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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.
Patients with acquired large angle esotropia (an inward deviation of the ocular axis by more than 5°) that develops after one year of age have a potential to regain binocular vision if a retinal image appears on corresponding retinal areas of both eyes. The main goal of therapy in these patients is the restoration of binocular vision.
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 goal is to shed light into this field of clinical research, which may help to guide future pediatric ophthalmologists in their management of strabismic patients.
The goal of the study is to test if, with a botulinum-toxin-based treatment regimen, strabismus can be successfully treated requiring less surgical interventions.
The primary objective is to test if the Botox-based treatment regimen is not inferior to surgical treatment in terms of orthotropic success. If this is shown, the number of surgeries required will be compared between the two groups (main secondary objective).
The hypothesis is that the Botox-based treatment regimen, which permits performance of rescue surgery, is successful in a similar proportion of patients as the purely surgical approach. The second hypothesis is that only about 20% of patients treated with Botox require surgery at all as compared to about 10% of patients in the surgical arm that need a second surgery.
Analysis of the primary outcome The proportion of orthotropic success for both groups will be calculated with a corresponding 95% confidence interval. For the comparison between the two groups, the stratified risk difference for the stratification factors used in randomization will be calculated with a corresponding one-sided lower 95% confidence limit. If the lower limit lies above -12%, non-inferiority will be claimed.
Analysis of the main secondary outcome The proportion of second interventions for both groups will be calculated with a corresponding 95% confidence interval. For the comparison between the two groups, a stratified risk difference for the stratification factors used in randomization will be calculated with a corresponding one-sided upper 95% confidence limit. If the upper limit lies below 40% and if non-inferiority for the primary outcome could be demonstrated, a clinical benefit of the new treatment will be claimed.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Botox-based treatment regimen | Experimental | First intervention is a Botulinum toxin type A injection. If further treatment is necessary, strabismus surgery can be performed. |
|
| Surgery-based treatment regimen | Active Comparator | First intervention is strabismus surgery. If further treatment is necessary, strabismus surgery can be repeated. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Botulinum toxin type A | Drug | Botulinum toxin injection in the horizontal extraocular muscles. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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:
Binocular tests:
| At 18 months |
| Measure | Description | Time Frame |
|---|---|---|
| Number of patients with second intervention | Rescue surgery in Botox-based treatment arm and second surgery in surgery arm | At 12 months, at 18 months |
| Number of patients with binocular vision |
| Measure | Description | Time Frame |
|---|---|---|
| Total duration of binocular vision (exploratory outcome) | The duration is calculated as the sum of time periods between consecutive assessments with presence of binocular vision. | At 12 months, at 18 months |
| Incidence of short-term adverse events (safety outcome) |
Inclusion Criteria:
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:
Positive test of binocular function at any time point in the past, including any of the following
Exclusion Criteria:
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:
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.
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| Name | Affiliation | Role |
|---|---|---|
| Mathias Abegg, Professor | Bern University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Institut Ophtalmologique Sourdille Atlantique | Saint-Herblain | France | ||||
| Basel University Hopital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 7243198 | Background | 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. | |
| 10381663 | Background | 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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The de-identified study dataset will be made publicly available for secondary analyses by publishing the data on a data sharing platform such as Dryad or BORIS, the public online data repository from the University of Bern.
Once the primary analysis is published.
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| ID | Term |
|---|---|
| D019274 | Botulinum Toxins, Type A |
| ID | Term |
|---|---|
| D001905 | Botulinum Toxins |
| D008666 | Metalloendopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
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| Strabismus surgery | Procedure | Strabismus surgery on the horizontal extraocular muscles |
|
Presence of binocular vision is a binary variable set to yes when either of the following criteria is fulfilled:
Binocular tests:
| At 12 months |
| Number of patients with incomitance | Incomitance is here defined as the absolute difference of strabismus angle measured with the alternate prism cover test at 25° left gaze and the angle measured at 25° right gaze | At 12 months, at 18 months |
| Number of patients with treatment-specific presence of binocular vision | For this outcome patients with a second intervention are defined as failures (no). | At 12 months, at 18 months |
| Number of surgeries per participant | At 12 months, at 18 months |
| Number of surgeries needed per successful outcome | Successful outcome = binocular vision | At 12 months, at 18 months |
| Change in strabismus angle, measured in percent | Measured as percentage of preoperative deviation from baseline. The strabismus angle measured with the alternate prism cover test, performed in primary position at distance is used. Change of deviation in percent of preoperative deviation is calculated as follows: 100*(preoperative deviation - postoperative deviation) / preoperative deviation | At 12 months, at 18 months |
| Binocular function, measured in arc seconds | When binocular vision is present, the binocular function is the best stereoscopic acuity, measured in arc seconds, achieved for any of the below mentioned tests.
