A phase IV clinical trial of gastrointestinal motility in adult patients with migraine before and after initiation of a calcitonin gene-related peptide ligand (galcanezumab) or receptor (erenumab) antagonist.

OBJECTIVE: To compare effects of an initial dose of calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) antagonists on gastrointestinal (GI) motility in patients with migraine and to explore if the mechanistic difference contributes to GI adverse events (AEs). BACKGROUND: Different frequencies of constipation have been observed between CGRP mAbs that target the ligand (galcanezumab [GMB]) or receptor (erenumab [ERE]). METHODS: Patients (n = 65) with migraine without significant GI symptoms were enrolled in a multi-center, single-blind phase IV clinical trial (NCT04294147) and randomized 1:1 to receive GMB (240 mg; n = 33) or ERE (140 mg; n = 32). GI whole and regional transit times were assessed using a wireless motility capsule 1 week before and 2 weeks after mAb administration. The primary endpoint was change from baseline in colonic transit time (CTT) within each treatment group. Other measures included GI Symptom Rating Scale (GSRS), Bristol Stool Form Scale (BSFS), and spontaneous bowel movement (SBM) evaluation. AEs were monitored throughout the study. RESULTS: Baseline characteristics indicated significant GI transit time variability with minimal GI reported symptoms. While not statistically significant, a numerical mean increase in CTT was observed in ERE patients (n = 28, mean [SD] at baseline: 33.8 [29.4] h; least square [LS] mean [SE] change: 5.8 [5.7] h, 95% confidence interval [CI] -5.7 to 17.2, p = 0.320), while GMB decreased CTT (n = 31, mean [SD] at baseline: 29.3 [24.5] h; LS mean [SE] change: -5.4 [5.4] h, 95% CI -16.2 to 5.5, p = 0.328) compared to baseline. No meaningful changes were observed in other regional transit times. ERE significantly reduced BSFS (LS mean [SE] score -0.5 [0.2], p = 0.004) and SBM (LS mean [SE] -1.2 [0.5], p = 0.0120), and increased GSRS-constipation compared to baseline (LS mean [SE] score 0.3 [0.1], p = 0.016). GMB increased GSRS-constipation (LS mean [SE] score 0.4 [0.1], p = 0.002). There were no discontinuations due to or serious AEs. A higher percentage of treatment-emergent AEs were reported with ERE than GMB (ERE: nine of 32 [28.1%] versus GMB: three of 33 [9.1%]), with constipation the most frequently reported (ERE: five of 32 [15.6%] versus GMB one of 33 [3.0%]). CONCLUSION: While the primary endpoint of this study was not met, secondary and tertiary endpoints support a within- and between-treatment change in GI effects suggesting possible mechanistic differences between ligand (GMB) and receptor (ERE) antagonism.

Rapid Onset of Effect of Galcanezumab for the Prevention of Episodic Migraine: Analysis of the EVOLVE Studies.

