A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS.
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.
Gordon
Paul H
PH
Department of Neurology, Columbia University, New York, USA. PHG8@columbia.edu
Cheung
Ying-Kuen
YK
Levin
Bruce
B
Andrews
Howard
H
Doorish
Carolyn
C
Macarthur
Robert B
RB
Montes
Jacqueline
J
Bednarz
Kate
K
Florence
Julaine
J
Rowin
Julie
J
Boylan
Kevin
K
Mozaffar
Tahseen
T
Tandan
Rup
R
Mitsumoto
Hiroshi
H
Kelvin
Elizabeth A
EA
Chapin
John
J
Bedlack
Richard
R
Rivner
Michael
M
McCluskey
Leo F
LF
Pestronk
Alan
A
Graves
Michael
M
Sorenson
Eric J
EJ
Barohn
Richard J
RJ
Belsh
Jerry M
JM
Lou
Jau-Shin
JS
Levine
Todd
T
Saperstein
David
D
Miller
Robert G
RG
Scelsa
Stephen N
SN
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
D018696:Neuroprotective Agents; D011720:Pyrazoles; D013449:Sulfonamides; D008911:Minocycline; D000068579:Celecoxib; D003401:Creatine