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Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials: A Post‐Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial

Mayo Clinic, 5777 E Mayo BlvdPhoenix, AZ 85054, USA

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Mayo Clinic, 5777 E Mayo BlvdPhoenix, AZ 85054, USA

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Neurology Department, Geisel School of Medicine at Dartmouth and Dartmouth‐Hitchcock Medical Center, One Medical Center DriveLebanon, NH 03756, USA

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University of California, San Francisco, 550 4th StreetSan Francisco, CA 94158, USA .

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Zosano Pharma, 34790 Ardentech CourtFremont, CA 94555, USA

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Corresponding Author

E-mail address:

UT Southwestern Medical Center, 5323 Harry Hines BlvdDallas, TX 75390, USA

Address all correspondence to P.C. Schmidt, Zosano Pharma, 34790 Ardentech Court, Fremont, CA 94555, USA, email: E-mail address:
First published: 21 May 2018

: DD has received compensation from serving on advisory boards and/or consulting within the past 5 years for: Allergan, Amgen, Alder, Arteaus, Pfizer, Colucid, Merck, NuPathe, Eli Lilly and Company, Autonomic Technologies, Ethicon JJ, Zogenix, Supernus, Labrys, Boston Scientific, Medtronic, St. Jude, Bristol‐Myers Squibb, Lundbeck, Impax, MAP, Electrocore, Tonix, Novartis, Teva, Alcobra, Zosano, Insys, GBS/Nocira, Acorda eNeura, Charleston Laboratories, Gore, Biohaven, Bioventric, Magellan, Theranica, Xenon, Dr. Reddy's/Promius Pharma. Dr. Dodick owns equity in Epien, GBS/Nocira, Second Opinion, Healint, and Theranica. Dr. Dodick has received funding for travel, speaking, editorial activities, or royalty payments from IntraMed, SAGE Publishing, Sun Pharma, Allergan, Oxford University Press, American Academy of Neurology, American Headache Society, West Virginia University Foundation, Canadian Headache Society, Healthlogix, Universal Meeting Management, WebMD, UptoDate, Medscape, Oregon Health Science Center, Albert Einstein University, University of Toronto, Starr Clinical, Decision Resources, Synergy, MedNet LLC, Peer View Institute for Medical Education, Medicom, Chameleon Communications, Academy for Continued Healthcare Learning, Haymarket Medical Education, Global Scientific Communications, HealthLogix, Miller Medical, MeetingLogiX, and Wiley Blackwell. Dr. Dodick, through his employer, has consulting use agreements with NeuroAssessment Systems and Myndshft. He holds Board of Director positions with King‐Devick Technologies and Epien Inc. He holds the following Patent 17189376.1‐1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis (no compensation).DF served on advisory boards for Supernus, Alder BioPharmaceuticals, Amgen, Avanir, Biohaven, Eli Lilly and Company, Teva, electoCore, and Zosano Pharma. She received grant support from Merck, Eli Lilly and Company, and Autonomic Technologies. She serves as a consultant for Eli Lilly and Company and Trigemina. She is a speaker for Allergan and Supernus. She is on the editorial board of Neurology Reviews and Headache, a contributing author to MedLink Neurology, and serves on the Board of Directors of the American Headache Society.ST serves as a consultant for Acorda Therapeutics, Alder Biopharmaceuticals, Allergan, Amgen, Autonomic Technologies, Inc., Avanir Pharmaceuticals, Biovision, electroCore, Eli Lilly and Company, eNeura, Gerson Lehman Group, Guidepoint Global, Kimberly‐Clark, Pernix Therapeutics, Pfizer, Slingshot Insights, Supernus, Teva Pharmaceutical Industries, and Zosano Pharma. He serves on the advisor's board for Alder Biopharmaceuticals, Allergan, Amgen, Autonomic Technologies, Inc, Avanir Pharmaceuticals, Charleston Laboratories, Dr. Reddy's, Kimberly‐Clark, Pfizer, Scion Neurostim, Teva Pharmaceutical Industries, and Zosano Pharma. He performs research (without personal compensation) for Alder Biopharmaceuticals, Allergan, Amgen, Autonomic Technologies, Inc., Avanir Pharmaceuticals, Dr. Reddy's, electroCore, eNeura, Scion Neurostim, Teva Pharmaceutical Industries, Theranica, and Zosano Pharma. He has received stock options from Autonomic Technologies, Inc. and receives royalties from University of Mississippi Press and Springer. He receives salary compensation from Dartmouth‐Hitchcock Medical Center and the American Headache Society.PS and DK are employees of Zosano Pharma.AG is a consultant for Zosano Pharma, Eli Lilly and Company, and Biohaven. She receives royalty payments from UpToDate and has received research funding from eNeura. She has received payment from for work as an associate editor. Her spouse consults for Genentech and receives research support from Genentech, Quest Diagnostics, and MedDay.


