Aim Evaluate the efficacy and safety of non-invasive vagus nerve stimulation for migraine prevention. Methods After completing a 4-week diary run-in period, adults who had migraine with or without aura were randomly assigned to receive active non-invasive vagus nerve stimulation or sham therapy during a 12-week double-blind period. Results Of 336 enrolled participants, 113 (active, n = 56; sham, n = 57) completed ≥70 days of the double-blind period and were ≥66% adherent with treatment, comprising the prespecified modified intention-to-treat population. The COVID-19 pandemic led to early trial termination, and the population was ∼60% smaller than the statistical target for full power. Mean reduction in monthly migraine days (primary endpoint) was 3.12 for the active group and 2.29 days for the sham group (difference, −0.83; p = 0.2329). Responder rate (i.e. the percentage of participants with a ≥50% reduction in migraine days) was greater in the active group (44.87%) than the sham group (26.81%; p = 0.0481). Prespecified subgroup analysis suggested that participants with aura responded preferentially. No serious device-related adverse events were reported. Conclusions These results suggest clinical utility of non-invasive vagus nerve stimulation for migraine prevention, particularly for patients who have migraine with aura, and reinforce the well-established safety and tolerability profile of this therapy. Trial Registration: ClinicalTrials.gov (NCT03716505).

OBJECTIVE:To evaluate the efficacy and safety of eptinezumab, a humanized anti-calcitonin gene-related peptide monoclonal antibody, in the preventive treatment of episodic migraine. METHODS:The PRevention Of Migraine via Intravenous ALD403 Safety and Efficacy-1 (PROMISE-1) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Adults with episodic migraine were randomized to eptinezumab 30 mg, 100 mg, 300 mg, or placebo for up to four intravenous (IV) doses administered every 12 weeks. The primary endpoint was change from baseline in monthly migraine days (MMDs) over weeks 1-12. RESULTS:A total of 888 patients received treatment across 84 study sites. Mean MMDs at baseline was ∼8.6 across treatment groups. Eptinezumab 100 mg and 300 mg met the primary endpoint, significantly reducing MMDs across weeks 1-12 compared with placebo (30 mg, -4.0; 100 mg, -3.9, p = 0.0182; 300 mg, -4.3; placebo, -3.2, p = 0.0001). Treatment-emergent adverse events were reported by 58.4% (30 mg), 63.2% (100 mg), 57.6% (300 mg), and 59.5% (placebo) of patients. Treatment-emergent adverse events reported by ≥2% of eptinezumab-treated patients at an incidence greater than placebo included: upper respiratory tract infection (30 mg, 11.4%; 100 mg, 9.9%; 300 mg, 10.3%; placebo, 7.2%), and fatigue (30 mg, 2.3%; 100 mg, 3.6%; 300 mg, 3.6%; placebo, <1%). CONCLUSION:Eptinezumab (100 mg or 300 mg) significantly reduced migraine frequency, was well tolerated, and had an acceptable safety profile when used for the preventive treatment of migraine in adults with episodic migraine. ClinicalTrials.gov identifier: NCT02559895.

Objective: To evaluate the efficacy and safety of eptinezumab for episodic migraine (EM) prevention through 1 year. Background: Eptinezumab, an anti-CGRP monoclonal antibody, selectively inhibits the CGRP ligand, which plays an important role in migraine pathophysiology. Design/Methods: Eligible adults (EM, ICHD-II) were randomized to eptinezumab 30mg, 100mg, 300mg, or placebo, administered intravenously every 12 weeks for 4 infusions. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) over Weeks 1–12. Key secondary endpoints included: ≥75% migraine responder rates (RRs) over Week 1–4; ≥75% and ≥50% migraine RRs over Weeks 1–12. Results: Baseline mean MMDs were ~8.5 across groups in the efficacy population (N=888). In 100mg-treated patients, changes from baseline in MMDs were −3.9 (Months1–3; p=0.018), −4.5 (Months4–6), −4.7 (Months7–9), and −4.5 (Months10–12). The ≥75% migraine RRs were: 30.8% (p=0.011), 22.2% (NS), 33.5%, 40.3%, and 39.4% over Months1, 1–3, 4–6, 7–9, and 10–12, respectively. The ≥50% migraine RRs were: 49.8% (Months1–3; p=0.009), 62.0% (Months4–6), 63.8% (Months7–9), and 64.7% (Months10–12). In 300mg-treated patients, changes from baseline in MMDs were −4.3 (Months1–3; p In placebo-treated patients, the change from baseline in MMDs was −3.2 (Months1–3), −3.8 (Months4–6), −4.0 (Months7–9), and −4.1 (Months10–12). The ≥75% migraine RRs were: 20.3% (Month1), 16.2% (Months1–3), 16.2% (Months4–6), 29.7% (Months7–9), and 39.6% (Months10–12). The ≥50% migraine RRs were: 37.4% (Months1–3), 51.4% (Months4–6), 58.1% (Months7–9), and 55.4% (Months10–12). Treatment-emergent adverse event rates were similar between groups. Conclusions: Eptinezumab reduced MMDs over the first 3 months with sustained or incremental reductions achieved with additional infusions. Migraine RRs were greater with eptinezumab vs placebo across dosing intervals. Disclosure: Dr. Saper has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder Biopharmaceuticals, Autonomic Technologies, Biohaven Pharmaceuticals, Eli Lilly, and Teva. Dr. Saper has received research support from Alder Biopharmaceuticals, Allergan, Amgen, Inc., Avanir Pharmaceuticals, Autonomic Technologies, Inc., Biohaven Pharmaceuticals, Colucid Pharm., Dr. Reddy’s Laboratories, Eli Lilly, lmpax Pharmaceuticals, Scion Neuro Stim LLC, Teva, and Zosano Pharma.. Dr. Wilks has nothing to disclose. Dr. Chakhava has nothing to disclose. Dr. Cady has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder BioPharmaceuticals, Inc. Dr. Schaeffler has nothing to disclose. Dr. Biondi has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder BioPharmaceuticals, Inc.. Dr. Biondi holds stock and/or stock options in Alder BioPharmaceuticals, Inc. Dr. Hirman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder BioPharmaceuticals, Inc. Dr. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alder. Dr. Smith holds stock and/or stock options in Alder.

