Natural History Study in Subjects With Usher Syndrome

Natural History Study in Subjects With Usher Syndrome (USH1B) is being conducted to understand the progression of disease in USH1B patients as measured by visual acuity and visual field testing and a number of other vision-related assessments. Disease progression will be evaluated as change over time in these measures and associations between the endpoints will be examined.

The primary objective of this study is to evaluate the natural progression of disease over time in USHIB patients using visual field testing and best corrected visual acuity.

The secondary objectives of this study are to evaluate the progression of disease over time in USHIB patients through additional assessments:

* Microperimetry (only in selected centres)
* Fundus autofluorescence (FAF)
* Optical Coherence Tomography (OCT)
* Full-field Electroretinogram (ERG),
* Multifocal Electroretinogram,
* Vision-related function and quality of life, as measured by the 25-Item National Eye Institute Visual Function Questionnaire (NEI VFQ-25)

Primary outcomes

• BCVA - Better Seeing Eyes [1 year follow up visit]: Change (from Baseline) in Best Corrected Visual acuity (BCVA) in the better-seeing eyes. BCVA in the better seeing eyes was assessed using the ETRS score (minimum value 0 and maximum value 100, with 0 representing the worst, and 100 the best visual functioning). The results are reported as the change in ETDRS score collected at the 1 year follow-up visit compared with the score at the baseline visit.
• BCVA - Better Seeing Eyes [2 year follow up visit]: Change (from Baseline) in Best Corrected Visual acuity (BCVA) in the better-seeing eyes. BCVA in the better seeing eyes was assessed using the ETRS score (minimum value 0 and maximum value 100, with 0 representing the worst, and 100 the best visual functioning). The results are reported as the change in ETDRS score collected at the 2 year follow-up visit compared with the score at the baseline visit.
• III4e Area - Better Seeing Eyes [1 year follow up visit]: Change (from Baseline) in visual field area using III4e stimulus size in the better seeing eyes. Visual field area using III4e stimulus size in the better seeing eyes is expressed in degree squared (minimum value 0, maximum value 20000). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• III4e Area - Better Seeing Eyes [2 year follow up visit]: Change (from Baseline) in visual field area using III4e stimulus size in the better seeing eyes. Visual field area using III4e stimulus size in the better seeing eyes is expressed in degree squared (minimum value 0, maximum value 20000). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.
• V4e Area - Better Seeing Eyes [1 year follow up visit]: Change (from Baseline) in visual field area using V4e stimulus size in the better seeing eyes. Visual field area using V4e stimulus size in the better seeing eyes is expressed in degree squared (minimum value 0, maximum value 20000). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• V4e Area - Better Seeing Eyes [2 year follow up visit]: Change (from Baseline) in visual field area using V4e stimulus size in the better seeing eyes. Visual field area using V4e stimulus size in the better seeing eyes is expressed in degree squared (minimum value 0, maximum value 20000). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.
• BCVA - Worse Seeing Eyes [1 year follow up visit]: Change (from Baseline) in Best Corrected Visual acuity (BCVA) in the worse seeing eyes. BCVA in the worse seeing eyes was assessed using the ETRS score (minimum value 0 and maximum value 100, with 0 representing the worst, and 100 the best visual functioning). The results are reported as the change in the ETDRS score collected at the 1 year follow-up visit compared with the score at the baseline visit.
• BCVA - Worse Seeing Eyes [2 years follow up visit]: Change (from Baseline) in Best Corrected Visual acuity in the worse seeing eyes. Best corrected visual acuity in the worse seeing eyes was assessed using the ETRS score (minimum value 0 and maximum value 100, with 0 representing the worst, and 100 the best visual functioning). The results are reported as the change in the ETDRS score collected at the 2 year follow-up visit compared with the score at the baseline visit.
• III4e Area - Worse Seeing Eyes [1 year follow up visit]: Change (from Baseline) in visual field area using III4e stimulus size in the worse-seeing eyes. Visual field area using III4e stimulus size in the worse-seeing eyes is expressed in degree squared (minimum value 0, maximum value 20000). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• III4e Area - Worse Seeing Eyes [2 years follow up visit]: Change (from Baseline) in visual field area using III4e stimulus size in the worse-seeing eyes. Visual field area using III4e stimulus size in the worse-seeing eyes is expressed in degree squared (minimum value 0, maximum value 20000). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.
• V4e Area - Worse Seeing Eyes [1 year follow up visit]: Change (from Baseline) in visual field area using V4e stimulus size in the worse-seeing eyes. Visual field area using V4e stimulus size in the worse-seeing eyes is expressed in degree squared (minimum value 0, maximum value 20000). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• V4e Area - Worse Seeing Eyes [2 years follow up visit]: Change (from Baseline) in visual field area using V4e stimulus size in the worse-seeing eyes. Visual field area using V4e stimulus size in the worse-seeing eyes is expressed in degree squared (minimum value 0, maximum value 20000). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.

