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    Summary
    EudraCT Number:2020-000280-23
    Sponsor's Protocol Code Number:BISS
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-07-10
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2020-000280-23
    A.3Full title of the trial
    A pragmatic, randomized, non-inferiority trial comparing the effectiveness of Botulinum toxin-based treatment with conventional strabismus surgery in acquired esotropia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Botox Instead of Strabismus Surgery (BISS)
    A.3.2Name or abbreviated title of the trial where available
    BISS study
    A.4.1Sponsor's protocol code numberBISS
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03459092
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorProf Mathias Abegg
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportSwiss National Science Foundation
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMathias Abegg
    B.5.2Functional name of contact pointMathias Abegg
    B.5.3 Address:
    B.5.3.1Street AddressInselspital Universitätsspital Bern, Freiburgstrasse
    B.5.3.2Town/ cityBern
    B.5.3.3Post code3010
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number41316322111
    B.5.6E-mailmathias.abegg@insel.ch
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Botox
    D.2.1.1.2Name of the Marketing Authorisation holderALLERGAN FRANCE
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBotox
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acquired esotropia (strabismus)
    E.1.1.1Medical condition in easily understood language
    Patients ( older than one year and younger than 17 years) with strabismus that requires an intervention.
    E.1.1.2Therapeutic area Body processes [G] - Ocular Physiological Phenomena [G14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10015475
    E.1.2Term Esotropia
    E.1.2System Organ Class 100000004853
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10042163
    E.1.2Term Strabismus NOS
    E.1.2System Organ Class 100000004853
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to assess the effectiveness of a Botox-based treatment regimen compared to a purely surgery-based treatment regimen in terms of binocular vision at 18 months.
    E.2.2Secondary objectives of the trial
    The main secondary objective is to assess secondary interventions in the Botox-based treatment arm compared to the purely surgery-based treatment arm at 18 months.
    Other secondary objectives are to evaluate the presence of binocular vision in each treatment arm at 12 months, the number of secondary interventions within 12 months, the number of surgeries per participant and per case with binocular vision up to 12 and 18 months and the effect of treatment on the strabismus angle at 12 and 18 months, the total ocular deviation (phoria and tropia) at the different time points and the horizontal incomitance.
    Incomitance is a gaze dependent variation of a strabismus angle, which usually results from changes in ocular motility.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Informed consent of trial participant and/or legal representative documented per signature
    2.Age > 1 and < 17 years
    3.Esotropia ≥ 10∆
    4.Indication for an intervention (either Botox or surgery) has been made including analysis of pre requirements or contraindications for both interventions .
    5.Any of the following:
    •Presence of a secondary strabismus (due to cataract, previous sixth nerve palsy for example) whereas the original cause of the strabismus is no longer present (for example, sixth nerve palsy has resolved)

    •Decompensated microstrabismus
    •Decompensated phoria
    •Acute acquired esotropia (Normosensorisches Spätschielen)
    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
    •Presumed orthotropia after 6 months of age on at least 2 photographs
    •Presence of binocular vision shown with the synoptophore
    E.4Principal 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 10∆
    6.Incomitance with more than 10∆ 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 or breastfeeding. A negative pregnancy test before randomization is required for female participants with childbearing potential (i.e. subjects who have reached menarche).
    11.Preterm children born before 36 weeks of gestation.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is presence of binocular vision at 18 months.

    The rational for the primary outcome is that the main goal of therapy in patients with acquired large angle esotropia is the restoration 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 10∆ is observed in the covertest at distance AND at near. In addition at least one of the binocular tests demonstrates binocular vision. This proves compensated microstrabismus with anomalous retinal correspondence.
    E.5.1.1Timepoint(s) of evaluation of this end point
    18 months
    E.5.2Secondary end point(s)
    The main secondary outcome is
    •Second intervention (yes/no) within 18 months (i.e. rescue surgery in Botox-based treatment arm and second surgery in surgery arm)
    This outcome is directly linked to the success rate of the two compared interventions, botulinum toxin injection and strabismus surgery.

    Further secondary outcomes are
    •Binocular vision, at 12 months
    •Second intervention as defined above, within 12 months
    •Incomitance at 12 and 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.
    •Treatment-specific presence of binocular vision (yes/no) at 12 and 18 months
    For this outcome patients with a second intervention are defined as failures (no).
    •Number of surgeries per participant at 12 and 18 months
    •Number of surgeries needed per successful outcome (binocular vision) at 12 and 18 months
    •Change in strabismus angle, measured as percentage of preoperative deviation, from baseline to 12 and 18 months. The strabismus angle measured with the alternate prism cover test, performed according to the study specific SOP for full orthoptic workup, 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
    •Binocular function at 12 and 18 months
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints of evaluation for secondary endpoints are specified within each definition of secondary endpoints (see E.5.2)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Surgery of strabismus
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Switzerland
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months24
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 140
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 20
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 80
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 40
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Minors up to 17 years old will be included. The majority of the included population will be between 1 and 7 years old. Age-specific informed consents forms are provided, together with an informed consent form for legal representative.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 140
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After participation into the trial, plans for treatment will follow standard of care practice in this condition.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-08-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-06-15
    P. End of Trial
    P.End of Trial StatusOngoing
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