Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
, 82 (10), 850-7

PRECREST: A Phase II Prevention and Biomarker Trial of Creatine in At-Risk Huntington Disease

Affiliations
Clinical Trial

PRECREST: A Phase II Prevention and Biomarker Trial of Creatine in At-Risk Huntington Disease

Herminia D Rosas et al. Neurology.

Abstract

Objective: To assess the safety and tolerability of high-dose creatine, the feasibility of enrolling premanifest and 50% at-risk subjects in a prevention trial, and the potential of cognitive, imaging, and blood markers.

Methods: Sixty-four eligible consenting participants were randomly allocated (1:1) 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. Subjects included premanifest (tested) and at-risk (not tested) individuals without clinical symptoms or signs of Huntington disease (HD). Primary outcomes were safety and tolerability. Exploratory endpoints included fine motor, visuospatial, and memory performance; structural and diffusion MRI; and selected blood markers.

Results: Forty-seven HD carriers and 17 non-HD controls were enrolled. Fifteen discontinued treatment (2 assigned to placebo); all were followed for the entire study period. Primary analysis was by intent to treat. The most common adverse events were gastrointestinal. Neuroimaging demonstrated treatment-related slowing of cortical and striatal atrophy at 6 and 18 months.

Conclusion: We describe a design that preserves the autonomy of subjects not wanting genetic testing while including controls for assessing the specificity of treatment effects. Our results demonstrate the feasibility of prevention trials for HD and the safety of high-dose creatine, provide possible evidence of disease modification, support future studies of creatine, and illustrate the value of prodromal biomarkers.

Classification of evidence: This study provides Class I evidence that high-dose creatine is safe and tolerable.

Figures

Figure 1
Figure 1. CONSORT flow diagram
CONSORT = Consolidated Standards of Reporting Trials; HC = healthy control; PHD = premanifest Huntington disease.
Figure 2
Figure 2. Baseline differences in neuroimaging between the control and PHD groups
(A, left) At baseline, the PHD group demonstrated early regionally selective cortical atrophy in several cortical regions including inferior parietal, lateral occipital, precentral, precuneus, superior parietal, and superior temporal regions (the color range indicates p values, red to yellow, p < 0.05 to p < 0.001, respectively). (A, right) Magnitude maps demonstrating cortical thinning in the PHD group as compared with HCs in the corresponding regions. Red reflects >0.1 mm thinning, corresponding to approximately 3% thinner cortex in the PHD group. (B) Voxel-based diffusion maps at baseline suggest extensive early white matter alterations. FA was reduced and AD, MD, and RD were increased in the PHD group as compared with HCs (p < 0.05, corrected), including the corpus callosum, corticospinal tracts, corona radiata, and superior longitudinal fasciculus. AD = axial diffusivity; CN = control; FA = fractional anisotropy; HC = healthy control; MD = mean diffusivity; PHD = premanifest Huntington disease; RD = radial diffusivity.
Figure 3
Figure 3. Surface-based maps showing cortical thinning to be slowed by creatine
(A) Rate maps, according to randomization. (B) Corresponding significance maps. Premanifest Huntington disease (PHD) subjects randomized to placebo demonstrated progressive thinning at rates as high as 0.2 mm/year in several cortical regions, including portions of frontal, temporal, and parietal cortex; these were significant compared with baseline. In contrast, in the PHD subjects randomized to creatine, cortical thinning primarily involved portions of the frontal and temporal cortex and was not significant compared with baseline. The differences in the rates of thinning in the creatine-treated and the placebo-treated groups were significant in a number of regions. These data suggest a beneficial effect of creatine on cortical thinning.
Figure 4
Figure 4. Repeated-measures modeling of 18-month changes confirms the slowing of cortical atrophy in the original placebo group
(A) Volume. Between visit 1 (V1) and V5, the changes in white matter, gray matter, caudate, and putamen volumes in premanifest Huntington disease (PHD) subjects randomized to creatine were similar to changes in healthy control (HC) subjects. The reduction in these volumes tended to be more rapid in PHD subjects treated with placebo. (B) Cortical thinning. Between V1 and V5, the rates of cortical thinning in PHD subjects treated with creatine were not significantly different than HCs. In contrast, the rates of cortical thinning were significantly faster in the PHD subjects randomized to placebo (p < 0.05). Between V5 and V8, the rate of thinning in the PHD group randomized to placebo slowed significantly after creatine was started (p < 0.01, illustrated in select regions of interest; red arrow indicates the end of the placebo-controlled phase), again suggesting slowed atrophy. Blue = HCs; solid black lines = PHD subjects randomized to creatine at V1; black dashed lines = PHD subjects randomized to placebo who subsequently crossed over to open label.
Figure 5
Figure 5. Axial diffusivity not affected by creatine treatment
Repeated-measures modeling of 18-month change. There was no effect of creatine on axial diffusivity for any region of interest (red arrow indicates the end of the placebo-controlled phase, p < 0.01 for all regions of interest). Blue = healthy controls; solid black lines = premanifest Huntington disease (PHD) subjects randomized to creatine at visit 1 (V1); black dashed lines = PHD subjects randomized to placebo who subsequently crossed over to open label.

Comment in

Similar articles

See all similar articles

Cited by 29 articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback