Clinical trial NCT03508882: Pretarsal Versus Preseptal Botulinum Toxin for Patients With Eyelid Spasm
Official title: Pretarsal Versus Preseptal Botulinum Toxin for Patients With Eyelid Spasm: a Randomized, Triple-blind, Placebo-controlled, Cross-over Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Blepharospasm
Hemifacial Spasm
Botulinum Toxins, Type A
Keywords: Eyelid
Dystonia
Botulinum injection
Oculoplastics
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Food and Health Bureau, Hong Kong
First posted: 2018-04-26
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Jankovic Rating Scale (JRS)
timeFrame: 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 outcomes:
measure: Toronto (TWSTRS)
timeFrame: C1 and C2 will take place at months 4 and 10.
measure: Blepharospasm Disability Index (BSDI)
timeFrame: C1 and C2 will take place at months 4 and 10.
measure: Craniocervical Dystonia Questionnaire (CDQ-24)
timeFrame: C1 and C2 will take place at months 4 and 10.
measure: Global Assessment Scale (GAS)
timeFrame: C1 and C2 will take place at months 4 and 10.
measure: Visual analogue scale (VAS) for pain
timeFrame: Measured at each injection visit (months 0, 3, 6, and 9).
measure: Ptosis monitoring
timeFrame: C1 and C2 will take place at months 4 and 10.
Other outcomes:
Locations:
Study officials:
affiliation: The University of Hong Kong
name: Marcus M Marcet, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jankovic J. Blepharospasm with basal ganglia lesions. Arch Neurol. 1986 Sep;43(9):866-8. doi: 10.1001/archneur.1986.00520090006004. No abstract available.
citation: Dutton JJ, Fowler AM. Botulinum toxin in ophthalmology. Surv Ophthalmol. 2007 Jan-Feb;52(1):13-31. doi: 10.1016/j.survophthal.2006.10.003.
citation: Czyz CN, Burns JA, Petrie TP, Watkins JR, Cahill KV, Foster JA. Long-term botulinum toxin treatment of benign essential blepharospasm, hemifacial spasm, and Meige syndrome. Am J Ophthalmol. 2013 Jul;156(1):173-177.e2. doi: 10.1016/j.ajo.2013.02.001. Epub 2013 Mar 28.
citation: Harrison AR, Erickson JP, Anderson JS, Lee MS. Pain relief in patients receiving periocular botulinum toxin A. Ophthalmic Plast Reconstr Surg. 2008 Mar-Apr;24(2):113-6. doi: 10.1097/IOP.0b013e31816386e1.
citation: Hilker R, Schischniaschvili M, Ghaemi M, Jacobs A, Rudolf J. Health related quality of life is improved by botulinum neurotoxin type A in long term treated patients with focal dystonia. J Neurol Neurosurg Psychiatry. 2001 Aug;71(2):193-9. doi: 10.1136/jnnp.71.2.193.
citation: Muller J, Wissel J, Kemmler G, Voller B, Bodner T, Schneider A, Wenning GK, Poewe W. Craniocervical dystonia questionnaire (CDQ-24): development and validation of a disease-specific quality of life instrument. J Neurol Neurosurg Psychiatry. 2004 May;75(5):749-53. doi: 10.1136/jnnp.2003.013441.
citation: Hall TA, McGwin G Jr, Searcey K, Xie A, Hupp SL, Owsley C, Kline LB. Health-related quality of life and psychosocial characteristics of patients with benign essential blepharospasm. Arch Ophthalmol. 2006 Jan;124(1):116-9. doi: 10.1001/archopht.124.1.116.
citation: Jankovic J, Schwartz K, Donovan DT. Botulinum toxin treatment of cranial-cervical dystonia, spasmodic dysphonia, other focal dystonias and hemifacial spasm. J Neurol Neurosurg Psychiatry. 1990 Aug;53(8):633-9. doi: 10.1136/jnnp.53.8.633.
citation: Thenganatt MA, Fahn S. Botulinum toxin for the treatment of movement disorders. Curr Neurol Neurosci Rep. 2012 Aug;12(4):399-409. doi: 10.1007/s11910-012-0286-3.
