Pretarsal Versus Preseptal Botulinum Toxin for Patients With Eyelid Spasm

Study Overview
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Brief Summary
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A triple-masked placebo-controlled trial assessing the efficacy and safety of pretarsal versus preseptal botulinum toxin for patients with eyelid spasm. The investigators hypothesize injection of botulinum toxin into the pretarsal orbicularis oculi muscle will have greater clinical efficacy, better measured quality of life, fewer complications, and better cost effectiveness in comparison to a preseptal pattern of injection.

Detailed Description
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The study design is a prospective, randomized, triple-blinded placebo controlled crossover trial. A computer-generated list of random numbers will be used for allocation of patients. The patients, treating physicians, and outcome assessors will be masked to the contents of the Botulinum Toxin Type A (BtA) and placebo syringe injections. The placebo will consist of vehicle only, which is the same sterile normal 0.9% saline used in reconstitution of the BtA. At month 6, each group will crossover and receive the alternative intervention. The primary outcome measure (JRS severity) will be the change as measured 1 month after the second cycle of each intervention. Secondary outcome measures include the TWSTRS (clinical response), Blepharospasm Disability Index (BSDI), CDQ-24 (quality of life), VAS (pain), and GAS (global) scores and incidence of side effects. The investigators plan to compare the outcome measures between groups with linear mixed models allowing for the crossover design. Data will be collected at each of the injection visits and at both of the clinical activity visits. The data will be processed by the research assistant and analysed by the project biostatistician. The investigators plan to compare the primary (JRS) and secondary outcome measures (TWSTRS, BSDI, CDQ-24, VAS, and GAS scores) between the Preseptal-pretarsal (Group 1) and the Pretarsal-preseptal (Group 2) allowing for the crossover design. Specifically, the investigators will use a 2-sample t-test to compare all values of the JRS in group 1 with all the values of the JRS in group 2. This will allow the investigators to determine whether carryover effects are present, and the investigators have specified a 3-month washout period between the first and second round of injections to minimise the chance of carryover effects. If carryover effects are present, the investigators will allow for these in further analysis. The investigators will then use linear mixed models to estimate the difference between the two interventions, allowing for the repeated measures, and if necessary for carryover effects. In secondary analyses, the investigators will evaluate the proportion of patients with relief of spasm, improvement in quality of life, and incidence of side effects, including eyelid ptosis measurements between the two interventions, using logistic regression. P values of 0.05 or less will be considered statistically significant. All analyses will be conducted under the principle of Intention to Treat, using multiple imputation to account for any missing data and to include all randomized patients in analysis.

Official Title
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Pretarsal Versus Preseptal Botulinum Toxin for Patients With Eyelid Spasm: a Randomized, Triple-blind, Placebo-controlled, Cross-over Clinical Trial

Conditions
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Blepharospasm, Hemifacial Spasm, Botulinum Toxins, Type A

Intervention / Treatment
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* Drug: Botulinum Toxin Type A 100Unit/Vial (Product)
* Drug: Saline Solution for Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients over 18 years-of-age Clinical diagnosis eyelid dystonia, consisting of either blepharospasm or hemifacial spasm Patient wish to have treatment with botulinum toxin type A (BtA). Exclusion Criteria: Patients unable to express their symptoms or history to the extent that they are not able to complete the study questionnaires, such as those suffering from dementia. Existence of potential contraindications to BtA treatment: Pregnancy Breastfeeding Prior allergic reaction Active infection or inflammation in the treatment area Neuromuscular and peripheral neuropathic disease Concomitant aminoglycoside therapy Patients with poor or unstable general health with activities of daily living severely affected by non-dystonia confounding factors, such as hospitalized or bed bound patients.

