under the curve (AUC) values within the 80 to125% bioequivalence range and stable pharmacokinetic profiles across fed and fasted conditions. Conclusion: The study confirmed that itopride hydrochloride 150 mg OD is non-inferior to the TID regimen for improving FD (or chronic gastritis) symptoms. The OD regimen demonstrated comparable efficacy, favorable treatment acceptance, and a positive benefit-risk profile, offering a more convenient therapeutic option for patients.

Background. Tandem colonoscopy meta-analyses estimate adenoma miss rates, which have been used as a proxy for colonoscopy sensitivity. Doing so overstates sensitivity because it ignores lesions missed by both exams. Methods. We introduce Bayesian and frequentist approaches to estimate white-light colonoscopy (WLC) sensitivity from tandem colonoscopy meta-analyses. Neither approach assumes that the second colonoscopy is perfect. We apply both approaches to reanalyze data from a recent tandem colonoscopy meta-analysis, overall and across ten subgroups. Sensitivity analyses assess how assumptions about the relative performance of enhanced colonoscopy versus WLC affect estimates. Results. Under our Baseline specification, overall WLC sensitivity estimated by the Bayesian model was 0.54 [0.41, 0.63] (posterior mean and 95% credible interval). Sensitivity rose with lesion size: 0.49 [0.35, 0.60] for 1-5 mm adenomas, 0.64 [0.43, 0.78] for 6-9 mm adenomas and 0.84 [0.70, 0.93] for lesions 10 mm or larger. The frequentist plausible range encompassed the Bayesian estimate. The model-implied miss rate (0.35 [0.30, 0.40]) matched the original meta-analysis estimate and was stable across prior specifications. Assuming enhanced colonoscopy was perfect overstated overall sensitivity by 0.12 [0.06, 0.20]. Limitations. Tandem colonoscopy data identify the miss rate but not WLC sensitivity, so estimates depend on an external assumption about the relative performance of enhanced colonoscopy versus WLC. As a result, WLC sensitivity estimates varied with the prior specification, especially for small and flat adenomas. Conclusions. WLC sensitivity may be meaningfully lower than previously assumed in CRC screening cost-effectiveness analyses. Modelers should use colonoscopy sensitivity estimates that do not assume a second colonoscopy exam is perfect.

Background: Real-world evidence on food-as-medicine programs for irritable bowel syndrome (IBS) is scarce, and single-arm evaluations overstate improvement because of regression to the mean (RTM). We estimated change in the IBS Symptom Severity Scale (IBS-SSS, 0-500) in a multi-omics personalized digital health food-as-medicine program, unadjusted and RTM-corrected. Methods: Retrospective single-arm cohort. Of 15,933 members with a valid baseline, 2,254 had a follow-up reading and 1,683 one at least 14 days after baseline. Change at 4, 12 (primary) and 26 weeks was estimated by baseline severity stratum, unadjusted and RTM-corrected by analysis of covariance. A responder fell by at least 50 points (the minimal clinically important difference benchmark). Sensitivity analyses covered equity, inverse-probability weighting and tipping-point analyses for members without a reading in each landmark window, a negative-control stratum and medication. The association of weight loss and dietary nutrient density with symptom change was evaluated within and between members. Results: At 12 weeks (n = 430) IBS-SSS fell by 43.88 points unadjusted (95% confidence interval [CI] -52.44 to -35.32; p < 0.001) and by 47.73 RTM-corrected (-55.48 to -39.98; p < 0.001); 720 of 1,339 symptomatic members (53.8%; 95% CI 51.1 to 56.4) fell by at least 50 points. Larger improvement in more severe members persisted after RTM correction (severe stratum, n = 37: unadjusted -127.43, RTM-corrected -60.71, 95% CI -97.75 to -23.68, p = 0.001). A higher meal nutrient density was associated with lower IBS-SSS within a member's own trajectory (p = 0.018) while weight change was not (p = 0.361). Improvement was similar across groups in spite of baseline differences by age and sex: RTM-corrected 12-week change did not differ by age (p = 0.458), body-mass index (p = 0.328), sex (p = 0.749), income (p = 0.486) or ethnicity (p = 0.170). Estimates were robust to weighting for members without a reading in the landmark window (RTM-corrected estimates moved by less than 2 points), and the change of those members would have had to be 39 to 73 points worse than observed before the mean change reached zero. Baseline medication use and starting a GLP-1 receptor agonist did not explain symptom changes. Conclusions: IBS-SSS fell significantly among program participants, with steeper improvement in the more severe group, even after RTM correction. The improvement was comparable across socioeconomic characteristics, age and sex and robust to the confounders and missing-data assumptions evaluated. These associations from a self-selected single-arm cohort warrant replication in independent studies.

