Sumatriptan-Naproxen for Acute Treatment of Migraine

A Randomized Trial

  • Brandes, Jan Lewis MD
  • Kudrow, David MD
  • Stark, Stuart R. MD
  • O'Carroll, C. Phillip MD
  • Adelman, James U. MD
  • O'Donnell, Francis J. DO
  • Alexander, W. James MD, MPH
  • Spruill, Susan E. MS
  • Barrett, Pamela S. PharmD
  • Lener, Shelly E. PharmD

  • Nashville Neuroscience Group, Nashville, Tenn (Dr Brandes); California Medical Clinic for Headache, Santa Monica (Dr Kudrow); The Innovative Clinical Research Center, Alexandria, Va (Dr Stark); Headache Institute, Newport Beach, Calif (Dr O'Carroll); Headache Wellness Center, Greensboro, NC (Dr Adelman); OrthoNeuro, Columbus, Ohio (Dr O'Donnell); Pozen Inc, Chapel Hill, NC (Dr Alexander and Ms Spruill); and GlaxoSmithKline, Research Triangle Park, NC (Drs Barrett and Lener).

Corresponding Author: Jan Lewis Brandes, MD, Nashville Neuroscience Group, 300 20th Ave N, #603, Nashville, TN 37203 ([email protected]).

Author Contributions: Dr Brandes, as principal investigator, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Brandes, Adelman, Spruill, Barrett, Lener.

Acquisition of data: Brandes, Kudrow, Stark, O'Carroll, Adelman, O'Donnell, Spruill.

Analysis and interpretation of data: Brandes, Kudrow, Stark, O'Carroll, Adelman, O'Donnell, Alexander, Spruill, Barrett, Lener.

Drafting of the manuscript: Brandes, Kudrow, Stark, O'Donnell, Spruill.

Critical revision of the manuscript for important intellectual content: Brandes, Kudrow, Stark, O'Carroll, Adelman, O'Donnell, Alexander, Spruill, Barrett, Lener.

Statistical analysis: Spruill.

Obtained funding: Barrett, Lener.

Administrative, technical, or material support: Brandes, Kudrow.

Study supervision: Brandes, Adelman, Alexander, Barrett, Lener.

Financial Disclosures: Dr Brandes reports having received clinical research or educational support from Merck, GlaxoSmithKline, UCB Pharma, Allergan, Johnson & Johnson, AstraZeneca, Pfizer, Bristol-Myers Squibb, Winston Laboratories, Sanofi-Aventis, Elan Pharmaceuticals, Novartis, Endo, POZEN, Vernalis, Ortho-McNeil, Advanced Bionics, Forest Laboratories, MedPointe Pharmaceuticals, and Aradigm Corp. Dr Kudrow reports having received research grants from Ortho-McNeil, Pfizer, GlaxoSmithKline, Merck, and Eisai and has served on the speaker's bureau for Pfizer and GlaxoSmithKline. Dr Stark reports having received clinical research or educational support from GlaxoSmithKline, Proethics, Allergan, Ortho-McNeil, Pfizer, and Merck. Dr O'Carroll reports having received clinical research or educational support from Allergan, GlaxoSmithKline, Merck, Pfizer, Eli Lilly, Sanofi-Aventis, Cephalon, Forest Pharmaceutical, AstraZeneca, Ortho-McNeil, POZEN, and Ligand Pharmaceuticals. Dr Adelman reports having received clinical research support from GlaxoSmithKline and POZEN and having served on advisory boards or speaker's bureaus for GlaxoSmithKline, AstraZeneca, Pfizer, Merck, and Ortho-McNeil. Dr O'Donnell reports having received research support from Merck, GlaxoSmithKline, and Allergan; having served as a consultant for Merck, GlaxoSmithKline, and Ortho-McNeil; and having received speaker's honoraria from Merck, GlaxoSmithKline, Pfizer, and Ortho-McNeil. Dr Alexander is a previous employee and shareholder of POZEN. Ms Spruill is a previous employee of and currently serves as a consultant to POZEN. Ms Barrett is a previous employee of GlaxoSmithKline, serves as a consultant to GlaxoSmithKline, and is a stockholder in Pfizer. Ms Lener is an employee of GlaxoSmithKline.

