Essential Tremor
Conditions
Brief summary
To compare the efficacy of botulinum toxin (BoNT) injections in forearm flexors plus extensor muscles versus flexors alone for the treatment of essential hand tremor (ET).
Detailed description
The investigators propose a pilot, single center, double blind, randomized, parallel, placebo controlled trial comparing 2 (BoNT) injection patterns for treatment of moderate to severe essential tremor. The investigators will recruit 20 patients with (ET).
Interventions
DRUGBotulinum toxin
Botulinum injections into dominant upper extremity using protocol outlined above.
OTHERPlacebo
Placebo injections in extensor carpi radialis (ECR) and extensor carpi ulnaris (ECU) per protocol outlined above
Sponsors
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 18 and over, male or female patient with (ET) involving at least their dominant hand, as diagnosed by a movement disorders neurologist. 2. Having bothersome hand tremor in dominant hand with a hand TRS ≥2 3. On stable medications during last 30 days prior to enrollment.
Exclusion criteria
1. Presence of secondary causes of tremor, such as dystonia and parkinsonism 2. Any contraindication to botulinum toxin injections (e.g. motor neuron disease, neuromuscular junction disease, etc.) 3. History of surgical treatment for (ET). 4. Dementia as defined by DSM-V criteria 5. Patients with suboptimally treated depression and significant depressive symptoms as defined by a PHQ-9 score of ≥15 (PHQ-9 scores 1-4 Minimal depression; 5-9 Mild depression; 10-14 Moderate depression; 15-19 Moderately severe depression; 20-27 Severe depression). Antidepressant medications, prescribed for depression or anxiety, will be allowed if the patient has been on a stable dose for at least 30 days. 6. Patients with suboptimally treated anxiety and significant anxiety symptoms as defined by a GAD-7 score of ≥15 (GAD-7 scores 0-4: minimal anxiety; 5-9: mild anxiety; 10-14: moderate anxiety; 15-21: severe anxiety). Anti-anxiety medications, prescribed for anxiety, will be allowed if the patient has been on a stable dose for at least 30 days. 7. Significant renal, hepatic, cardiac and thyroid disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in the 6 Week Post Injection Patient Global Impression of Improvement Scale (PGIS) Between Flexors Along and Flexors Plus Extensors Groups. | 6 weeks | 6 weeks post injection Clinician Global Impression if improvement Scale (CGIS) Assessment of improvement graded by the patient on a -4 to +4 scale * -4 = severe worsening * 0 = no change * +4 = complete abolishment of symptoms Higher scores represent better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in the 6 Week Post Injection Clinician Global Impression of Improvement Scale (CGIS) Between Flexors Along and Flexors Plus Extensors Groups. | 6 weeks | 6 weeks post injection Clinician Global Impression if improvement Scale (CGIS) Assessment of improvement graded by clinician on a -4 to +4 scale * -4 = severe worsening * 0 = no change * +4 = complete abolishment of symptoms Higher scores represent better outcome. |
| Difference of the Quality of Life in Essential Tremor Questionnaire (QUEST) Summary Index Change at Week 6 Compared to Baseline Between Wrist Flexors Versus Wrist Flexors Plus Extensors Group. | Baseline and 6 weeks | QUEST( Quality of Life in Essential Tremor Questionnaire ) is a 30-item, ET-specific quality of life scale . Items contribute to five dimensions. Physical/ADL (9 items ), Psychosocial (9 items), Communication (3 items), Hobbies/Leisure (3 items), and Work/Finances (6 items). The score on each scale is expressed as a percentage of the total score possible, with a higher score indicating greater dissatisfaction with that domain of QOL. A total or summary index corresponds to the mean of the five domain scores. The total summary index corresponds to the mean of the five domain scores. Maximal score 100: worse quality of life. Minimal Score 0: best quality of life. This outcome represents the median of the differences between baseline and week 6 in QUEST summary index.Positive index change values indicate that the score increased and negative values indicate that the score decreased. |
| Difference in the Post Injection Grip Strength Change Between Flexor Only Group and Flexor and Extensors Group at 6 Weeks. | 6 weeks | the median of the differences in grip strength between baseline and week 6, A negative value indicates a decrease in grip strength in Kg at week 6. |
| Difference in Tremor Rating Scale Score (TSR)Change From Baseline to Week 6 Between Flexors Alone and Flexors Plus Extensors Groups. | Baseline and 6 weeks | TRS: Tremor Rating Scale : scale composed of 6 items rated from 0-4. 0=none/normal and 4 = very severe/high level of disability. Total score is the sum of all items. Max score 24 ( maximal severity of tremor) Minimal score 0= no tremor/normal. |
| 12 Week Post Injection in Clinician Global Impression Scale-Improvement Subscale (CGIS) | 12 weeks | 12 week post injection in Clinician Global Impression Scale-Improvement Subscale (CGIS) Assessment of improvement graded by the clinician on a -4 to +4 scale * -4 = severe worsening * 0 = no change * +4 = complete abolishment of symptoms Higher scores represent better outcome. |
