| ID | Type | Description | Link |
|---|---|---|---|
| 05-N-0092 |
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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.
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.
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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). |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Blood Plasma Levels of Octanoic Acid After 64 mg/kg 1-Octanol Dose | 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. | 5, 20, 45, 70, 100, 130, 160, 210, 270 and 360 minutes post-dose |
| Heart Rate Post 1-Octanol Dose |
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INCLUSION CRITERIA:
EXCLUSION CRITERIA:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | 20892 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 10561404 | Background | 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. | |
| 1745359 | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Part A: Dose Escalation | Subjects fasted overnight for 6 hours and received 1, 4, 8, 16, 32 and 64 mg/kg 1-octanol at 6AM on different days. There were 2 formulations: 1) 2 participants received 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; and 2) two participants received 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). |
| FG001 | Part B Then C: Fixed Dose | In Part B, subjects fasted overnight for 6 hours and received 64 mg/kg 1-octanol at 6AM of both formulations: 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). At the completion of Parts A and B, an exploratory Part C was added in which subjects fasted overnight for 6 hours and received 128 mg/kg 1-octanol at 6AM of both formulations. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Part A |
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| Part B |
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| Part C |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | Baseline is included for all participants who passed screening and received at least 1 dose of 1-octanol, whether in Part A, B or C |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | All participants who received both formulations of 64 mg/kg 1-octanol in Part B | Posted | Mean | Standard Error | normalized score on a scale | 0, 15, 30, 60, 90, 120, 150, 180, 240 and 360 minutes post-dose |
|
6 hours
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 1-octanol Dose | Subjects fasted overnight for 6 hours. At 6AM subjects received 1-128 mg/kg of 1-octanol |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fever | Infections and infestations | Non-systematic Assessment | due to flu |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Taste Change | Gastrointestinal disorders | Systematic Assessment |
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mark Hallett, M.D. | NINDS/NIH | 301-496-9526 | hallettm@ninds.nih.gov |
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| ID | Term |
|---|---|
| D020329 | Essential Tremor |
| D009069 | Movement Disorders |
| ID | Term |
|---|---|
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D020003 | 1-Octanol |
| ID | Term |
|---|---|
| D000442 | Octanols |
| D005233 | Fatty Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
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| 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 |
| 14718713 | 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. |
| 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. |
| 21594724 | Result | 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. |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Height | Mean | Standard Deviation | centimeters |
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| Weight | Mean | Standard Deviation | kg |
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| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
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| Age of onset | Mean | Standard Deviation | years |
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| Disease Duration | Mean | Standard Deviation | years |
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| History of alcohol-responsive tremors | Number | participants |
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| Number of alcohol servings required for tremor response | One serving of alcohol is 50 ml of 40% ethanol | Mean | Standard Deviation | servings |
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| Family history of essential tremor | Number | participants |
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| Fahn Tolosa Marin Tremor Rating Scale | Only available for the 10 participants who entered Part B. The Fahn Tolosa Marin Tremor Rating Scale was used. Minimum of this scale is 0, maximum is 164 points. Higher scores indicate more tremor. See Fahn S, Tolosa E, and Marin C (1993) "Clinical rating scale for tremor" reference provided in Protocol for full information. | Mean | Standard Deviation | scores on a scale |
|
| OG001 | 64 mg/kg 1-Octanol Soybean Oil Embedded (SOY) Formulation | Subjects fasted overnight for 6 hours. At 6AM subjects received 64 mg/kg of the 1-octanol in 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). |
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| Secondary | Blood Plasma Levels of Octanoic Acid After 64 mg/kg 1-Octanol Dose | 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. | All participants who received either formulation 64 mg/kg 1-octanol in Part A or B | Posted | Mean | Standard Deviation | ng/ml | 5, 20, 45, 70, 100, 130, 160, 210, 270 and 360 minutes post-dose |
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| Secondary | Heart Rate Post 1-Octanol Dose | All participants who received at least 1 dose of 1-octanol in Part A, B or C | Posted | Least Squares Mean | Standard Error | beats per minute | 0 minutes, 15 minutes, 100 minutes and 24 hours post-dose |
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| Secondary | PR and QTc Intervals Post 1-Octanol Dose | All participants who received at least 1 dose of 1-octanol in Part A, B or C | Posted | Least Squares Mean | Standard Error | ms | 0 minutes, 15 minutes, 100 minutes and 24 hours post-dose |
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| 2 |
| 15 |
| 14 |
| 15 |
| Fall | Injury, poisoning and procedural complications | Non-systematic Assessment | leading to fracture of one rib, accidental nature (patient slipped) |
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| Headache | General disorders | Systematic Assessment |
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| Heartburn | Gastrointestinal disorders | Systematic Assessment |
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| Gas/Bloating | Gastrointestinal disorders | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | Systematic Assessment |
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| Dry Mouth | Gastrointestinal disorders | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | Systematic Assessment |
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| Sedation | General disorders | Systematic Assessment |
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| Dizziness | General disorders | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Worsening of tremor | Nervous system disorders | Systematic Assessment |
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| Anxiety | Psychiatric disorders | Systematic Assessment |
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| Insomnia | General disorders | Systematic Assessment |
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| Hypotension | Cardiac disorders | Systematic Assessment |
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| Numbness | Nervous system disorders | Systematic Assessment |
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| Vertigo | Nervous system disorders | Systematic Assessment |
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| Fainting | Nervous system disorders | Systematic Assessment |
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| Blurred Vision | Eye disorders | Systematic Assessment |
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| Dry Eyes | Eye disorders | Systematic Assessment |
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| Sweating | General disorders | Systematic Assessment |
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| D008055 |
| Lipids |
| Plasma Octanoic Acid Level at 45 min post-dose |
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| Plasma Octanoic Acid Level at 70 min post-dose |
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| Plasma Octanoic Acid Level at 100 min post-dose |
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| Plasma Octanoic Acid Level at 130 min post-dose |
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| Plasma Octanoic Acid Level at 160 min post-dose |
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| Plasma Octanoic Acid Level at 210 min post-dose |
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| Plasma Octanoic Acid Level at 270 min post-dose |
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| Plasma Octanoic Acid Level at 360 min post-dose |
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| Heart Rate at 24 hours |
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| PR Interval at 24 hours |
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| QTc Interval at 0 min |
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| QTc Interval at 15 min |
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| QTc Interval at 100 min |
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| QTc Interval at 24 hours |
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