Higher-Dose DHA Supplementation Modulates Immune Responses in Pregnancy and Is Associated with Decreased Preterm Birth

Pregnancy and parturition involve extensive changes in the maternal immune system. In our randomized, multi-site, double-blind superiority trial using a Bayesian adaptive design, we demonstrated that 1000 mg/day of docosahexaenoic acid (DHA) was superior to 200 mg/day in preventing both early preterm birth (less than 34 weeks’ gestation) and preterm birth (less than 37 weeks’ gestation). The goal of this secondary study is to compare the effects of 1000 mg/day versus 200 mg/day on maternal inflammation, a possible mechanism by which DHA may prevent preterm birth. Maternal blood samples were collected at enrollment (12–20 weeks’ gestation) and at delivery. Red blood cell DHA levels were measured by gas chromatography, and plasma concentrations of sRAGE, IL-6, IL-1β, TNFα, and INFγ were measured by ELISA. Data were analyzed for associations with the DHA dose, gestational age at birth, and preterm birth (<37 weeks). Higher baseline and lower delivery levels of maternal sRAGE were associated with a greater probability of longer gestation and delivery at term gestation. Higher-dose DHA supplementation increased the probability of a smaller decrease in delivery sRAGE levels. Higher IL-6 concentrations at delivery were associated with the probability of delivering after 37 weeks, and higher-dose DHA supplementation increased the probability of greater increases in IL-6 concentrations between enrollment and delivery. These data provide a proposed mechanistic explanation of how a higher dose of DHA during pregnancy provides immunomodulatory regulation in the initiation of parturition by influencing sRAGE and IL-6 levels, which may explain its ability to reduce the risk of preterm birth.

Ibrexafungerp versus placebo for vulvovaginal candidiasis treatment: a phase 3, randomized, controlled superiority trial (VANISH 303)

Background Current treatment of vulvovaginal candidiasis (VVC) is largely limited to azole therapy. Ibrexafungerp is a first-in-class triterpenoid antifungal with broad-spectrum anti-Candida fungicidal activity. The objective of this study was to evaluate the efficacy and safety of ibrexafungerp compared with placebo in patients with acute VVC. Study Design Patients were randomly assigned 2:1 to receive ibrexafungerp (300 mg twice for 1 day) or placebo. The primary endpoint was the percentage of patients with a clinical cure (complete resolution of vulvovaginal signs and symptoms [VSS]=0) at test-of-cure (day 11±3). Secondary endpoints included the percentage of patients with mycological eradication, overall success (clinical cure and mycological eradication), clinical improvement (VSS≤1) at test-of-cure, and symptom resolution at follow-up (day 25±4). Results Patients receiving ibrexafungerp had significantly higher rates of clinical cure (50.5% [95/188] vs 28.6% [28/98]; P=0.001), mycological eradication (49.5% [93/188] vs 19.4% [19/98]; P&lt;0.001), and overall success (36.0% [64/178] vs 12.6% [12/95]; P&lt;0.001) compared with placebo. Symptom resolution was sustained and further increased with ibrexafungerp compared with placebo (59.6% [112/188] vs 44.9% [44/98]; P=0.009) at follow-up. Post hoc analysis showed similar rates of clinical cure and clinical improvement at test-of-cure for African American patients (54.8% [40/73] and 63.4% [47/73], respectively) and patients with a body mass index &gt;35 (54.5% [24/44] and 68.2% [30/44], respectively) compared with overall rates. Ibrexafungerp was well tolerated. Adverse events were primarily gastrointestinal and mild in severity. Conclusion Ibrexafungerp provides a promising safe and efficacious oral treatment that mechanistically differs from current azole treatment options for acute VVC.

