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Retinitis PigmentosaPhase 3NAC AttackNCT05537220

Oral N-acetylcysteine for Retinitis Pigmentosa

A Phase 3 study testing N-acetylcysteine in people with Retinitis Pigmentosa, run by Johns Hopkins University at 31 sites in 7 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Retinitis Pigmentosa
What is being tested?
N-acetylcysteine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
485 participants
Where
31 sitesin 7 countries
Study dates
11 Oct 2023to May 2030
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 12Show fewer
  • 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.

Who cannot join

  • 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
Show all 30Show fewer
  • 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

Trial locations and contacts

31 sites in 7 countries.

31 sites in 7 countries

United States24 sites

  • University of Michigan, Kellogg Eye Center

    Ann Arbor, Michigan, 48105

  • Emory University, Emory Eye Center

    Atlanta, Georgia, 30322

  • Wilmer Eye Institute- Johns Hopkins University

    Baltimore, Maryland, 21287

  • Harvard University, Mass. Eye and Ear

    Boston, Massachusetts, 02114

  • University Of Illinois At Chicago

    Chicago, Illinois, 60612

  • Retina Foundation of the Southwest

    Dallas, Texas, 75231

  • University of California - Davis, Department of Ophthalmology & Vision Science

    Davis, California, 95817

  • Northwestern University

    Evanston, Illinois, 60208

  • Vitreo Retinal Associates

    Gainesville, Florida, 32607

  • University of Iowa, Carver College of Medicine

    Iowa City, Iowa, 52242

  • University of Florida - Jacksonville, UF Health Jacksonville

    Jacksonville, Florida, 32209

  • University of Southern California, Keck School of Medicine

    Los Angeles, California, 90089

  • University of Wisconsin - Madison, McPherson Eye Research Institute

    Madison, Wisconsin, 53705

  • University of Miami, Bascom Palmer Eye Institute

    Miami, Florida, 33136

  • Medical College of Wisconsin, The Eye Institute

    Milwaukee, Wisconsin, 53226

  • University of Minnesota, Department of Ophthalmology and Visual Neurosciences

    Minneapolis, Minnesota, 55455

  • Vanderbilt University, Vanderbilt Eye Institute

    Nashville, Tennessee, 37211

  • University of Oklahoma, Dean McGee Eye Institute

    Oklahoma City, Oklahoma, 73104

  • Scheie Eye Institute

    Philadelphia, Pennsylvania, 19104

  • Mayo Clinic, Department of Ophthalmology

    Rochester, Minnesota, 55905

  • University of Utah, Moran Eye Center

    Salt Lake City, Utah, 84132

  • University of California - San Francisco, Department of Ophthalmology

    San Francisco, California, 94158

  • University of Washington, Department of Ophthalmology

    Seattle, Washington, 98109

  • Stanford University, Byers Eye Institute

    Stanford, California, 94303

Other trials in United States

Netherlands2 sites

  • University of Amsterdam, Amsterdam Medical Center

    Amsterdam, Northern Holland, 1105 AZ

  • Radboud University, Radboud University Medical Centre

    Nijmegen, Gelderland, 6500 HB

Other trials in Netherlands

Austria1 site

  • Medical University of Graz, Department of Ophthalmology

    Graz, Styria, 8036

Other trials in Austria

Canada1 site

  • McGill University, The Research Institute of the McGill University Health Center

    Montreal, Quebec, H4A 3J1

Other trials in Canada

Germany1 site

  • University of Tübingen, Department für Augenheilkunde

    Tübingen, Baden-Wurttemberg, 72076

Other trials in Germany

Switzerland1 site

  • Universitätsspital Basel, Eye Clinic

    Basel, CH-4031

Other trials in Switzerland

United Kingdom1 site

  • University College London, Moorfields Eye Hospital

    London, England

Other trials in United Kingdom

About this study

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

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.

Read the 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.

Being tested
N-acetylcysteine, Placebo
Keywords
N-acetylcysteine, Ellipsoid zone, Macular sensitivity, Best corrected visual acuity, Ellipsoid zone width, Ellipsoid zone area, Oxidative damage, Usher Syndrome, Antioxidants
Medical subject headings
Retinitis Pigmentosa, Usher Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • N-acetylcysteineDrug

    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.

  • PlaceboDrug

    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.

Study groups in NCT05537220
Study groupRoleWhat they receive
Group 1 - N-acetylcysteineExperimentalThis 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.
Receives: Drug: N-acetylcysteine
Group 2 - PlaceboPlacebo comparatorPatients in the placebo group will receive identical effervescent tablets lacking active drug.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline and 45 months

Secondary outcomes (2)

  1. 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.

    Measured: Baseline and 45 months

  2. 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.

    Measured: Baseline and 45 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Sep 2022
  2. Study start11 Oct 2023
  3. Primary completionMay 2029 (estimated)
  4. Study completionMay 2030 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
485 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05537220
Sponsor's protocol ID
IRB00337490
Other IDs
2022-003023-17, 1UG1EY033293, 2022-501438-46-00
Acronym
NAC Attack
Status last verified
Jun 2026
First submitted
8 Sep 2022
Last updated
15 Jun 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: In accord with the NIH guidelines, a summary, de-identified NAC Attack data set will be made available through submission of the dataset to a government or other health research database. The investigators will share individual-participant level data (IPD) together with their associated data dictionaries. The rights and privacy of people who participated in the Study will be protected at all times by stripping all identifiers including study identification numbers that could lead to disclosing the identity of individual research participants from the data. This commitment to privacy-protected data sharing will be incorporated in all levels of data sharing activities. In addition, redacted clinical study reports, retinal images, and other summary reports may be provided to researchers upon approval of their requests by the study leadership. The requesting researchers will be required to sign a data use agreement before given access to study reports or images.

