A Phase 1 Open Label Dose Ranging Study to Assess the Safety and Tolerability of N-Acetylcysteine (NAC) in Patients With Retinitis Pigmentosa (FIGHT-RP1 Study)
Phase: PHASE1
Conditions: Retinitis Pigmentosa
Sponsor: Johns Hopkins University

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PROTOCOL 
STUDY TITLE: 
 
A Phase 1 Open Label Dose Ranging Study to Assess 
the Safety and Tolerability of N-Acetylcysteine (NAC) 
in Patients with Retinitis Pigmentosa (FIGHT-RP1 
Study) 
 
EIRB STUDY 
NUMBER 
IRB00103296 
STUDY DRUG 
N-Acetylcysteine (NAC) 
SPONSOR 
 
N/A 
 
IND: 
133525 
PRINCIPAL 
INVESTIGATOR 
Peter A. Campochiaro 
SUB-
INVESTIGATORS 
Mandeep S. Singh 
Gulnar Hafiz 
Mustafa Iftikhar 
Saleema Kherani 
Mohamed Ahmed 
 
DATE FINAL: 
 
 04-12-2018 (Version 1.6) 

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TABLE OF CONTENTS                                                                                                 Page no. 
1. 
BACKGROUND .............................................................................................. ………4 
 
1.1         Pathophysiology .......................................................................................... ………4 
         1.2         Study Rationale…………………………………………………………................5 
2. 
OBJECTIVES .................................................................................................. ............7 
 
2.1      Primary Objective.……………………………………………………...................7 
 
2.2      Secondary Objective ………………………………………………………...........7 
3. 
STUDY DESIGN ............................................................................................. ............7  
         3.1         DESCRIPTION OF THE STUDY .............................................................. ……....7  
         3.2         OUTCOME MEASURES ........................................................................... ………9  
  3.3.1               Primary Outcome Measures ................................................. ………9  
  3.3.2               Secondary Outcome Measures ............................................. ………9 
   3.3         Safety Plan ................................................................................................... ………9  
         3.5         Compliance with Laws and Regulations ..................................................... ………10 
4. 
MATERIALS AND METHODS ..................................................................... ………10 
         4.1         Subjects ....................................................................................................... ………11 
   4.1.1                Subject Selection .................................................................. ………11 
  4.1.2                Inclusion Criteria ................................................................. ………11 
    4.1.3                Exclusion Criteria ............................................................... ………11 
       4.2          Study Assessments ....................................................................................... ………11 
       4.3          Dosing and Dose Escalation ……………………………………………………...16 
       4.4          Study Discontinuation .................................................................................. ……..17 
       4.5          Statistical Methods  ...................................................................................... ……..17 
              4.5.1                 Safety Analysis…………………………………………………..17 
  4.5.2                 Secondary Analysis ............................................................ ……..17 
  4.5.3                 Power Analysis…………………………………………………..17 
  4.5.4                 Missing Data ....................................................................... ……..17 
  4.5.5                 Interim Analysis  ................................................................ ……..17 
  4.5.6                 Early Termination………………………………………………..18 
       4.6           Data Quality Assurance…………………………………………………………..18 
   5.            ASSESSMENT OF SAFETY .......................................................................... ..........18 

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       5.1           Adverse Events ............................................................................................ ..........18 
       5.2           Baseline Medical Conditions ....................................................................... ……..19 
       5.3           Procedures for Recording and Reporting Adverse Events .......................... ……..19 
             5.3.1 
            Recording Adverse Events ................................................. ……..19 
 5.3.2 
            Serious Adverse Events ...................................................... ……..20 
 5.3.3 
            Serious Adverse Event Reporting…………………………….....21 
 5.3.4 
            Type and Duration of Follow-up After Adverse Events .... ……..21 
 5.5.5                 Plans to Decrease Potential Risks and Increase Safety…………21 
  6.             INVESTIGATOR REQUIREMENTS…………………………………………........22 
       6.1          Study Initiation………………………………………………………………......22 
       6.2          Study Completion……………………………………………………………......22 
       6.3          Informed Consent……………………………………………………………......23 
       6.4          Institutional Review Board or Ethics Committee Approval………………….....24 
       6.5          Case Report Forms………………………………………………………………25 
       6.6          Study Drug Accountability……………………………………………………...25 
       6.7           Disclosure of Data……………………………………………………………....25 
        6.8          Retention of Records……………………………………………………………25 
  7.             PAYMENTS, REMUNERATIONS AND COSTS TO PARTICIPANTS………..26 
        7.1          Payment and Remuneration………………………………………………….....26 
        7.2          Costs……………………………………………………………………………26 
  8.             REFERENCES ................................................................................................. …...26  
  APPENDICES 
  Appendix A: Schedule of Activities 
 
  
 
 
 
 
 
 
 

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1.      BACKGROUND 
1.1           PATHOPHYSIOLOGY 
Retinitis Pigmentosa (RP) is the term used for a genetically heterogeneous group of inherited retinal 
degenerations caused by a mutation in one of the many genes which cause rod photoreceptors to die. 
Photoreceptors are cells in the retina that are stimulated by light, initiating the translation of visual 
images into nerve impulses that travel to the brain. There are two types of photoreceptors, rods and 
cones.  Rods enable vision in dim illumination; cones are responsible for more detailed central vision, 
vision in bright light, and perception of color.  The vast majority (95%) of photoreceptors are rods.  
 