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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Preseptal-pretarsal<br>The Preseptal-pretarsal group will receive injections of Botulinum Toxin Type A 100Unit/Vial (Product) in the preseptal site (Injection pattern A) and Saline Solution for Injection (placebo control) in the pretarsal site for 2 cycles at 3 months apart. Both groups will crossover and receive the alternative intervention. Hence in the second half of the trial, the Preseptal-pretarsal group will be injected with BtA in Pattern B and Pretarsal-preseptal group will receive Pattern A. | Drug: Botulinum Toxin Type A 100Unit/Vial (Product)<br>* Botulinum Toxin Type A 100Unit/Vial (Product) comes as a dry powder and is routinely reconstituted with Saline Solution for Injection<br>* Other names: Botox;Drug: Saline Solution for Injection<br>* The placebo consists of vehicle only. Saline Solution for Injection is the vehicle substance normally used to reconstitute Botulinum Toxin Type A (see 1st Intervention above).<br>* Other names: Placebo;|
| Active Comparator: Pretarsal-preseptal<br>The Pretarsal-preseptal group will initially receive injections Botulinum Toxin Type A 100Unit/Vial (Product) in the reverse with the intervention at the pretarsal site (Injection pattern B) for 2 cycles at 3 months apart. Groups 1 and 2 will crossover and receive the alternative intervention. Both groups will crossover and receive the alternative intervention. Hence in the second half of the trial, the Preseptal-pretarsal group will be injected with BtA in Pattern B and Pretarsal-preseptal group will receive Pattern A. | Drug: Botulinum Toxin Type A 100Unit/Vial (Product)<br>* Botulinum Toxin Type A 100Unit/Vial (Product) comes as a dry powder and is routinely reconstituted with Saline Solution for Injection<br>* Other names: Botox;Drug: Saline Solution for Injection<br>* The placebo consists of vehicle only. Saline Solution for Injection is the vehicle substance normally used to reconstitute Botulinum Toxin Type A (see 1st Intervention above).<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Jankovic Rating Scale (JRS) | The severity of the patient's spasm employing the widely used JRS scale. The JRS is scored between 0 and 4 (0 = no spasm, 1 = mild, barely noticeable, 2 = mild, without functional impairment, 3 = moderate spasm, moderate functional impairment, 4 = severe incapacitating spasm). The JRS will be scored independently by two graders from a video clip of approximately 30-60 seconds in duration. Differences between the 2 scores will be arbitrated by a third reviewer. | The videos will be taken at the clinical activity visits (C1 and C2) will be scheduled for months 4 and 10. The primary outcome measure will consist of the change from C1 to C2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toronto (TWSTRS) | TWSTRS instrument measuring clinical response. Scored between -1 and 5 (-1 = worse, 0 = no benefit, 1 = minimal or equivocal reduction in spasm, 2 = mild response with some reduction in spasm, 3 = moderate response with some reduction in spasm, 4 = marked reduction of spasm but spasm still present, 5 = major improvement with little or no residual spasm). The change between the 2 clinical activity visits (C1-C2) will be assessed. | C1 and C2 will take place at months 4 and 10. | 
| Blepharospasm Disability Index (BSDI) | Measure of disability. The change between the 2 clinical activity visits (C1-C2) will be assessed. | C1 and C2 will take place at months 4 and 10. | 
| Craniocervical Dystonia Questionnaire (CDQ-24) | Measure of quality of life. The change between the 2 clinical activity visits (C1-C2) will be assessed. | C1 and C2 will take place at months 4 and 10. | 
| Global Assessment Scale (GAS) | To assess the overall status of the patient's disease. The GAS is determined by asking the patient the percentage of function the patient is experiencing. The analogue instrument ranges from Free of complaints on the left side to Suffering extremely on the right side of a line. Patients self-rate by marking where on the line best represents their current condition. The line measures 100 millimeters long. The mark is measured and the value recorded, ranging from 0 (Free of complaints) to 100 (Suffering extremely). Thus a lower value represents a better outcome. The change between the 2 clinical activity visits (C1-C2) will be assessed. | C1 and C2 will take place at months 4 and 10. | 
| Visual analogue scale (VAS) for pain | VAS (range 0-10, no pain = 0, unbearable pain = 0) will be used to assess. The change between the 2 clinical activity visits (C1-C2) will be assessed. patients' perception of pain for each of the 2 injections patterns | Measured at each injection visit (months 0, 3, 6, and 9). | 
| Ptosis monitoring | Specifically, cropped photographs of both eyelids will be analysed using ImageJ (National Institutes of Health, USA). The Margin-Reflex-Distance 1 (MRD1) measurements will be calculated using the ImageJ software's line tool to capture the height of the upper eyelid and evaluate and quantify the development of any ptosis complications. The change between the 2 clinical activity visits (C1-C2) will be assessed. | C1 and C2 will take place at months 4 and 10. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eyelid, Dystonia, Botulinum injection, Oculoplastics