Dr. Hersch at the 2010 HDSA convention

Interview with Dr. Steven Hersch on the CREST-E Trial

Dr. Hersch is the lead investigator in a phase III (final) clinical trial to determine whether high dose creatine can safely and effectively slow the progression of Huntington's disease. The CREST-E study is actively recruiting and needs many more participants to complete enrollment.

Q. Why did you select creatine for a clinical trial?

A. We have been working with creatine for many years, going back to the studies in HD mice. Although there are other candidates for slowing down HD, there are more promising data indicating neuroprotection in HD mouse models with creatine than for any other compound. Impaired energy production in cells, which creatine helps, has been increasingly linked to the mechanisms of brain pathology in that occur in HD. Some of that impairment can be linked to the crucial enzyme, creatine kinase, which uses creatine to make energy in every cell of the body. Our first human study in HD subjects used conventional doses of creatine and showed that it improved a biomarker linked with brain injury. We have since used higher doses and have found that blood and brain levels of creatine can be further increased, that the biomarker of brain injury returns to normal levels, and if we use sophisticated imaging techniques to study what happens to the brain on creatine, it seems to slow down the shrinkage of the brain. This is very exciting evidence that creatine could change the course of HD.

The NIH (National Institutes of Health) agreed and is supporting the CREST-E study to test whether these findings translate into a clinically meaningful slowing of the disease. CREST-E is the largest therapeutic trial ever funded for HD supported by grants from the NIH and the FDA (Food and Drug Administration). The CREST-E study is being conducted by the Huntington Study Group in North America, Australia, and New Zealand.

Q. Why should people participate in the trial and possibly receive placebo treatment rather than take creatine on their own?

A. Although creatine is available to the public, there are many reasons why qualified subjects should participate in the study rather than take it on their own. Some of these reasons relate to safety. We are using high doses that have never been used before so safety should be monitored closely as it is in a clinical trial. We are also using the only available pharmaceutical grade creatine that has been reviewed as a drug by the FDA, which is provided, free of charge by the study. The creatine products available in stores and over-the-counter are nutritional supplements, which are regulated as food by the FDA and may contain impurities. Even though creatine has been around for a while and many have the impression either that it is good to take it or that it doesn't do much, it actually has never been tested properly to determine what exactly it can do and what doses are necessary until now. Participating in the study will help the entire HD community learn whether creatine is effective, especially at higher doses. My experience has also been that most HD families, in general, find that participating in clinical trials provides other benefits, particularly in the positive relationships they develop with the study investigators and staff that work with them.

There is also another extremely important goal of the study, which goes beyond determining whether creatine is a safe and effective treatment. That goal is to develop biomarkers for HD, in particular blood and imaging tests that can be used in future clinical trials to help us determine much earlier whether a therapy might be affecting the course of HD. The right biomarkers can help us eliminate unpromising treatments in smaller studies and help us pick more likely "winners" for the very large studies needed to test whether HD can be slowed. CREST-E is integrated with our extensive NIH supported biomarker effort, known as REVEAL-HD, to assess a variety of blood and imaging markers for HD. This is our first chance to look at how potential biomarkers change over years as HD progresses and whether they can predict a treatment response. This kind of study is necessary for the FDA to consider whether a biomarker can supplement or even substitute for the much less efficient clinical measurements we use currently to assess the efficacy of a treatment. We will depend on biomarkers more and more in the future to help us look at more promising treatments, more quickly than we can now. CREST-E provides a rare opportunity to develop and test them.

Q. How often do participants come in for assessments? How long does a visit take? What is involved?

A. We have designed the protocol to help people figure out the highest doses they can take during the first six months. With this slow increase almost everyone has been able to move up to the highest dose. Some have not, mainly because of gastrointestinal problems, which are expected side effects of creatine. After the initial six month period, when people get up to forty grams or find their highest dose, they come in for visits every three months through the first year and about every four months in the last two years. Visit times vary. Most are short "safety" visits where the participant might just give blood and urine samples and discusses any side effects. Some visits include additional testing and may take a few hours. The FDA and NIH safety oversight committee have allowed us to reduce the number of those visits since we have not encountered many problems so far.

Q. Will there be an open label trial extension where everyone gets creatine?

A.We would like to do this but it will depend on securing additional drug supply and funding going forward.

Q. You've been doing HD research for over twenty years. What changes have you seen?

A. The changes have been extraordinary. When I started most research was based on looking at postmortem brain specimens. We learned a lot about the pathology of the disease but didn't make much progress to determine what causes it. Everything was revolutionized by the discovery of the gene. This gave us the protein that causes the disease and that opened up a huge amount of research to try to figure out what happens to the protein, what it interacts with, and what goes wrong in cells. The discovery of the gene also led to increasingly useful cell culture and animal models where we really can discover and test therapeutics. These models also have provided the impetus for drug companies to see in HD, an opportunity to develop treatments. Research has led us to new hypotheses and understandings, promising treatment targets that are being tested, and will lead us to what will become the most important therapeutics, those that target the HD protein itself. CREST-E is actually a great example of how the discovery of the gene has empowered the ‘bench to bedside' scientific progression that we hope will lead successfully to a treatment that slows HD. Our work with creatine started with animal studies, was enriched by sophisticated biochemical studies and novel biomarker discoveries, and now has proceeded through early phase clinical testing to the definitive study of its efficacy.

Q: Where can people go to find out more about the study or find a site close to them?

A. For more information, people should call the Huntington Study Group toll-free number at 1-800-487-7671. They can also visit the HSG website or (NCT00712426) for a list of active sites.

Endnote: Updated clinical trial information can also be found here. CREST-E.  Visit the HD Lighthouse for an HD family member's account of participating in the CREST-E trial: Allison's Clinical Trial.


- Marsha L. Miller, Ph.D., April 21, 2011