MT400-301 Study Group:Alabama:Birmingham: Gregory M. Flippo, MD; Radiant Research, Birmingham, Gordon T. Connor, MD; Montgomery: Drug Research and Analysis Corp, Norman A. Garrison, Jr, MD; Arizona:Tucson: Northwest NeuroSpecialists PLLC, Jeanette Wendt; Arkansas: Hot Springs: Palmetto Clinical Research, Richard G. Pellegrino, MD; Little Rock: Clinical Study Centers LLC, Gordon L. Gibson, MD; California:San Diego: Medical Center for Clinical Research, William D. Koltun, MD; Santa Monica: California Medical Clinic for Headache, David Kudrow, MD; Oceanside: The Neurology Center, Benjamin M. Frishberg, MD; Walnut Creek: Neurological Research Institute of the East Bay, Michael Stein, MD; Florida:Hialeah: Medical Research Unlimited, Steven D. Wheeler, MD; Melbourne: Comprehensive Neuroscience Inc, Murray A. Kimmel, DO; Miami: Miami Research Associates Inc, Bruce Kohrman, MD; Palm Beach Gardens: Palm Beach Neurological Center, Michael M. Tuchman, MD; Plantation: Neurology Clinical Research Inc, Richard P. Singer, MD; Port Orange: Coastal Medical Research, Alex White, MD; West Palm Beach: Premiere Research Institute, Paul K. Winner, DO; Georgia:Augusta: Walton Headache Center, Marc Husid; Decatur: Neurology and Headache Specialists of Atlanta, Sarah E. DeRossett; Illinois:Chicago: Diamond Headache Clinic, Merle Lea Diamond, MD; Indiana:Evansville: MediSphere Medical Research Center LLC, Steven K. Elliott, MD; Research Solutions, Jennifer S. Wahle, MD; Indianapolis: Midwest Institute for Clinical Research, Phillip D. Toth, MD; Louisiana:Lake Charles: The Clinic, Alan Sconzert, MD, PhD; Metairie: New Orleans Medical Institute, Robert B. De Trinis, MD; Massachusetts:Milford: Milford Emergency Associates Inc, Anthony Puopolo, MD; North Dartmouth: Northeast Medical Research Associates Inc, S. David Miller, MD; Worcester: New England Regional Headache Center, Herbert G. Markley, MD; Michigan:Ann Arbor: Michigan Head-Pain and Neurological Institute, Todd Rozen, MD; Kalamazoo: Westside Family Medical Center, Gary Ruoff, MD; Missouri:St. Louis: Mercy Health Research, Timothy R. Smith, MD; Radiant Research Inc, Mohammed Z. Abudalu, MD; Nevada:Las Vegas: Lovelace Scientific Resources, James Snyder, MD; New Mexico:Albuquerque: Lovelace Scientific Resources, Lydia Lawson, MD; New York:Endwell: Regional Clinical Research Inc, Victor A. Elinoff, MD; New York City: Analgesic Development Ltd, Abraham Sunshine, MD; New York Headache Center, Alexander Mauskop, MD; North Carolina:Charlotte: Charlotte Clinical Research Inc, Greg V. Collins, MD; Greensboro: Headache Wellness Center, James U. Adelman, MD; Raleigh: Multi-Specialty Research Associates of North Carolina, John Rubino, MD; Ohio:Cincinnati: Community Research, Bruce C. Corser, MD; Radiant Research Inc, Michael J. Noss, MD; Oklahoma:Tulsa: Neurological Associates of Tulsa Inc, Harvey J. Blumenthal, MD, James Dean, MD; Oregon:Portland: Radiant Research Inc, Keith D. Klatt, MD; The Neurology Clinic, Hubert A. Leonard, MD, PhD; Pennsylvania:Lancaster: Oyster Point Family Health Center Research Across America, Michael Warren, MD; Philadelphia: Jefferson Headache Center, Stephen D. Silberstein, MD; Rhode Island:Warwick: Omega Medical Research, David L. Fried, MD; South Carolina:Mt Pleasant: Coastal Carolina Research Center, Cynthia Strout, MD; Summerville: Palmetto Clinical Research, Michael Otruba, DO; Tennessee:Nashville: Nashville Neuroscience Group PC, Jan Lewis Brandes, MD; Texas:Austin: Benchmark Research Austin, Teresa L. Coats, MD; Fort Worth: Benchmark Research, William Seger, MD; San Angelo: West Texas Medical Associates, Darrell T. Herrington, DO; San Antonio: Integra Clinical Research LLC, Susanne K. Gazda, MD; Radiant Research, San Antonio, William P. Jennings, MD; Richardson: KRK Medical Research, Roy S. Kiser, MD; Virginia:Roanoke: Blue Ridge Research Center, Gordon Burch, MD; Wisconsin:Milwaukee: Advanced Healthcare SC, Daniel J. Thompson, MD.

