Creatine Safety, Tolerability, and Efficacy in Huntington's Disease: CREST-E Cellular energy depletion and secondary oxidative injury are present early, even presymptomatically in Huntington's disease (HD), and play a significant role in its pathogenesis. Creatine is an inexpensive and well-tolerated nutritional supplement that is converted in the body to phosphocreatine that acts as a high- energy phosphate store for restoring ATP from ADP. We have extensively shown creatine to delay the onset and slow the progression of the pathologic phenotypes in HD transgenic and knockin mice in a dose dependent manner and to correct their ATP deficiencies in brain. In our double-blind placebo-controlled study of 8 grams per day of creatine for 16 weeks in HD patients, we demonstrated that creatine is safe and tolerable, increases serum and brain levels of creatine, and markedly reduces a serum biomarker of oxidative injury to DNA (8OH2'dG) suggesting beneficial effects on a fundamental mechanism of pathogenesis in HD. We subsequently completed an open-label dose escalation study pushing creatine up to 40 grams daily. We found 30 grams daily to be the optimal dose based on serum and brain bioavailability, reduced tolerability at higher doses, dose dependent suppression of 8OH2'dG levels, evidence for slowed cognitive decline, and a sustained reduction in brain atrophy as determined by MRI morphometry. We now propose a multi-center, randomized, double-blind, placebo-controlled trial of 30 grams daily creatine in 650 symptomatic individuals with HD recruited from about 42 Huntington Study Group (HSG) sites, treated for 36 months to test the hypothesis that it will slow the progressive functional decline of HD. Our secondary clinical aims are to assess safety and tolerability by analyzing clinical and laboratory adverse events and to assess the clinical impact of creatine on impressions of global health (CGI), quality of life measures (SF-36), and on motor, cognitive, psychiatric, behavioral, and functional symptoms of HD. We also propose collaborating with a program project on HD biomarkers to provide additional secondary endpoints and to exploit this first opportunity to assess and validate particular biomarkers in a large prospective HD clinical trial. We have conceived a design incorporating interim analyses of safety, futility, and efficacy that would provide early and repeated safety data and also permit early stopping or modification. A companion application is also submitted to support study coordination, data management, and biostatistical support under the auspices of the HSG (Bernard Ravina, principal investigator). ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AT000613-07
Application #
7502059
Study Section
Special Emphasis Panel (ZAT1-JH (23))
Program Officer
Nahin, Richard
Project Start
2007-09-30
Project End
2013-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
7
Fiscal Year
2008
Total Cost
$2,264,317
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Hersch, Steven M; Schifitto, Giovanni; Oakes, David et al. (2017) The CREST-E study of creatine for Huntington disease: A randomized controlled trial. Neurology 89:594-601
Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95-102
Rosenthal, Liana S; Drake, Daniel; Alcalay, Roy N et al. (2016) The NINDS Parkinson's disease biomarkers program. Mov Disord 31:915-23
Rosas, Herminia D; Doros, Gheorghe; Bhasin, Swati et al. (2015) A systems-level ""misunderstanding"": the plasma metabolome in Huntington's disease. Ann Clin Transl Neurol 2:756-68
Rosas, Herminia D; Doros, Gheorghe; Gevorkian, Sona et al. (2014) PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology 82:850-7
Santiago, Jose A; Scherzer, Clemens R; Potashkin, Judith A (2014) Network analysis identifies SOD2 mRNA as a potential biomarker for Parkinson's disease. PLoS One 9:e109042
Santiago, Jose A; Scherzer, Clemens R; Harvard Biomarker Study et al. (2013) Specific splice variants are associated with Parkinson's disease. Mov Disord 28:1724-7
LeDoux, Mark S (2012) Exome sequencing for gene discovery: time does not stand still. Ann Neurol 72:628-9
Rosas, H Diana; Chen, Y Iris; Doros, Gheorghe et al. (2012) Alterations in brain transition metals in Huntington disease: an evolving and intricate story. Arch Neurol 69:887-93
Iverson, D J; Gronseth, G S; Reger, M A et al. (2010) Practice parameter update: evaluation and management of driving risk in dementia: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 74:1316-24

Showing the most recent 10 out of 19 publications