Clinical Trial Characterizing the Bioavailability of 1-Octanol in Adults With Ethanol-responsive Essential Tremor
Condition: Essential Tremor
MeSH terms: Tremor; Essential Tremor
Intervention: 1-Octanol
Intervention description: 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).
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: No
Keywords: Ethanol; Alcohol Responsive; Movement Disorder; Gas Chromatography; Bioavailability; Pharmacokinetics; Essential Tremor

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.
    

Eligibility 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