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Kim, Chung, Kim, Paik, Kim, La, Son, Ahn, Yang, Woo, Lew, Yoon, Lee, Lee, Lee, Jang, Choung, Chi, and Yang: Efficacy and Safety of Letibotulinum Toxin A for the Treatment of Essential Blepharospasm
Original Article

J Korean Ophthalmol Soc 2020;61(3):227-234.

Published online: 25 September 2020

DOI: https://doi.org/10.3341/jkos.2020.61.3.227

Efficacy and Safety of Letibotulinum Toxin A for the Treatment of Essential Blepharospasm

Ji Hyun Kim, MD1, Doh Hoon Chung, MD1, Sung Eun Kim, MD1, Ji-Sun Paik, MD, PhD1, Namju Kim, MD, PhD2, Tae Yoon La, MD, PhD3, Jun Hyuk Son, MD, PhD4, Hee Bae Ahn, MD, PhD5, Jae Wook Yang, MD, PhD6, Kyung In Woo, MD, PhD7, Helen Lew, MD, PhD8, Jin Sook Yoon, MD, PhD9, Sang Un Lee, MD, PhD10, Sung Bok Lee, MD, PhD11, Jeong Kyu Lee, MD, PhD12, Jae Woo Jang, MD, PhD13, Ho Kyung Choung, MD, PhD14, Mijung Chi, MD, PhD15, Suk-Woo Yang, MD, PhD1

1Department of Ophthalmology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

2Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

3Department of Ophthalmology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea

4Department of Ophthalmology, Yeungnam University College of Medicine, Daegu, Korea

5Department of Ophthalmology, Dong-A University College of Medicine, Busan, Korea

6Department of Ophthalmology, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea

7Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

8Department of Ophthalmology, CHA Bundang Medical Center, CHA University, Seongnam, Korea

9Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea

10HanGil Eye Hospital, Incheon, Korea

11Department of Ophthalmology, Chungnam National University School of Medicine, Daejeon, Korea

12Department of Ophthalmology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea

13Myung-Gok Eye Research Institute, Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea

14Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea

15Department of Ophthalmology, Gachon University Gil Medical Center, Incheon, Korea

Address reprint requests to Suk-Woo Yang, MD, PhD Department of Ophthalmology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, #222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: 82-2-2258-2846, Fax: 82-2-599-7405 E-mail: yswoph@hanmail.net

Received 22 May 2019       Revised 19 August 2019       Accepted 21 February 2020

Copyright © 2020 Korean Ophthalmological Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

To evaluate the efficacy and safety of BOTULAX® in subjects with essential blepharospasm.

Methods

In this study, a total of 250 subjects with essential blepharospasm were enrolled at 15 investigational sites and a total of 220 subjects completed the study. The efficacy and safety were evaluated at weeks 4 and 16 after treatment compared with baseline. In total, 240 subjects were enrolled, treated with the investigational product, and evaluable for the primary efficacy assessment at week 4 after treatment; these subjects were included in the intention-to-treat (ITT) population. With the ITT set as the main efficacy set, efficacy assessment included Jankovic rating scale (JRS), functional disability score, investigator evaluation of global response and quality of life. Safety assessment including the incidence of adverse events was also performed.

Results

In terms of the primary efficacy endpoint (i.e., change in JRS total score at week 4 after treatment from baseline [ITT set]), mean change indicated a statistically significant reduction (p < 0.0001) and demonstrated the non-inferiority of the test drug to similar drugs. In terms of the secondary efficacy endpoints, mean change in JRS total score at week 16 after treatment and mean change in functional disability score at weeks 4 and 16 after treatment both exhibited a statistically significant reduction compared with baseline (p < 0.0001 for all). Among the 249 subjects treated with the investigational product in this study, 44 (17.67%) experienced 76 treatment emergent adverse events but no serious adverse events were observed.

Conclusions

Based on the study results, BOTULAX® is considered to be an effective and safe treatment for essential blepharospasm.

