Sustained response to atogepant in episodic migraine: post hoc analyses of a 12-week randomized trial and a 52-week long-term safety trial.

BACKGROUND: Atogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine in adults. These analyses evaluated the proportions of clinical trial participants who experienced sustained responses to atogepant over 12 or 52 weeks of treatment. METHODS: These were post hoc analyses of ADVANCE, a 12-week, double-blind, randomized trial of atogepant 10, 30, and 60 mg once daily vs. placebo for the preventive treatment of episodic migraine, and a separate open-label long-term safety (LTS) trial of atogepant 60 mg once daily over 52 weeks. The 60 mg dose of atogepant was used to detect safety issues. An initial response was defined as ≥50%, ≥75%, or 100% reduction from baseline in MMDs in month 1 for ADVANCE or quarter 1 for the LTS trial. The proportions of participants who continued to experience a response above each response-defining threshold through each subsequent month (for ADVANCE) or each quarter (for LTS) were calculated. RESULTS: In ADVANCE, sustained response rates during months 2 and 3 varied with dose and were as follows: 70.8-81.1% following an initial ≥50% response, 47.3-61.9% following an initial ≥75% response, and 34.8-41.7% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during month 1, more than 79% continued to experience at least a 50% response during both months 2 and 3. During the LTS trial, sustained response rates through quarters 2, 3, and 4 were 84.7% following an initial ≥50% response, 72.6% following an initial ≥75% response, and 37.8% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during quarter 1, more than 90% continued to experience at least a 50% response through quarters 2, 3, and 4. CONCLUSION: Over 70% of participants who experienced an initial response with atogepant treatment had a sustained response with continued treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03777059 (submitted: December 13, 2018); NCT03700320 (submitted: September 25, 2018).

Ubrogepant for the treatment of migraine attacks during the prodrome: a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial in the USA.

BACKGROUND: Ubrogepant is a calcitonin gene-related peptide (CGRP) receptor antagonist that is approved for acute treatment of migraine. The prodrome is the earliest phase of a migraine attack and is characterised by non-aura symptoms that precede headache onset. The aim of this trial was to evaluate the efficacy, safety, and tolerability of ubrogepant 100 mg compared with placebo for the acute treatment of migraine when administered during the prodrome. METHODS: This PRODROME trial was a phase 3, multicentre, randomised, double-blind, placebo-controlled, crossover trial of ubrogepant 100 mg conducted at 75 research centres and headache clinics in the USA. Eligible participants were adults aged 18-75 years who had at least a 1-year history of migraine with or without aura and a history of two to eight migraine attacks per month with moderate to severe headache in each of the 3 months before screening. Eligible participants were randomly assigned (1:1) to either receive placebo to treat the first qualifying prodrome event and ubrogepant 100 mg to treat the second qualifying prodrome event or to receive ubrogepant 100 mg to treat the first qualifying prodrome event and placebo to treat the second qualifying prodrome event. An automated interactive web-response system used permuted blocks of four to manage randomisation. All people giving interventions and assessing outcomes were masked to group assignment during the study. People doing data analysis, which occurred after study completion, were not masked to group assignment. During the double-blind treatment period, each participant was instructed to orally take two tablets of the study drug at the onset of each qualifying prodrome event. The primary endpoint was absence of moderate or severe intensity headache within 24 h after study-drug dose; efficacy analyses were conducted with the modified intention-to-treat (mITT) population, defined as all randomly assigned participants with at least one headache assessment within 24 h after taking the study drug during the treatment period. The safety population included all treated participants who took at least one administration of study drug. The trial is registered with ClinicalTrials.gov (NCT04492020). FINDINGS: Between Aug 21, 2020, and April 19, 2022, 518 participants were randomly assigned to double-blind crossover treatment. The safety population included 480 participants and the mITT population included 477 participants; 421 (88%) of 480 participants were female and 59 (12%) were male. Absence of moderate or severe headache within 24 h after a dose occurred after 190 (46%) of 418 qualifying prodrome events that had been treated with ubrogepant and after 121 (29%) of 423 qualifying prodrome events that had been treated with placebo (odds ratio 2·09, 95% CI 1·63-2·69; p<0·0001). Adverse events that occurred within 48 h after study-drug administration were reported after 77 (17%) of 456 qualifying prodrome events that had been treated with ubrogepant and after 55 (12%) of 462 events that had been treated with placebo. INTERPRETATION: Ubrogepant was effective and well tolerated for the treatment of migraine attacks when taken during the prodrome. FUNDING: AbbVie.

