Creatine for amyotrophic lateral sclerosis/motor neuron disease.
BACKGROUND
Creatine, a naturally-occurring nitrogenous organic acid involved in adenosine triphosphate (ATP) production, has been shown to increase survival in mouse models of amyotrophic lateral sclerosis (ALS). Results from human trials, however, have been mixed. Given conflicting results regarding creatine's efficacy, we conducted a systematic review.


OBJECTIVE
To systematically examine creatine's efficacy in prolonging ALS survival and in slowing ALS disease progression.


METHODS
We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 4, 2009), MEDLINE and EMBASE in October 2009 for any trial involving creatine in the treatment of ALS. We also contacted experts in the field for any additional studies.


METHODS
Randomized trials of treatment with creatine or placebo in patients diagnosed with ALS. Our primary outcome was tracheostomy-free survival time; secondary outcomes were ALS progression as measured by changes in ALS functional rating revised scores (ALSFRS-R) and percent predicted forced vital capacity (FVC) over time.


METHODS
Two authors independently selected studies, assessed risk of bias and extracted data. We obtained and analyzed individual participant data from each study.


RESULTS
We included three trials involving 386 participants randomized to either creatine 5 to 10 g per day or placebo. Creatine was reportedly well-tolerated in all three included studies, with no evidence of renal failure or serious adverse events specifically attributable to creatine. Using a pooled log-rank statistical test, we found no statistical difference in survival between the placebo and creatine groups across all three studies (Chi(2) = 0.09, P = 0.76). In addition, we found no statistical difference in ALSFRS-R slopes between the two groups across all three studies using a pooled linear mixed-effects model (slope difference of +0.03 ALSFRS-R/month in the creatine group; P = 0.76). Interestingly, there was a trend towards slightly worsened FVC slope in the creatine group (slope difference of -0.63 FVC/month in the creatine group) using a pooled linear mixed-effects model across the two studies which included FVC as an outcome, but this difference was not statistically significant (P = 0.054).


CONCLUSIONS
In patients already diagnosed with clinically probable or definite amyotrophic lateral sclerosis (ALS), creatine at doses ranging from 5 to 10 g per day did not have a statistically significant effect on survival, ALS functional rating revised scores (ALSFRS-R) progression or percent predicted forced vital capacity (FVC) progression.
Pastula
Daniel M
DM
Neurology, UCSF Medical Center, UCSF Neurology, Box 0114, 505 Parnassus Ave, San Francisco, California, 94143-0114, USA. Daniel.Pastula@ucsfmedctr.org.
Moore
Dan H
DH
Bedlack
Richard S
RS
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000401:mortality; D003401:Creatine / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D006801:Humans; D016472:Motor Neuron Disease / Q000188:drug therapy / Q000401:mortality; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D014797:Vital Capacity / Q000187:drug effects
D018696:Neuroprotective Agents; D003401:Creatine