Creatine Safety and Tolerability in Premanifest HD: PRECREST

There is extensive evidence that neurodegeneration begins many years before HD can be
diagnosed clinically. Thus, it is most desirable to begin a neuroprotective therapy before
or during this premanifest period with the aim of delaying onset, as well as slowing
functional decline. Cellular energy depletion is present early in HD and can be ameliorated
by creatine, which helps regenerate cellular ATP. There is extensive preclinical evidence
for creatine being neuroprotective in animal models of HD. Before the clinical efficacy of
creatine can be tested in premanifest HD, its long-term safety and tolerability must be
assessed in these individuals and its ability to favorably modify biomarkers of HD should be
confirmed. A two phase protocol is proposed in which 60 premanifest and at-risk subjects
will first be randomized into a double blind placebo controlled dose titration study
bringing them to 30 grams daily or their highest tolerated dose. This phase will permit the
detection of toxicity and intolerability with attribution to active compound versus placebo,
and enable a dose response assessment of biomarkers. In the second phase, all subjects will
enter a year long open-label treatment on 30 grams daily of creatine. This phase will
maximize the subjects on active compound to promote recruitment and retention, to expand the
safety database to all 60 subjects and to increase the 'n' for detecting biomarkers and
measuring their prospective responses to creatine. The clinical impact of creatine will be
assessed using the United Huntington's Disease Rating Scale. Safety and tolerability will be
assessed by analyzing clinical and laboratory adverse events. Serum levels of creatine will
be used to assess compliance and whether there is a relationship between bioavailability and
response. 8OH2'dG and related markers will be assessed to determine whether creatine
treatment can chronically suppress markers of energy depletion and oxidative injury and
whether suppression correlates with slowing the progression of HD. Morphometric MRI will be
used to determine whether creatine can slow brain atrophy in premanifest HD. This study will
provide the pilot data needed to plan a future study to determine whether creatine can delay
the onset or slow the progress of HD in premanifest individuals.