High-Dose Creatine Promising in Prodromal Huntington's

Pauline Anderson

March 14, 2014

High doses of creatine, a nutritional supplement with suspected neuroprotective properties, appears to be safe, tolerable, and possibly efficacious in patients at risk for Huntington's disease (HD), according to results of a new phase 2 trial.

The Creatine Safety and Tolerability in Premanifest HD (PRECREST) trial was undertaken in the prodromal phase of the disease when participants were clinically unaffected. It protected the anonymity of those patients who didn't want to know their genetic status.

Such a study design is a major step forward and could be considered a prototype for future trials in HD, said lead study author Herminia D. Rosas, MD, associate professor, Departments of Neurology and Radiology, Massachusetts General Hospital, and Harvard Medical School, Boston.

"We hope to have discussions about ways to continue to do our science without actually requiring testing and making sure that people's confidentiality is protected."

The study was published in the March 11 issue of Neurology.

Creatine Maintains Intracellular Energy

Creatine helps maintain intracellular energy levels and so may prevent or impede the neurodegenerative process. Past studies have reported that reduced energy stores play a role in neuronal loss.

The new study included 64 asymptomatic persons at least 26 years of age. Some in this group were known genetic carriers; others were at a 50% risk based on an affected first-degree relative but didn't want to know their genotype. Double-blind genetic testing established that there were 47 carriers and 17 healthy matched controls.

Researchers randomly assigned the participants to receive creatine (25 carriers and 7 controls) or a matching placebo (22 carriers and 10 controls). The 6-month randomized, double-blind, placebo-controlled phase was followed by 12 months of open-label creatine.

The drug or placebo came in packets, each with of 5 g of powder that could be added to foods such as yogurt or apple juice. Participants could take the maximum tolerated dose of the drug (30 g) daily. The creatine was pharmaceutical grade (and thus not available in health food or other stores).

More than two thirds of participants taking creatine tolerated the maximum dose and more than three quarters tolerated doses of 15 g or more. About 13% of participants taking placebo were unable to tolerate the study drug.

Interestingly, more carriers (9 of 10) dropped out of the study during the placebo-controlled phase, 7 of whom knew their genetic status (2 had been assigned to placebo). During the open-label phase, 5 more participants (2 carriers and 3 controls) were unable to tolerate creatine.

That so many carriers dropped out of the study was "completely counterintuitive," said Dr. Rosas. "You come in with this notion that if you know what your risk is, with a 100% certainty, you're going to do whatever it takes to keep yourself as healthy as possible."

It's possible, she said, that some patients were already experiencing cognitive changes that typically precede motor problems and that these affected judgment or tolerance for adverse effects. It may also have been stressful to have to be constantly reminded about their genetic risk.

"Denial is a powerful thing," said Dr. Rosas. "These subjects could put off thinking about their situation, but once they started taking these packets and mixing them, this might have reminded them that the day will come when they will need to do something about it."

Whatever the reason, this unexpectedly high rate of intolerability may be important for future trial design considerations, noted the authors.

Similar Adverse Events

In terms of adverse events, the only significant differences between the groups were an increase in diarrhea and nausea associated with creatine (P = .007). None of the 5 serious adverse events that occurred during the trial, including a fracture and a hysterectomy, were expected or were related to the study drug.

These results, said the authors, provide class 1 evidence that high-dose creatine is safe and tolerable.

Gene carriers performed less well on some cognitive measures, but those measures over time didn't reflect much, said Dr. Rosas. "There may have been trends with some of these measures, but none of them met statistical significance, partly because of the variability of these measures."

The study found significant regional atrophy at baseline in the carrier group compared with healthy controls, particularly in sensorimotor, superior temporal, and portions of parietal and occipital cortex. In some regions, this corresponded to as much as 10% thinner compared with controls.

