PRECREST is a two phase protocol for Huntington's disease 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 establish the highest tolerable doses in premanifest HD and 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 (or their highest dose) of creatine to assess long term exposure to high dose creatine and its long term impact on various biomarkers.

Extensive evidence exists that neurodegeneration begins many years before HD can be diagnosed clinically. Therefore, 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. Preclinical evidence for creatine's potential neuroprotective effects in animal models of HD has been well-documented. 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 also be confirmed. A two phase protocol is proposed in which 60 premanifest and at-risk subjects will randomized into a double blind placebo controlled dose titration study bringing them to 30 grams daily or their highest tolerated dose. The placebo-controlled phase will permit the detection of toxicity and intolerability due to the active compound (creatine), 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 assessment of safety data on all subjects, and increase the power to detect and measure potential biological markers and any response to the active compound. 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.

Inclusion Criteria:

- Expansion positive or 50% at risk for HD and not diagnosed clinically

Exclusion Criteria:

- Unstable medical conditions

Additional inclusion and exclusion criteria apply.