Comparative Efficacy of Three Preparations of Botox-A in Treating Spasticity

Study Overview
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Brief Summary
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The study seeks to compare the effectiveness of three preparations of BOTOX-A® in treating muscle tightness and spasms in the feet and ankles of people with stroke.

Detailed Description
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Spasticity is one of the most debilitating complications of neurologic conditions, such as stroke, brain injury, spinal cord injury, cerebral palsy, and multiple sclerosis. Although the exact pathophysiology is unknown, it is believed to result from an imbalance of ascending excitatory influences on and descending inhibitory components of the central nervous system. Clinically, spasticity manifests as abnormally increased muscle tone, associated with loss of range of motion, increased muscle stretch reflexes, clonus, weakness, and incoordination. If inadequately treated, spasticity leads to more disability and increase health care costs. Common complications of inadequately treated spasticity include joint and muscle contracture, pain, difficulty with performing activities of daily living and hygiene, and impaired transfers and ambulation. Acquired brain injuries (ABI), including stroke, traumatic brain injury, and encephalopathy, often lead to long-term impairments, including spasticity. In severe cases, spasticity is difficult and frustrating to treat in this patient population, since the individuals may not tolerate the side effects of conventional therapies because of ABI-related deficits in arousal and cognition. Systemic medications, such as baclofen and tizanidine, are effective in controlling spasticity; however, they may also cause sleepiness and drowsiness, and impair memory and thinking processes---adverse effects that individuals with ABI may not tolerate. Thus, local treatments, such as neurolysis and chemodenervation using botulinum toxin, have become superior treatment options in individuals with ABI, since they are devoid of the usual side effects of systemic medications. They are also effective in controlling spasticity, yet they do not impair arousal and cognition. The medical literature is replete with reports of the efficacy of botulinum toxin-A in the management of spasticity. Thus, the current challenge for clinicians and researchers at this time is to find ways to further enhance the efficacy of botulinum toxin. One way to achieve this is by exploiting certain properties of the toxin. Animal studies and clinical experience have shown that the effects of the drug is dose-dependent. One other property is the flexibility in preparing the volume of drug injected. Since botulinum toxin, as it is currently available (as BOTOX-A®) in the United States, requires reconstitution with preservative-free saline, there is flexibility for clinicians to manipulate the volume of solution that will be administered, without altering the dose. We recently completed a trial comparing the effects of two volume preparations of BOTOX-A® on wrist and finger flexor spasticity of individuals with ABI. One group of patients received BOTOX-A® prepared as 100 units/cc, while another received BOTOX-A® prepared as 50 units/cc. Although there was no statistically significant difference between the two groups, there was a trend in favor of the group that received the higher volume, i.e.; they appeared to improve more based on decrease in muscle tone (measured by the Modified Ashworth Scale). This was compared by the clinician's global impression that the high volume group improved more. The latter measure achieved statistical significance. One possible reason for the absence of statistical significance was that the high volume (50 units/cc) was not high enough. Thus, we are proposing this study to investigate the comparative effects of three preparations of BOTOX-A®.

Official Title
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Comparative Efficacy of Three Preparations of Botox-A in Treating Spasticity

Conditions
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Stroke, Brain Injuries, Spasticity

Intervention / Treatment
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* Drug: Botox


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - Spasticity resulting from ABI (stroke, including vascular malformations, traumatic brain injury) Ashworth Score (resting) of at least 2 of the primary ankle plantarflexor (gastrocnemius) Onset of primary illness at least six months prior to study inclusion At least 12 years of age Exclusion Criteria - Hypersensitivity or allergy to botulinum toxin History of myasthenia gravis or other neuromuscular disease Current use of aminoglycosides Botulinum toxin or phenol injection to study limb within six months prior to recruitment Current use of other spasmolytic drug, such as diazepam, baclofen, dantrolene, tizanidine Presence of contracture or significant muscle atrophy Pregnancy

