A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS

Paul H. Gordon, Ying Kuen Cheung, Bruce Levin, Howard Andrews, Carolyn Doorish, Robert B. MacArthur, Jacqueline Montes, Kate Bednarz, Julaine Florence, Julie Rowin, Kevin Boylan, Tahseen Mozaffar, Rup Tandan, Hiroshi Mitsumoto, Elizabeth A. Kelvin, John Chapin, Richard Bedlack, Michael Rivner, Leo F. McCluskey, Alan PestronkMichael Graves, Eric J. Sorenson, Richard Barohn, Jerry M. Belsh, Jau Shin Lou, Todd Levine, David Saperstein, Robert G. Miller, Stephen N. Scelsa

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Combining agents with different mechanisms of action may be necessary for meaningful results in treating ALS. The combinations of minocycline-creatine and celecoxib-creatine have additive effects in the murine model. New trial designs are needed to efficiently screen the growing number of potential neuroprotective agents. Our objective was to assess two drug combinations in ALS using a novel phase II trial design. We conducted a randomized, double-blind selection trial in sequential pools of 60 patients. Participants received minocycline (100 mg)-creatine (10 g) twice daily or celecoxib (400 mg)-creatine (10 g) twice daily for six months. The primary objective was treatment selection based on which combination best slowed deterioration in the ALS Functional Rating Scale-Revised (ALSFRS-R); the trial could be stopped after one pool if the difference between the two arms was adequately large. At trial conclusion, each arm was compared to a historical control group in a futility analysis. Safety measures were also examined. After the first patient pool, the mean six-month decline in ALSFRS-R was 5.27 (SD=5.54) in the celecoxib-creatine group and 6.47 (SD=9.14) in the minocycline-creatine group. The corresponding decline was 5.82 (SD=6.77) in the historical controls. The difference between the two sample means exceeded the stopping criterion. The null hypothesis of superiority was not rejected in the futility analysis. Skin rash occurred more frequently in the celecoxib-creatine group. In conclusion, the celecoxib-creatine combination was selected as preferable to the minocycline-creatine combination for further evaluation. This phase II design was efficient, leading to treatment selection after just 60 patients, and can be used in other phase II trials to assess different agents.

Original languageEnglish
Pages (from-to)212-222
Number of pages11
JournalAmyotrophic Lateral Sclerosis
Volume9
Issue number4
DOIs
StatePublished - Aug 5 2008

Keywords

  • ALS
  • Amyotrophic lateral sclerosis
  • Celecoxib
  • Clinical trial
  • Combination therapy
  • Creatine
  • Minocycline
  • Neuroprotection
  • Selection trial

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    Gordon, P. H., Cheung, Y. K., Levin, B., Andrews, H., Doorish, C., MacArthur, R. B., Montes, J., Bednarz, K., Florence, J., Rowin, J., Boylan, K., Mozaffar, T., Tandan, R., Mitsumoto, H., Kelvin, E. A., Chapin, J., Bedlack, R., Rivner, M., McCluskey, L. F., ... Scelsa, S. N. (2008). A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS. Amyotrophic Lateral Sclerosis, 9(4), 212-222. https://doi.org/10.1080/17482960802195632