| 12 Week Post Injection Patient Global Impression Scale-Improvement Subscale (PGIS) | 12 weeks | Patient Global Impression Scale-Improvement Subscale (PGIS) Assessment of improvement graded by patient on a -4 to +4 scale * -4 = severe worsening * 0 = no change * +4 = complete abolishment of symptoms Higher scores represent better outcome. |
| Difference of Quality of Life in Essential Tremor Questionnaire (QUEST) Summary Index Change at Week 12 Compared to Baseline Between Wrist Flexors Versus Wrist Flexors Plus Extensors Group. | Baseline and 12 weeks. | QUEST( Quality of Life in Essential Tremor Questionnaire ) is a 30-item, ET-specific quality of life scale . Items contribute to five dimensions. Physical/ADL (9 items ), Psychosocial (9 items), Communication (3 items), Hobbies/Leisure (3 items), and Work/Finances (6 items). The score on each scale is expressed as a percentage of the total score possible, with a higher score indicating greater dissatisfaction with that domain of QOL. A total or summary index corresponds to the mean of the five domain scores. The total summary index corresponds to the mean of the five domain scores. Maximal score 100: worse quality of life. Minimal Score 0: best quality of life. This outcome represents the median of the differences between baseline and week 6 in QUEST summary index. Positive index change values indicate that the score increased and negative values indicate that the score decreased. |
| 12 Weeks Post Injection Tremor Rating Scale for Flexors Group and Flexors Plus Extensors Group. | 12 weeks | TRS: Tremor Rating Scale : scale composed of 6 items rated from 0-4. 0=none or normal and 4 = very severe or high level of disability. Total score is the sum of all items. Max score 24 ( maximal severity of tremor) Minimal score 0= no tremor/normal. |
Countries
United States
Participant flow
Recruitment details
This was a 12-week, pilot, randomized (1:1 ratio), double-blind, placebo-controlled study of 21 patients with ET evaluated by a movement disorders specialist at the Cleveland Clinic.
Pre-assignment details
Twenty-one patients were enrolled to participate, but one patient was removed from the sample due to being an extreme outlier on most outcomes of interest, and another patient dropped out after the baseline visit.
Participants by arm
| Arm | Count |
|---|---|
| Flexors Alone 75 units of abobotulinumtoxinA in FCR and FCU and 25 units in ECR and ECU
Botulinum toxin: Botulinum injections into dominant upper extremity using protocol outlined above. | 10 |
| Flexors Plus Extensors 150 units of abobotulinumtoxinA in flexor compartment of dominant arm (75 units in flexor carpi radialis \[FCR\] and 75 units in flexor carpi ulnaris \[FCU\]) along with placebo in extensor carpi radialis (ECR) and extensor carpi ulnaris (ECU)
Botulinum toxin: Botulinum injections into dominant upper extremity using protocol outlined above.
Placebo: Placebo injections in extensor carpi radialis (ECR) and extensor carpi ulnaris (ECU) per protocol outlined above | 9 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Flexors Alone | Flexors Plus Extensors | Total |
|---|---|---|---|
| Age, Continuous | 73.1 years STANDARD_DEVIATION 12 | 64.9 years STANDARD_DEVIATION 9.1 | 69.2 years STANDARD_DEVIATION 11.2 |
| Age of onset, med (IQR) | 55.5 years | 58 years | 58 years |
| Disease duration, med (IQR) | 5.5 Years | 5 Years | 5 Years |
| GAD-7, med (IQR) | 0 Score on a scale | 2 Score on a scale | 0 Score on a scale |
| Main Grip Strength | 30.8 Kg | 28 Kg | 29.7 Kg |
| PHQ-9, med (IQR) | 0.5 units on a scale | 4 units on a scale | 2 units on a scale |
| QUEST Communication, med (IQR) | 0 units on a scale | 0 units on a scale | 0 units on a scale |
| QUEST Health status self-report, med(IQR) | 82.5 units on a scale | 82.5 units on a scale | 82.5 units on a scale |
| QUEST Hobbies, med (IQR) | 0 units on a scale | 0 units on a scale | 0 units on a scale |
| QUEST Physical, med (IQR) | 44.4 units on a scale | 61.1 units on a scale | 61.1 units on a scale |
| QUEST Psychosocial, med (IQR) | 8.3 units on a scale | 25 units on a scale | 11.1 units on a scale |
| QUEST Quality of Life self-report, mean(SD) | 84 units on a scale STANDARD_DEVIATION 9.7 | 82.8 units on a scale STANDARD_DEVIATION 6.7 | 83.4 units on a scale STANDARD_DEVIATION 8.2 |
| QUEST Summary Index, med (IQR) | 12.2 units on a scale | 26.4 units on a scale | 17.8 units on a scale |
| QUEST Work, med (IQR) | 0 units on a scale | 8.3 units on a scale | 0 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 9 Participants | 18 Participants |
| Right-handed | 9 participants | 7 participants | 16 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 9 Participants |
| TRS mean | 12.9 units on a scale STANDARD_DEVIATION 4.6 | 11.3 units on a scale STANDARD_DEVIATION 4.1 | 12.1 units on a scale STANDARD_DEVIATION 4.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 |
| other Total, other adverse events | 4 / 10 | 5 / 9 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 |
Outcome results
Primary
Difference in the 6 Week Post Injection Patient Global Impression of Improvement Scale (PGIS) Between Flexors Along and Flexors Plus Extensors Groups.