Keywords: BOTULAX®, Botulinum neurotoxin type A, Essential blepharospasm, Letibotulinum Toxin A

References

1. Hallett M, Evinger C, Jankovic J, et al. Update on blepharospasm: report from the BEBRF International Workshop. Neurology. 2008; 71:1275–82.
crossref
2. Daly K. Blepharospasm: an Australian survey. Int J Rehabil Res. 1997; 20:41–50.
3. Hunt T, Clarke K. Potency evaluation of a formulated drug product containing 150-kd botulinum neurotoxin type A. Clin Neuropharmacol. 2009; 32:28–31.
crossref
4. Pekmezovic T, Svetel M, Ivanovic N, et al. Quality of life in abdominals with focal dystonia. Clin Neurol Neurosurg. 2009; 111:161–4.
5. Tarsy D, Simon DK. Dystonia. N Engl J Med. 2006; 355:818–29.
crossref
6. Truong DD, Jost WH. Botulinum toxin: clinical use. Parkinsonism Relat Disord. 2006; 12:331–55.
crossref
7. Jankovic J, Comella C, Hanschmann A, Grafe S. Efficacy and safety of incobotulinumtoxinA (NT 201, Xeomin) in the treatment of blepharospasm-a randomized trial. Mov Disord. 2011; 26:1521–8.
crossref
8. Jankovic J, Orman J. Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology. 1987; 37:616–23.
crossref
9. Roggenkämper P, Jost WH, Bihari K, et al. Efficacy and safety of a new Botulinum Toxin Type A free of complexing proteins in the treatment of blepharospasm. J Neural Transm (Vienna). 2006; 113:303–12.
crossref
10. Truong D, Comella C, Fernandez HH, et al. Efficacy and safety of purified botulinum toxin type A (Dysport) for the treatment of abdominal essential blepharospasm: a randomized, placebo-controlled, phase II trial. Parkinsonism Relat Disord. 2008; 14:407–14.
11. Jost WH, Kohl A. Botulinum toxin: evidence-based medicine criteria in blepharospasm and hemifacial spasm. J Neurol. 2001; 248(Suppl 1):21–4.
crossref
12. Lee JH, Jung SK, Baik JS, Yang SW. Comparative study of Hugel-tox (R) versus Botox (R) for the treatment of essential blepharospasm. J Korean Ophthalmol Soc. 2015; 56:811–4.
13. Iwashige H, Nemeto Y, Takahashi H, Maruo T. Botulinum toxin type A purified neurotoxin complex for the treatment of blepharospasm: a dose-response study measuring eyelid force. Jpn J Ophthalmol. 1995; 39:424–31.
14. Truong DD, Gollomp SM, Jankovic J, et al. Sustained efficacy and safety of repeated incobotulinumtoxinA (Xeomin([R]) injections in blepharospasm. J Neural Transm (Vienna). 2013; 120:1345–53.
15. Jankovic J, Kenney C, Grafe S, et al. Relationship between various clinical outcome assessments in patients with blepharospasm. Mov Disord. 2009; 24:407–13.
crossref
16. Grivet D, Robert PY, Thuret G, et al. Assessment of blepharospasm surgery using an improved disability scale: study of 138 patients. Ophthalmic Plast Reconstr Surg. 2005; 21:230–4.
crossref
17. Shin JH, Jeon C, Woo KI, Kim YD. Clinical comparability of dys-port and botox in essential blepharospasm. J Korean Ophthalmol Soc. 2009; 50:331–5.
crossref
18. Min SK, Kim KI, Lee CI, et al. Development of the Korean versions of WHO Quality of Life scale and WHOQOL-BREF. Qual Life Res. 2002; 11:593–600.
19. Wabbels B, Reichel G, Fulford-Smith A, et al. Double-blind, randomised, parallel group pilot study comparing two botulinum toxin type A products for the treatment of blepharospasm. J Neural Transm (Vienna). 2011; 118:233–9.
crossref
20. Fernandez HH, Jankovic J, Holds JB, et al. Observational study of incobotulinumtoxinA for cervical dystonia or blepharospasm (XCiDaBLE): Interim results for the first 170 subjects with blepharospasm. Tremor Other Hyperkinet Mov (N Y). 2014; 4:238.

