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Abstract Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 ).

Three studies so far have investigated the effect of prenatal non-steroidal anti-inflammatory drug (NSAID) exposure on birth weight and gestational age. The aim in this study was to evaluate the association of prenatal ibuprofen with birth weight and gestational age at birth, using a sibling design in an attempt to adjust for the possibility of familial confounding.Using data from the Norwegian Mother and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway (MBRN), we identified 28 597 siblings, of whom 1080 were prenatally exposed to ibuprofen and 26 824 were not exposed to any NSAID. Random and fixed effects models with propensity score adjustment were used to evaluate the effects of ibuprofen exposure on birth weight and gestational age.Ibuprofen exposure during the first trimester was associated with a decrease in birth weight of 79 grams (95% confidence interval -133 to -25 grams). In contrast, second and/or third trimester exposure, and duration of exposure had no impact on the effect estimates. We found no association between ibuprofen exposure and gestational age at birth.Our results suggest that prenatal exposure to ibuprofen during the first trimester is associated with a slight decrease in birth weight. The association does not seem to be attributable to shared genetics and family environment, and could be explained by either exposure to ibuprofen, or to non-shared confounding between pregnancies.

Preterm neonates require parenteral nutrition (PN) in addition to intravenous drug therapy. Due to limited venous access, drugs are often co-administered with PN via the same lumen. If incompatible, precipitation and emulsion destabilization may occur with the consequent risk of embolism and hyper-immune reactions. Information on intravenous compatibility is scarce. Our aim was to analyse the compatibility of Numeta G13E with paracetamol, vancomycin and fentanyl because of the frequency of their use. A panel of methods was chosen to assess precipitation (sub-visual particle counting, turbidity measurement, Tyndall beam effect and pH measurement) and emulsion destabilization (mean droplet diameter measurement and sub-visual counting of oil droplets, followed by estimation of PFAT5 (percentage of fat residing in globules larger than 5 µm) and pH measurement). Samples in clinically relevant mixing ratios were tested immediately and after 4 h. All samples of drugs mixed with Numeta G13E were compared to unmixed controls. None of the tested drugs precipitated in contact with Numeta G13E, and we did not see any sign of emulsion destabilization when clinically relevant mixing ratios were applied. These results are reassuring. However, when contact time exceeds the established norm, caution in the form of filter utilisation and close inspection is advised.