Open-Label Non-Inferiority Study Evaluating the Efficacy and Safety of Xeomin® in Subjects With Cervical Dystonia Flex

Study Overview
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Brief Summary
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This study will compare Xeomin®, a botulinum toxin medication, in shorter treatment intervals (Short Flex dosing) to the standard interval dosing (Long Flex dosing) to determine if the response to treatment is comparable in both how it works and any side effects. Xeomin® is approved by the United States Food and Drug Administration (FDA) for the treatment of cervical dystonia (CD). The use of Xeomin® is investigational in regards to shorter treatment intervals. An investigational use is one that is not approved by the FDA.

Detailed Description
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Dystonia is a movement disorder which is characterized by sustained, involuntary muscle contractions which frequently causes twisting and repetitive movements or abnormal postures of the trunk, neck, face, or arms and legs. In focal dystonia, the abnormal movements involve a single area of the body. A commonly described form of focal dystonia is cervical dystonia (CD). Botulinum toxin treatment can be offered as a treatment option for the treatment of CD. The current practice for botulinum toxin injection treatment is to inject patients every 3 months. However, not all patients receive continuing benefit from botulinum toxin injections for an entire 3 months. In a recent survey, approximately 45% of patients report that they would prefer a treatment cycle of less than 10 weeks.This study will compare Xeomin®, a botulinum toxin treatment, in shorter treatment intervals (Short Flex dosing) to the standard interval dosing (Long Flex dosing) to determine if the response to treatment is comparable in both how it works and any side effects. Xeomin® is approved by the United States Food and Drug Administration (FDA) for the treatment of CD. The use of Xeomin® is investigational in regards to shorter treatment intervals. An investigational use is one that is not approved by the FDA. The purpose of this research study is to evaluate the efficacy of the Short Flex dosing of Xeomin® compared to the Long Flex dosing regimen of Xeomin®, using a standard scale completed by the doctors and subjects as well as questionnaires that ask subjects to rate symptoms of CD.

Official Title
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An Open-Label, Non-Inferiority Study Evaluating the Efficacy and Safety of Two Injection Schedules of Xeomin® (incobotulinumtoxinA) [Short Flex Versus Long Flex] in Subjects With Cervical Dystonia With < 10 Weeks of Benefit From OnabotulinumtoxinA Treatment

Conditions
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Cervical Dystonia

