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Creatine slows progression of Huntington's disease in clinical trial
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In the first clinical trial of a drug intended to slow onset of Huntington’s disease (HD) symptoms, a study from Massachusetts General Hospital has provided evidence that the nutritional supplement creatine slows progression of brain atrophy in Huntington’s disease (HD) patients as well we being safe and well-tolerated by most study participants. The phase II PRECREST trial also pioneered a novel design that allowed participants- who were recruited as they were at potential genetic risk of HD due to family history- to enrol in the study without having to find out whether or not they were carriers of the HD mutation.

HD is a devastating a hereditary neurological disorder that causes brain cell degeneration. It is caused by an autosomal dominant mutation in the Huntingtin gene, resulting in a mutated form of the huntingtin protein. The disease causes physical, cognitive and emotional decline and can typically be associated with symptoms such as involuntary movements and speech impairment. Symptoms are most commonly first noticed between the ages of 30 and 45. The corresponding author of the study, Dr H. Diana Rosas, pointed out that: "More than 90 percent of those in the United States who know they are at risk for HD because of their family history have abstained from genetic testing, often because they fear discrimination or don't want to face the stress and anxiety of knowing they are destined to develop such a devastating disease." Thus the option offered in the trial of not finding out their HD status while still gaining access to a potentially helpful drug was attractive to many participants.

One mode of action of mutated huntingtin protein in HD is interference with brain cell energy production. This leads to depletion of ATP. This is where the creatine comes in, as it is known to help restore ATP and hence maintain cellular energy. Animal studies had previously shown that creatine can increase brain ATP and ward off neurodegeneration. However, previous human trials in HD patients had been limited as the daily dosage was low at only 10 g or less and did not indicate potential clinical efficacy. The PRECREST trial, by contrast, used daily dosages of up to 30 g. The researchers recruited sixty-four eligible consenting participants. These were randomly allocated to 15 g twice daily of creatine monohydrate or placebo for a 6-month double-blind phase followed by a 12-month open-label extension. Of the study subjects, 19 already knew they carried the HD mutation. The other 45 were at risk due to family history; of these 26 were found to be pre-symptomatic carriers of the mutated gene. Thus the final tally for the study was a total of 47 participants with pre-symptomatic HD and 17 controls. Primary outcomes for the trial were safety and tolerability of the creatine. Exploratory endpoints included fine motor, visuospatial, and memory performance, MRI brain scans and selected blood markers; these were measured at the beginning of the trial, at the end of the six month first phase and at the end of the trial.

Participants were regularly monitored for adverse events throughout the trial, with dosage levels being modified as necessary. The majority of the participants (more than two-thirds) tolerated the 30 g dosage. A total of fifteen participants stopped creatine because of factors including, gastrointestinal discomfort, the taste of the drug, inconvenience, or the stress of being constantly reminded of their HD risk. The most common adverse events were gastrointestinal. However, MRI neuroimaging demonstrated treatment-related slowing of cortical and striatal atrophy at 6 months in the creatine-treated participants versus the placebo-treated. At the 18 months trial endpoint, the rate of brain atrophy had also slowed in pre-symptomatic participants that started taking creatine after 6 months on placebo.

These results suggest both that creatine could slow the progression of HD and that neuroimaging may provide a useful biomarker of disease modification in studies of other potential treatments. A note of caution may be sounded by the fact that during the time period covered by the trial, there was no evidence of creatine having a positive effect on cognitive tests. The researchers noted that this may possibly be because the tests were not sensitive enough to detect subtle changes that might occur during such a brief time period. Senior author on the study, Dr Steven Hersch, concluded that: "The results of this trial suggest that the prevention or delay of HD symptoms is feasible, that at-risk individuals can participate in clinical trials – even if they do not want to learn their genetic status – and that useful biomarkers can be developed to help assess therapeutic benefits.”

Sources

http://www.eurekalert.org/pub_releases/2...020514.php [Accessed 11 February 2014].

ROSAS, H. D., DOROS, G., GEVORKIAN, S., MALARICK, K., REUTER, M., COUTU, J.-P., TRIGGS, T. D., WILKENS, P. J., MATSON, W., SALAT, D. H. and HERSCH. S. M., 2014. PRECREST: A phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology, 2014; DOI: 10.1212/WNL.0000000000000187

http://www.huntingtons.ie/ [Accessed 11 February 2014].
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Creatine slows progression of Huntington's disease in clinical trial00