Atogepant for the preventive treatment of chronic migraine (PROGRESS): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In this study, we aimed to evaluate the efficacy, safety, and tolerability of atogepant for the preventive treatment of chronic migraine. METHODS: We did this randomised, double-blind, placebo-controlled, phase 3 trial at 142 clinical research sites across the USA, the UK, Canada, China, Czech Republic, Denmark, France, Germany, Italy, Japan, South Korea, Poland, Russia, Spain, Sweden, and Taiwan. Adults aged 18-80 years with a 1-year or longer history of chronic migraine were randomly assigned (1:1:1) to receive oral atogepant 30 mg twice a day, oral atogepant 60 mg once a day, or placebo. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) across the 12-week treatment period. The primary analysis was done in the modified intent-to-treat population and included all randomly assigned participants who received at least one dose of study intervention, had an evaluable baseline period of electronic diary (eDiary) data, and had at least one evaluable post-baseline 4-week period (weeks 1-4, 5-8, and 9-12) of eDiary data during the double-blind period. The safety population consisted of all participants who received at least one dose of study intervention. This trial is registered with ClinicalTrials.gov (NCT03855137). FINDINGS: Between March 11, 2019 and Jan 20, 2022, 1489 participants were assessed for eligibility. 711 were excluded, and 778 participants were randomly assigned to atogepant 30 mg twice a day (n=257), atogepant 60 mg once a day (n=262), or placebo (n=259). Participants in the safety population were aged 18-74 years (mean 42·1 years). 459 (59%) of 773 patients were White, 677 (88%) patients were female, and 96 (12%) were male. 84 participants discontinued treatment during the trial, and 755 comprised the modified intent-to-treat population (atogepant 30 mg twice a day n=253, atogepant 60 mg once a day n=256, and placebo n=246). Baseline mean number of MMDs were 18·6 (SE 5·1) with atogepant 30 mg twice a day, 19·2 (5·3) with atogepant 60 mg once a day, and 18·9 (4·8) with placebo. Change from baseline in mean MMDs across 12 weeks was -7·5 (SE 0·4) with atogepant 30 mg twice a day, -6·9 (0·4) with atogepant 60 mg once a day, and -5·1 (0·4) with placebo. Least squares mean difference from placebo was -2·4 with atogepant 30 mg twice a day (95% CI -3·5 to -1·3; adjusted p<0·0001) and -1·8 with atogepant 60 mg once a day (-2·9 to -0·8; adjusted p=0·0009). Most common adverse events for atogepant were constipation (30 mg twice a day 28 [10·9%]; 60 mg once a day 26 [10%]; and placebo 8 [3%]) and nausea (30 mg twice a day 20 [8%]; 60 mg once a day 25 [10%]; and placebo 9 [4%]). Potentially clinically significant weight decrease (≥7% reduction at any time post-baseline) was observed in each treatment group (atogepant 30 mg twice a day 14 [6%]; atogepant 60 mg once a day 15 [6%]; and placebo 5 [2%]). INTERPRETATION: Atogepant 30 mg twice a day and 60 mg once a day showed clinically relevant reductions in MMDs across 12 weeks in chronic migraine patients. Both atogepant doses were well tolerated, consistent with the known safety profile of atogepant. FUNDING: Allergan (now AbbVie).

Safety and tolerability results of atogepant for the preventive treatment of episodic migraine from a 40-week, open-label multicenter extension of the phase 3 ADVANCE trial.

BACKGROUND: Atogepant is a United States Food and Drug Administration-approved oral calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. The study objective was to evaluate the long-term safety and tolerability of atogepant in participants who completed the phase 3 ADVANCE trial (NCT03777059). METHODS: This 40-week, open-label extension trial (NCT03939312) monitored safety in participants receiving oral atogepant 60 mg once daily, followed by a four-week safety follow-up period. RESULTS: Of the 685 participants taking at least one dose of atogepant, the treatment period was completed by 74.6% of participants with a mean (standard deviation) treatment duration of 233.6 (89.3) days. Treatment-emergent adverse events occurred in 62.5% of participants, with upper respiratory tract infection (5.5%), urinary tract infection (5.3%), nasopharyngitis (4.8%), sinusitis (3.6%), constipation (3.4%), and nausea (3.4%) occurring at ≥3%. Serious adverse events were observed in 3.4% of participants (none were treatment-related), and there were no deaths. Adverse events leading to discontinuation occurring at >0.1% were nausea (0.4%) and abdominal pain, vomiting, weight decrease, dizziness, and migraine (0.3% each). CONCLUSION: These results are consistent with atogepant's known safety profile and support long-term use of atogepant 60 mg once daily dosing as safe and well tolerated.ClinicalTrials.gov Registration Number: NCT03939312.

Once-daily oral atogepant for the long-term preventive treatment of migraine: Findings from a multicenter, randomized, open-label, phase 3 trial.