MT400-302 Study Group:Alabama: Huntsville: AmDoc Inc, Medical Affiliated Research Center Inc, Harry Lee McDaris, M.D; Mobile: USA Neurology, John F. Rothrock, MD; Arizona: Phoenix: Lovelace Scientific Resources Inc, Philip B. James, MD, Richard V. Albery, MD; Valley Neurological Headache Clinic, Carol Foster, MD; Scottsdale: Radiant Research-Scottsdale, Timm McCarty, MD; Tucson: Radiant Research-Tucson, Frank Dunlap, MD, Robert Hirsch, MD; Arkansas: Little Rock: Little Rock Family Practice Clinic, Kevin Roberts, MD; California:Carlsbad: Sanjeev Sharma, MD; Irvine: Radiant Research-Irvine, Sid Rosenblatt, MD; Newport Beach: Christopher Philip O'Carroll, MD; Northridge: Northridge Neurological Center; Ronald B. Ziman, MD; Redondo Beach: George J. Rederich, MD, PhD; Colorado: Denver: Radiant Research Inc, Leslie Moldauer, MD; Connecticut: Stamford: The New England Center for Headache, Alan M. Rapoport, MD; Stratford: Clinical Research Consultants Inc, Selwyn A. Cohen, MD; Florida: Clearwater: Tampa Bay Medical Research Inc, Steven C. Bowman, MD; Coral Gables: Clinical Research of South Florida, Jeffrey B. Rosen, MD; Ft Myers: Internal Medicine Associates-Department of Research, Stephen R. Zellner, MD; Gainesville: Florida Medical Research Institute PA, C. Richard King, MD; St Petersburg: Comprehensive NeuroScience Inc, Margarita Nunez, MD; Meridian Research, Mildred (Mimi) Farmer, MD; Georgia: Atlanta: Child Neurology Associates LLC, Frank Berenson, MD; Illinois:Peoria: NTouch Research, Daniel Brune, MD; Maryland:Towson: International Research Center, Alberto Yataco, MD; Minnesota: Plymouth: Clinical Research Institute, Gary Berman, MD; Missouri: Kansas City: The Center for Pharmaceutical Research, John Ervin, MD; Springfield: Headache Care Center, Roger Cady, MD; New Hampshire: Lebanon: Neurology Studies Group, Dartmouth-Hitchcock Medical Center, Thomas N. Ward, MD; New Jersey: Morristown: Neuroscience Center of Northern New Jersey, Stuart W. Fox, MD; Princeton: Global Medical Institute, Jeffrey Apter, MD; Ridgewood: Neurology Group of Bergen County, PA, Kenneth A. Levin, MD; New York: Albany: Upstate Clinical Research, James P. Wymer, MD; Manlius: Central New York Clinical Research, Douglas P. Zmolek, MD; North Carolina: Raleigh: North Carolina Clinical Research, Craig F. LaForce, MD; Winston-Salem: Piedmont Medical Research Associates, Thomas Littlejohn, MD; Ohio: Cleveland: Health Research Associates, Robert S. Kunkel, MD; Columbus: Columbus Neurological Group Inc, Kenneth A. Mankowski, MD; Radiant Research Inc, Douglas Schumacher, MD; Mogadore: Radiant Research Inc, Dennis C. McCluskey, MD; Toledo: Headache Center of Ohio, Gary Gerard, MD; West Chester: ClinExcel Research, Lisa K. Mannix, MD; Westerville: Ortho Neuro Inc, Francis O'Donnell, DO; Pennsylvania: Philadelphia: Radiant Research-Einstein Center One, Barry Packman, MD; South Carolina: Anderson: Radiant Research Inc, Harry I. Geisberg, MD; Greer: Radiant Research-Greer, William Travis Ellison, MD; Statesville: Statesville Research Institute, Neil M. Kassman, MD; Tennessee:Memphis: Wesley Headache Clinic, Stephen H. Landy, MD; Nashville: Clinical Research Associates Inc, Stephen C. Sharp, MD; Texas: Dallas: Harold Urschel, MD; Houston: The Houston Headache Clinic, Ninan T. Mathew, MD; Lubbock: Bhupesh Dihenia, MD; San Antonio: Texas Association of Pediatric Neurology PA, Jerry Tomasovic, MD; Utah: Salt Lake City: Jean Brown Research-JBA Research Inc, Gilbert Podolsky, MD; Vermont: Burlington: Department of Neurology, College of Medicine, University of Vermont, Robert Shapiro, MD; Virginia: Alexandria: The Innovative Clinical Research Center, Stuart R. Stark, MD; Washington: Spokane: Rockwood Research Department, Timothy W. Powell, MD, Steven Pugh, MD; Tacoma: Neurology and Neurosurgery Associates of Tacoma, John Huddlestone, MD; Wenatchee: Clinical Research-Wenatchee Valley Medical Center, James R. Cook, MD.

Funding/Support: The 2 clinical trials (MT-400:301 and MT-400:302) described in this article were funded by GlaxoSmithKline in partnership with POZEN, the IND sponsor of the investigational drug MT-400 (sumatriptan–naproxen sodium).