Rods are the major consumers of oxygen in the retina and the loss of rods causes an increase in the 
tissue oxygen level in the outer retina.[1] This activates NADPH oxidase causing accumulation of 
superoxide radicals in the cytosol [2] and also increases their generation in mitochondria of cones.  The 
excess superoxide radicals overwhelm superoxide dismutase 1 (SOD1) and SOD2 and cause a chain 
reaction by which other free radicals are generated including some that are even more damaging than 
superoxide radicals, such as hydroxyl radicals and peroxynitrite.[3] The free radicals attack proteins, 
lipids, and DNA causing specific modifications that indicate that oxidative damage has occurred.  The 
most common modification to proteins from oxidative damage is the formation of carbonyl adducts.[4, 
5] Measurements of these markers of oxidative damage provide a quantitative assessment of the amount 
of oxidative damage that has occurred in a tissue.[6]  These modifications can impair the function of 
macromolecules and while there are endogenous repair processes, they are overwhelmed by severe 
oxidative stress resulting in reduced cellular function and eventually apoptosis. After rods are eliminated 
from the photoreceptor layer, oxidative stress in the outer retina is severe and leads to gradual cone cell 
death usually starting in the midperiphery where cone density is low and then spreading peripherally and 
posteriorly.[7-9] The posterior spread of cone death results in visual field constriction and eventually a 
central island of vision and its elimination causes blindness.   
 
Clinical signs of RP include pigmentary changes in the retina, often around blood vessels and 
characterized as “bone spicule-like pigmentation”, constriction of retinal vessels, and optic disc pallor.  
Spectral domain optical coherence tomography can show thinning of the retina in areas of photoreceptor 
cell loss and with segmentation the loss is seen in the outer nuclear layer.  Visual field testing shows 
constriction of the visual fields and electroretinography shows reduced a- and b-wave amplitudes.  . 

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1.1          STUDY RATIONALE 
 
Retinitis Pigmentosa (RP) is a devastating eye disease and at present there are no known treatment 
options that can alter the rate of vision loss and eventual blindness. In a series of studies in animal 
models, the effects of exposing cones in the periphery of the retina to a large excess of oxygen results in 
progressive oxidative damage to cone photoreceptors and cone cell death.[2, 3, 7-11]  Cone cell death 
gradually spreads from the periphery of the retina toward its center, narrowing the visual field and 
eventually resulting in tunnel vision.  Compared to control patients, those with RP showed significant 
reduction in the reduced to oxidized glutathione ratio (GSH/GSSG) in aqueous humor and a significant 
increase in protein carbonyl content.[12] This demonstration of oxidative stress and oxidative damage in 
the eyes of patients with RP, suggests that oxidative damage-induced cone cell death in animal models 
of RP may translate to humans with RP and support the hypotheses that (1) potent antioxidants will 
promote cone survival and function in patients with RP and (2) aqueous GSH/GSSG ratio and carbonyl 
content on proteins provide useful biomarkers of disease activity in this patient population. Orally 
administered N-Acetylcysteine (NAC) has been found to be a particularly effective antioxidant that 
promotes prolonged cone survival and maintenance of cone function in a mouse model of RP.[13] Since 
oral and/or topical administration of NAC is feasible for long-term treatment in humans, and NAC has a 
good safety profile, there is good rationale to test the effect of NAC in patients with RP. The first step is 
to do test different dosing regimens to identify the lowest dose that is able restore aqueous GSH/GSSG 
ratio and reduce carbonyl adducts on aqueous proteins.  
 
Oxidative damage has been implicated in several diseases including cystic fibrosis, chronic obstructive 
pulmonary disease (COPD), and Idiopathic Pulmonary Fibrosis. NAC also has a mucolytic effect which 
makes it particularly useful for treatment of these pulmonary diseases. The effect of oral NAC has been 
tested in these indications in several clinical trials providing extensive safety data. In COPD, NAC 
600mg bid improves airway function and reduces the frequency of acute exacerbations.[14, 15] Doses of 
up to 1800mg/day have been well-tolerated in the treatment of Idiopathic Pulmonary Fibrosis.[16]  
Paracetamol (acetaminophen) toxicity is treated with a loading dose of 140 mg/kg NAC followed by 70 
mg/kg every 4 hours for 17 doses.[17] Normal volunteers tolerated a dose of 11.2 grams NAC/day for 
three months without any serious undesirable effects [18] and in another study a dose of 500mg/kg/day 
was tolerated.[19] The most frequent adverse events associated with the oral administration of NAC are 

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gastrointestinal in nature and include vomiting, diarrhea, stomatitis, abdominal pain and nausea 
(incidence rate >1/1000 to <1/100). Hypersensitivity reactions including anaphylactic shock and 
anaphylactic/anaphylactoid reaction (incidence rate <1/10,000), dyspnea, bronchospasm (incidence rate 
>1/10,000 to <1/1000), angioedema, tachycardia, urticaria, rash and pruritus (incidence rate >1/1000 to 
<1/100) have been reported less frequently. Finally, reports of headache, tinnitus, pyrexia, blood 
pressure decreased (incidence rate >1/1000 to <1/100), face edema and hemorrhage have also been 
collected with oral NAC. In this study, we will use NAC 600 mg effervescent tablets which are 
generally more pleasant and more tolerable than large capsules; however, because the formulation 
contains sodium, we will exclude patients with uncontrolled arterial hypertension defined as diastolic 
blood pressure > 95 mm Hg or systolic blood pressure > 160 mm Hg. 
 
