To determine whether efficacy outcomes from the pivotal single-dose, placebo-controlled, ZOTRIP trial were replicated in a subsequent trial using M207 (intracutaneous microneedle zolmitriptan) repeatedly over the course of a year for the acute treatment of migraine.

Background.-In October 2014, the US Food and Drug Administration released a draft guidance for the development of drugs for the acute treatment of migraine. This guidance offered the option of replacing the previously required 4 co-primary endpoints: pain freedom, freedom from nausea, freedom from photophobia, and freedom from phonophobia, all at 2 hours posttreatment, with 2 co-primary endpoints: pain freedom and freedom from most bothersome symptom (MBS) other than pain, both at 2 hours posttreatment. At the time the new draft guidance was released, no large clinical trials had been undertaken with these 2 co-primary endpoints, posing a challenge in determining the sample size that might be required to achieve statistical significance. As a number of trials have now been completed, we conducted a review of the observed placebo responses, drug effect sizes, and sample sizes to better inform the design of future trials. Methods.-We searched PubMed, Embase, Web of Science, and the Cochrane library for primary publications of phase 3 randomized, placebo-controlled, double-blind acute migraine treatment trials that used pain freedom and MBS freedom as primary or planned secondary endpoints. For each endpoint, placebo response rates were determined and used to generate estimates of sample size, assuming differences between placebo and active treatment groups of 10%, 15%, and 20%. Sample size calculations were based on 80% power using a 2-group continuity corrected chi-square test with a 5% 2-sided significance level. Results.-We identified abstracts or full-length papers describing results of 8 clinical trials employing the new coprimary endpoints. The mean placebo response rate for 2-hour pain freedom was 16.75% (range 11.8-21.3%) and treatment effect (difference in response rates between active and placebo groups) ranged from 5.0% to 27.2%. For 2-hour MBS freedom, the mean placebo response rate was 32.8% (range 25.2-48.1%), and the range of treatment effect was 8.9% to 25.4%. Based on a placebo response rate of 17% for pain freedom, the sample sizes that would have been required to achieve statistical significance were n = 269, n = 128, and n = 77, for treatment effect sizes of 10%, 15%, and 20%, respectively. For MBS, assuming a placebo response rate of 33%, the corresponding required sample sizes would have been n = 389, n = 181, and n = 105. Conclusions.-The observed range of placebo response and treatment effect sizes suggests that use of the newly recommended 2 co-primary endpoints could reduce the sample sizes required to achieve significance compared with past trials using 4 primary endpoints (in which mean and median group sizes for recent trials were 375 and 362, respectively). However, the initial trials using the newly recommended co-primary endpoints tended to treat more participants than would have been minimally required. We anticipate that with the growing body of information regarding the use of these new endpoints, samples sizes may be more aligned with treatment efficacy, enabling faster and more cost-effective trials for acute migraine treatment.

April 25, 2018April 10, 2018Free AccessEffectiveness and Safety of a New Zolmitriptan Rapid Absorption Microneedle Array (M207) for the Acute Treatment of Migraine (The ZOTRIP Study) (P4.125)Egilius Spierings, Donald Kellerman, and Pete SchmidtAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement) Letters to the Editor