Role of the Sponsors: GlaxoSmithKline and Pozen Inc provided financial and material support, monitoring, data collection and management, and data analysis to the authors and study investigators.

Independent Statistical Analysis: Eugene Laska, PhD (director, Statistical Sciences Laboratory, Nathan S. Kline Institute for Psychiatric Research, and professor, Department of Psychiatry, New York University School of Medicine, Orangeburg), had full access to all of the efficacy data and was provided the SAS programs and statistical output produced by POZEN/GlaxoSmithKline. Dr Laska reviewed the appropriateness of the analytic approach to the analysis of the primary efficacy measures and select secondary outcomes, suggested additional analyses, and verified the primary results reported in the article. POZEN/GlaxoSmithKline Pharmaceutical Research and Development paid Dr Laska for the time he spent on the review. Research assistance was provided to Dr Laska by Joseph Wanderling, a research scientist at the Nathan S. Kline Institute for Psychiatric Research.

Acknowledgment: We acknowledge Meredith A. Cucuel, BA, of Nashville Neuroscience Group, Nashville, Tenn, for editorial assistance, Michael H. Ames, PhD, of GlaxoSmithKline, Research Triangle Park, NC, for statistical input, Jane Saiers, PhD, of The WriteMedicine Inc, Chapel Hill, NC, for assistance with preparation of the manuscript, and Susan A. McDonald, MA, of GlaxoSmithKline, Research Triangle Park, NC, for critical review of the manuscript. Ms Cucuel's work on the manuscript was funded by Nashville Neuroscience Group and Dr Saiers' work on the manuscript was funded by GlaxoSmithKline.

JAMA: The Journal of the American Medical Association 297(13):p 1443-1454, April 4, 2007.

Context

Multiple pathogenic mechanisms may be involved in generating the migraine symptom complex, and multimechanism-targeted therapy may confer advantages over monotherapy.

Objective

To evaluate the efficacy and safety of a fixed-dose tablet containing sumatriptan succinate and naproxen sodium relative to efficacy and safety of each monotherapy and placebo for the acute treatment of migraine.

Design, Setting, and Participants

Two replicate, randomized, double-blind, single-attack, parallel-group studies conducted among 1461 (study 1) and 1495 (study 2) patients at 118 US clinical centers who were diagnosed as having migraine and received study treatment for a moderate or severe migraine attack.

Interventions

Patients were randomized in a 1:1:1:1 ratio to receive a single tablet containing sumatriptan, 85 mg, and naproxen sodium, 500 mg; sumatriptan, 85 mg (monotherapy); naproxen sodium, 500 mg (monotherapy); or placebo, to be used after onset of a migraine with moderate to severe pain.

Main Outcome Measures

Primary outcome measures included the percentages of patients with headache relief 2 hours after dosing, absence of photophobia, absence of phonophobia, and absence of nausea for the comparison between sumatriptan–naproxen sodium and placebo, and the percentages of patients with sustained pain-free response for the comparison between sumatriptan–naproxen sodium and each monotherapy.

Results

Sumatriptan–naproxen sodium was more effective than placebo for headache relief at 2 hours after dosing (study 1, 65% vs 28%; P<.001 and study 2, 57% vs 29%; P<.001), absence of photophobia at 2 hours (58% vs 26%; P<.001 and 50% vs 32%; P<.001), and absence of phonophobia at 2 hours (61% vs 38%; P<.001 and 56% vs 34%; P<.001). The absence of nausea 2 hours after dosing was higher with sumatriptan–naproxen sodium than placebo in study 1 (71% vs 65%; P = .007), but in study 2 rates of absence of nausea did not differ between sumatriptan–naproxen sodium and placebo (65% vs 64%; P = .71). For 2- to 24-hour sustained pain-free response, sumatriptan–naproxen sodium was superior at P<.01 (25% and 23% in studies 1 and 2, respectively) to sumatriptan monotherapy (16% and 14% in studies 1 and 2), naproxen sodium monotherapy (10% and 10% in studies 1 and 2), and placebo (8% and 7% in studies 1 and 2). The incidence of adverse events was similar between sumatriptan–naproxen sodium and sumatriptan monotherapy.

Conclusion

Sumatriptan, 85 mg, plus naproxen sodium, 500 mg, as a single tablet for acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy, with an acceptable and well-tolerated adverse effect profile.

Trial Registration

clinicaltrials.gov Identifiers: NCT00434083 (study 1); NCT00433732 (study 2)

Copyright © 2007 by the American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use. American Medical Association, 515 N. State St, Chicago, IL 60610.
View full text|Download PDF