In patients with Idiopathic Pulmonary Fibrosis, polymorphisms within the TOLLIP gene were found to 
influence outcomes of NAC-treated patients.[20] The product of the TOLLIP gene, toll-interacting 
protein, is an inhibitory adaptor protein acting downstream of toll-like receptors, mediators of innate and 
adaptive immunity. The identification of the influence of TOLLIP polymorphisms on the effect of NAC 
in Idiopathic Pulmonary Fibrosis provides rationale for collecting DNA and genotyping the same SNPs 
in the current trial. In addition to this candidate gene genetic analysis, we plan to collect and bank 
patient RNA for future transcriptome analysis. The rationale for this is to identify gene expression 
changes that modify disease progression in RP. There is substantial variability in rate of progression 
among patients with RP. A patient who loses all vision early in life can have a sibling with the same 
mutation who maintains vision into advanced age. This suggests that modifier genes can have a major 
impact on cone survival. We hypothesize that level of expression of gene products that contribute to the 
antioxidant defense system may influence cone cell death and hence the rate of loss of visual field. It is 
also possible that gene expression differences may contribute to differences in response to NAC. For 
these reasons we plan to collect RNA from patients which will allow us to do next generation 
sequencing in the future to understand the transcriptome background on which our intervention has been 
performed. This is an ambitious undertaking that will require additional funding, but it is critical to plan 
for it and collect the samples as part of this protocol. Also, while it is not critical to know the pathogenic 
mutation in each patient for our intervention that is directed at cone survival, the rate of rod cell death 
influences the rate of cone cell death and it may be useful to know the underlying mutation in each of 
our patients. The underlying mutation may be known in some patients who enter the trial, but it is not a 

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requirement. In those patients for whom the pathogenic mutation is not known, we will collect DNA to 
enable future genotyping studies including next generation sequencing. These studies are not part of the 
current study and will require additional funding, but it is important to obtain and store the samples for 
future use.  
 
2.     OBJECTIVES 
2.1           Primary Objectives 
• To assess the safety and tolerability of N-acetylcysteine (NAC) in patients with RP 
2.2           Secondary Objectives 
• To measure the change from baseline aqueous GSH/GSSG ratio and protein carbonyl content. 
• To measure change from baseline central retinal sensitivity by microperimetry. 
• To measure change from baseline spectral domain optical coherence tomography (SD-OCT). 
• To genotype TOLLIP SNPs 
• To collect samples for future genotyping and transcriptome analysis.  
 
3.     STUDY DESIGN 
3.          DESCRIPTION OF THE STUDY 
This study is a phase 1 dose escalation study with 3 cohorts, designed to assess the safety and 
tolerability of NAC in subjects with RP. Thirty subjects with RP will be enrolled from the clinic 
population of the Wilmer Eye Institute, Johns Hopkins. Informed consent will be obtained from all study 
subjects prior to enrollment. Each cohort will have an experimental and an exploratory arm. Subjects 
with RP will be enrolled in the experimental arm if they have a high carbonyl content (>0.6) and a 
reduced GSH/GSSG ratio (<3.0) in the aqueous. Subjects with RP who don’t have a high carbonyl 
content (>0.6) and a reduced GSH/GSSG ratio (<3.0) but otherwise are good candidates for the study 
will be enrolled in the exploratory arm. The reason for this stratification is that the primary outcome is 
the change from baseline carbonyl content and GSH/GSSG caused by each dose of NAC and patients 
who have reduced chance to show improvement could skew the data and reduce the ability to identify 
the minimally effect dose. In a previous study, 17 of 20 patients with RP fit these criteria, so we 
anticipate that 8-9 subjects in each cohort will be in the experimental group.  We do not want to 

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completely exclude RP patients who do not fit these criteria, because they may experience substantial 
decrease in carbonyl content and substantial increase in GSH/GSSG and their inclusion in the 
exploratory arm will help to determine if patients who do not fit the criteria should be excluded from the 
next trial, a longer trial with a functional endpoint.  
 
Baseline testing will include: (1) detailed medical and ophthalmological history, (2) measurement of 
vital signs (3) slit lamp examination, (4) funduscopic examination, (5) best-corrected visual acuity 
(BCVA), (6) MP1 and MAIA microperimetry, (7) SD-OCT, and (8) ultrawide angle fundus 
photographs. One eye will be selected as the study eye and an anterior chamber tap will done for 
measurement of GSH/GSSG and protein carbonyl content. Serum GSH/GSSG, protein carbonyl content 
and bilirubin levels will also be measured.  Blood will be obtained for RNA and DNA samples. The 
following is the dosing of NAC 600 mg effervescent tablets in each cohort.  
 
