Efficacy and safety of eptinezumab for migraine prevention in patients with prior preventive treatment failures: subgroup analysis of the randomized, placebo-controlled DELIVER study.

BACKGROUND: Migraine is a disabling neurological disease adversely affecting many aspects of life. Most patients are still required to have failed several older oral preventive therapies before being reimbursed for a preventive, migraine-specific anti-calcitonin gene-related peptide treatment. In the 24-week placebo-controlled portion of DELIVER, eptinezumab was shown to reduce migraine frequency and resulted in higher migraine responder rates compared with placebo in patients with two to four previous preventive treatment failures. This subgroup analysis assessed if demographic or clinical characteristics were associated with differences in preventive benefits. METHODS: Migraine frequency reductions and responder rates (i.e., the proportion of patients reaching a ≥50% and ≥75% reduction in monthly migraine days relative to baseline) were determined in the total population and predefined subgroups by sex, age, migraine frequency (chronic migraine, episodic migraine, high-frequency episodic migraine, low-frequency episodic migraine), medication overuse, medication-overuse headache, and previous preventive treatment failures (2, >2). The primary endpoint was change from baseline in monthly migraine days over weeks 1-12. RESULTS: Eptinezumab 100 and 300 mg reduced monthly migraine days more than placebo over weeks 1-12 (-4.8 and -5.3 vs -2.1, respectively; p < 0.0001). In most subgroups, eptinezumab-treated patients demonstrated larger monthly migraine days reductions from baseline over weeks 1-12 than patients receiving placebo, with reductions maintained or increased over weeks 13-24. For ≥50% and ≥75% migraine responder rates, the odds ratios versus placebo all numerically favored eptinezumab. CONCLUSION: Eptinezumab had larger monthly migraine days reductions and higher responder rates than placebo across clinically relevant subgroups showing that, across different demographic populations and clinical characteristics, eptinezumab is effective in patients with migraine and prior preventive treatment failures.Trial Registration: ClinicalTrials.gov (Identifier: NCT04418765).

Eptinezumab improved patient-reported outcomes and quality of life in patients with migraine and prior preventive treatment failures.

BACKGROUND AND PURPOSE: In the phase 3b, randomized, double-blind, placebo-controlled DELIVER clinical trial, eptinezumab reduced migraine frequency and headache in adults with two to four prior preventive treatment failures. Here, the effect of eptinezumab on coinciding patient-reported outcomes is reported. METHODS: Adults were randomized to receive eptinezumab 100, 300 mg or placebo intravenously at weeks 12 and 24. The EQ-5D-5L, measuring overall patient health, and the six-item Headache Impact Test were completed every 4 weeks. The Patient Global Impression of Change was completed at weeks 4, 12 and 24. Patient-identified most bothersome symptom and the Migraine-Specific Quality of Life Questionnaire were administered at weeks 12 and 24. RESULTS: Eptinezumab improved patient-reported outcomes more than placebo, starting at week 4 and at all subsequent time points. By week 12, patients' overall health (EQ-5D-5L visual analog scale score) improved with eptinezumab treatment (difference from placebo in change from baseline: 100 mg, 5.1, 95% confidence interval [CI] 2.2, 8.1, p < 0.001; 300 mg, 7.5, 95% CI 4.5, 10.4, p < 0.0001). At week 12, eptinezumab improved headache-related quality of life (difference from placebo in change from baseline in Headache Impact Test total score: 100 mg, -3.8, 95% CI -5.0, -2.5, p < 0.0001; 300 mg, -5.4, 95% CI -6.7, -4.2, p < 0.0001), including each Migraine-Specific Quality of Life Questionnaire domain (p ≤ 0.0001, all comparisons). Over twice as many patients receiving eptinezumab than placebo reported much or very much improvement on the Patient Global Impression of Change and patient-identified most bothersome symptom. CONCLUSION: Patients with two to four prior preventive treatment failures receiving eptinezumab versus placebo reported greater improvements in well-being, quality of life and most bothersome symptoms compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04418765; EudraCT identifier: 2019-004497-25.

Effects of eptinezumab on self-reported work productivity in adults with migraine and prior preventive treatment failure in the randomized, double-blind, placebo-controlled DELIVER study.