OBJECTIVE: To assess long-term safety, tolerability, and efficacy of once-daily oral atogepant 60 mg in adults with migraine. BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of episodic migraine. METHODS: A 52-week, multicenter, randomized, open-label trial of adults (18-80 years) with migraine. Lead-in trial completers or newly enrolled participants with 4-14 migraine days/month were enrolled and randomized (5:2) to atogepant 60 mg once daily or oral standard care (SC) migraine preventive medication. The primary objective was to evaluate the safety and tolerability of atogepant; safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, vital signs, and Columbia-Suicide Severity Rating Scale scores. Efficacy assessments (atogepant only) included change from baseline in mean monthly migraine days (MMDs) and the proportion of participants with reductions from baseline of ≥50%, ≥75%, and 100% in MMDs. RESULTS: The trial included 744 participants randomized to atogepant 60 mg (n = 546) or SC (n = 198). The atogepant safety population was 88.2% female (n = 479/543) with a mean (standard deviation) age of 42.5 (12.0) years. TEAEs occurred in 67.0% (n = 364/543) of participants treated with atogepant 60 mg. The most commonly reported TEAEs (≥5%) were upper respiratory tract infection (10.3%; 56/543), constipation (7.2%; 39/543), nausea (6.3%; 34/543), and urinary tract infection (5.2%; 28/543). Serious TEAEs were reported in 4.4% (24/543) for atogepant. Mean (standard error) change in MMDs for atogepant was -3.8 (0.1) for weeks 1-4 and -5.2 (0.2) at weeks 49-52. Similarly, the proportion of participants with ≥50%, ≥75%, and 100% reductions in MMDs increased from 60.4% (310/513), 37.2% (191/513), and 20.7% (106/513) at weeks 1-4 to 84.2% (282/335), 69.9% (234/335), and 48.4% (162/335), at weeks 49-52. CONCLUSION: Daily use of oral atogepant 60 mg for preventive treatment of migraine during this 1-year, open-label trial was safe, well tolerated, and efficacious.

Total plasma homocysteine measurement: Evaluation of the Abbott immunoassay, comparison with the JEOL ion exchange chromatography and investigation of its clinical utility.

Objectives: Homocysteine is an intermediary amino acid formed in methionine metabolism, with elevated total homocysteine (tHCY) being a biomarker of cardiovascular and cerebrovascular diseases. We evaluated the Abbott ARCHITECT tHCY immunoassay, compared it with the current established JEOL ion exchange chromatography (IEC) method and evaluated its clinical utility. Design and methods: Following immunoassay method verification, plasma samples of 91 patients were analysed for tHCY using immunoassay and IEC. Results: For the Abbott immunoassay, accuracy was assessed, with UK NEQAS EQA specimens, by the correlation of our Abbott immunoassay measurements to the Abbott ARCHITECT immunoassay mean (bias = 1.6%), and to the overall immunoassay mean (bias = 2.0%). The total imprecision was 2.7% (11.00 µmol/L), 2.4% (16.80 µmol/L) and 2.8% (24.30 µmol/L) respectively. Bias in linearity assessment was 0.12%-2.58%. The inter-method correlation was strong in Passing-Bablok regression: immunoassay = IEC x0.857 + 2.445 (95% CI: slope = [0.742,0.947], intercept = [1.340,3.582]), with Spearman correlation = 0.803 (p < 0.001). The Bland-Altman plot showed an average difference of -0.284 µmol/L (95% CI: [-1.043,0.474]) with limits of agreement (mean ± 1.96SD) from -7.425 µmol/L to 6.857 µmol/L.No significant difference in tHCY was found using both methods in patients with cerebrovascular diseases and cardiovascular diseases. Most tHCY measurements were within the reference ranges of both methods. All homocystinuria patients had tHCY values above the reference ranges of both methods. Conclusions: The immunoassay demonstrated robust performance in its verification and showed good comparability with the IEC but with some biases so caution is needed if both are used interchangeably. The immunoassay offers an automated alternative to IEC in the assessment of hyperhomocysteinaemia.

Efficacy of Ubrogepant in the Acute Treatment of Migraine With Mild Pain vs Moderate or Severe Pain.

BACKGROUND AND OBJECTIVES: To examine the efficacy of ubrogepant in the treatment of migraine with mild vs moderate or severe pain. METHODS: This was a phase 3, open-label, dose-blinded, 52-week extension trial. Adults with migraine were randomized 1:1:1 (usual care, ubrogepant 50 mg, or ubrogepant 100 mg). Participants treated up to 8 migraine attacks of any pain intensity every 4 weeks. Efficacy outcomes (only collected for ubrogepant) included 2-hour pain freedom (2hPF), freedom from associated symptoms, and from disability. A generalized linear mixed model with binomial distribution and logit link function was used to assess the influence of baseline pain intensity on treatment outcomes in this post hoc analysis. RESULTS: Data for 19,291 attacks from 808 participants were included. 2hPF rates were higher for attacks treated when pain was mild vs moderate or severe: ubrogepant 50 mg (47.1% vs 23.6%; odds ratio [95% CI] 2.89 [2.57-3.24]) and ubrogepant 100 mg (55.2% vs 26.1%; 3.50 [3.12-3.92]; p < 0.0001 both doses). Rates of freedom from photophobia, phonophobia, and nausea 2 hours after treatment were also significantly higher following the treatment of mild vs moderate or severe pain (p < 0.001 all symptoms, both doses). At 2 hours, the proportion of attacks with normal function was more than double for both doses of ubrogepant (p < 0.001). The most common adverse event was upper respiratory tract infection (∼11% both doses). Serious adverse events were reported by 2% in ubrogepant 50 mg and 3% in ubrogepant 100 mg. DISCUSSION: Relative to treatment of attacks with moderate or severe pain, treatment with ubrogepant during mild pain resulted in significantly higher rates of freedom from pain, freedom from associated symptoms, and achieving normal function 2 hours after administration. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov, NCT02873221. CLASSIFICATION OF EVIDENCE: This trial provides Class III evidence that treatment of migraine with ubrogepant when pain is mild vs moderate or severe increases the likelihood of achieving pain freedom, absence of symptoms, and normal function within 2 hours postdose.

