Essential Tremor
Conditions
Brief summary
This is a pilot trial to evaluate the safety and efficacy of a combined oral formulation of THC and CBD in patients with Essential Tremor.
Detailed description
Essential tremor (ET) is the most common neurological movement disorder, affecting up to 1% of the population and up to 5% of individuals over the age of 65. ET is characterized by often disabling tremors that occur when an individual moves. The tremors most commonly affect the hands, head, voice, and legs in order of frequency, leading to impairment in activities of daily living and morbidity. No pharmacological agent has been developed for ET, though existing agents such as propranolol and primidone are used off-label to reduce tremor amplitude. Deep brain stimulation surgery is often reserved for only individuals with the most severe tremors. Patients with ET have long reported tremor benefits with the use of cannabis, though no controlled trials have been conducted. The investigators plan to conduct the first double-blind, placebo-control clinical trial of cannabis in an oral capsule. Various validated tremor rating methods will be used to quantify tremor severity, while looking at tolerability and safety.
Interventions
DRUGCBD/THC
Oral formulation of combined Cannabidiol (CBD) and Tetrahydrocannabinol (THC).
DRUGPlacebo oral capsule
Matched Placebo
Sponsors
International Essential Tremor Foundation
Tilray
Center for Medicinal Cannabis Research
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of ET by a Movement Disorder Neurologist * Stable dose of tremor medication for a period of at least 6 weeks prior to screening * Tremor in the arms * Tremor(s) is/are moderately severe (amplitude of at least 1cm)
Exclusion criteria
* Significant non-ET related abnormal findings on neurological exam * Tremor at rest, or other features suggestive of Parkinson disease * Diagnosis of dementia * Pregnant or nursing * Childbearing potential and unable or unwilling to use contraception during course of the trial * On medications known to interact with the study drug * Current or prior history of alcohol or substance abuse * Recent exposure to primidone (within the past 21 days) or benzodiazepines (such as Valium, Ativan or Klonopin), ketoconazole, ritonavir, clarithromycin, rifampin, carbamazepine, St. Johns Wort, digoxin or other medications known to affect your liver enzymes (within the past 7 days). * Unwilling to abstain from consuming grapefruits, grapefruit juice or grapefruit containing products. * Taking medications such as warfarin, cyclosporine, and amphotericin B that are highly protein-bound * Do not wish to take a cannabis-derived agent * Allergy or sensitivity to sorbitol, xylitol, stevia or other natural sweeteners * Allergy or sensitivity to cannabis * Used cannabis or a cannabis-derived product (such as CBD oil) within the past 4 weeks or plan to use it during this research study. * Diagnosis of a psychiatric disorder (e.g., mania, bipolar depressive disorder, schizophrenia, schizoaffective disorder, or other major psychiatric disorder) * Current or prior history of suicidal thoughts and/or behavior * Active medical problem affecting the immune system, liver, gastrointestinal tract, lungs, heart, endocrine system (such as diabetes and/or thyroid), and/or a blood clotting disorder * Current infection * Reduced kidney function (GFR \<60)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Digital Spirography | Day 22 (100 minutes post-dose) | The tremor mean amplitude calculated using computerized spirography to measure kinetic tremors. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Global Impression of Change | Day 22 | The Global impression of change will be calculated based on both physician and patient report. The scale ranges from a score of 1 (very much improved) to 7 (very much worse) with a score of 4 indicating 'no change'. |
| Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Days 1, 3, 6, 22 | Side effects survey |
| Change in Score on a Scale From Baseline of the Tremor Research Group Essential Tremor Rating Scale (TETRAS) | Baseline and Day 22 | The performance sub scale of the TETRAS will be used to measure tremor severity. The scale ranges from 0 to 60 points (0 being no tremor). |
| Number of Participants With New Study-related Electrocardiogram (EKG) Abnormalities | Day 22 | Electrocardiographic changes from baseline measures will trigger further evaluation. EKG's will be rated as normal/abnormal relative to the baseline EKG reading, and abnormal findings will be rated as clinically significant/not clinically significant. |
| Accelerometry-based Assessment of Tremor Severity | Baseline and Day 22 | The spectral power density measure of accelerometry data to measure will serve as a measure of tremor severity, comparing tremor amplitude from this digital biomarker at the time of the primary outcome to the same measure at baseline. |
| Number of Participants at Risk for Suicide Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Day 22 | This is a scale looking at risk assessment of suicidality. The presence of any positive responses will lead to further evaluation. |
Countries
United States
Participant flow
Recruitment details
This is a cross-over design where each subject receives both a placebo and treatment arm in blinded random order.
Participants by arm
| Arm | Count |
|---|---|
| All Participants After randomization, each patient will receive study medication in two study periods. Each study period includes 1-week titration, 2-week treatment, and 1-week tapering. There is a 3-week washout period between the two study periods. During the titration period, patients will have a starting dose of 1 capsule (placebo or 5mg THC/100mg CBD) per day; 2 capsules per day on day 3; 3 capsules per day on day 6. If the patient or investigator feel that the higher study drug dose of 3 caps per day is causing troublesome side effects, the dosage may be lowered to 2 caps per day. Patients will continue on this target dose during the 2-week treatment and then gradually taper from medication over one week. Patients will crossover to the alternate treatment after a 3-week washout period. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Second Intervention - 4 Weeks | Adverse Event | 0 | 2 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 67.0 years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 7 / 7 | 6 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 |
Outcome results
Primary
Digital Spirography
The tremor mean amplitude calculated using computerized spirography to measure kinetic tremors.
