Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response

• Sponsor: University of California, San Diego (Other)
• Overall Status: Completed
• CT.gov ID: NCT02495883
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 56
• Location: 1
• Arms: 2
• Actual Duration (Months): 40
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

Essential Tremor (ET) is the most common tremor disorder, currently affecting an estimated 2.9 million Americans and leading to disability and decreased quality of life in 75% of cases. The pathophysiology of ET is poorly understood, with the source of the tremor remaining controversial since all studies show increased activity in the cerebellum (including mimicked tremor in controls), while animal models of ET using harmaline and a single human PET study implicate the inferior olivary nucleus in the brainstem.

There is evidence from the investigator's laboratory that the use of resting-state functional magnetic resonance imaging (rs-fMRI) is useful for characterizing the abnormal tremor neural network in ET compared with controls. The goal is to identify the source of the tremor, which is hypothesized to remain active during rest.

Current ET diagnostic criteria require the presence of postural and/or kinetic tremor, which are assumed to be different manifestations of the same tremor oscillator. This long-standing assumption may be incorrect based on several lines of evidence from the investigator's laboratory, and has major implications for understanding ET pathophysiology and treatment. The investigators will test the hypothesis that postural and kinetic tremors are generated through different neural mechanisms.

Treatment of ET focuses on pharmacological agents of various mechanisms and rarely deep brain stimulation of the Vim thalamus. Despite the assortment of agents used to treat ET, only ~50% of patients benefit from a particular agent. Furthermore, the mechanisms of action on tremor are not generally known. Understanding the mechanisms of action of various tremor-suppressing agents is critical for future drug development. In this proposal, the investigators plan to study the effects of ethanol (the most efficacious tremor-suppressant currently available) and propranolol (a non-specific β-adrenergic blocker with proven efficacy and unknown mechanism of action) on the tremor neural network.

Condition or Disease	Intervention/Treatment	Phase
Essential Tremor; Tremor	Other: Ethanol; Drug: Propranolol	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response
• Actual Study Start Date: Dec 1, 2013
• Actual Primary Completion Date: Apr 1, 2017
• Actual Study Completion Date: Apr 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Other: Essential Tremor Group Patients will be randomized to start in one of two treatment arms: 1) 50ml of 40% ethanol or 2) Propranolol SR 60-120mg. In patients who receive ethanol first, they will return for a second visit when they will receive Propranolol, and vice versa. Ethanol will be administered to participants diagnosed with Essential Tremor during the study visit, whereas patients receiving Propranolol SR will be administered daily over an estimated period of two weeks prior to the fMRI visit.	Other: Ethanol; 50ml of 40% Ethanol; Drug: Propranolol; Beta blocker; Other Names: Propranolol SR Inderal LA
No Intervention: Health Volunteer Group Healthy Volunteers will receive no interventions.

Outcome Measures

Primary Outcome Measures

1. Regions With fMRI Differences Between ET and Controls [At visit 1 or 2 based on randomization table.]

   Regions that were differentially activated in ET as measured by number of statistically significant voxels (cluster size). This represents the number of activated voxels seen in the ET group that were not present in the Healthy Control group.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Diagnosed with ET by a Movement Disorder Neurologist.

• Tremors that improve with alcohol.

• Ability to abstain from drinking alcohol or caffeine for at least 2 days before both the screening and fMRI visits

• Over the age of 21.

Exclusion Criteria:

• Significant non-ET related abnormal findings during neurological exam.

• Presence of a tremor at rest.

• Pregnant or nursing.

• Unable to safely undergo MRI based on completion of a safety questionnaire.

• History of dementia, brain tumor, stroke, head trauma or a vascular malformation based on history or MRI findings.

• Severe active medical condition, such as cardiovascular disease, that prevents subject from lying flat for up to 120 minutes.

• Unable or unwilling to provide informed consent.

• Claustrophobia (a fear of tight spaces) or other restrictions that prevent subject from undergoing an MRI in a confined space for up to 120 minutes.

• Unable to temporarily stop taking medications that may influence liver metabolism or brain function.

