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Total migraine freedom, a potential primary endpoint to assess acute treatment in migraine: comparison to the current FDA requirement using the complete rizatriptan study database.

AbstractOBJECTIVE:
To examine total migraine freedom (TMF), defined as pain freedom and absence of associated symptoms, using rizatriptan clinical trial data and to explore advantages of TMF as a single primary composite efficacy endpoint.
BACKGROUND:
The FDA has set a higher regulatory hurdle for registration of new migraine agents requiring both pain freedom (or relief) and absence of each associated symptom (phonophobia, photophobia, and nausea).
METHODS:
Twelve studies representing phase III + efficacy/safety studies of rizatriptan 10 mg in adults treating migraine were included in the meta-analysis. The percentage of patients achieving TMF at 2 hours by study and combined by treatment group was summarized by treatment paradigm (early/mild pain, moderate/severe, menstrual migraine). To demonstrate the impact of the strict migraine regulatory hurdle on clinical trial design and to compare it to TMF, simulation via bootstrap sampling was used.
RESULTS:
Odds ratios (rizatriptan vs placebo, all P < .001) for TMF were 6.2 (95% CI: [4.9, 7.7]) for moderate/severe, 2.7 (95% CI: [1.8, 4.0]) for menstrual, and 3.1 (95% CI: [2.4, 4.0]) for early/mild. Most with moderate/severe migraine reported photophobia and/or phonophobia at baseline, but only half had nausea. Simulation results showed a substantial loss of power analyzing absence of pain and each symptom compared with the composite TMF endpoint across all treatment paradigms.
CONCLUSION:
Rizatriptan 10 mg was superior to placebo in achieving TMF at 2 hours post-dose across all treatment paradigms. Given that the majority of patients with migraine do not exhibit all 3 associated symptoms, the TMF endpoint has significant advantages vs establishing efficacy on pain and each symptom individually.
AuthorsAnthony J Rodgers, Carolyn M Hustad, Roger K Cady, Vincent T Martin, Paul Winner, Karen E Ramsey, Tony W Ho
JournalHeadache (Headache) Vol. 51 Issue 3 Pg. 356-368 (Mar 2011) ISSN: 1526-4610 [Electronic] United States
PMID21039453 (Publication Type: Comparative Study, Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't)
Copyright© 2010 American Headache Society.
Chemical References
  • Serotonin Receptor Agonists
  • Triazoles
  • Tryptamines
  • rizatriptan
Topics
  • Adult
  • Clinical Trials, Phase III as Topic
  • Databases, Factual
  • Endpoint Determination
  • Female
  • Humans
  • Male
  • Migraine Disorders (drug therapy)
  • Serotonin Receptor Agonists (therapeutic use)
  • Treatment Outcome
  • Triazoles (therapeutic use)
  • Tryptamines (therapeutic use)
  • United States
  • United States Food and Drug Administration

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