Official Title: “Clinical Trial Characterizing the Bioavailability of 1-Octanol in Adults With Ethanol-Responsive Essential Tremor”

OVERVIEW

Essential tremor (ET) is a common movement disorder affecting 0.4% of the general population and up to 14% of people 65 years and older. Response to medications such as beta blockers and primidone may be of benefit, but are often accompanied by intolerable side effects.

Response to ethanol, on the other hand, has a roughly 80% chance of significant tremor reduction, though daily use of this as a treatment has potentially serious medical, social, and legal consequences.

The leading hypothesis for ET pathophysiology is an unmasking of spontaneous oscillations originating in neurons of the inferior olive. Both ethanol and 1-octanol have been shown to reduce these spontaneous oscillations in an animal model of ET; however, 1-octanol does this at a dose much lower than that leading to intoxication, suggesting in may be useful in the treatment of essential tremor. Our initial studies with 1-octanol have shown it to be safe at dosages up to 64mg/kg without signs of intoxication, while at the same time showing benefit.

OBJECTIVE

We plan to evaluate the efficacy of different 1-octanol formulations in humans based on accelerometry and spirography. We will also evaluate drug and metabolite bioavailabilities using a high performance liquid chromatography (HPLC) detection method from plasma and urine samples.

STUDY POPULATION

We will study adult subjects with ethanol-responsive Essential Tremor (ET).

DESIGN

This study is designed as a two-phase unblinded inpatient study of adults with ET receiving weight-adjusted oral dosages of 2 different formulations of 1-octanol in a crossover fashion.

Phase I of the study is designed to develop an octanol detection assay using GC. Four subjects will receive daily escalating dosages (1-16 mg/kg) of a single 1-octanol formulation followed by a crossover trial of both formulations at a dosage of 32 mg/kg. Phase II will study 20 subjects receiving one of the two formulations as 32 mg/kg on inpatient day 1 followed by a 24 hour period of close monitoring. The second formulation will be given on day 3 and the patient will again undergo close monitoring for 24 hours.

OUTCOME MEASURES

The primary outcome measures for the study will be efficacy based on tremor ratings from accelerometry and spirography. Secondary outcome measures will be the determination of bioavailability, pharmacodynamic and pharmacokinetic profiles of octanol #61864 and octanol #68751 and their metabolites.

Study Type: Interventional

Study Design: Treatment, Open Label, Single Group Assignment, Pharmacokinetics/Dynamics Study

OVERVIEW

Essential tremor (ET) is a common movement disorder affecting 0.4% of the general population and up to 14% of people 65 years and older. Response to medications such as beta blockers and primidone may be of benefit, but are often accompanied by intolerable side effects.

Response to ethanol, on the other hand, has a roughly 80% chance of significant tremor reduction, though daily use of this as a treatment has potentially serious medical, social, and legal consequences.

The leading hypothesis for ET pathophysiology is an unmasking of spontaneous oscillations originating in neurons of the inferior olive. Both ethanol and 1-octanol have been shown to reduce these spontaneous oscillations in an animal model of ET; however, 1-octanol does this at a dose much lower than that leading to intoxication, suggesting it may be useful in the treatment of essential tremor. Our initial studies with 1-octanol have shown it to be safe at dosages up to 64mg/kg without signs of intoxication, while at the same time showing benefit.

OBJECTIVE

We plan to evaluate the efficacy of different 1-octanol formulations in humans based on accelerometry and spirography. We will also evaluate drug and metabolite bioavailabilities using a high performance liquid chromatography (HPLC) detection method from plasma and urine samples.

STUDY POPULATION

We will study adult subjects with ethanol-responsive Essential Tremor (ET).

DESIGN

This study is designed as a two-phase unblinded inpatient study of adults with ET receiving weight-adjusted oral dosages of 2 different formulations of 1-octanol in a crossover fashion.

Phase I of the study is designed to develop an octanol detection assay using HPLC. Four subjects will receive daily escalating dosages (1-32 mg/kg) of a single 1-octanol formulation followed by a crossover trial of both formulations at a dosage of 64 mg/kg. Phase II will study 20 subjects receiving one of the two formulations at 64 mg/kg on inpatient day 1 followed by a 24 hour period of close monitoring. The second formulation will be given on day 3 and the patient will again undergo close monitoring for 24 hours.

OUTCOME MEASURES

The primary outcome measures for the study will be efficacy based on tremor ratings from accelerometry and spirography. Secondary outcome measures will be the determination of bioavailability, pharmacodynamic and pharmacokinetic profiles of octanol #61864 and octanol #68751 and their metabolites.

Addendum: Based on the results of the assays for alll subjects who participated in Part 1 and 2 of this protocol, we would like to conduct an exploratory study (Part 3) consisting of two subjects receiving a dose of 128mg/kg of 1-octanol. This is meant to primarily explore the plasma concentration of 1-octanol, while also providing valualbe information regarding the safety and efficacy at this higher dose. The remainder of the experimental design will be maintained, with exception of additional safety prcautions which will be discussed in the protocol and consent.

Intervention(s) in this Clinical Trial

• Drug: 1-Octanol
  • 1-Octanol is an long-chain alcohol with potential therapeutic benefits in treating alcohol-responsive tremors based on unknown mechanisms.@@@

Primary Measures

• 1-octanol concentration-time data to determine pharmacokinetic. Assess bioequivalence between the two formulations based on the ratio of the peak concentrations and the ratio of the areas under the concentration-time curves for the 2 formulations.
  • Time Frame: 6-hours post-dose
    Safety Issue?: No

Secondary Measures

• Tremor severity based on accelerometric data will be assessed along with safety based on intoxication ratings and EKG monitoring.
  • Time Frame: Duration of inpatient hospitalization (4 days)@@@
    Safety Issue?: Yes

INCLUSION CRITERIA:

• Patients with alcohol-responsive Essential Tremor
• Limb involvement should be a prominent feature of the Essential tremor
• Patients must be willing and able to safely stop and remain off any medications used to treat essential tremor for at least 4 half-lives
• Patients must be willing to abstain from ethanol and caffeine intake for at least 48 hours prior to starting the study hospitalization until study termination
• Patients must be willing and able to fast for periods of up to 12 hours during the study

EXCLUSION CRITERIA:

• Patients with abnormalities other than tremor on neurological exam
• Patients with active or past alcohol abuse or dependence
• Patients with acute or chronic severe medical conditions such as renal failure, hepatic failure or lung disease
• Patients taking primodone
• Patients on other acute or chronic medications that influence hepatic metabolism or CSN function and cannot be temporarily discontinued for the length of the study
• Patients who do not wish to take a potentially intoxicating drug
• Patients with abnormalities on their baseline screening laboratory tests
• Women who are pregnant or lactating
• Patients younger than age 21
• The presence of cognitive impairment preventing informed consent or cooperation during the study
• People of Far East Asian or Native American descent, who may possess variant alleles of the genes for alcohol metabolism, i.e., alcohol dehydrogenase and aldehyde dehydrogenase, resulting in altered (slower) metabolism and potentially increased sensitivity to alcohols and their metabolites

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 21 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Information obtained from ClinicalTrials.gov on November 18, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00102596

Study ID Number: 050092

ClinicalTrials.gov Identifier: NCT00102596

Health Authority: United States: Federal Government

NIH Clinical Center Detailed Web Page