Objectives: To evaluate change in physical function and probable sarcopenia following a 36-week community multicomponent exercise programme (Vivifrail model) across two consecutive cycles, and to assess the consistency of this change between cohorts. Study design: Quasi-experimental, single-arm, repeated-measures service evaluation. Ninety-two older adults (2025-2026 cohort; mean age 75.9 years, 88.0% women) completed baseline and post-intervention assessments; an independent 2024-2025 cohort (n = 86) was analysed jointly for replication (n = 178). Main outcome measures: Short Physical Performance Battery (SPPB) score (primary); Timed Up and Go (TUG), handgrip strength, 6-metre walk time and Mini-Mental State Examination (MMSE) (secondary); probable sarcopenia (EWGSOP2), SPPB-based frailty category, and a fall-risk indicator computed identically in both cohorts. Results: SPPB improved by a mean of 1.33 points (Cohen's d = 0.96; p < .001), with concordant improvement in all four secondary outcomes (all q < .005). 72.8% reached the substantial minimal clinically important difference. Probable sarcopenia fell from 17.4% to 5.4% (p = .006), and frailty category shifted toward higher functional levels (p < .001). Effect sizes were consistent between cohorts for SPPB, handgrip and 6-metre walk; the Time x Cohort interaction was significant for TUG only. In the pooled sample, elevated fall risk fell from 19.7% to 11.2% (p = .002). Conclusions: A 36-week multicomponent exercise programme was associated with clinically meaningful, reproducible improvement in physical function and a reduction in probable sarcopenia across two independent cohorts. The single-arm design precludes causal inference.

Importance: The ASPREE randomized trial found no overall benefit of low-dose aspirin for disability-free survival among older adults. However, individual estimates in pre-specified subgroups indicated potential benefit among racial and ethnic minoritized participants in the United States (US). Objective: To evaluate whether the effect of low-dose aspirin vs placebo on disability-free survival differed across US Black and Hispanic ASPREE participants using individualized treatment-effect estimation. Design, Setting, and Participants: Post hoc clinical trial analysis of ASPREE, a randomized, double-blind, placebo-controlled clinical trial of daily low-dose aspirin vs placebo. This analysis included US ASPREE participants who self-identified as non-Hispanic Black or Hispanic, were aged 65 years or older, and had complete baseline predictor and outcome data. Interventions: Randomization to daily 100-mg aspirin or placebo. Main Outcomes and Measures: The primary outcome was loss of disability-free survival, defined as death, persistent physical disability, or dementia. Individualized treatment effects were estimated post hoc using a Random Survival Forest X-learner. Heterogeneity was evaluated on the relative scale with Cox proportional hazards models and on the absolute scale with 5-year risk differences. Results: Among 2411 US ASPREE participants, 1270 were included in the Black and Hispanic analytic cohort (897 non-Hispanic Black and 373 Hispanic participants; mean age, 71.8 years). Aspirin was associated with lower risk of disability-free survival loss compared with placebo (hazard ratio [HR], 0.65; 95% CI, 0.45-0.93). In model-derived tertiles, aspirin was associated with lower risk in the greatest predicted-benefit group (HR, 0.36; 95% CI, 0.19-0.71; 5-year absolute risk difference [ARD], -11.1 percentage points; 95% CI, -22.0 to -0.1) but not in the lowest predicted-benefit group (HR, 1.26; 95% CI, 0.70-2.27; ARD, +3.9 percentage points; 95% CI, -5.9 to 13.6). Conclusions and Relevance: In these analyses of US Black and Hispanic ASPREE participants, aspirin effects on disability-free survival appear to be heterogeneous, with benefit concentrated in a subset of participants. Because these findings are from post-hoc models, they should be externally validated before being incorporated into clinical decision-making. Trial Registration: ClinicalTrials.gov Identifier: NCT01038583; https://clinicaltrials.gov/study/NCT01038583