| At 12 months, at 18 months |
Adverse event groups that will be evaluated separately are:
|
| Within two weeks of intervention |
| Incidence of ocular adverse events | Within 18 months |
| Incidence of serious adverse events related to the treatment | Within 18 months |
| Basel |
| Switzerland |
| Bern University Hospital | Bern | Switzerland |
| Geneva University Hospital, HUG | Geneva | Switzerland |
| Lausanne Univeristy Hospital, CHUV | Lausanne | Switzerland |
| Luzerner Kantonsspital | Lucerne | Switzerland |
| Kantonsspital St. Gallen | Sankt Gallen | Switzerland |
| University Hospital Zürich | Zurich | Switzerland |
| 9613374 | Background | 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. |
| 7837013 | Background | 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. |
| 2222277 | Background | 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. |
| 20451851 | Background | 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. |
| 9366672 | Background | 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. |
| 21996305 | Background | 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. |
| 22681945 | Background | 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. |
| 19878118 | Background | 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. |
| 11392405 | Background | Campos EC, Schiavi C, Bellusci C. Critical age of botulinum toxin treatment in essential infantile esotropia. J Pediatr Ophthalmol Strabismus. 2000 Nov-Dec;37(6):328-32; quiz 354-5. doi: 10.3928/0191-3913-20001101-05. |
| 2771360 | Background | 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. |
| 6377903 | Background | 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. |
| 6881245 | Background | 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. |
| 2644332 | Background | Scheiman M, Ciner E, Gallaway M. Surgical success rates in infantile esotropia. J Am Optom Assoc. 1989 Jan;60(1):22-31. |
| 22541935 | Background | 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. |
| 28057455 | Background | 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. |
| 25788706 | 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. |
| 26830708 | Background | Dysli M, Abegg M. Gaze-dependent phoria and vergence adaptation. J Vis. 2016;16(3):2. doi: 10.1167/16.3.2. |
| 28650877 | Background | 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. |
| 26917081 | Background | 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. |
| 21261223 | Background | 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. |
| 14700677 | Background | 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. |
| 23352718 | Background | Bradbury JA, Taylor RH. Severe complications of strabismus surgery. J AAPOS. 2013 Feb;17(1):59-63. doi: 10.1016/j.jaapos.2012.10.016. Epub 2013 Jan 23. |
| 17189162 | Background | Ares C, Superstein R. Retrobulbar hemorrhage following strabismus surgery. J AAPOS. 2006 Dec;10(6):594-5. doi: 10.1016/j.jaapos.2006.04.005. Epub 2006 Oct 2. |
| 28253424 | Background | Rowe FJ, Noonan CP. Botulinum toxin for the treatment of strabismus. Cochrane Database Syst Rev. 2017 Mar 2;3(3):CD006499. doi: 10.1002/14651858.CD006499.pub4. |
| 10696312 | Background | Lyons CJ, Tiffin PA, Oystreck D. Acute acquired comitant esotropia: a prospective study. Eye (Lond). 1999 Oct;13 ( Pt 5):617-20. doi: 10.1038/eye.1999.169. |
| 13520873 | Background | BURIAN HM, MILLER JE. Comitant convergent strabismus with acute onset. Am J Ophthalmol. 1958 Apr;45(4 Pt 2):55-64. doi: 10.1016/0002-9394(58)90223-x. No abstract available. |
| D006867 |
| Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D045726 | Metalloproteases |
| D001426 | Bacterial Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001427 | Bacterial Toxins |
| D014118 | Toxins, Biological |
| D001685 | Biological Factors |