The AXIS Study: the Efficacy of Acetazolamide for the Treatment of Cystoid Fluid Collections in Retinoschisis

Study Overview
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Brief Summary
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X-linked retinoschisis (XLRS) is a rare hereditary eye disease that causes irreversible vision loss in boys and young men. This disease occurs in 1 in 10,000-30,000. This inherited condition is caused by pathogenic variants in a single gene, namely the Retinoschisin 1 (RS1). This gene encodes the retinoschisin protein. Pathological variants of retinoschisin lead to loss of retinal integrity, resulting in the characteristic cystoid fluid collections (CFC). From a young age, XLRS patients experience a gradual deterioration of vision. In middle-aged patients however, XLRS may be associated with macular atrophy because of the confluence of the cystoid lesions. No permanent treatment is yet available for XLRS patients. Currently, two different phase I/II studies are investigating the safety and effectivity of subretinal gene therapy. To create optimal retinal condition before gene therapy, CFC, a hallmark of XLRS, should not be present. Topical and oral carbonic anhydrase II inhibitors are used to combat CME. This drug is still off-label prescribed for various hereditary retinal dystrophies. Consequently, there is no treatment regimen for prescribing acetazolamide to XLRS patients. A thorough understanding of the safety and efficacy of acetazolamide in reducing the central foveal thickness in XLRS patients is required before applying future gene therapy. The proposed study is a investigator-initiated, single-center, prospective, experimental study consisting of seven visits at 2, 4, 12, 16, 20 and 32 weeks after the baseline evaluation visit. During each visit, participants will perform several ophthalmological measurements. In this study, participants with XLRS will be randomized into either a treatment or control group. The null-hypothesis of this study is that acetazolamide effectively reduces the central foveal thickness in patients with XLRS and significantly improves their visual function. The alternative hypothesis is that acetazolamide reduces not effectively the central foveal thickness in patients with XLRS and has no significant impact on their visual function. Treatment success will be based not only on anatomical improvement, but also on functional endpoints, which are most important from a patient's perspective. The study will last 32 weeks per participant. Each participant will come physically for seven visits. The whole study will last for max. 24 months. The examinations and number of visits are reduced to a minimum. In contrast to clinical care, the participants receive examinations that consist of a more extensive measurement of visual acuity, microperimetry and a questionnaire. These extra examinations are required to evaluate the functional vision-related endpoints of the study.

Official Title
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Prospective Clinical Trial to Evaluate the Efficacy of Acetazolamide for the Treatment of Cystoid Fluid Collections in Retinoschisis: The AXIS Trial

Conditions
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Retinoschisis

Intervention / Treatment
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* Drug: Acetazolamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with XLRS with cystoid fluid collections involving the fovea confirmed on SD- OCT are willing to undergo ophthalmic examinations at seven separate occasions; have no visual dysfunction that is also significantly associated with other ocular diseases besides XLRS (e.g., glaucoma, perforating trauma); have no known (non-)ocular disease/disorder which may influence the results of the measurements. Exclusion Criteria: Severe hepatic impairment Severe renal insufficiency Sodium and Potassium Depletion Addison's disease Hyperchloremic Acidosis Cor pulmonale Chronic non-congestive angle-closure glaucoma Usage of acetazolamide Known allergy or intolerance for ocular anesthetic eye drops oxybuprocaine 0.4% or mydriatics tropicamide 0.5% and/or phenylephrine 5%;

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized into the treatment group or the control group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acetazolomide group<br> | Drug: Acetazolamide<br>* The used intervention in this study is acetazolamide, which belongs to a class of drugs known as carbonic anhydrase inhibitors and has been used with other medications to treat high ocular pressure due to certain types of glaucoma Patients in the treatment group will receive 250 milligrams of oral acetazolamide twice daily for 16 weeks. Patients randomized to the treatment group will switch to 125 milligrams of oral acetazolamide twice daily for another four weeks when the central foveal thickness (CFT) on OCT is reduced by ≥25% at the evaluation visit at 16 weeks after the baseline visit. These patients will continue with this dose till the end of the study when the CFT on OCT is stable or further reduced. If the CFT on OCT has increased, they switch back to 250 milligrams of oral acetazolamide twice daily for another 12 weeks.<br>* Other names: Diamox;|
| No Intervention: Control Group<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine effect of oral acetazolamide treatment on the cystoid fluid collections in XLRS compared within the treated group and control group. |  | Change from baseline to Week 32 in reduction of the central foveal thickness (CFT) in µm on SD-OCT. The direction of improvement from baseline is an significant reduction of the CFT over time | 
| To determine effect of oral acetazolamide treatment on the visual function in XLRS compared within the treated group and control group. | As primary endpoints for visual function, we will look at the following parameter that reflect the patient's vision-related functioning: a standardized measurement of best-corrected visual acuity (BCVA) according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) standards. | Change from baseline to Week 32 in BCVA using ETDRS chart letter score. | 
| To determine effect of oral acetazolamide treatment on the visual function in XLRS | As primary endpoints for visual function, we will look at the following parameter that reflect the patient's vision-related functioning: a standardized measurement of low luminance visual acuity (LLVA) according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) standards. | Change from baseline to Week 32 in BCVA using ETDRS chart letter score. | 
| To determine effect of oral acetazolamide treatment on the visual function in XLRS | As primary endpoints for visual function, we will look at the following parameter that reflect the patient's vision-related functioning: a standardized measurement of sensitivity of the macula with microperimetry. | Change from baseline to Week 32 in retinal sensitivity (dB) on micropermetry | 
| To determine effect of oral acetazolamide treatment on the visual function in XLRS | As primary endpoints for visual function, we will look at the following parameter that reflect the patient's vision-related functioning: standardized assessment of the patient's vision-related quality of life using a validated questionnaire, the Michigan Retinal Degeneration Questionnaire (MRDQ). | Change from baseline to Week 32 in patients perspective on visual funcitoning | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the optimal acetazolamide dose for maximum effect on cystoid fluid collections and minimal side effects |  | The optimal dosage is determined after 32 weeks | 
| To determine the proportion of XLRS patients with cystoid fluid collections in which acetazolamide treatment is able to completely resolve these cystoid fluid collections. |  | The propoprtion of XLRS patients with completely resolved cystoid fluid collections is determined after 16 weeks and 32 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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X-Linked Retinoschisis, X-Linked Juvenile Retinoschisis