title: A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS.
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.
authors.affiliation: Department of Neurology, Columbia University, New York, USA. PHG8@columbia.edu
authors.forename: Paul H
authors.initials: PH
authors.lastname: Gordon
authors.forename: Ying-Kuen
authors.initials: YK
authors.lastname: Cheung
authors.forename: Bruce
authors.initials: B
authors.lastname: Levin
authors.forename: Howard
authors.initials: H
authors.lastname: Andrews
authors.forename: Carolyn
authors.initials: C
authors.lastname: Doorish
authors.forename: Robert B
authors.initials: RB
authors.lastname: Macarthur
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Montes
authors.forename: Kate
authors.initials: K
authors.lastname: Bednarz
authors.forename: Julaine
authors.initials: J
authors.lastname: Florence
authors.forename: Julie
authors.initials: J
authors.lastname: Rowin
authors.forename: Kevin
authors.initials: K
authors.lastname: Boylan
authors.forename: Tahseen
authors.initials: T
authors.lastname: Mozaffar
authors.forename: Rup
authors.initials: R
authors.lastname: Tandan
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsumoto
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kelvin
authors.forename: John
authors.initials: J
authors.lastname: Chapin
authors.forename: Richard
authors.initials: R
authors.lastname: Bedlack
authors.forename: Michael
authors.initials: M
authors.lastname: Rivner
authors.forename: Leo F
authors.initials: LF
authors.lastname: McCluskey
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: Michael
authors.initials: M
authors.lastname: Graves
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorenson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Barohn
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Belsh
authors.forename: Jau-Shin
authors.initials: JS
authors.lastname: Lou
authors.forename: Todd
authors.initials: T
authors.lastname: Levine
authors.forename: David
authors.initials: D
authors.lastname: Saperstein
authors.forename: Robert G
authors.initials: RG
authors.lastname: Miller
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Scelsa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000068579:Celecoxib; D003401:Creatine / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D003875:Drug Eruptions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018579:Patient Selection; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D011720:Pyrazoles; D013449:Sulfonamides; D008911:Minocycline; D000068579:Celecoxib; D003401:Creatine