Background: Recruitment of diverse participants remains a challenge in cardiovascular clinical trials. Little is known about how recruitment efficiency and advertising costs with web-based tools vary across US communities. We evaluated an online recruitment platform and examined the cost of acquiring both all-comers and diverse participants in relation to community-level income. Methods: The Heartbeat Study evaluated a digital recruitment strategy to identify US participants for the ongoing Phase 3 LIBREXIA-AF trial. Online advertisements directed individuals with atrial fibrillation to a pre-screening website, where demographic and health data were collected. Advertising impressions, clicks, and costs were recorded. Participant ZIP codes were linked to Core Based Statistical Areas (CBSAs) and CBSA-level income. We measured recruits from underrepresented groups (women, African Americans, Latinos) completing online registration per $100,000 in advertising expenses. Click-weighted linear regression evaluated associations between CBSA income and advertising efficiency. Results: A total of 1,406 recruits completed online registration, with 1,319 participants from 260 CBSAs included in the geographic analysis. Participants were 73 years old on average; 547 (41.5%) were women, 59 (4.5%) African American, and 44 (3.3%) Latino. A total of $163,949.13 was spent on 82,681,711 impressions and 454,750 clicks. Recruits per $100,000 in advertising spend were 334 for women, 36 for African Americans, and 27 for Latinos. CBSA-level income was modestly inversely associated with cost per impression (R2=0.058; p<0.001) and cost per click (R2=0.038; p=0.005), but not recruitment yield for African Americans (p=0.99), Latinos (p=0.37), or women (p=0.21) (R2 range, 0.000-0.13). Conclusions: In this national analysis, online advertising enabled broad engagement across diverse US communities, but income was not associated with recruitment yield among women, African American, or Latino participants. Minority representation remained limited, suggesting digital recruitment alone may be insufficient to improve trial diversity. Targeted, culturally and linguistically tailored strategies may be needed to enhance diverse recruitment.

Background: Systematic reviews are critical for informing evidence-based medicine, policy, and future research. However, conducting a systematic review is labour- and cost-intensive and error-prone. Elicit is an AI tool that claims to replicate the systematic review process. Methods: Our study investigated Elicit's ability to replicate a systematic review by comparing its results with those of an existing systematic review recently published by our research group. We calculated accuracy, precision, sensitivity, error rate, and person-time savings at each stage of the systematic review. Results: At search, Elicit had poor overlap, finding 158 of the 5285 studies. For abstract and full-text screening, Elicit had moderate sensitivity and accuracy but poor precision, with a skew toward false positives. Elicit's data extraction tool was promising, with sentence-specific citations, and provided helpful information for 85% of values even when it did not find exact matches. Elicit offered person-time savings, taking 3.16 hours to complete the full systematic review process. Conclusions: Elicit shows promise as an adjunct screening and extraction AI tool, but in its current form, it is not ready as a standalone tool to replace the systematic review process.

