Daily Creatine Fails to Show Benefits in Early Huntington Disease

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Creatine had previously shown evidence of slowing functional decline.
Creatine had previously shown evidence of slowing functional decline.

A recent multinational study published in Neurology provided class II evidence that creatine monohydrate does not slow functional decline in early progressive Huntington disease (HD). The multicenter, double-blind study, which evaluated 40 g monohydrate creatine daily for up to 48 months, found no benefits to active therapy, and actually favored placebo.

A team of investigators from the Creatine Safety, Tolerability, & Efficacy in Huntington's Disease (CREST-HD) Study Group recruited 533 participants aged 18 years or older, with a familial history of HD and a clinical stage I or II of HD, from 46 sites in North America, Australia, and New Zealand, starting in December 2009 with follow-up through December 2014. Mean age of the participants was 50 years (standard deviation [SD], 11.5 years), with a mean age at HD onset of 46 years (SD, 12 years). The cohort was mostly white (93%), with slightly more female participants (53%).

Participants were randomly assigned to receive either creatine (n=275) or placebo (n=278) for up to 48 months, toward a primary outcome of a 25% slowing of total functional capacity score (TCS). Before reaching that point, however, interim analysis pointed to estimated rates of reduction of TCS of 0.82 per year for creatine compared with 0.70 for placebo. The criterion for futility was met and the study was halted early on the recommendation of the Data Safety Monitoring Board, even before planned enrollment reached 650.

Adverse effects led to the withdrawal of 35% of participants receiving creatine (n=97) compared with 26% taking placebo (n=72), and the investigators noted a slightly higher degree of impairment at baseline among those who withdrew compared with those who did not (mean total functional capacity, 9.9 vs 10.3). Only 58% of participants assigned to creatine reached the study dose of 40 mg/day, for an average dose of 31.6 g/day at 2 years, compared with 91% on placebo who reached 40 mg (average 38.3 g/day).

Overall, there were no differences in outcomes by age, baseline TCS, or CAG mutation length. Differences in rates of TCS decline were noted by sex, however, significantly favoring men over women (0.25 vs 0.42 points per year, respectively).

On the basis of 2 previous trials by the CREST-HD group, the team had expectations of benefits of creatine monohydrate in early HD.2,3 The first of these found that 8 g/day creatine significantly reduced levels of 8-hydroxy 2-deoxyguanosine, a marker of oxidative DNA damage.2 A second CREST-HD phase 2 secondary prevention trial evaluated 35 mg/day creatine in 70 patients who were at risk or presymptomatic for HD and found that it significantly slowed brain atrophy, while providing good safety and tolerability.3

The investigators stated conclusively that, "[o]ur data do not support the use of creatine treatment for functional decline in early manifest HD."

References

  1. Hersch SM, Schifitto G, Oakes D, et al. The CREST-E study of creatine for Huntington's disease: a randomized controlled trial. Neurology. 2017;89:594-601.
  2. Hersch SM, Gevorkian S, Marder K, et al. Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG. Neurology. 2006;66:250-252.
  3. Rosas HD, Doros G, Gevorkian S, et al. PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology. 2014;82:850-857.
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