Ages Eligible for Study
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Minimum Age: 12 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 |
| --- | --- |
| Experimental: 1 - Low Volume, High Dose<br>Botox (onabotulinumtoxinA), 150 units prepared as 100 units per 1 ml of preservative-free normal saline | Drug: Botox<br>* Botox 75-150 units, single treatment only<br>* Other names: generic name: botulinum toxin type A;|
| Active Comparator: 2 - High Volume, High Dose<br>Botox (onabotulinumtoxinA), 150 units prepared as 50 units per 1 ml of preservative-free normal saline | Drug: Botox<br>* Botox 75-150 units, single treatment only<br>* Other names: generic name: botulinum toxin type A;|
| Other: 3 - High Volume, Low Dose<br>Botox (onabotulinumtoxinA), 75 units prepared as 25 units per 1 ml of preservative-free normal saline | Drug: Botox<br>* Botox 75-150 units, single treatment only<br>* Other names: generic name: botulinum toxin type A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spastic Hypertonia as Measured by the Ashworth Scale | The Ashworth Scale measures resistance during passive soft-tissue stretching and is used as a simple measure of spasticity. Score on the Ashworth scores ranges from 0-4, with 4 being the worst: 0 - No increase in muscle tone - Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion when the affected part(s) is moved in flexion or extension - More marked increase in muscle tone through most of the range of motion, but affected limb easily flexed - Considerable increase in muscle tone, passive movement difficult - Limb in flexion or extension | Baseline | 
| Spastic Hypertonia as Measured by the Ashworth Scale | The Ashworth Scale measures resistance during passive soft-tissue stretching and is used as a simple measure of spasticity. Score on the Ashworth scores ranges from 0-4, with 4 being the worst: 0: No increase in muscle tone Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion when the affected part(s) is moved in flexion or extension More marked increase in muscle tone through most of the range of motion, but affected limb easily flexed Considerable increase in muscle tone, passive movement difficult Limb in flexion or extension | Four weeks | 
| Spastic Hypertonia as Measured by the Ashworth Scale | The Ashworth Scale measures resistance during passive soft-tissue stretching and is used as a simple measure of spasticity. Score on the Ashworth scores ranges from 0-4, with 4 being the worst: 0: No increase in muscle tone Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion when the affected part(s) is moved in flexion or extension More marked increase in muscle tone through most of the range of motion, but affected limb easily flexed Considerable increase in muscle tone, passive movement difficult Limb in flexion or extension | Eight Weeks | 
| Spastic Hypertonia as Measured by the Ashworth Scale | The Ashworth Scale measures resistance during passive soft-tissue stretching and is used as a simple measure of spasticity. Score on the Ashworth scores ranges from 0-4, with 4 being the worst: 0: No increase in muscle tone Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion when the affected part(s) is moved in flexion or extension More marked increase in muscle tone through most of the range of motion, but affected limb easily flexed Considerable increase in muscle tone, passive movement difficult Limb in flexion or extension | Twelve Weeks | 
| Spastic Hypertonia as Measured by the Ashworth Scale | The Ashworth Scale measures resistance during passive soft-tissue stretching and is used as a simple measure of spasticity. Score on the Ashworth scores ranges from 0-4, with 4 being the worst: 0: No increase in muscle tone Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion when the affected part(s) is moved in flexion or extension More marked increase in muscle tone through most of the range of motion, but affected limb easily flexed Considerable increase in muscle tone, passive movement difficult Limb in flexion or extension | Sixteen Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Range of Motion as Measured by Goniometry | This outcome reports the angle formed during ankle dorsiflexion by an imaginary line drawn on the outer side of the leg with an imaginary line drawn on the outside of the foot. The angle changes as the ankle is curled up (dorsiflexed) or down (plantarflexed). Many people with stroke develop muscle tightness (a condition called spasticity) or contracture, which leads to ankle plantarflexion and results in a foot drop appearance and limits range of motion. When the ankle is neutral and the foot is flat, the angle between the leg and the foot is roughly a right angle, and this neutral position is indicated as 0 degrees from the neutral position. If the foot is below the neutral position during maximum ankle dorsiflexion, then the angle reported is the number of degrees below the neutral position (reported as a negative value). If the foot is above the neutral position, then the angle reported is the number of degrees above the neutral position (positive value). | Baseline | 
| Range of Motion as Measured by Goniometry | This outcome reports the angle formed during ankle dorsiflexion by an imaginary line drawn on the outer side of the leg with an imaginary line drawn on the outside of the foot. The angle changes as the ankle is curled up (dorsiflexed) or down (plantarflexed). Many people with stroke develop muscle tightness (a condition called spasticity) or contracture, which leads to ankle plantarflexion and results in a foot drop appearance and limits range of motion. When the ankle is neutral and the foot is flat, the angle between the leg and the foot is roughly a right angle, and this neutral position is indicated as 0 degrees from the neutral position. If the foot is below the neutral position during maximum ankle dorsiflexion, then the angle reported is the number of degrees below the neutral position (reported as a negative value). If the foot is above the neutral position, then the angle reported is the number of degrees above the neutral position (positive value). | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke, Brain Injuries, Spasticity, Botulinum Toxins