Clinical Trial Characterizing the Bioavailability of 1-Octanol in Adults With Ethanol-responsive Essential Tremor
Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Essential Tremor
Intervention: 1-Octanol (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: National Institute of Neurological Disorders and Stroke (NINDS)
Summary
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.
Clinical Details
Official title: Clinical Trial Characterizing the Bioavailability of 1-Octanol in Adults With Ethanol-responsive Essential Tremor
Study design: Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Normalized Mean Tremor Amplitude for Both Formulations of 64 mg/kg 1-Octanol in Part B
Secondary outcome: Blood Plasma Levels of Octanoic Acid After 64 mg/kg 1-Octanol DoseHeart Rate Post 1-Octanol Dose PR and QTc Intervals Post 1-Octanol Dose
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.
Eligibility
Minimum age: 21 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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
Locations and Contacts
National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States
Additional Information
Related publications: Bikson M, Ghai RS, Baraban SC, Durand DM. Modulation of burst frequency, duration, and amplitude in the zero-Ca(2+) model of epileptiform activity. J Neurophysiol. 1999 Nov;82(5):2262-70. Busenbark KL, Nash J, Nash S, Hubble JP, Koller WC. Is essential tremor benign? Neurology. 1991 Dec;41(12):1982-3. Bushara KO, Goldstein SR, Grimes GJ Jr, Burstein AH, Hallett M. Pilot trial of 1-octanol in essential tremor. Neurology. 2004 Jan 13;62(1):122-4. Fahn S, Tolosa E, MarĂn C. Clinical rating scale for tremor. In: Jankovic J, Tolosa E, editors. Parkinson's Disease and Movement Disorders. 2nd ed. Baltimore: Williams & Wilkins; 1993. p. 225-34.
Starting date: January 2005
Last updated: January 31, 2012
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