NAC Attack: Oral N-acetylcysteine for Retinitis Pigmentosa

Sponsor

Johns Hopkins University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05537220

Collaborator

National Eye Institute (NEI) (NIH), Duke University (Other), Emory University (Other), Massachusetts Eye and Ear Infirmary (Other), Mayo Clinic (Other), Medical College of Wisconsin (Other), Retina Foundation of the Southwest (Other), Stanford University (Other), University of California, Davis (Other), University of Florida (Other), University of Illinois at Chicago (Other), University of Iowa (Other), University of Miami (Other), University of Michigan (Other), University of Minnesota (Other), University of Oklahoma (Other), University of Southern California (Other), University of Utah (Other), University of Washington (Other), University of Wisconsin, Madison (Other), Vanderbilt University (Other), Vitreo Retinal Associates, PA (Other), University of Houston (Other), Medical University of Graz (Other), McGill University (Other), Universität Tübingen (Other), Centro Medico ABC (Other), Radboud University Medical Center (Other), University of Amsterdam (Other), University Hospital, Basel, Switzerland (Other), University College London Hospitals (Other), Northwestern University (Other)

438

Enrollment

Locations

Arms

60.9

Anticipated Duration (Months)

14.1

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

Anticipated 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.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

Anticipated Study Start Date :

Feb 1, 2023

Anticipated Primary Completion Date :

Mar 1, 2028

Anticipated Study Completion Date :

Mar 1, 2028

Arms and Interventions

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.

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

Primary Outcome Measures

Progressive change of ellipsoid zone (EZ) width [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

Change in mean macular sensitivity measured by microperimetry (MP) [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.
Change in best-corrected visual acuity [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

Cumulative change of EZ area assessed as the area above curve (AAC) [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.
Change in mean macular sensitivity measured by MP [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.
Change in BCVA [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.
Change in cone spacing measured by adaptive optics-scanning laser ophthalmoscopy (AOSLO) [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.
Change in cone regularity measured by AOSLO [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.
Change in cone reflectivity measured by AOSLO [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.
Proportion of eyes with ≥ 5 loci change (improvement) from baseline by ≥ 6 decibels (dB) [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.
Proportion of eyes with ≥ 5 loci change (decrease) from baseline by ≥ 6 dB [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) ≥ 6dB in eyes of RP patients treated with NAC versus eyes of RP patients treated with placebo.
Change in patient reported outcome assessed using NEI-VFQ 25 [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.
Safety of oral NAC as assessed by adverse events [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

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	University of California - Davis, Department of Ophthalmology & Vision Science	Davis	California	United States	95817
2	University of Southern California, Keck School of Medicine	Los Angeles	California	United States	90089
3	University of California - San Francisco, Department of Ophthalmology	San Francisco	California	United States	94158
4	Stanford University, Byers Eye Institute	Stanford	California	United States	94303
5	Vitreo Retinal Associates	Gainesville	Florida	United States	32607
6	University of Florida - Jacksonville, UF Health Jacksonville	Jacksonville	Florida	United States	32209
7	University of Miami, Bascom Palmer Eye Institute	Miami	Florida	United States	33136
8	Emory University, Emory Eye Center	Atlanta	Georgia	United States	30322
9	University of Illinois - Chicago, UI Health	Chicago	Illinois	United States	60612
10	Northwestern University	Evanston	Illinois	United States	60208
11	University of Iowa, Carver College of Medicine	Iowa City	Iowa	United States	52242
12	University of Wisconsin - Madison, McPherson Eye Research Institute	Madison	Maryland	United States	53705
13	Harvard University, Mass. Eye and Ear	Boston	Massachusetts	United States	02114
14	University of Michigan, Kellogg Eye Center	Ann Arbor	Michigan	United States	48105
15	University of Minnesota, Department of Ophthalmology and Visual Neurosciences	Minneapolis	Minnesota	United States	55455
16	Mayo Clinic, Department of Ophthalmology	Rochester	Minnesota	United States	55905
17	Duke University	Durham	North Carolina	United States	27710
18	University of Oklahoma, Dean McGee Eye Institute	Oklahoma City	Oklahoma	United States	73104
19	Vanderbilt University, Vanderbilt Eye Institute	Nashville	Tennessee	United States	37211
20	Retina Foundation of the Southwest	Dallas	Texas	United States	75231
21	University of Utah, Moran Eye Center	Salt Lake City	Utah	United States	84132
22	University of Washington, Department of Ophthalmology	Seattle	Washington	United States	98109
23	Medical College of Wisconsin, The Eye Institute	Milwaukee	Wisconsin	United States	53226
24	Medical University of Graz, Department of Opthalmology	Graz	Styria	Austria	8036
25	McGill University, The Research Institute of the McGill University Health Center	Montréal	Quebec	Canada	H4A 3J1
26	University of Tübingen, Department für Augenheilkunde	Tübingen	Baden-Württemberg	Germany	72076
27	Centro Médico ABC, Department of Ophthalmology	Ciudad de mexico	Cdmx	Mexico	01120
28	Radboud University, Radboud University Medical Centre	Nijmegen	Gelderland	Netherlands	6500 HB
29	University of Amsterdam, Amsterdam Medical Center	Amsterdam	Northern Holland	Netherlands	1105 AZ
30	Universitätsspital Basel, Eye Clinic	Basel		Switzerland	CH-4031
31	University College London, Moorfields Eye Hospital	London	England	United Kingdom