Rapid resolution of migraine symptoms after initiating the preventive treatment eptinezumab during a migraine attack: results from the randomized RELIEF trial.

BACKGROUND: Eptinezumab is an anti-calcitonin gene-related peptide (CGRP) monoclonal antibody approved for the preventive treatment of migraine. In the phase 3 RELIEF study, eptinezumab resulted in shorter time to headache pain freedom and time to absence of most bothersome symptom (MBS; including nausea, photophobia, or phonophobia) compared with placebo when administered during a migraine attack. The objective of this exploratory analysis was to examine the earliest time points that eptinezumab separated from placebo (P < .05) on headache- and migraine-associated symptoms when administered during a migraine attack. METHODS: RELIEF, a multicenter, parallel-group, double-blind trial, occurred from November 7, 2019, through July 8, 2020. Adults considered candidates for preventive treatment were randomized to eptinezumab 100 mg (N = 238) or placebo (N = 242) administered intravenously over 30 min within 1-6 h of migraine onset. Outcome measures included headache pain freedom/relief and absence of MBS, patient's choice of photophobia, phonophobia, or nausea, at regular intervals from 0.5 to 48 h after infusion start. Censoring was applied at time of acute rescue medication use. RESULTS: At hour 1, more eptinezumab-treated patients achieved headache pain freedom (9.7%), headache pain relief (38.7%), and absence of MBS (33.2%) versus placebo (4.1%, 26.9%, and 22.1%, respectively; P < .05 all), with separation from placebo (P < .05) through hour 48. Eptinezumab separated from placebo (P < .05) at hour 1 in absence-of-photophobia (29.4% vs 17.0%) and absence-of-phonophobia (41.2% vs 27.2%) and through hour 48. Initial separation from placebo (P < .05) in absence-of-nausea occurred at end-of-infusion (0.5 h; 36.7% vs 25.4%, respectively). CONCLUSION: Preventive treatment with eptinezumab initiated during a migraine attack resulted in more patients achieving headache pain freedom/relief and absence of MBS, with separation from placebo (P < .05) as early as 0.5-1 h following the start of infusion. Rapid resolution of headache- and migraine-associated symptoms by a peripherally acting, intravenously administered antibody suggest a peripheral site of pharmacological action for CGRP blockade. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04152083 .

Patient preference for early onset of efficacy of preventive migraine treatments.

OBJECTIVE: The objective of this study was to ascertain to what extent adults with migraine value an early onset of efficacy for preventive migraine treatments. BACKGROUND: In placebo-controlled clinical trials, treatment with eptinezumab resulted in a lower proportion of adults with migraine on the first day following infusion (day 1; 14% point-reduction for chronic migraine [CM] in PROMISE-2 and 8% point-reduction for episodic migraine [EM] in PROMISE-1). METHODS: Adults with migraine completed an online preference-elicitation thresholding exercise to ascertain to what extent they value not having a migraine on day 1 postdosing relative to a clinically relevant reduction in number of migraine days during the first month postdosing (≥2 migraine-free days for CM and ≥1 migraine-free days for EM). RESULTS: One hundred and one participants (mean age, 50.6 ± 12.4 years; 81 [80%] women) were included. In participants with CM, 29 of 50 (58%) considered the eptinezumab-generated reduction in the likelihood of migraine on day 1 postdosing to be at least as important as a clinically relevant reduction in number of migraine days the first month postdosing, whereas 37 of 50 (74%) considered a clinically relevant reduction of migraine days the first month postdosing to have a value equivalent to the eptinezumab-generated reduction in the likelihood of migraine on day 1 postdosing. In participants with EM, 18 of 35 (51%) considered the eptinezumab-generated reduction in the likelihood of migraine on day 1 postdosing to be at least as important as a clinically relevant reduction in migraine days the first month postdosing, whereas 24 of 35 (69%) considered a clinically relevant reduction of migraine days the first month postdosing to have a value equivalent to the eptinezumab-generated reduction in the likelihood of migraine on day 1 postdosing. CONCLUSION: Most participants considered the reduction in the likelihood of migraine offered by eptinezumab on day 1 postdosing to be at least as important as a clinically relevant reduction in migraine days the first month postdosing.

Erenumab dosage for migraine prevention: An evidence-based narrative review with recommendations.

BACKGROUND: Therapeutic monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor or its ligand have changed the landscape of treatment options for migraine. Erenumab is the first and only fully human monoclonal antibody designed to target and block the CGRP receptor. It is approved by the Food and Drug Administration for preventive treatment of migraine in adults. The recommended dose of erenumab is 70 mg monthly, with guidance that some patients may benefit from the 140 mg monthly dose. There is a need for information to guide clinical practice on the comparative efficacy and safety of these two dosing options. OBJECTIVE: To evaluate therapeutic and tolerability differences between erenumab 70 and 140 mg based on evidence from published literature. METHODS: This narrative review evaluates therapeutic and tolerability differences between erenumab 70 and 140 mg based on a literature search using PubMed interface, Embase and Ovid MEDLINE(R) databases. The key search terms included migraine, AMG 334, AMG334, erenumab, erenumab-aooe, and Aimovig. The search was limited to English language articles or conference abstracts published up to May 2021. RESULTS: From the literature search, we retrieved 23 relevant articles/conference abstracts (19 articles [5 randomized, double-blind studies] and 4 conference abstracts) for inclusion in this narrative review. Although the recommended starting dosage of erenumab is 70 mg, this narrative review of the literature indicates that some patients may benefit from a dosage of 140 mg erenumab once monthly-especially those with difficult-to-treat disease and prior treatment failures. The evidence indicates that erenumab at 140 mg has a numerically better efficacy than 70 mg across a broad spectrum of migraine outcomes, including preventing progression to chronic migraine. CONCLUSION: Cumulative data from the literature support a therapeutic gain with an increase from erenumab 70 to 140 mg and a rationale for initiating 140 mg in selected patients.