 
             Baseline        Week 4          Week 8            Week 12          Week 20          Week 24 
Cohort 1     600mg bid      600mg bid     600mg bid       600mg tid          600mg tid       600mg tid 
Cohort 2    1200mg bid   1200mg bid    1200mg bid     1200mg tid        1200mg tid    1200mg tid        
Cohort 3    1800mg bid    1800mg bid   1800mg bid      1800mg tid       1800mg tid     1800mg tid 
 
There will be 8 study visits (screening, baseline and month 1-6), all study visits after the baseline visit 
will be 28±7 days apart, followed by a 12 week observation period. At each visit, patients will have 
medical history, measurement of vital signs (blood pressure, heart rate, respiratory rate and 
temperature), review of concomitant medications, review of study drug diary, recording of adverse 
events, BCVA, eye examination, and anterior chamber tap. MP1 microperimetry will be done at 
screening and baseline visit. Optical Coherence tomography will be done at the screening and baseline 
visit and repeated every 3 months. MAIA microperimetry will be done at screening and baseline visit 
and repeated every month. Fundus autofluorescence and Ultrawide field fundus photographs will be 
obtained at screening and month 6 visit. At all visits where needed, microperimetry will be performed 
first followed by OCT, FAF and UWFP. Serum levels of NAC pre- and post-dose will be measured at 
baseline, week 12 and 24. When all 10 subjects in cohort 1 have had a week 4 visit, the PI will review 
safety and tolerability with study team members and if there has been good safety and tolerability, 
enrollment will begin for cohort 2. When all 10 subjects in cohort 2 have had a week 4 visit, the PI will 

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review safety and tolerability with study team members and if there has been good safety and 
tolerability, enrollment will begin for cohort 3. 
 
 
3.2          OUTCOME MEASURES  
 
      3.2.1          Primary Outcome Measures 
• Assessment of safety and tolerability of NAC including incidence and severity of systemic and 
ocular adverse events (AEs) and changes from baseline vital signs and physical examination. 
3.2.2           Secondary Outcome Measures 
• Change from baseline aqueous and serum carbonyl content and GSH/GSSG ratio at 1, 2, 3, 4, 5, 
6, 7, 8 and 9 months after initiation of NAC. 
• Change from baseline BCVA 6 months after initiation of NAC. 
• Change from baseline central retinal sensitivity by microperimetry 3, 6, and 9 months after 
initiation of NAC. 
• Change from baseline ellipsoid zone (EZ) width by SD-OCT 6 month after initiation of NAC . 
 
3.3         SAFETY PLAN 
The safety assessments to be conducted for this study are listed in Section 5  
Potential safety issues are associated with anterior chamber taps and peripheral blood draw.  Subjects 
will be instructed to contact their physician at any time should they have health-related concerns. All 
adverse events (serious and non-serious) will be recorded for up to 14 days after the last study visit. 
 
Anterior chamber tap in the clinic in patients with RP 
The patient will be seated at a slit lamp and a drop of topical anesthetic will be placed in the study eye.  
A 30 gauge needle will be passed through the limbus into the anterior chamber and 0.15 ml of aqueous 
humor will be removed.  There are no nerves at the limbus below the epithelium and therefore the 
topical anesthetic provides complete anesthesia and there is no pain associated with the procedure.  
Anterior chamber tap is a routine procedure that is extremely safe.  It is done to deal with severe 

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increased intraocular pressure after intravitreous injections, or injection of gas during pneumatic 
retinopexy. Anterior chamber taps have been done as part of several prior studies and there have been no 
related complications or adverse events. 
 
Peripheral blood draw 
The peripheral blood will be drawn to collect RNA and DNA samples and serum bilirubin levels at the 
screening visit (BL-28 to 56 days). Blood draw for measurement of serum carbonyl content and 
GSH/GSSG ratio will be performed at each study visit. At the baseline (Day 1 +7days), week 12 and 
week 24 visit, peripheral blood will be drawn before as well as 1 and 2 hours after administration of oral 
NAC in the clinic for measurement of plasma  NAC levels. The 2 hour blood draw will be optional, 
based on the convenience of the subject and at the discretion of the investigator. The peripheral blood 
draw is commonplace procedure and there are no risks to exposure to transmissible diseases if ones 
blood is being drawn using aseptic conditions. A patient may feel light headed or faint, or experience 
pain or discomfort at the site of puncture during the procedure. There may be possible bruising or 
swelling at the puncture site, rarely there may be an infection. 
 
The Principal Investigator will review all adverse events on an ongoing basis. JHU IRB 3 will be 
notified immediately of any serious adverse events and will be notified in yearly renewals of all other 
adverse events. The IRB will be notified of any interruption in enrollment or change in the conduct of 
the study.  
 
3.4           COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with current U.S. Food and Drug Administration (FDA) 
Good Clinical Practices (GCPs), and local ethical and legal requirements. 
 

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4.     MATERIALS AND METHODS 
4.1          SUBJECTS 
     4.1.1          Subject Selection 
Thirty eligible subjects with RP will be enrolled. Subjects will be identified and recruited 
through the clinic population at the Wilmer Eye Institute and it is expected that enrollment will 
be completed over an 12 month period. 
 
     4.1.2 
     Inclusion Criteria   
            All subjects must meet the following criteria to be eligible for study entry: 
• Signed informed consent and authorization of use and disclosure of protected health information 
• Age ≥18 years 
• Patients diagnosed with RP by the investigators, based on clinical phenotype and diagnostic tests  
 
    4.1.3          Exclusion Criteria 
            Subjects who meet any of the following criteria will be ineligible for study entry: 
• Patients with concurrent retinal pathologies that result in vision loss, including but not limited to 
retinal vein occlusion, diabetic retinopathy and neovascular age-related macular degeneration. If 
one eye does not have any retinal pathology other than RP, it may be enrolled in the study. 
• Patients with uncontrolled arterial hypertension defined as diastolic blood pressure > 95 mm Hg 
or systolic blood pressure > 160 mm Hg despite medical therapy.  
 