Evaluate efficacy and safety of quarterly iv infusion of eptinezumab for prevention of frequent episodic migraine (FEM).

Background Safety findings from a Phase 2b study of galcanezumab, a humanized monoclonal antibody against calcitonin gene-related peptide, for prevention of migraine (NCT02163993) are reported here. Methods Patients aged 18–65 years with episodic migraine were evaluated in this multicenter, double-blind, randomized study. After randomization, 410 patients were administered 5, 50, 120 or 300 mg of galcanezumab or placebo subcutaneously once every 4 weeks for 12 weeks, followed by a post-treatment off-drug period lasting 12 weeks. Results Treatment-emergent adverse events (TEAEs) were primarily rated as mild to moderate. Serious adverse events reported in galcanezumab dose groups were appendicitis, Crohn’s disease, suicidal ideation, and congenital ankyloglossia in an infant of a paternal pregnancy; each of these were reported by one patient. Adverse events leading to discontinuation with galcanezumab treatment were abdominal pain, visual impairment, and upper limb fracture, each reported by one patient. Treatment-emergent injection-site reactions were reported significantly more frequently ( p = 0.013) with galcanezumab (13.9%) than with placebo (5.8%). Injection-site pain was the most common injection-site reaction (galcanezumab 11.4%; placebo 2.9%, p = 0.004). Upper respiratory tract infection (galcanezumab 10.0%; placebo 8.8%) and nasopharyngitis (galcanezumab 7.0%; placebo 2.2%) also occurred more frequently with galcanezumab treatment. Potential hypersensitivity events were reported at similar frequencies in galcanezumab (3.3%) and placebo (5.1%) groups. Incidence of treatment-emergent anti-drug antibodies in galcanezumab dose groups (4.6% of patients during treatment period) did not appear to have any meaningful effects on safety, the pharmacokinetics of galcanezumab, or its ability to bind to the target ligand. Conclusion The results from this 3-month Phase 2b study support the initiation of larger Phase 3 trials of longer duration.

ObjectiveTo evaluate the safety and efficacy of a novel solid‐state, caloric vestibular stimulation (CVS) device to provide adjuvant therapy for the prevention of episodic migraine in adult migraineurs.BackgroundMigraine causes significant disability in ∼12% of the world population. No current migraine preventive treatment provides full clinical relief, and many exhibit high rates of discontinuation due to adverse events. Thus, new therapeutic options are needed. CVS may be an effective and safe adjuvant‐therapy for the prevention of episodic migraine.MethodsIn a multicenter, parallel‐arm, block‐randomized, placebo‐controlled clinical trial (clinicaltrials.gov: NCT01899040), subjects completed a 3‐month treatment with the TNM™ device for CVS (refer to Fig. 2 for patient enrollment and allocation). The primary endpoint was the change in monthly migraine days from baseline to the third treatment month. Secondary endpoints were 50% responder rates, change in prescription analgesic usage and difference in total subjective headache‐related pain scores. Device safety assessments included evaluation of any impact on mood, cognition, or balance.ResultsPer‐protocol, active‐arm subjects showed immediate and continued steady declines in migraine frequency over the treatment period. After 3 months of treatment, active‐arm subjects exhibited significantly fewer migraine days (−3.9 ± 0.6 from a baseline burden of 7.7 ± 0.5 migraine days). These improvements were significantly greater than those observed in control subjects (−1.1 ± 0.6 from a baseline burden = 6.9 ± 0.7 migraine days) and represented a therapeutic gain of −2.8 migraine days, CI = −0.9 to −4.7, P = .012. Active arm subjects also reported greater reductions in acute medication usage and monthly pain scores compared to controls. No adverse effects on mood, cognition, or balance were reported. Subjects completed the trial with an average rate of 90% treatment adherence. No serious or unexpected adverse events were recorded. The rate of expected adverse events was similar across the active and the placebo groups, and evaluation confirmed that subject blinding remained intact.ConclusionThe TNM™ device for CVS appears to provide a clinically efficacious and highly tolerable adjuvant therapy for the prevention of episodic migraine.