After the placebo-controlled phase, the rate of cortical thinning in several regions, including portions of precentral, superior and middle-temporal, superior and middle frontal precuneus, posterior parietal and occipital was significantly slower in the carriers taking creatine compared with the carriers receiving placebo, in whom thinning progressed as much as 5% per year (P < .0001 in select regions).

In those crossing over from placebo to creatine, atrophy rates slowed, replicating the initial treatment benefit.

The significantly slower rate of cortical thinning suggests potential beneficial effects of the treatment on prodromal progression, commented Dr. Rosas. "We are not saying that the creatine did anything — this is not targeted as an efficacy study — but this is a signal that certainly supports moving forward."

A phase 3 trial using high-dose creatine in patients with HD who already have symptoms is underway — the Creatine Safety, Tolerability and Efficacy in HD (CREST-E) study. "The hope is that if there is a clinically relevant signal, if we do see slowing in that population, that this would become an accepted treatment and become available to those at risk," said Dr. Rosas.

Including persons who were at risk but not aware of their genetic status greatly expands the pool of potential study participants, said the authors. The vast majority — more than 90% — of at-risk patients in the United States don't choose to be tested, they said.

Maintaining confidentiality is "huge" in trials such as this, and was what made the study possible in the first place, said Dr. Rosas. "Our feeling is that people have the right to make their own decision about what they want to know and what they don't want to know."

Although in theory, laws are in place to protect the anonymity of someone with a genetic disease, there is no guarantee, for example, that an HD mutation won't at some point cause discrimination in the workforce.

It will become increasingly more challenging to assure privacy for carriers in an age of more sophisticated technology and electronic medical records, she said. "But the onus is on us to protect these people because we see what happens when there are inadvertent disclosures; for example, they can't get long-term disability or life insurance."

Preserving Confidentiality

In an accompanying editorial, Elizabeth A. McCusker, MB, BS, Department of Neurology, Westmount Hospital and Sydney Medical School, Australia, and Richard H. Myers, PhD, Department of Neurology, Genome Science Institute, Boston University School of Medicine, praised the design of the study.

"The trial design defines methods to preserve confidentiality and overcomes the difficulty of studying HD at its earliest phase by avoiding the requirement to include only the genetically tested," write the editorialists. "The success of this study demonstrates that sufficient discriminant power can be obtained without the exclusion of generically untested at-risk individuals."

Unlike Parkinson's disease and Alzheimer's disease (AD), HD has a single cause and so is ideal to use in trials during the prodromal phase. However, note the editorial writers, a study of the prodrome "is not without complexity" because it is subject to "rigorous statistical analysis and power calculations to avoid expensive but inconclusive assessments and investigations."

Ethical issues must also be considered, they say. Prospective trial participants may be concerned about discrimination because of the "irrefutable" brain-related changes in the prodrome. Also, ways to address the onset of disease during a trial in participants who don't want to know their HD status "poses a dilemma for neurologists."

During the 18 months of the current trial "no one pheno-converted," but if that were to occur, said Dr. Rosas, "one's right to know or not know should be maintained no matter what, unless there is concern about safety."

Karl Kieburtz, MD, director, Center for Human Therapeutics, University of Rochester Medical Center, New York, said studies such as PRECREST illustrate the possibility of treating diseases — in this case HD but also others including, AD — before the first clinical symptoms occur but when its effects are measureable.

"This is a new day for neurodegenerative diseases and mirrored in part by new regulatory thinking to go along with it," said Dr. Kieburtz.

He was referring to the new US Food and Drug Administration (FDA) guidance for the design and execution of AD-related clinical trials that involve patients who don't present with dementia. One aspect of the FDA guidance covers the selection of patients for trials in early-stage AD, and suggests potential approaches to trial design that allow for regulatory flexibility and innovation.

Dr. Rosas, Dr. McCusker, and Dr. Myers have disclosed no relevant financial relationships. Dr. Kieburtz reports being involved in the CREST-E study, which aims to enroll 650 participants and should be complete by mid-2016.

Neurology. 2014;82:850-857, 824-825. Abstract Editorial

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