Early response to eptinezumab indicates high likelihood of continued response in patients with chronic migraine.

BACKGROUND: A clinical ability to describe the response trajectory of patients receiving preventive migraine treatment could expedite and improve therapeutic management decisions. This post hoc analysis of the PROMISE-2 study evaluated the consistency and predictive power of Month 1 treatment response on later response in patients with chronic migraine. METHODS: PROMISE-2 was a double-blind, placebo-controlled trial that randomized adults with chronic migraine to eptinezumab 100 mg, 300 mg, or placebo administered IV every 12 weeks for up to 24 weeks (2 infusions over 6 study months). Migraine responder rates (MRRs) were calculated from monthly migraine days over 4-week intervals compared with baseline. Patients were grouped by MRR during Month 1 (< 25%, 25-< 50%, 50-< 75%, and ≥ 75%), with the number of subsequent study months (Months 2-6) with ≥50% and ≥ 75% MRR calculated in each subgroup. A similar analysis was conducted using Patient Global Impression of Change (PGIC) rating to define Month 1 subgroups (very much improved, much improved, minimally improved, and no change/worse) and rates of very much improved or much improved PGIC during Months 2-6. RESULTS: In the eptinezumab 100 mg, 300 mg, and placebo groups, respectively, 194/356 (54.5%), 212/350 (60.6%), and 132/366 (36.1%) patients were ≥ 50% migraine responders during Month 1. More eptinezumab-treated patients were ≥ 75% migraine responders (100 mg, 110/356 [30.9%]; 300 mg, 129/350 [36.9%]; placebo, 57/366 [15.6%]) and more placebo-treated patients were < 25% migraine responders (eptinezumab 100 mg, 103/356 [28.9%]; 300 mg, 80/350 [22.9%]; placebo, 153/366 [41.8%]). Among patients who achieved ≥75% migraine response in Month 1, more than one-third attained ≥75% migraine response for all 5 subsequent study months and more than two-thirds achieved ≥75% migraine response for ≥3 months. More than two-thirds of those in the very much improved (PGIC) subgroup at Month 1 were much or very much improved for all 5 subsequent months. CONCLUSIONS: In this post hoc analysis of data from PROMISE-2, more eptinezumab-treated than placebo-treated patients were early (Month 1) responders, and most early responders went on to achieve a high level of response for at least half of the 24-week treatment period. Potential for later response in early non-responders was also observed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02974153 ; registered November 23, 2016.

Eptinezumab treatment initiated during a migraine attack is associated with meaningful improvement in patient-reported outcome measures: secondary results from the randomized controlled RELIEF study.

BACKGROUND: Demonstrating therapeutic value from the patient perspective is important in patient-centered migraine management. The objective of this study was to investigate the impact of eptinezumab, a preventive migraine treatment, on patient-reported headache impact, acute medication optimization, and perception of disease change when initiated during a migraine attack. METHODS: RELIEF was a randomized, double-blind, placebo-controlled trial conducted between 2019 and 2020 in adults with ≥1-year history of migraine and 4-15 migraine days per month in the 3 months prior to screening. Patients were randomized (1:1) to a 30-min infusion of eptinezumab 100 mg or placebo within 1-6 h of a qualifying migraine attack onset. The 6-item Headache Impact Test (HIT-6) and 6-item Migraine Treatment Optimization Questionnaire (mTOQ-6) were administered at baseline and week 4, and the Patient Global Impression of Change (PGIC) at week 4. A post hoc analysis of these measures was conducted in patients who reported headache pain freedom at 2 h after infusion start. RESULTS: Of 480 patients enrolled and treated, 476 completed the study and are included in this analysis. Mean baseline HIT-6 total scores indicated severe headache impact (eptinezumab, 65.1; placebo, 64.8). At week 4, the eptinezumab-treated group demonstrated clinically meaningful improvement in HIT-6 total score compared with placebo (mean change from baseline: eptinezumab, - 8.7; placebo, - 4.5; mean [95% CI] difference from placebo: - 4.2 [- 5.75, - 2.63], P < .0001), with greater reductions in each item score vs placebo (P < .001 all comparisons). Change in HIT-6 total score in the subgroup with 2-h headache pain freedom was - 13.8 for the eptinezumab group compared with - 4.9 for the placebo group. mTOQ-6 total score mean change from baseline favored eptinezumab (change, 2.1) compared with placebo (1.2; mean [95% CI] difference: 0.9 [0.3, 1.5], P < .01). More eptinezumab-treated patients rated PGIC as much or very much improved than placebo patients (59.3% vs 25.9%). CONCLUSIONS: When administered during a migraine attack, eptinezumab significantly improved patient-reported outcomes after 4 weeks compared with placebo, with particularly pronounced effects in patients reporting headache pain freedom at 2 h after infusion start. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04152083 . November 5, 2019.

STOP 301: A Phase 3, open-label study of safety, tolerability, and exploratory efficacy of INP104, Precision Olfactory Delivery (POD® ) of dihydroergotamine mesylate, over 24/52 weeks in acute treatment of migraine attacks in adult patients.

