Pretarsal Versus Preseptal Botulinum Toxin for Patients With Eyelid Spasm

Phase 4

Completed

• Conditions: Blepharospasm; Hemifacial Spasm; Botulinum Toxins, Type A
• Interventions: Drug: Botulinum Toxin Type A 100Unit/Vial (Product); Drug: Saline Solution for Injection

• Registration Number: NCT03508882
• Lead Sponsor: 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.

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.

Study Timeline

• Study Start: 2015-07-01
• Primary Completion: 2017-10-31
• Study First Submitted: 2018-03-18
• Study First Submitted QC: 2018-04-24
• Study First Posted: 2018-04-26
• Study Completion: 2019-02-20
• Status Verified: 2019-04
• Last Update Submitted: 2019-04-25
• Last Update Posted: 2019-04-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 100

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Preseptal-pretarsal	Botulinum Toxin Type A 100Unit/Vial (Product)	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.
Preseptal-pretarsal	Saline Solution for Injection	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.
Pretarsal-preseptal	Botulinum Toxin Type A 100Unit/Vial (Product)	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.
Pretarsal-preseptal	Saline Solution for Injection	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.

Primary Outcome Measures

Name	Time	Method
Jankovic Rating Scale (JRS)	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

Name	Time	Method
Visual analogue scale (VAS) for pain	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
Toronto (TWSTRS)	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.
Blepharospasm Disability Index (BSDI)	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.
Craniocervical Dystonia Questionnaire (CDQ-24)	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.
Global Assessment Scale (GAS)	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.
Ptosis monitoring	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.