Objective: To evaluate long-term prevention of episodic migraine with AMG334, a human anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody. Background: CGRP plays a major role in migraine pathogenesis. Methods: Double-blind phase 2 study (NCT01952574) randomized adults (N=483) with episodic migraine to monthly subcutaneous injections of AMG334 (7-mg, 21-mg, or 70-mg) or placebo (2:2:2:3). Primary endpoint (change from baseline in monthly migraine days) and secondary endpoints (50[percnt] responder rate and change in monthly migraine attacks) were assessed at Week 12. After completing the double blind phase (12-week), patients could continue in an open-label extension (OLE) to receive 70-mg AMG334 up to 5 years. This interim analysis is based on available efficacy data up to week 52 from the ongoing OLE and safety data up to Week 76. Results: Baseline mean (SD) monthly migraine days was 8.7 (2.7). At Week 12, reductions from baseline in monthly migraine days were significantly greater with 70-mg AMG334 than placebo (-3.40 vs -2.28; p=0.021), but not with lower AMG334 doses (pu003e0.05). Responder rates (50[percnt]) were significantly higher with 70-mg AMG334 than placebo (47[percnt] vs 30[percnt]; p=0.011). Changes in monthly migraine attacks were not statistically significant from placebo.Of 395 eligible patients, 383 entered the At data cutoff, median exposure was 34.1 weeks. During the OLE, further reductions from baseline in mean monthly migraine days were sustained for at least 52 weeks. At Week 52, 62[percnt], 38[percnt] and 19[percnt] of patients experienced ≥50[percnt], ≥75[percnt], and 100[percnt] reduction from baseline in migraine days, respectively .There were no major safety findings during the double-blind phase; tolerability was similar between AMG334 and placebo. No new safety signals were identified during the OLE. Conclusions: AMG334 70-mg demonstrated sustained efficacy in prevention of episodic migraine. The safety/tolerability profile of AMG334 in this phase 2 study supports continued development. Disclosure: Dr. Lenz hold stock and/or stock options in Amgen. Dr. Dodick has received personal compensation for activities with Allergan, Amgen, Alder, Merck Serono, ENeuro, Eli Lilly, Autonomic Technologies, Boston Scientific, Novartis, Tonix, Teva, Trigemina as a consultant and for activities with SAGE Publishing, Dr. Goadsby has received personal compensation for activities with Allergan, Inc., eNeura, Autonomic Technologies, Amgen, AlderBio, Pfizer, DrReddy, Zosano, Colucid, Eli-Lilly, Avanir, Gore, Heptares, Nupathe, Teva, Cipla, Ajinomoto, Akita, Wells Fargo, E Dr. Silberstein9s employer receives research support from Allergan, Inc.; Amgen; Cumberland Pharmaceuticals, Inc.; ElectroCore Medical, LLC; Labrys Biologics; Eli Lilly and Company; Merz. Dr. Reuter has received personal compensation for activities with Amgen, Co-Lucid, Allergan, Electrocore, and Autonomic Technologies. Dr. Ashina has received research support from ATI and Amgen. Dr. Saper has received research support from Allergan, Merck, St. Jude Medical, Eli Lilly, Pfizer, Vanda, Forest Research Institute, Johnson u0026 Johnson, Endo Pharmaceuticals Inc., Astellas, Bristo-Meyers Squibb Company, SK Lifesciences, Optinose, and Nu Pa Dr. Cady has received personal compensation for activities with Aerocrine, Allergan, Avanir, Autonomic Technologies, Boston Scientific, DepoMed, Dr. Reddy’s Laboratories, ElectroCore, Novartis, Suda, Teva Pharmaceuticals, Amgen, and Becker Pharma. Dr. Zhang holds stock and/or stock options in Amgen Inc. Dr. Trotman holds stock and/or stock options in Amgen Inc. Dr. Dietrich has nothing to disclose. Dr. Sun holds stock and/or stock options in Amgen Inc.