OBJECTIVE: To report the safety, tolerability, exploratory efficacy, and patient acceptability of INP104 for the acute treatment of migraine from the Phase 3 STOP 301 trial. BACKGROUND: Dihydroergotamine (DHE) has long been used to treat migraine, but intravenous administration is invasive, frequently associated with adverse events (AEs), and not suitable for at-home administration. INP104 is an investigational drug device that delivers DHE mesylate to the upper nasal space using a Precision Olfactory Delivery technology and was developed to overcome the shortcomings of available DHE products. METHODS: STOP 301 was an open-label, 24-week safety study, with a 28-week extension period. After a 28-day screening period where patients used their "best usual care" to treat migraine attacks, patients were given INP104 (1.45 mg) to self-administer nasally with self-recognized attacks. The primary objective of this study was to assess safety and tolerability, with a specific focus on nasal mucosa and olfactory function. Exploratory objectives included efficacy assessments of migraine measures and a patient acceptability questionnaire. RESULTS: A total of 360 patients entered the 24-week treatment period, with 354 patients dosing at least once. INP104-related treatment-emergent AEs were reported by 36.7% (130/354) of patients, and 6.8% (24/354) discontinued treatment due to AEs over 24 weeks. No new safety signals were observed following delivery to the upper nasal space. Pain freedom, the most bothersome symptom freedom, and pain relief at 2 h post-INP104 were self-reported by 38.0% (126/332), 52.1% (173/332), and 66.3% (167/252) of patients, respectively. A low recurrence rate at 24 and 48 h was observed (7.1% [9/126] and 14.3% [18/126], respectively). Most patients found INP104 easy to use and preferred it over their current therapy. CONCLUSIONS: INP104 has the potential to deliver rapid symptom relief, without injection, that is well tolerated and suitable for outpatient use. Results suggest INP104 may be a promising treatment for patients with migraine.

Effects of Intravenous Eptinezumab vs Placebo on Headache Pain and Most Bothersome Symptom When Initiated During a Migraine Attack: A Randomized Clinical Trial.

Importance: Intravenous eptinezumab, an anti-calcitonin gene-related peptide antibody, is approved for migraine prevention in adults. It has established onset of preventive efficacy on day 1 after infusion. Objective: To evaluate the efficacy of and adverse events related to eptinezumab when initiated during a migraine attack. Design, Setting, and Participants: Phase 3, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial conducted from November 4, 2019, to July 8, 2020, at 47 sites in the United States and the country of Georgia. Participants (aged 18-75 years) with a greater than 1-year history of migraine and migraine on 4 to 15 days per month in the 3 months prior to screening were treated during a moderate to severe migraine attack. Interventions: Eptinezumab, 100 mg (n = 238), or placebo (n = 242), administered intravenously within 1 to 6 hours of onset of a qualifying moderate to severe migraine. Main Outcomes and Measures: Co-primary efficacy end points were time to headache pain freedom and time to absence of most bothersome symptom (nausea, photophobia, or phonophobia). Key secondary end points were headache pain freedom and absence of most bothersome symptom at 2 hours after start of infusion. Additional secondary end points were headache pain freedom and absence of most bothersome symptom at 4 hours and use of rescue medication within 24 hours. Results: Of 480 randomized and treated patients (mean age, 44 years; 84% female), 476 completed the study. Patients treated with eptinezumab vs placebo, respectively, achieved statistically significantly faster headache pain freedom (median, 4 hours vs 9 hours; hazard ratio, 1.54 [P < .001]) and absence of most bothersome symptom (median, 2 hours vs 3 hours; hazard ratio, 1.75 [P < .001]). At 2 hours after infusion, in the respective eptinezumab and placebo groups, headache pain freedom was achieved by 23.5% and 12.0% (between-group difference, 11.6% [95% CI, 4.78%-18.31%]; odds ratio, 2.27 [95% CI, 1.39-3.72]; P < .001) and absence of most bothersome symptom by 55.5% and 35.8% (between-group difference, 19.6% [95% CI, 10.87%-28.39%]; odds ratio, 2.25 [95% CI, 1.55-3.25]; P < .001). Results remained statistically significant at 4 hours after infusion. Statistically significantly fewer eptinezumab-treated patients used rescue medication within 24 hours than did placebo patients (31.5% vs 59.9%, respectively; between-group difference, -28.4% [95% CI, -36.95% to -19.86%]; odds ratio, 0.31 [95% CI, 0.21-0.45]; P < .001). Treatment-emergent adverse events occurred in 10.9% of the eptinezumab group and 10.3% of the placebo group; the most common was hypersensitivity (eptinezumab, 2.1%; placebo, 0%). No treatment-emergent serious adverse events occurred. Conclusions and Relevance: Among patients eligible for preventive migraine therapy experiencing a moderate to severe migraine attack, treatment with intravenous eptinezumab vs placebo shortened time to headache and symptom resolution. Feasibility of administering eptinezumab treatment during a migraine attack and comparison with alternative treatments remain to be established. Trial Registration: ClinicalTrials.gov Identifier: NCT04152083.

Long-term safety and efficacy of erenumab in patients with chronic migraine: Results from a 52-week, open-label extension study.