BACKGROUND: The multinational phase 3b DELIVER trial was designed to evaluate the efficacy and safety of eptinezumab for migraine prevention in patients with prior preventive treatment failures across 17 countries. In the placebo-controlled portion, eptinezumab relative to placebo demonstrated greater reductions in migraine and headache frequency, migraine and headache severity, and acute medication use. The objective of this report is to describe the effects of eptinezumab on self-reported work productivity in the placebo-controlled portion of DELIVER. METHODS: Adults 18-75 years of age with migraine and documented evidence of 2 to 4 prior preventive treatment failures in the past 10 years were randomized to receive eptinezumab 100 mg, 300 mg, or placebo intravenously (IV) every 12 weeks. The Work Productivity and Activity Impairment questionnaire specific to migraine (WPAI:M), which comprises 6 items (4 of which are completed by currently employed patients only), was administered every 4 weeks. Changes from baseline in subscores (absenteeism, presenteeism, work productivity loss, and activity impairment) were calculated based on item responses. A mixed model for repeated measures was used to analyze changes from baseline in WPAI:M subscores. RESULTS: A total of 890 adults (mean age, 43.8 years) were included in the full analysis set (eptinezumab 100 mg, n = 299; eptinezumab 300 mg, n = 293; placebo, n = 298). Mean WPAI:M subscores at baseline indicated a negative impact of migraine attacks on work productivity and ability to complete normal daily activities. Eptinezumab improved WPAI:M subscores more than placebo at all assessment points throughout the study. Mean changes from baseline in self-reported work productivity loss were -19.5, -24.0, and -9.7 at Week 12; and -22.6, -20.2, and -7.2 at Week 24 (all P < 0.001 vs placebo) for eptinezumab 100 mg, eptinezumab 300 mg, and placebo, respectively. Mean changes from baseline in activity impairment were -21.3, -23.8, and -11.2 at Week 12; and -24.7, -22.6, and -10.1 at Week 24 (all P < 0.0001 vs placebo). Similarly, mean improvements in absenteeism and presenteeism were greater in the eptinezumab groups than in the groups receiving placebo at all timepoints (P < 0.05). CONCLUSION: In adults with migraine and prior preventive treatment failure, eptinezumab 100 mg and 300 mg IV every 12 weeks improved absenteeism, presenteeism, work productivity loss, and activity impairment more than placebo. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765 ); EudraCT (Identifier: 2019-004497-25) ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004497-25/PL ). Eptinezumab improves self-reported work productivity in patients with migraine and prior preventive treatment failures.

Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): a multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial.

BACKGROUND: The monoclonal antibody eptinezumab, which targets calcitonin gene-related peptide, has shown migraine preventive effects starting the day following infusion and acceptable safety and tolerability in phase 3 trials, but benefits in the subpopulations of patients with previous preventive treatment failures were not examined. We aimed to investigate the safety and efficacy of eptinezumab for migraine prevention in adults with migraine and two-to-four previous preventive treatment failures. METHODS: DELIVER was a multicentre, multi-arm, phase 3b trial comprising a 24-week double-blind, placebo-controlled period and a 48-week dose-blinded extension. We recruited adults with episodic or chronic migraine with at least 4 monthly migraine days (as per International Headache Society guidelines) and documented evidence of two-to-four previous preventive treatment failures within the past 10 years, from 96 study locations across Europe (n=93) and the USA (n=3). Patients were randomly assigned (1:1:1) via a centralised randomisation system, stratified by baseline monthly headache days and country, to eptinezumab 100 mg, eptinezumab 300 mg, or placebo. The primary efficacy endpoint was the change from baseline in mean monthly migraine days (captured using a daily electronic diary) in weeks 1-12, assessed in the full analysis set. All participants and study personnel were masked to study drug assignments. The dose-blinded extension period is ongoing. The trial is registered with ClinicalTrials.gov, NCT04418765, and EudraCT, 2019-004497-25. FINDINGS: Between June 1, 2020, and Oct 7, 2021, 891 individuals were randomly assigned and received at least one dose of study drug (safety population; eptinezumab 100 mg n=299 [34%], eptinezumab 300 mg n=294 [33%], placebo n=298 [33%]). 865 patients completed the placebo-controlled period. The change from baseline to weeks 1-12 in mean monthly migraine days was -4·8 (SE 0·37) with eptinezumab 100 mg, -5·3 (0·37) with eptinezumab 300 mg, and -2·1 (0·38) with placebo. The difference from placebo in change in mean monthly migraine days from baseline was significant with eptinezumab 100 mg (-2·7 [95% CI -3·4 to -2·0]; p<0·0001) and eptinezumab 300 mg (-3·2 [-3·9 to -2·5]; p<0·0001). Treatment-emergent adverse events occurred in 127 (42%) of 299 patients in the eptinezumab 100 mg group, in 120 (41%) of 294 in the eptinezumab 300 mg group, and in 119 (40%) of 298 in the placebo group. The most common treatment-emergent adverse event was COVID-19 (20 [7%] of 299 patients in the eptinezumab 100 mg group, 17 [6%] of 294 in the eptinezumab 300 mg group, and 16 [5%] of 298 in the placebo group). Serious adverse events were uncommon (five [2%] of 299 in the eptinezumab 100 mg group, seven [2%] of 294 in the eptinezumab 300 mg group, four [1%] of 298 in the placebo group) and included anaphylactic reaction (eptinezumab 300 mg n=2) and COVID-19 (eptinezumab 100 mg n=1 and eptinezumab 300 mg n=1). INTERPRETATION: In adults with migraine and two-to-four previous preventive treatment failures, eptinezumab provided significant migraine preventive effects compared with placebo, with acceptable safety and tolerability, indicating that eptinezumab might be an effective treatment option for this patient population. The dose-blinded extension period will provide additional long-term safety data in patients with migraine and previous preventive treatment failures. FUNDING: H Lundbeck.