4.2           STUDY ASSESSMENTS 
For a complete overview of the study assessments, see Flow Charts in Appendix section. 
Screening Visit  
• 
Obtain Informed Consent 
• 
Record demographics, medical and ocular history; concomitant medications, smoking history,   
alcohol intake and supplement usage 

12 
 
• 
Vital sign measurements (blood pressure, pulse rate, temperature and respiratory rate) 
• 
Slit lamp examination 
• 
Indirect Ophthalmoscopy 
• 
BCVA by Early Treatment Diabetic Retinopathy Study (ETDRS) Protocol 
• 
SD-OCT 
• 
Fundus autofluorescence 
• 
Ultrawide field fundus photography 
• 
MP1 and MAIA microperimetry 
• 
Anterior chamber tap (for measurement of carbonyl content and GSH/GSSG) 
• 
Blood draw for RNA and DNA samples, serum carbonyl content, GSH/GSSG ratio and 
bilirubin levels. 
 
Baseline Visit (Day 1) 
• 
Record any change in medical and ocular history; concomitant medications, smoking history, 
alcohol intake, supplement usage and adverse events 
• 
Vital sign measurements (blood pressure, pulse rate, temperature and respiratory rate) 
• 
Slit lamp examination 
• 
Indirect Ophthalmoscopy 
• 
BCVA by Early Treatment Diabetic Retinopathy Study (ETDRS) Protocol 
• 
SD-OCT 
• 
MP1 and MAIA microperimetry 
• 
Anterior chamber tap (for measurement of carbonyl content and GSH/GSSG) 
• 
Obtain blood for serum carbonyl content, GSH/GSSG ratio and  blood for plasma NAC      
Levels (before and after drug administration). 
• 
Initiation of NAC treatment, first dose of NAC to be administered in the clinic 
 
Four Week Visit (Week 4/ 28+7days)    
• 
Record any change in medical and ocular history; concomitant medications, smoking history, 
alcohol intake, supplement usage and adverse events 
• 
Vital sign measurements (blood pressure, pulse rate, temperature and respiratory rate) 

13 
 
• 
Slit lamp examination 
• 
Indirect Ophthalmoscopy 
• 
BCVA 
• 
MAIA microperimetry 
• 
Anterior chamber tap (for measurement of carbonyl content and GSH/GSSG) 
• 
Blood Draw for serum carbonyl content and GSH/GSSG ratio 
 
Eight Week Visit (Week 8/ 56+7days)       
• 
Record any change in medical and ocular history; concomitant medications, smoking history, 
alcohol intake, supplement usage and adverse events 
• 
Vital sign measurements (blood pressure, pulse rate, temperature and respiratory rate) 
• 
Slit lamp examination 
• 
Indirect Ophthalmoscopy 
• 
BCVA 
• 
MAIA microperimetry 
• 
Anterior chamber tap (for measurement of carbonyl content and GSH/GSSG) 
• 
Blood Draw for serum carbonyl content and GSH/GSSG ratio 
 
Twelve Week Visit (Week 12/ 84+7days)       
• 
Record any change in medical and ocular history; concomitant medications, smoking history, 
alcohol intake, supplement usage and adverse events 
• 
Vital sign measurements (blood pressure, pulse rate, temperature and respiratory rate) 
• 
Slit lamp examination 
• 
Indirect Ophthalmoscopy 
• 
BCVA 
• 
SD-OCT 
• 
MAIA microperimetry 
• 
Anterior chamber tap (for measurement of carbonyl content and GSH/GSSG) 
• 
Obtain blood for serum carbonyl content, GSH/GSSG ratio and blood for plasma NAC levels 
(before and after drug administration). 

14 
 
• 
NAC to be administered in the clinic 
 
Sixteen Week Visit (Week 16/ 112+7days)       
• 
Record any change in medical and ocular history; concomitant medications, smoking history, 
alcohol intake, supplement usage and adverse events 
• 
Vital sign measurements (blood pressure, pulse rate, temperature and respiratory rate) 
• 
Slit lamp examination 
• 
Indirect Ophthalmoscopy 
• 
BCVA 
• 
MAIA microperimetry 
• 
Anterior chamber tap (for measurement of carbonyl content and GSH/GSSG) 
• 
Blood Draw for serum carbonyl content and GSH/GSSG ratio 
 
Twenty Week Visit (Week 20/ 140+7days)   
• 
Record any change in medical and ocular history; concomitant medications, smoking history, 
alcohol intake, supplement usage and adverse events 
• 
Vital sign measurements (blood pressure, pulse rate, temperature and respiratory rate) 
• 
Slit lamp examination 
• 
Indirect Ophthalmoscopy 
• 
BCVA 
• 
MAIA microperimetry 
• 
Anterior chamber tap (for measurement of carbonyl content and GSH/GSSG) 
• 
Blood Draw for serum carbonyl content and GSH/GSSG ratio 
 
Twenty-Four Week Visit (Week 24/ 168+7days) 
• 
Record any change in medical and ocular history; concomitant medications, smoking history, 
alcohol intake, supplement usage and adverse events 
• 
Vital sign measurements (blood pressure, pulse rate, temperature and respiratory rate) 
• 
Slit lamp examination 
• 
Indirect Ophthalmoscopy 