Publications

  • Bunker CH, Berson EL, Bromley WC, Hayes RP, Roderick TH. Prevalence of retinitis pigmentosa in Maine. Am J Ophthalmol. 1984 Mar;97(3):357-65. doi: 10.1016/0002-9394(84)90636-6.

    PubMed 6702974

  • Haim M. Epidemiology of retinitis pigmentosa in Denmark. Acta Ophthalmol Scand Suppl. 2002;(233):1-34. doi: 10.1046/j.1395-3907.2002.00001.x.

    PubMed 11921605

  • Rivolta C, Sharon D, DeAngelis MM, Dryja TP. Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns. Hum Mol Genet. 2002 May 15;11(10):1219-27. doi: 10.1093/hmg/11.10.1219.

    PubMed 12015282

  • Boughman JA, Vernon M, Shaver KA. Usher syndrome: definition and estimate of prevalence from two high-risk populations. J Chronic Dis. 1983;36(8):595-603. doi: 10.1016/0021-9681(83)90147-9.

    PubMed 6885960

  • Athanasiou D, Aguila M, Bellingham J, Li W, McCulley C, Reeves PJ, Cheetham ME. The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy. Prog Retin Eye Res. 2018 Jan;62:1-23. doi: 10.1016/j.preteyeres.2017.10.002. Epub 2017 Oct 16.

    PubMed 29042326

  • Cao SS, Kaufman RJ. Unfolded protein response. Curr Biol. 2012 Aug 21;22(16):R622-6. doi: 10.1016/j.cub.2012.07.004. No abstract available.

    PubMed 22917505

  • Bowes C, Li T, Danciger M, Baxter LC, Applebury ML, Farber DB. Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase. Nature. 1990 Oct 18;347(6294):677-80. doi: 10.1038/347677a0.

    PubMed 1977087

  • Chang B, Hawes NL, Pardue MT, German AM, Hurd RE, Davisson MT, Nusinowitz S, Rengarajan K, Boyd AP, Sidney SS, Phillips MJ, Stewart RE, Chaudhury R, Nickerson JM, Heckenlively JR, Boatright JH. Two mouse retinal degenerations caused by missense mutations in the beta-subunit of rod cGMP phosphodiesterase gene. Vision Res. 2007 Mar;47(5):624-33. doi: 10.1016/j.visres.2006.11.020. Epub 2007 Jan 30.

    PubMed 17267005

  • McLaughlin ME, Sandberg MA, Berson EL, Dryja TP. Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nat Genet. 1993 Jun;4(2):130-4. doi: 10.1038/ng0693-130.

    PubMed 8394174

  • Farber DB, Lolley RN. Cyclic guanosine monophosphate: elevation in degenerating photoreceptor cells of the C3H mouse retina. Science. 1974 Nov 1;186(4162):449-51. doi: 10.1126/science.186.4162.449.

    PubMed 4369896

  • Iribarne M, Masai I. Neurotoxicity of cGMP in the vertebrate retina: from the initial research on rd mutant mice to zebrafish genetic approaches. J Neurogenet. 2017 Sep;31(3):88-101. doi: 10.1080/01677063.2017.1358268. Epub 2017 Aug 16.

    PubMed 28812418

  • Vithana EN, Abu-Safieh L, Allen MJ, Carey A, Papaioannou M, Chakarova C, Al-Maghtheh M, Ebenezer ND, Willis C, Moore AT, Bird AC, Hunt DM, Bhattacharya SS. A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). Mol Cell. 2001 Aug;8(2):375-81. doi: 10.1016/s1097-2765(01)00305-7.

    PubMed 11545739

  • Buskin A, Zhu L, Chichagova V, Basu B, Mozaffari-Jovin S, Dolan D, Droop A, Collin J, Bronstein R, Mehrotra S, Farkas M, Hilgen G, White K, Pan KT, Treumann A, Hallam D, Bialas K, Chung G, Mellough C, Ding Y, Krasnogor N, Przyborski S, Zwolinski S, Al-Aama J, Alharthi S, Xu Y, Wheway G, Szymanska K, McKibbin M, Inglehearn CF, Elliott DJ, Lindsay S, Ali RR, Steel DH, Armstrong L, Sernagor E, Urlaub H, Pierce E, Luhrmann R, Grellscheid SN, Johnson CA, Lako M. Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nat Commun. 2018 Oct 12;9(1):4234. doi: 10.1038/s41467-018-06448-y.

    PubMed 30315276

  • Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa. Clin Genet. 2013 Aug;84(2):132-41. doi: 10.1111/cge.12203. Epub 2013 Jun 19.

    PubMed 23701314

  • Yu DY, Cringle SJ, Su EN, Yu PK. Intraretinal oxygen levels before and after photoreceptor loss in the RCS rat. Invest Ophthalmol Vis Sci. 2000 Nov;41(12):3999-4006.

    PubMed 11053305

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing N-acetylcysteine in people with Retinitis Pigmentosa, run by Johns Hopkins University at 31 sites in 7 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 15 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 31 sites in United States, Netherlands, Austria, Canada, Germany and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progressive change of ellipsoid zone (EZ) width (time frame: Baseline and 45 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05537220, which also lists 89 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jun 2026.

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