Botulinum Toxin A to Treat Arm Tremor

Study Overview
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Brief Summary
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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.

Official Title
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Prospective, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of the Efficacy and Safety of NT 201 in the Unilateral Treatment of Essential Tremor of the Upper Limb

Conditions
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Essential Tremor of the Upper Limbs

Intervention / Treatment
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* Drug: IncobotulinumtoxinA
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 200 Units incobotulinumtoxinA (Xeomin)<br>Single injection cycle, total dose of up to 200 Units, intramuscular injection into muscles of wrist (mandatory) and shoulder and/or elbow (both optional). | Drug: IncobotulinumtoxinA<br>* 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).<br>* Other names: Botulinum toxin type A (150 kiloDalton), free from complexing proteins;|
| Placebo Comparator: Placebo<br>Single injection cycle, intramuscular injection into muscles of wrist (mandatory) and shoulder and/or elbow (both optional). | Drug: Placebo<br>* Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to Week 4 | 
| 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. | Baseline up to Week 4 | 
| 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. | Baseline up to Week 4 | 
| 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). | Week 4 | 
| 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). | Week 4 |