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

NCT00102596 | Completed Phase 2 Results

• 2 other identifiers: 05009205-N-0092
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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.

Conditions

Essential Tremor

Keywords

Ethanol; Alcohol Responsive; Movement Disorder; Gas Chromatography; Bioavailability; Pharmacokinetics; Essential Tremor

Outcome Measures

Primary Outcomes (1)

• Normalized Mean Tremor Amplitude for Both Formulations of 64 mg/kg 1-Octanol in Part B

  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 Outcomes (3)

• Blood Plasma Levels of Octanoic Acid After 64 mg/kg 1-Octanol Dose

  5, 20, 45, 70, 100, 130, 160, 210, 270 and 360 minutes post-dose

• Heart Rate Post 1-Octanol Dose

  0 minutes, 15 minutes, 100 minutes and 24 hours post-dose

• PR and QTc Intervals Post 1-Octanol Dose

  0 minutes, 15 minutes, 100 minutes and 24 hours post-dose

Interventions

1-Octanol DRUG

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).

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• 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. doi: 10.1152/jn.1999.82.5.2262.

  PMID: 10561404 BACKGROUND

• Busenbark KL, Nash J, Nash S, Hubble JP, Koller WC. Is essential tremor benign? Neurology. 1991 Dec;41(12):1982-3. doi: 10.1212/wnl.41.12.1982.

  PMID: 1745359 BACKGROUND

• 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. doi: 10.1212/01.wnl.0000101722.95137.19.

  PMID: 14718713 BACKGROUND

• Fahn S, Tolosa E, Marín 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.

  BACKGROUND

• 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. doi: 10.1007/s13311-011-0045-1.

  PMID: 21594724 RESULT

MeSH Terms

Conditions

Essential Tremor; Movement Disorders

Interventions

1-Octanol

Condition Hierarchy (Ancestors)

Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Octanols; Fatty Alcohols; Alcohols; Organic Chemicals; Lipids

Limitations and Caveats

Enrollment to study was ended early, as evidence became available, that a metabolite of the study substance promised significantly higher feasibility for treatment in ET.

Results Point of Contact

• Title: Mark Hallett, M.D.
• Organization: NINDS/NIH

hallettm@ninds.nih.gov

301-496-9526

Publication Agreements

• PI is Sponsor Employee: Yes
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 30, 2005
• First Posted: January 31, 2005
• Study Start: January 1, 2005
• Primary Completion: September 1, 2009
• Study Completion: September 1, 2009
• Last Updated: February 1, 2012
• Results First Posted: February 1, 2012

Record last verified: 2012-01

Locations

US (1)