Pre-CREST-2X: Premanifest Huntington's Disease Extension Study II: Creatine Safety & Tolerability
Study Details
Study Description
Brief Summary
The purpose of this clinical trial is to extend the Pre-Crest-X study to further assess the long-term safety and tolerability of up to 30 grams daily creatine in individuals at-risk for Huntington's Disease (HD) and to assess whether biomarkers responsive to creatine in symptomatic individuals are informative in premanifest individuals over a longer duration.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
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. This extension trial will continue to follow eligible individuals who completed the Pre-CREST-X extension study on open-label creatine (up to 30 grams daily) for long term safety and tolerability for an additional 24 months. Other biological and imaging biomarkers of disease progression and potential response to treatment will also be assessed.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Creatine
|
Drug: Creatine monohydrate
Up to 30 grams daily creatine monohydrate
|
Outcome Measures
Primary Outcome Measures
- Safety [24 months]
Frequency of adverse events
- Tolerability [24 months]
Proportion of subjects completing the extension study at given dose level
Secondary Outcome Measures
- Clinical measures [24 months]
Components of the UHDRS (Unified Huntington Disease Rating Scale)
- Biological Markers of Disease Progression [24 months]
Biological indicators that creatine treatment might affect the progression of HD: plasma levels of creatine, serum levels of 8OH2'dG and 8OHG, magnetic resonance imaging (MRI), morphometric neuroimaging (biomarker of neurodegeneration), metabolomic profiling, and gene expression analysis to assess transcriptional effects of HD and creatine therapy.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Individuals who have completed the Pre-CREST Study.
-
Individuals capable of providing independent informed consent and complying with trial procedures.
Exclusion Criteria:
-Clinical evidence of unstable medical or psychiatric illness in the investigator's judgment.
Additional eligibility criteria apply.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Massachusetts General Hospital | Charlestown | Massachusetts | United States | 02129 |
Sponsors and Collaborators
- Massachusetts General Hospital
- National Institutes of Health (NIH)
Investigators
- Principal Investigator: Diana Rosas, MD, MS, Massachusetts General Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
- Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F, Rosas HD, Hersch SM, Hogarth P, Bouzou B, Jensen RV, Krainc D. Genome-wide expression profiling of human blood reveals biomarkers for Huntington's disease. Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11023-8. Epub 2005 Jul 25.
- Dedeoglu A, Kubilus JK, Yang L, Ferrante KL, Hersch SM, Beal MF, Ferrante RJ. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice. J Neurochem. 2003 Jun;85(6):1359-67.
- Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M, Como P, Zimmerman C, Lin M, Zhang L, Ulug AM, Beal MF, Matson W, Bogdanov M, Ebbel E, Zaleta A, Kaneko Y, Jenkins B, Hevelone N, Zhang H, Yu H, Schoenfeld D, Ferrante R, Rosas HD. Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG. Neurology. 2006 Jan 24;66(2):250-2.
- Hersch SM, Rosas HD. Neuroprotection for Huntington's disease: ready, set, slow. Neurotherapeutics. 2008 Apr;5(2):226-36. doi: 10.1016/j.nurt.2008.01.003. Review.
- Hersch SM, Rosas HD. Neuroprotective therapy for Huntington's disease: new prospects and challenges. Expert Rev Neurother. 2001 Sep;1(1):111-8. doi: 10.1586/14737175.1.1.111.
- Kim J, Amante DJ, Moody JP, Edgerly CK, Bordiuk OL, Smith K, Matson SA, Matson WR, Scherzer CR, Rosas HD, Hersch SM, Ferrante RJ. Reduced creatine kinase as a central and peripheral biomarker in Huntington's disease. Biochim Biophys Acta. 2010 Jul-Aug;1802(7-8):673-81. doi: 10.1016/j.bbadis.2010.05.001. Epub 2010 May 9.
- Rosas HD, Liu AK, Hersch S, Glessner M, Ferrante RJ, Salat DH, van der Kouwe A, Jenkins BG, Dale AM, Fischl B. Regional and progressive thinning of the cortical ribbon in Huntington's disease. Neurology. 2002 Mar 12;58(5):695-701.
- Rosas HD, Reuter M, Doros G, Lee SY, Triggs T, Malarick K, Fischl B, Salat DH, Hersch SM. A tale of two factors: what determines the rate of progression in Huntington's disease? A longitudinal MRI study. Mov Disord. 2011 Aug 1;26(9):1691-7. doi: 10.1002/mds.23762. Epub 2011 May 24.
- Rosas HD, Salat DH, Lee SY, Zaleta AK, Hevelone N, Hersch SM. Complexity and heterogeneity: what drives the ever-changing brain in Huntington's disease? Ann N Y Acad Sci. 2008 Dec;1147:196-205. doi: 10.1196/annals.1427.034. Review.
- Rosas HD, Salat DH, Lee SY, Zaleta AK, Pappu V, Fischl B, Greve D, Hevelone N, Hersch SM. Cerebral cortex and the clinical expression of Huntington's disease: complexity and heterogeneity. Brain. 2008 Apr;131(Pt 4):1057-68. doi: 10.1093/brain/awn025. Epub 2008 Mar 12.
- Rosas HD, Tuch DS, Hevelone ND, Zaleta AK, Vangel M, Hersch SM, Salat DH. Diffusion tensor imaging in presymptomatic and early Huntington's disease: Selective white matter pathology and its relationship to clinical measures. Mov Disord. 2006 Sep;21(9):1317-25.
- Ryu H, Rosas HD, Hersch SM, Ferrante RJ. The therapeutic role of creatine in Huntington's disease. Pharmacol Ther. 2005 Nov;108(2):193-207. Epub 2005 Aug 1. Review.
- Stack EC, Dedeoglu A, Smith KM, Cormier K, Kubilus JK, Bogdanov M, Matson WR, Yang L, Jenkins BG, Luthi-Carter R, Kowall NW, Hersch SM, Beal MF, Ferrante RJ. Neuroprotective effects of synaptic modulation in Huntington's disease R6/2 mice. J Neurosci. 2007 Nov 21;27(47):12908-15.
- 2010P000511