Objective: To evaluate the feasibility, safety, and tolerability of noninvasive vagus nerve stimulation (nVNS) for the prevention of chronic migraine (CM) attacks. Methods: In this first prospective, multicenter, double-blind, sham-controlled pilot study of nVNS in CM prophylaxis, adults with CM (≥15 headache d/mo) entered the baseline phase (1 month) and were subsequently randomized to nVNS or sham treatment (2 months) before receiving open-label nVNS treatment (6 months). The primary endpoints were safety and tolerability. Efficacy endpoints in the intent-to-treat population included change in the number of headache days per 28 days and acute medication use. Results: Fifty-nine participants (mean age, 39.2 years; mean headache frequency, 21.5 d/mo) were enrolled. During the randomized phase, tolerability was similar for nVNS (n = 30) and sham treatment (n = 29). Most adverse events were mild/moderate and transient. Mean changes in the number of headache days were −1.4 (nVNS) and −0.2 (sham) (Δ = 1.2; p = 0.56). Twenty-seven participants completed the open-label phase. For the 15 completers initially assigned to nVNS, the mean change from baseline in headache days after 8 months of treatment was −7.9 (95% confidence interval −11.9 to −3.8; p < 0.01). Conclusions: Therapy with nVNS was well-tolerated with no safety issues. Persistent prophylactic use may reduce the number of headache days in CM; larger sham-controlled studies are needed. ClinicalTrials.gov identifier: NCT01667250. Classification of evidence: This study provides Class II evidence that for patients with CM, nVNS is safe, is well-tolerated, and did not significantly change the number of headache days. This pilot study lacked the precision to exclude important safety issues or benefits of nVNS.

ObjectiveTo evaluate non‐invasive vagus nerve stimulation (nVNS) as an acute cluster headache (CH) treatment.BackgroundMany patients with CH experience excruciating attacks at a frequency that is not sufficiently addressed by current symptomatic treatments.MethodsOne hundred fifty subjects were enrolled and randomized (1:1) to receive nVNS or sham treatment for ≤1 month during a double‐blind phase; completers could enter a 3‐month nVNS open‐label phase. The primary end point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes. Secondary end points included the sustained response rate (15‐60 minutes). Subanalyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were prespecified.ResultsThe intent‐to‐treat population comprised 133 subjects: 60 nVNS‐treated (eCH, n = 38; cCH, n = 22) and 73 sham‐treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7% of nVNS‐treated subjects and 15.1% of sham‐treated subjects (P = .1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2%; sham, 10.6%; P = .008) but not the cCH cohort (nVNS, 13.6%; sham, 23.1%; P = .48). Sustained response rates were significantly higher with nVNS for the eCH cohort (P = .008) and total population (P = .04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double‐blind phase and 18/128 subjects in the open‐label phase. No serious ADEs occurred.ConclusionsIn one of the largest randomized sham‐controlled studies for acute CH treatment, the response rate was not significantly different (vs sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected results in the total population. This safe and well‐tolerated treatment represents a novel and promising option for eCH. ClinicalTrials.gov identifier: NCT01792817.

Objective:To evaluate long-term prevention of episodic migraine with AMG334, a human anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody. Background:CGRP plays a major role in migraine pathogenesis. Methods:Double-blind phase 2 study (NCT01952574) randomized adults (N=483) with episodic migraine to monthly subcutaneous injections of AMG334 (7-mg, 21-mg, or 70-mg) or placebo (2:2:2:3). Primary endpoint (change from baseline in monthly migraine days) and secondary endpoints (50[percnt] responder rate and change in monthly migraine attacks) were assessed at Week 12. After completing the double blind phase (12-week), patients could continue in an open-label extension (OLE) to receive 70-mg AMG334 up to 5 years. This interim analysis is based on available efficacy data up to week 52 from the ongoing OLE and safety data up to Week 76. Results:Baseline mean (SD) monthly migraine days was 8.7 (2.7). At Week 12, reductions from baseline in monthly migraine days were significantly greater with 70-mg AMG334 than placebo (-3.40 vs -2.28; p=0.021), but not with lower AMG334 doses (p>0.05). Responder rates (50[percnt]) were significantly higher with 70-mg AMG334 than placebo (47[percnt] vs 30[percnt]; p=0.011). Changes in monthly migraine attacks were not statistically significant from placebo. Of 395 eligible patients, 383 entered the OLE. At data cutoff, median exposure was 34.1 weeks. During the OLE, further reductions from baseline in mean monthly migraine days were sustained for at least 52 weeks. At Week 52, 62[percnt], 38[percnt] and 19[percnt] of patients experienced ≥50[percnt], ≥75[percnt], and 100[percnt] reduction from baseline in migraine days, respectively . There were no major safety findings during the double-blind phase; tolerability was similar between AMG334 and placebo. No new safety signals were identified during the OLE. Conclusions:AMG334 70-mg demonstrated sustained efficacy in prevention of episodic migraine. The safety/tolerability profile of AMG334 in this phase 2 study supports continued development.