Secondary outcomes

• MS - Better Seeing Eyes [1 year follow up visit]: Change (from Baseline) in macular sensitivity, assessed by microperimetry, in the better-seeing eyes. Macular sensitivity, assessed by microperimetry is expressed in decibels (minimum value 0, maximum value 30). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• MS - Better Seeing Eyes [2 years follow up visit]: Change (from Baseline) in macular sensitivity, assessed by microperimetry, in the better-seeing eyes. Macular sensitivity, assessed by microperimetry is expressed in decibels (minimum value 0, maximum value 30). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.
• CMT - Better Seeing Eyes [1 year follow up visit]: Change (from Baseline) in Central Macular Thickness (CMT), evaluated with Optical Coherence tomography, in the better-seeing eyes. CMT was reported in micrometers (minimum value 0, maximum value 1000). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• CMT - Better Seeing Eyes [2 years follow up visit]: Change (from Baseline) in Central Macular Thickness (CMT), evaluated with Optical Coherence tomography, in the better-seeing eyes. CMT was reported in micrometers (minimum value 0, maximum value 1000). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.
• EZ Band Horizontal - Better Seeing Eyes [1 year follow up visit]: Change (from Baseline) in Ellipsoid Zone Band Width, evaluated with Optical Coherence tomography (horizontal scan), in the better-seeing eyes. EZ Band Horizontal is reported in micrometers (minimum value 0, maximum value 4000). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• EZ Band Horizontal - Better Seeing Eyes [2 years follow up visit]: Change (from Baseline) in Ellipsoid Zone Band Width, evaluated with Optical Coherence tomography (horizontal scan), in the better-seeing eyes. EZ Band Horizontal is reported in micrometers (minimum value 0, maximum value 4000). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.
• EZ Band Vertical - Better Seeing Eyes [1 year follow up visit]: Change (from Baseline) in Ellipsoid Zone Band Width, evaluated with Optical Coherence tomography (Vertical scan), in the better-seeing eyes. EZ Band Vertical is reported in micrometers (minimum value 0, maximum value 4000). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• EZ Band Vertical - Better Seeing Eyes [2 years follow up visit]: Change (from Baseline) in Ellipsoid Zone Band Width, evaluated with Optical Coherence tomography (Vertical scan), in the better-seeing eyes. EZ Band Vertical is reported in micrometers (minimum value 0, maximum value 4000). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.
• MS - Worse Seeing Eyes [1 year follow up visit]: Change (from Baseline) in macular sensitivity, assessed by microperimetry, in the worse-seeing eyes. Macular sensitivity, assessed by microperimetry is expressed in decibels (minimum value 0, maximum value 30). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• MS - Worse Seeing Eyes [2 years follow up visit]: Change (from Baseline) in macular sensitivity, assessed by microperimetry, in the worse-seeing eyes. Macular sensitivity, assessed by microperimetry is expressed in decibels (minimum value 0, maximum value 30). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.
• CMT - Worse Seeing Eyes [1 year follow up visit]: Change (from Baseline) in Central Macular Thickness (CMT), evaluated with Optical Coherence tomography, in the worse-seeing eyes. CMT is expressed in micrometers (minimum value 0, maximum value 1000). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• CMT - Worse Seeing Eyes [2 years follow up visit]: Change (from Baseline) in Central Macular Thickness, evaluated with Optical Coherence tomography, in the worse-seeing eyes. CMT is expressed in micrometers (minimum value 0, maximum value 1000). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.
• EZ Band Horizontal - Worse Seeing Eyes [1 year follow up visit]: Change (from Baseline) in Ellipsoid Zone Band Width, evaluated with Optical Coherence tomography (horizontal scan), in the worse-seeing eyes. EZ Band Horizontal is expressed in micrometers (minimum value 0, maximum value 4000). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• EZ Band Horizontal - Worse Seeing Eyes [2 years follow up visit]: Change (from Baseline) in Ellipsoid Zone Band Width, evaluated with Optical Coherence tomography (horizontal scan), in the worse-seeing eyes. EZ Band Horizontal is expressed in micrometers (minimum value 0, maximum value 4000). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.
• EZ Band Vertical - Worse Seeing Eyes [1 year follow up visit]: Change (from Baseline) in Ellipsoid Zone Band Width, evaluated with Optical Coherence tomography (Vertical scan), in the worse-seeing eyes. EZ Band Vertical is expressed in micrometers (minimum value 0, maximum value 4000). The results are reported as the change in the values collected at the 1 year follow-up visit compared with the values at the baseline visit.
• EZ Band Vertical - Worse Seeing Eyes [2 years follow up visit]: Change (from Baseline) in Ellipsoid Zone Band Width, evaluated with Optical Coherence tomography (Vertical scan), in the worse-seeing eyes. EZ Band Vertical is expressed in micrometers (minimum value 0, maximum value 4000). The results are reported as the change in the values collected at the 2 year follow-up visit compared with the values at the baseline visit.