Time frame: Day 22 (100 minutes post-dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CBD/THC | Digital Spirography | 1.04 millimeters of tremor amplitude | Standard Deviation 0.57 |
| Placebo | Digital Spirography | 1.00 millimeters of tremor amplitude | Standard Deviation 0.42 |
Secondary
Accelerometry-based Assessment of Tremor Severity
The spectral power density measure of accelerometry data to measure will serve as a measure of tremor severity, comparing tremor amplitude from this digital biomarker at the time of the primary outcome to the same measure at baseline.
Time frame: Baseline and Day 22
Population: Participants in both treatment arms will undergone tremor measurement using accelerometry as a surrogate of tremor severity.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CBD/THC | Accelerometry-based Assessment of Tremor Severity | 0.012 Proportion of baseline spectral power | Standard Deviation 0.03 |
| Placebo | Accelerometry-based Assessment of Tremor Severity | 0.007 Proportion of baseline spectral power | Standard Deviation 0.011 |
Secondary
Change in Score on a Scale From Baseline of the Tremor Research Group Essential Tremor Rating Scale (TETRAS)
The performance sub scale of the TETRAS will be used to measure tremor severity. The scale ranges from 0 to 60 points (0 being no tremor).
Time frame: Baseline and Day 22
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CBD/THC | Change in Score on a Scale From Baseline of the Tremor Research Group Essential Tremor Rating Scale (TETRAS) | -8.07 score on a scale | Standard Deviation 5.71 |
| Placebo | Change in Score on a Scale From Baseline of the Tremor Research Group Essential Tremor Rating Scale (TETRAS) | -10.3 score on a scale | Standard Deviation 3.9 |
Secondary
Global Impression of Change
The Global impression of change will be calculated based on both physician and patient report. The scale ranges from a score of 1 (very much improved) to 7 (very much worse) with a score of 4 indicating 'no change'.
Time frame: Day 22
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| CBD/THC | Global Impression of Change | Clinical Global Impression of Change | 3 score on a scale |
| CBD/THC | Global Impression of Change | Patient Global Impression of Change | 3 score on a scale |
| Placebo | Global Impression of Change | Clinical Global Impression of Change | 4 score on a scale |
| Placebo | Global Impression of Change | Patient Global Impression of Change | 4 score on a scale |
Secondary
Number of Participants at Risk for Suicide Based on Columbia-Suicide Severity Rating Scale (C-SSRS)
This is a scale looking at risk assessment of suicidality. The presence of any positive responses will lead to further evaluation.
Time frame: Day 22
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CBD/THC | Number of Participants at Risk for Suicide Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | 0 Participants |
| Placebo | Number of Participants at Risk for Suicide Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | 0 Participants |
Secondary
Number of Participants Reporting Adverse Events Based on Common Terminology Criteria
Side effects survey
Time frame: Days 1, 3, 6, 22
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Dry mouth | 1 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Memory problems | 3 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Ringing in ears | 7 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Runny nose | 3 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Sleepiness | 4 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Insomnia | 0 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Increased sleepiness | 2 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Numbness/tingling | 4 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Dyspnea on exertion | 4 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Watery eyes | 3 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Decreased concentration | 7 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Imbalance | 3 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Mild headache | 0 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Groggy | 0 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Tired | 0 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Thumb pain | 0 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Anxiety | 2 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Headache | 2 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Lightheaded | 2 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Felt high | 1 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Decreased libido | 1 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Diarrhea | 1 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Dizziness | 4 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Euphoria | 1 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Fatigue | 1 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Feels relaxed | 1 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Increased thirst | 1 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Felt buzzed | 1 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Quivering voice | 1 Participants |
| CBD/THC | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Visual slowing | 1 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Tired | 1 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Dizziness | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Visual slowing | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Thumb pain | 1 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Watery eyes | 3 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Increased thirst | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Anxiety | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Sleepiness | 1 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Euphoria | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Insomnia | 2 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Headache | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Increased sleepiness | 1 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Dry mouth | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Ringing in ears | 6 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Quivering voice | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Numbness/tingling | 4 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Lightheaded | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Dyspnea on exertion | 4 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Fatigue | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Runny nose | 2 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Felt high | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Decreased concentration | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Memory problems | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Felt buzzed | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Imbalance | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Decreased libido | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Mild headache | 1 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Feels relaxed | 0 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Groggy | 1 Participants |
| Placebo | Number of Participants Reporting Adverse Events Based on Common Terminology Criteria | Diarrhea | 0 Participants |
Secondary
Number of Participants With New Study-related Electrocardiogram (EKG) Abnormalities
Electrocardiographic changes from baseline measures will trigger further evaluation. EKG's will be rated as normal/abnormal relative to the baseline EKG reading, and abnormal findings will be rated as clinically significant/not clinically significant.
Time frame: Day 22
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CBD/THC | Number of Participants With New Study-related Electrocardiogram (EKG) Abnormalities | 0 Participants |
| Placebo | Number of Participants With New Study-related Electrocardiogram (EKG) Abnormalities | 0 Participants |
p-value: 0.52Regression, Logistic