• Tremors so severe that subject cannot safely and effectively undergo MRI

• Past/current problems with alcohol abuse or dependence.

• Unwillingness to take alcohol (ethanol), which is a potentially intoxicating drug

• History of deep brain stimulation or thalamotomy surgery.

• Sinus bradycardia, bronchial asthma, or a known allergy to propranolol (Inderal).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	La Jolla	California	United States	92037

Sponsors and Collaborators

• University of California, San Diego
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Fatta B Nahab, MD, UCSD

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 8, 2014

More Information

Publications

None provided.

• Responsible Party: Fatta B Nahab, Associate Professor of Neurosciences, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT02495883
• Other Study ID Numbers: 131202; 1R01NS073683-01A1
• First Posted: Jul 13, 2015
• Last Update Posted: Dec 2, 2020
• Last Verified: Dec 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Fatta B Nahab, Associate Professor of Neurosciences, University of California, San Diego: Essential Tremor; Magnetic Resonance Imaging; Therapy; Alcohol; Propranolol
• Additional relevant MeSH terms: Tremor; Essential Tremor; Ethanol; Propranolol

Study Results

Participant Flow

Arm/Group Title	Essential Tremor Group	Health Volunteer Group
Arm/Group Description	50ml of 40% ethanol will be administered to participants diagnosed with Essential Tremor. Propranolol SR 60-120mg will be administered daily to participants over an estimated period of two weeks. Ethanol: 50ml of 40% Ethanol Propranolol: Beta blocker	Healthy Volunteers
Period Title: Overall Study
STARTED	32	24
COMPLETED	31	24
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Essential Tremor Group	Health Volunteer Group	Total
Arm/Group Description	50ml of 40% ethanol will be administered to participants diagnosed with Essential Tremor. Propranolol SR 60-120mg will be administered daily to participants over an estimated period of two weeks. Ethanol: 50ml of 40% Ethanol Propranolol: Beta blocker	Healthy Volunteers	Total of all reporting groups
Overall Participants	31	24	55
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.5 (15.4)	60.5 (11.5)	62.2 (13.7)
Sex: Female, Male (Count of Participants)
Female	14 45.2%	16 66.7%	30 54.5%
Male	17 54.8%	8 33.3%	25 45.5%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Montreal Cognitive Assessment (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	27.9 (1.7)	28.1 (1.6)	28.0 (1.7)
Tremor Research Group Essential Tremor Rating Scale (TETRAS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	37.8 (19.0)	NA (NA)	37.8 (19.0)

Outcome Measures

1. Primary Outcome

Title	Regions With fMRI Differences Between ET and Controls
Description	Regions that were differentially activated in ET as measured by number of statistically significant voxels (cluster size). This represents the number of activated voxels seen in the ET group that were not present in the Healthy Control group.
Time Frame	At visit 1 or 2 based on randomization table.

Outcome Measure Data

Analysis Population Description

The methodology of this trial utilizes functional MRI measures. In order to understand the significance of a group's unique brain responses, the data between the two groups (Essential Tremor vs. Healthy Controls) are statistically compared to derive regions that are unique. The output of the analyses show regions that are unique to ET. NOTE: Data structure cannot be provided separately for each group based on the experiment paradigm and analysis methods.

Arm/Group Title	All Subjects
Arm/Group Description	All subject data
Measure Participants	55
Right Cerebellum	139
Left Putamen	93
Right Posterior Cingulate/Thalamus	85
Right Sensorimotor Cortex	74

Adverse Events

Time Frame	2 study visits, each lasting up to 4 hours.
Adverse Event Reporting Description	Adverse events were collected in combination across both arms since the goal of the trial was to observe the differences in brain activations between the two groups (ET and healthy controls) and study the brain effects of two therapies on the ET population.
Arm/Group Title	ET Group		Healthy Volunteers
Arm/Group Description	Patient Cohort		Control Cohort
All Cause Mortality
	ET Group		Healthy Volunteers
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/24 (0%)
Serious Adverse Events
	ET Group		Healthy Volunteers
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	ET Group		Healthy Volunteers
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/24 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.