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Oral N-acetylcysteine for Retinitis Pigmentosa (NAC Attack)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05537220
Recruitment Status : Recruiting
First Posted : September 13, 2022
Last Update Posted : April 12, 2024
Sponsor:
Collaborators:
National Eye Institute (NEI)
Duke University
Emory University
Massachusetts Eye and Ear Infirmary
Mayo Clinic
Medical College of Wisconsin
Retina Foundation of the Southwest
Stanford University
University of California, Davis
University of Florida
University of Iowa
University of Miami
University of Michigan
University of Minnesota
University of Oklahoma
University of Southern California
University of Utah
University of Washington
University of Wisconsin, Madison
Vanderbilt University
Vitreo Retinal Associates, PA
University of Houston
Medical University of Graz
McGill University
Universität Tübingen
Centro Medico ABC
Radboud University Medical Center
University of Amsterdam
University Hospital, Basel, Switzerland
University College London Hospitals
Northwestern University
University of Pennsylvania
Information provided by (Responsible Party):
Johns Hopkins University

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

Condition or disease Intervention/treatment Phase
Retinitis Pigmentosa Drug: N-acetylcysteine Drug: Placebo Phase 3

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 438 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : October 11, 2023
Estimated Primary Completion Date : December 2028
Estimated Study Completion Date : December 2028

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Group 1 - N-acetylcysteine
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
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.
Placebo Comparator: Group 2 - Placebo
Patients in the placebo group will receive identical effervescent tablets lacking active drug.
 Drug: Placebo
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.


Outcome Measures
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Primary Outcome Measures :
  1. Progressive change of ellipsoid zone (EZ) width [ Time Frame: Baseline and 45 months ]
    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.


Secondary Outcome Measures :
  1. Change in mean macular sensitivity measured by microperimetry (MP) [ Time Frame: Baseline and 45 months ]
    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.

  2. Change in best-corrected visual acuity [ Time Frame: Baseline and 45 months ]
    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.


Other Outcome Measures:
  1. Cumulative change of EZ area assessed as the area above curve (AAC) [ Time Frame: Baseline and 45 months ]
    EZ area is determined by measuring EZ width of multiple horizontal SD-OCT scans ranging from the superior to the inferior part of the macula. A line drawn connecting contiguous points where the EZ ends provides a 3-dimensional map of the region where there are photoreceptors with intact inner and outer segments.

  2. Change in mean macular sensitivity measured by MP [ Time Frame: Baseline, 4.5 months, 9 months, 18 months, 27 months, 36 months, 40.5 months ]
    To assess whether compared to placebo, NAC promotes maintenance of macular function, it is necessary to compare the two study groups over a long period of time. It is useful to determine how differences in mean macular sensitivity between the two groups evolve over time and therefore an exploratory outcome is change in mean macular sensitivity between baseline and each time point at which it is measured throughout the study.

  3. Change in BCVA [ Time Frame: Baseline, 4.5 months, 9 months, 18 months, 27 months, 36 months, 40.5 months ]
    To assess whether compared to placebo, NAC promotes maintenance of BCVA, it is necessary to compare the two study groups over a long period of time. It is useful to determine how differences in BCVA between the two groups evolve over time and therefore an exploratory outcome is change in BCVA between baseline and each time point at which it is measured throughout the study.

  4. Change in cone spacing measured by adaptive optics-scanning laser ophthalmoscopy (AOSLO) [ Time Frame: Baseline, 9 months, 27 months, 45 months ]
    AOSLO provides unique ability to monitor cones at single cell resolution over time. As cone degeneration occurs, there is reduction in cone density even in areas where EZ is intact and therefore assessment of cone spacing by AOSLO provides a more sensitive assessment of cone health than SD-OCT derived EZ measurements. This will provide an anatomical assessment of the efficacy of NAC and will help evaluate the feasibility of using AOSLO-derived outcome measures in future interventional studies in RP.

  5. Change in cone regularity measured by AOSLO [ Time Frame: Baseline, 9 months, 27 months, 45 months ]
    AOSLO provides unique ability to monitor cones at single cell resolution over time. As cone degeneration occurs, there is reduction in cone density even in areas where EZ is intact and therefore assessment of cone regularity by AOSLO provides a more sensitive assessment of cone health than SD-OCT derived EZ measurements. This will provide an anatomical assessment of the efficacy of NAC and will help evaluate the feasibility of using AOSLO-derived outcome measures in future interventional studies in RP.

  6. Change in cone reflectivity measured by AOSLO [ Time Frame: Baseline, 9 months, 27 months, 45 months ]
    Measurements of EZ width and EZ area provide assessments of remaining cones with intact inner and outer segments, but do not have the resolution to assess individual cone structure and density. AOSLO provides unique ability to monitor cones at single cell resolution over time. As cone degeneration occurs, there is reduction in cone density even in areas where EZ is intact and therefore assessment of cone reflectivity by AOSLO provides a more sensitive assessment of cone health than SD-OCT derived EZ measurements. This will provide an anatomical assessment of the efficacy of NAC and will help evaluate the feasibility of using AOSLO-derived outcome measures in future interventional studies in RP.