Sex: All, ages: 8 Years to any

Inclusion Criteria:

1. Must be willing to adhere to protocol for long-term follow-up as evidenced by written informed consent or parental permission and subject assent.
2. Subjects diagnosed with USH1.
3. Molecular diagnosis of USH1B due to MYO7A mutations (homozygotes or compound heterozygotes).
4. Age eight years old or older at the time of baseline.
5. Visual acuity ≥ 20/640 in at least one eye

Exclusion Criteria:

1. Unable or unwilling to meet requirements of the study.
2. Unable to communicate with suitable verbal/auditory and/or tactile sign language (in the opinion of the investigator)
3. Participation in a clinical study with an investigational drug in the past six months.
4. Pre-existing eye conditions that would interfere with the interpretation of study endpoints (for example, glaucoma, corneal or significant lenticular opacities, cystoid macular oedema, macular hole).
5. Complicating systemic diseases in which the disease itself, or the treatment for the disease, can alter ocular function. Examples are malignancies whose treatment could affect central nervous system function (for example, radiation treatment of the orbit; leukemia with CNS/optic nerve involvement). Also excluded would be subjects with immuno- compromising diseases, as there could be susceptibility to opportunistic infection \[such as cytomegalovirus (CMV) retinitis\].
6. Subjects with diabetes or sickle cell disease would be excluded if they had any manifestation of advanced retinopathy (e.g. macular edema or proliferative changes).
7. Prior ocular surgery within three months.
8. Any other condition that would not allow the potential subject to complete follow-up examinations during the course of the study and, in the opinion of the investigator, makes the potential subject unsuitable for the study.