Background. Long COVID affects an estimated 400 million people worldwide, and is associated with low quality of life. Nearly all completed Long COVID clinical trials reported no benefit, and most required participants to travel to study sites. This requirement systematically excludes severely affected patients. Because there are numerous candidate therapeutics with established safety profiles and regulatory approvals for other indications, scaled, efficient evaluation of therapeutics is needed. Methods. We designed and are conducting a double-blind, placebo-controlled, phase two trial of tirzepatide for Long COVID fatigue, using an entirely remote infrastructure. Design elements included electronic consent, identity and diagnosis verification through document upload, cold-chain delivery of an injectable study drug through a central pharmacy, shared decision-making for dose titration, repeated at-home capillary blood collection in a biospecimen subcohort, weekly participant touch points through study application, wrist-worn wearable monitoring, and clinical support. The trial is operating under FDA Investigational New Drug authorization. Results. This trial enrolled 1,058 participants in 73 days, at least double the rate of any other Long COVID trial. Mean baseline metrics include mean Fatigue Severity Scale of 59.3 (standard deviation [SD] 4.9), daily step count of 3,611 (SD 2,706, general population reference mean 7,731), EQ-5D-5L of 0.6 (SD 0.2), and FUNCAP27 4.0 (SD 1.0), which was a more severely affected population than other clinical trials that collected comparable data. Study processes are working as designed. Participants use existing advocacy and support channels to gather and communicate. Conclusions. A direct-to-participant, siteless infrastructure can support a double-blind placebo-controlled trial of an injectable drug at scale, accelerate accrual, and reach severely affected participants who are routinely excluded by site-based designs. Modernizing drug distribution and regulatory pathways is needed to realize the full potential of decentralized infrastructure for drug repurposing clinical trials.

Background: Fear of falling may limit mobility in older adults, particularly during winter. Pragmatic, community-based interventions are needed to support safe, sustainable walking. Objective: To assess the feasibility and acceptability of a co-created intervention (MABIDA) promoting utilitarian and recreational walking among older adults. Method: Fifty-two older adults with fear of falling participated in a 12-week group intervention (summer/winter) consisting of one 60-minute supervised walking session/week, incorporating exercises. Walking group level was assessed using a subjective decisional tree. Results: Forty-one participants (73.3{+/-}5.7years) completed the study (dropout: winter only). Retention and adherence exceeded 75%. Intervention settings were considered appropriate ([&ge;]81%). The decisional tree correctly classified 72% of participants. Participants reported satisfaction (82%) and enjoyment (81%). No differences were observed between seasons or walking groups (p>0.05). Group walking was the main facilitator (59%), while weather was the main barrier (17%). Conclusion: MABIDA appears feasible, acceptable, and adapted across seasons and walking speed profiles.

Background: The optimal P2Y12 inhibitor after percutaneous coronary intervention (PCI) remains debated. A recent frequentist network meta-analysis (NMA) concluded prasugrel provided optimal efficacy-safety balance. We update our previous Bayesian NMA with recent trials and contrast our findings with the frequentist NMA. Methods: We extended our 2023 systematic review by adding two trials published after our search cutoff. The primary efficacy endpoint was a composite of all-cause mortality, a recurrent non-fatal myocardial infarction, or non-fatal stroke (MACE). The primary safety endpoint was study-reported major bleeding events. Bayesian network meta-analysis with a primary binomial complementary log-log model with log(time) offset and random effects was performed. A statistical workflow with prior and posterior predictive checks, convergence diagnostics, model comparisons, sensitivity analyses and probabilities for a range of practical equivalence (ROPE: HR 0.90-1.11) are also reported. Results: 19 RCTs (n = 60,619) were identified. For MACE, prasugrel's probability of a clinical efficacy benefit (hazard ratio (HR) <0.9) was 70% compared to clopidogrel (HR 0.87, 95% credible interval (CrI )0.76-1.03) and 54% compared to ticagrelor. (HR 0.89, 95% CrI 0.73-1.12). For the ticagrelor versus clopidogrel comparison 76% of the posterior probability (HR 0.98, 95%CrI 0.82-1.18) lies in the ROPE. Ticagrelor (HR 1.26, 95%CrI 1.01-1.63) and prasugrel (HR 1.1, 95%CrI 0.88-1.26) showed 86% and 51% probabilities respectively of meaningful bleeding harm (HR > 1.1) versus clopidogrel. Conclusions: Despite 19 RCTs and approximately 60,000 patients, the Bayesian framework revealed clinically important uncertainties and identified probable regions of equivalence among the different P2Y12 inhibitors that were under appreciated with the previous frequentist publication.