Rates of Response to Atogepant for Migraine Prophylaxis Among Adults: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Some patients with migraine, particularly those in primary care, require effective, well-tolerated, migraine-specific oral preventive treatments. Objective: To examine the efficacy of atogepant, an oral, small-molecule, calcitonin gene-related peptide receptor antagonist, using 4 levels of mean monthly migraine-day (MMD) responder rates. Design, Setting, and Participants: This secondary analysis of a phase 3, double-blind, placebo-controlled randomized clinical trial evaluated the efficacy and safety of atogepant for the preventive treatment of migraine from December 14, 2018, to June 19, 2020, in adults with 4 to 14 migraine-days per month at 128 sites in the US. Interventions: Patients were administered 10 mg of atogepant (n = 222), 30 mg of atogepant (n = 230), 60 mg of atogepant (n = 235), or placebo (n = 223) once daily in a 1:1:1:1 ratio for 12 weeks. Main Outcomes and Measures: These analyses evaluated treatment responder rates, defined as participants achieving 50% or greater (α-controlled, secondary end point) and 25% or greater, 75% or greater, and 100% (prespecified additional end points) reductions in mean MMDs during the 12-week blinded treatment period. Results: Of 902 participants (mean [SD] age, 41.6 [12.3] years; 801 [88.8%] female; 752 [83.4%] White; 825 [91.5%] non-Hispanic), 873 were included in the modified intention-to-treat population (placebo, 214; 10 mg of atogepant, 214; 30 mg of atogepant, 223; and 60 mg of atogepant, 222). For the secondary end point, a 50% or greater reduction in the 12-week mean of MMDs was achieved by 119 of 214 participants (55.6%) treated with 10 mg of atogepant (odds ratio, 3.1; 95% CI, 2.1-4.6), 131 of 223 participants (58.7%) treated with 30 mg atogepant (odds ratio, 3.5; 95% CI, 2.4-5.3), 135 of 222 participants (60.8%) treated with 60 mg of atogepant (odds ratio, 3.8; 95% CI, 2.6-5.7), and 62 of 214 participants (29.0%) given placebo (P < .001). The numbers of participants who reported a 25% or greater reduction in the 12-week mean of MMDs were 157 of 214 (73.4%) for 10 mg of atogepant, 172 of 223 (77.1%) for 30 mg of atogepant, and 180 of 222 (81.1%) for 60 mg of atogepant vs 126 of 214 (58.9%) for placebo (P < .002). The numbers of participants who reported a 75% or greater reduction in mean MMDs were 65 of 214 (30.4%) for 10 mg of atogepant, 66 of 223 (29.6%) for 30 mg of atogepant, and 84 of 222 (37.8%) for 60 mg of atogepant compared with 23 of 214 (10.7%) for placebo (P < .001). The numbers of participants reporting 100% reduction in mean MMDs were 17 of 214 (7.9%) for 10 mg of atogepant (P = .004), 11 of 223 (4.9%) for 30 mg of atogepant (P = .02), and 17 of 222 (7.7%) for 60 mg of atogepant (P = .003) compared with 2 of 214 (0.9%) for placebo. Conclusions and Relevance: At all doses, atogepant was effective during the 12-week double-blind treatment period beginning in the first 4 weeks, as evidenced by significant reductions in mean MMDs at every responder threshold level. Higher atogepant doses appeared to produce the greatest responder rates, which can guide clinicians in individualizing starting doses. Trial Registration: ClinicalTrials.gov Identifier: NCT03777059.

Time course of efficacy of atogepant for the preventive treatment of migraine: Results from the randomized, double-blind ADVANCE trial.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of migraine. METHODS: In the double-blind, phase 3 ADVANCE trial, participants with 4-14 migraine days/month were randomized to atogepant 10 mg, 30 mg, 60 mg, or placebo once daily for 12 weeks. We evaluated the time course of efficacy of atogepant for the preventive treatment of migraine. Analyses included change from baseline in mean monthly migraine days during each of the three 4-week treatment periods, change in weekly migraine days during weeks 1-4, and proportion of participants with a migraine on each day during the first week. RESULTS: We analyzed 873 participants (n = 214 atogepant 10 mg, n = 223 atogepant 30 mg, n = 222 atogepant 60 mg, n = 214 placebo). For weeks 1-4, mean change from baseline in mean monthly migraine days ranged from -3.1 to -3.9 across atogepant doses vs -1.6 for placebo (p < 0.0001). For weeks 5-8 and 9-12, reductions in mean monthly migraine days ranged from -3.7 to -4.2 for atogepant vs -2.9 for placebo (p ≤ 0.012) and -4.2 to -4.4 for atogepant vs -3.0 for placebo (p < 0.0002), respectively. Mean change from baseline in weekly migraine days in week 1 ranged from -0.77 to -1.03 for atogepant vs -0.29 with placebo (p < 0.0001). Percentages of participants reporting a migraine on post-dose day 1 ranged from 10.8% to 14.1% for atogepant vs 25.2% with placebo (p ≤ 0.0071). CONCLUSION: Atogepant demonstrated treatment benefits as early as the first full day after treatment initiation, and sustained efficacy across each 4-week interval during the 12-week treatment period.Clinical trial registration: ClinicalTrials.gov identifier: NCT03777059.

