Concentration-QTc and cardiac safety analysis of single and multiple zavegepant nasal spray doses in healthy participants to support approval.

Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.

No clinically relevant electrocardiogram effects in a randomized TQT study of single therapeutic/supratherapeutic rimegepant doses in healthy adults.

A single-center, phase I, partially double-blind (double-blind regarding doses of rimegepant and placebo, and open label with respect to moxifloxacin), randomized, 12-sequence, four-period crossover study of therapeutic (75 mg) and supratherapeutic (300 mg) doses of rimegepant with placebo and moxifloxacin (400 mg) controls was designed to evaluate drug effect on the Fridericia corrected QT (QTcF) interval in healthy fasted adults. A total of 38 participants were randomized and dosed in the study. Electrocardiogram (ECG) data were available from 37 participants in the rimegepant 75-mg group, 38 participants in the rimegepant 300-mg group, and 36 participants in the moxifloxacin and placebo groups. Both the 75- and 300-mg doses of rimegepant had no clinically relevant effect on ECG parameters, including QTcF, heart rate, PR and QRS interval, T-wave morphology, and U-wave presence. All upper 90% confidence intervals for the QTcF effect with rimegepant were less than or equal to 4.69 ms, well below the 10-ms threshold for potential clinical significance. Assay sensitivity was demonstrated by the QT effect of moxifloxacin. Using both by-timepoint and concentration-QTc analysis, a placebo-corrected change-from-baseline QTcF greater than 10 ms could be excluded for rimegepant plasma concentrations up to ~10,000 ng/mL, representing concentrations at least 10.8-fold the maximum observed concentration of the 75-mg therapeutic dose of rimegepant.

A placebo-controlled, randomized, single and multiple dose study to evaluate the safety, tolerability, and pharmacokinetics of rimegepant in healthy participants.

BACKGROUND: Rimegepant is an oral, small molecule calcitonin gene-related peptide receptor antagonist for acute treatment of migraine and migraine prevention. METHODS: This was a single-site, placebo-controlled, sequential, single and multiple ascending dose study in healthy males and females, aged 18-55 years, with no clinically significant medical history. The objectives were to assess the safety, tolerability, and pharmacokinetics of the oral capsule free-base formulation. Single oral doses of rimegepant from 25-1500 mg were evaluated in the single ascending dose phase, and 75-600 mg/day doses administered for 14 days were evaluated in the multiple ascending dose phase. RESULTS: No dose-related trends were observed in orthostatic systolic and diastolic blood pressure or heart rate after rimegepant administration. Rimegepant was rapidly absorbed with the median time of maximum observed plasma concentration from 1-3.5 hours. Rimegepant showed a more than dose-proportional increase in exposure from 25-1500 mg following a single dose and from 75-600 mg/day following multiple doses. CONCLUSIONS: Rimegepant was safe and generally well tolerated at single oral doses up to 1500 mg and multiple doses up to 600 mg/day for 14 days in healthy participants in this study. Median terminal half-life ranged from 8-12 hours across the wide range of single doses studied.

Efficacy of rimegepant for the acute treatment of migraine based on triptan treatment experience: Pooled results from three phase 3 randomized clinical trials.

BACKGROUND: This post-hoc analysis from three phase 3 treatment trials of rimegepant 75 mg - an oral small molecule calcitonin gene-related peptide receptor antagonist for acute and preventive treatment of migraine - assessed efficacy in adults with migraine based on triptan treatment experience. METHODS: Participants were assigned to one of four groups based on triptan treatment experience: insufficient response (e.g. lack of efficacy and/or poor tolerability) to 1 triptan, insufficient response to ≥2 triptans, current triptan users, and triptan-naïve participants. The co-primary efficacy endpoints were pain freedom and most bothersome symptom freedom at two hours postdose. RESULTS: In the three trials (N = 3507; rimegepant n = 1749, placebo n = 1758), 1235 (35.2%) participants had a history of insufficient response to 1 triptan (n = 910 [25.9%]) or ≥2 triptans (n = 325 [9.3%]), and 2272 (64.8%) had no history of insufficient response to triptans (current use = 595 [17.0%], naïve = 1677 [47.8%]). Rimegepant was effective on the co-primary endpoints in all subgroups (p ≤ 0.013), except for freedom from the most bothersome symptom in the triptan-naïve group (p = 0.06). No differences on co-primary endpoints were found in pairwise comparisons of rimegepant-treated participants. CONCLUSIONS: Rimegepant was effective for the acute treatment of migraine in adults with a history of insufficient response to 1 or ≥2 triptans and in current triptan users. Efficacy on co-primary endpoints did not differ based on the number of insufficient triptan responses.Trial registration: Clinicaltrials.gov: NCT03235479, NCT03237845, NCT03461757.

Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine.

BACKGROUND: Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene-related peptide receptor antagonist that may be effective in acute migraine treatment. METHODS: In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered. RESULTS: A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The most common adverse events were nausea and urinary tract infection. CONCLUSIONS: Treatment of a migraine attack with the oral calcitonin gene-related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo. (Funded by Biohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.).

Effect of Decreasing County Mental Health Services on the Emergency Department.

