Octanoic Acid for Essential Tremor
Octanoic Acid for Essential Tremor
Background:

 - Essential tremor (ET) is a condition of out-of-control shaking. Several drugs are used to
 treat ET. However, they are often only partly helpful and can have side effects. Many people
 with ET get some relief from drinking alcohol. Octanol, a food additive similar to alcohol,
 can improve tremor in animals and is less likely to make people feel drunk. One form of
 octanol, called 1-octanol, has been shown to improve tremor in some people and had few side
 effects. 1-octanol is converted to octanoic acid, and research suggests that octanoic acid
 itself might suppress ET with no significant side effects such as drunkenness. Researchers
 want to see what dose of octanoic acid is most useful in reducing ET.

 Objectives:

 - To test different doses of octanoic acid to treat essential tremor.

 Eligibility:

 -  Individuals at least 21 years of age who have ET that responds to treatment with
 alcohol.

 -  Participants must be able to stop taking certain ET medications during the study.

 Design:

 -  This study requires three visits. Visit 1 is a screening visit that will take up to 5
 hours. Visit 2 is a 2- to 3-day inpatient admission to the National Institutes of Health
 Clinical Center. Visit 3 is a followup outpatient visit 1 to 2 weeks after the hospital
 admission.

 -  At the screening visit, participants will have a physical exam, neurological exam, and
 medical history. Blood and urine samples will be collected. Participants will also have
 an alcohol dose test to measure the tremor s response to alcohol.

 -  For the study visit, participants will enter the hospital for testing. Participants will
 have the study drug and test the tremor's response to it. Frequent blood samples will be
 collected.

 -  One to two weeks after leaving the hospital, participants will have a final followup
 study visit. Blood samples will be collected.
OBJECTIVE:

 To determine the maximum tolerated dose of oral octanoic acid (OA) in patients with essential
 tremor. Further study objectives include the evaluation of the efficacy and tolerability of
 octanoic acid with escalation doses, as well as the pharmacokinetic and pharmacodynamic
 profile.

 STUDY POPULATION:

 Up to 30 subjects with ethanol-responsive essential tremor (ET) will be included in the
 study. Subjects will be recruited in groups of 6 per dose level.

 DESIGN:

 The study objectives will be tested using a 3+3 dose escalation design. Per dose level, 3
 subjects will be recruited, and dose levels will be 8, 16, 32, 64, and 128 mg/kg, with
 additional 3 subjects at the same level if one of the three subjects exhibits dose limit
 toxicity. Subjects will undergo a screening visit, followed by a 2 to 3-day inpatient
 admission during which the study drug OA will be administered. An outpatient follow-up visit
 will conclude the study.

 OUTCOME MEASURES:

 The primary outcome will be measured by evaluating dose-limiting toxicity, which will be
 reached once 2 or more subjects exhibit a grade 2 adverse event (CTCAE) on the same
 dose-level, which is related to OA. The dose below the level at which 2 or more grade 2
 OA-related adverse events have been observed, will then be defined as maximum tolerated dose
 (MTD) and the study stopped. Toxicity for the primary outcome will be monitored by an
 unblinded independent data safety monitoring board (DSMB), who will determine when the
 primary outcome is reached.

 Secondary measures will include safety measures such as routine laboratory parameters, EKG
 measures, vital signs as well as a standardized assessment for signs of intoxication.
 Additional secondary outcome measures will include efficacy measures such as tremor
 accelerometry and digital spiral analysis, as well as a standardized clinical tremor rating
 scale. Furthermore, pharmacokinetic sampling will be performed.
-  INCLUSION CRITERIA:

 -  Diagnosis of essential tremor with bilateral hand tremor as the predominant feature,
 which is known to be responsive to ethanol.

 -  Unequivocal accelerometric tremor of both hands on screening examination (bilateral
 central tremor component during postural tremor accelerometry, consistent with ET)

 -  Reduction of accelerometric tremor power of at least 35% following a formal ethanol
 challenge during the screening visit.

 -  Subjects must be willing and safely able to abstain from any medication for the
 treatment of tremor for a period of at least 5 plasma half-lives of the individual
 drug prior to study participation. (For Propranolol/Inderal , Gabapentin/Neurontin
 this will be 1 day; for Primidone/Mysoline : 26 days).

 Subjects must be willing to refrain from alcohol and drinks or food containing caffeine
 starting 48 hours prior to the study visits

 EXCLUSION CRITERIA:

 -  Patients with any other significant pathological finding in the neurological
 examination other than typical symptoms of ET

 -  Acute or chronic severe medical conditions which would preclude the subject from
 participating (e.g., severe heart disease NYHA grade 3 or 4, renal failure, hepatic
 failure, lung disease, uncontrolled hyperthyroidism)

 -  Subjects with concomitant therapy with warfarin or NSAIDs (other than aspirin), when
 taken on a regular basis and cannot be discontinued at least 14 days prior to study
 participation, because of potential interactions with octanoic acid (displacement of
 albumin binding in human serum)(Noctor et al. 1992)

 -  Established diagnosis of diabetes mellitus, as fasting-periods of up to 12 hours are
 required in the protocol.

 -  Subjects with active or past alcohol abuse or dependence (AUDIT score greater than or
 equal to 8)

 -  Elevated liver function parameters (AST, ALT, GGT), higher than the 1.5 fold upper
 limit of the normal range (as defined by the NIH Clinical Center Laboratory Medicine
 Department), or any other clinically significant abnormalities on their baseline
 laboratory tests. The limit for AST therefore will be 51 U/l, for ALT 62 U/L, and GGT
 128 U/l.

 -  Female subjects who are pregnant or breastfeeding

 -  Subjects aged < 21 years

 -  Known flushing symptoms after alcohol intake or allergy to alcohol (any yes answer in
 the standardized Alcohol Flushing Questionnaire)