Atogepant for the Preventive Treatment of Migraine.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine. METHODS: In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D). RESULTS: A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo. The mean differences from placebo in the change from baseline were -1.2 days with 10-mg atogepant (95% confidence interval [CI], -1.8 to -0.6), -1.4 days with 30-mg atogepant (95% CI, -1.9 to -0.8), and -1.7 days with 60-mg atogepant (95% CI, -2.3 to -1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group. CONCLUSIONS: Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.).

Efficacy of ubrogepant based on prior exposure and response to triptans: A post hoc analysis.

OBJECTIVE: To determine the potential efficacy of ubrogepant for acute treatment of migraine based on historical experience with triptans. BACKGROUND: Although triptans have improved migraine treatment, their efficacy and tolerability may limit their utility in some individuals. Ubrogepant is a small-molecule, oral calcitonin gene-related peptide receptor antagonist approved by the Food and Drug Administration for acute treatment of migraine in adults. METHODS: This post hoc analysis of pooled data from the pivotal trials ACHIEVE I and II, identically designed, randomized, double-blind, phase 3, single-attack trials of ubrogepant in adults with a history of migraine with/without aura, examined the efficacy and tolerability of ubrogepant 50 mg versus placebo based on participants' historical experience with triptans: triptan responder, triptan-insufficient responder, and triptan naïve. Co-primary efficacy endpoints were pain freedom and absence of most bothersome migraine-associated symptom (MBS) 2 h post initial dose. Adverse events (AEs) within historical triptan experience subgroups were evaluated. RESULTS: In the pooled analysis population (n = 1799), 682 (placebo, n = 350; ubrogepant 50 mg, n = 332), 451 (placebo, n = 223; ubrogepant, n = 228), and 666 (placebo, n = 339; ubrogepant, n = 327) participants were triptan responders, triptan-insufficient responders, and triptan-naïve, respectively. Response rates on co-primary efficacy endpoints were higher for ubrogepant versus placebo across all groups. Treatment-by-subgroup interaction p values based on odds ratios for pain freedom (p = 0.290) and absence of MBS (p = 0.705) indicated no significant impact of historical triptan experience on ubrogepant efficacy. AE incidence for ubrogepant did not differ appreciably across historical triptan experience subgroups. CONCLUSIONS: Ubrogepant efficacy and tolerability did not differ for the acute treatment of migraine in participants classified as triptan responders, triptan-insufficient responders, and triptan-naïve based on their historical experience with triptans.

Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial.

BACKGROUND: Atogepant is an orally administered, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist under investigation for treatment of migraine. We aimed to examine a range of oral doses for safety, tolerability, and efficacy for the preventive treatment of migraine. METHODS: In this double-blind, phase 2b/3 trial, adults (aged 18-75 years), with a history (≥1 year) of migraine and 4-14 migraine days per month, were randomly assigned 2:1:2:2:1:1 (by means of a sequence generated by the statistical programming department of the sponsor, and operationalised through an automated interactive web-based response system) to receive placebo or atogepant 10 mg once daily, 30 mg once daily, 60 mg once daily, 30 mg twice daily, or 60 mg twice daily, in matching capsules. Participants, site personnel, and all study sponsor personnel were masked to treatment allocations. The study was done in 78 academic and private practice settings in the USA. The primary outcome was change from baseline in monthly migraine days across 12 weeks of treatment using a modified intention-to-treat approach. The overall type I error rate for multiple comparisons across active treatment doses was controlled at the 0·05 level by means of a graphic approach. The main outcomes to assess safety and tolerability were adverse event recordings. The trial is registered with ClinicalTrials.gov, NCT02848326 and is completed. FINDINGS: Between Sept 6, 2016, and April 23, 2018, of 1772 individuals screened, 834 were randomly assigned and 825 received one dose or more of study medication: 186 received placebo, 93 atogepant 10 mg once daily, 183 atogepant 30 mg once daily, 186 atogepant 60 mg once daily, 86 atogepant 30 mg twice daily, and 91 atogepant 60 mg twice daily. Overall, 714 (87%) of 825 participants were female, 628 (76%) were white, median migraine duration was 17·5 years (IQR 10·0-28·0), and 232 (28%) had previously used preventive treatment. The primary efficacy analysis included 795 patients: 178 received placebo, 92 atogepant 10 mg once daily, 182 atogepant 30 mg once daily, 177 atogepant 60 mg once daily, 79 atogepant 30 mg twice daily, and 87 atogepant 60 mg twice daily. Across the 12-week treatment period, all five atogepant groups showed significant least-squares mean (SE) change from baseline in mean monthly migraine days versus placebo: atogepant 10 mg once daily -4·0 (0·3; p=0·024), 30 mg once daily -3·8 (0·2; p=0·039), 60 mg once daily -3·6 (0·2; p=0·039), 30 mg twice daily -4·2 (0·4; p=0·0034), and 60 mg twice daily -4·1 (0·3; p=0·0031); placebo -2·9 (0·2). The most common treatment-emergent adverse events (TEAEs) across all groups were nausea (range 5% [5/93] for 10 mg once daily to 12% [22/186] for 60 mg once daily vs 5% [9/186] for placebo) and fatigue (1% [1/93] for 10 mg once daily to 10% [9/91] for 60 mg twice daily vs 3% [6/186] for placebo). Treatment-related TEAE frequency ranged from 18% (17/93) for 10 mg once daily to 26% (24/91) for 60 mg twice daily, versus 16% (30/186) for placebo. Seven participants reported a total of eight serious TEAEs (two participants each in the placebo, 30 mg once-daily, and 60 mg once-daily groups, and one participant in the 10 mg once-daily group). TEAEs leading to discontinuation were reported in 33 (5%) of 639 atogepant participants and 5 (3%) of 186 of those randomised to placebo. All serious TEAEs were unrelated to treatment. INTERPRETATION: All doses of oral atogepant were associated with a significant decrease in monthly migraine days over 12 weeks compared with placebo. Atogepant was safe and well tolerated over 12 weeks, supporting its phase 3 development for the preventive treatment of migraine. FUNDING: Allergan (before its acquisition by AbbVie).

