Can we eliminate placebo in ALS clinical trials?
BACKGROUND
Previous studies concluded that the decline in strength in patients with amyotrophic lateral sclerosis (ALS) is a linear function. If so, a patient's natural history might serve as the control, instead of placebo, in a clinical trial.


METHODS
A placebo-controlled ALS clinical trial included a natural history phase, followed by a 6-month treatment phase. Each patient's forced vital capacity (FVC) score and maximal voluntary isometric contraction (MVIC) raw scores were measured monthly, standardized, and averaged into megascores. For 138 patients, the arm, leg, FVC, arm+leg combination, and arm+leg+FVC combination megascore slopes during the natural history phase and during the placebo phase were compared.


RESULTS
The mean slope of megascores during the natural history phase and the mean slope during the placebo phase were not different for the arm, leg, and arm+leg megascores, but were different for the FVC and arm+leg+FVC combination megascores.


CONCLUSIONS
Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.
Bryan
W W
WW
Department of Neurology, University of Texas Southwestern Medical School, Dallas, USA.
Hoagland
R J
RJ
Murphy
J
J
Armon
C
C
Barohn
R J
RJ
Goodpasture
J C
JC
Miller
R G
RG
Parry
G J
GJ
Petajan
J H
JH
Ross
M A
MA
Stromatt
S C
SC
D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000188:drug therapy* / Q000503:physiopathology; D001132:Arm / Q000503:physiopathology; D004311:Double-Blind Method; D005500:Follow-Up Studies; D006801:Humans; D007866:Leg / Q000503:physiopathology; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000627:therapeutic use*; D010808:Physical Examination / Q000379:methods; D010919:Placebos; D011786:Quality Control; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000639:trends; D012107:Research Design; D012132:Respiratory Muscles / Q000503:physiopathology; D013223:Statistics as Topic; D016896:Treatment Outcome; D014797:Vital Capacity
D009414:Nerve Growth Factors; D010919:Placebos