Burden of Medication Overuse in Migraine: A Cross-sectional, Population-Based Study in Five European Countries Using the 2020 National Health and Wellness Survey (NHWS).

INTRODUCTION: Overuse of medication to treat migraine attacks can lead to development of a new type of headache or significant worsening of pre-existing headache, known as medication overuse headache. However, data concerning the burden of medication overuse (MO) in migraine are limited. This study aimed to assess the humanistic burden of MO in individuals with migraine from five European countries. METHODS: Data are from the 2020 National Health and Wellness Survey-a cross-sectional, population-based survey conducted in France, Germany, Italy, Spain, and the UK. Data were included from adults (≥ 18 years) with a self-reported diagnosis of migraine and at least one migraine attack and one headache in the past 30 days. MO was defined as (i) use of simple analgesics/over-the-counter medications on ≥ 15 days/month; or (ii) use of migraine medication, including combination analgesics, on ≥ 10 days/month. Humanistic burden of MO was assessed using the 12-Item Short-Form Health Survey (SF-12v2), EuroQol 5-Dimensions 5-Levels (EQ-5D), Short-Form 6-Dimensions (SF-6D), and Migraine Disability Assessment (MIDAS). The association of MO with humanistic burden was evaluated using generalized linear models adjusted for potential confounders in the full migraine population and in subgroups defined by headache frequency (monthly headache days [MHDs] 1-3, 4-7, 8-14, or ≥ 15). RESULTS: Among individuals with migraine, humanistic burden (SF-12v2, SF-6D, EQ-5D, and MIDAS) was higher in individuals who reported MO (n = 431) versus no MO (n = 3554), even after adjustment for confounding variables (p < 0.001 for all measures). MIDAS and EQ-5D scores were higher in individuals with MO than without, at all levels of headache frequency. For SF-12v2 and SF-6D, differences between groups with/without MO were seen only at lower levels of headache frequency (MHD 1-3 and 4-7). CONCLUSION: Among people with migraine, those who report MO face a greater humanistic burden than those without MO, irrespective of headache frequency.

Adding eptinezumab to brief patient education to treat chronic migraine and medication-overuse headache: Protocol for RESOLUTION-A phase 4, multinational, randomized, double-blind, placebo-controlled study.

Introduction: Migraine is a highly prevalent and disabling neurological disease. Excessive use of acute medications can lead to medication-overuse headache (MOH), occurring when a patient experiences an increasing number of headache and migraine days, despite taking greater amounts of acute medication. To treat MOH, a preventive migraine treatment and/or withdrawal of the overused medication(s) are advised. Brief Educational Intervention (BEI) has been shown to be an effective tool with promising results for MOH. Here, we report the design of a clinical trial that aims to evaluate the efficacy of eptinezumab, an anti-calcitonin gene-related peptide preventive migraine treatment, as an add-on to BEI for treatment of MOH in those with chronic migraine. Methods and analysis: RESOLUTION will be a phase 4, multi-national, randomized, double-blind, placebo-controlled study. This study will enroll approximately 570 participants with dual diagnoses of chronic migraine and MOH. Eligible patients will be randomly allocated to one of two treatment groups, BEI and eptinezumab (100 mg; n = 285) or BEI and placebo (n = 285), in a 1:1 ratio. The primary endpoint is the change from baseline in monthly migraine days over weeks 1-4. Secondary and exploratory endpoints will assess monthly migraine days over weeks 1-12, MOH remission, transition from chronic to episodic migraine, health-related quality of life, work productivity, and the safety and tolerability of eptinezumab in this patient population. Ethics and dissemination: This study will be conducted in accordance with good clinical practice. All patients will be fully informed about the study, including the risks and benefits of participation, and all participants will provide informed consent for participation in the trial and dissemination of results.

Evaluating the clinical utility of the patient-identified most bothersome symptom measure from PROMISE-2 for research in migraine prevention.

