We tested 104 residents and 141 staff for COVID-19 who failed daily symptom screening in homeless shelters in Hamilton, Canada. We detected one resident (1%), seven staff (5%) and one case of secondary spread. Shelter restructuring to allow physical distancing, testing and isolation can decrease outbreaks in shelters.

Background In non-inferiority trials, there is a concern that intention-to-treat (ITT) analysis, by including participants who did not receive the planned interventions, may bias towards making the treatment and control arms look similar and lead to mistaken claims of non-inferiority. In contrast, per protocol (PP) analysis is viewed as less likely to make this mistake and therefore preferable in non-inferiority trials. In a systematic review of antibiotic non-inferiority trials, we compared ITT and PP analyses to determine which analysis was more conservative. Methods In a secondary analysis of a systematic review, we included non-inferiority trials that compared different antibiotic regimens, used absolute risk reduction (ARR) as the main outcome and reported both ITT and PP analyses. All estimates and confidence intervals (CIs) were oriented so that a negative ARR favored the control arm, and a positive ARR favored the treatment arm. We compared ITT to PP analyses results. The more conservative analysis between ITT and PP analyses was defined as the one having a more negative lower CI limit. Results The analysis included 164 comparisons from 154 studies. In terms of the ARR, ITT analysis yielded the more conservative point estimate and lower CI limit in 83 (50.6%) and 92 (56.1%) comparisons respectively. The lower CI limits in ITT analysis favored the control arm more than in PP analysis (median of − 7.5% vs. -6.9%, p = 0.0402). CIs were slightly wider in ITT analyses than in PP analyses (median of 13.3% vs. 12.4%, p < 0.0001). The median success rate was 89% (interquartile range IQR 82 to 93%) in the PP population and 44% (IQR 23 to 60%) in the patients who were included in the ITT population but excluded from the PP population (p < 0.0001). Conclusions Contrary to common belief, ITT analysis was more conservative than PP analysis in the majority of antibiotic non-inferiority trials. The lower treatment success rate in the ITT analysis led to a larger variance and wider CI, resulting in a more conservative lower CI limit. ITT analysis should be mandatory and considered as either the primary or co-primary analysis for non-inferiority trials. Trial registration PROSPERO registration number CRD42020165040.

Background Antibiotic non-inferiority randomized controlled trials (RCTs) are used for approval of new antibiotics and making changes to antibiotic prescribing in clinical practice. We conducted a systematic review to assess the methodological and reporting quality of antibiotic non-inferiority RCTs. Methods We searched MEDLINE, Embase, the Cochrane Database of Systematic Reviews and the FDA drug database from inception until Nov 22, 2019 for non-inferiority RCTs comparing different systemic antibiotic therapies. Comparisons between antibiotic types, doses, administration routes or durations were included. Methodological and reporting quality indicators were based on the CONSORT reporting guidelines. Two independent reviewers extracted the data. Results The systematic review included 227 studies. Of these, 135 (59.5%) studies were supported by pharmaceutical industry. Only 83 (36.6%) studies provided a justification for the non-inferiority margin. Reporting of both intention-to-treat (ITT) and per-protocol (PP) analyses were done in 165 (72.7%) studies. The conclusion was misleading in 34 (15.0%) studies. The studies funded by pharmaceutical industry were less likely to be stopped early due to logistical reasons (3.0% vs. 19.1%, OR=0.13 95% CI 0.04-0.37) and to show inconclusive results (11.1% vs. 42.9%, OR=0.17 95% CI 0.08-0.33). The quality of studies decreased over time with respect to blinding, early stopping, reporting of ITT with PP analysis and having misleading conclusions. Conclusions There is room for improvement in the methodology and reporting of antibiotic non-inferiority trials. Quality can be improved across the entire spectrum from investigators, funding agencies, as well as during the peer-review process.

Objectives 1. To compare the effectiveness of four different surveillance strategies in detecting COVID-19 within the homeless shelter population. 2. To assess the participant adherence over time for each surveillance method. Trial Design This is a prospective cluster-randomized study to compare the effectiveness of four different surveillance regimens across eight homeless shelters in the city of Hamilton. Participants Participants will include both residents of, and the staff working within, the homeless shelters. All participants aged 18 or older who consent to the study and are able to collect a swab sample (where relevant) are eligible for the study. The study will take place across eight homeless shelters (four men-only and four women-only) in the City of Hamilton in Ontario, Canada. Intervention and Comparator Groups The comparator group will receive active daily surveillance of symptoms and testing will only be completed in symptomatic participants (i.e. those who fail screening or who seek care for potential COVID-19 related symptoms). The three intervention arms will all receive active daily surveillance of symptoms and testing of symptomatic participants (as in the comparator group) in addition to one of the following: 1. Once weekly self-collected oral swabs (OS) regardless of symptoms using written and visual instructions. 2. Once weekly self-collected oral-nares swab (O-NS) regardless of symptoms using written and visual instructions. 3. Once weekly nurse collected nasopharyngeal swab (NPS) regardless of symptoms. Participants will follow verbal and written instructions for the collection of OS and O-NS specimens. For OS collection, participants are instructed to first moisten the swab on their tongue, insert the swab between the cheek and the lower gums and rotate the swab three times. This is repeated on the other side. For O-NS collection, after oral collection, the swab is inserted comfortably (about 2-3 cm) into one nostril, parallel to the floor and turned three times, then repeated in the other nostril. NPS specimens were collected by the nurse following standard of care procedure. All swabs were placed into a viral inactivation medium and transported to the laboratory for COVID-19 testing. Briefly, total nucleic acid was extracted from specimens and then amplified by RT-PCR for the UTR and Envelope genes of SARS-CoV-2 and the human RNase P gene, which is used as a sample adequacy marker. Main Outcomes 1. Primary outcome: COVID-19 detection rate, i.e. the number of new positive cases over the study period of 8 weeks in each arm of the study. 2. Secondary outcomes: Qualitative assessment of study enrollment over 8 weeks. Percentage of participants who performed 50% or more of the weekly swabs in the intervention arms in the 8 week study period. Randomization We will use a computer-generated random assignment list to randomize the shelters to one of four interventions. Shelters were stratified by gender, and the simple randomization scheme was applied within each stratum. The randomization scheme was created using WinPEPI. Blinding This is an open-label study in which neither participants nor assessors are blinded. Numbers to be randomized (sample size) Since we are including our total sample frame, a sample size estimation at the cluster level is not required. However, if we succeed to enroll 50 participants per shelter from 8 shelters (n=400), and the detection rate is 3 times higher in the intervention groups (0.15) than in the comparator groups (0.05), we will have 90% power to detect a statistically significant and clinically important difference at a type I error rate of alpha=0.05 (one tailed), assuming an intraclass correlation of ~0.008. These computations were done using WinPEPI, and informed by conservative estimates from other studies on respiratory illness in the homeless (see Full protocol). Trial Status The protocol version number is 3.0. Recruitment began on April 17, 2020 and is ongoing. Due to low numbers of COVID cases in the community and shelter system during the initial study period, the trial was extended. The estimated date for the end of the extended recruitment period is Feb 1, 2021. Trial Registration The trial was registered with ClinicalTrials.gov on June 18, 2020 with the identifier NCT04438070. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Novel antibiotics approved by non-inferiority trials may become less effective over time in two scenarios: the treatment effect in studies on novel antibiotics may be consistently worse than studies on older antibiotics; or when a decreasingly effective control arm is used in a series of non-inferiority trials. Our systematic review of 175 non-inferiority antibiotic trials found these scenarios to be rare.