6 weeks post injection Clinician Global Impression if improvement Scale (CGIS) Assessment of improvement graded by the patient on a -4 to +4 scale * -4 = severe worsening * 0 = no change * +4 = complete abolishment of symptoms Higher scores represent better outcome.
Time frame: 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Flexors Alone | Difference in the 6 Week Post Injection Patient Global Impression of Improvement Scale (PGIS) Between Flexors Along and Flexors Plus Extensors Groups. | 1.2 score on a scale |
| Flexors Plus Extensors | Difference in the 6 Week Post Injection Patient Global Impression of Improvement Scale (PGIS) Between Flexors Along and Flexors Plus Extensors Groups. | 2.2 score on a scale |
Secondary
12 Week Post Injection in Clinician Global Impression Scale-Improvement Subscale (CGIS)
12 week post injection in Clinician Global Impression Scale-Improvement Subscale (CGIS) Assessment of improvement graded by the clinician on a -4 to +4 scale * -4 = severe worsening * 0 = no change * +4 = complete abolishment of symptoms Higher scores represent better outcome.
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Flexors Alone | 12 Week Post Injection in Clinician Global Impression Scale-Improvement Subscale (CGIS) | 3 score on a scale |
| Flexors Plus Extensors | 12 Week Post Injection in Clinician Global Impression Scale-Improvement Subscale (CGIS) | 3 score on a scale |
Secondary
12 Week Post Injection Patient Global Impression Scale-Improvement Subscale (PGIS)
Patient Global Impression Scale-Improvement Subscale (PGIS) Assessment of improvement graded by patient on a -4 to +4 scale * -4 = severe worsening * 0 = no change * +4 = complete abolishment of symptoms Higher scores represent better outcome.
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Flexors Alone | 12 Week Post Injection Patient Global Impression Scale-Improvement Subscale (PGIS) | 1 score on a scale |
| Flexors Plus Extensors | 12 Week Post Injection Patient Global Impression Scale-Improvement Subscale (PGIS) | 3 score on a scale |
Secondary
12 Weeks Post Injection Tremor Rating Scale for Flexors Group and Flexors Plus Extensors Group.
TRS: Tremor Rating Scale : scale composed of 6 items rated from 0-4. 0=none or normal and 4 = very severe or high level of disability. Total score is the sum of all items. Max score 24 ( maximal severity of tremor) Minimal score 0= no tremor/normal.
Time frame: 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Flexors Alone | 12 Weeks Post Injection Tremor Rating Scale for Flexors Group and Flexors Plus Extensors Group. | 6 score on a scale |
| Flexors Plus Extensors | 12 Weeks Post Injection Tremor Rating Scale for Flexors Group and Flexors Plus Extensors Group. | 6 score on a scale |
Secondary
Difference in the 6 Week Post Injection Clinician Global Impression of Improvement Scale (CGIS) Between Flexors Along and Flexors Plus Extensors Groups.
6 weeks post injection Clinician Global Impression if improvement Scale (CGIS) Assessment of improvement graded by clinician on a -4 to +4 scale * -4 = severe worsening * 0 = no change * +4 = complete abolishment of symptoms Higher scores represent better outcome.