Background: Non-pharmacological interventions may enhance motor-cognitive integration in prodromal Alzheimer's disease (pAD). Partnered Rhythmic Rehabilitation (PRR), an adapted dance-based intervention, is designed to engage the motor, cognitive, and social domains. However, no randomized trial has evaluated its feasibility or efficacy in pAD. This study evaluated the feasibility, safety, and preliminary efficacy of PRR compared to group walking (WALK) in adults with pAD and amnestic mild cognitive impairment (aMCI). Methods: In this single-blind, randomized controlled pilot trial (NCT04029623), 68 adults with pAD and aMCI were randomized to PRR or WALK. Prespecified feasibility criteria were attrition [&le;]15% and no injurious falls during interventions. Preliminary efficacy was examined on the primary outcome, the Four-Square Step Test (FSST). Secondary cognitive, motor, and psychosocial outcomes were also assessed to inform future definitive trials. Several modifications were made to the original protocol to ensure compliance with safety measures associated with the COVID-19 pandemic. Results: Attrition in the PRR group (15.2%) did not significantly exceed the prespecified threshold (P = .848), and 0 injurious falls were reported during the supervised sessions, meeting both feasibility and safety criteria. No significant group-by-time interactions were observed for FSST, but significant group-by-time interactions favoring PRR were identified for Timed Up-and-Go (TUG; P = .021) and jump distance (P = .014). Conclusion: PRR was feasible and safe in adults with aMCI consistent with pAD but did not meet the prespecified efficacy endpoint on FSST. Our results showed that TUG and standing board jump distance may serve as potential outcomes in future definitive trials.

Background/Objectives Tooth loss may impair masticatory function, potentially affecting gastrointestinal health. This study examined the association between clinically examined tooth loss and abnormal bowel habits among US adults. Methods This cross-sectional study used NHANES 2005-2010 data. Adults aged [&ge;]20 with clinical oral examination (OHX) and Bristol Stool Scale (BSS) data were included. Missing teeth (0-28) were categorized as 0, 1-5, 6-10, 11-27, and 28. The primary outcome was abnormal bowel habits (BSS 1-2 or 6-7 vs. 3-5); secondary outcomes included constipation, diarrhea, and fecal incontinence symptoms. Survey-weighted logistic regression with progressive covariate adjustment was used, with Benjamini-Hochberg FDR correction for secondary outcomes. Results Among 9,988 participants (14.5% prevalence), the P-for-trend for abnormal bowel habits was significant (OR = 1.015, 95% CI: 1.006-1.024, P = 0.001), corroborated by omnibus Wald (P = 0.006) and restricted cubic spline analyses (P = 0.019). Complete edentulism was associated with 1.5-fold higher odds (OR = 1.545, P = 0.006). Constipation survived FDR correction (FDR-adjusted P = 0.032). Results were robust across most of five sensitivity analyses, with modest attenuation noted after denture use adjustment in a restricted subset. Conclusions Tooth loss was significantly associated with abnormal bowel habits, with constipation surviving FDR correction. These findings support the oral-gut axis hypothesis and highlight the importance of maintaining natural dentition for gastrointestinal health.