Participant flow

Outcome results

• BCVA - Better Seeing Eyes (Primary), Mean, ETDRS score: Group of Subjects With Usher Syndrome Type 1B -2.26 +/- 3.838 (p <0.01)
• BCVA - Better Seeing Eyes (Primary), Mean, ETDRS score: Group of Subjects With Usher Syndrome Type 1B -1.468 +/- 4.999 (p <0.01)
• III4e Area - Better Seeing Eyes (Primary), Mean, degree squared: Group of Subjects With Usher Syndrome Type 1B 561.966 +/- 2043.612 (p 0.3269)
• III4e Area - Better Seeing Eyes (Primary), Mean, degree squared: Group of Subjects With Usher Syndrome Type 1B 70.286 +/- 1451.128 (p 0.4265)
• V4e Area - Better Seeing Eyes (Primary), Mean, degree squared: Group of Subjects With Usher Syndrome Type 1B 273.309 +/- 2432.785 (p 0.4782)
• V4e Area - Better Seeing Eyes (Primary), Mean, degree squared: Group of Subjects With Usher Syndrome Type 1B 700.245 +/- 3942.6 (p 0.2716)
• BCVA - Worse Seeing Eyes (Primary), Mean, ETDRS score: Group of Subjects With Usher Syndrome Type 1B -0.625 +/- 5.35 (p 0.4178)
• BCVA - Worse Seeing Eyes (Primary), Mean, ETDRS score: Group of Subjects With Usher Syndrome Type 1B -0.909 +/- 7.041 (p 0.2677)
• III4e Area - Worse Seeing Eyes (Primary), Mean, degree squared: Group of Subjects With Usher Syndrome Type 1B -445.569 +/- 2920.491 (p 0.3364)
• III4e Area - Worse Seeing Eyes (Primary), Mean, degree squared: Group of Subjects With Usher Syndrome Type 1B -407.928 +/- 3209.147 (p 0.1124)
• V4e Area - Worse Seeing Eyes (Primary), Mean, degree squared: Group of Subjects With Usher Syndrome Type 1B 391.212 +/- 2726.331 (p 0.2649)
• V4e Area - Worse Seeing Eyes (Primary), Mean, degree squared: Group of Subjects With Usher Syndrome Type 1B 610.017 +/- 5658.524 (p 0.216)
• MS - Better Seeing Eyes (Secondary), Mean, decibels: Group of Subjects With Usher Syndrome Type 1B 0.137 +/- 2.89 (p 0.9032)
• MS - Better Seeing Eyes (Secondary), Mean, decibels: Group of Subjects With Usher Syndrome Type 1B -0.315 +/- 7.174 (p 0.7889)
• CMT - Better Seeing Eyes (Secondary), Mean, micrometers: Group of Subjects With Usher Syndrome Type 1B 7 +/- 21.532 (p 0.0242)
• CMT - Better Seeing Eyes (Secondary), Mean, micrometers: Group of Subjects With Usher Syndrome Type 1B -5.667 +/- 18.877 (p 0.5092)
• EZ Band Horizontal - Better Seeing Eyes (Secondary), Mean, micrometers: Group of Subjects With Usher Syndrome Type 1B -42.795 +/- 324.893 (p 0.3634)
• EZ Band Horizontal - Better Seeing Eyes (Secondary), Mean, micrometers: Group of Subjects With Usher Syndrome Type 1B -160.556 +/- 628.761 (p 0.0677)
• EZ Band Vertical - Better Seeing Eyes (Secondary), Mean, micrometers: Group of Subjects With Usher Syndrome Type 1B -289.75 +/- 1107.784 (p 0.156)
• EZ Band Vertical - Better Seeing Eyes (Secondary), Mean, micrometers: Group of Subjects With Usher Syndrome Type 1B 190.553 +/- 1276.729 (p 0.3148)
• 8 more outcome measures not shown.

Adverse events

Time frame: 1 year, 2 years

• Study Protocol and Statistical Analysis Plan (PDF, 2018-03-16)
• Informed Consent Form (PDF, 2018-03-16)

• FRANCESCA SIMONELLI, Principal investigator, Eye Clinic of the University of Campania Luigi Vanvitelli, Naples, Italy
• Ingeborgh van den Born, Principal investigator, Stichting Oogziekenhuis Rotterdam, Rotterdam, The Netherland.
• Carmen Ayuso, Principal investigator, Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz, Madrid, Spain