E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acquired esotropia (strabismus) |
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E.1.1.1 | Medical condition in easily understood language |
Patients ( older than one year and younger than 17 years) with strabismus that requires an intervention. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Ocular Physiological Phenomena [G14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015475 |
E.1.2 | Term | Esotropia |
E.1.2 | System Organ Class | 100000004853 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042163 |
E.1.2 | Term | Strabismus NOS |
E.1.2 | System Organ Class | 100000004853 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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E.4 | Principal 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.
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E.5 End points |
E.5.1 | Primary 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.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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
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E.5.2.1 | Timepoint(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) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 24 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |