Retinitis Pigmentosa, Usher Syndrome Type 2, Usher Syndrome Type 3
Conditions
Keywords
Retinitis pigmentosa, Usher syndrome type 2, Usher syndrome type 3, Cone photoreceptor, Vision, Blind
Brief summary
This clinical trial is a single-site, 30 patient study for participants who have early stage retinitis pigmentosa, or Usher syndrome (type 2 or 3). Funding Source - FDA OOPD and Foundation Fighting Blindness.
Detailed description
This clinical trial is a prospective, randomized, double-masked, sham-controlled trial of 30 study participants who have early-stage retinitis pigmentosa, or Usher syndrome (type 2 or 3). The trial will be conducted at the University of California, San Francisco. Individuals with these diseases experience gradually worsening vision that ultimately may lead to blindness due to a genetic condition in which specialized cells in the eye's retina called photoreceptor cells cease functioning and/or die. The study is intended to use a relatively new, non-invasive technology called AOSLO (adaptive optics scanning laser ophthalmoscopy) in combination with a routine standard of care measurement called sdOCT (Spectral Domain Optical Coherence Tomography) to demonstrate that when a device that secretes an investigational drug called CNTF (Ciliary Neurotrophic Factor) is surgically placed in the patient's eye, one type of photoreceptor called cone photoreceptors is preserved such that the gradual loss of vision is halted.
Interventions
DRUGNT-501
Study participants will undergo surgery to have an NT-501 Encapsulated Cell Therapy implant placed into the study eye.
PROCEDURESham
Non-penetrating sham procedure to mimic implant procedure in the other eye.
Sponsors
University of California, San Francisco
Neurotech Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Participants are considered in screening upon signing of the consent. Enrollment does not occur until participant is deemed eligible, as per screening, and randomized for implant. As such, there were 22 total participants enrolled in the study. There was a participant who died prior to screening procedures being conducted of which was captured in the AE section as the death occurred after consent to enter screening period. However, this participant was not enrolled as they had not completed screening or randomization for implant.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Participant must be between 18 and 55 years of age. 2. Participant must have a diagnosis of retinitis pigmentosa or Usher Syndrome type 2 or 3 (without profound deafness or cochlear implants). 3. Participant must understand and sign the protocol informed consent. If the participant's vision is impaired to the point where he/she cannot read the informed consent document, the document will be read to the participant in its entirety. 4. Best-corrected visual acuity must be no worse than 20/63 (at least 59 letters). 5. Participants must have clear natural lenses. 6. Participants must have less than 6 diopters myopia. 7. Participants must be medically able to undergo ophthalmic surgery for the NT-501 device insertion and able to undergo all assessments and tests associated with the protocol. 8. Females of childbearing potential (women with last menses \<1 year prior to screening) must agree to use an effective form of birth control from study onset until they complete the study. 9. Participants must have reproducible baseline AOSLO image at 2 baseline imaging sessions with quality suitable to identify a minimum of 7 regions of interest (ROIs) at which reliable cone spacing and/or density measures can be made over the central 5.7 degrees. 10. Participants must have interocular symmetry of disease severity as measured by cone spacing, with a difference of less than 2 standard deviations in average cone spacing z-scores at the selected ROIs between the 2 eyes. 11. Participant's clinical diagnosis must be consistent with retinal degeneration in the set of retinitis pigmentosa (RP) dystrophies.
Exclusion criteria
1. Participant is medically unable to comply with study procedures or follow-up visits. 2. Participant who has any of the following lens opacities: cortical opacity \> standard 3, posterior subcapsular opacity \> standard 3, or a nuclear opacity \> standard 3 as measured on the AREDS clinical lens grading system; or participant is pseudophakic or aphakic. 3. Participant has history of corneal opacification or lack of optical clarity. 4. Participant has undergone LASIK surgery or other refractive surgery for either eye. 5. Participant has nystagmus. 6. Participant has greater than 6 diopters myopia. 7. Participant has cystoid macular edema with cysts present within 4 degrees of the foveal center that prevent acquisition of at least 7 regions of interest with clear images of cone photoreceptors. 8. Participant has fewer than 7 regions of interest (ROIs) present on 2 baseline AOSLO image montages. 9. Participant has retinal vascular disease such as diabetic retinopathy or prior retinal vascular occlusive disease. 10. Participant has chronic requirement (e.g., ≥4 weeks at a time) for ocular medications or has disease(s) that in the judgment of the examining physician are vision threatening, toxic to the lens, retina, or optic nerve or may affect the primary outcome. 11. Participant has a requirement of acyclovir and/or related products during study duration. To be eligible for this study, the participant must discontinue use of these products prior to enrollment and must not continue with the products until after they have completed the study. 12. Participant is receiving systemic steroids or other immunosuppressive medications. 13. Participant is currently participating in or has participated in any other clinical trial of a drug by ocular or systemic administration within the last 6 months. 14. Participant has previous exposure to an intra-ocular device or implant into the eye (excluding intra-ocular lens). 15. Participant has uveitis or other retinal inflammatory disease. 16. Participant has a history of myocardial infarction within the last 12 months. 17. Participant is pregnant or lactating. 18. Participant is considered immunodeficient or has a known history of HIV. A laboratory test for HIV will be performed, and a positive result is also an exclusion criterion. 19. Participant with a history of ocular herpes zoster. 20. Participant is on chemotherapy. 21. Participant has a history of malignancy, except study participant with cancer treated successfully ≥5 years prior to inclusion in the trial. 22. Participant with severe hearing disabilities in both ears. 23. Participant who has been diagnosed and treated for amblyopia as an infant. 24. Participant who, in the opinion of the study doctor, will not be a good study subject.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Cone Spacing in Arcminutes (Z Score) of 2 Baseline Values Were Compared With Measurements Obtained at Post-op Month 36 | Post-op Month 36 | Average of cone spacing (nearest neighbor distance) at all regions of interest with at least 50 contiguous unambiguous cones identified over the central 5.7 degrees of the macula using confocal AOSLO at two baseline visits within each eye. Cone spacing measures were converted to Z scores based on normal mean values at similar distances from the fovea from a database of 27 age-similar normal eyes. The mean of 2 baseline cone spacing Z-score values were subtracted from the cone spacing Z score values obtained at post-op month 36 A Z-score of 0 represents the mean cone spacing value at the distance from the fovea measured from 27 healthy subjects. A Z-score greater than +2 represents an abnormally increased cone spacing value at the distance from the fovea where the measurement was performed. This suggests fewer cones are present than normal at that location. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in logMAR Visual Acuity Change Between CNTF- and Sham Treated Eyes | Post-op Month 36 | Difference in change in logMAR visual acuity between NT-501 and contralateral sham-treated eyes. Change in visual acuity was measured based on the number of letters read on a vision chart using a standard protocol. The log of the mean angle of resolution (logMAR) was used to describe the size of the smallest letters that the patient could read. A logMAR value of 0.00 corresponds to visual acuity of 20/20, a logMAR value of 0.3 corresponds to visual acuity of 20/40, a logMAR value of 0.7 corresponds to visual acuity of 20/100, and a logMAR value of 1.00 corresponds to visual acuity of 20/200. |
Countries
United States
Participant flow
Recruitment details
Eligible subjects were \>18 years old with retinitis pigmentosa or Usher syndrome and adaptive optics scanning laser ophthalmoscopy (AOSLO) images in each eye with at least 7 regions having at least 50 contiguous unambiguous cones in the central 5.7 degrees of the macula at 2 baseline visits. Exclusion criteria included visual acuity worse than 20/40, lens opacity, \> -6.00 D myopia, nystagmus, cystoid macular edema, retinal vascular disease, unstable fixation, and severe hearing loss.
