A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS, Amyotrophic Lateral Sclerosis, Informa Healthcare

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

2008, Vol. 9, No. 4 , Pages 212-222 (doi:10.1080/17482960802195632)

Paul H. Gordon¹ ^†, Ying-Kuen Cheung³, Bruce Levin³, Howard Andrews³, Carolyn Doorish¹, Robert B. Macarthur², Jacqueline Montes¹, Kate Bednarz¹, Julaine Florence²⁰, Julie Rowin¹⁵, Kevin Boylan⁷, Tahseen Mozaffar¹², Rup Tandan¹⁹, Hiroshi Mitsumoto¹, Elizabeth A. Kelvin³, John Chapin¹⁷, Richard Bedlack⁶, Michael Rivner⁹, Leo F. Mccluskey¹⁸, Alan Pestronk²⁰, Michael Graves¹³, Eric J. Sorenson⁸, Richard J. Barohn¹⁴, Jerry M. Belsh¹⁶, Jau-Shin Lou¹⁰, Todd Levine¹¹, David Saperstein¹¹, Robert G. Miller⁵, Stephen N. Scelsa⁴ and The Combination Drug Selection Trial Study Group

¹From the Departments of Neurology, , , , , USA

²Research Pharmacy, , , , USA

³Biostatistics, Columbia University, , New York, , USA

⁴Departments of Neurology, Beth Israel Medial Center, , New York, , USA

⁵California Pacific Medical Center, , California, , USA

⁶Duke University, , , , USA

⁷Mayo Clinic Jacksonville, , Florida, , USA

⁸Mayo Clinic Rochester, , Minnesota, , USA

⁹Medical College of Georgia, , Georgia, , USA

¹⁰Oregon Health and Science University, , Oregon, , USA

¹¹Phoenix Neurological Associates, , Arizona, , USA

¹²University of California Irvine, , California, , USA

¹³University of California Los Angeles, , California, , USA

¹⁴University of Kansas, , Kansas, , USA

¹⁵University of Illinois, , Illinois, , USA

¹⁶UMDNJ-Robert Wood Johnson Medical School, , New Jersey, , USA

¹⁷University of New Mexico, , New Mexico, , USA

¹⁸University of Pennsylvania, , Pennsylvania, , USA

¹⁹University of Vermont, , Vermont, , USA

²⁰Washington University, , Montana, , USA

^†Correspondence: Paul H. Gordon, Eleanor and Lou Gehrig MDA/ALS Research Center Neurological Institute, 9th Floor, 710 West 168th Street, New York, NY, 10032, USA PHG8@columbia.edu

See also commentary by Shefner & Leigh, page 254–256.

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.