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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 200 Units incobotulinumtoxinA (Xeomin) | Experimental | Single injection cycle, total dose of up to 200 Units, intramuscular injection into muscles of wrist (mandatory) and shoulder and/or elbow (both optional). |
|
| Placebo | Placebo Comparator | Single injection cycle, intramuscular injection into muscles of wrist (mandatory) and shoulder and/or elbow (both optional). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IncobotulinumtoxinA | Drug | 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). |
| 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 |
| 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. |
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Main Inclusion Criteria:
Diagnosis of 'definite essential tremor' in accordance with modified TRIG criteria, as follows:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Merz Medical Expert | Merz Pharmaceuticals GmbH | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Merz Investigational Site #0010191 | New York | New York | 10029 | United States | ||
| Merz Investigational Site #0010317 |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33419261 | Result | Jog M, Lee J, Scheschonka A, Chen R, Ismail F, Boulias C, Hobson D, King D, Althaus M, Simon O, Dersch H, Frucht S, Simpson DM. Tolerability and Efficacy of Customized IncobotulinumtoxinA Injections for Essential Tremor: A Randomized, Double-Blind, Placebo-Controlled Study. Toxins (Basel). 2020 Dec 20;12(12):807. doi: 10.3390/toxins12120807. |
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A total of 52 participants were screened, out of which 30 participants were randomized and treated.
The multicenter study was conducted at 6 investigational sites in the United States and Canada.
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| ID | Title | Description |
|---|---|---|
| FG000 | IncobotulinumtoxinA 30 to 200 Units | Participants received incobotulinumtoxinA (also known as NT 201) between 30 to 200 units (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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The safety evaluation set (SES) was the subset of all participants who received study medication (incobotulinumtoxinA or placebo) at least once.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Mean | Standard Deviation | degree | Baseline up to Week 4 |
|
From screening up to Week 24
The investigator asked the participant for adverse events (AEs) systematically at each visit.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Influenza like illness | General disorders | MedDRA (19.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper respiratory tract infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Public Disclosure Manager | Merz Pharmaceuticals GmbH | +49 69 1503 1 | clinicaltrials@merz.com |
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| ID | Term |
|---|---|
| C545476 | incobotulinumtoxinA |
| D019274 | Botulinum Toxins, Type A |
| ID | Term |
|---|---|
| D001905 | Botulinum Toxins |
| D008666 | Metalloendopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
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|
| Placebo | Drug | Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl). |
|
| 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 |
| Winnipeg |
| Manitoba |
| R3J2H7 |
| Canada |
| Merz Investigational Site #0010089 | Halifax | Nova Scotia | B3P 1M3 | Canada |
| Merz Investigational Site #0010078 | Toronto | Ontario | M5T 2S8 | Canada |
| Merz Investigational Site #0010305/1 | Toronto | Ontario | M6M 2J5 | Canada |
| Merz Investigational Site #0010305/2 | Toronto | Ontario | M6M 2J5 | Canada |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
Participants received incobotulinumtoxinA (also known as NT 201) between 30 to 200 units (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.
| OG001 | 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. |
|
|
|
| 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. | 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. | Posted | Mean | Standard Deviation | log[m/s˄2] | Baseline up to Week 4 |
|
|
|
| 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Baseline up to Week 4 |
|
|
|
| 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. | 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. | Posted | Mean | Standard Deviation | score on a scale | Baseline up to Week 4 |
|
|
|
| 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). | 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. | Posted | Mean | Standard Deviation | score on a scale | Week 4 |
|
|
|
| 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). | 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. | Posted | Mean | Standard Deviation | score on a scale | Week 4 |
|
|
|
| 0 |
| 19 |
| 0 |
| 19 |
| 9 |
| 19 |
| EG001 | 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. | 0 | 11 | 2 | 11 | 6 | 11 |
| Chest discomfort | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Cystitis | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Eyelid infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Genital infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Nail infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Tooth infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Appendicitis | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Exostosis | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Arthritis | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
|
| Ankle fracture | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
|
| Head injury | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
|
| Joint injury | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA (19.0) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Glaucoma | Eye disorders | MedDRA (19.0) | Systematic Assessment |
|
| Injection site bruising | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Injection site pain | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA (19.0) | Systematic Assessment |
|
| Blood cholesterol increased | Investigations | MedDRA (19.0) | Systematic Assessment |
|
| Diabetes mellitus | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
|
| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hypoaesthesia | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
|
| Breast mass | Reproductive system and breast disorders | MedDRA (19.0) | Systematic Assessment |
|
Publication of study information usually requires agreement with the sponsor. In case of justified doubts by the sponsor, the INVESTIGATOR will consider these doubts in the publication as long as the scientific neutrality is not affected.
| D006867 |
| Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D045726 | Metalloproteases |
| D001426 | Bacterial Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001427 | Bacterial Toxins |
| D014118 | Toxins, Biological |
| D001685 | Biological Factors |