Protocol for NAC Attack, a phase-3, multicenter randomized, parallel, double masked, placebo controlled trial evaluating the efficacy and safety of oral N-acetylcysteine (NAC) in patients with retinitis pigmentosa.

Background: Retinitis pigmentosa (RP) is the most common inherited retinal disease. Genetic mutations of many genes have been linked to RP. The mutations cause rod photoreceptor degeneration while sparing cone photoreceptors. However, loss of rod photoreceptors results in oxidative stress leading to cone photoreceptors degeneration, causing constriction of visual fields. In animal models of RP, treatments that reduce oxidative stress, including N-acetylcysteine (NAC), promote cone survival and maintenance of function. Methods: NAC Attack, funded by the US National Institutes of Health, is a multicenter, randomized, double-masked, parallel and placebo-controlled clinical trial testing whether oral NAC can delay disease progression in RP. A total of about 483 RP patients aged 18-65 are recruited from 31 sites in America and Europe, and randomized 2:1 to take NAC 1800 mg bid or placebo for 45 months. Eligible eyes have best-corrected visual acuity (BCVA) of 20/63 or better and the ellipsoid zone (EZ) width on the horizontal fovea optical coherence tomography (OCT) scan between 1500 µm and 8000 µm. The primary outcome is the cumulative loss of EZ, calculated as the area above the curve using EZ width measured every 9 months over 45 months. Secondary outcomes are change in mean macular sensitivity (MMS) measured by microperimetry and change in BCVA best-corrected visual acuity (BCVA) from baseline to M45. The long-term safety and tolerability of oral NAC 1800 mg bid will be assessed based upon the incidence and severity of ocular and systemic adverse events. Discussion: Data from NAC Attack will provide clinical evidence (or lack of) on the role of oxidative stress in human RP. Findings from NAC Attack have the potential to change clinical management of a blinding disease and will lead to a better understanding of basic mechanisms in RP. Moreover, data from NAC Attack will advance our knowledge on safety and drug interaction of NAC, informing studies in other medical areas where NAC is of interest for its potential in treating many medical conditions. Therefore, the trial is of high public health, clinical, and scientific significances. Trial registration: The ClinicalTrials.gov ID for NAC Attack is NCT05537220 .