Botox Instead of Strabismus Surgery (BISS)

NCT03459092 | Completed Phase 3

• 1 other identifier: 33IC30 173533
• Study Type: interventional
• Target: 63
• Locations: 2 countries
• Sites: 8

Brief Summary

The purpose of the study is to evaluate if strabismus can be successfully treated requiring less surgical interventions with a Botox-based treatment regimen compared to a purely surgery based treatment regimen. Experimental arm: Botulinum toxin injection in the horizontal extraocular muscles. Control (active comparator) arm: Strabismus surgery on the horizontal extraocular muscles. No investigational product is used. In Switzerland the standard procedure for treating large angle esotropia is surgery, which is performed on the horizontal eye muscles that may be either recessed or shortened leading to reduced or increased muscle function respectively. As an alternative to strabismus surgery, botulinum toxin (Botox) can be applied in extraocular muscles. Botox prevents the release of acetylcholine in the synaptic cleft and thereby blocks the neuromuscular transmission thus inducing a palsy. Current evidence on the use of Botox in strabismus is incoherent, is poorly supported by basic research findings and leaves dedicated clinicians in the dark. The objective is to shed light into this field of clinical research, which may help to guide future pediatric ophthalmologists in their management of strabismic patients. In a best case scenario, the results from this trial will prevent strabismus operation for many children with acquired large angle esotropia.

Conditions

Acquired Esotropia

Keywords

Botulinum toxin, strabismus surgery, binocular vision

Outcome Measures

Primary Outcomes (1)

• Number of patients with presence of binocular vision

  Presence of binocular vision is a binary variable set to yes when either of the following criteria is fulfilled: 1. No eye movement can be observed in the simultaneous prism covertest, performed according to the study specific SOP for full orthoptic workup, for both eyes measured at distance. This proves orthotropia and thus binocular vision can be assumed. 2. An esotropia of less than 5° is observed in the covertest at distance AND at near. In addition at least one binocular test demonstrates binocular vision. This proves compensated microstrabismus with anomalous retinal correspondence. Binocular tests: 1. Lang-Stereotest 2. Butterfly- Stereotest 3. Titmus test 4. Bagolini striated glasses test 5. TNO-Test 6. Pencil-Test

  At 18 months

Secondary Outcomes (8)

• Number of patients with second intervention

  At 12 months, at 18 months

• Number of patients with binocular vision

  At 12 months

• Number of patients with incomitance

  At 12 months, at 18 months

• Number of patients with treatment-specific presence of binocular vision

  At 12 months, at 18 months

• Number of surgeries per participant

  At 12 months, at 18 months

Other Outcomes (4)

• Total duration of binocular vision (exploratory outcome)

  At 12 months, at 18 months

• Incidence of short-term adverse events (safety outcome)

  Within two weeks of intervention

• Incidence of ocular adverse events

  Within 18 months

Study Arms (2)

Botox-based treatment regimen

EXPERIMENTAL

First intervention is a Botulinum toxin type A injection. If further treatment is necessary, strabismus surgery can be performed.

Drug: Botulinum toxin type A; Procedure: Strabismus surgery

Surgery-based treatment regimen

ACTIVE COMPARATOR

First intervention is strabismus surgery. If further treatment is necessary, strabismus surgery can be repeated.

Procedure: Strabismus surgery

Interventions

Botulinum toxin type A DRUG

Botulinum toxin injection in the horizontal extraocular muscles.

Botox-based treatment regimen

Strabismus surgery PROCEDURE

Strabismus surgery on the horizontal extraocular muscles

Botox-based treatment regimen; Surgery-based treatment regimen

Eligibility Criteria

• Age: 1 Year - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Informed consent of trial participant and/or legal representative documented per signature
• Age \> 1 year and \<17 years
• Esotropia \> 10Prisms
• Indication for an intervention (either Botox or surgery) has been made.
• Any of the following:
• Presence of a secondary strabismus from binocular disruption the cause of the binocular disruption is no longer present
• Decompensated microstrabismus
• Decompensated phoria
• Acute acquired esotropia
• Positive test of binocular function at any time point in the past, including any of the following
• Titmus test
• Bagolini striated glasses test
• Lang-stereo-test with correct naming of at least one panel
• Good ocular alignment after 6 months of age on at least 2 photographs