Intervention / Treatment
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* Biological: Xeomin®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented clinical diagnosis of idiopathic or genetic Cervical Dystonia Exclusion Criteria: Current treatment with botulinum toxin of any type for any other indication (including aesthetic indications) and for any body region during the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 81 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Xeomin® Short Flex<br>short flex dosing of Xeomin. It is a botulinum toxin type A produced from fermentation of Hall strain Clostridium botulinum serotype A. | Biological: Xeomin®<br>* Xeomin is botulinum toxin type A produced from fermentation of Hall strain Clostridium botulinum serotype A<br>* Other names: botulinum toxin type A;|
| Active Comparator: Xeomin® Long Flex<br>long flex dosing of Xeomin. It is a botulinum toxin type A produced from fermentation of Hall strain Clostridium botulinum serotype A. | Biological: Xeomin®<br>* Xeomin is botulinum toxin type A produced from fermentation of Hall strain Clostridium botulinum serotype A<br>* Other names: botulinum toxin type A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Subscale Score Based on Blinded Rater Assessment at Week 4 After the 8th Injection | The validated assessment scale TWSTRS was used to measure the impact of cervical dystonia (CD) on participants. A blinded rater performed all TWSTRS-Severity subscale assessments for a given participant. TWSTRS-Severity subscale score ranges from 0 (=absence of severity) to 35 points (=maximum severity). | Baseline and Week 4 after the 8th injection (Week 44 to 68 for Short Flex and Week 84 to 104 for Long Flex) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in TWSTRS Total Score Based on Blinded Rater Assessment at Week 4 After the 8th Injection | The validated assessment scale TWSTRS was used to measure the impact of CD on participants. The scale comprised of 3 subscales: Severity, Disability, and Pain, each of which was scored independently. A blinded rater performed all TWSTRS assessments for a given participant. TWSTRS-Severity subscale score ranges from 0 (=absence of severity) to 35 points (=maximum severity); TWSTRS-Disability subscale score ranges from 0 (no disability) to 30 (maximum disability); and TWSTRS-Pain subscale score ranges from 0 (no pain) to 20 (maximum pain). The total of these 3 comprises the TWSTRS total score which is scored from 0 (no symptoms) to 85 (worst symptoms). Higher scores indicate a greater impact of CD on participant. | Baseline and Week 4 after the 8th injection (Week 44 to 68 for Short Flex and Week 84 to 104 for Long Flex) | 
| Change From Baseline in TWSTRS Total Score Based on Unblinded Rater Assessment at Week 4 After the 8th Injection | The validated assessment scale TWSTRS was used to measure the impact of CD on participant. The scale comprised of 3 subscales: Severity, Disability, and Pain, each of which was scored independently. An unblinded rater performed all TWSTRS assessments for a given participant. TWSTRS-Severity subscale score ranges from 0 (=absence of severity) to 35 points (=maximum severity); TWSTRS-Disability subscale score ranges from 0 (no disability) to 30 (maximum disability); and TWSTRS-Pain subscale score ranges from 0 (no pain) to 20 (maximum pain). The total of these 3 comprises the TWSTRS total score which is scored from 0 (least symptoms) to 85 (worst symptoms). Higher scores indicate a greater impact of CD on participant. | Baseline and Week 4 after the 8th injection (Week 44 to 68 for Short Flex and Week 84 to 104 for Long Flex) | 
| Change From Baseline in TWSTRS Severity Subscale Based on Unblinded Rater Assessment at Week 4 After the 8th Injection | The validated assessment scale TWSTRS was used to measure the impact of cervical dystonia (CD) on participants. An unblinded rater performed all TWSTRS-Severity subscale assessments for a given participant. TWSTRS-Severity score ranges from 0 (absence of severity) to 35 (maximum severity). | Baseline and Week 4 after the 8th injection (Week 44 to 68 for Short Flex and Week 84 to 104 for Long Flex) | 
| Change From Baseline in TWSTRS Disability Subscale Based on Unblinded Rater Assessment at Week 4 After the 8th Injection | The validated assessment scale TWSTRS was used to measure the impact of CD on participant. An unblinded rater performed all TWSTRS-Disability subscale assessments for a given participant. TWSTRS-Disability score ranges from 0 (no disability) to 30 (maximum disability). | Baseline and Week 4 after the 8th injection (Week 44 to 68 for Short Flex and Week 84 to 104 for Long Flex) | 
| Change From Baseline in TWSTRS Pain Subscale Based on Unblinded Rater Assessment at Week 4 After the 8th Injection | The validated assessment scale TWSTRS was used to measure the impact of CD on participants. An unblinded rater performed all TWSTRS-Pain subscale assessments for a given participant. TWSTRS-Pain score ranges from 0 (no pain) to 20 (maximum pain). | Baseline and Week 4 after the 8th injection (Week 44 to 68 for Short Flex and Week 84 to 104 for Long Flex) | 