15 
 
• 
BCVA 
• 
SD-OCT 
• 
Fundus auto-fluorescence 
• 
Ultra-wide field fundus photography 
• 
MAIA microperimetry 
• 
Anterior chamber tap (for measurement of carbonyl content and GSH/GSSG) 
• 
Blood Draw for serum carbonyl content, GSH/GSSG ratio and blood for plasma NAC levels 
(before and after drug administration) 
• 
NAC to be administered in the clinic 
 
Twenty-Eight Week Visit (Week 28/ 196+7days) 
• 
Record any change in medical and ocular history; concomitant medications, smoking history, 
alcohol intake, supplement usage and adverse events 
• 
Vital sign measurements (blood pressure, pulse rate, temperature and respiratory rate) 
• 
Slit lamp examination 
• 
Indirect Ophthalmoscopy 
• 
BCVA 
• 
MAIA microperimetry 
• 
Anterior chamber tap (for measurement of carbonyl content and GSH/GSSG) 
• 
Blood Draw for serum carbonyl content and GSH/GSSG ratio 
 
Thirty-Two Week Visit (Week 32/ 224+7days) 
• 
Record any change in medical and ocular history; concomitant medications, smoking history, 
alcohol intake, supplement usage and adverse events 
• 
Vital sign measurements (blood pressure, pulse rate, temperature and respiratory rate) 
• 
Slit lamp examination 
• 
Indirect Ophthalmoscopy 
• 
BCVA 
• 
MAIA microperimetry 
• 
Anterior chamber tap (for measurement of carbonyl content and GSH/GSSG) 

16 
 
• 
Blood Draw for serum carbonyl content and GSH/GSSG ratio 
 
Thirty-Six Week Visit (Week 36/ 252+7days) 
• 
Record any change in medical and ocular history; concomitant medications, smoking history,       
alcohol intake, supplement usage and adverse events 
• 
Vital sign measurements (blood pressure, pulse rate, temperature and respiratory rate) 
• 
Slit lamp examination 
• 
Indirect Ophthalmoscopy 
• 
BCVA 
• 
SD-OCT 
• 
MAIA microperimetry 
• 
Anterior chamber tap (for measurement of carbonyl content and GSH/GSSG) 
• 
Blood Draw for serum carbonyl content and GSH/GSSG ratio 
 
4.3           DOSING AND DOSE ESCALATION 
This is a dose-escalation study in which 6 doses of NAC effervescent tablets are being tested: 600mg 
bid, 600mg tid, 1200mg bid, 1200mg tid, 1800mg bid and 1800mg tid. Patients will be given the 
dose pre-determined for the cohort they enter upon enrollment. The most common side effect of 
NAC is nausea and vomiting. If a patient cannot tolerate the assigned dose of NAC due to nausea 
and/or vomiting, the dose will be reduced to the dose immediately below the current dose. If that 
dose cannot be tolerated, the dose will be reduced to the next lowest level. This will be done until a 
tolerated dose is identified and the patient will be maintained on that dose throughout the trial. If a 
patient cannot tolerate the starting dose of 600mg bid, they will be reduced to 600mg qd.  If a patient 
cannot tolerate a dose of 600mg qd, they will be exited from the trial. If 3 of the first 5 subjects in a 
cohort or a total of 5 subjects are unable to tolerate a particular dose of NAC, no additional subjects 
will be treated with that dose and the dose immediately below it will be designated the maximum 
tolerated dose. All subsequent subjects enrolled in the study will be treated with the maximum 
tolerated dose. 
 

17 
 
4.4          STUDY DISCONTINUATION 
The Wilmer Eye Institute may terminate this study at any time.  Reasons for terminating the study may 
include the following: 
• The incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to subjects 
• Subject enrollment is unsatisfactory 
 
4.5 STATISTICAL METHODS 
     4.5.1          Safety Analysis 
The primary outcome measure is the safety and tolerability of N-acetyl cysteine (NAC) in patients with RP. 
Adverse events and results of ocular examinations from all 30 patients will be utilized to summarize safety data.  
The number and percentage of patients with treatment emergent adverse events (i.e. started or increased in 
severity after the patient received study treatment and includes abnormal lab results etc) will be summarised. 
The adverse events recorded prior to NAC administration will not be summarised and will be separated from 
the adverse events that are recorded post NAC administration in the final listings.  
 
     4.5.2          Secondary Analysis 
To measure the change from baseline aqueous and serum carbonyl content and GSH/GSSG ratio at 
1, 2, 3, 4, 5, 6, 7, 8 and 9 months after initiation of NAC treatment and correlate it with changes in 
BCVA, retinal sensitivity, and ellipsoid zone (EZ) width.  
4.5.3           Power Analysis 
Power analysis was conducted and a sample size of 30 was found to achieve 89% power to detect a 
mean of paired difference of 50% in aqueous carbonyl content with an estimated standard deviation 
of 0.8 and with significance level of 0.05 (95% confidence interval) using a 2 sided paired t-test. 
     4.5.4          Missing Data 
Analyses of efficacy and safety will be based on available cases without imputation for missing 
values. 
     4.5.5         Interim Analysis 

18 
 
No formal schedule of interim analyses is planned.  Reports of adverse events from this study may 
be reviewed and summarized periodically while the study is ongoing to ensure the safety of subjects.   
4.5.6        Early Termination and Replacement of Subjects 
Subjects withdrawn from the study prior to completion will be asked to return for an end of 
treatment assessment visit (all study procedures on the EOT assessment visit will be similar to those 
conducted on the month 9 visit) and the 3 months observational period. Subjects who are terminated 
prior to the week 24 visit will be replaced.  
 
