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

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

ClinicalTrials.gov Identifier:

NCT00102596

First received: January 30, 2005

Last updated: January 31, 2012

Last verified: January 2012

History of Changes

Tracking Information
First Received Date ^ICMJE	January 30, 2005
Last Updated Date	January 31, 2012
Start Date ^ICMJE	January 2005
Primary Completion Date	September 2009 (final data collection date for primary outcome measure)
Current Primary Outcome Measures ^ICMJE (submitted: January 31, 2012)	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 ] [ Designated as safety issue: No ] 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.
Original Primary Outcome Measures ^ICMJE	Not Provided
Change History	Complete list of historical versions of study NCT00102596 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ^ICMJE (submitted: January 31, 2012)	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 ] [ Designated as safety issue: No ] 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. Heart Rate Post 1-Octanol Dose [ Time Frame: 0 minutes, 15 minutes, 100 minutes and 24 hours post-dose ] [ Designated as safety issue: Yes ] PR and QTc Intervals Post 1-Octanol Dose [ Time Frame: 0 minutes, 15 minutes, 100 minutes and 24 hours post-dose ] [ Designated as safety issue: Yes ]
Original Secondary Outcome Measures ^ICMJE	Not Provided
Current Other Outcome Measures ^ICMJE	Not Provided
Original Other Outcome Measures ^ICMJE	Not Provided

Descriptive Information
Brief Title ^ICMJE	Clinical Trial Characterizing the Bioavailability of 1-Octanol in Adults With Ethanol-responsive Essential Tremor
Official Title ^ICMJE	Clinical Trial Characterizing the Bioavailability of 1-Octanol in Adults With Ethanol-responsive Essential Tremor
Brief 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.
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 ^ICMJE	Interventional
Study Phase	Phase 2
Study Design ^ICMJE	Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Condition ^ICMJE	Essential Tremor
Intervention ^ICMJE	Drug: 1-Octanol 1-Octanol is an long-chain alcohol with potential therapeutic benefits in treating alcohol-responsive tremors based on unknown mechanisms. The intervention consisted of either 1) 1-octanol adsorbed to microcrystalline cellulose, NF (Avicel PH 102, FMC Corp., Philadelphia, PA), and fine particle silica (Sipernat 50S, Evonik Degussa Corp., Parsippany, NJ) and encapsulated in 50 mg and 250 mg dosages; or 2) a soft-gel capsule containing 1-octanol embedded in soybean oil at 50 mg and 800 mg dosages (Best Formulations Inc, City of Industry, CA).
Study Arm (s)	Not Provided
Publications *	Nahab FB, Wittevrongel L, Ippolito D, Toro C, Grimes GJ, Starling J, Potti G, Haubenberger D, Bowen D, Buchwald P, Dong C, Kalowitz D, Hallett M. An open-label, single-dose, crossover study of the pharmacokinetics and metabolism of two oral formulations of 1-octanol in patients with essential tremor. Neurotherapeutics. 2011 Oct;8(4):753-62. 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information
Recruitment Status ^ICMJE	Completed
Enrollment ^ICMJE	21
Completion Date	September 2009
Primary Completion Date	September 2009 (final data collection date for primary outcome measure)
Eligibility Criteria ^ICMJE	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
Gender	Both
Ages	21 Years and older
Accepts Healthy Volunteers	No
Contacts ^ICMJE	Contact information is only displayed when the study is recruiting subjects
Location Countries ^ICMJE	United States

Administrative Information
NCT Number ^ICMJE	NCT00102596
Other Study ID Numbers ^ICMJE	050092, 05-N-0092
Has Data Monitoring Committee	No
Responsible Party	National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
Study Sponsor ^ICMJE	National Institute of Neurological Disorders and Stroke (NINDS)
Collaborators ^ICMJE	Not Provided
Investigators ^ICMJE	Not Provided
Information Provided By	National Institutes of Health Clinical Center (CC)
Verification Date	January 2012
^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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