Clinical trial NCT05537220: Oral N-acetylcysteine for Retinitis Pigmentosa
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Retinitis Pigmentosa
Keywords: N-acetylcysteine
Ellipsoid zone
Macular sensitivity
Best corrected visual acuity
Ellipsoid zone width
Ellipsoid zone area
Oxidative damage
Usher Syndrome
Antioxidants
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Eye Institute (NEI)
name: Duke University
name: Emory University
name: Massachusetts Eye and Ear Infirmary
name: Mayo Clinic
name: Medical College of Wisconsin
name: Retina Foundation of the Southwest
name: Stanford University
name: University of California, Davis
name: University of Florida
name: University of Iowa
name: University of Miami
name: University of Michigan
name: University of Minnesota
name: University of Oklahoma
name: University of Southern California
name: University of Utah
name: University of Washington
name: University of Wisconsin, Madison
name: Vanderbilt University
name: Vitreo Retinal Associates, PA
name: University of Houston
name: Medical University of Graz
name: McGill University
name: Universität Tübingen
name: Radboud University Medical Center
name: University of Amsterdam
name: University Hospital, Basel, Switzerland
name: University College London Hospitals
name: Northwestern University
name: University of Pennsylvania
First posted: 2022-09-13
Enrollment: 483
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Progressive change of ellipsoid zone (EZ) width
timeFrame: Baseline and 45 months
Secondary outcomes:
measure: Change in mean macular sensitivity measured by microperimetry (MP)
timeFrame: Baseline and 45 months
measure: Change in best-corrected visual acuity
timeFrame: Baseline and 45 months
Other outcomes:
measure: Cumulative change of EZ area assessed as the area above curve (AAC)
timeFrame: Baseline and 45 months
measure: Change in mean macular sensitivity measured by MP
timeFrame: Baseline, 4.5 months, 9 months, 18 months, 27 months, 36 months, 40.5 months
measure: Change in BCVA
timeFrame: Baseline, 4.5 months, 9 months, 18 months, 27 months, 36 months, 40.5 months
measure: Change in cone spacing measured by adaptive optics-scanning laser ophthalmoscopy (AOSLO)
timeFrame: Baseline, 9 months, 27 months, 45 months
measure: Change in cone regularity measured by AOSLO
timeFrame: Baseline, 9 months, 27 months, 45 months
measure: Change in cone reflectivity measured by AOSLO
timeFrame: Baseline, 9 months, 27 months, 45 months
measure: Proportion of eyes with ≥ 5 loci change (improvement) from baseline by ≥ 6 decibels (dB)
timeFrame: Baseline, 4.5 months, 9 months, 18 months, 27 months, 36 months, 40.5 months, 45 months
measure: Proportion of eyes with ≥ 5 loci change (decrease) from baseline by ≥ 6 decibels (dB)
timeFrame: Baseline, 4.5 months, 9 months, 18 months, 27 months, 36 months, 40.5 months, 45 months
measure: Change in patient reported outcome assessed using NEI-VFQ 25
timeFrame: Baseline, 27 months, 45 months
measure: Safety of oral NAC as assessed by adverse events
timeFrame: 45 months
Locations:
city: Davis
country: United States
facility: University of California - Davis, Department of Ophthalmology & Vision Science
state: California
city: Los Angeles
country: United States
facility: University of Southern California, Keck School of Medicine
state: California
city: San Francisco
country: United States
facility: University of California - San Francisco, Department of Ophthalmology
state: California
city: Stanford
country: United States
facility: Stanford University, Byers Eye Institute
state: California
city: Gainesville
country: United States
facility: Vitreo Retinal Associates
state: Florida
city: Jacksonville
country: United States
facility: University of Florida - Jacksonville, UF Health Jacksonville
state: Florida
city: Miami
country: United States
facility: University of Miami, Bascom Palmer Eye Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University, Emory Eye Center
state: Georgia
city: Chicago
country: United States
facility: University Of Illinois At Chicago
state: Illinois
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa, Carver College of Medicine
state: Iowa
city: Baltimore
country: United States
facility: Wilmer Eye Institute- Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Harvard University, Mass. Eye and Ear
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan, Kellogg Eye Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota, Department of Ophthalmology and Visual Neurosciences
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic, Department of Ophthalmology
state: Minnesota
city: Oklahoma City
country: United States
facility: University of Oklahoma, Dean McGee Eye Institute
state: Oklahoma
city: Philadelphia
country: United States
facility: Scheie Eye Institute
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University, Vanderbilt Eye Institute
state: Tennessee
city: Dallas
country: United States
facility: Retina Foundation of the Southwest
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Moran Eye Center
state: Utah
city: Seattle
country: United States
facility: University of Washington, Department of Ophthalmology
state: Washington
city: Madison
country: United States
facility: University of Wisconsin - Madison, McPherson Eye Research Institute
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin, The Eye Institute
state: Wisconsin
city: Graz
country: Austria
facility: Medical University of Graz, Department of Ophthalmology
state: Styria
city: Montréal
country: Canada
facility: McGill University, The Research Institute of the McGill University Health Center
state: Quebec
city: Tübingen
country: Germany
facility: University of Tübingen, Department für Augenheilkunde
state: Baden-Württemberg
city: Nijmegen
country: Netherlands
facility: Radboud University, Radboud University Medical Centre
state: Gelderland
city: Amsterdam
country: Netherlands
facility: University of Amsterdam, Amsterdam Medical Center
state: Northern Holland
city: Basel
country: Switzerland
facility: Universitätsspital Basel, Eye Clinic
city: London
country: United Kingdom
facility: University College London, Moorfields Eye Hospital
state: England
Study officials:
affiliation: Johns Hopkins University
name: Peter A Campochiaro, MD
role: STUDY_CHAIR
affiliation: Johns Hopkins University
name: Xiangrong Kong
role: STUDY_DIRECTOR
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