OBJECTIVE: To evaluate onset of effect of galcanezumab in patients with episodic migraine. BACKGROUND: Galcanezumab is a monoclonal antibody that binds to calcitonin gene-related peptide and is indicated for preventive treatment of migraine. DESIGN/METHODS: Data on the primary outcome measure were analyzed from 2 previously published double-blind, Phase 3 studies (EVOLVE-1 [N = 858] and EVOLVE-2 [N = 915]) wherein adult patients with episodic migraine were randomized to receive monthly subcutaneous injections of galcanezumab 120 mg (with 240-mg loading dose) or 240 mg or placebo for up to 6 months. Monthly onset of effect was defined as the earliest month at which galcanezumab achieved and subsequently maintained statistical superiority to placebo on the mean change from baseline in the number of monthly migraine headache days (MHDs). If onset occurred in Month 1, weekly onset was evaluated and defined as the earliest week at which galcanezumab statistically separated from placebo and maintained statistical separation for remaining weeks in that month. Day of onset of effect was also analyzed, as were monthly and weekly onset, for occurrence of ≥50% reduction from baseline in number of MHDs. RESULTS: For both studies, change from baseline in monthly MHDs showed a statistically significant separation of galcanezumab from placebo at Month 1 and each subsequent month (each P < .001). Analysis of the first month for both studies indicated onset of effect in the first week, with galcanezumab-treated patients having significantly higher odds of having fewer MHDs in the first week (odds ratio [95% confidence interval] for EVOLVE-1, 2.71 [2.00, 3.66], and for EVOLVE-2, 2.88 [2.16, 3.86]; both P < .001) and each subsequent week compared with placebo-treated patients (P ≤ .004). Daily analysis showed onset of effect at Day 1 (first day after injection day). Galcanezumab also demonstrated superiority to placebo on occurrence of ≥50% reduction in MHDs starting at Week 1 (percentage of patients with 50% response in galcanezumab group vs placebo group for EVOLVE-1, 54.3% vs 32.4% [P < .001], and for EVOLVE-2, 59.4% vs 38.0% [P < .001]). CONCLUSION: Rapid onset of preventive effect on the first day after injection of galcanezumab was confirmed in both studies of episodic migraine.

Galcanezumab Provides Consistent Efficacy Throughout the Dosing Interval Among Patients with Episodic and Chronic Migraine: A Post Hoc Analysis.

INTRODUCTION: The consistency of the treatment effect of galcanezumab throughout the dosing interval is examined in patients with episodic and chronic migraine. METHODS: This study was a post hoc analysis of clinical trial data from episodic (EVOLVE-1; EVOLVE-2; both 6-month duration) and chronic (REGAIN; 3-month duration) migraine double-blind trials evaluating the efficacy of a once-monthly injection of galcanezumab 120 mg relative to placebo. Adults with episodic (placebo, n = 894; galcanezumab, n = 444) or chronic migraine (placebo, n = 558; galcanezumab, n = 278) were included. Mean change from baseline in weekly migraine headache days, averaged across all months for each week of the dosing interval, was compared between groups and within the galcanezumab group during weeks 1 and 4. Additional analyses examined the mean difference from placebo in weekly migraine headache days and a day-by-day analysis. RESULTS: Weekly migraine headache day reduction was significantly greater with galcanezumab relative to placebo every week (P < 0.001) and did not differ during weeks 1 and 4 for those with episodic (P = 0.740) or chronic migraine (P = 0.231) taking galcanezumab. Estimated probabilities of migraine on day 2 and day 30 did not differ for those with episodic (P = 0.61) or chronic migraine (P = 0.616) taking galcanezumab. CONCLUSION: This analysis demonstrates once monthly galcanezumab exhibits consistent efficacy throughout the dosing interval among the population of patients with migraine in three clinical trials evaluating the efficacy of galcanezumab. There is no evidence from these trials that the effect of galcanezumab "wears off" at the end of the dosing interval. TRIAL REGISTRATION: ClinicalTrials.gov identifier: EVOLVE-1 (NCT02614183); EVOLVE-2 (NCT02614196); REGAIN (NCT02614261).

Demographic and clinical characteristics of prevention-eligible patients with migraine in the US: a linked national survey and administrative claims database study.

