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

A review of in vivo and in vitro aspects of alcohol-induced dose dumping

Abstract This review provides a comprehensive list of in vivo and in vitro studies that have investigated alcohol induced dose dumping (AIDD) in modified release dosage forms. Of the numerous classes of drugs commercially available as modified release products, opioids, centrally acting drugs, and drugs with a narrow therapeutic index present high risks from dose dumping, despite being formulated in a manner that releases drug in a tailored or delayed fashion. Awareness of AIDD has led to the withdrawal of a few marketed products by Regulatory Agencies, and black box warnings on others. Since then, significant effort has focused on proving the robustness of a formulation when co-ingested with alcohol. Patient risk is deemed to be low if the formulation and its performance is unimpaired by the presence of 0–40% alcohol under in vivo and in vitro conditions

Effect of Hydration on Physicochemical Properties of End-Capped PLGA

The objective of this study was to assess the physicochemical effects of hydrating a hydrophobic end-capped poly(lactide-coglycolide)(PLGA)polymerintheliquidandvaporstate.PLGARG503polymerwasincubatedat37∘Cin0.5%polyvinylalcohol (PVA)solutionandat90%RH.Sampleswerewithdrawnatpredeterminedintervalsandchangestopolymerpropertieslikeglass transition temperature (Tg), moisture uptake, molecular weight change, and % acid number were determined using differential scanningcalorimetry,KarlFishertitrimetry,gelpermeationchromatography,andacidbasetitrimetry,respectively.Studyresults showed that Tg was depressed instantaneously upon hydration, indicating that bulk water acted as a plasticizer of hydrophobic end-cappedPLGA.Tg valuesdecreasedtolevelsbelowtheincubationtemperaturewhenhydratedin0.5%PVAsolutionbutnotin 90%RH.ThedropinTg exhibitedalinearrelationship(2 > 0.99)totheamountofwateruptakebythepolymer;highermoisture uptakewasnotedwithliquidwater.RemovalofmoisturefromthepolymermatrixresultedinrecoveryofTg,onlyuptoaperiod of14days.Presenceofwaterinliquidorvaporformcausedareductioninmolecularweightofthepolymerandacorresponding increasein%acidnumberoverthedurationofthestudy

A Short Term Quality Control Tool for Biodegradable Microspheres

Accelerated in vitro release testing methodology has been developed as an indicator of product performance to be used as a discriminatory quality control (QC) technique for the release of clinical and commercial batches of biodegradable microspheres. While product performance of biodegradable microspheres can be verified by in vivo and/or in vitro experiments, such evaluation can be particularly challenging because of slow polymer degradation, resulting in extended study times, labor, and expense. Three batches of Leuprolide poly(lactic-co-glycolic acid) (PLGA) microspheres having varying morphology (process variants having different particle size and specific surface area) were manufactured by the solvent extraction/evaporation technique. Tests involving in vitro release, polymer degradation and hydration of the microspheres were performed on the three batches at 55°C. In vitro peptide release at 55°C was analyzed using a previously derived modification of the Weibull function termed the modified Weibull equation (MWE). Experimental observations and data analysis confirm excellent reproducibility studies within and between batches of the microsphere formulations demonstrating the predictability of the accelerated experiments at 55°C. The accelerated test method was also successfully able to distinguish the in vitro product performance between the three batches having varying morphology (process variants), indicating that it is a suitable QC tool to discriminate product or process variants in clinical or commercial batches of microspheres. Additionally, data analysis utilized the MWE to further quantify the differences obtained from the accelerated in vitro product performance test between process variants, thereby enhancing the discriminatory power of the accelerated methodology at 55°C. © 2014 American Association of Pharmaceutical Scientists