Clinical Trial Characterizing the Bioavailability of 1-Octanol in Adults With Ethanol-responsive Essential Tremor

January 31, 2012 updated by: National Institute of Neurological Disorders and Stroke (NINDS)

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 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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 all 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 valuable information regarding the safety and efficacy at this higher dose. The remainder of the experimental design will be maintained, with exception of additional safety precautions which will be discussed in the protocol and consent.

Study Type

Interventional

Enrollment (Actual)

21

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 primidone
  • Patients on other acute or chronic medications that influence hepatic metabolism or central nervous system (CNS) 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Normalized Mean Tremor Amplitude for Both Formulations of 64 mg/kg 1-Octanol in Part B
Time Frame: 0, 15, 30, 60, 90, 120, 150, 180, 240 and 360 minutes post-dose
Spirography mean tremor amplitudes were measured in the right hand of each participant at 0, 15, 30, 60, 90, 120, 150, 180, 240 and 360 minutes post-dose. Then, the scores of each participant were normalized (i.e., divided by) by their baseline tremor severity scores so that all scores are expressed as a proportion of the baseline score. Therefore, 1 is the baseline tremor severity, and lower scores indicate tremor reduction.
0, 15, 30, 60, 90, 120, 150, 180, 240 and 360 minutes post-dose

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood Plasma Levels of Octanoic Acid After 64 mg/kg 1-Octanol Dose
Time Frame: 5, 20, 45, 70, 100, 130, 160, 210, 270 and 360 minutes post-dose
Octanoic Acid is a metabolite of 1-octanol. Blood plasma levels of octanoic acid were measured at 5, 20, 45, 70, 100, 130, 160, 210, 270 and 360 minutes post-dose.
5, 20, 45, 70, 100, 130, 160, 210, 270 and 360 minutes post-dose
Heart Rate Post 1-Octanol Dose
Time Frame: 0 minutes, 15 minutes, 100 minutes and 24 hours post-dose
0 minutes, 15 minutes, 100 minutes and 24 hours post-dose
PR and QTc Intervals Post 1-Octanol Dose
Time Frame: 0 minutes, 15 minutes, 100 minutes and 24 hours post-dose
0 minutes, 15 minutes, 100 minutes and 24 hours post-dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2005

Primary Completion (Actual)

September 1, 2009

Study Completion (Actual)

September 1, 2009

Study Registration Dates

First Submitted

January 30, 2005

First Submitted That Met QC Criteria

January 29, 2005

First Posted (Estimate)

January 31, 2005

Study Record Updates

Last Update Posted (Estimate)

February 1, 2012

Last Update Submitted That Met QC Criteria

January 31, 2012

Last Verified

January 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 050092
  • 05-N-0092

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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