Protocol for a multicentre, randomised, parallel-control, superiority trial comparing administration of clotting factor concentrates with a standard massive haemorrhage protocol in severely bleeding trauma patients: the FiiRST 2 trial (a 2020 EAST multicentre trial)

IntroductionAcute traumatic coagulopathy (ATC) in bleeding trauma patients increase in-hospital mortality. Fibrinogen concentrate (FC) and prothrombin complex concentrate (PCC) are two purified concentrates of clotting factors that have been used to treat ATC. However, there is a knowledge gap on their use compared with the standard of care, the transfusion of plasma.Methods and analysisThe factors in the initial resuscitation of severe trauma 2 trial is a multicentre, randomised, parallel-control, single-blinded, phase IV superiority trial. The study aims to address efficacy and safety of the early use of FC and PCC compared with a plasma-based resuscitation. Adult trauma patients requiring massive haemorrhage protocol activation on hospital arrival will receive FC 4 g and PCC 2000 IU or plasma 4 U, based on random allocation. The primary outcome is a composite of the cumulative number of all units of red cells, plasma and platelets transfused within 24 hours following admission. Secondary outcomes include measures of efficacy and safety of the intervention. Enrolment of 350 patients will provide an initial power >80% to demonstrate superiority for the primary outcome. After enrolment of 120 patients, a preplanned adaptive interim analysis will be conducted to reassess assumptions, check for early superiority demonstration or reassess the sample size for remainder of the study.Ethics and disseminationThe study has been approved by local and provincial research ethics boards and will be conducted according to the Declaration of Helsinki, Good Clinical Practice guidelines and regulatory requirements. As per the Tri-Council Policy Statement, patient consent will be deferred due to the emergency nature of the interventions. If superiority is established, results will have a major impact on clinical practice by reducing exposure to non-virally inactivated blood products, shortening the time for administration of clotting factors, correct coagulopathy more efficaciously and reduce the reliance on AB plasma.Trial registration numberNCT04534751, pre results.

Diagnostic role of the ‘white test’ with lipidic solution in the early intraoperative identification of open bile ducts for the prevention of bile leakage after liver resection: study protocol for a randomised controlled multicentric superiority trial (BiLe-Trial)

IntroductionBile leakage is a frequent complication after liver resection associated with the need of interventional drainage, endoscopic retrograde cholangio pancreatography (ERCP) or reoperation. The intraoperative application of the white test could be a promising strategy to reduce the occurrence of bile leakages. Therefore, we propose to conduct the first multicentric randomised controlled trial with rate of postoperative bile leakage as primary endpoint with and without the white test.Methods and analysisThe Bile-Leakage Trial trial is an investigator-initiated randomised controlled, parallel group, double-blinded, multicentric, superiority trial in four Swiss centres. A total of 210 patients undergoing a resection of at least 2 liver segments will be randomly allocated intraoperatively to either the intervention (identification of open bile ducts with administration of 20–40 mL SMOFlipid5% in the bile tract) or the control group (identification with a white gauze on the liver resection surface).Primary outcome will be the comparison of the postoperative bile leakage rate in both groups within 30 days after liver resection, defined according to the classification of the International Study Group of Liver Surgery. Secondary outcomes will be operative and postoperative complication, including severity grade of the bile leakage, rate of ERCP, interventional drainage, morbidity, intensive care unit stay, and mortality.Ethics and disseminationThe cantonal ethics committees of all participating centres and Swissmedic approved the study. SMOFlipid20% consists of a mixture of oils, no side effects resulting from the intraoperative application of 20–40 mL in the biliary tract with consecutive enteral absorption are expected nor are side effects described in the literature. SMOFlipid20% will be diluted intraoperatively with isotonic saline solution to a concentration of 5%. The results of the BiLe-Trial will be submitted to a peer-reviewed journal regardless of the outcome. As this is an investigator-initiated trial, data are property of the sponsor investigator and can be obtained on request.Trial registration numberClinicaltrials.gov, ID: NCT04523701. Registered on 25 August 2020.Swiss National Clinical Trials Portal (SNCTP), ID: SNCTP000004200. Registered on 20 January 2021.Protocol versionV3.2_14-12-2020_clean.pdf