Participants by arm
| Arm | Count |
|---|---|
| NT-501 Implant A pre-determined randomization scheme will be utilized to designate each of the patient's eyes as the primary eye (to receive the NT-501 implant) or the fellow eye (Control-to receive sham surgery). Primary eye will receive the NT-501 implant | 22 |
| NT-501 Implant A pre-determined randomization scheme will be utilized to designate each of the patient's eyes as the primary eye (to receive the NT-501 implant) or the fellow eye (Control-to receive sham surgery). Primary eye will receive the NT-501 implant | 22 |
| Sham Surgery A pre-determined randomization scheme will be utilized to designate each of the patient's eyes as the primary eye (to receive the NT-501 implant) or the fellow eye (Control-to receive sham surgery). | 22 |
| Sham Surgery A pre-determined randomization scheme will be utilized to designate each of the patient's eyes as the primary eye (to receive the NT-501 implant) or the fellow eye (Control-to receive sham surgery). | 22 |
| Total | 88 |
Baseline characteristics
| Characteristic | NT-501 Implant | Sham Surgery | Total |
|---|---|---|---|
| Age, Continuous | 39.8 Years STANDARD_DEVIATION 11.9 | 39.8 Years STANDARD_DEVIATION 11.9 | 39.8 Years STANDARD_DEVIATION 11.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Eyes | 2 Eyes | 4 Eyes |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Eyes | 20 Eyes | 40 Eyes |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Eyes | 0 Eyes | 0 Eyes |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Eyes | 1 Eyes | 2 Eyes |
| Race (NIH/OMB) Asian | 2 Eyes | 2 Eyes | 4 Eyes |
| Race (NIH/OMB) Black or African American | 0 Eyes | 0 Eyes | 0 Eyes |
| Race (NIH/OMB) More than one race | 0 Eyes | 0 Eyes | 0 Eyes |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Eyes | 1 Eyes | 2 Eyes |
| Race (NIH/OMB) Unknown or Not Reported | 0 Eyes | 0 Eyes | 0 Eyes |
| Race (NIH/OMB) White | 18 Eyes | 18 Eyes | 36 Eyes |
| Region of Enrollment United States | 22 Eyes | 22 Eyes | 44 Eyes |
| Sex: Female, Male Female | 9 Eyes | 9 Eyes | 18 Eyes |
| Sex: Female, Male Male | 13 Eyes | 13 Eyes | 26 Eyes |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 22 | 1 / 1 |
| other Total, other adverse events | 2 / 22 | 1 / 22 | 0 / 0 |
| serious Total, serious adverse events | 4 / 22 | 4 / 22 | 0 / 0 |
Outcome results
Primary
Mean Change in Cone Spacing in Arcminutes (Z Score) of 2 Baseline Values Were Compared With Measurements Obtained at Post-op Month 36
Average of cone spacing (nearest neighbor distance) at all regions of interest with at least 50 contiguous unambiguous cones identified over the central 5.7 degrees of the macula using confocal AOSLO at two baseline visits within each eye. Cone spacing measures were converted to Z scores based on normal mean values at similar distances from the fovea from a database of 27 age-similar normal eyes. The mean of 2 baseline cone spacing Z-score values were subtracted from the cone spacing Z score values obtained at post-op month 36 A Z-score of 0 represents the mean cone spacing value at the distance from the fovea measured from 27 healthy subjects. A Z-score greater than +2 represents an abnormally increased cone spacing value at the distance from the fovea where the measurement was performed. This suggests fewer cones are present than normal at that location.
Time frame: Post-op Month 36
Population: Measure type: difference from mean baseline to 36 months in change between intervention and control eyes in mean cone spacing Z score averaged over regions of interest in each eye.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NT-501 Implant | Mean Change in Cone Spacing in Arcminutes (Z Score) of 2 Baseline Values Were Compared With Measurements Obtained at Post-op Month 36 | 1.13 Difference in change in Z score | Standard Deviation 1.03 |
| Sham Surgery | Mean Change in Cone Spacing in Arcminutes (Z Score) of 2 Baseline Values Were Compared With Measurements Obtained at Post-op Month 36 | 0.85 Difference in change in Z score | Standard Deviation 1.78 |
Secondary
Difference in logMAR Visual Acuity Change Between CNTF- and Sham Treated Eyes
Difference in change in logMAR visual acuity between NT-501 and contralateral sham-treated eyes. Change in visual acuity was measured based on the number of letters read on a vision chart using a standard protocol. The log of the mean angle of resolution (logMAR) was used to describe the size of the smallest letters that the patient could read. A logMAR value of 0.00 corresponds to visual acuity of 20/20, a logMAR value of 0.3 corresponds to visual acuity of 20/40, a logMAR value of 0.7 corresponds to visual acuity of 20/100, and a logMAR value of 1.00 corresponds to visual acuity of 20/200.
Time frame: Post-op Month 36
Population: Difference in change in logMAR visual acuity between NT-501 and contralateral sham-treated eyes.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NT-501 Implant | Difference in logMAR Visual Acuity Change Between CNTF- and Sham Treated Eyes | 0.004 logMAR | Standard Deviation 0.01 |
| Sham Surgery | Difference in logMAR Visual Acuity Change Between CNTF- and Sham Treated Eyes | 0.014 logMAR | Standard Deviation 0.082 |