BACKGROUND: This study reports the long-term safety and efficacy of erenumab in chronic migraine patients. METHODS: This was a 52-week open-label extension study of a 12-week double-blind treatment phase study. During the double-blind treatment phase, patients received placebo or once-monthly erenumab 70 mg or 140 mg. During the open-label treatment phase, the initial monthly dose was erenumab 70 mg. Following protocol amendment, patients continued to receive erenumab 70 mg if they had already completed their Week 28 visit, otherwise, patients switched from 70 mg to 140 mg; if enrolled after the amendment, patients received 140 mg monthly throughout. RESULTS: In all, 451/609 (74.1%) enrolled patients completed the study. The exposure-adjusted patient incidence rate for any adverse event was 126.3/100 patient-years for the overall erenumab group. Overall, the adverse event profile was similar to that observed in the double-blind treatment phase. Adverse event incidence rates did not increase with long-term erenumab treatment compared with the double-blind treatment phase, and no new serious or treatment-emergent events were seen. Efficacy was sustained throughout the 52 weeks. Clinically significant reductions from double-blind treatment phase baseline (about half) were observed for monthly migraine days and migraine-specific medication days. Achievement of ≥50%, ≥75% and 100% reductions from the double-blind treatment phase baseline in monthly migraine days at Week 52 were reported by 59.0%, 33.2% and 8.9% of patients, respectively, for the combined dose group. A numerically greater benefit was observed with 140 mg compared with 70 mg at Weeks 40 and 52. CONCLUSIONS: Sustained efficacy of long-term erenumab treatment in patients with chronic migraine is demonstrated, with safety results consistent with the known safety profile of erenumab and adverse event rates comparable to placebo adverse event rates in the double-blind treatment phase. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT02174861).

The spectrum of response to erenumab in patients with chronic migraine and subgroup analysis of patients achieving ≥50%, ≥75%, and 100% response.

OBJECTIVE: To assess the efficacy of erenumab across the spectrum of response thresholds (≥50%, ≥75%, 100%) based on monthly migraine days (MMD) reduction in patients with chronic migraine from a 12-week, randomized study (NCT02066415). METHODS: Patients (n = 667) received (3:2:2) placebo or erenumab 70/140 mg once-monthly. The proportion of patients achieving a given response threshold was assessed. A post-hoc analysis was conducted to contextualize the actual treatment benefit in subgroups of patients achieving (or not) specified response thresholds. Outcome measures included MMD, acute migraine-specific medication treatment days (MSMD) and disability. RESULTS: The proportion of patients responding to erenumab exceeded that of placebo at the ≥50% and ≥75% response thresholds. At month 3, 39.9% and 41.2% of patients on erenumab 70 and 140 mg, respectively, achieved ≥50% response versus placebo (23.5%). Similarly, at month 3, 17.0% and 20.9% of patients on erenumab 70 and 140 mg, respectively, achieved ≥75% response versus placebo (7.8%). Compared with the overall erenumab-treated population (change in MMD: -6.6 [both 70 and 140 mg]), ≥50% responders showed MMD reductions of -12.2/-12.5 for 70 mg/140 mg versus -2.6/-2.2 for those not achieving ≥50% response. ≥75% responders showed MMD reductions of -13.9/-14.8 for 70 mg/140 mg versus -5.0/-4.3 for those not achieving ≥75% response. Relative improvements in MSMD and disability were observed in responders versus overall erenumab-treated population. CONCLUSION: For erenumab-treated patients achieving ≥50% response, the actual reduction in MMD was almost twice that of the overall population. These findings provide context for setting realistic expectations regarding actual treatment benefit experienced by patients responding to treatment.

A Randomized Trial to Evaluate OnabotulinumtoxinA for Prevention of Headaches in Adolescents With Chronic Migraine.

OBJECTIVE: As a post-approval commitment, this dose-ranging study was undertaken to evaluate efficacy and safety of onabotulinumtoxinA in adolescents. BACKGROUND: In adolescents, migraine is often undiagnosed or misdiagnosed and can present unique management challenges. OnabotulinumtoxinA was approved for prevention of chronic migraine (CM) in adults in 2010. METHODS: This multicenter, double-blind, parallel-group, randomized trial assessed a single treatment of onabotulinumtoxinA (155 U or 74 U) vs placebo (intramuscular saline) administered via the recommended fixed-dose fixed site paradigm in adolescents with CM aged 12 to <18 years. The primary efficacy measure was change in frequency of headache days from baseline at week 12; other measures included change in frequency of headache days at weeks 4 and 8 and change in frequency of severe headache days. Safety and tolerability were assessed. RESULTS: Of 125 randomized patients (onabotulinumtoxinA 155 U, n = 45; onabotulinumtoxinA 74 U, n = 43; placebo, n = 37), all were included in the primary efficacy analysis, and 115 (92.0%) completed the study. Lack of efficacy was the primary reason for discontinuing (n = 4; 3.2%); no patients discontinued because of adverse events. All treatments reduced frequency of headache days at week 12, with no significant differences between treatments. The mean (95% confidence interval) changes from baseline in the frequency of headache days during the 28-day period ending at week 12 (primary endpoint) were -6.3 (-8.5, -4.2), -6.4 (-8.8, -4.0), and -6.8 (-9.6, -4.1) days in the onabotulinumtoxinA 155 U, onabotulinumtoxinA 74 U, and placebo groups, respectively (P ≥ .474). All treatments reduced frequency of severe headache days and were well-tolerated; serious adverse events (n = 3) were considered unrelated to treatment and resolved without sequelae. The most commonly reported treatment-emergent adverse events were neck pain (n = 8), upper respiratory tract infection (n = 7), migraine, and nasopharyngitis (n = 5 each). CONCLUSION: Although this study did not meet its efficacy endpoints, onabotulinumtoxinA was well tolerated in this adolescent population. Given previous data demonstrating the benefits of onabotulinumtoxinA in adults with CM, additional studies with design modifications, including adequate statistical power, to assess the efficacy of multiple treatment cycles of onabotulinumtoxinA for CM prevention in adolescents may be informative.

