Botox Instead of Strabismus Surgery (BISS) (BISS)

November 6, 2023 updated by: Insel Gruppe AG, University Hospital Bern

A Pragmatic, Randomized, Non-inferiority Trial Comparing the Effectiveness of Botulinum Toxin-based Treatment With Conventional Strabismus Surgery in Acquired Esotropia.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

63

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Saint-Herblain, France
        • Institut ophtalmologique Sourdille Atlantique
  • Switzerland
      • Basel, Switzerland
        • Basel University Hopital
      • Bern, Switzerland
        • Bern University Hospital
      • Geneva, Switzerland
        • Geneva University Hospital, HUG
      • Lausanne, Switzerland
        • Lausanne Univeristy Hospital, CHUV
      • Lucerne, Switzerland
        • Luzerner Kantonsspital
      • Saint Gallen, Switzerland
        • Kantonsspital St. Gallen
      • Zürich, Switzerland
        • University Hospital Zurich

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 months to 15 years (Child)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Botox-based treatment regimen
First intervention is a Botulinum toxin type A injection. If further treatment is necessary, strabismus surgery can be performed.
Drug: Botulinum toxin type A
Botulinum toxin injection in the horizontal extraocular muscles.
Procedure: Strabismus surgery
Strabismus surgery on the horizontal extraocular muscles
Active Comparator: Surgery-based treatment regimen
First intervention is strabismus surgery. If further treatment is necessary, strabismus surgery can be repeated.
Procedure: Strabismus surgery
Strabismus surgery on the horizontal extraocular muscles

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with presence of binocular vision
Time Frame: At 18 months

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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with second intervention
Time Frame: At 12 months, at 18 months
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
Time Frame: At 12 months

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 12 months
Number of patients with incomitance
Time Frame: At 12 months, at 18 months
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
Time Frame: At 12 months, at 18 months
For this outcome patients with a second intervention are defined as failures (no).
At 12 months, at 18 months
Number of surgeries per participant
Time Frame: At 12 months, at 18 months
At 12 months, at 18 months
Number of surgeries needed per successful outcome
Time Frame: At 12 months, at 18 months
Successful outcome = binocular vision
At 12 months, at 18 months
Change in strabismus angle, measured in percent
Time Frame: At 12 months, at 18 months

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
Time Frame: At 12 months, at 18 months

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.

  1. Lang-Stereotest
  2. Butterfly- Stereotest
  3. Titmus test
  4. Bagolini striated glasses test
  5. TNO-Test
  6. Pencil-Test
At 12 months, at 18 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Total duration of binocular vision (exploratory outcome)
Time Frame: At 12 months, at 18 months
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)
Time Frame: Within two weeks of intervention

Adverse event groups that will be evaluated separately are:

  • Ptosis
  • Double vision
  • Subjective post-treatment discomfort/pain
  • New vertical strabismus >1°
  • Limitations of ocular motility
Within two weeks of intervention
Incidence of ocular adverse events
Time Frame: Within 18 months
Within 18 months
Incidence of serious adverse events related to the treatment
Time Frame: Within 18 months
Within 18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Insel Gruppe AG, University Hospital Bern

Investigators

  • Principal Investigator: Mathias Abegg, Professor, Bern University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 16, 2018

Primary Completion (Actual)

July 31, 2023

Study Completion (Actual)

July 31, 2023

Study Registration Dates

First Submitted

March 2, 2018

First Submitted That Met QC Criteria

March 2, 2018

First Posted (Actual)

March 8, 2018

Study Record Updates

Last Update Posted (Actual)

November 7, 2023

Last Update Submitted That Met QC Criteria

November 6, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 33IC30 173533

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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.

IPD Sharing Time Frame

Once the primary analysis is published.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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