Another major supplement, creatine, proven ineffective in the fight against Huntington’s disease

For the second time in less than three months, a widely taken and long-studied dietary supplement envisioned as a potential treatment for Huntington’s disease has been proven ineffective, bringing a halt to a clinical trial.

Creatine, a supplement popular among body builders and readily available in health food stores, was studied in a clinical trial called CREST-E (Creatine Safety, Tolerability, and Efficacy in Huntington’s Disease), which began in 2009 and was to be completed in 2016.

On October 29, the National Center for Complementary and Alternative Medicine, part of the National Institutes of Health (NIH), announced that it was discontinuing CREST-E because a preliminary analysis of the data “showed with high confidence that it was unlikely that the study would be able to show that creatine was effective in slowing loss of function in early symptomatic Huntington’s Disease.”

The study was carried out by the Huntington Study Group (HSG) and led by Dr. Steven Hersch of Massachusetts General Hospital and Dr. Giovanni Schifitto of the University of Rochester School of Medicine.

“The entire point of the CREST-E study was to determine whether creatine slows the course of HD or not, and the answer is, no, it does not,” Martha Nance, M.D., a member of the HSG executive committee, said in an e-mail. “Although this result is disappointing, it is still important, as it gives us a definite answer to the question: ‘I have HD. Should I take creatine?’ The answer is, ‘no.’”

“I recommend that all stop taking creatine,” Dr. LaVonne Goodman, the founder of Huntington’s Disease Drug Works (HDDW), said in an e-mail.

False hopes

Huntington’s disease typically reduces people’s energy levels. Scientists thought that creatine, which cells use to store energy, might help compensate for the energy deficit in brain cells and enable them to survive.

Positive results in animal studies regarding the impact of creatine, the rise of HDDW’s “treatment now” program ten years ago, and the advent of both CREST-E and a companion study in presymptomatic individuals known as PRECREST led to much discussion about the supplement in the HD community.

Many people have taken or considered taking creatine in the hopes of avoiding or ameliorating symptoms.

I have taken creatine for about ten years, beginning with my participation in the HDDW program.

Just after receiving the news about CREST-E yesterday, I received an e-mail from an individual inquiring about where to purchase creatine and what amount to take. I responded that “it is now recommended that nobody take creatine.”

HDBuzz.net also reported on the end of CREST-E, calling the new evidence against creatine “compelling.”

Awaiting HD-specific remedies

In mid-August, the National Institute of Neurological Disorders and Stroke and the HSG stopped a clinical trial for coenzyme Q10, another widely taken supplement.

I outlined my approach to HD supplements and the pros and cons of the matter in a February article titled “To take, or not to take, unproven supplements in the fight against Huntington’s disease.” That article also reported on the hopes for PRECREST and CREST-E.

With the elimination of both coenzyme Q10 and creatine in rapid succession, the HD community is suddenly left without two potential treatments that supplied significant  hope.

However, supplements lack what researchers refer to as HD-specific approaches to treatments. They were not designed or marketed with HD in mind, whereas the new treatments currently under study will potentially attack the specific causes of Huntington’s.

Hope for effective treatments is on the rise as researchers and pharmaceutical firms gear up for new clinical trials such as the Isis Pharmaceuticals, Inc., gene-silencing approach announced for the first half of 2015.

“The important thing right now is to learn from ‘negative’ outcomes like this,” the HDBuzz article observed. “Studies like CREST-E have helped us, as a community, to get really good at designing, enrolling and running clinical trials, and understanding why particular treatments don’t work. Now we have the result of CREST-E, all that energy, enthusiasm and experience can be directed into testing other experimental treatments with a higher chance of success. One very solid benefit is that hundreds of volunteers are now freed up to sign up for other clinical trials enrolling now or in the near future.”

For the latest news on HD research and clinical trials, watch the video below for the update by Jody Corey-Bloom, M.D., Ph.D. (Note that the talk took place on October 27, before the announcement about creatine.)

2014 Huntington's Disease Research Update: A presentation by Dr. Jody Corey-Bloom from Gene Veritas on Vimeo.

The dire need for neurological treatments

I am now rethinking my approach to supplements. I have stopped taking coenzyme Q10.

I agree with the doctors’ recommendations to halt creatine. My breakfasts and dinners will no longer include a heaping teaspoon of fruit-flavored creatine dissolved in a glass of water.

Container with over-the-counter creatine (photo by Gene Veritas)

I will discard my remaining supply of creatine but keep the container as a piece of historical evidence in the quest for HD treatments.

It will also serve as a reminder of the dire need for truly effective approaches against a devastating disease that has reminded the world how the discovery of the first effective drug for any neurological disorder has continued to elude science.

To take, or not to take, unproven supplements in the fight against Huntington’s disease

Should people facing Huntington’s disease take creatine and other supplements to relieve or prevent symptoms?

I do.

I saw HD inexorably destroy my mother’s ability to walk, talk, and care for herself. She died eight years ago this month. I tested positive for HD in 1999 and since then have worried daily about when it will strike.