Early Onset of Efficacy With Fremanezumab for the Preventive Treatment of Chronic Migraine.

OBJECTIVE: To assess the onset of efficacy for fremanezumab in chronic migraine by evaluating pain-related clinical measures at different time points. BACKGROUND: Faster onset of efficacy of preventive treatments could benefit patients with migraine. Fremanezumab is a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, a neuropeptide involved in the pathophysiology of migraine. In 12-week clinical trials, subcutaneous fremanezumab significantly reduced the frequency of migraine headaches, headache hours, and headaches in general, without serious treatment-related adverse events. New drug classes of migraine preventive treatment demonstrate markedly different clinical profiles from standard-of-care treatments. METHODS: In this double-blind phase III study, eligible patients were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline, placebo at weeks 4 and 8), fremanezumab monthly (675 mg at baseline, 225 mg at weeks 4 and 8), or placebo at each time point. This study included secondary, exploratory, and post hoc analyses of the primary trial, evaluating the change in headache days of at least moderate severity or migraine days during the first 4 weeks of the trial. RESULTS: A total of 1130 patients were randomized (fremanezumab quarterly, n = 376; fremanezumab monthly, n = 379; or placebo, n = 375). During the 4-week period after the first dose, the mean number of monthly headache days of at least moderate severity was reduced for the all-fremanezumab group (mean reduction [95% confidence interval]: -4.6 days [-5.1, -4.1]) compared with the placebo group (-2.3 days [-2.9, -1.6]; P < .0001). Treatment effects were observed at Week 1 for the all-fremanezumab group (-1.1 days [-1.3, -1.0]) vs placebo (-0.5 days [-0.7, -0.3]; P < .0001), with separation from placebo by Day 2 (P = .003). Similar effects were observed for the monthly average number of migraine days and mean number of monthly headache hours. CONCLUSIONS: The early onset of efficacy of fremanezumab may have the potential to improve patient compliance and clinical outcomes.

Early Onset of Efficacy and Consistency of Response Across Multiple Migraine Attacks From the Randomized COMPASS Study: AVP-825 Breath Powered® Exhalation Delivery System (Sumatriptan Nasal Powder) vs Oral Sumatriptan.

OBJECTIVE: To further characterize the clinical utility of AVP-825 based on additional prespecified outcomes and post hoc analyses of COMPASS, a Phase 3 comparative efficacy trial of AVP-825 vs 100 mg oral sumatriptan (NCT01667679). AVP-825 was approved in January 2016 by the US Food and Drug Administration under the name ONZETRA® Xsail® (sumatriptan nasal powder) for the acute treatment of migraine with or without aura in adults. BACKGROUND: AVP-825 is a delivery system that uses a patient's own breath to deliver low-dose sumatriptan powder to the upper posterior regions of the nasal cavity beyond the narrow nasal valve, areas lined with vascular mucosa conducive to rapid drug absorption into the systemic circulation. The recommended dose of AVP-825 is 22 mg sumatriptan powder administered as one 11 mg nosepiece in each nostril, which delivers approximately 15-16 mg of sumatriptan intranasally. The COMPASS trial compared AVP-825 22-100 mg oral sumatriptan across multiple migraine attacks for efficacy, safety, and tolerability endpoints. DESIGN/METHODS: COMPASS was a randomized, multicenter, double-dummy, crossover, multiattack, comparative efficacy study with two 12-week double-blind periods. Patients with 2-8 migraine attacks/month were randomized 1:1 to AVP-825 (22 mg) plus oral placebo or an identical placebo delivery system plus 100 mg oral sumatriptan for the first period, and then patients switched treatments for the second period. Patients treated up to 5 qualifying migraines per period within 1 h of onset, even if the intensity of the attack was mild. Results from the primary endpoint (SPID-30, defined as the sum of pain intensity differences from dosing to 30 minutes), key secondary efficacy endpoints and safety assessments have been reported in the primary publication (Tepper et al., 2015). This article reports additional prespecified outcomes, including the SPID-30 for attacks treated when baseline severity was mild vs moderate/severe, measures of sustained response and consistency of effect in patients who experienced multiple migraine attacks, and the results of post hoc analyses performed to assess total migraine freedom (defined as no pain and no migraine-associated symptoms, including nausea, vomiting, photophobia, and phonophobia), time to pain freedom, time to meaningful pain relief, and local (occurring at the site of administration in the nose) vs systemic treatment-emergent adverse events (TEAEs). RESULTS: A total of 185 patients completed both treatment periods, yielding 1,531 migraine attacks which were treated and assessed (765 AVP-825, 766 oral sumatriptan). Treatment with AVP-825 provided greater reduction in migraine pain intensity which was statistically significant vs oral sumatriptan in the first 30 minutes postdose regardless of whether attacks were treated when pain was mild (least squares mean SPID-30 = 3.90 vs 0.24, P = .0013) or moderate/severe (least squares mean SPID-30 = 13.83 vs 10.07, P = .0002). At every time point from 15 to 90 minutes postdose, the proportion of attacks achieving total migraine freedom was greater and statistically significant after treatment with AVP-825 vs 100 mg oral sumatriptan. AVP-825 treatment resulted in greater odds of achieving pain freedom (odds ratio, OR = 1.29, P < .01) and meaningful pain relief (OR = 1.32, P < .0001), which were also statistically significant compared with oral sumatriptan. In addition, a greater proportion of attacks treated with AVP-825 vs oral sumatriptan was associated with sustained pain freedom, achieving statistical significance when assessed from 1 h postdose through 24 hours postdose (33.3% vs 27.9%; P < .05) and through 48 hours postdose (32.7% vs 27.4%; P < .05). For patients who treated multiple migraine attacks in both treatment periods, a greater proportion had consistent pain relief and pain freedom following treatment with AVP-825 compared to oral sumatriptan across multiple attacks, a difference that achieved statistical significance at 30 minutes postdose. Local TEAEs of abnormal taste and nasal discomfort were more common following AVP-825 treatment. Of the patients experiencing either of these TEAEs, about 90% described the intensity as mild, and only one discontinued treatment because of either of these two TEAEs. CONCLUSIONS: These results from the COMPASS study further demonstrate that treatment with AVP-825 provides earlier onset and more consistent across-episode improvement of pain and migraine-associated symptoms compared with oral sumatriptan, highlighting the clinical advantages of this newly approved intranasal delivery system for low-dose sumatriptan powder.

