Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial—Protocol and statistical analysis plan

Introduction

Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods

The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion

The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

     

Probing insulin's secondary structure after entrapment into alginate/chitosan nanoparticles.

The aim of the present study was to probe the structural integrity of insulin after being entrapped into chitosan/alginate nanoparticles produced by ionotropic polyelectrolyte pre-gelation. By manipulating the alginate:chitosan mass ratio and the pH during nanoparticle production, desired nanoparticles with a mean size of 850 (+/-88)nm and insulin association efficiency of 81 (+/-2)% were obtained. Insulin secondary structure was assessed by Fourier transform infrared (FTIR) and circular dichroism (CD) after entrapment into nanoparticles and after release from the particles under gastrointestinal simulated conditions. FTIR second-derivative spectra and area-overlap compared to an insulin standard confirmed that no significant conformational changes of insulin occurred in terms of alpha-helix and beta-sheet content. Far-UV-CD spectra corroborated the preservation of insulin structure during the nanoparticle production procedure. The presented nanoparticulate system is a promising carrier for insulin oral delivery since it preserves insulin structure and therefore also, potentially, its bioactivity.     

Comparison of Ampicillin-Sulbactam and Ticarcillin-Clavulanic Acid in Patients With Chronic Renal Failure: Effects of Differential Pharmacokinetics on Serum Bactericidal Activity

Study Objectives . To evaluate the pharmacodynamic antibacterial activity of ticarcillin-clavulanic acid (T-C) and ampicillin-sulbactam (A-S) combinations against reference bacterial strains in patients with end-stage renal disease maintained on long-term hemodialysis. Design . Randomized, crossover, controlled study. Setting . National Institutes of Health-funded general clinical research unit in a Veterans Administration Medical Center. Patients . Nine adult men with end-stage renal disease maintained on long-term hemodialysis. Two subjects did not complete the study due to problems of vascular access, and another withdrew for personal reasons. Interventions . On a nondialysis day, each subject was randomly administered either T-C 3.1 g or A-S 3 g as a slow intravenous infusion over 30 minutes. Serial blood samples were collected for measurement of antibiotic serum concentrations and determination of serum bactericidal titers. Following a washout period, the study was repeated with the alternative antibiotic combination. Measurements and Main Results . The mean observed apparent β-half-life of clavulanic acid was substantially shorter than that for the other three drugs. The bactericidal activity of both A-S and T-C against non-β-lactamase-producing (Nβ-LP) strains of S. aureus and E. coli was consistently high, as indicated by geometric mean SBTs of at least 1:5 at 24 hours. Against β-lactamase-producing (β-LP) S. aureus, the geometric mean SBTs for A-S were at least 1:25 throughout the study period, while the geometric mean SBTs for T-C decreased over 24 hours from 1:29 to 1:6. Against β-LP E. coli, the bactericidal activities for both A-S and T-C were poor, with geometric mean peak SBTs of only 1:6 and 1:3, respectively. The geometric mean SBT for T-C against this E. coli strain had declined to 1:1 at 6 hrs. Conclusion . Increasing the dosing interval for T-C in patients with end-stage renal disease may lead to periods of insufficient clavulanic acid to protect ticarcillin from β-lactamase degradation.     

004Topical Zinc Oxide for Open Pilonidal Wounds

Extended healing time and lack of documented effective treatments of sacrococcygeal pilonidal disease create substantial problems. Locally applied zinc oxide has been reported to promote wound healing. We have compared topical zinc oxide (3%) with placebo meshes for pilonidal wounds healing by secondary intention in a randomized, double‐blind, placebo‐controlled multicenter trial. Sixty‐four consecutive patients, 53 males, aged between 18 and 60 years (median 26 years) with excised pilonidal wounds were centrally randomized to local zinc oxide (30 mg/g, n = 33) or to placebo (n = 31) mesh treatment. Patients were followed with strict recording of beneficial and harmful effects. The median healing times were 54 days (42–71 days, interquartile range, n = 33) for the zinc group and 62 days (55–82 days, n = 31) for the placebo group. This difference was not statistically different (p = 0.32). Based on Cox regression analysis initial wound volume influenced healing negatively (p = 0.016) while smoking (p = 0.011) was associated with faster wound healing. Significantly (p < 0.01) more placebo (n = 12) than zinc oxide‐treated patients (n = 3) needed antibiotics postoperatively. Although topical zinc oxide increased (p < 0.001) wound fluid zinc levels (1830 ± 405 μM, mean ± SEM) compared with placebo (3.1 ± 1.6 μM) serum‐zinc levels did not differ significantly between the zinc (13.5 ± 0.4 μM) and placebo (12.8 ± 0.4 μm) groups on postoperative day 7. No adverse events were recorded. Topical zinc oxide treatment did not accelerate time to closure of open pilonidal wounds but was associated with reduced antibiotic usage.     

Gender differences in young adults' beliefs about sunscreen use.

This study employs focus group methodology to explore gender differences in sunscreen use. Guided by the theory of reasoned action, males and females were found to differ on each of the following constructs: behavior, behavioral beliefs, and normative beliefs. Males and females differed in their sunscreen use, with females adopting a more preventive style of sunscreen use and males a more reactive style. Males and females differed in their salient beliefs that motivated their sunscreen use, many of which were related to traditional American gender roles. In addition, although males and females were aware of both positive and negative sources of normative beliefs regarding sunscreen use, females received more encouragement from their mothers and peers than males. Findings are discussed in terms of their implications for the design of future interventions.