To better understand the utility of using pain freedom and most bothersome headache‐associated symptom (MBS) freedom as co‐primary endpoints in clinical trials of acute migraine interventions.


Adhesive dermally applied microarray (ADAM) is an investigational system for intracutaneous drug administration. The recently completed pivotal Phase 2b/3 study (ZOTRIP), evaluating ADAM zolmitriptan for the treatment of acute moderate to severe migraine, was one of the first large studies to incorporate MBS freedom and pain freedom as co‐primary endpoints per recently issued guidance by the US Food and Drug Administration. In this trial, the proportion of patients treated with ADAM zolmitriptan 3.8 mg, who were pain‐free and MBS‐free at 2 hours post‐dose, was significantly higher than for placebo.


We undertook a post‐hoc analysis of data from the ZOTRIP trial to examine how the outcomes from this trial compare to what might have been achieved using the conventional co‐primary endpoints of pain relief, nausea, photophobia, and phonophobia.


Of the 159 patients treated with ADAM zolmitriptan 3.8mg or placebo, prospectively designated MBS were photophobia (n = 79), phonophobia (n = 43), and nausea (n = 37). Two‐hour pain free rates in those with photophobia as the MBS were 36% for ADAM zolmitriptan 3.8 mg and 14% for placebo ( = .02). Corresponding rates for those with phonophobia as the MBS were 14% and 41% ( = .05). For those whose MBS was nausea, corresponding values were 56% and 16%, respectively ( = .01). Two‐hour freedom from the MBS for active drug vs placebo were 67% vs 35% ( < .01) for photophobia, 55% vs 43% ( = .45) for phonophobia, and 89% vs 58% for nausea ( = .04). MBS freedom but not pain freedom was achieved in 28%. Only 1 patient (1%) achieved pain freedom, but not MBS freedom. The proportion with both pain and MBS freedom was highest (56%) among those whose MBS was nausea.


In this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co‐primary endpoints.

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Subject age and elevated blood pressure are the 2 risk factors for which the strongest, supportive evidence exists. Honeystore Womens Rhinestone Peacock Patterned Handmade Sandals with Chunky Heel Silver01 100% guaranteed for sale best prices online free shipping 2014 unisex 2014 newest VL40HsVZx
Other apparent factors are summarized in Figure 3 and include carotid disease, coronary artery disease, chronic renal disease, and metabolic syndromes. Heart failure, coronary artery disease, hyperhomocysteinemia, obstructive sleep apnoea, migraines, and certain immunologic/hematologic disorders, especially those associated with hypercoagulable states, are also likely of significance. Despite their established risk for clinically apparent stroke, any association among SBI and sex, ethnicity, tobacco and alcohol consumption, obesity, dyslipidemia, atrial fibrillation, and diabetes mellitus remains unclear.

Figure 3.

Risk factors for silent brain infarction. AF indicates atrial fibrillation; CEA/CAS, carotid endarterectomy/carotid stenting; CI, cardiovascular interventions; CKD, chronic kidney disease; CTS, cardiothoracic surgery; eNOS, endothelial nitric oxide synthetase; GA, general anesthetic; Hct, homocysteine; hs-CRP, high-sensitivity-C-reactive protein; ICAM-1, intracellular adhesion molecule-1; MTHFR, methylenetetrahydrofolate reductase; OSA, obstructive sleep apnoea; PRKCH, protein kinase Cη (human); TAVI, transcatheter aortic valve implantation; VEGF, vascular endothelial growth factor; and vWF, von Willebrand Factor.

To date, because studies have taken place in settings where multiple possible risk factors coincide, multivariate analysis techniques have been emphasized to allow the relative importance of various factors to be determined. However, the extent to which these risk factors are independent is questionable, and an understanding of interactions and covariance between factors has not yet developed. Further confounding the assessment of various risk factors, it is not always clear whether an identified association is a cause or an effect of SBI.

Although there must be similarities, it is overly simplistic to assume that the same mechanisms underlie all types of cerebrovascular events. For SBI, however, it is difficult to determine these mechanisms because the vast majority of lesions are detected incidentally and the time of their occurrence is unknown. Furthermore, as discussed, SBI is not a homogenous entity resulting from both large- and small-vessel disease and presenting in varying anatomic locations, potentially reflecting differences in the underlying pathophysiology. Explanations on causative mechanisms are, therefore, largely speculative and rely on an assessment of the correlations and differences between risk factors, disease states (including overt stroke), biochemical markers, and imaging findings. Moreover, the paucity of methods for the assessment of the cerebral microvasculature, which is likely of greater significance to the pathogenesis of SBI than other cerebrovascular events, poses significant challenges to hypothesis testing. As such, SBI has received considerably less attention from vascular biology researchers than overt stroke.

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