Background: Although the acute phase of the COVID-19 pandemic has passed, SARS-CoV-2 continues to cause outpatient morbidity. Antioxidant micronutrients support immune regulation and may offer a low-cost, scalable adjunctive treatment in early infection. Objective: To evaluate a pilot combination antioxidant therapy within CanTreatCOVID. Methods: This pilot sub-protocol enrolled non-hospitalized adults across five Canadian provinces (September 5th, 2024-March 31st, 2025) with mild-to-moderate SARS-CoV-2 infection within five days of symptom onset. Participants were randomized to usual care plus a 10-day antioxidant regimen (selenium 300 g, zinc 40 mg, lycopene 45 mg, vitamin C 1.5 g) or usual care alone. Pilot objectives assessed feasibility, retention, adherence, and safety. The primary outcome was hospitalization or death within 28 days; exploratory outcomes included recovery and symptom measures by day 14. Results: Eighty-one participants were randomized (41 antioxidant; 40 usual care). Retention was high 85.4% antioxidant; 82.5% usual care), and 90.2% of antioxidant participants completed the intervention course. Adverse events were infrequent (9.8% vs 2.5%), with no serious adverse events reported. No deaths occurred in either group; no hospitalizations occurred in the antioxidant arm versus 2/40 (5%) in usual care. By day 14, recovery was reported in 32/40 (80.0%) participants receiving antioxidants versus 23/36 (63.9%) in usual care (OR 2.128; 95% CI 0.7474.871). Sustained alleviation of all symptoms occurred in 38/40 (95.0%) versus 29/36 (80.6%), respectively (OR 3.498; 95% CI 0.872 --10.017). Return to usual activity by day 14 occurred in 38/40 (95.0%) versus 30/36 (83.3%) (OR 3.113; 95% CI 0.762--9.022). Adjusted between-group differences in dietary intake were not statistically significant. Conclusions: Combination antioxidant therapy was feasible to deliver in a decentralized outpatient setting, with high adherence and tolerability. While the trial was not powered for definitive efficacy conclusions, consistent directional improvements across symptom outcomes support evaluation of this host-directed antioxidant strategy in larger trials. Keywords: Adaptive Platform Trial; Antioxidant Therapy; SARS-CoV-2 ; Outpatient Therapeutics; Micronutrient Supplementation Trial registration number: https://clinicaltrials.gov/study/NCT05614349

Importance. Systematic reviews and meta-analyses inform suicide-prevention policy and practice, but broad database searches are difficult to screen manually. This limits capture of upstream interventions, such as economic policies, with indirect effects on suicide. Reliable automated screening could make broader and more comprehensive evidence syntheses feasible. Objective. To develop and validate ScreenAgent, a large language model (LLM) agent for title and abstract screening, and a review-specific method for prospectively estimating screening performance. Design, Setting, and Participants. ScreenAgent was validated internally on a prospective meta-analysis, and externally on two published systematic reviews. The correct include and exclude decisions followed standard systematic-review screening methodology. Exposures. ScreenAgent, an LLM agent returning structured include-or-exclude decisions. Records it marked for inclusion were re-checked by a second, cascade pass using a higher-effort LLM. For the external reviews, the agent's prompt was tuned automatically on a small set of labeled examples. Main Outcomes and Measures. We calculated sensitivity, specificity, workload reduction (the percentage of records removed from human review), and agent-versus-human reliability via Cohen kappa. Sensitivity was estimated by direct comparison (internal) and 5-fold cross-validation (external). Results. In the internal validation, ScreenAgent identified 43 of 44 eligible studies (sensitivity 97.7%; 95% CI, 88.2%-99.6%) with a generic prompt applied without any review-specific optimization, specificity 98.0%, and a measured full-corpus workload reduction of 99.4%. The cost was $855.91 for the full 201,064-record corpus (0.43 US cents per record). Agent-versus-human-consensus agreement exceeded human-versus-human agreement (Cohen kappa 0.75 vs 0.64; percent agreement 97.3% vs 95.4%). For two external validation studies, automatic tuning resulted in a cross-validated sensitivity of 95.9% (95% CI, 90.0%-98.4%) and 97.4% (90.9%-99.3%), with workload reductions of 97.4% and 98.4%. Conclusions and Relevance. Suicide prevention efforts often require rapid consolidation of evidence because of the inherent challenges of single studies trying to prevent rare outcomes. On both internal and external validation sets, ScreenAgent identified nearly all eligible studies with human-level reliability for a fraction of a US cent per record while keeping human reviewers as the final arbiters. By making broad searches feasible and screening performance measurable beforehand, this approach can serve as a transparent methodology to strengthen the speed at which we can inform and advance suicide prevention efforts.