Long-Term Safety Evaluation of Ubrogepant for the Acute Treatment of Migraine: Phase 3, Randomized, 52-Week Extension Trial.

OBJECTIVE: To evaluate the long-term safety and tolerability of ubrogepant for the acute treatment of migraine. BACKGROUND: Ubrogepant is an oral, calcitonin gene-related receptor antagonist in development for the acute treatment of migraine. The efficacy of ubrogepant was demonstrated in 2 phase 3 trials in which a significant improvement was observed in migraine headache pain, migraine-associated symptoms, and ability to function. METHODS: This was a phase 3, multicenter, randomized, open-label, 52-week extension trial. Adults with migraine with or without aura entered the trial after completing one of 2 phase 3 lead-in trials and were re-randomized 1:1:1 to usual care, ubrogepant 50 mg, or ubrogepant 100 mg. Randomization to ubrogepant dose was blinded. Those randomized to usual care continued to treat migraine attacks with their own medication. The usual care arm was included in this trial to capture background rates of hepatic laboratory parameters and contextualize hepatic safety assessments. Safety and tolerability were the primary outcome measures. The safety population for the ubrogepant arms included all randomized participants who received at least 1 dose of treatment. All cases of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations of ≥3 times the upper limit of normal were adjudicated by an independent panel of liver experts who were blinded to dose. RESULTS: The safety population included 1230 participants (404 in the ubrogepant 50-mg group, 409 in the ubrogepant 100-mg group, and 417 in the usual care group). Participants were on average 42 years of age, 90% (1106/1230) female and 85% (1043/1230) white, with an average BMI of 30 kg/m2 . Throughout the trial, 21,454 migraine attacks were treated with 31,968 doses of ubrogepant. Treatment-emergent adverse events (TEAEs) were reported by 268/404 (66%) participants receiving ubrogepant 50 mg and 297/409 (73%) receiving ubrogepant 100 mg. The most commonly reported TEAE was upper respiratory tract infection (<12%); findings were similar across dose groups. Treatment-related TEAEs were reported by 42/404 (10%) participants in the ubrogepant 50-mg group and 43/409 (11%) in the ubrogepant 100-mg group. Serious adverse events (SAEs) were reported by 9/404 (2%) participants in the ubrogepant 50-mg group and 12/409 (3%) participants in the ubrogepant 100-mg group. Twenty cases of ALT/AST levels of ≥3 times the upper limit of normal were reported and reviewed by an independent clinical adjudication committee of liver experts. There were no cases of Hy's Law. CONCLUSIONS: Long-term intermittent use of ubrogepant 50 and 100 mg given as 1 or 2 doses per attack for the acute treatment of migraine was safe and well tolerated, as indicated by a low incidence of treatment-related TEAEs and SAEs and discontinuations due to adverse events in this 1-year trial.

Ubrogepant for the Treatment of Migraine.