Efficacy and tolerability of zolmitriptan nasal spray for the treatment of acute migraine in adolescents: Results of a randomized, double-blind, multi-center, parallel-group study (TEENZ).

OBJECTIVE: The primary objective of the TEENZ Study (NCT01211145) was to assess the efficacy of zolmitriptan nasal spray in the acute treatment of adolescent migraine patients (ages 12 to 17 years), as measured by the primary outcome variable of pain-free status at 2 hours post-treatment. METHODS: This randomized, double-blind, placebo-controlled, four-arm parallel group study compared zolmitriptan nasal spray with placebo in the treatment of a single episode of adolescent migraine. Patients completed a 30-day run-in period to treat a single migraine attack with single-blind placebo nasal spray. Eligible patients, who had not responded to placebo, were randomized to one of three zolmitriptan nasal spray doses (5, 2.5, or 0.5 mg) or placebo in a ratio of 5:3:3:5 according to a computer-generated randomization scheme. Patients completed diaries for 24 hours after treatment, recording headache pain scores, adverse events (AEs), and medications taken. RESULTS: In an interim futility analysis, zolmitriptan nasal spray doses of 0.5 and 2.5 mg were declared futile relative to placebo and further randomization to these treatment arms was discontinued. Of 1653 patients enrolled into the study, 855 patients failed to meet study eligibility criteria and were considered screen failures. The most common reason for screen failure was response to placebo challenge (325 patients [38.0%]). Of the 798 patients who were randomized to treatment, 721 (90.4%) completed the study period. Of these, 657 (82.3%) treated a migraine within the study period and contributed data for analysis. Zolmitriptan nasal spray 5 mg was significantly more effective than placebo in achieving pain-free status at 2 hours after treatment (P < .001), with 30% of patients achieving pain-free status at 2 hours vs 17% of placebo-treated patients (OR 2.18; 95% CI 1.40, 3.39). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving pain-free status at 3 and 4 hours post-treatment (45 vs 24%, and 56 vs 39%; both P < .001). Zolmitriptan nasal spray 5 mg was also more effective than placebo in achieving headache response at 2, 3, and 4 hours after treatment (51 vs 39%, 61 vs 48%, and 69 vs 57%, respectively; all P ≤ .011). Zolmitriptan nasal spray was well-tolerated at all doses. Dysgeusia was the most frequently reported AE, with greater frequencies reported in active treatment groups versus placebo. No serious AEs or AEs leading to discontinuation were reported. Most AEs were mild or moderate in severity, and consistent with the known profile of zolmitriptan in adult and adolescent populations. CONCLUSION: Zolmitriptan nasal spray was well-tolerated in the acute treatment of adolescent (ages 12 to 17 years) migraine. Zolmitriptan 5 mg nasal spray demonstrated superior efficacy compared with placebo for the primary efficacy endpoint of pain-free status 2 hours after treatment and the efficacy of the 5 mg dose was supported by the majority of secondary efficacy endpoints.

A Phase I, Open-Label, Single-Dose Safety, Pharmacokinetic, and Tolerability Study of the Sumatriptan Iontophoretic Transdermal System in Adolescent Migraine Patients.

OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients. BACKGROUND: Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults. DESIGN: Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax ), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and t½ (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments. RESULTS: The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax , tmax , AUC0-∞ , and t½ values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (±6.43) ng/mL in adolescents vs 21.89 (±6.15) ng/mL in adults; mean AUC0-∞ 98.1 (±28.1) ng·h/mL in adolescents vs 109.7 (±26.1) ng·h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed. CONCLUSIONS: The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger and older adolescents, in line with what was seen in adult subjects. It was generally well tolerated.

Consistency of response to sumatriptan/naproxen sodium in a randomized placebo-controlled, cross-over study for the acute treatment of migraine in adolescence.

