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Introduction: There have been no prior trials directly comparing the efficacy of different calcitonin gene-related peptide (CGRP) antagonists for migraine prevention. Reported are the results from the first head-to-head study of two CGRP antagonists, galcanezumab (monoclonal antibody) versus rimegepant (gepant), for the prevention of episodic migraine., Methods: In this 3-month, double-blind, double-dummy study, participants were randomized (1:1) to subcutaneous (SC) galcanezumab 120 mg per month (after a 240 mg loading dose) and a placebo oral disintegrating tablet (ODT) every other day (q.o.d.) or to rimegepant 75 mg ODT q.o.d. and a monthly SC placebo. The primary endpoint was the proportion of participants with a ≥ 50% reduction in migraine headache days per month from baseline across the 3-month double-blind treatment period. Key secondary endpoints were overall mean change from baseline in: migraine headache days per month across 3 months and at month 3, 2, and 1; migraine headache days per month with acute migraine medication use; Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive domain score at month 3; and a ≥ 75% and 100% reduction from baseline in migraine headache days per month across 3 months., Results: Of 580 randomized participants (galcanezumab: 287, rimegepant: 293; mean age: 42 years), 83% were female and 81% Caucasian. Galcanezumab was not superior to rimegepant in achieving a ≥ 50% reduction from baseline in migraine headache days per month (62% versus 61% respectively; P = 0.70). Given the pre-specified multiple testing procedure, key secondary endpoints cannot be considered statistically significant. Overall, treatment-emergent adverse events were reported by 21% of participants, with no significant differences between study intervention groups., Conclusions: Galcanezumab was not superior to rimegepant for the primary endpoint; however, both interventions demonstrated efficacy as preventive treatments in participants with episodic migraine. The efficacy and safety profiles observed in galcanezumab-treated participants were consistent with previous studies., Trial Registration: ClinTrials.gov-NCT05127486 (I5Q-MC-CGBD)., (© 2023. The Author(s).)

Objective: To determine the efficacy and safety of extended drotrecogin alfa (activated) (DAA) therapy., Design: Multicentre, randomised, double-blind, placebo-controlled study., Setting: Sixty-four intensive care units in nine countries., Patients: Adults with severe sepsis and vasopressor-dependent hypotension after a 96-h infusion of standard DAA., Interventions: A total of 193 patients received an intravenous infusion of extended DAA 24 microg/kg/h or sodium chloride placebo for a maximum of 72 h., Measurements and Results: At extended therapy initiation (baseline), DAA-group patients had lower protein C levels (P = 0.23) and higher vasopressor requirements, particularly for the primary vasopressor used, norepinephrine (P = 0.03), compared with placebo-group patients. DAA treatment did not result in a difference in the primary outcome of time to resolution of vasopressor-dependent hypotension versus placebo (P = 0.419). However, few patients reached resolution (DAA 34%, placebo 40%) as most continued to require vasopressor support after 72 additional hours of treatment. Treatment did not reduce 28-day all-cause mortality and in-hospital mortality or improve organ function compared with placebo, although there was a lower percentage change in D-dimers (P < 0.001) and increases in protein C levels were numerically greater on extended infusion. There was no difference in serious adverse events including bleeding events., Conclusions: Extended DAA treatment did not result in more rapid resolution of vasopressor-dependent hypotension, despite demonstrating anticipated biological effects on D-dimer and protein C levels. A reduced planned sample size combined with baseline imbalances in protein C levels and vasopressor requirements may have limited the ability to demonstrate a clinical benefit.