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

Authors

  • Anthony J. Rodgers MS,

    1. From Merck, North Wales, PA, USA (A.J. Rodgers, C.M. Hustad, K.E. Ramsey, and T.W. Ho); Banyan Group Inc., Springfield, MO, USA (R.K. Cady); University of Cincinnati, Cincinnati, OH, USA (V.T. Martin); Palm Beach Headache Center, Nova Southeastern University, West Palm Beach, FL, USA (P. Winner).
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  • Carolyn M. Hustad PhD,

    1. From Merck, North Wales, PA, USA (A.J. Rodgers, C.M. Hustad, K.E. Ramsey, and T.W. Ho); Banyan Group Inc., Springfield, MO, USA (R.K. Cady); University of Cincinnati, Cincinnati, OH, USA (V.T. Martin); Palm Beach Headache Center, Nova Southeastern University, West Palm Beach, FL, USA (P. Winner).
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  • Roger K. Cady MD,

    1. From Merck, North Wales, PA, USA (A.J. Rodgers, C.M. Hustad, K.E. Ramsey, and T.W. Ho); Banyan Group Inc., Springfield, MO, USA (R.K. Cady); University of Cincinnati, Cincinnati, OH, USA (V.T. Martin); Palm Beach Headache Center, Nova Southeastern University, West Palm Beach, FL, USA (P. Winner).
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  • Vincent T. Martin MD,

    1. From Merck, North Wales, PA, USA (A.J. Rodgers, C.M. Hustad, K.E. Ramsey, and T.W. Ho); Banyan Group Inc., Springfield, MO, USA (R.K. Cady); University of Cincinnati, Cincinnati, OH, USA (V.T. Martin); Palm Beach Headache Center, Nova Southeastern University, West Palm Beach, FL, USA (P. Winner).
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  • Paul Winner DO,

    1. From Merck, North Wales, PA, USA (A.J. Rodgers, C.M. Hustad, K.E. Ramsey, and T.W. Ho); Banyan Group Inc., Springfield, MO, USA (R.K. Cady); University of Cincinnati, Cincinnati, OH, USA (V.T. Martin); Palm Beach Headache Center, Nova Southeastern University, West Palm Beach, FL, USA (P. Winner).
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  • Karen E. Ramsey RPh,

    1. From Merck, North Wales, PA, USA (A.J. Rodgers, C.M. Hustad, K.E. Ramsey, and T.W. Ho); Banyan Group Inc., Springfield, MO, USA (R.K. Cady); University of Cincinnati, Cincinnati, OH, USA (V.T. Martin); Palm Beach Headache Center, Nova Southeastern University, West Palm Beach, FL, USA (P. Winner).
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  • Tony W. Ho MD

    1. From Merck, North Wales, PA, USA (A.J. Rodgers, C.M. Hustad, K.E. Ramsey, and T.W. Ho); Banyan Group Inc., Springfield, MO, USA (R.K. Cady); University of Cincinnati, Cincinnati, OH, USA (V.T. Martin); Palm Beach Headache Center, Nova Southeastern University, West Palm Beach, FL, USA (P. Winner).
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  • Financial support: Funded by Merck.

  • Conflict of Interest: Drs. Cady, Martin, and Winner are consultants for and have received research grants and honoraria from Merck. Mr. Rodgers, Ms. Ramsey, and Drs. Hustad and Ho are employed by Merck and may own stock or hold stock options in the company.

A.J. Rodgers, Merck, 351 N. Sumneytown Pike, UG1C-36, North Wales, PA 19454-2505, USA.

Abstract

Objective.— 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 < .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.

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