| Change From Control Visit Week 4 After First Injection in Investigator-Rated Global Response at Week 4 After the 8th Injection | The Investigator-Rated Global Response assessment for each Xeomin treatment was scored using a 9-point scale with a score ranging from -4 to +4 as follows: -4 (very marked worsening); -3 (marked worsening); -2 (moderately worsening); 1 (minimally worsening); 0 (no change); +1 (minimally improved); +2 (moderately improved); +3 (significantly improved); +4 (complete abolishment of signs and symptoms). | Week 4 and Week 4 after the 8th injection (Week 44 to 68 for Short Flex and Week 84 to 104 for Long Flex) | 
| Change From Control Visit Week 4 After First Injection in Subject-Rated Global Response at Week 4 After the 8th Injection | The Subject-Rated Global Response assessment for each Xeomin treatment was scored using a 9-point scale with a score ranging from -4 to +4 as follows: -4 (very marked worsening); -3 (marked worsening); -2 (moderately worsening); 1 (minimally worsening); 0 (no change); +1 (minimally improved); +2 (moderately improved); +3 (significantly improved); +4 (complete abolishment of signs and symptoms). | Week 4 and Week 4 after the 8th injection (Week 44 to 68 for Short Flex and Week 84 to 104 for Long Flex) | 
| Change From Control Visit Week 4 After First Injection in Subject Satisfaction Score at Week 4 After the 8th Injection | The Subject Satisfaction assessment for each Xeomin treatment was scored using a 10-point scale to answer the question, How satisfied are you at the moment with your current therapy? Score ranges from: 1 (completely satisfied) to 10 (completely unsatisfied). | Week 4 and Week 4 after the 8th injection (Week 44 to 68 for Short Flex and Week 84 to 104 for Long Flex) | 
| Change From Baseline in Clinical Global Impression-Severity | Assessment of Clinical Global Impression Severity was scored using a 7-point scale for severity of illness, in response to the question, Considering your total clinical experience with this particular population, how ill is the participant at this time? With scores as: 0 (not assessed); 1 (normal, not ill at all); 2 (borderline ill); 3 (mildly ill); 4 (moderately ill); 5 (markedly ill); 6 (severely ill); and 7 (among the most extremely ill participants). | Baseline and 8th injection (Week 44 for Short Flex and Week 84 for Long Flex) | 
| Change From Baseline in Cervical Dystonia Impact Profile-58 (CDIP-58) Total Score at Week 4 After the 8th Injection | The CDIP-58 assesses the health impact of CD. The CDIP-58 is composed of eight domains: head and neck (6 items; 6 to 30 points), pain and discomfort (5 items; 5 to 25 points), upper limb activities (9 items; 9 to 45 points), walking (9 items; 9 to 45 points), sleep (4 items; 4 to 20 points), annoyance (8 items; 8 to 40 points), mood (7 items; 7 to 35 points), and psychosocial functioning (10 items; 10 to 50 points). Subscale scores were transformed to a common theoretical range of 0 (no impact) to 100 (most impact). Transformation to a 0 to 100 scale for the sum scores of the sub- and total scales were done using the following formula (all single items have scores from 1 to 5): S0 to 100 =25 * ([ SO / NI] - 1), S0 to 100 = transformed sum score. SO = sum score of the original sub- / total scale. NI = number of items in the sub- / total scale. Negative changes from the baseline total score indicate improvement in the impact of CD on health whereas positive changes indicate worsening. | Baseline and Week 4 after the 8th injection (Week 44 to 68 for Short Flex and Week 84 to 104 for Long Flex) | 
| Change From Baseline in CDIP-58 Subscales' Scores at Week 4 After the 8th Injection | The CDIP-58 assesses the health impact of CD. The CDIP-58 is composed of eight domains: head and neck (6 items; 6 to 30 points), pain and discomfort (5 items; 5 to 25 points), upper limb activities (9 items; 9 to 45 points), walking (9 items; 9 to 45 points), sleep (4 items; 4 to 20 points), annoyance (8 items; 8 to 40 points), mood (7 items; 7 to 35 points), and psychosocial functioning (10 items; 10 to 50 points). Subscale scores were transformed to a common theoretical range of 0 (no impact) to 100 (most impact). Negative changes from the baseline scores indicate improvement in the impact of CD on health whereas positive changes indicate worsening. | Baseline and Week 4 after the 8th injection (Week 44 to 68 for Short Flex and Week 84 to 104 for Long Flex) | 
| Time to Offset of Xeomin Effects by Injection Cycle | The Offset Questionnaire was a single question: On most days last week, have you noticed that your CD symptoms are better, worse or the same as the week prior? Time to offset of effect was calculated from date of first onset of effect to date of offset of effects. | Week 4 up to Week 112 |