Hypersensitivity incidence after sugammadex administration in healthy subjects: a randomised controlled trial.

BACKGROUND: We evaluated the incidence of hypersensitivity or anaphylaxis after repeated single-dose sugammadex administration in non-anaesthetised adults. METHODS: In this multicentre, double-blind study (NCT02028065), healthy volunteer subjects were randomised (2:2:1 ratio) to one of three groups to receive three repeated intravenous injections of sugammadex 4 or 16 mg kg-1, or placebo, separated by a ∼5 week intervals. Targeted hypersensitivity assessments were performed 0.5, 4, and 24 h post-dosing, and hypersensitivity signs/symptoms were referred to a blinded independent Adjudication Committee. Anaphylaxis was determined per Sampson (Criterion 1). The primary endpoint was the proportion with confirmed hypersensitivity. RESULTS: Of 375 evaluable subjects, 25 had confirmed hypersensitivity [sugammadex 4 mg kg-1: 10/151 (6.6%); sugammadex 16 mg kg-1: 14/148 (9.5%); placebo: 1/76 (1.3%)]. The differences in incidence rates vs placebo were 5.3% (95% confidence interval: -0.9, 10.7) for sugammadex 4 mg kg-1 and 8.1% (1.7, 14.2) for 16 mg kg-1. Incidence was similar across sugammadex doses and dosing occasions, including in subjects with reactions to previous doses. Three subjects (16 mg kg-1 group) required antihistamines/corticosteroids and discontinued the study, per protocol; symptoms resolved and no subject required epinephrine. One subject with anaphylaxis after the first 16 mg kg-1 dose recovered completely post-treatment. There were no clinically relevant anti-sugammadex antibody or tryptase findings. CONCLUSIONS: Hypersensitivity in response to sugammadex administration can occur in healthy subjects without history of previous sugammadex exposure. Hypersensitivity incidence was similar across sugammadex doses and numerically higher than placebo, with no evidence of sensitisation with repeated administration. Hypersensitivity is unlikely to be mediated through sugammadex-specific immunoglobulin G- or E-mediated mast cell stimulation in healthy volunteers. CLINICAL TRIAL REGISTRATION: NCT02028065.

Randomized, controlled trial of telcagepant for the acute treatment of migraine.

BACKGROUND: The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. In this large phase 3 clinical trial, we sought to confirm the efficacy of telcagepant, the first orally bioavailable CGRP receptor antagonist. METHODS: Adults with migraine with or without aura (International Headache Society criteria) treated a moderate or severe attack with oral telcagepant 50 mg (n = 177), 150 mg (n = 381), 300 mg (n = 371), or placebo (n = 365) in a randomized, double-blind trial. The 5 co-primary endpoints were pain freedom, pain relief, and absence of photophobia, absence of phonophobia, and absence of nausea, all at 2 hours postdose. The key secondary endpoint was 2-24 hour sustained pain freedom. The prespecified primary efficacy analyses evaluated the 150 mg and 300 mg groups; the 50-mg group was included on an exploratory basis to further characterize the dose response but was not prespecified for analysis. Tolerability was assessed by adverse experience reports. RESULTS: Telcagepant 300 mg was more effective (p

Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine.

OBJECTIVE: To determine an effective and tolerable dose of a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, for the acute treatment of migraine. METHODS: Randomized, double-blind, parallel-group, clinical trial with a two-stage, adaptive, dose-ranging design. Patients were allocated to treat a moderate or severe migraine attack with MK-0974 (25, 50, 100, 200, 300, 400, or 600 mg), rizatriptan 10 mg, or placebo taken orally. The primary endpoint was pain relief (reduction to mild or none) 2 hours after dosing. Secondary endpoints included pain freedom at 2 hours and sustained pain relief at 24 hours. A prespecified, blinded, automated interim analysis was used to discontinue randomization to less effective doses. RESULTS: Per the adaptive study design, the four lowest MK-0974 groups (25, 50, 100, 200 mg) were discontinued due to insufficient efficacy. For the remaining treatment groups, the estimated pain relief proportions at 2 hours were 300 mg (n = 38) 68.1%, 400 mg (n = 45) 48.2%, 600 mg (n = 40) 67.5%, rizatriptan 10 mg (n = 34) 69.5%, and placebo (n = 115) 46.3%. The prespecified primary efficacy hypothesis test, which compared the average 2-hour pain relief response proportion of the combined 300, 400, and 600 mg MK-0974 groups to placebo, was significant (P = 0.015). A generally similar efficacy pattern was seen for other endpoints. MK-0974 was generally well tolerated and there did not appear to be an increase in adverse events with increasing dose. CONCLUSIONS: The novel, orally administered calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, was effective and generally well tolerated for the acute treatment of migraine.