OBJECTIVE: To assess the utility of the novel patient-identified (PI) most bothersome symptom (MBS) measure from PROMISE-2, a phase 3 trial of eptinezumab for the preventive treatment of chronic migraine. BACKGROUND: Relief of bothersome migraine symptoms can influence satisfaction with treatment and therapeutic persistence. Understanding the impact of preventive treatment on a PI-MBS could improve clinical decision-making. METHODS: In PROMISE-2, patients with chronic migraine received eptinezumab 100, 300 mg, or placebo administered intravenously every 12 weeks for up to 2 doses (n = 1072). PI-MBS was an exploratory outcome requiring each patient to self-report their MBS in response to an open-ended question. At baseline and week 12, patients rated overall improvement in PI-MBS. The relationships among PI-MBS at week 12 and change in monthly migraine days (MMDs) from baseline to month 3 (weeks 9-12), Patient Global Impression of Change at week 12, and changes from baseline to week 12 in the 6-item Headache Impact Test total, EuroQol 5-dimensions 5-levels visual analog scale, and 36-item Short-Form Health Survey component scores were assessed. RESULTS: Treatment groups had similar baseline characteristics and reported a total of 23 unique PI-MBS, most commonly light sensitivity (200/1072, 18.7%), nausea/vomiting (162/1072, 15.1%), and pain with activity (147/1072, 13.7%). Improvements in PI-MBS at week 12 correlated with changes in MMDs (ρ = -0.49; p < 0.0001) and other patient-reported outcomes. Controlling for changes in MMDs, PI-MBS improvement predicted other patient-reported outcomes in expected directions. The magnitude of the standardized mean differences between placebo and active treatment for PI-MBS were 0.31 (p < 0.0001 vs. placebo) and 0.54 (p < 0.0001 vs. placebo) for eptinezumab 100 and 300 mg, respectively. CONCLUSIONS: Improvement in PI-MBS at week 12 was associated with improvement in other patient-reported outcome measures, and PI-MBS may be an important patient-centered measure of treatment benefits in patients with chronic migraine.

Brief international cognitive assessment for multiple sclerosis (BICAMS): A danish validation study of sensitivity in early stages of MS.

BACKGROUND: Cognitive impairment is highly prevalent in multiple sclerosis (MS). Due to the lack of specialized neuropsychological resources in many MS clinics, a brief cognitive monitoring tool that can be administered by other MS clinic staff is needed. BICAMS (Brief International Cognitive As-sessment for Multiple Sclerosis) has been developed and recommended by MS experts to monitor MS-related cognitive impairment. International validations of the tool are warranted. OBJECTIVE: The primary aim of the study was to establish a Danish translation of BICAMS as a feasible cognitive monitoring tool and to provide a Danish contribution to the international validation of BI-CAMS. A secondary aim was to determine if BICAMS correlated with self-reported cognition. The study population comprised people with MS (pwMS) with relatively early MS and newly diagnosed. METHODS: 65 pwMS were compared to healthy controls (HCs) matched on age, sex and education. PwMS and controls completed the BICAMS test battery which includes the Symbol Digit Modalities Test (SDMT, oral version), California Verbal Learning Test-II (CVLT-II) and the Brief Visuospatial Memory Test-Revised (BVMT-R). In addition, self-reported cognition, fatigue, depression and quality of life were assessed. To evaluate the reliability of the BICAMS test, all participants were retested 2-3 weeks later with alternate versions of the tests. RESULTS: Mean age of the MS group was 37.2 years; 63% were female and all pwMS had a relapsing-remitting disease course. MS disease duration was relatively short; mean disease duration was 3.9 years and 32 of 65 pwMS (49%) were newly diagnosed with MS, i.e. diagnosed within the last 2 years. Mean EDSS was 1.8 with a span from 0-4. Comparison of the groups showed that the MS group performed significantly below the control group on the 3 BICAMS measures: SDMT (p<0.005), CVLT-II (p<0.05) and BVMT-R (p<0.05). When the results were controlled for influence from depression and fatigue by regression analysis, group differences were limited to the SDMT (p<0.05) and the BVMT-R (p<0.05) and these group differences were only found at the retest session. The BICAMS measures were reliable over time (r = 0.90 for SDMT, r = 0.82 for CVLT-II and r = 0.68 for BVMT-R). 32.3% of the MS population was cognitively impaired on at least one of the 3 BICAMS tests (defined as -1.5 SD compared to HCs). In the MS group 20% were impaired on the SDMT; 16.9% were impaired on the BVMT-R and 10.7% were impaired on the CVLT-II. There was no relationship between BICAMS test-scores and subjectively reported cognition, fatigue or depression. CONCLUSION: The Danish translation of BICAMS was a reliable and feasible cognitive assessment tool. This finding was confirmed even in an MS population characterized by relatively early MS and high cognitive reserve. Frequency of cognitive dysfunction detected by BICAMS in this study was relatively low due to population characteristics.