OBJECTIVE: To characterize burden of migraine in prevention-eligible patients compared with prevention non-eligible patients in the United States (US). Receipt of preventive therapy was also examined among prevention-eligible patients. METHODS: This retrospective study utilized data from the 2017 US National Health and Wellness Survey linked with medical and pharmacy claims. Patients aged ≥18 years who self-reported experiencing migraine and had confirmed evidence of migraine (≥1 medical or pharmacy claim) were included. Prevention eligibility was based on number of headache days in the past 30 days (prevention-eligible: ≥4 and prevention non-eligible: <4). Descriptive statistics summarized study variables; bivariate and multivariable analyses were conducted to examine the association of prevention-eligibility status with outcomes. RESULTS: Analyses included 450 patients, 291 (65%) prevention-eligible, and of these 56 (19%) received preventive therapy. Overall, patients were 42.98 ± 14.51 years old; 84% were female. Prevention-eligible patients reported significantly more migraine headache days in the past 6 months (29.27 ± 37.96 vs. 8.61 ± 7.88), had lower mental component summary scores (35.80 ± 2.73 vs. 37.90 ± 2.96), and more presenteeism (47.30 ± 2.98% vs. 37.90 ± 2.60%), overall work impairment (46.30 ± 2.87% vs. 37.90 ± 2.55%) and activity days missed due to migraine (8.16 ± 3.05 vs. 3.82 ± 1.58) than prevention non-eligible patients (all p<.001). Prevention-eligible patients receiving preventive therapy reported more migraine headache days during the past month (9.21 ± 7.99 vs. 6.06 ± 7.10; p=.002) and activity days lost due to migraine (18.39 ± 28.08 vs. 10.69 ± 21.43, p=.015) than those not receiving preventive therapy. CONCLUSIONS: Prevention-eligible patients experience greater burden due to migraine, including more headache days, worse health-related quality-of-life, and greater work and activity impairment than prevention non-eligible patients.

Efficacy and Safety of Galcanezumab for the Preventive Treatment of Migraine: A Narrative Review.

Migraine is a debilitating neurologic disease. People who experience migraine can have substantial disability, impaired functioning and a decreased quality of life (QoL). Expert recommendations suggest that people with frequent migraine attacks or severe impairment related to attacks may benefit from preventive treatment. Despite these recommendations and the existence of evidence-based guidelines for the use of preventive medication, many people who are candidates for preventive therapies do not receive them. Thus, there is still a substantial unmet need for preventive migraine treatment. Calcitonin gene-related peptide (CGRP) has a demonstrated role in the pathophysiology of migraine. Galcanezumab-gnlm (galcanezumab) is a humanized monoclonal antibody that binds to the CGRP ligand and prevents binding to its receptor. It is administered as a once-monthly subcutaneous injection. The aim of this review is to present a comprehensive overview of the existing short- and long-term efficacy and safety data for galcanezumab in patients with migraine. Data from the phase 3, randomized, double-blind, placebo-controlled EVOLVE-1, EVOLVE-2 and REGAIN studies show that galcanezumab treatment for 3 or 6 months results in overall reduction in mean monthly migraine headache days in patients with episodic (EVOLVE-1 and EVOLVE-2) and chronic (REGAIN) migraine. Greater proportions of patients with episodic migraine receiving galcanezumab versus placebo demonstrated a ≥ 50%, ≥ 75% and 100% response to therapy and reported a lower level of disability and an improvement in functioning and QoL. Similarly, when compared with placebo, greater proportions of patients with chronic migraine treated with galcanezumab demonstrated a ≥ 50% and ≥ 75% response and reported improved functioning. A 12-month open-label study demonstrated the continued efficacy of galcanezumab for up to 12 months. In all studies galcanezumab was well tolerated. In conclusion, data from pivotal studies show that galcanezumab may fulfill an unmet need in the treatment of patients with migraine who require preventive therapy.

Migraine is a significant contributor to the global burden of disease. Migraine symptoms can lead to substantial disability and can significantly impact an individual's ability to perform everyday tasks and their overall quality of life. While individuals with infrequent migraine attacks might have success with acute treatments alone, those with more frequent attacks or who have severe migraine-related impairment may require preventive treatment. Although recommendations on the use of preventive treatment exist, only about one-third of individuals who qualify for preventive therapy actually receive it, resulting in a substantial unmet need. Calcitonin gene-related peptide (CGRP) has a demonstrated role in migraine. Galcanezumab is a humanized monoclonal antibody that binds to the CGRP ligand and prevents receptor binding. In clinical trials of patients with ≥ 4 migraine headache days per month, treatment with galcanezumab was associated with a reduction in the average number of migraine headache days per month. The majority of galcanezumab groups had greater responder rates compared with the placebo groups, and levels of disability and daily functioning were generally improved. Galcanezumab was well tolerated, with the most common adverse events being injection site reactions. The results from the clinical trials of galcanezumab suggest that this drug may fulfill an unmet need in the treatment of individuals with migraine who require preventive therapy.

