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Pretarsal Versus Preseptal Botulinum Toxin for Patients With Eyelid Spasm

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ClinicalTrials.gov Identifier: NCT03508882
Recruitment Status : Completed
First Posted : April 26, 2018
Last Update Posted : April 26, 2019
Sponsor:
Collaborator:
Food and Health Bureau, Hong Kong
Information provided by (Responsible Party):
Marcus M. Marcet, MD, The University of Hong Kong

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Blepharospasm Hemifacial Spasm Botulinum Toxins, Type A Drug: Botulinum Toxin Type A 100Unit/Vial (Product) Drug: Saline Solution for Injection Phase 4

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Pretarsal Versus Preseptal Botulinum Toxin for Patients With Eyelid Spasm: a Randomized, Triple-blind, Placebo-controlled, Cross-over Clinical Trial
Actual Study Start Date : July 1, 2015
Actual Primary Completion Date : October 31, 2017
Actual Study Completion Date : February 20, 2019


Arm Intervention/treatment
Active Comparator: Preseptal-pretarsal
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)
Botulinum Toxin Type A 100Unit/Vial (Product) comes as a dry powder and is routinely reconstituted with Saline Solution for Injection
Other Name: Botox

Drug: Saline Solution for Injection
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).
Other Name: Placebo

Active Comparator: Pretarsal-preseptal
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)
Botulinum Toxin Type A 100Unit/Vial (Product) comes as a dry powder and is routinely reconstituted with Saline Solution for Injection
Other Name: Botox

Drug: Saline Solution for Injection
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).
Other Name: Placebo




Primary Outcome Measures :
  1. Jankovic Rating Scale (JRS) [ Time Frame: 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. ]
    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.


Secondary Outcome Measures :
  1. Toronto (TWSTRS) [ Time Frame: C1 and C2 will take place at months 4 and 10. ]
    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.

  2. Blepharospasm Disability Index (BSDI) [ Time Frame: C1 and C2 will take place at months 4 and 10. ]
    Measure of disability. The change between the 2 clinical activity visits (C1-C2) will be assessed.

  3. Craniocervical Dystonia Questionnaire (CDQ-24) [ Time Frame: C1 and C2 will take place at months 4 and 10. ]
    Measure of quality of life. The change between the 2 clinical activity visits (C1-C2) will be assessed.

  4. Global Assessment Scale (GAS) [ Time Frame: C1 and C2 will take place at months 4 and 10. ]

    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.


  5. Visual analogue scale (VAS) for pain [ Time Frame: Measured at each injection visit (months 0, 3, 6, and 9). ]

    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


  6. Ptosis monitoring [ Time Frame: C1 and C2 will take place at months 4 and 10. ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03508882


Sponsors and Collaborators
The University of Hong Kong
Food and Health Bureau, Hong Kong
Investigators
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Principal Investigator: Marcus M Marcet, MD The University of Hong Kong

Additional Information:
Publications:

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Responsible Party: Marcus M. Marcet, MD, Honorary Clinical Assistant Professor, The University of Hong Kong
ClinicalTrials.gov Identifier: NCT03508882     History of Changes
Other Study ID Numbers: HMRF Project No.: 12133171
Protocol : MMBT; v1.3;1Mar16 ( Other Identifier: HKU )
First Posted: April 26, 2018    Key Record Dates
Last Update Posted: April 26, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Marcus M. Marcet, MD, The University of Hong Kong:
Eyelid
Dystonia
Botulinum injection
Oculoplastics

Additional relevant MeSH terms:
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Hemifacial Spasm
Spasm
Blepharospasm
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Eyelid Diseases
Eye Diseases
Mouth Diseases
Stomatognathic Diseases
Pharmaceutical Solutions
Botulinum Toxins
Botulinum Toxins, Type A
abobotulinumtoxinA
Acetylcholine Release Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Neuromuscular Agents
Peripheral Nervous System Agents