There is no treatment to slow HD’s devastation of the brain. So I’ve been open to taking supplements that might help.

In early 1996, just shortly after learning of my mother’s diagnosis, I started taking coenzyme Q-10 (Co-Q), a vitamin-like substance found throughout our bodies and seen by researchers as a possible way to help remedy the energy deficits suffered in HD.

In 2004, when Dr. LaVonne Goodman introduced a “treatment now” regimen and clinical trial of safe supplements that had shown promising results in animal testing, I jumped at the chance to participate. I was the only presymptomatic individual in the small, three-year study, run under the auspices of Dr. Goodman’s Huntington’s Disease Drug Works (HDDW).

Starting in 2005, I introduced the supplements into my diet in steps. I worked up to a daily routine in which I took 75 grams of trehalose, a sugar that seems to help the brain clear cellular debris; 600 mg of medical-grade Co-Q; two g of omega-3 oil; two g of blueberry extract; and ten g of medical-grade creatine. The trial paid for and delivered the supplements.

The trial did not show significant improvement for any of the symptomatic participants. “The only thing that appeared to be helpful was trehalose,” Dr. Goodman said in a February 9 phone interview. Today, almost a decade later, the supplements remain medically unproven to affect HD.

Nevertheless, scientists still think that trehalose, Co-Q, and creatine might still provide help in treating HD. Since the end of the HDDW, I have continued to take all of the supplements, spending about $2,000 per year. In fact, several years ago, relying on medical advice, I roughly doubled my daily intake of creatine to about 20 g.

I get semi-annual blood tests to monitor potential kidney damage, which creatine can cause. I also drink plenty of water throughout the day to prevent dehydration, which can occur at doses higher than 10 g. Creatine also can cause weight gain.

Am I wasting money and endangering my health?

I don’t think so. A few years ago, one of the doctors at the local Huntington’s disease clinic told me to stay on the supplements, observing that the combination of substances might be helping to delay my HD onset. I inherited the same degree of mutation as my mother, but, at 54, have passed the age of her onset.

The yin-yang of supplements

Whether others in the HD community should take creatine and other supplements is an individual choice ideally made in consultation with a doctor.

During our interview, the Seattle-based Dr. Goodman reviewed the pros and cons of taking creatine.

She cautioned against taking high doses of the substance, because more serious side effects occur at higher dosage, and urged people to consult a physician before starting any supplement.

She stressed that people need to understand the “yin-yang” involved in the decision to take supplements.

“Yes, you want to take care of yourself,” Dr. Goodman said. If they do nothing else, supplements can at least furnish a “very important” placebo effect and the prospect of hope, she said.

Dr. LaVonne Goodman (photo by Gene Veritas)

The placebo effect is a “real” phenomenon, she observed. “If you could bottle it, it would be great.”

However, taking supplements also reminds asymptomatic gene carriers of their risk, she added.

More importantly, people’s use of supplements could also obstruct the path to other, potentially far more promising treatments, she said.

The benefits of supplements “need to be counterbalanced with the need to test promising new drugs, or we will never have better treatments for Huntington’s,” she explained.

Interfering with clinical trials?

“There are so many competing interests here,” Dr. Goodman continued. “We all want to believe that (creatine) is helpful, because it’s available, and we can take it, so why not do it, we say. This is what I said with HDDW trials. Well, yes, but it needs to be measured. Otherwise, we’re going to know nothing more than we did.”

“It is important for people to know that if they take these things, they can’t be in clinical trials at the same time. We deplete our clinical trial participant base, which is going to impede progress for finding better treatments. There’s the yin-yang. And people need to hear both.”

However, Dr. Goodman noted that individuals could do both: to become eligible for a clinical trial, individuals could clear the supplements out of their system so that they don’t interfere with the measurement of the tested drug’s effects, then resume the supplements after completing the trial.

I would stop taking my supplements in order to qualify for a trial, although until the most recent creatine trial (see below), practically every trial has targeted only symptomatic individuals.

Dr. Goodman underscored the need to treat creatine and all other supplements as “medicines.” Supplements should meet USP (U.S. Pharmacopeial Convention) standards, she added. The HDDW website contains information on supplement safety. Further information on supplements is available at Huntington’s Disease Lighthouse Families.

(I buy my creatine from my local GNC outlet but plan to search for a better grade of the product.)

All drugs, including FDA-approved ones, produce side effects and can affect individuals differently, Dr. Goodman noted.

Regarding creatine, she concluded: “If it’s not watched closely, it may cause more harm than good.”

A historic trial

People in the HD community became excited about creatine as a potential treatment after Harvard University’s online news service on February 7 published an article titled “Nutritional supplement slows onset of Huntington’s.”

According to the article, a team of researchers based at the Harvard-affiliated Massachusetts General Hospital had finished a historic Phase II clinical trial that produced MRI scans showing evidence of the slowing of brain atrophy (shrinkage) in HD gene carriers who have yet to manifest the classic symptoms of the disorder. Sixty-four people took part.

Participants took up to 30 g of creatine per day.