A multi-centered, randomized, placebo-controlled, early intervention, cross-over study was conducted to evaluate the consistency of response of sumatriptan/naproxen sodium 85/500 mg (S/NS) over 4 attacks in the acute treatment of migraine in adolescents. Inclusion of subjects was dependent on their age of 12-17 years, frequency, and history of migraine headaches (1-8 per month) over the previous 6 months prior to screening and generally healthy males and females of non-childbearing potential that were not on excluded medications. Subjects were instructed to treat within 1 hour of pain onset, including when the pain was still mild. Subjects were randomized in a double-blind fashion using a computer-generated randomization list in which the study drug was prepared prior to study start, and subjects were allocated to a number in sequential order for each site. Each site was allocated number blocks in sets of 10 depending of the rate of enrollment. The objective of this study was to examine the efficacy of S/NS vs placebo in the primary end-points of pain-free response at 2 hours (2hPF), 24-hour sustained pain-free response (24hPF), and pain-free response at 2 hours with early intervention (2hPFE) calculated as percentage out of all attacks. In the study, 94 subjects treated 347 attacks in total: treating 277 with S/NS and 70 with placebo. Compared with placebo, S/NS produced higher 2hPF rates (S/NS 37%, placebo 18%; P < .004), and 2hPFE with rates (S/NS 32%, 18% placebo; P < .03). Compared with placebo, 24hPF rates were S/NS 86%, placebo 78%, P < .17, which were higher than placebo but not clinically significant. 2hPF was reported in at least 2 of the 3 migraines treated with S/NS in 40.4% of subjects. 24hPF was reported in at least 2 of the 3 migraine treated with S/NS in 86.2% subjects. Adverse reactions were generally low and comparable between S/NS and placebo.

Migraine-related symptoms in childhood.

Periodic disorders of childhood often represent precursors of migraine. As we advance our knowledge of migraine and its complicated phenotypic presentation in childhood, we have noted the similarities in overlapping symptoms of children presenting with childhood periodic syndromes. There is often a positive family history of migraine in children that present with periodic syndromes. There is a known transformation of periodic syndromes from childhood into adult migraine with and without aura phenotype. There has been an evolution of our understanding of what was initially referred to as periodic symptoms of childhood and more recently been called childhood periodic syndromes and is now evolving into the terminology of episodic symptoms that are associated with migraine. International classification of headache disorders has been instrumental in the evolution of the classification of headache and children adults. The most recent classification utilizes and replaces the periodic symptom terminology with episodic symptoms that will no longer be limited to just childhood. This article will address the evolution of our understanding of the diagnostic criteria, pathophysiology and management of the episodic syndromes that may be associated with migraine.

Concurrent onabotulinumtoxinA treatment of cervical dystonia and concomitant migraine.

OBJECTIVE: The objective of this study was to assess the clinical benefits of onabotulinumtoxinA (BOTOX®) treatment on the symptoms of cervical dystonia and the frequency, severity, and associated symptoms of migraine in patients with cervical dystonia and concurrent migraine. BACKGROUND: Botulinum toxin is established as first-line treatment of cervical dystonia. Recent clinical trials have shown onabotulinumtoxinA to be an effective prophylactic therapy for patients with chronic migraine, and onabotulinumtoxinA has been approved for use in this patient population by the Food and Drug Administration. Patients with headache associated with cervical dystonia have been identified as a specific subpopulation of patients in whom botulinum toxin treatment may be effective for controlling the symptoms of both conditions. METHODS: An open-label pilot study was conducted for 7.5 months in patients at least 18 years old with primary cervical dystonia of moderate severity (baseline rating of at least 20 on the Toronto Western Spasmodic Torticollis Rating Scale) complicated by migraine headache meeting the International Classification of Headache Disorders-II criteria for migraines with or without aura. Each patient received 2 cycles of treatment at Visit 3 (baseline) and Visit 6 (Day 90). For cervical dystonia, each patient was injected with a maximum of 175 units. At the same visit, a maximum of 125 units was also injected for migraine using a fixed-site, fixed-dose injection paradigm, with additional cervical dystonia injection-site treatment to a maximum dose of 300 units. Patients were assessed following onabotulinumtoxinA injection and at follow-up on Visit 4 (Day 30), Visit 5 (Day 60), Visit 6 (Day 90), and at Visits 7, 8, and 9 (Days 120, 150, and 180). The primary outcome measures for this study were change in Toronto Western Spasmodic Torticollis Rating Scale total score for cervical dystonia and frequency of headache episodes per 28-day period. Migraine episodes were defined as at least 4 hours of sustained pain with no upper limit. An episode was considered new if the patient was pain free for at least 24 hours. Secondary study end points included number of headache days per month, headache intensity, headache disability (assessed using Headache Impact Test-6 and the Migraine Disability Assessment score scales), acute headache medication use, resource utilization, and allodynia pain. Adverse events were reported. RESULTS: A total of 25 patients (24 women, mean age 50.5 years; mean age of disease onset 21.9 years) were enrolled in the study. Patients experienced improvement in cervical dystonia symptoms with significant reductions from baseline in Toronto Western Spasmodic Torticollis Rating Scale scores at 30, 60, 90, 120, 150, and 180 days (-9.84 ± 8.49, -12.67 ± 8.22, -13.63 ± 7.27, -14.92 ± 7.05, -14.76 ± 6.97, -14.49 ± 6.14, respectively, P < .0001 at all time points from a baseline of 31.03 ± 3.61). Changes from baseline were assessed using the t-test. Reductions in the number of headache episodes from baseline on concurrent onabotulinumtoxinA treatment for coexistent chronic migraine did not attain significance. However, patients experienced significant reductions from baseline in the number of headache days at 90, 120, and 180 days (-3.39 ± 6.78, P = .0289; -4.29 ± 7.94, P = .0194; -4.38 ± 7.99, P = .0178, respectively, from a baseline of 15.33 ± 6.76). Changes from baseline were assessed using the t-test. The change from baseline in Headache Impact Test-6 total scores was significant at 30, 60, 90, 150, and 180 days (3.21 ± 4.14, P = .0009; -3.04 ± 4.04, P = .0012; -2.41 ± 2.79, P = .0006; -2.59 ± 3.87, P = .0050; -3.09 ± 3.80, respectively, from a baseline of 22.68 ± 3.20). Changes from baseline were assessed using the t-test. The change from baseline in Migraine Disability Assessment was significant at 120, 150, and 180 days (-38.09 ± 47.87, P < .0001, Wilcoxon signed rank test; -16.91 ± 62.69, P = .0358, Wilcoxon signed rank test; -23.73 ± 40.57, P = .0122, t-test, respectively, from a baseline of 56.68 ± 50.41). There were no serious adverse events or treatment-related discontinuations. CONCLUSIONS: Concurrent treatment with onabotulinumtoxinA is effective and well tolerated in controlling the symptoms of cervical dystonia complicated by concurrent migraine.

