Retinitis Pigmentosa
Conditions
Keywords
N-acetylcysteine, Ellipsoid zone, Macular sensitivity, Best corrected visual acuity, Ellipsoid zone width, Ellipsoid zone area, Oxidative damage, Usher Syndrome, Antioxidants
Brief summary
Retinitis pigmentosa (RP) is an inherited retinal degeneration caused by one of several mistakes in the genetic code. Such mistakes are called mutations. The mutations cause degeneration of rod photoreceptors which are responsible for vision in dim illumination resulting in night blindness. After rod photoreceptors are eliminated, gradual degeneration of cone photoreceptors occurs resulting in gradual constriction of side vision that eventually causes tunnel vision. Oxidative stress contributes to cone degeneration. N-acetylcysteine (NAC) reduces oxidative stress and in animal models of RP it slowed cone degeneration. In a phase I clinical trial in patients with RP, NAC taken by month for 6 months caused some small improvements in two different vision tests suggesting that long-term administration of NAC might slow cone degeneration in RP. NAC Attack is a clinical trial being conducted at many institutions in the US, Canada, and Europe designed to determine if taking NAC for several years provides benefit in patients with RP.
Detailed description
Retinitis Pigmentosa (RP) is a disease in which one of several different mutations differentially causes degeneration of rod photoreceptors while sparing cone photoreceptors. The loss of rod photoreceptors results in poor vision in dim illumination (night blindness), but does not affect most activities of daily life including reading or driving. However, after most rod photoreceptors are eliminated, cone photoreceptors begin to die, resulting in gradual constriction of visual fields which over time causes visual disability. Rods outnumber cones by a ratio of 95:5 and therefore after mutation-induced degeneration of rods, the majority of cells in the outer retina have been eliminated, markedly reducing oxygen utilization. However, oxygen supply is unchanged resulting in a large excess of tissue oxygen surrounding cones. This results in progressive oxidative damage that contributes to slowly progressive degeneration of cone photoreceptors. N-acetylcysteine (NAC) is a strong antioxidant that is approved for acetaminophen overdose. Orally administered NAC in a mouse model of RP reduced oxidative damage to cones and promoted maintenance of function and survival of cones. In a phase I clinical trial in patients with RP, oral administration of NAC for 6 months was well-tolerated and resulted in a small but statistically significant improvement in visual acuity and light sensitivity in the retina. This suggests that long-term administration of NAC may promote survival and maintenance of function of cones. NAC Attack is a phase III, multicenter, randomized, placebo controlled trial that will determine if oral NAC provides benefit and is safe in patients with RP.
Interventions
DRUGN-acetylcysteine
After randomization, participants will be given about 10-months supply of study drug (intervention), with instructions to take 3 effervescent tablets in water twice a day. They will return to the clinic at M4.5 for evaluation and then at M9, M18, M27, M36, M40.5 and M45. At each in-clinic visit, drug reconciliation will occur. At each visit at Baseline, M9, M18, M27, M36, that is, every 9 months, participants will be given another 10-month supply of study drug.
DRUGPlacebo
After randomization, participants will be given about 10-months supply of placebo, with instructions to take 3 effervescent tablets in water twice a day. They will return to the clinic at M4.5 for evaluation and then at M9, M18, M27, M36, M40.5 and M45. At each in-clinic visit, efficacy and safety assessments will be done and drug reconciliation will occur. At baseline, M9, M18, M27, and M36 participants will be given another 10-month supply of placebo.