4.6           DATA QUALITY ASSURANCE 
• Accurate, consistent, and reliable data will be ensured through the use of standard practices and 
procedures.     
 
5.     ASSESSMENT OF SAFETY 
5.1          ADVERSE EVENTS 
For this protocol, an AE is any “on study” untoward medical occurrence (e.g., sign, symptom, disease, 
syndrome, intercurrent illness) that occurs in a study subject, regardless of the suspected cause.  
Unchanged, chronic conditions are NOT AEs and should not be recorded on the AE pages of the CRF.  
An exacerbation or worsening of a chronic condition should be recorded as an AE. 
Both serious and non-serious AEs should be graded on a three-point scale (mild, moderate, severe) and 
reported in detail on the appropriate AE page of the CRF.   
The suggested definitions are as follows:  
Mild: 
Discomfort noticed but no disruption of normal daily activity 
Moderate: 
Discomfort sufficient to reduce or affect normal daily activity 
Severe: 
 
 
Incapacitating with inability to work or perform normal daily activity 
Using the following criteria, investigators also need to assess whether there is a reasonable possibility 
that study intervention caused or contributed to the AE. 

19 
 
• Yes (possibly or probably) 
There is a clinically plausible time sequence between onset of the AE and study intervention; and/or 
There is a biologically plausible mechanism for study intervention causing or contributing to the AE; 
and 
The AE may or may not be attributed to concurrent/underlying illness, other drugs, or procedures. 
• No 
A clinically plausible temporal sequence is inconsistent with the onset of the AE and study intervention; 
and/or 
A causal relationship is considered biologically implausible. 
 
5.2           BASELINE MEDICAL CONDITIONS 
It is not necessary to complete an AE CRF page for chronic medical conditions present at enrollment 
that do not worsen in intensity or frequency during the trial.  These medical conditions should be 
adequately documented on the appropriate page of the CRF (medical history and/or physical 
examination).  However, medical conditions present at enrollment that worsen in intensity or frequency 
during the treatment or post-treatment periods and ongoing AEs that started during the previous study 
should be reported and recorded as AEs.   
5.3           PROCEDURES FOR RECORDING AND REPORTING ADVERSE EVENTS 
     5.3.1          Recording Adverse Events  
To improve the quality and precision of acquired AE data, investigators should observe the following 
guidelines: 
• Whenever possible, use recognized medical terms when recording AEs on the AE pages of the CRF.  
Do not use colloquialisms and/or abbreviations. 
• If known, record the diagnosis (i.e., disease or syndrome) rather than component signs and 
symptoms on AE pages of the CRF (e.g., record congestive heart failure rather than dyspnea, rales, and 
cyanosis).  However, signs and symptoms that are considered unrelated to an encountered syndrome or 

20 
 
disease should be recorded as individual AEs on the CRF (e.g., if congestive heart failure and severe 
headache are observed at the same time, each events should be recorded as an individual AE). 
• AEs occurring secondary to other events (e.g., sequelae) should be identified by the primary cause.  
A “primary” AE, if clearly identifiable, generally represents the most accurate clinical term to record on 
AE pages of the CRF.  If a primary serious AE (SAE) is recorded on an SAE CRF, events occurring 
secondary to the primary event should be described in the narrative description of the case.   
 
     5.3.2          Serious Adverse Events 
An AE should be classified as SERIOUS if: 
• 
It resulted in death (i.e., the AE caused or led to death). 
• 
It was life threatening (i.e., the AE placed the subject at immediate risk of death; it does not 
apply to an AE that hypothetically might have caused death if it were more severe). 
• 
It required or prolonged inpatient hospitalization (i.e., the AE required at least a 24-hour 
inpatient hospitalization or prolonged a hospitalization beyond the expected length of stay; 
hospitalizations for elective medical/surgical procedures, scheduled treatments, or routine 
check-ups are not SAEs by this criterion). 
• 
It was disabling (i.e., the AE resulted in a substantial disruption of the subject’s ability to carry 
out normal life functions). 
• 
It resulted in a congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of a 
subject exposed to the molecule or study drug prior to conception or during pregnancy). 
• 
It does not meet any of the above serious criteria but may jeopardize the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
Sight-threatening adverse events 
An adverse event is considered to be sight-threatening if it meets one or more of the following criteria 
and will be reported as a serious adverse event (SAE): 
• 
The event causes a decrease in visual acuity of greater >30 letters (compared with the last 
assessment of visual acuity prior to the most recent treatment) lasting >1 hour. 

21 
 
• 
The event causes a decrease in visual acuity to the level of light perception or worse lasting >1 
hour. 
• 
The event requires surgical intervention (e.g, conventional surgery, vitreous tap or biopsy with 
intravitreal injection of antibiotics, or laser or retinal cryopexy with gas) to prevent permanent 
loss of sight. 
• 
The event is associated with severe intraocular inflammation (i.e., 4+ anterior chamber 
cell/flare or 4+ vitritis). 
• 
In the opinion of the investigator, the event may require medical intervention to prevent 
permanent loss of sight. 
 