You may not qualify if:

• Known hypersensitivity to botulinum toxin
• Known neuromuscular disorder
• Known present neurological disorder affecting the central nervous system Including paresis on cranial nerves number 3, 4 and 6
• Any of the following:
• nystagmus
• dissociated vertical deviation
• Vertical deviation in any gaze direction greater than 5°
• Incomitance with more than 5° of difference between the left and right horizontal gaze direction
• Previous strabismus surgery
• Previous Botulinum toxin treatment on extraocular muscles
• Presence of ophthalmic pathologies significantly preventing binocular functions.
• A significant alteration of binocular function is assumed if vision is smaller than 0.1 or the visual field has a horizontal diameter of less than 20°.
• Pregnancy. A negative pregnancy test before randomization is required for all women of child-bearing potential.
• Preterm children born before 36 weeks of gestation.

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead

Study Sites (8)

Institut Ophtalmologique Sourdille Atlantique

Saint-Herblain, France

Location

Basel University Hopital

Basel, Switzerland

Location

Bern University Hospital

Bern, Switzerland

Location

Geneva University Hospital, HUG

Geneva, Switzerland

Location

Lausanne Univeristy Hospital, CHUV

Lausanne, Switzerland

Location

Luzerner Kantonsspital

Lucerne, Switzerland

Location

Kantonsspital St. Gallen

Sankt Gallen, Switzerland

Location

University Hospital Zürich

Zurich, Switzerland

Location

Related Publications (28)

• Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology. 1980 Oct;87(10):1044-9. doi: 10.1016/s0161-6420(80)35127-0.

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• Tejedor J, Rodriguez JM. Early retreatment of infantile esotropia: comparison of reoperation and botulinum toxin. Br J Ophthalmol. 1999 Jul;83(7):783-7. doi: 10.1136/bjo.83.7.783.

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• Tejedor J, Rodriguez JM. Retreatment of children after surgery for acquired esotropia: reoperation versus botulinum injection. Br J Ophthalmol. 1998 Feb;82(2):110-4. doi: 10.1136/bjo.82.2.110.

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• Lee J, Harris S, Cohen J, Cooper K, MacEwen C, Jones S. Results of a prospective randomized trial of botulinum toxin therapy in acute unilateral sixth nerve palsy. J Pediatr Ophthalmol Strabismus. 1994 Sep-Oct;31(5):283-6. doi: 10.3928/0191-3913-19940901-03.

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• Carruthers JD, Kennedy RA, Bagaric D. Botulinum vs adjustable suture surgery in the treatment of horizontal misalignment in adult patients lacking fusion. Arch Ophthalmol. 1990 Oct;108(10):1432-5. doi: 10.1001/archopht.1990.01070120080033.

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• de Alba Campomanes AG, Binenbaum G, Campomanes Eguiarte G. Comparison of botulinum toxin with surgery as primary treatment for infantile esotropia. J AAPOS. 2010 Apr;14(2):111-6. doi: 10.1016/j.jaapos.2009.12.162.

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• McNeer KW, Tucker MG, Spencer RF. Botulinum toxin management of essential infantile esotropia in children. Arch Ophthalmol. 1997 Nov;115(11):1411-8. doi: 10.1001/archopht.1997.01100160581010.

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• Lueder GT, Galli M, Tychsen L, Yildirim C, Pegado V. Long-term results of botulinum toxin-augmented medial rectus recessions for large-angle infantile esotropia. Am J Ophthalmol. 2012 Mar;153(3):560-3. doi: 10.1016/j.ajo.2011.08.019. Epub 2011 Oct 13.

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• Gursoy H, Basmak H, Sahin A, Yildirim N, Aydin Y, Colak E. Long-term follow-up of bilateral botulinum toxin injections versus bilateral recessions of the medial rectus muscles for treatment of infantile esotropia. J AAPOS. 2012 Jun;16(3):269-73. doi: 10.1016/j.jaapos.2012.01.010.

