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Botox Instead of Strabismus Surgery (BISS) (BISS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03459092
Recruitment Status : Recruiting
First Posted : March 8, 2018
Last Update Posted : March 27, 2020
Sponsor:
Information provided by (Responsible Party):
University Hospital Inselspital, Berne

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.


Condition or disease Intervention/treatment Phase
Acquired Esotropia Drug: Botulinum toxin type A Procedure: Strabismus surgery Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Pragmatic, Randomized, Non-inferiority Trial Comparing the Effectiveness of Botulinum Toxin-based Treatment With Conventional Strabismus Surgery in Acquired Esotropia.
Actual Study Start Date : August 16, 2018
Estimated Primary Completion Date : August 2023
Estimated Study Completion Date : August 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Botox

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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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).

  5. Number of surgeries per participant [ Time Frame: At 12 months, at 18 months ]
  6. Number of surgeries needed per successful outcome [ Time Frame: At 12 months, at 18 months ]
    Successful outcome = binocular vision

  7. 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


  8. 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


Other Outcome Measures:
  1. 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.

  2. 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

  3. Incidence of ocular adverse events [ Time Frame: Within 18 months ]
  4. Incidence of serious adverse events related to the treatment [ Time Frame: Within 18 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03459092


Contacts
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Contact: Muriel Dysli, MD, PhD +41 31 632 29 08 muriel.dysli@insel.ch

Locations
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France
Institut Ophtalmologique Sourdille Atlantique Not yet recruiting
Saint-Herblain, France
Switzerland
Basel University Hopital Recruiting
Basel, Switzerland
Bern University Hospital Recruiting
Bern, Switzerland
Geneva University Hospital, HUG Recruiting
Geneva, Switzerland
Lausanne Univeristy Hospital, CHUV Recruiting
Lausanne, Switzerland
Luzerner Kantonsspital Recruiting
Lucerne, Switzerland
Kantonsspital St. Gallen Recruiting
Saint Gallen, Switzerland
University Hospital Zürich Recruiting
Zürich, Switzerland
Sponsors and Collaborators
University Hospital Inselspital, Berne
Investigators
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Principal Investigator: Mathias Abegg, Professor Bern University Hospital
Publications:

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Responsible Party: University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier: NCT03459092    
Other Study ID Numbers: 33IC30 173533
First Posted: March 8, 2018    Key Record Dates
Last Update Posted: March 27, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Once the primary analysis is published.

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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
Keywords provided by University Hospital Inselspital, Berne:
Botulinum toxin, strabismus surgery, binocular vision
Additional relevant MeSH terms:
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Strabismus
Esotropia
Ocular Motility Disorders
Cranial Nerve Diseases
Nervous System Diseases
Eye Diseases
Botulinum Toxins
Botulinum Toxins, Type A
abobotulinumtoxinA
Acetylcholine Release Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Neuromuscular Agents
Peripheral Nervous System Agents