HD Lighthouse Contributing Editor's Comment:

CREATINE 2000 Finding: Creatine helps the HD mouse both before and after symptom development.

CREATINE 2003 Creatine helps HD people in Tabrizi’s pilot study. Close to two years ago Jerry Lampson posted the first creatine study by Tabrizi et al (Neurology: July 2003) on the HD Lighthouse web site. http://hdlighthouse.org/TreatmentNow/updates/0058creatine.php The results from their one year pilot trial of creatine (10 grams/day) in thirteen Huntington’s people were promising: At the one year mark (using group analysis) no disease progression was documented using standard UHDRS motor, cognitive and total functional capacity (TFC) scores.

Further, when individual results are studied, those participants with earlier stage disease improved while those with later stage disease either stabilized or declined. Creatine was safe and well tolerated at this dosage, had excellent brain penetration and (in this pilot trial) showed benefit in HD people.

CREATINE 2005 Tabrizi and colleagues have now published (Neurology: May 2005) results for the much awaited two year follow-up study on these same study participants. The good news is that benefit continued. Using group statistics, there was stability; no significant change in UHDRS motor or neuropsychological testing. There was a “trend” toward worsoning in the group measure of functional capacity (which was not statistically significant) over the two year period.

Further, the authors point out that there were differing responses among the individual Huntington’s participants. Over the two year study period several HD trial participants improved. Those who improved tended to be in earlier stage disease. Those individuals who declined tended to have later disease. There were several who remained stable. In the final group analysis those who improved and those that declined balanced each other out, so that the group result was stable.

HDDW TRIALS 2005 Results from participants who have completed one year of HDDW’s individual therapeutic trials are strikingly similar. Those with early Huntington’s improve by web interactive motor and cognitive measures along with improvements in functional capacity (TFC). Most with more advanced disease have stabilized, while some have declined.

Contributing Editor: A Confession and Comments

My confession: it was startling to have the word “improved” appear in the same sentence as Huntington’s; several of them. But that “improved” possibility is starting to sink in.

My comments: Of course all of us; researchers, doctors and HD people, all know that pilot trials don’t offer “definitive” gold standard results. As such, the majority of Huntington’s disease specialists won’t recommend use of creatine based on these Tabrizi reports. They will wait (no matter how long) until a large placebo-controlled trial is completed. But . . I’m willing to bet that a significant number of HD doctors would take creatine now if they had HD. For while the evidence is limited; it is positive. And this is a safe agent/drug. Further, the evidence points that greater benefit is attained when given early. Even if recruitment for a phase three human creatine trial were announced today, it would take in the range of five years to complete. And we all know that a lot of brain (in both the pre-symptomatic and the symptomatic) can be lost in the years it will take to complete a definitive trial. These same years might represent the window of opportunity for the person with HD now or for those close to onset.

CAUTION

While creatine is quite safe, it can have side effects that are harmful. One participant in Tabrizi’s study and two in HDDW (picked up during enrollment) developed kidney dysfunction while taking creatine. It is essential for HD people to inform their doctors about the use of this over-the-counter agent; and likewise essential for doctors to inquire about creatine use and follow through with appropriate blood tests.

CLINICAL TRIALS NOW

HD people have spent long years waiting for knowledge of whether agents that work in model systems will translate to benefit in people. HD people are restless for first treatment. Now there are human pilot trial results that look promising for creatine; trial results that might make it first therapy. While “cautious optimism” is the catchword from HD organizations, success doe raise the expectations of HD families.

HD families are asking for more clinical trials because there has been success. In many ways, all the superb professionals who work for HD in research laboratories and Huntington’s clinics and organizations are victims of their own success. They have brought about the explosion of knowledge that has in turn brought a burgeoning list of potential therapeutic agents.

HD people want and desperately need larger clinical trials on creatine and other agents that will bring first treatments. First treatments can bridge the gap (in HDSA words) between care and cure. Marsha Miller, editor in chief of HD Lighthouse, has designed a button (available at the upcoming HDSA convention) that will symbolize the people’s request for clinical trials (now).

But we need trials that will give answers in our lifetime. HD clinicians and HD people are well aware that standard clinical trials (such as the Coenzyme Q-10/Ramacemide (CARE) trial) are terribly difficult. In addition they are prohibitively time consuming and expensive. But, most importantly to HD people, they are the obvious roadblock to timely agent testing in HD people. Innovative trial designs are mandatory: mandatory unless we accept that there will be no first therapy for a long, long time. Innovation is valued in HD research. Isn’t it time for the same type of innovation for HD clinical trials for those agents that can bridge the gap between “care and cure” for people now.

Remember the HDSA convention T-shirt from a few years ago that featured cartoon pictures of HD yeast, flies, worms and mice? Let’s make it the goal that people will soon be in the picture.

--LaVonne Veatch Goodman, M.D.
Posted to the HDL: 19 May 2005

High-dose creatine therapy for Huntington disease: a 2-year clinical and MRS study.

Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH, Warner TT.

Our 2-year pilot study demonstrates that 10 g/day of creatine is safe and well-tolerated. This is comparable with the dose given to the R6/2 mice. MRS [Magnetic resonance spectroscopy] data showed the creatine was significantly elevated in vivo in both brain and muscle tissue at 6 months, as assessed by a fall in NAA/creatine and an increase in PCr/ATP ratios. The reduction in brain NAA/creatine (implying an increase in creatine while NAA remains constant) was sustained at 12 and 24 months (NS at 24 months due to reduced patient numbers). The increase in PCr/ATP was not sustained with time, which may also reflect the small patient numbers.

TMS, functional capacity, and neuropsychological testing using the UHDRS showed no significant difference from baseline, although the trend was for a decline in function, a finding to be expected in a cohort of patients with HD. However, there were differences in patients at similar clinical stages, with some showing deterioration after two years and others showing improvement in their scores, suggesting that some individuals may benefit from creatine. The lack of weight loss suggests that creatine may also impact this aspect of the disease. Our data suggests that high-dose creatine is tolerated but whether it stabilizes symptoms is unclear. A large placebo-controlled double-blind of high-dose creatine in HD would answer this issue, and we await the outcome of the CREST-HD trail of 8 g daily creatine supplementation.

Tracked on the Lighthouse:
creatine

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Source: Neurology. 2005 May 10;64(9):1655-6

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