Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Strategies to Adjust for Response Bias in Clinical Trials: A Simulation Study

Background: Response bias can distort treatment effect estimates and inferences in clinical trials. Although prevention, quantification, and adjustments have been developed, current methods are not applicable when subject-level reliability is used as the measure of response bias. Thus, the objective of the current study is to develop, test, and recommend a series of bias correction strategies for use in these cases. Methods: Monte Carlo simulation and logistic regression modeling were used to develop the strategies, examining the collective impact of sample size (N), effect size (ES), reliability distribution, and response style on estimating the treatment effect size in a series of hypothetical clinical trials. The strategies included a linear (LW), quadratic (QW), or cubic weight (CW) applied to the subject-level reliability; a reliability threshold (%); or a combination of the two (W-%). Bias and percent relative root mean square error (RRMSE (%)) were calculated for each treatment effect estimate and RRMSE (%) was compared to inform the bias correction recommendations. Results: The following recommendations are made for each N and ES combination: N=200/ES=small: no adjustment, N=200/ES=medium: 40%-LW, N=200/ES=large: 40%-QW, N=2000/ES=small: 40%-LW, N=2000/ES=medium: 55%-CW, N=2000/ES=large: 75%-CW, N=20000/ES=small: 70%-CW, N=20000/ES=medium: 85%-CW, N=20000/ES=large: 95%-CW. Conclusion: Employing these bias correction strategies in clinical trials where subject-level reliability can be calculated will decrease error and increase accuracy of estimates and validity of inferences

Parents’ Perception of Stepped Care and Standard Care Trauma-Focused Cognitive Behavioral Therapy for Young Children

Delivery systems other than in-office therapist-led treatments are needed to address treatment barriers such as accessibility, efficiency, costs, and parents wanting an active role in helping their child. To address these barriers, stepped care trauma focused-cognitive behavioral therapy (SC-TF-CBT) was developed as a parent-led, therapist-assisted therapy that occurs primarily at-home so that fewer in-office sessions are required. The current study examines caregivers’ perceptions of parent-led (SC-TF-CBT) and therapist-led (TF-CBT) treatment. Participants consisted of 52 parents/caregivers (25–68 years) of young trauma-exposed children (3–7 years) who were randomly assigned to SC-TF-CBT (n = 34) or to TF-CBT (n = 18). Data were collected at mid- and post-treatment via interviews inquiring about what participants liked, disliked, found most helpful, and found least helpful about the treatment. Results indicated that parents/caregivers favored relaxation skills, affect modulation and expression skills, the trauma narrative, and parenting skills across both conditions. The majority of parents/caregivers in SC-TF-CBT favored the at-home parent–child meetings and the workbook that guides the parent-led treatment, and there were suggestions for improving the workbook. Reported disliked and least helpful aspects of treatments were minimal across conditions, but themes that emerged that will need further exploration included the content and structure, and implementation difficulties for both conditions. Collectively, these results highlight the positive impact that a parent-led, therapist-assisted treatment could have in terms of providing caregivers with more tools to help their child after trauma and reduce barriers to treatment

Efficacy and safety of topically applied therapeutic ammonia oxidising bacteria in adults with mild-to-moderate atopic dermatitis and moderate-to-severe pruritus: a randomised, double-blind, placebo-controlled, dose-ranging, phase 2b trial

BACKGROUND: Topical anti-inflammatory therapy is a cornerstone of treatment for atopic dermatitis (AD). However, many unmet needs remain with existing therapies. B244 is a live topical biotherapeutic being tested for the reduction of pruritus and improvement of eczema signs in patients with AD. We aimed to assess the safety and efficacy of B244, compared to vehicle, for patients with mild-to-moderate AD and moderate-to-severe pruritus. METHODS: In this randomised, placebo-controlled, double-blind phase 2b trial, adults aged 18-65 years with mild-to-moderate AD and moderate-to-severe pruritus were enrolled across 56 sites in the USA. Patients were randomised 1:1:1 into a low-dose (optical density at 600 nm [OD] 5.0), high-dose (OD 20.0), or vehicle group for the 4-week treatment period and a 4 week follow-up period. Patients were instructed to apply the topical spray twice daily throughout the treatment period. Randomisation was centrally based (random alternating blocks of 6 and 3) and stratified by site. All participants, investigators, and those assessing outcomes were blinded to the treatment group assignments. The primary endpoint was the mean change in pruritus as measured by the Worst Itch Numeric Rating Scale (WI-NRS) at 4 weeks. Safety was tracked throughout the study. Primary efficacy analyses included the modified intent-to-treat (mITT) population, encompassing those who received at least one dose of study drug and attended at least one post-baseline visit. The safety population included all participants who received at least one does of study drug. This study is registered with ClinicalTrials.gov, NCT04490109. FINDINGS: Between June 4, 2020 and October 22, 2021, 547 eligible patients were enrolled. All study endpoints were meaningfully improved with B244 compared to vehicle. The WI-NRS score was reduced by 34% (-2.8 B244 vs -2.1 placebo, p = 0.014 and p = 0.015 for OD 20.0 and OD 5.0), from a baseline score of \u3e8. B244 was well tolerated with no serious adverse events (SAEs); treatment-emergent adverse events (TEAEs) and treatment related TEAEs were low in incidence, mild in severity, and transient. 33 (18%) of 180 patients given B244 OD 5.0, 29 (16%) of 180 patients given B244 OD 20.0, and 17 (9%) of 186 patients given placebo reported treatment-emergent adverse events; headache was the most frequent (3%, 2%, and 1%, respectively). INTERPRETATION: B244 was well tolerated and demonstrated improved efficacy compared to vehicle in all primary, secondary, and exploratory endpoints and should be further developed as a novel, natural, fast-acting topical spray treatment option for AD and associated pruritus. FUNDING: AOBiome Therapeutics