Time frame: 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Flexors Alone | Difference in the 6 Week Post Injection Clinician Global Impression of Improvement Scale (CGIS) Between Flexors Along and Flexors Plus Extensors Groups. | 1 score on a scale |
| Flexors Plus Extensors | Difference in the 6 Week Post Injection Clinician Global Impression of Improvement Scale (CGIS) Between Flexors Along and Flexors Plus Extensors Groups. | 3 score on a scale |
Secondary
Difference in the Post Injection Grip Strength Change Between Flexor Only Group and Flexor and Extensors Group at 6 Weeks.
the median of the differences in grip strength between baseline and week 6, A negative value indicates a decrease in grip strength in Kg at week 6.
Time frame: 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Flexors Alone | Difference in the Post Injection Grip Strength Change Between Flexor Only Group and Flexor and Extensors Group at 6 Weeks. | -6.2 Kilograms |
| Flexors Plus Extensors | Difference in the Post Injection Grip Strength Change Between Flexor Only Group and Flexor and Extensors Group at 6 Weeks. | -11 Kilograms |
Secondary
Difference in Tremor Rating Scale Score (TSR)Change From Baseline to Week 6 Between Flexors Alone and Flexors Plus Extensors Groups.
TRS: Tremor Rating Scale : scale composed of 6 items rated from 0-4. 0=none/normal and 4 = very severe/high level of disability. Total score is the sum of all items. Max score 24 ( maximal severity of tremor) Minimal score 0= no tremor/normal.
Time frame: Baseline and 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Flexors Alone | Difference in Tremor Rating Scale Score (TSR)Change From Baseline to Week 6 Between Flexors Alone and Flexors Plus Extensors Groups. | -5 score on a scale |
| Flexors Plus Extensors | Difference in Tremor Rating Scale Score (TSR)Change From Baseline to Week 6 Between Flexors Alone and Flexors Plus Extensors Groups. | -5 score on a scale |
Secondary
Difference of Quality of Life in Essential Tremor Questionnaire (QUEST) Summary Index Change at Week 12 Compared to Baseline Between Wrist Flexors Versus Wrist Flexors Plus Extensors Group.
QUEST( Quality of Life in Essential Tremor Questionnaire ) is a 30-item, ET-specific quality of life scale . Items contribute to five dimensions. Physical/ADL (9 items ), Psychosocial (9 items), Communication (3 items), Hobbies/Leisure (3 items), and Work/Finances (6 items). The score on each scale is expressed as a percentage of the total score possible, with a higher score indicating greater dissatisfaction with that domain of QOL. A total or summary index corresponds to the mean of the five domain scores. The total summary index corresponds to the mean of the five domain scores. Maximal score 100: worse quality of life. Minimal Score 0: best quality of life. This outcome represents the median of the differences between baseline and week 6 in QUEST summary index. Positive index change values indicate that the score increased and negative values indicate that the score decreased.
Time frame: Baseline and 12 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Flexors Alone | Difference of Quality of Life in Essential Tremor Questionnaire (QUEST) Summary Index Change at Week 12 Compared to Baseline Between Wrist Flexors Versus Wrist Flexors Plus Extensors Group. | -1.67 score on a scale |
| Flexors Plus Extensors | Difference of Quality of Life in Essential Tremor Questionnaire (QUEST) Summary Index Change at Week 12 Compared to Baseline Between Wrist Flexors Versus Wrist Flexors Plus Extensors Group. | 0 score on a scale |
Secondary
Difference of the Quality of Life in Essential Tremor Questionnaire (QUEST) Summary Index Change at Week 6 Compared to Baseline Between Wrist Flexors Versus Wrist Flexors Plus Extensors Group.
QUEST( Quality of Life in Essential Tremor Questionnaire ) is a 30-item, ET-specific quality of life scale . Items contribute to five dimensions. Physical/ADL (9 items ), Psychosocial (9 items), Communication (3 items), Hobbies/Leisure (3 items), and Work/Finances (6 items). The score on each scale is expressed as a percentage of the total score possible, with a higher score indicating greater dissatisfaction with that domain of QOL. A total or summary index corresponds to the mean of the five domain scores. The total summary index corresponds to the mean of the five domain scores. Maximal score 100: worse quality of life. Minimal Score 0: best quality of life. This outcome represents the median of the differences between baseline and week 6 in QUEST summary index.Positive index change values indicate that the score increased and negative values indicate that the score decreased.
Time frame: Baseline and 6 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Flexors Alone | Difference of the Quality of Life in Essential Tremor Questionnaire (QUEST) Summary Index Change at Week 6 Compared to Baseline Between Wrist Flexors Versus Wrist Flexors Plus Extensors Group. | 1.1 score on a scale |
| Flexors Plus Extensors | Difference of the Quality of Life in Essential Tremor Questionnaire (QUEST) Summary Index Change at Week 6 Compared to Baseline Between Wrist Flexors Versus Wrist Flexors Plus Extensors Group. | -5.3 score on a scale |