Oral N-acetylcysteine for Retinitis Pigmentosa

NCT05537220 | Active Not Recruiting Phase 3 DMC FDA Drug

• 4 other identifiers: IRB003374902022-003023-171UG1EY0332932022-501438-46-00
• Study Type: interventional
• Target: 485
• Locations: 7 countries
• Sites: 31

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.

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

Outcome Measures

Primary Outcomes (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.

  Baseline and 45 months

Secondary Outcomes (2)

• Change in mean macular sensitivity measured by microperimetry (MP)

  Baseline and 45 months

• Change in best-corrected visual acuity

  Baseline and 45 months

Other Outcomes (10)

• Cumulative change of EZ area assessed as the area above curve (AAC)

  Baseline and 45 months

• Change in mean macular sensitivity measured by MP

  Baseline, 4.5 months, 9 months, 18 months, 27 months, 36 months, 40.5 months

• Change in BCVA

  Baseline, 4.5 months, 9 months, 18 months, 27 months, 36 months, 40.5 months

Study Arms (2)

Group 1 - N-acetylcysteine

EXPERIMENTAL

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

Group 2 - Placebo

PLACEBO COMPARATOR

Patients in the placebo group will receive identical effervescent tablets lacking active drug.

Drug: Placebo

Interventions

N-acetylcysteine DRUG

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.

Group 1 - N-acetylcysteine

Placebo DRUG

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.

Group 2 - Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Johns Hopkins University: lead
• National Eye Institute (NEI): collaborator
• Medical College of Wisconsin: collaborator
• Retina Foundation of the Southwest: collaborator
• University of Florida: collaborator
• University of Iowa: collaborator
• University of Michigan: collaborator
• University of Oklahoma: collaborator
• University of Southern California: collaborator
• University of Utah: collaborator
• University of Washington: collaborator
• Vanderbilt University: collaborator
• University of Houston: collaborator
• McGill University: collaborator
• University of Amsterdam: collaborator
• University College London Hospitals: collaborator
• Medical University of Graz: collaborator
• Vitreo Retinal Associates, PA: collaborator
• Mayo Clinic: collaborator
• Stanford University: collaborator
• University of California, Davis: collaborator
• University of Miami: collaborator
• University of Minnesota: collaborator
• University of Wisconsin, Madison: collaborator
• Universität Tübingen: collaborator
• Radboud University Medical Center: collaborator
• University Hospital, Basel, Switzerland: collaborator
• Northwestern University: collaborator
• University of Pennsylvania: collaborator
• Duke University: collaborator
• Emory University: collaborator
• Massachusetts Eye and Ear Infirmary: collaborator

Study Sites (31)

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

Davis, California, 95817, United States

Location

University of Southern California, Keck School of Medicine

Los Angeles, California, 90089, United States

Location

University of California - San Francisco, Department of Ophthalmology

San Francisco, California, 94158, United States

Location

Stanford University, Byers Eye Institute

Stanford, California, 94303, United States

Location

Vitreo Retinal Associates

Gainesville, Florida, 32607, United States

Location

University of Florida - Jacksonville, UF Health Jacksonville

Jacksonville, Florida, 32209, United States

Location

University of Miami, Bascom Palmer Eye Institute

Miami, Florida, 33136, United States

Location

Emory University, Emory Eye Center

Atlanta, Georgia, 30322, United States

Location

University Of Illinois At Chicago

Chicago, Illinois, 60612, United States

Location

Northwestern University

Evanston, Illinois, 60208, United States

Location

University of Iowa, Carver College of Medicine

Iowa City, Iowa, 52242, United States

Location

Wilmer Eye Institute- Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Harvard University, Mass. Eye and Ear

Boston, Massachusetts, 02114, United States

Location

University of Michigan, Kellogg Eye Center

Ann Arbor, Michigan, 48105, United States

Location

University of Minnesota, Department of Ophthalmology and Visual Neurosciences

Minneapolis, Minnesota, 55455, United States

Location

Mayo Clinic, Department of Ophthalmology

Rochester, Minnesota, 55905, United States

Location

University of Oklahoma, Dean McGee Eye Institute

Oklahoma City, Oklahoma, 73104, United States

Location

Scheie Eye Institute

Philadelphia, Pennsylvania, 19104, United States

Location

Vanderbilt University, Vanderbilt Eye Institute

Nashville, Tennessee, 37211, United States

Location

Retina Foundation of the Southwest

Dallas, Texas, 75231, United States

Location

University of Utah, Moran Eye Center

Salt Lake City, Utah, 84132, United States

Location

University of Washington, Department of Ophthalmology

Seattle, Washington, 98109, United States

Location

University of Wisconsin - Madison, McPherson Eye Research Institute

Madison, Wisconsin, 53705, United States

Location

Medical College of Wisconsin, The Eye Institute

Milwaukee, Wisconsin, 53226, United States

Location

Medical University of Graz, Department of Ophthalmology

Graz, Styria, 8036, Austria

Location

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

Montreal, Quebec, H4A 3J1, Canada

Location

University of Tübingen, Department für Augenheilkunde

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

Radboud University, Radboud University Medical Centre

Nijmegen, Gelderland, 6500 HB, Netherlands

Location

University of Amsterdam, Amsterdam Medical Center

Amsterdam, Northern Holland, 1105 AZ, Netherlands

Location

Universitätsspital Basel, Eye Clinic

Basel, CH-4031, Switzerland

Location

University College London, Moorfields Eye Hospital

London, England, United Kingdom

Location

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Related Links

• FDA. E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials.
• Description of retinitis pigmentosa
• Sensitivity Analysis in Multiple Imputation for Missing Data: Sensitivity analysis for multiple interpolation of missing data
• DRCR. N. Anti-VEGF vs. Prompt Vitrectomy for VH From PDR - Full Text View - ClinicalTrials.gov
• FDA. Guidance for Industry E9 Statistical Principles for Clinical Trials

MeSH Terms

Conditions

Retinitis Pigmentosa; Usher Syndromes

Interventions

Acetylcysteine

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Retinal Dystrophies; Retinal Degeneration; Retinal Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Deaf-Blind Disorders; Deafness; Hearing Loss; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Hearing Loss, Sensorineural; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Blindness; Vision Disorders; Abnormalities, Multiple; Congenital Abnormalities; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Peter A Campochiaro, MD

  Johns Hopkins University

  STUDY CHAIR

• Xiangrong Kong

  Johns Hopkins University

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 8, 2022
• First Posted: September 13, 2022
• Study Start: October 11, 2023
• Primary Completion (Estimated): May 1, 2029
• Study Completion (Estimated): May 1, 2030
• Last Updated: May 4, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: The data will be made available 1 year after publication of the primary findings of the study, in a de-identified format. For how long will we share the data?
• Access Criteria: The study data sharing will follow the NIH's Data Sharing Policy published in the NIH Guide on February 26, 2003.

Locations

GB (1); DE (1); AU (1); NL (2); CH (1); CA (1); US (24)