OBJECTIVE: To assess satisfaction with the TEMPO ® inhaler delivery system and with MAP0004 (orally inhaled dihydroergotamine [DHE]) compared with previous migraine medications (eg, triptans) . BACKGROUND: MAP0004, an investigational orally inhaled DHE administered through the TEMPO ® inhaler, has demonstrated efficacy in treating migraine. Subjects completed a voluntary survey to assess satisfaction with the use of the inhaler and perceived efficacy of the investigational drug. DESIGN/METHODS: Subjects who were still participating at week 24 in an open-label, long-term, phase 3 study were invited to complete a nonvalidated survey consisting of 16 questions categorized into comparison with previous medications (n=8), convenience of use (n=4), medication aftertaste (n=3), and overall satisfaction (n=1). Surveys were completed voluntarily at 24 or 54 weeks. Response options ranged from strongly agree to strongly disagree (5-point scale). No formal statistical inferences were made and responses are presented as a normalized percentage of the respondents agreeing or disagreeing with the statements. RESULTS: 197 subjects completed 蠅1 survey question. Compared with their previous medications, subjects reported that MAP0004 works more consistently (68%), works faster (63%), provides better pain relief (53%), longer pain relief (54%), faster return to normal activity (63%), works even when taken late (57%), prevents recurrence (62%), and works better when taken early (83%). 58% preferred MAP0004 over their previous medications; 88% felt it was easy and 83% convenient to use. 58% reported medication aftertaste, but 77% said that aftertaste was tolerable and 69% indicated that they would ask for a MAP0004 prescription if the product was available. CONCLUSIONS: In this nonvalidated survey, most respondents preferred MAP0004 over their previous migraine medication and most reported that the inhaler was easy and convenient to use. Aftertaste was associated with the drug, but would not prevent participants from requesting a MAP0004 prescription. Study Supported by: Allergan, Inc., Irvine, CA. Disclosure: Dr. Aurora has received personal compensation for activities with Merck & Co., Inc., Allergan, Inc., and eNeura. Dr. Aurora has received research support from Merck & Co., Inc., Allergan, Inc., and eNeura. Dr. Buse has received personal compensation for activities with Allergan Inc., and Zogenix. Dr. Buse has received research support from Allergan Inc., Merck & Co. Inc., and Zogenix. Dr. Lu has received personal compensation for activities with Allergan, Inc. Dr. Lu holds stock and/or stock options in MAP Pharmaceuticals, which sponsored research in which Dr. Lu was involved as an investigator. Dr. Lu has received research support from Allergan, Inc. Dr. Kellerman has received personal compensation for activities with Allergan Inc. as an employee, and Ockham as a member of the board of directors. Dr. Kellerman holds stock and/or stock options in MAP Pharmaceuticals which sponsored research in which Dr. Kellerman was involved as an investigator. Dr. Cooper has received personal compensation for activities with Zogenix. Dr. Kori has received personal compensation for activities with Allergan Inc. as an employee. Dr. Kori holds stock and/or stock options in MAP Pharmaceuticals. Dr. Kori has received research support from Allergan Inc.

Migraine is a disabling condition affecting approximately 30 million people in the USA. Most clinical trials evaluating the efficacy of the acute treatment of migraine use endpoints measuring relief of pain over time. Associated symptoms, such as nausea, photophobia and phonophobia are included in the International Headache Society diagnostic criteria for migraine and relief of these symptoms are usually also included as clinical trial endpoints. MAP0004, an investigational product which delivers dihydroergotamine via a breath-synchronized metered dose inhaler (TEMPO®), was shown to be superior to placebo in effectively relieving migraine pain at 30 minutes, 2, 4, 24 and 48 hours in a large randomized double-blind placebo-controlled Phase 3 trial. In an effort to evaluate a more robust measure of efficacy, this post-hoc analysis assessed the combined relief from migraine pain (defined as pain reduction from moderate or severe to mild or none) and freedom from nausea, photophobia and phonophobia at several time points post-treatment without the use of rescue medication prior to those time points. Additionally, the sustainability of this effect 2-24 hours without the use of rescue medication was assessed. 794 subjects treated a qualifying migraine and had at least one post-dose efficacy assessment. Significantly higher percentage of MAP0004-treated subjects achieved combined relief from migraine pain and freedom from associated symptoms compared to placebo at: 1 hour (20.9% vs. 14.1%; p=0.0131), 2 hours (36.8% vs. 19.4%, p<0.0001), 4 hours (45.8% vs. 23.9%, p<0.0001), 24 hours (49.6% vs. 31.7%, p<0.0001) and 48 hours (41.1% vs. 28.5%, p=0.0002) post-treatment. This combined efficacy endpoint was sustained 2-24 hours in a significantly higher percentage of subjects treated with MAP004 than with placebo (28% vs. 11.3%, p<0.0001). The most common adverse events during the double-blind period in ≥ 2% of MAP0004-treated subjects and > placebo were medication aftertaste (6.1%), nausea (4.4%) and cough (2.4%).