NS11821, a partial subtype-selective GABAA agonist, elicits selective effects on the central nervous system in randomized controlled trial with healthy subjects.

NS11821 is a partial GABAA agonist with relatively dominant α2,3 and α5 subtype efficacy but negligible α1 agonism. This first-in-human study was performed in healthy male subjects using a single-dose, parallel, double blind, placebo-controlled, randomized, dose-escalation study design. In total six cohorts (N=48) were enrolled. The eight subjects of each cohort received NS11821 (10 mg, 30 mg, 75 mg, 150 mg, 300 mg or 600 mg) or placebo in a 6:2 ratio. At low dose levels, NS11821 had a relatively low exposure and a more-than-proportional increase of the area under the curve and maximum plasma concentrations, probably due to poor solubility. Saccadic peak velocity decreased in a dose-related manner while limited impairments were seen on body sway and the visual analogue scale for alertness. The most common adverse events were somnolence and dizziness, which were more prominent with the higher doses. Although no positive control was used in this study, the results were compared post hoc with a Centre for Human Drug Research dataset for lorazepam 2 mg. The maximum saccadic peak velocity effects seemed comparable to the typical effects of lorazepam, whereas the other central nervous system effects were smaller. These results support the pharmacological selectivity of NS11821 and show that pharmacodynamic effective doses of NS11821 were safe and well tolerated in healthy subjects.

Pharmacokinetics of desmopressin administrated as an oral lyophilisate dosage form in children with primary nocturnal enuresis and healthy adults.

The population pharmacokinetics of desmopressin in children with nocturnal enuresis and in healthy adults were compared using a 1-compartment model with first-order absorption and first-order elimination. In addition, the model consisted of a number of transit compartments before absorption to describe a lag-time. The model gave an adequate description of adult as well as children data and provided a statistically significant better fit to data than a standard lag-time model. The main difference in the pharmacokinetics between children and adults was the absorption delay. The pharmacokinetic difference was minor and presumably of no clinical relevance.

Pharmacokinetic and pharmacodynamic properties of insulin aspart and human insulin.

The preferred approach to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of insulin analogues is the euglycemic glucose clamp. Currently non-compartmental data analytical approaches are used to analyze data. The purpose of the present study is to propose a novel compartmental-model for analysis of data from glucose clamp studies. Data used in this trial only involved 18 of the 20 originally treated subjects. Data was obtained from a crossover trial where 18 healthy subjects each received a single subcutaneous (s.c.) dose of 1.2 nmol/kg (body weight) insulin aspart (IAsp) or 1.2 nmol/kg human insulin (HI) during a euglycemic glucose clamp after overnight fast. Serum insulin and glucose concentrations were measured and the glucose infusion rate (GIR) was adjusted after dosing, to maintain blood glucose near basal levels. Individual model parameters were estimated for IAsp, HI, and the corresponding glucose and GIR data. We found statistically significant differences between most of the HI and IAsp pharmacokinetic parameters, including the sigmoidicity of the time course of absorption (1.5 for HI vs. 2.1 for IAsp (unit less), P = 0.0005, Wilcoxon Signed-rank test), elimination rate constant (0.010 min-1 for HI vs. 0.016 min-1 for IAsp (P = 0.002)). The PD model parameters were mostly not different, except for the rate of insulin action (0.012 min-1 for HI vs. 0.017 min-1 for IAsp (P = 0.03)). The model may provide a framework to account for different PK properties when estimating the PD properties of insulin and insulin analogues in glucose clamp experiments.