Sponsors
Johns Hopkins University
National Eye Institute (NEI)
Duke University
Emory University
Massachusetts Eye and Ear Infirmary
Mayo Clinic
Medical College of Wisconsin
Retina Foundation of the Southwest
Stanford University
University of California, Davis
University of Florida
University of Iowa
University of Miami
University of Michigan
University of Minnesota
University of Oklahoma
University of Southern California
University of Utah
University of Washington
University of Wisconsin, Madison
Vanderbilt University
Vitreo Retinal Associates, PA
University of Houston
Medical University of Graz
McGill University
Universität Tübingen
Radboud University Medical Center
University of Amsterdam
University Hospital, Basel, Switzerland
University College London Hospitals
Northwestern University
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
483 participants will be enrolled and randomized at approximately 30 clinical sites in the Americas and Europe. Patients will be eligible if both eyes have an RP phenotype consisting of severe loss of rod function (night blindness) followed by progressive constriction of visual fields with best-corrected visual acuity (BCVA) of 20/60 or better. Gradable ellipsoid zone (EZ) width on the horizontal fovea spectral domain-optical coherence tomography (SD-OCT) scan must be \< 8000 µm and ≥ 1500 µm. Eligible patients will be randomized 2:1 to NAC 1800 mg bid versus placebo. The primary efficacy objective is to determine if the progressive loss in EZ width measured as the cumulative loss of EZ (calculated as the area above the curve) between baseline and month (M) 45 is significantly less in eyes of participants taking NAC 1800 mg bid compared with that in eyes of participants taking placebo. The safety objective is to evaluate the long-term safety and tolerability of oral NAC for 45 months.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
General * Ability and willingness to provide informed consent * Age ≥ 18 and ≤65 years at time of signing Informed Consent Form * Ability and willingness to comply with the study protocol and to participate in all study visits and assessments in the investigator's judgement * For candidates of childbearing potential: willingness to use a method of contraception * Agreement not to take supplements other than vitamin A Ocular Inclusion Criteria * Both eyes must exhibit the RP phenotype with evidence of loss of night vision, gradual constriction of visual fields, and maintenance of visual acuity; * In addition, an eye must meet the following criteria to be included in the study: * Gradable EZ on a horizontal SD-OCT scan through the fovea center with width ≤ 8000 µm and ≥1500 µm and with well-defined truncation at both the nasal and temporal sides; * BCVA ≥ ETDRS letter score of 61 (20/60 Snellen equivalent); * Sufficiently clear ocular media and adequate pupillary dilation to allow good quality images sufficient for analysis and grading by central reading center.
Exclusion criteria
General
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progressive change of ellipsoid zone (EZ) width | Baseline and 45 months | The EZ is a hyperreflective band seen on SD-OCT scans that corresponds to photoreceptors with intact inner and outer segments. In RP patients at the stage of those participating in this trial, the EZ consists primarily of remaining cones with intact inner and outer segments. The EZ width is the length of the EZ on a horizontal SD-OCT scan through the fovea and provides a quantitative measure of surviving cones. The primary outcome measure is the progressive change (loss) in EZ width measured as the cumulative loss of EZ (calculated as the area above the curve) between baseline and month (M) 45. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in mean macular sensitivity measured by microperimetry (MP) | Baseline and 45 months | The macula is the functional center of the retina. Macular sensitivity is a measure of the sensitivity to light assessed at focal points within the macula. It is measured by microperimetry (MP), a test in which light stimuli of many different intensities are presented at multiple loci in the macula and the response or lack of response to those stimuli are recorded. Sensitivity is determined by the weakest light stimulus that is detected at a locus. The mean macular sensitivity is the average of the sensitivity measurements at the test loci and provides a quantitative assessment of macula function. |
| Change in best-corrected visual acuity | Baseline and 45 months | Visual acuity is the vision mediated by the fovea (the center of the macula) that is used for fine visual tasks including reading and driving. In order to measure the best-corrected visual acuity (BCVA), it is necessary to eliminate all refractive error with lenses to optimally focus images on the fovea. This is done using a standardized protocol established in the Early Treatment Diabetic Retinopathy Study (ETDRS); it measures the number of letters read at 4 meters on a standardized chart under standardized lighting conditions. Since the fovea is made up of cones, BCVA is a measure of cone function. |
Countries
Austria, Canada, Germany, Netherlands, Switzerland, United Kingdom, United States
Contacts
STUDY_CHAIRPeter A Campochiaro, MD
Johns Hopkins University
STUDY_DIRECTORXiangrong Kong
Johns Hopkins University
Outcome results
None listed