Oral N-acetylcysteine for Retinitis Pigmentosa

Study Overview
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Brief Summary
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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, Mexico, and Europe designed to determine if taking NAC for several years provides benefit in patients with RP.

Detailed Description
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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.

Official Title
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NAC Attack, A Phase III, Multicenter, Randomized, Parallel, Double Masked, Placebo-Controlled Study Evaluating the Efficacy and Safety of Oral N-Acetylcysteine in Patients With Retinitis Pigmentosa

Conditions
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Retinitis Pigmentosa

Intervention / Treatment
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* Drug: N-acetylcysteine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 Exclusion Criteria Active cancer within the past 12 months, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or prostate cancer with Gleason score ≤ 6 and stable prostate specific antigen for > 12 months Renal failure requiring renal transplant, hemodialysis, peritoneal dialysis, or anticipated to require hemodialysis or peritoneal dialysis during the study Liver disease, cystic fibrosis, asthma, or chronic obstructive pulmonary disease (COPD), history of thrombocytopenia not due to a reversible cause or other blood dyscrasia Uncontrolled blood pressure (defined as systolic > 180 and/or diastolic > 100 mmHg while at rest) at screening. If a patient's initial measurement exceeds these values, a second reading may be taken 30 or more minutes later. If the patient's blood pressure must be controlled by antihypertensive medication, the patient may become eligible if medication is taken continuously for at least 30 days. History of other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion that oral NAC may be contraindicated or that follow up may be jeopardized Cerebrovascular accident or myocardial infarction within 6 months of screening Participation in an investigational study that involves treatment with any drug or device within 6 months of screening Three relatives already enrolled in study Pregnant, breast feeding, or intending to become pregnant during the study treatment period. Women of childbearing potential who have not had tubal ligation must have a urine pregnancy test at screening. Known history of allergy to NAC Having taken NAC in any form in the past 4 months Phenylketonuria Fructose intolerance Glucose-galactose malabsorption Sucrase-isomaltase insufficiency Abnormal laboratory value including the value of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin being greater than 1.5 x the upper limit of normal Any major abnormal findings on blood chemistry, hematology, and renal function lab tests that in the opinion of the Site Investigator and/or the Study Chair makes the candidate not suitable to participate in the trial HIV or hepatitis B infection Ocular Exclusion Criteria Evidence of cone-rod dystrophy or pattern dystrophy including focal areas of atrophy or pigmentary changes in the central macula Cystoid spaces involving the fovea substantially reducing vision Glaucoma or other optic nerve disease causing visual field loss or reduced visual acuity Intra ocular pressure >27 mm Hg from two measurements. If a patient's initial measurement exceeds 27 mm Hg, a second reading must be taken. Any retinal disease other than RP causing reduction in visual field or visual acuity Any prior macular laser photocoagulation Intraocular surgery within 3 months prior to screening High myopia with spherical equivalent refractive error > 8 diopters. If an eye has had cataract surgery or refractive surgery, a pre-operative refractive error spherical equivalent > 8 diopters is an exclusion Any concurrent ocular condition that might affect interpretation of results History of uveitis in either eye

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 438 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - N-acetylcysteine<br>This is the intervention group. Patients in this group will be receiving 1800 mg of N-acetylcysteine in the form of 3 effervescent 600 mg tablets dissolved in water twice a day for 45 months. | Drug: N-acetylcysteine<br>* 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.<br>|
| Placebo Comparator: Group 2 - Placebo<br>Patients in the placebo group will receive identical effervescent tablets lacking active drug. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progressive change of ellipsoid zone (EZ) width | 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. | Baseline and 45 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mean macular sensitivity measured by microperimetry (MP) | 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. | Baseline and 45 months | 
| Change in best-corrected visual acuity | 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. | Baseline and 45 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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N-acetylcysteine, Ellipsoid zone, Macular sensitivity, Best corrected visual acuity, Ellipsoid zone width, Ellipsoid zone area, Oxidative damage, Usher Syndrome, Antioxidants