STUDY OBJECTIVE: We evaluate the effect of decreasing county mental health services on the emergency department (ED). METHODS: This is a retrospective before-and-after study at a Level I academic university hospital adjacent to the county mental health treatment center. On October 1, 2009, the county decreased its inpatient psychiatric unit from 100 to 50 beds and closed its outpatient unit. Electronic health record data were collected for ED visits for the 8 months before the decrease in county services (October 2008 to May 2009) and the 8 months after the decrease (October 2009 to May 2010). Data for all adult patients (≥18 years) evaluated for a psychiatric consultation by a licensed clinical social worker were included. Outcome measures included the number of patients evaluated and the ED length of stay for those patients. RESULTS: One thousand three hundred ninety-two patient visits included a psychiatry consultation for the study period. The median age was 38 years (interquartile range [IQR] 27, 49), with no difference in age between periods. The mean number of daily psychiatry consultations increased from 1.3 (95% confidence interval [CI] 1.2 to 1.5) before closure to 4.4 (95% CI 4.1 to 4.7) afterward, with a difference in means of 3.0 visits (95% CI 2.7 to 3.3 visits). Average ED length of stay for psychiatry consultation patients was 14.1 hours (95% CI 13.1 to 15.0 hours) before closure and 21.9 hours (95% CI 20.7 to 23.2 hours) afterward, with a difference in means of 7.9 hours (95% CI 5.5 to 10.2 hours). CONCLUSION: The number of visits and length of stay for patients undergoing psychiatric consultation in the ED increased significantly after a decrease in county mental health services. This phenomenon has important implications for future policy to address the challenges of caring for patients with psychiatric needs in our communities.

Variation in specialists' reported hospitalization practices of children sustaining blunt abdominal trauma.

INTRODUCTION: Children with blunt abdominal trauma (BAT) are often hospitalized despite no intervention. We identified factors associated with emergency department (ED) disposition of children with BAT and differing computed tomography (CT) findings. METHODS: We surveyed pediatric and general emergency physicians (EPs), pediatric and trauma surgeons regarding care of 2 hypothetical asymptomatic patients: a 9-year-old struck by a slow-moving car (Case 1) and an 11-month-old who fell 10 feet (Case 2). We presented various abdominal CT findings and asked physicians about disposition preferences. We evaluated predictors of patient discharge using multivariable regression analysis, adjusting for hospital and ED characteristics, and clinician experience. Pediatric EPs served as the reference group. RESULTS: Of 2,003 eligible surveyed, 636 (32%) responded. For normal CTs, 99% would discharge in Case 1 and 88% in Case 2. Prominent specialty differences included: for trace intraperitoneal fluid (TIF), 68% would discharge in Case 1 and 57% in Case 2. Patients with TIF were less likely to be discharged by pediatric surgeons (Case 1: OR 0.52, 95% CI 0.32, 0.82; Case 2: OR 0.49, 95% CI 0.30, 0.79). Patients with renal contusions were less likely to be discharged by pediatric surgeons (Case 1: OR 0.55, 95% CI 0.32, 0.95) and more likely by general EPs (Case 1: OR 1.83, 95% CI 1.25, 2.69; Case 2: OR 2.37, 95% CI 1.14, 4.89). CONCLUSION: Substantial variation exists between specialties in reported hospitalization practices of asymptomatic children after abdominal trauma with minor CT findings. Better evidence is needed to guide disposition decisions.

Variation in specialists' reported hospitalization practices of children sustaining blunt head trauma.

INTRODUCTION: Questions surround the appropriate emergency department (ED) disposition of children who have sustained blunt head trauma (BHT). Our objective was to identify physician disposition preferences of children with blunt head trauma (BHT) and varying computed tomography (CT) findings. METHODS: WE SURVEYED PEDIATRIC AND GENERAL EMERGENCY PHYSICIANS (EP), PEDIATRIC NEUROSURGEONS (PNSURG), GENERAL NEUROSURGEONS (GNSURG), PEDIATRIC SURGEONS (PSURG) AND TRAUMA SURGEONS REGARDING CARE OF TWO HYPOTHETICAL PATIENTS: Case 1: a 9-year-old who fell 10 feet and Case 2: an 11-month-old who fell 5 feet. We presented various CT findings and asked physicians about disposition preferences. We evaluated predictors of patient discharge using multivariable regression analysis adjusting for hospital and ED characteristics and clinician experience. Pediatric EPs served as the reference group. RESULTS: Of 2,341 eligible surveyed, 715 (31%) responded. Most would discharge children with linear skull fractures (Case 1, 71%; Case 2, 62%). Neurosurgeons were more likely to discharge children with small subarachnoid hemorrhages (Case 1 PNSurg OR 6.87, 95% CI 3.60, 13.10; GNSurg OR 6.54, 95% CI 2.38, 17.98; Case 2 PNSurg OR 5.38, 95% CI 2.64, 10.99; GNSurg OR 6.07, 95% CI 2.08, 17.76). PSurg were least likely to discharge children with any CT finding, even linear skull fractures (Case 1 OR 0.14, 95% CI 0.08, 0.23; Case 2 OR 0.18, 95% CI 0.11, 0.30). Few respondents (<6%) would discharge children with small intraventricular, subdural, or epidural bleeds. CONCLUSION: Substantial variation exists between specialties in reported hospitalization practices of neurologically-normal children with BHT and traumatic CT findings.

The impact of inpatient boarding on ED efficiency: a discrete-event simulation study.

In this study, a discrete-event simulation approach was used to model Emergency Department's (ED) patient flow to investigate the effect of inpatient boarding on the ED efficiency in terms of the National Emergency Department Crowding Scale (NEDOCS) score and the rate of patients who leave without being seen (LWBS). The decision variable in this model was the boarder-released-ratio defined as the ratio of admitted patients whose boarding time is zero to all admitted patients. Our analysis shows that the Overcrowded(+) (a NEDOCS score over 100) ratio decreased from 88.4% to 50.4%, and the rate of LWBS patients decreased from 10.8% to 8.4% when the boarder-released-ratio changed from 0% to 100%. These results show that inpatient boarding significantly impacts both the NEDOCS score and the rate of LWBS patient and this analysis provides a quantification of the impact of boarding on emergency department patient crowding.