Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials

A Post-Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial

David William Dodick, Stewart J. Tepper, Deborah I. Friedman, Amy A. Gelfand, Donald J. Kellerman, Peter C. Schmidt

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
JournalHeadache
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Migraine Disorders
zolmitriptan
Randomized Controlled Trials
Clinical Trials
Hyperacusis
Photophobia
Nausea
Pain
Placebos
United States Food and Drug Administration
Pharmaceutical Preparations
Headache

Keywords

  • Adhesive dermally applied microarray
  • Drug delivery
  • Headache
  • Intracutaneous
  • Migraine
  • Triptan
  • Zolmitriptan

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials : A Post-Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial. / Dodick, David William; Tepper, Stewart J.; Friedman, Deborah I.; Gelfand, Amy A.; Kellerman, Donald J.; Schmidt, Peter C.

In: Headache, 01.01.2018.

Research output: Contribution to journalArticle

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title = "Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials: A Post-Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial",
abstract = "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.",
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AU - Tepper, Stewart J.

AU - Friedman, Deborah I.

AU - Gelfand, Amy A.

AU - Kellerman, Donald J.

AU - Schmidt, Peter C.

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