Memantine and brain atrophy in Alzheimer's disease: a 1-year randomized controlled trial.

The primary objective of this study was to evaluate the rate of total brain atrophy (TBA) with serial magnetic resonance imaging (MRI), using the Brain Boundary Shift Integral (BBSI), in patients with probable Alzheimer's disease (AD) over the course of 52 weeks of treatment with memantine or placebo. This was a multi-national, randomized, double-blind, placebo-controlled, fixed-dose 1-year study. Patients were randomized (1 : 1) to treatment with placebo or memantine. Patients randomized to memantine were up-titrated to the target dose of 20 mg/day over 4 weeks. MRI scans were collected at screening and at Weeks 4, 42, and 52. Secondary efficacy assessments included several cognitive and behavioral scales. 518 patients were screened, 278 patients were randomized, and 217 patients completed the study. In the primary efficacy analysis, the differences in TBA rates between memantine (15.2 mL/year) and placebo (15.3 mL/year) were not statistically significant (-0.04 mL/year [(95% CI: -2.60, 2.52), p = 0.98]). There was a statistically significant correlation between change in TBA and change in most cognitive and behavioral scale scores. Patients who were not treated with acetyl cholinesterase inhibitors (AChEIs) showed a significantly lower TBA rate than patients treated with AChEIs. Memantine had a placebo-level incidence of adverse events. There were no statistically significant differences between memantine and placebo in total brain or hippocampal atrophy rates in patients with probable AD treated for 1 year. The biological relevance of cerebral atrophy was supported by a significant correlation between rate of atrophy and decline in cognitive and behavioral outcomes.

Safety and tolerability of once-daily versus twice-daily memantine: a randomised, double-blind study in moderate to severe Alzheimer's disease.

OBJECTIVE: To assess the safety and tolerability of three different dosing schedules of memantine in patients with moderate to severe Alzheimer's disease (AD). METHOD: This 12-week, randomised, double-blind study, investigated three dosing schedules of memantine: OD1 (20 mg once daily with a 1-step up-titration); OD3 (20 mg once daily with a 3-step up-titration); and BID3 (10 mg twice daily with a 3-step up-titration as currently recommended in the memantine labelling). The study comprised 78 patients with moderate to severe AD (DSM-IV-TR criteria; MMSE score < or = 18), 70% of whom were on stable dosing of acetylcholinesterase inhibitor (AChEI) initiated > or = 3 months prior to study start. Safety and tolerability were assessed by the number of withdrawals, adverse events (AEs) and monitoring of vital signs. RESULTS: The number of patient withdrawals was low: 3 of 27 in OD1, 1 of 25 in OD3 and 2 of 26 in BID3. One or more AEs were reported in 9 patients in OD1, 7 patients in OD3 and 12 patients in BID3. Most AEs were mild or moderate, and typical for the population studied; no clinically important differences in AEs or vital signs were observed between the different dosing schedules. There were no between-group differences in efficacy, as assessed by clinical global severity and clinical global change. These results are consistent with the good safety profile of memantine observed in larger studies. CONCLUSIONS: Although relatively small in size, the study indicates that once-daily dosing and twice-daily dosing of memantine are similar in terms of safety and tolerability.