citation: Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum toxin. J Am Acad Dermatol. 2000 Aug;43(2 Pt 1):249-59. doi: 10.1067/mjd.2000.105567.
citation: Harrison AR. Chemodenervation for facial dystonias and wrinkles. Curr Opin Ophthalmol. 2003 Oct;14(5):241-5. doi: 10.1097/00055735-200310000-00003.
citation: Costa J, Espirito-Santo C, Borges A, Ferreira JJ, Coelho M, Moore P, Sampaio C. Botulinum toxin type A therapy for blepharospasm. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD004900. doi: 10.1002/14651858.CD004900.pub2.
citation: Aramideh M, Ongerboer de Visser BW, Brans JW, Koelman JH, Speelman JD. Pretarsal application of botulinum toxin for treatment of blepharospasm. J Neurol Neurosurg Psychiatry. 1995 Sep;59(3):309-11. doi: 10.1136/jnnp.59.3.309.
citation: Jankovic J. Pretarsal injection of botulinum toxin for blepharospasm and apraxia of eyelid opening. J Neurol Neurosurg Psychiatry. 1996 Jun;60(6):704. doi: 10.1136/jnnp.60.6.704. No abstract available.
citation: Albanese A, Bentivoglio AR, Colosimo C, Galardi G, Maderna L, Tonali P. Pretarsal injections of botulinum toxin improve blepharospasm in previously unresponsive patients. J Neurol Neurosurg Psychiatry. 1996 Jun;60(6):693-4. doi: 10.1136/jnnp.60.6.693-a. No abstract available.
citation: Cakmur R, Ozturk V, Uzunel F, Donmez B, Idiman F. Comparison of preseptal and pretarsal injections of botulinum toxin in the treatment of blepharospasm and hemifacial spasm. J Neurol. 2002 Jan;249(1):64-8. doi: 10.1007/pl00007849.
citation: Albanese A, Sorbo FD, Comella C, Jinnah HA, Mink JW, Post B, Vidailhet M, Volkmann J, Warner TT, Leentjens AF, Martinez-Martin P, Stebbins GT, Goetz CG, Schrag A. Dystonia rating scales: critique and recommendations. Mov Disord. 2013 Jun 15;28(7):874-83. doi: 10.1002/mds.25579.
citation: Wabbels B, Jost WH, Roggenkamper P. Difficulties with differentiating botulinum toxin treatment effects in essential blepharospasm. J Neural Transm (Vienna). 2011 Jun;118(6):925-43. doi: 10.1007/s00702-010-0546-9. Epub 2011 Jan 9.
citation: Wabbels B, Roggenkamper P. Botulinum toxin in hemifacial spasm: the challenge to assess the effect of treatment. J Neural Transm (Vienna). 2012 Aug;119(8):963-80. doi: 10.1007/s00702-011-0762-y. Epub 2012 Jan 10.
citation: Sarifakioglu N, Sarifakioglu E. Evaluating effects of preservative-containing saline solution on pain perception during botulinum toxin type-a injections at different locations: a prospective, single-blinded, randomized controlled trial. Aesthetic Plast Surg. 2005 Mar-Apr;29(2):113-5. doi: 10.1007/s00266-004-0062-0. Epub 2005 Apr 14.
citation: Jankovic J, Kenney C, Grafe S, Goertelmeyer R, Comes G. Relationship between various clinical outcome assessments in patients with blepharospasm. Mov Disord. 2009 Feb 15;24(3):407-13. doi: 10.1002/mds.22368.
citation: Marcet MM, Lemke BN, Greenwald MJ, Fountain TR, Roth S, Dubovy SR. Eyelid eversion for visualisation of the upper eyelid lamellae: an anatomical cadaver study. Br J Ophthalmol. 2011 Oct;95(10):1376-8. doi: 10.1136/bjophthalmol-2011-300020. Epub 2011 Jul 11.
citation: Marcet MM, Meyer DR, Greenwald MJ, Roth S, Selva D. Proximal tarsal attachments of the levator aponeurosis: implications for blepharoptosis repair. Ophthalmology. 2013 Sep;120(9):1924-9. doi: 10.1016/j.ophtha.2013.02.012. Epub 2013 Apr 16.