Pharmacokinetics and tolerability of rizatriptan in pediatric migraineurs in a randomized study.

OBJECTIVE: To evaluate the pharmacokinetic profile and tolerability of single doses of rizatriptan oral disintegrating tablets (ODTs) in pediatric migraineurs. BACKGROUND: Acute migraine treatment options for children are limited despite a rising migraine prevalence. No triptans are approved in those under 12, and only sumatriptan nasal spray (European Union) and almotriptan tablets (USA) are approved for those aged 12-17. Appropriate dose selection based on body weight may be a factor in establishing treatment efficacy in this population. METHODS: Randomized, double-blind, placebo-controlled, parallel group, single-dose study in 6- to 17-year-old migraineurs. The study was performed between acute migraine attacks. Subjects were allocated to 1 of 2 groups based on body weight: (1) those weighing <40kg received rizatriptan ODT 5mg or placebo; (2) those weighing ≥40kg received rizatriptan 10mg ODT or placebo. Pharmacokinetic data were compared with historical data on rizatriptan ODT 10mg in healthy adults. RESULTS: The geometric mean area under the plasma concentration-time curve from time 0 to infinity (AUC((0-∞)) ) (hours·ng/mL) and maximum peak plasma concentration (C(max) ) (ng/mL) were 56.68 (95% confidence interval [CI]: 48.60, 66.09) and 22.39 (95% CI: 17.90, 28.02), respectively, for the <40kg group and 78.49 (95% CI: 68.93, 89.38) and 22.27 (95% CI: 18.43, 26.92), respectively, for the ≥40kg group. For the comparison of children vs adults, the geometric mean ratios for rizatriptan AUC((0-∞)) and C(max) were 0.85 (90% CI: 0.73, 0.98) and 1.07 (90% CI: 0.86, 1.34), respectively, for the <40kg group vs historical adult data and 1.17 (90% CI: 1.02, 1.34) and 1.06 (90% CI: 0.87, 1.30), respectively, for the ≥40kg group vs historical adult data. There were no serious adverse events, and rizatriptan was generally well tolerated. CONCLUSIONS: In pediatric migraineurs, a weight-based dosing scheme generated plasma rizatriptan AUC((0-∞)) and C(max) values that were generally similar to those historically observed in adults administered a 10-mg dose of rizatriptan ODT (a proven effective dose). The data support further evaluation of the safety, tolerability, and efficacy of this rizatriptan dosing scheme in larger scale clinical trials in the pediatric migraineur population.

Rizatriptan for treatment of acute migraine in patients taking topiramate for migraine prophylaxis.

OBJECTIVE: To assess efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treatment of acute migraine in patients using topiramate for migraine prophylaxis. BACKGROUND: There are limited data from prospective controlled trials demonstrating the benefit of triptans in patients who experience migraine attacks while taking prophylactic medication. METHODS: This was a worldwide, randomized, placebo-controlled, double-blind, multiple-attack study in adults with a >1-year history of migraine taking a stable dose of topiramate for migraine prophylaxis and experiencing ≥2 moderate/severe attacks per month. Participants treated 3 moderate/severe attacks in crossover fashion (2 with rizatriptan 10-mg ODT, 1 with placebo) following random assignment to 1 of 3 treatment sequences. The primary end point was 2-hour pain relief. RESULTS: Two-hour pain relief was significantly greater with rizatriptan compared with placebo (55.0% vs 17.4%, P < .001). Response rates also favored rizatriptan for sustained pain relief from 2-24 hours (32.6% vs 11.1%, P < .001), 2-hour pain freedom (36.0% vs 6.5%, P < .001), normal functional ability at 2 hours (42.2% vs 12.7%, P < .001), and overall treatment satisfaction at 24 hours (60.8% vs 33.6%, P < .001). Few participants reported adverse experiences (16 [15.8%] with rizatriptan, 3 [3.2%] with placebo); none were serious. CONCLUSION: Rizatriptan 10-mg ODT was superior to placebo at all pain end points for treatment of acute migraine in patients using topiramate for migraine prophylaxis. Rizatriptan was generally well tolerated in this population. These results are comparable with those from clinical trials in patients not using prophylaxis, suggesting that the use of topiramate does not affect the efficacy or tolerability of rizatriptan for acute migraine treatment.