Introduction: The TREOCAPA (Prophylactic TREatment Of the duCtus Arteriosus in Preterm infants by Acetaminophen) trial was a pan-European, multi-centre, phase II/III trial investigating the impact of prophylactic paracetamol (also known as acetaminophen) given during the first 5 days of life for children born before 29 weeks' gestational age (GA) on survival to 36 weeks' post-menstrual age without severe neonatal morbidities. However, due to time restrictions, long-term follow-up was not planned as part of the initial trial despite recommendations for neonatal trials to include endpoints measuring efficacy after discharge from the neonatal unit and on-going debate about the long-term effects of paracetamol in the neonatal period. This protocol describes a study to follow-up participants in the TREOCAPA trial at 2 years corrected age initiated after the trial's onset. Methods and analysis: The TREOCAPA Long Term (TREOCAPA-LT) study population consists of all children included in the TREOCAPA phase III trial in centres in countries participating in the follow-up study who are aged between 23.5 and 27.5 months corrected age during the study period. Families are contacted by the clinical teams and a parent or guardian is invited to complete an internet-based (online) questionnaire. The primary outcome is cognition, as measured by the non-verbal Cognitive Scale standard score from the Parent Report of Children's Abilities-Revised (PARCA-R) questionnaire. Secondary outcomes are moderate to severe neurodevelopment, health service use and costs. Data will be analysed according to the study groups to which children were randomised in the original TREOCAPA RCT. Ethics and Dissemination: The TREOCAPA-LT protocol was first approved by ethics' committees in France (the study's sponsor) and subsequently by all participating countries. Results from TREOCAPA-LT will be published in open access journals in accordance with the funder's regulations. Registration: https://clinicaltrials.gov/study/NCT06064825

BACKGROUND: Federal policy now requires sponsors to submit diversity action plans for clinical trials, yet the modifiable features of trial design associated with enrolled composition remain poorly characterized. English-language proficiency requirements are written into eligibility criteria and recorded as free text in a public registry, making them visible and, in principle, amenable to revision, but their relationship to enrolled composition has been examined only within single disease areas and in small samples of trials. We examined whether these requirements and documented language accommodation were associated with the racial and ethnic composition of enrolled participants. METHODS AND FINDINGS: We conducted a cross-sectional study of interventional trials registered on ClinicalTrials.gov with at least one US site and posted results, using a registry snapshot retrieved in October 2026. The primary cohort comprised the 44,487 trials with exclusively US sites, of which 21,924 (49.3%) reported baseline race and 17,434 (39.2%) reported baseline ethnicity with counts that reconciled with the posted denominator. Both exposures were classified from free-text eligibility criteria using regular expressions validated against independent physician review of 150 trials. For the English-language requirement classifier, sensitivity was 88.2% and specificity was 99.2%. The outcome was the trial-level proportion of enrolled participants in each category, analyzed using generalized linear models adjusted for intervention class, therapeutic area, sponsor, phase, enrollment, sites, start year, US Census region, and the population composition of the trial's site states. An English-language proficiency requirement appeared in 5,736 trials (12.9%); its prevalence rose from 7.4% of trials starting in 2010 to 26.2% in 2023 (odds ratio [OR] per decade 2.91, P<0.001), whereas documented accommodation, an eligibility statement allowing participation in a language other than English (Spanish in 99.9% of flagged trials), remained rare (788 trials, 1.8%). The requirement was associated with lower enrolled proportions of Asian (OR=0.85, 95% CI 0.77-0.93, P=0.001) and Hispanic/Latinx participants (OR=0.85, 95% CI 0.79-0.91, P<0.001), with no evidence of an association for White participants (OR=0.99, 95% CI 0.95-1.04, P=0.75). Documented accommodation was associated with a higher proportion of Hispanic/Latinx participants (OR=3.23, 95% CI 2.82-3.71, P<0.001). Geographic adjustment did not change the statistical significance of the requirement associations and attenuated the accommodation association. The main limitations were the cross-sectional design, which precludes causal inference; the restriction of enrollment analyses to trials reporting baseline demographics, which were more recent than those without such reporting; and possible misclassification of automatically classified exposures. CONCLUSIONS: English-language proficiency requirements became more than three times as common between 2010 and 2023 and were associated with lower enrolled proportions of Asian and Hispanic/Latinx participants. Less common documented language accommodation was associated with a higher enrolled proportion of Hispanic/Latinx participants. Because these criteria are investigator-written and publicly recorded, they may be a tractable target for improving enrollment equity, although whether revising them changes who enrolls requires prospective evaluation

