Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response

NCT02495883 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: 1312021R01NS073683-01A1
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

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.

Conditions

Essential Tremor; Tremor

Keywords

Essential Tremor; Magnetic Resonance Imaging; Therapy; Alcohol; Propranolol

Outcome Measures

Primary Outcomes (1)

• Regions With fMRI Differences Between ET and Controls

  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.

  At visit 1 or 2 based on randomization table.

Study Arms (2)

Essential Tremor Group

OTHER

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; Drug: Propranolol

Health Volunteer Group

NO INTERVENTION

Healthy Volunteers will receive no interventions.

Interventions

Ethanol OTHER

50ml of 40% Ethanol

Essential Tremor Group

Propranolol DRUG

Beta blocker

Also known as: Propranolol SR, Inderal LA

Essential Tremor Group

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

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

Study Sites (1)

University of California, San Diego

La Jolla, California, 92037, United States

Location

MeSH Terms

Conditions

Essential Tremor; Tremor

Interventions

Ethanol; Propranolol

Condition Hierarchy (Ancestors)

Movement Disorders; Central Nervous System Diseases; Nervous System Diseases; Dyskinesias; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Alcohols; Organic Chemicals; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds

Results Point of Contact

• Title: Fatta Nahab, MD
• Organization: UCSD

fnahab@health.ucsd.edu

858-822-5871

Study Officials

• Fatta B Nahab, MD

  UCSD

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Neurosciences

Study Record Dates

• First Submitted: September 26, 2013
• First Posted: July 13, 2015
• Study Start: December 1, 2013
• Primary Completion: April 1, 2017
• Study Completion: April 1, 2017
• Last Updated: December 2, 2020
• Results First Posted: December 2, 2020

Record last verified: 2020-12

Locations

US (1)