Malnutrition in the ICU patient population.

Malnutrition has been identified as a cause for disease as well as a condition resulting from inflammation associated with acute or chronic disease. Malnutrition is common in acute-care settings, occurring in 30% to 50% of hospitalized patients. Inflammation has been associated with malnutrition and malnutrition has been associated with compromised immune status, infection, and increased intensive care unit (ICU) and hospital length of stay. The ICU nurse is in the best position to advocate for appropriate nutritional therapies and facilitate the safe delivery of nutrition.

Practice tips and tools for the successful use of U-500 regular human insulin: the diabetes educator is key.

This review provides information to equip diabetes educators to instruct and guide patients in using U-500 human regular insulin (U-500R). The article includes an overview of U-500R pharmacology and clinical data, strategies for outpatient and inpatient use, and tools for patient education. U-500R is useful for treating patients with any type of diabetes who require high doses of insulin. U-500R alleviates the volume-related problems associated with high doses of U-100 insulin, making treatment with high doses of insulin more feasible (because of the need for fewer injections for patients) as well as more cost-efficient and potentially more effective. These tools can help diabetes educators feel more comfortable and confident as they advise and educate patients who receive high-dose U-500R as part of their overall diabetes care plan. The diabetes educator plays a vital role in helping patients use U-500R safely and successfully.

Seizure prophylaxis in neurocritical care: a review of evidence-based support.

Seizures are a well-described complication of acute brain injury and neurosurgery. Antiepileptic drugs (AEDs) are frequently utilized for seizure prophylaxis in neurocritical care patients. In this review, the Neurocritical Care Society Pharmacy Section describes the evidence associated with the use of AEDs for seizure prophylaxis in patients with intracerebral tumors, traumatic brain injury, aneurysmal subarachnoid hemorrhage, craniotomy, ischemic stroke, and intracerebral hemorrhage. Clear evidence indicates that the short-term use of AEDs for seizure prophylaxis in patients with traumatic brain injury and aneurysmal subarachnoid hemorrhage may be beneficial; however, evidence to support the use of AEDs in other disease states is less clear.

Addressing safety concerns about U-500 insulin in a hospital setting.

PURPOSE: Safety precautions for the use of U-500 insulin in a hospital setting are described. SUMMARY: St. Vincent Indianapolis Hospital, a 500-bed community hospital, formed a committee to develop a U-500 insulin policy to address the unique considerations required for this drug at all steps of the medication management process. An order set was designed by the multidisciplinary team to standardize prescribing and ensure safety measures are consistently applied. Home dose verification by a pharmacist or certified diabetes educator is required to avoid inaccurate dosing. U-500 insulin is not stocked or stored in the automated dispensing machines on the nursing unit. When an order for U-500 insulin is received, a two-pharmacist order-entry process unique to this drug is followed. The total dose in units is entered, and the computer converts the dose to volume. A pharmacist checklist and dispensing kit are stored with the product to ensure that all safety precautions have been completed. A pharmacist hand delivers the insulin to the charge nurse and bedside nurse, at which time a safety time-out is taken to review the key characteristics of the drug, the physician order, and the medication administration record. Tuberculin syringes are used to administer U-500 insulin, and patients are taught how to use this syringe. Staff members also receive education regarding the U-500 insulin policy and procedure. CONCLUSION: Safety precautions for hospital use of U-500 insulin employed a multilayered, multidisciplinary process using safeguards at every step in the medication management process.