Clinical trial NCT03459092: Botox Instead of Strabismus Surgery (BISS)
Official title: A Pragmatic, Randomized, Non-inferiority Trial Comparing the Effectiveness of Botulinum Toxin-based Treatment With Conventional Strabismus Surgery in Acquired Esotropia.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acquired Esotropia
Keywords: Botulinum toxin, strabismus surgery, binocular vision
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2018-03-08
Enrollment: 63
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Informed consent of trial participant and/or legal representative documented per signature
2. Age \> 1 year and \<17 years
3. Esotropia \> 10Prisms
4. Indication for an intervention (either Botox or surgery) has been made.
5. 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
6. 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

Exclusion Criteria:

1. Known hypersensitivity to botulinum toxin
2. Known neuromuscular disorder
3. Known present neurological disorder affecting the central nervous system Including paresis on cranial nerves number 3, 4 and 6
4. Any of the following:

   * nystagmus
   * dissociated vertical deviation
5. Vertical deviation in any gaze direction greater than 5°
6. Incomitance with more than 5° of difference between the left and right horizontal gaze direction
7. Previous strabismus surgery
8. Previous Botulinum toxin treatment on extraocular muscles
9. 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°.
10. Pregnancy. A negative pregnancy test before randomization is required for all women of child-bearing potential.
11. Preterm children born before 36 weeks of gestation.

Primary outcomes:
measure: Number of patients with presence of binocular vision
timeFrame: At 18 months
Secondary outcomes:
measure: Number of patients with second intervention
timeFrame: At 12 months, at 18 months
measure: Number of patients with binocular vision
timeFrame: At 12 months
measure: Number of patients with incomitance
timeFrame: At 12 months, at 18 months
measure: Number of patients with treatment-specific presence of binocular vision
timeFrame: At 12 months, at 18 months
measure: Number of surgeries per participant
timeFrame: At 12 months, at 18 months
measure: Number of surgeries needed per successful outcome
timeFrame: At 12 months, at 18 months
measure: Change in strabismus angle, measured in percent
timeFrame: At 12 months, at 18 months
measure: Binocular function, measured in arc seconds
timeFrame: At 12 months, at 18 months
Other outcomes:
measure: Total duration of binocular vision (exploratory outcome)
timeFrame: At 12 months, at 18 months
measure: Incidence of short-term adverse events (safety outcome)
timeFrame: Within two weeks of intervention
measure: Incidence of ocular adverse events
timeFrame: Within 18 months
measure: Incidence of serious adverse events related to the treatment
timeFrame: Within 18 months
Locations:
city: Saint-Herblain
country: France
facility: Institut Ophtalmologique Sourdille Atlantique
city: Basel
country: Switzerland
facility: Basel University Hopital
city: Bern
country: Switzerland
facility: Bern University Hospital
city: Geneva
country: Switzerland
facility: Geneva University Hospital, HUG
city: Lausanne
country: Switzerland
facility: Lausanne Univeristy Hospital, CHUV
city: Lucerne
country: Switzerland
facility: Luzerner Kantonsspital
city: Saint Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Zürich
country: Switzerland
facility: University Hospital Zürich
Study officials:
affiliation: Bern University Hospital
name: Mathias Abegg, Professor
role: PRINCIPAL_INVESTIGATOR
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