  7. Proportion of eyes with ≥ 5 loci change (improvement) from baseline by ≥ 6 decibels (dB) [ Time Frame: Baseline, 4.5 months, 9 months, 18 months, 27 months, 36 months, 40.5 months, 45 months ]
    Mean macular sensitivity provides a global assessment of macular function. In addition to this global assessment, It is also useful to assess changes at individual loci which is afforded by MP. A change of 6 dB at a locus is unlikely to be due to chance, because it is well above test-retest variability and it is approximately 2 times the standard deviation of the locus level sensitivity changes that were seen in RP patients treated with NAC for 6 months. A useful assessment of whether or not NAC provides benefit in the macula of patients with RP is to determine if compared to eyes of participants treated with placebo, a greater proportion of eyes of participants treated with NAC have 5 or more loci with change (improvement) from baseline ≥ 6 dB at M4.5, M9, M18, M27, M36, M40.5, and M45.

  8. Proportion of eyes with ≥ 5 loci change (decrease) from baseline by ≥ 6 decibels (dB) [ Time Frame: Baseline, 4.5 months, 9 months, 18 months, 27 months, 36 months, 40.5 months, 45 months ]
    In addition to determining if more macular loci show improvement ≥ 6 dB in eyes of RP patients treated with NAC versus eyes of RP patients treated with placebo, it is important to determine if fewer macular loci show a change (decrease) ≥ 6 dB in eyes of RP patients treated with NAC versus eyes of RP patients treated with placebo.

  9. Change in patient reported outcome assessed using NEI-VFQ 25 [ Time Frame: Baseline, 27 months, 45 months ]
    It is useful to obtain the perspective of patients regarding the impact of treatment on their activities of daily life and quality of life. This is provided by the National Eye Institute Visual Function Questionnaire 25 (VFQ-25), a short form of the National Eye Institute Visual Function Questionnaire (NEI-VFQ), a self reported 51 item questionnaire. It is scored from 0 to 100 that is meant to be a measure of the subject's visual ability. A higher score signifies good visual ability and a lower score signifies poor visual ability that is negatively impacting quality of life.

  10. Safety of oral NAC as assessed by adverse events [ Time Frame: 45 months ]
    Oral NAC has a good safety profile but this study will use a higher dose of NAC and a longer treatment period in a different patient population than any prior study. It is important to assess safety of long term administration of NAC 1800 mg bid in patients with RP. This will be assessed by determining the incidence of ocular and non-ocular adverse events (AEs) in participants treated with NAC versus those treated with placebo.


Eligibility Criteria
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Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05537220


Contacts
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Contact: Dagmar Wehling, COA, CCRP 4105027621 dwehlin1@jhu.edu
Contact: Gulnar Hafiz, MD, MPH 4105020768 ghafiz1@jhmi.edu

Locations
Show Show 31 study locations
Sponsors and Collaborators
Johns Hopkins University
National Eye Institute (NEI)
Duke University
Emory University
Massachusetts Eye and Ear Infirmary
Mayo Clinic
Medical College of Wisconsin
Retina Foundation of the Southwest
Stanford University
University of California, Davis
University of Florida
University of Iowa
University of Miami
University of Michigan
University of Minnesota
University of Oklahoma
University of Southern California
University of Utah
University of Washington
University of Wisconsin, Madison
Vanderbilt University
Vitreo Retinal Associates, PA
University of Houston
Medical University of Graz
McGill University
Universität Tübingen
Centro Medico ABC
Radboud University Medical Center
University of Amsterdam
University Hospital, Basel, Switzerland
University College London Hospitals
Northwestern University
University of Pennsylvania
Investigators
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Study Chair: Peter A Campochiaro, MD Johns Hopkins University
Study Director: Xiangrong Kong Johns Hopkins University
More Information
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Additional Information:

Publications:
FDA. E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e9r1-statistical-principles-clinical-trials-addendum-estimands-and-sensitivity-analysis-clinical. 2019.
O'Neal T, Luther E. Retinitis Pigmentosa. [Updated 2019 Apr 10]. In: Treasure Island (FL): StatPearls Publishing; 2019: https://www.ncbi.nlm.nih.gov/books/NBK519518/
Little R, Rubin D. Statistical Analysis with Missing Data. Wiley; 2002
SAS. SAS/STAT ® 14.1 User's Guide The MI Procedure. . 2015.
Horton NJ, Lipsitz SR. Multiple imputation in practice: Comparison of software packages for regression models with missing variables. Am Stat. 2001;55(3):244-254.
von Hippel PT. How to Impute Interactions, Squares and Other Transformed Variables. Sociol Methodol. 2009;39:265-291.
Campion WM. Multiple Imputation for Nonresponse in Surveys - Rubin,Db. J Marketing Res. 1989;26(4):485-486
Piantadosi S. Clinical trials : a methodologic perspective. 2005.

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Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT05537220    
Other Study ID Numbers: IRB00337490
2022-003023-17 ( EudraCT Number )
1UG1EY033293 ( U.S. NIH Grant/Contract )
2022-501438-46-00 ( Other Identifier: Clinical Trials Application )
First Posted: September 13, 2022    Key Record Dates
Last Update Posted: April 12, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (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.
URL: https://sharing.nih.gov/data-management-and-sharing-policy/about-data-management-and-sharing-policy/data-management-and-sharing-policy-overview

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Johns Hopkins University:
N-acetylcysteine
Ellipsoid zone
Macular sensitivity
Best corrected visual acuity
Ellipsoid zone width
 Ellipsoid zone area
Oxidative damage
Usher Syndrome
Antioxidants
Additional relevant MeSH terms:
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Retinitis
Retinitis Pigmentosa
Retinal Diseases
Eye Diseases
Eye Diseases, Hereditary
Retinal Dystrophies
Retinal Degeneration
Genetic Diseases, Inborn
Acetylcysteine
N-monoacetylcystine
 Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes