Essential Tremor of the Upper Limbs
Conditions
Brief summary
The objective of this study is to assess the efficacy and safety of a single, kinematic-analysis-based intramuscular injection of NT 201, compared with placebo, in moderate to marked essential tremor of the upper limb.
Interventions
Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).
DRUGPlacebo
Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).
Sponsors
Merz Pharmaceuticals GmbH
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
Main Inclusion Criteria: * Diagnosis of 'definite essential tremor' in accordance with modified TRIG criteria, as follows: * Bilateral postural tremor with or without kinetic tremor, involving hands and forearms, that is visible and persistent. * It is to be noted that: * Tremor of other body parts may be present in addition to upper limb tremor. * Bilateral tremor may be asymmetric. * Tremor is reported by patient to be persistent, although the amplitude may fluctuate. * First onset of essential tremor at least 6 months before screening with stability of the tremor symptoms over 4 weeks and in the opinion of the investigator definite diagnosis of essential tremor. * Moderate-to-marked upper-limb postural and/or kinetic tremor at wrist level, corresponding to Fahn-Tolosa-Marin upper-limb tremor rating of at least 2 categories (scale part C, items 16-23) in the limb to be treated between of 2 or higher. * Visible tremor at wrist level in at least one of the four positions/tasks used in kinematic assessments * Tremor deemed by the investigator to require a treatment with 30 - 200 U NT 201 for a treatment of up to three joints of the selected upper limb (wrist treatment mandatory). * Stable concomitant anti-tremor medication and no clinically relevant findings in routine laboratory examinations. Main
Exclusion criteria
* Any neurological signs abnormal for the subject's age, other than the tremor itself and Froment's maneuver. * Exposure to the following tremorogenic drugs: Lithium, Valproic acid, Amiodarone, typical and atypical neuroleptics. Exposure to other than the listed tremorogenic or potentially tremorogenic drugs is allowed only if, in the opinion of the investigator, this will not interfere with the study drug evaluation. In these cases, a stable medication should be reached 4 weeks before screening and intended for the time during the study drug evaluation. * Trauma to the central nervous system or the nerves of the target limb within the three months preceding the onset of tremor. * Evidence of psychogenic origins of tremor. * Life habits (e.g. smoking, alcohol or substance abuse) prejudicial to study participation. * Prior surgery to treat tremor * Recent (16 weeks) treatment with any Botulinum toxin product for any reason. * Relevant recent or planned surgery or other specified relevant treatments and/or concomitant disorders.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 4 in Maximum Angular Tremor Amplitude of the Wrist (Injected Limb) | Baseline up to Week 4 | No primary efficacy variables are defined for this study. One of the secondary outcome measures is used for CTgov protocol registration and results reporting purposes only. TremorTek is a tremor kinematic analytics investigational device which is used to measure maximum angular tremor amplitude at wrist of the injected limb (unit: degrees). Angular tremor amplitude is the measure of tremor severity. Reduction of angular tremor amplitude at wrist of the injected limb represents tremor improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 4 in Maximum Log-transformed Accelerometric Tremor Amplitude at Wrist Level (Injected Limb) | Baseline up to Week 4 | TremorTek is a tremor kinematic analytics investigational device which is used to measure maximum log-transformed accelerometric tremor amplitude at wrist level of the injected limb (unit: meter per square second \[m/s˄2\]). Log-transformed accelerometric tremor amplitude is a measure of tremor severity reflecting the non-vectoral intensity of tremor. Reduction of log-transformed accelerometric tremor amplitude at wrist level of the injected limb represents a tremor improvement. |
| Change From Baseline to Week 4 in Fahn-Tolosa-Marin (FTM) Tremor Score in Injected Limb (Item 5 [Right Upper Extremity] or 6 [Left Upper Extremity]) | Baseline up to Week 4 | The FTM tremor rating scale is used for evaluation of tremor severity and function and consists of three parts (A, B, C). For this outcome measure the score of FTM scale item 5 (right upper extremity) or item 6 (left upper extremity) is used (both items are from part A). The outcome values are calculated as the sum of the three functions at rest, with posture holding, and with action and intention. The score for each item ranges from 0 (normal) to 4 (severe), that is, the possible values range from 0 to 12. |
| Change From Baseline to Week 4 in FTM Motor Performance Score (Items 11-15) | Baseline up to Week 4 | The FTM tremor rating scale was used for evaluation of tremor severity and function. This investigator-assessed scale consists of 3 parts (A, B and C). Part A: Tremor location/Severity rating (items 1-10); Part B: Specific motor tasks / Function rating (items 11-15). Ratings for five motor tasks (handwriting, drawing \[large/small spiral, line\], and pouring); and Part C: Functional disabilities resulting from tremor/activities of daily living (items 16-23). For this outcome measure, the sum of the five FTM motor performance items (from Part B) were used: item 11 ('handwriting for dominant hand only' - irrespective of its injection or non-injection), items 12 to 15 ('drawing large and small spiral', 'line drawing', 'pouring' for the injected upper limb). The score for each item ranges from 0 (normal) to 4 (severe). Possible values range for total FTM motor performance score: 0-20. |
| Participant's Global Impression of Change Scale (GICS) at Week 4 | Week 4 | The GICS was used to measure the participant's impression of change due to treatment. The response option was a common 7-point Likert scale, with the following values: +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse). |
| Investigator's Global Impression of Change Scale (GICS) at Week 4 | Week 4 | The GICS was used to measure the investigator's impression of change due to treatment. The response option was a common 7-point Likert scale, with the following values: +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse). |
Countries
Canada, United States
Participant flow
Recruitment details
The multicenter study was conducted at 6 investigational sites in the United States and Canada.
Pre-assignment details
A total of 52 participants were screened, out of which 30 participants were randomized and treated.
Participants by arm
| Arm | Count |
|---|---|
| IncobotulinumtoxinA 30 to 200 U Participants received incobotulinumtoxinA (also known as NT 201) between 30 to 200 U, powder for solution for injection, intramuscular injection, unilaterally into the muscles of the wrist, and optionally, into the elbow and shoulder as based upon kinematic analysis, in a single injection session on Day 1 (Visit 2). The maximum dose per injection site (more than one site per muscle were possible) was 25 U incobotulinumtoxinA. | 19 |
| Placebo Participants received placebo solution matched to the volume of incobotulinumtoxinA solution, intramuscular injection, unilaterally into the muscles of the wrist, and optionally, into the elbow and shoulder as based upon kinematic analysis, in a single injection session on Day 1 (Visit 2). The maximum dose per injection site (more than one site per muscle were possible) was 25 U incobotulinumtoxinA placebo. | 11 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | IncobotulinumtoxinA 30 to 200 U | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 68.1 years STANDARD_DEVIATION 10.6 | 68.2 years STANDARD_DEVIATION 10.2 | 68.1 years STANDARD_DEVIATION 10.3 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 17 Participants | 11 Participants | 28 Participants |
| Sex: Female, Male Female | 10 Participants | 5 Participants | 15 Participants |
| Sex: Female, Male Male | 9 Participants | 6 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 11 |
| other Total, other adverse events | 9 / 19 | 6 / 11 |
| serious Total, serious adverse events | 0 / 19 | 2 / 11 |
Outcome results
Primary
Change From Baseline to Week 4 in Maximum Angular Tremor Amplitude of the Wrist (Injected Limb)
No primary efficacy variables are defined for this study. One of the secondary outcome measures is used for CTgov protocol registration and results reporting purposes only. TremorTek is a tremor kinematic analytics investigational device which is used to measure maximum angular tremor amplitude at wrist of the injected limb (unit: degrees). Angular tremor amplitude is the measure of tremor severity. Reduction of angular tremor amplitude at wrist of the injected limb represents tremor improvement.
Time frame: Baseline up to Week 4
Population: The full analysis set (FAS) was defined as the subset of participants who received study medication (incobotulinumtoxinA or placebo) at least once, and for whom a post-baseline value of any efficacy variable was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IncobotulinumtoxinA 30 to 200 U | Change From Baseline to Week 4 in Maximum Angular Tremor Amplitude of the Wrist (Injected Limb) | -0.47 degree | Standard Deviation 0.63 |
| Placebo | Change From Baseline to Week 4 in Maximum Angular Tremor Amplitude of the Wrist (Injected Limb) | 0.07 degree | Standard Deviation 0.88 |
Comparison: Least square (LS) means are from analysis of covariance (ANCOVA) with treatment and site included as fixed factors and baseline included as covariate.p-value: 0.14495% CI: [-1.02, 0.16]ANCOVA
Secondary
Change From Baseline to Week 4 in Fahn-Tolosa-Marin (FTM) Tremor Score in Injected Limb (Item 5 [Right Upper Extremity] or 6 [Left Upper Extremity])
The FTM tremor rating scale is used for evaluation of tremor severity and function and consists of three parts (A, B, C). For this outcome measure the score of FTM scale item 5 (right upper extremity) or item 6 (left upper extremity) is used (both items are from part A). The outcome values are calculated as the sum of the three functions at rest, with posture holding, and with action and intention. The score for each item ranges from 0 (normal) to 4 (severe), that is, the possible values range from 0 to 12.
