TY - JOUR
T1 - Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials
T2 - A Post-Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial
AU - Dodick, David W.
AU - Tepper, Stewart J.
AU - Friedman, Deborah I.
AU - Gelfand, Amy A.
AU - Kellerman, Donald J.
AU - Schmidt, Peter C.
N1 - Funding Information:
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 JAMA Neurology for work as an associate editor. Her spouse consults for Genentech and receives research support from Genentech, Quest Diagnostics, and MedDay.
Funding Information:
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.
Publisher Copyright:
© 2018 The Authors Headache: The Journal of Head and Face Pain published by Wiley Periodicals, Inc. on behalf of American Headache Society
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Objective: 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. Background: 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. Methods: 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. Results: Of the 159 patients treated with ADAM zolmitriptan 3.8 mg 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 (P =.02). Corresponding rates for those with phonophobia as the MBS were 14% and 41% (P =.05). For those whose MBS was nausea, corresponding values were 56% and 16%, respectively (P =.01). Two-hour freedom from the MBS for active drug vs placebo were 67% vs 35% (P <.01) for photophobia, 55% vs 43% (P =.45) for phonophobia, and 89% vs 58% for nausea (P =.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. Conclusion: In this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co-primary endpoints.
AB - Objective: 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. Background: 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. Methods: 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. Results: Of the 159 patients treated with ADAM zolmitriptan 3.8 mg 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 (P =.02). Corresponding rates for those with phonophobia as the MBS were 14% and 41% (P =.05). For those whose MBS was nausea, corresponding values were 56% and 16%, respectively (P =.01). Two-hour freedom from the MBS for active drug vs placebo were 67% vs 35% (P <.01) for photophobia, 55% vs 43% (P =.45) for phonophobia, and 89% vs 58% for nausea (P =.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. Conclusion: In this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co-primary endpoints.
KW - adhesive dermally applied microarray
KW - drug delivery
KW - headache
KW - intracutaneous
KW - migraine
KW - triptan
KW - zolmitriptan
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U2 - 10.1111/head.13327
DO - 10.1111/head.13327
M3 - Article
C2 - 29782049
AN - SCOPUS:85047637736
VL - 58
SP - 986
EP - 992
JO - Headache
JF - Headache
SN - 0017-8748
IS - 7
ER -