BACKGROUND: Ubrogepant is an oral, small-molecule calcitonin gene-related peptide receptor antagonist for acute migraine treatment. METHODS: We conducted a randomized trial to evaluate the efficacy, safety, and side-effect profile of ubrogepant. We assigned adults with migraine, with or without aura, in a 1:1:1 ratio to receive an initial dose of placebo, ubrogepant at a dose of 50 mg, or ubrogepant at a dose of 100 mg for treatment of a single migraine attack, with the option to take a second dose. The coprimary efficacy end points were freedom from pain at 2 hours after the initial dose and absence of the most bothersome migraine-associated symptom at 2 hours. Secondary end points included pain relief (at 2 hours), sustained pain relief (from 2 to 24 hours), sustained freedom from pain (from 2 to 24 hours), and absence of symptoms associated with migraine (photophobia, phonophobia, and nausea) at 2 hours. RESULTS: A total of 1672 participants were enrolled; 559 were assigned to receive placebo, 556 to receive 50 mg of ubrogepant, and 557 to receive 100 mg of ubrogepant. The percentage of participants who had freedom from pain at 2 hours was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P = 0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<0.001). The percentage of participants who had freedom from the most bothersome symptom at 2 hours was 27.8% in the placebo group, 38.6% in the 50-mg ubrogepant group (P = 0.002), and 37.7% in the 100-mg ubrogepant group (P = 0.002). Adverse events within 48 hours after the initial or optional second dose were reported in 12.8% of participants in the placebo group, in 9.4% in the 50-mg ubrogepant group, and in 16.3% in the 100-mg ubrogepant group. The most common adverse events were nausea, somnolence, and dry mouth (reported in 0.4 to 4.1%); these events were more frequent in the 100-mg ubrogepant group (reported in 2.1 to 4.1%). Serious adverse events reported within 30 days in the ubrogepant groups included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none of the events occurred within 48 hours after the dose. CONCLUSIONS: A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine. (Funded by Allergan; ClinicalTrials.gov number, NCT02828020.).

Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial.

Importance: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine. Objective: To evaluate the efficacy and tolerability of ubrogepant compared with placebo for acute treatment of a single migraine attack. Design, Setting, and Participants: Phase 3, multicenter, randomized, double-blind, placebo-controlled, single-attack, clinical trial (ACHIEVE II) conducted in the United States (99 primary care and research clinics; August 26, 2016-February 26, 2018). Participants were adults with migraine with or without aura experiencing 2 to 8 migraine attacks per month. Interventions: Ubrogepant 50 mg (n = 562), ubrogepant 25 mg (n = 561), or placebo (n = 563) for a migraine attack of moderate or severe pain intensity. Main Outcomes and Measures: Co-primary efficacy outcomes were pain freedom and absence of the participant-designated most bothersome migraine-associated symptom (among photophobia, phonophobia, and nausea) at 2 hours after taking the medication. Results: Among 1686 randomized participants, 1465 received study treatment (safety population; mean age, 41.5 years; 90% female); 1355 of 1465 (92.5%) were evaluable for efficacy. Pain freedom at 2 hours was reported by 101 of 464 participants (21.8%) in the ubrogepant 50-mg group, 90 of 435 (20.7%) in the ubrogepant 25-mg group, and 65 of 456 (14.3%) in the placebo group (absolute difference for 50 mg vs placebo, 7.5%; 95% CI, 2.6%-12.5%; P = .01; 25 mg vs placebo, 6.4%; 95% CI, 1.5%-11.5%; P = .03). Absence of the most bothersome associated symptom at 2 hours was reported by 180 of 463 participants (38.9%) in the ubrogepant 50-mg group, 148 of 434 (34.1%) in the ubrogepant 25-mg group, and 125 of 456 (27.4%) in the placebo group (absolute difference for 50 mg vs placebo, 11.5%; 95% CI, 5.4%-17.5%; P = .01; 25 mg vs placebo, 6.7%; 95% CI, 0.6%-12.7%; P = .07). The most common adverse events within 48 hours of any dose were nausea (50 mg, 10 of 488 [2.0%]; 25 mg, 12 of 478 [2.5%]; and placebo, 10 of 499 [2.0%]) and dizziness (50 mg, 7 of 488 [1.4%]; 25 mg, 10 of 478 [2.1%]; placebo, 8 of 499 [1.6%]). Conclusions and Relevance: Among adults with migraine, acute treatment with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose. Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations. Trial Registration: ClinicalTrials.gov Identifier: NCT02867709.

Myofascial pain and treatment: Editorial.

The first article featured in this quarter's overview deserves special attention. Margalef and colleagues developed the first viable animal model of trigger points (TrPs). They also provided evidence of glycosaminoglycans (GAGs) near TrPs, which is a new finding that deserves further scientific inquiry (Margalef et al 2019). In 2011, Stecco et al. already mentioned a possible role of hyaluronan, which constitutes a subgroup of GAGs, in the etiology of myofascial pain (Stecco et al 2011). Mayoral Del Moral and colleagues published an excellent study that showed very good inter-examiner reliability for identifying subjects with MPS for identifying specific muscles (Mayoral Del Moral et al 2018). Sollmann and colleagues described a new and objective method to identify TrPs, using T2 mapping with quantitative MRI-based techniques (Sollmann et al 2016). As usual, many new dry needling (DN) studies, reviews, manual TrP papers and case reports are included. Finally, we would like to thank Dr. Michelle Finnegan for her contributions to this overview paper during the past 5 years. Dr. Finnegan will be focusing on other professional endeavors and she will not return as a contributing author.

Safety and tolerability of ubrogepant following intermittent, high-frequency dosing: Randomized, placebo-controlled trial in healthy adults.