Time frame: Baseline up to Week 4
Population: The FAS was defined as the subset of participants who received study medication (incobotulinumtoxinA or placebo) at least once, and for whom a post-baseline value of any efficacy variable was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IncobotulinumtoxinA 30 to 200 U | Change From Baseline to Week 4 in Fahn-Tolosa-Marin (FTM) Tremor Score in Injected Limb (Item 5 [Right Upper Extremity] or 6 [Left Upper Extremity]) | -1.9 score on a scale | Standard Deviation 1.9 |
| Placebo | Change From Baseline to Week 4 in Fahn-Tolosa-Marin (FTM) Tremor Score in Injected Limb (Item 5 [Right Upper Extremity] or 6 [Left Upper Extremity]) | -0.5 score on a scale | Standard Deviation 1.8 |
Secondary
Change From Baseline to Week 4 in FTM Motor Performance Score (Items 11-15)
The FTM tremor rating scale was used for evaluation of tremor severity and function. This investigator-assessed scale consists of 3 parts (A, B and C). Part A: Tremor location/Severity rating (items 1-10); Part B: Specific motor tasks / Function rating (items 11-15). Ratings for five motor tasks (handwriting, drawing \[large/small spiral, line\], and pouring); and Part C: Functional disabilities resulting from tremor/activities of daily living (items 16-23). For this outcome measure, the sum of the five FTM motor performance items (from Part B) were used: item 11 ('handwriting for dominant hand only' - irrespective of its injection or non-injection), items 12 to 15 ('drawing large and small spiral', 'line drawing', 'pouring' for the injected upper limb). The score for each item ranges from 0 (normal) to 4 (severe). Possible values range for total FTM motor performance score: 0-20.
Time frame: Baseline up to Week 4
Population: The FAS was defined as the subset of participants who received study medication (incobotulinumtoxinA or placebo) at least once, and for whom a post-baseline value of any efficacy variable was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IncobotulinumtoxinA 30 to 200 U | Change From Baseline to Week 4 in FTM Motor Performance Score (Items 11-15) | -2.8 score on a scale | Standard Deviation 1.6 |
| Placebo | Change From Baseline to Week 4 in FTM Motor Performance Score (Items 11-15) | -0.8 score on a scale | Standard Deviation 2 |
Secondary
Change From Baseline to Week 4 in Maximum Log-transformed Accelerometric Tremor Amplitude at Wrist Level (Injected Limb)
TremorTek is a tremor kinematic analytics investigational device which is used to measure maximum log-transformed accelerometric tremor amplitude at wrist level of the injected limb (unit: meter per square second \[m/s˄2\]). Log-transformed accelerometric tremor amplitude is a measure of tremor severity reflecting the non-vectoral intensity of tremor. Reduction of log-transformed accelerometric tremor amplitude at wrist level of the injected limb represents a tremor improvement.
Time frame: Baseline up to Week 4
Population: The FAS was defined as the subset of participants who received study medication (incobotulinumtoxinA or placebo) at least once, and for whom a post-baseline value of any efficacy variable was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IncobotulinumtoxinA 30 to 200 U | Change From Baseline to Week 4 in Maximum Log-transformed Accelerometric Tremor Amplitude at Wrist Level (Injected Limb) | -0.73 log[m/s˄2] | Standard Deviation 0.63 |
| Placebo | Change From Baseline to Week 4 in Maximum Log-transformed Accelerometric Tremor Amplitude at Wrist Level (Injected Limb) | 0.05 log[m/s˄2] | Standard Deviation 0.38 |
Secondary
Investigator's Global Impression of Change Scale (GICS) at Week 4
The GICS was used to measure the investigator's impression of change due to treatment. The response option was a common 7-point Likert scale, with the following values: +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse).
Time frame: Week 4
Population: The FAS was defined as the subset of participants who received study medication (incobotulinumtoxinA or placebo) at least once, and for whom a post-baseline value of any efficacy variable was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IncobotulinumtoxinA 30 to 200 U | Investigator's Global Impression of Change Scale (GICS) at Week 4 | 0.8 score on a scale | Standard Deviation 0.7 |
| Placebo | Investigator's Global Impression of Change Scale (GICS) at Week 4 | 0.1 score on a scale | Standard Deviation 0.7 |
Secondary
Participant's Global Impression of Change Scale (GICS) at Week 4
The GICS was used to measure the participant's impression of change due to treatment. The response option was a common 7-point Likert scale, with the following values: +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse).
Time frame: Week 4
Population: The FAS was defined as the subset of participants who received study medication (incobotulinumtoxinA or placebo) at least once, and for whom a post-baseline value of any efficacy variable was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IncobotulinumtoxinA 30 to 200 U | Participant's Global Impression of Change Scale (GICS) at Week 4 | 0.6 score on a scale | Standard Deviation 0.6 |
| Placebo | Participant's Global Impression of Change Scale (GICS) at Week 4 | 0.3 score on a scale | Standard Deviation 0.6 |