According to Steven Hersch, M.D., Ph.D., the trial, called PRECREST (Creatine Safety and Tolerability in Premanifest HD), was a “huge step” for three reasons – including its impact on a separate creatine trial for symptomatic patients called CREST-E (Creatine Safety, Tolerability, and Efficacy in Huntington’s Disease)

“One, it’s the first therapeutic trial that has tried doing prevention,” Dr. Hersch, the study’s senior author and a long-time HD researcher, said in a February 11 phone interview. “Two, because we created a design that let anybody participate who’s at 50% risk, as well as those who have tested positive. And three, the imaging finding increases the probability that CREST-E will show a clinical benefit.”

Dr. Steven Hersch (photo from HDSA website)

Currently in progress and still recruiting participants, CREST-E is a phase III trial – the final step before drug approval (click here to learn how to enroll).

The PRECREST administrators recruited untested at-risk individuals who were then tested for the purposes of the trial as well as individuals who already knew that they have the HD mutation. However, those who entered the study untested did not receive their results, which were only known to the statistician. Thus, they avoided the potentially traumatic psychological aftermath and remained protected from genetic discrimination.

“The ethical challenges for those recruiting and conducting trials include how to accommodate nontested at-risk individuals while preserving a noncoercive choice regarding genetic testing,” states an editorial about PRECREST in the March 2014 issue of the prestigious journal Neurology, adding that “unequivocal changes” occur in the brain of presymptomatic individuals “15 to 20 years before conventional clinic-based diagnosis.” An article on PRECREST by Dr. Hersch, lead author Herminia D. Rosas, M.D., and nine other collaborators appears in the same issue.

For these and other reasons, 90 percent of at-risk individuals choose not to test, Dr. Hersch explained.

The MRI changes and other data from PRECREST will eventually be assessed in CREST-E, Dr. Hersch explained. CREST-E is also doing MRI imaging. With nearly 600 participants so far, it will be large enough to show whether the benefits shown in PRECREST images correspond to a significant slowing of HD.

Avoiding false hopes

As with many news articles about clinical trials and other scientific experiments, the Harvard report’s headline, which claimed the supplement slowed the onset of HD, inaccurately reflected the researchers’ results as reported in the actual scientific article.

“While slowed atrophy suggests that creatine could slow preclinical progression, the potential clinical impact of these findings on delaying the onset of HD is unknown and must be defined by an efficacy study designed to measure it,” the Neurology article states.

Nor can the public buy the high-quality creatine used in the study, as it’s prepared specially for clinical trials.

“I don’t want people to take from this study that they ought to go running out and take a bunch of creatine or take it at these doses,” said Dr. Hersch. “Even though the imaging benefit is very exciting, we don’t know what it means clinically. It doesn’t provide the evidence that would lead me to recommend that people take it. The high doses that we used should also not be used without medical supervision.”

As noted in the Neurology article, some PRECREST participants suffered stomach upset and diarrhea caused by the creatine. About a dozen people had to drop out of the study.

Regarding the study’s clinical significance, Dr. Goodman offered an assessment similar to that of Dr. Hersch.

The widely read HD research website HDBuzz.net also weighed in.

“How much hope and how my hype?” an HDBuzz article asked. While recognizing the importance of the study, it pointed out that the causes and effects of the slowed shrinkage in the brains of the PRECREST participants need further study.

“It’s possible that creatine causes HD brain cells to bulge or swell without making them healthier,” it states. “Swelling like that could produce false optimism and might even be harmful. That’s not something this trial can tell us either way, because the patients weren’t followed long enough to see whether creatine treatment delayed the onset of symptoms.”

“The participants in PRECREST who took creatine but did not have the HD mutation did not experience any brain swelling, so this is an unlikely explanation for our findings,” said Dr. Hersch. “Including and treating these subjects was very unusual. However, we did so to allow us to answer questions like this.”

Awaiting the Holy Grail

“HD researchers face a major challenge in finding a treatment for the pre-manifest,” I wrote in 2011. “It’s really the Holy Grail not only for HD, but also for other neurological diseases such as Alzheimer’s in which brain damage occurs many years before symptoms appear. Ideally, researchers want to design medications that will completely prevent these diseases.”

The Neurology editorial used the term “Holy Grail,” too, in noting how the PRESCREST study “investigates a potentially neuroprotective agent designed to delay disease onset.”

The word “potentially” is key.

As Dr. Hersch explained, the PRECREST findings about slower shrinkage “suggest” that creatine provides a benefit, but they don’t permit researchers to say anything about delayed onset of symptoms in presymptomatic individuals or a longer lifespan for patients.

It remains for the CREST-E Phase III trial to produce similar brain scan results – and an actual effect on symptoms.

“If CREST-E shows efficacy in slowing down the disease in people who are symptomatic, I would think that most people would think that you may be slowing down the disease in people who aren’t symptomatic yet as well,” he said.

Until treatments become available, presymptomatic gene carriers like me will continue to face the extremely difficult decision about whether to take supplements.

I’m grasping at creatine and other supplements in the hopes of delaying onset until researchers succeed.