Monitoring and auditing protocol adherence, data integrity and ethical conduct of a randomized clinical trial: A case study.

PURPOSE: To categorize, quantify and interpret findings documented in feedback letters of monitoring or auditing visits for an investigator-initiated, peer-review funded multicenter randomized trial testing probiotics for critically ill patients. MATERIALS & METHODS: In 37 Canadian centers, monitoring and auditing visits were performed by 3 trained individuals; findings were reported in feedback letters. At trial termination, we performed duplicate content analysis on letters, categorizing observations first into unique findings, followed by 10 pre-determined trial quality management domains. We further classified each observation into a) missing operational records, b) errors in process, and potential threats to c) data integrity, d) patient privacy or e) safety. RESULTS: Across 37 monitoring or auditing visits, 75 unique findings were categorized into 10 domains. Most frequently, observations were in domains of training documentation (180/566 [32%]) and the informed consent process (133/566 [23%]). Most observations were missing operational records (438/566 [77%]) rather than errors in process (128/566 [23%]). Of 75 findings, 13 (62/566 observations [11%]) posed a potential threat to data integrity, 1 (1/566 observation [0.18%]) to patient privacy, and 9 (49/566 observations [8.7%]) to patient safety. CONCLUSIONS: Monitoring and auditing findings predominantly concerned missing documentation with minimal threats to data integrity, patient privacy or safety. TRIAL REGISTRATION: PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial): NCT02462590.

Evidence-informed consensus statements to guide COVID-19 patient visitation policies: results from a national stakeholder meeting.

PURPOSE: Hospital policies forbidding or limiting families from visiting relatives on the intensive care unit (ICU) has affected patients, families, healthcare professionals, and patient- and family-centered care (PFCC). We sought to refine evidence-informed consensus statements to guide the creation of ICU visitation policies during the current COVID-19 pandemic and future pandemics and to identify barriers and facilitators to their implementation and sustained uptake in Canadian ICUs. METHODS: We created consensus statements from 36 evidence-informed experiences (i.e., impacts on patients, families, healthcare professionals, and PFCC) and 63 evidence-informed strategies (i.e., ways to improve restricted visitation) identified during a modified Delphi process (described elsewhere). Over two half-day virtual meetings on 7 and 8 April 2021, 45 stakeholders (patients, families, researchers, clinicians, decision-makers) discussed and refined these consensus statements. Through qualitative descriptive content analysis, we evaluated the following points for 99 consensus statements: 1) their importance for improving restricted visitation policies; 2) suggested modifications to make them more applicable; and 3) facilitators and barriers to implementing these statements when creating ICU visitation policies. RESULTS: Through discussion, participants identified three areas for improvement: 1) clarity, 2) accessibility, and 3) feasibility. Stakeholders identified several implementation facilitators (clear, flexible, succinct, and prioritized statements available in multiple modes), barriers (perceived lack of flexibility, lack of partnership between government and hospital, change fatigue), and ways to measure and monitor their use (e.g., family satisfaction, qualitative interviews). CONCLUSIONS: Existing guidance on policies that disallowed or restricted visitation in intensive care units were confusing, hard to operationalize, and often lacked supporting evidence. Prioritized, succinct, and clear consensus statements allowing for local adaptability are necessary to guide the creation of ICU visitation policies and to optimize PFCC.

