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

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

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 CFC. 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.

Study Overview

• Status: Completed
• Conditions: Retinoschisis
• Intervention / Treatment: Drug: Acetazolamide

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1105AZ
      • Amsterdam University Medical Centers

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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%;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control Group
Experimental: Treatment group; Patients in the treatment group receives twice daily a 250mg tablet acetazolamide for 16 weeks. At week 16, depending on the results, the treated group will stop the treatment or continue with a lower dose twice daily a 125mg tablet acetazolamide for 4 weeks. At week 20, depending on the results, the initial treated group will continue with twice daily a 125mg tablet or go back to twice daily a 250mg tablet acetazolamide till week 32.	Drug: Acetazolamide; 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.; Other Names: Diamox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Macular structure as assessed by spectral domain optical coherence tomography	Change in Central subfield thickness on spectral domain optical coherence tomography (SD-OCT).	Change from baseline to Week 32

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual acuity as assessed by best-corrected visual acuity	Change in in best-corrected visual acuity (BCVA).	Change from baseline to Week 32
Visual acuity as assessed by low-luminance visual acuity	Change in low luminance visual acuity (LLVA)	Change from baseline to Week 32
Visual function as assessed by microperimetry	Change in microperimetry.	Change from baseline to Week 32
Subject-reported visual function as assessed by the Michigan Retinal Degeneration Questionnaire (MRDQ).	Change in the functional (dis)ability score, theta score (θ), in the measured trait or domain. Θ is centred at the mean trait level of the patient population of the developers with a variance of 1, and extreme Θ-values -3 and + 3 indicate lowest and highest visual disability respectively of each patients.	Change from baseline to Week 32
Absence of cystoid fluid collections on OCT scan	Absence of cystoid fluid collections on OCT scan	At evaluation visits during study (assessed up to 32 weeks)

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: Camiel JF Boon, Prof. dr., Amsterdam UMC

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2023
• Primary Completion (Actual): September 13, 2024
• Study Completion (Actual): September 13, 2024

Study Registration Dates

• First Submitted: October 24, 2023
• First Submitted That Met QC Criteria: October 27, 2023
• First Posted (Actual): November 2, 2023

Study Record Updates

• Last Update Posted (Actual): May 31, 2025
• Last Update Submitted That Met QC Criteria: May 28, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: X-Linked Retinoschisis; X-Linked Juvenile Retinoschisis
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Diseases; Retinal Degeneration; Retinoschisis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Diuretics; Natriuretic Agents; Anticonvulsants; Carbonic Anhydrase Inhibitors; Acetazolamide
• Other Study ID Numbers: NL80249.018.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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