June 8, 2011 (Toronto, Ontario) — A small proof-of-concept study suggests safety and some potential benefit in terms of efficacy from administration of octanoic acid, a metabolite of the long-chain alcohol 1-octanol, in patients with essential tremor (ET).

A single administration was well tolerated, and although the primary efficacy outcome, postural tremor power measured by accelerometry at 80 minutes, was not met, a greater benefit was seen for later periods out to 5 hours.

"We did have some suggestion that there is efficacy, that there is some superiority for octanoic acid in secondary outcome parameters, which mainly are at later time points, which is something that we were surprised to see," lead study author Dietrich Haubenberger, MD, from the National Institutes of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland, told Medscape Medical News.

"Octanoic acid distinguishes from placebo actually at later time points than we expected, 2 and a half hours up to 5 hours, with the strongest effect for the right hand even after 5 hours," he added. "If both hands are combined for the analysis, we see clearer trends again starting at 2.5 hours up to 5 hours."

The results were presented here at the Movement Disorders Society (MDS) 15th International Congress of Parkinson's Disease and Movement Disorders.

Alcohol and ET

Patients with ET often report relief from tremor symptoms after drinking alcohol, but regular use of alcohol as a treatment is clearly problematic. 1-Octanol, a long-chain alcohol, has been shown previously to be effective in relieving tremor in ET patients. 1-Octanol is rapidly converted to octanoic acid, suggesting it may be the active substance, the researchers point out.

Octanoic acid is already approved as a food additive by the US Food and Drug Administration (FDA) and has already been used as a nutritional component in formula regimens, for example, Dr. Haubenberger noted. "It has also been studied in ketogenic diet, but it's never been studied in essential tremor," he said.

For this double-blind, placebo-controlled, crossover, phase 1/2 study, they recruited 19 subjects (5 female and 14 male), limiting enrollment to ET patients whose tremor was ethanol responsive, to assess the safety, efficacy, and pharmacokinetics of octanoic acid.

Patients were given a single oral dose of octanoic acid (4 mg/kg) or placebo on 2 consecutive days in the morning in a double-blind fashion. Safety and efficacy outcomes were measured out to 5 hours after administration. The primary efficacy outcome was postural tremor power recorded at 80 minutes using accelerometry.

No signs of intoxication were seen with the single dose. There were 2 serious adverse events, a food poisoning that occurred before administration of any study drug and an adverse reaction related to a pick line implanted to allow pharmacokinetic sampling for the study. No changes were seen in other safety measures, including liver function or vital signs.

Adverse events considered not serious were equally distributed between groups, he said, "which was also expected since we were giving a rather low dose compared with other studies that used it as a nutritional component where much larger doses are being used."

Again, no significant difference was seen between groups on the primary outcome at 80 minutes, but octanoic acid improved right hand tremor beginning with a trend at 150 minutes (P = .057) and developing to a significant benefit at 300 minutes (P = .032). Taking both hands together, they add, a maximum benefit was seen at 180 minutes after administration of octanoic acid (P = .025).

An analysis of the difference of efficacy within each subject between octanoic acid and placebo showed a significant reduction of tremor amplitudes with active treatment, and patients receiving octanoic acid reduced right hand median tremor power up to 40% compared with baseline, the study authors note.

"It's important to know that this was a study that was purely done with objective outcome measures — accelerometry," Dr. Haubenberger noted. "This was not yet a study where we looked at functional outcomes or clinical scores."

The next step will be a dose-escalation study to look further at these effects, Dr. Haubenberger said.

Exploiting a Known Mechanism

Asked for comment on these findings, session moderator David Riley, MD, Case Western Reserve University in Cleveland, Ohio, University Hospital's Neurological Institute, pointed out that current medical treatment options for ET are "sorely lacking."

"We have 2 mediocre drugs and a bunch of anecdotally useful drugs and precious little else," he said bluntly. "What we really need is something that's generally more effective."

We have 2 mediocre drugs and a bunch of anecdotally useful drugs and precious little else. What we really need is something that's generally more effective.

"One of the nice things about the octanoic acid is that it exploits a known mechanism of benefit for essential tremor, which is alcohol, and to be able to translate that into an oral medication that is not controlled by the FDA would be a great boon for patients with essential tremor, so it's very intriguing," Dr. Riley said.

The study presented here contains data that are very preliminary, he cautioned, "so it's important not to get too excited about it."

Still, he adds, "I think it's important because it shows that there are people who are actively working on the problem, and I think that's a message of hope to people with ET. And secondly, because it exploits a known mechanism, it is something that logically sounds like it should be useful, and therefore there's more reason to believe that it will be ultimately."

Rodger Elble, MD, PhD, of Southern Illinois University School of Medicine, Carbondale, who comoderated the session here, noted that senior author on this paper, Mark Hallett, MD, and colleagues at NINDS have previously shown that 1-octanol was superior to placebo in ethanol-responsive ET patients.

"In this study, Haubenberger found that the metabolite of octanol, octanoic acid, is superior to placebo, suggesting that octanoic acid is the active agent," Dr. Elble said in a statement from MDS. "This was only a single-dose study, and the efficacy of octanol/octanoic acid needs to be confirmed in a longer randomized, placebo-controlled trial."

"The effect of octanoic acid was no better than that previously reported for propranolol and primidone," he added. Further, it is unclear from this study whether all ET patients respond or only those that are ethanol responsive.

The work was supported by the NINDS Intramural Research Program. Dr. Haubenberger reports receiving support for this study from the Austrian Science Fund. The researchers also have a collaborative agreement with Ariston Pharmaceuticals to fund further trials.

Movement Disorders Society (MDS) 15th International Congress of Parkinson's Disease and Movement Disorders: Abstract 1131. Presented June 7, 2011.


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