RéSUMé: OBJECTIF: Les politiques hospitalières interdisant ou limitant les visites des familles à des proches à l'unité de soins intensifs (USI) ont affecté les patients, les familles, les professionnels de la santé et les soins centrés sur le patient et la famille (SCPF). Nous avons cherché à affiner les déclarations de consensus fondées sur des données probantes afin de guider la création de politiques de visite aux soins intensifs pendant la pandémie actuelle de COVID-19 et les pandémies futures, et dans le but d'identifier les obstacles et les critères facilitants à leur mise en œuvre et à leur adoption répandue dans les unités de soins intensifs canadiennes. MéTHODE: Nous avons créé des déclarations de consensus à partir de 36 expériences fondées sur des données probantes (c.-à-d. impacts sur les patients, les familles, les professionnels de la santé et les SCPF) et 63 stratégies fondées sur des données probantes (c.-à-d. moyens d'améliorer les restrictions des visites) identifiées au cours d'un processus Delphi modifié (décrit ailleurs). Au cours de deux réunions virtuelles d'une demi-journée tenues les 7 et 8 avril 2021, 45 intervenants (patients, familles, chercheurs, cliniciens, décideurs) ont discuté et affiné ces déclarations de consensus. Grâce à une analyse descriptive qualitative du contenu, nous avons évalué les points suivants pour 99 déclarations de consensus : 1) leur importance pour l'amélioration des politiques de restriction des visites; 2) les modifications suggérées pour les rendre plus applicables; et 3) les critères facilitants et les obstacles à la mise en œuvre de ces déclarations lors de la création de politiques de visite aux soins intensifs. RéSULTATS: En discutant, les participants ont identifié trois domaines à améliorer : 1) la clarté, 2) l'accessibilité et 3) la faisabilité. Les intervenants ont identifié plusieurs critères facilitants à la mise en œuvre (énoncés clairs, flexibles, succincts et hiérarchisés disponibles dans plusieurs modes), des obstacles (manque perçu de flexibilité, manque de partenariat entre le gouvernement et l'hôpital, fatigue du changement) et des moyens de mesurer et de surveiller leur utilisation (p. ex., satisfaction des familles, entrevues qualitatives). CONCLUSION: Les directives existantes sur les politiques qui interdisaient ou limitaient les visites dans les unités de soins intensifs étaient déroutantes, difficiles à mettre en oeuvre et manquaient souvent de données probantes à l'appui. Des déclarations de consensus hiérarchisées, succinctes et claires permettant une adaptabilité locale sont nécessaires pour guider la création de politiques de visite en soins intensifs et pour optimiser les soins centrés sur le patient et la famille.

Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

Effect of Awake Prone Positioning on Endotracheal Intubation in Patients With COVID-19 and Acute Respiratory Failure: A Randomized Clinical Trial.

Importance: The efficacy and safety of prone positioning is unclear in nonintubated patients with acute hypoxemia and COVID-19. Objective: To evaluate the efficacy and adverse events of prone positioning in nonintubated adult patients with acute hypoxemia and COVID-19. Design, Setting, and Participants: Pragmatic, unblinded randomized clinical trial conducted at 21 hospitals in Canada, Kuwait, Saudi Arabia, and the US. Eligible adult patients with COVID-19 were not intubated and required oxygen (≥40%) or noninvasive ventilation. A total of 400 patients were enrolled between May 19, 2020, and May 18, 2021, and final follow-up was completed in July 2021. Intervention: Patients were randomized to awake prone positioning (n = 205) or usual care without prone positioning (control; n = 195). Main Outcomes and Measures: The primary outcome was endotracheal intubation within 30 days of randomization. The secondary outcomes included mortality at 60 days, days free from invasive mechanical ventilation or noninvasive ventilation at 30 days, days free from the intensive care unit or hospital at 60 days, adverse events, and serious adverse events. Results: Among the 400 patients who were randomized (mean age, 57.6 years [SD, 12.83 years]; 117 [29.3%] were women), all (100%) completed the trial. In the first 4 days after randomization, the median duration of prone positioning was 4.8 h/d (IQR, 1.8 to 8.0 h/d) in the awake prone positioning group vs 0 h/d (IQR, 0 to 0 h/d) in the control group. By day 30, 70 of 205 patients (34.1%) in the prone positioning group were intubated vs 79 of 195 patients (40.5%) in the control group (hazard ratio, 0.81 [95% CI, 0.59 to 1.12], P = .20; absolute difference, -6.37% [95% CI, -15.83% to 3.10%]). Prone positioning did not significantly reduce mortality at 60 days (hazard ratio, 0.93 [95% CI, 0.62 to 1.40], P = .54; absolute difference, -1.15% [95% CI, -9.40% to 7.10%]) and had no significant effect on days free from invasive mechanical ventilation or noninvasive ventilation at 30 days or on days free from the intensive care unit or hospital at 60 days. There were no serious adverse events in either group. In the awake prone positioning group, 21 patients (10%) experienced adverse events and the most frequently reported were musculoskeletal pain or discomfort from prone positioning (13 of 205 patients [6.34%]) and desaturation (2 of 205 patients [0.98%]). There were no reported adverse events in the control group. Conclusions and Relevance: In patients with acute hypoxemic respiratory failure from COVID-19, prone positioning, compared with usual care without prone positioning, did not significantly reduce endotracheal intubation at 30 days. However, the effect size for the primary study outcome was imprecise and does not exclude a clinically important benefit. Trial Registration: ClinicalTrials.gov Identifier: NCT04350723.

Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial: Statistical Analysis Plan.

BACKGROUND: The LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor. OBJECTIVE: We aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database. METHODS: The SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses. RESULTS: The SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status. CONCLUSIONS: We have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36261.