BACKGROUND: Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine. This trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing to healthy participants. METHODS: In this phase 1, multicenter, double-blind, parallel-group trial, healthy adults (age 18-50 years) were randomized 1:1 to placebo or ubrogepant. Ubrogepant was dosed at 100 mg (2 × 50 mg tablets) on 2 consecutive days followed by 2 consecutive days of placebo, alternating for 8 weeks. Primary outcome measures were safety and tolerability. RESULTS: Of participants randomized (n = 518), 516 were included in the safety population (n = 260 placebo; n = 256 ubrogepant). Treatment-emergent adverse events were reported in 45% of placebo and 44% of ubrogepant participants. The most common was headache (10% placebo; 11% ubrogepant). Overall, seven cases of alanine aminotransferase and/or aspartate aminotransferase levels ≥ 3 × the upper limit of normal (five placebo, two ubrogepant) were reported and adjudicated by a panel of independent liver experts blinded to treatment. Four cases were judged unlikely related to treatment. Two cases (one placebo, one ubrogepant) were judged possibly related, and one (ubrogepant) probably related. Alanine aminotransferase increases to ≥ 3 × the upper limit of normal in the two ubrogepant cases (possibly or probably related) were transient and resolved with continued dosing; both cases were asymptomatic, with no concurrent bilirubin elevation. CONCLUSION: Ubrogepant was well tolerated following intermittent, high-frequency dosing in healthy participants, with no clinically relevant signal of hepatotoxicity. TRIAL REGISTRATION: NA.

A critical overview of the current myofascial pain literature - February 2019.

This edition of the overview of current myofascial pain literature features several interesting and important publications. From Australia, Braithwaite and colleagues completed an outstanding systematic review of blinding procedures used in dry needling (DN) studies. Other papers tackled the interrater reliability of the identification of trigger points (TrP), the presence of muscle hardness related to latent TrPs, pelvic floor examination techniques, and the links between TrPs, headaches and shoulder pain. Israeli researchers developed a theoretical model challenging the contributions of the Cinderella Hypothesis to the development of TrPs. As in almost all issues, we included many DN, injection and acupuncture studies, which continue to be the focus of researchers all over the world.

The relative risk to the femoral nerve as a function of patient positioning: potential implications for trigger point dry needling of the iliacus muscle.

Objectives: Prudent dry needling techniques are commonly practiced with the intent to avoid large neurovascular structures, thereby minimizing potential excessive bleeding and neural injury. Patient position is one factor thought to affect the size of the safe zone during dry needling of some muscles. This study aimed to compare the size of the needle safe zone of the iliacus muscle during two different patient positions using ultrasound imaging. Methods: The distance from the anterior inferior iliac spine (AIIS) to the posterior pole of the femoral nerve was measured in 25 healthy participants (11 male, 14 female, mean age = 40) in both supine and sidelying positions using a Chison Eco1 musculoskeletal ultrasound unit. The average distance was calculated for each position and a two-tailed, paired t-test (α < 0.05) was used to examine the difference between positions. Results: The mean distance from the AIIS to the posterior pole of the femoral nerve was statistically greater with participants in the sidelying position (mean[SD] = 35.7 [6.2] mm) than in the supine position (mean[SD] = 32.1 [7.3] mm, p < .001). Discussion: Although more study is needed, these results suggest that patient positioning is one of several potential variables that should be considered in the optimization of patient safety/relative risk when performing trigger point dry needling. Level of Evidence: Level 4 (Pre-Post Test).

A critical overview of the current myofascial pain literature - November 2018.

This is the first issue of this review column since the passing of Dr. Leon Chaitow. We would like to take a brief moment to acknowledge how much his mentorship, friendship, and confidence have meant to us. Leon was a force in osteopathic and naturopathic medicine and his influence reaches to all corners of the musculoskeletal realm crossing over many disciplines through his lectures, workshops, and of course, his many books, editorials, and articles. In the foreword to one of his books, Jan Dommerholt wrote that "Leon Chaitow […] continued the work of Travell and Simons, but also of many others, whose contributions he has skillfully woven into an intricate tapestry of clinical pearls, practical tips, and solid evidence-informed research." Dr. Chaitow was a synthesizer, who always considered what different clinicians and researchers could possibly contribute to a better understanding of pain and dysfunction and provide real solutions to real problems. Even when he would not necessarily agree with all suggested remedies, he maintained an open mind and was able to take a step back and consider the bigger picture. For example, Leon was not a big fan of dry needling, yet, he valued the importance of this approach and encouraged the inclusion of dry needling papers in this review article and in his journal. The Journal of Bodywork and Movement Therapies became his baby and, considering the growth of the journal, there is no question that Leon's intense focus and efforts are appreciated by many around the globe. We wish to extend our condolences to Leon's wife Alkmini and daughter Sasha. He will surely be missed, but we can find peace in knowing that his legacy will stay with us forever. In this issue, we have included several basic myofascial pain research articles. As usual, dry needling (DN) studies and case reports are the most commonly referenced papers, but we also included neuroscience and electromyography studies, sleep studies, interrater reliability studies, and case reports of adverse events.