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• Baggesen K, Arnljot HM. Treatment of congenital esotropia with botulinum toxin type A. Acta Ophthalmol. 2011 Aug;89(5):484-8. doi: 10.1111/j.1755-3768.2009.01737.x. Epub 2009 Oct 30.

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• Biglan AW, Burnstine RA, Rogers GL, Saunders RA. Management of strabismus with botulinum A toxin. Ophthalmology. 1989 Jul;96(7):935-43. doi: 10.1016/s0161-6420(89)32776-x.

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• Kushner BJ, Morton GV. A randomized comparison of surgical procedures for infantile esotropia. Am J Ophthalmol. 1984 Jul 15;98(1):50-61. doi: 10.1016/0002-9394(84)90188-0.

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• Helveston EM, Ellis FD, Schott J, Mitchelson J, Weber JC, Taube S, Miller K. Surgical treatment of congenital esotropia. Am J Ophthalmol. 1983 Aug;96(2):218-28. doi: 10.1016/s0002-9394(14)77790-6.

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• Hatt SR, Leske DA, Liebermann L, Holmes JM. Comparing outcome criteria performance in adult strabismus surgery. Ophthalmology. 2012 Sep;119(9):1930-6. doi: 10.1016/j.ophtha.2012.02.035. Epub 2012 Apr 26.

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• Wan MJ, Mantagos IS, Shah AS, Kazlas M, Hunter DG. Comparison of Botulinum Toxin With Surgery for the Treatment of Acute-Onset Comitant Esotropia in Children. Am J Ophthalmol. 2017 Apr;176:33-39. doi: 10.1016/j.ajo.2016.12.024. Epub 2017 Jan 3.

  PMID: 28057455 BACKGROUND

• Dysli M, Keller F, Abegg M. Acute onset incomitant image disparity modifies saccadic and vergence eye movements. J Vis. 2015 Mar 18;15(3):12. doi: 10.1167/15.3.12.

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• Dysli M, Abegg M. Gaze-dependent phoria and vergence adaptation. J Vis. 2016;16(3):2. doi: 10.1167/16.3.2.

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• Mahan M, Engel JM. The resurgence of botulinum toxin injection for strabismus in children. Curr Opin Ophthalmol. 2017 Sep;28(5):460-464. doi: 10.1097/ICU.0000000000000408.

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• Pediatric Eye Disease Investigator Group; Christiansen SP, Chandler DL, Lee KA, Superstein R, de Alba Campomanes A, Bothun ED, Morin J, Wallace DK, Kraker RT. Tonic pupil after botulinum toxin-A injection for treatment of esotropia in children. J AAPOS. 2016 Feb;20(1):78-81. doi: 10.1016/j.jaapos.2015.09.011.

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• Pehere N, Jalali S, Mathai A, Naik M, Ramesh K. Inadvertent intraocular injection of botulinum toxin A. J Pediatr Ophthalmol Strabismus. 2011 Jan 25;48 Online:e1-3. doi: 10.3928/01913913-20110118-06.

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• Liu M, Lee HC, Hertle RW, Ho AC. Retinal detachment from inadvertent intraocular injection of botulinum toxin A. Am J Ophthalmol. 2004 Jan;137(1):201-2. doi: 10.1016/s0002-9394(03)00837-7.

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MeSH Terms

Interventions

Botulinum Toxins, Type A

Intervention Hierarchy (Ancestors)

Botulinum Toxins; Metalloendopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Metalloproteases; Bacterial Proteins; Proteins; Amino Acids, Peptides, and Proteins; Bacterial Toxins; Toxins, Biological; Biological Factors

Study Officials

• Mathias Abegg, Professor

  Bern University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 2, 2018
• First Posted: March 8, 2018
• Study Start: August 16, 2018
• Primary Completion: July 31, 2023
• Study Completion: July 31, 2023
• Last Updated: November 7, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Once the primary analysis is published.

Locations

CH (7); FR (1)