Table 1.
Jankovic rating scale15
Blepharospasm severity
0 None
1 Minimal, increased blinking present only with external stimuli (e.g., bright light, wind, reading, driving, etc.)
2 Mild, but spontaneous eyelid fluttering (without actual spasm), definitely noticeable, possibly embarrassing, but not functionally disabling
3 Moderate, very noticeable spasm of eyelids only, mildly incapacitating
4 Severe, incapacitating spasm of eyelids and possibly other facial muscles
Blepharospasm frequency
0 None
1 Slightly increased frequency of blinking
2 Eyelid fluttering lasting less than 1 second in duration
3 Eyelid spasm lasting more than 1 second, but eyes open more than 50% of the waking time
4 Functionally “blind” due to persistent eye closure (blepharospasm) more than 50% of the waking time
Table 2.
Functional disability assessment scale16
Type of activity Disability
1. Reading □ 0 No disability
□ Not applicable □ 1 Mild disability, but with no limitation over time
  □ 2 High disability, limited to a newspaper page
  □ 3 Very high disability, limited to newspaper headlines
  □ 4 Activity impossible
2. Watching TV □ 0 No disability
□ Not applicable □ 1 Mild disability, limited to one film (about 2 hours)
  □ 2 High disability, limited to news or one sitcom (30 minutes environ)
  □ 3 Very high disability, “listen more than watch”
  □ 4 Activity impossible
3. Household activities □ 0 No disability
□ Not applicable □ 1 Mild disability, household activities with no time limit
  □ 2 High disability, household activities with time limit
  □ 3 Very high disability, household activities reduced to the minimum
  □ 4 Activities impossible
4. Mobility □ 0 No disability
□ Not applicable □ 1 Mild disability, no space limit
  □ 2 High disability, difficult to cross the road
  □ 3 Very high disability, difficult to leave usual residence
  □ 4 Activity impossible
5. Driving □ 0 No disability
□ Not applicable □ 1 Moderate disability, but driving not restricted
  □ 2 High disability, driving restricted short inter-urban journeys
  □ 3 Very high disability, driving restricted to the minimum
  □ 4 Activity impossible
6. Work □ 0 No disability
□ Not applicable □ 1 Moderate disability, professional activities with no time limit
  □ 2 High disability, professional activities with time limit
  □ 3 Very high disability, activities reduced to the minimum (high absenteeism)
  □ 4 Activity impossible
Table 3.
Baseline demographics and clinical characteristics of ITT population
Characteristic BOTULAX® (n = 240)
Demographics  
Sex (male) 43 (17.92)
Mean age (years) 64.77 ± 9.67
Post-menopausal* 192 (97.46)
Mean duration since first diagnosis of blepharospasm (months) 44.55 ± 47.01
Disease characteristics  
Mean JRS sum score 5.69 ± 1.51
Mean functional disability score† 1.67 ± 0.91

Values are presented as mean ± standard deviation or number (%).

ITT = intent-to-treat; JRS = Jankovic rating score.

* 197 female subjects were included

† according to the questionnaire change, 66 patients who responded to the previous questionnaire and those who checked “not applicable” in all items were excluded.

Table 4.
Summary of efficacy variables of ITT population
Variable Value p-value
Changes in JRS sum score in week 4 –4.04 ± 2.03 <0.0001*
Changes in JRS sum score in week 16 –1.65 ± 1.85 <0.0001*
Changes in functional disability score in week 4 –0.56 ± 0.86 <0.0001†
Changes in functional disability score in week 16 –0.32 ± 0.91 <0.0001*
Changes in WHO-QOL in week 4 0.67 ± 6.10 0.1674*
Changes in WHO-QOL in week 16 0.37 ± 6.26 0.3558†

Values are presented as mean ± standard deviation.

ITT = intent-to-treat; JRS = Jankovic rating score; WHO-QOL = the world health organization quality of life.

* Wilcoxon signed rank test were used for statistical analysis

† paired t-test were used for statistical analysis.

Table 5.
Adverse drug reactions following BOTULAX® injection (n = 249)
Adverse drug reactions (MedDRA preferred term) Subject Number of event
Eye disorders    
 Dry eye 9 (3.61) 9
 Eyelid ptosis 5 (2.01) 5
 Diplopia 3 (1.20) 3
 Eye pain 3 (1.20) 3
 Lacrimation increased 3 (1.20) 3
 Lagophthalmos 3 (1.20) 3
 Eyelid edema 2 (0.80) 2
 Corneal erosion 1 (0.40) 1
 Erythema of eyelid 1 (0.40) 1
 Eye irritation 1 (0.40) 1
 Ophthalmoplegia 1 (0.40) 1
 Visual acuity reduced 1 (0.40) 1
General disorders and administration site conditions    
 Face edema 2 (0.80) 2
Injury, poisoning and procedural complications    
 Contusion 1 (0.40) 1
 Total 28 (11.24) 36

Values are presented as number (%).

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