Background Falls in hospitals are associated with injuries, deaths and poor patient outcomes. Although clinical guidelines recommend educating hospital patients about how to prevent falls, not all hospitals systematically deliver evidence-based patient falls education. The primary aim of this study is to implement and evaluate the effectiveness of delivering a research-informed education program called the Safe Recovery Program with ward support on rates of falls and falls-related injuries in hospitals. The secondary aims include measuring changes in patient and staff knowledge and awareness about falls prevention and identifying barriers and facilitators to staff and patients taking action to reduce hospital falls. Methods The trial will adhere to the Consolidated Standards of Reporting Trials guidelines. Twelve wards will be recruited from five Australian hospitals over a 65-week period. A stepped-wedge cluster randomised controlled trial design will be used with unidirectional crossover from control to experimental conditions together with randomisation of when each cluster makes the transition. The crossovers will occur at 12 timepoints, each five weeks apart. Alongside the trial, patients and staff on participating wards will be recruited for interviews and qualitative data analyses will be conducted to understand how to optimise implementation. The experimental condition involves usual care plus delivery of the Safe Recovery Program. For the Safe Recovery Program, supervised allied health assistants will deliver brief falls education programs to all suitable patients in designated wards, reinforced by all ward staff. Falls champions, who are registered nurses and allied health professionals, will provide Safe Recovery Program training for staff, using a train-the-trainer model. The ward staff will also be trained in how to support hospital patients to adopt safe behaviours. The primary outcome will be falls per 1000 patient bed days. The secondary outcomes will be: (i) injurious falls per 1000 patient bed days (ii) patient and staff changes in falls awareness, knowledge and motivation; and (iii) barriers and enablers to hospital staff engaging in behaviour change and program implementation. An economic evaluation will also be conducted to estimate the incremental cost effectiveness of implementing the Safe Recovery intervention. Ethics and Dissemination Ethics approvals have been obtained from The Royal Melbourne Hospital Human Research Ethics Committee (HREC/113864/MH-2024). The findings will be disseminated through peer-reviewed journals, workshops and conferences. Consumer team investigators will guide the communication of findings to the target audiences, including older patients, hospital staff, healthcare managers and policy makers. Trial Registration Number: ACTRN12624001469505

Objectives: To develop consensus on core domains and items to inform a reporting guideline for intervention fidelity in non-drug, non-surgical trials (ReFiND). Design: International, online three-round Delphi process. Methods: We invited researchers with expertise in intervention fidelity, non-drug, non-surgical trials, trial reporting, and process evaluation methods to take part in a three-round Delphi study. They rated the importance of 7 intervention fidelity domains and 79 items using a 9-point scale (1 to 3= not important, 4 to 6= important but not essential, 7 to 9= very important). A comment box was provided along with each domain and item for panellists to provide the rationale for their ratings. Consensus was defined as more than 70% of panellists rating 1-3 (exclusion) or 7-9 (inclusion) after two voting rounds. A summary of ratings and panellists rationale from Rounds One and Two were provided to panellists in Round Two and Three, respectively. We conducted a thematic analysis to synthesise qualitative data. Results: Sixty-one panellists completed Round One, 55 completed Round Two and 56 completed Round Three. Panellists had diverse backgrounds and were from 21 countries, including six low- and middle-income countries. After three rounds, five domains (Intervention Design, Intervention Fidelity Measurement Methods, Provider Training, Intervention Delivery by Providers, Intervention Receipt by Participants) and 20 items reached consensus for inclusion in the reporting guideline. Panellists rationale for their ratings was based on how specifically each domain and item related to intervention fidelity, how feasible it would be to implement in practice, and how broadly it could be applied across different contexts. Conclusions: Using systematic methods, this study reached consensus on a core set of domains and items for inclusion in ReFiND. This core set provides a foundation for consistent and transparent reporting of intervention fidelity and helps researchers and clinicians better interpret and replicate interventions tested in non-drug, non-surgical trials.