     5.3.3          SAE Reporting 
Sub-Investigators should report all SAEs to the PI within 48 hours of observing or learning of the event.  
For initial SAE reports, investigators should record all case details that can be gathered within 48 hours 
on the SAE page of the CRF. The PI will inform the IRB within 1 week of being informed of the SAE. 
     5.3.4          Type and Duration Of Follow-Up After Adverse Events 
All reported AEs should be followed until resolution or until 1 month after the procedure.  Subjects who 
have an ongoing study related SAE will be followed by the investigator or his or her designee until the 
event is resolved or determined to be irreversible, chronic, or stable by the investigator.   
5.3.5        Plans to Decrease Potential Risks and Increase Safety 
Detailed ocular examinations (e.g., VA, slit lamp examination and dilated fundus examination) will be 
performed every month. The Principal Investigator will review all adverse events. The appropriate IRB 
will be notified immediately of any serious adverse events and will be notified in yearly renewals of all 
other adverse events. The IRB and FDA will be notified of any interruption in enrollment or change in 
the conduct of the study. Study drug administration will be held for subjects who experience certain 
systemic or ocular adverse events related to the drug. In the event any subject develops an adverse event 
in the study eye that is considered by the designated evaluating physician to be severe in intensity, 
serious consideration should be given to withdrawing the subject from the study.  
 

22 
 
6.      INVESTIGATOR REQUIREMENTS 
6.1           STUDY INITIATION 
Before the start of this study, the following documents must be on file at Johns Hopkins University or its 
appointed representative:  
• Current curricula vitae of the Principal Investigator  
• Written documentation of IRB approval of protocol (identified by Johns Hopkins University, 
protocol number or title and date of approval) and informed consent document (identified by 
Johns Hopkins University protocol number or title and date of approval) 
• A copy of the IRB-approved informed consent document 
• Written documentation of IRB review and approval of any advertising materials to be used for 
study recruitment, if applicable 
• The informed consent document and any advertising materials must also be reviewed and 
approved by the Johns Hopkins University Legal Department. 
• Certified translations of IRB approval letters, pertinent correspondence, and approved informed 
consent document (when applicable) 
 
6.2           STUDY COMPLETION 
The following data and materials are required by Johns Hopkins University before a study can be 
considered complete or terminated: 
• Laboratory findings, clinical data, and all special test results from screening through the end of 
the study follow-up period (if applicable) 
• Case Report Forms properly completed by appropriate study personnel and signed and dated by 
the investigator (if applicable) 
• Copies of protocol amendments and IRB approval/notification (if applicable) 

23 
 
• A summary of the study prepared by the Principal Investigator (will accept IRB summary close 
letter) (if applicable) 
• All regulatory documents (e.g., curricula vitae for each Principal Investigator) 
 
6.3           INFORMED CONSENT 
Informed consent documents will be provided to each subject.  
The informed consent document must be signed and dated by the subject or the subject’s legally 
authorized representative before his or her participation in the study.  The case history for each subject 
shall document that informed consent was obtained prior to participation in the study.  A copy of the 
informed consent document must be provided to the subject or the subject's legally authorized 
representative.  If applicable, it will be provided in a certified translation of the local language. 
Signed consent forms must remain in each subject’s study file and must be available for verification at 
any time. 
The following basic elements must be included: 
A statement that the study involves research, an explanation of the purposes of the research and the 
expected duration of the patient’s participation, a description of the procedures to be followed, and 
identification of any procedures or drug used for purposes which are experimental 
• A description of any reasonably foreseeable risks or discomforts to the patients 
• A description of any benefits to the patient or to others which may reasonably be expected from 
the research. A description that there may be no benefit from this research. 
• A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the patient 
• A statement describing the extent, if any, to which confidentiality records identifying the patient 
will be maintained and that notes the possibility that the FDA and the Johns Hopkins University 
and the drug manufacturer may inspect the records 

24 
 
• For research involving more than minimal risk, an explanation as to whether any compensation 
and any medical treatments are available should injury occur and, if so, what they consist of or 
where further information may be obtained 
• An explanation of whom to contact for answers to pertinent questions about the research and 
research patient’s rights, and whom to contact in the event of a research-related injury to the 
patient 
• A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the patient is otherwise entitled, and that the patient may discontinue 
participation at any time without penalty or loss of benefits to which the patient is otherwise 
entitled 
 
6.4          INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE APPROVAL 
This protocol, the informed consent document, and relevant supporting information must be submitted 
to the IRB/EC for review and must be approved before the study is initiated.  The study will be 
conducted in accordance with U.S. FDA, applicable national and local health authorities, and IRB/EC 
requirements. 
The Principal Investigator is responsible for keeping the IRB/EC apprised of the progress of the study 
and of any changes made to the protocol as deemed appropriate, but in any case the IRB/EC must be 
updated at least once a year.  The Principal Investigator must also keep the IRB/EC informed of any 
significant adverse events. 
Investigators are required to promptly notify their respective IRB/EC of all adverse drug reactions that 
are both serious and unexpected.  This generally refers to serious adverse events that are not already 
identified in the package insert and that are considered possibly or probably related to the study drug by 
the investigator.  Some IRBs or ECs may have other specific adverse event requirements that 
investigators are expected to adhere to.  Investigators must immediately forward to their IRB/EC any 
written safety report or update provided by Johns Hopkins University (e.g., IND safety report, 
Investigator Brochure, safety amendments and updates, etc.). 
 

25 
 
6.5           CASE REPORT FORMS 
All CRFs should be filled out completely by appropriate personnel.  The CRF should be reviewed, 
signed, and dated by the investigator. 
All CRFs should be completed in a neat, legible manner to ensure accurate interpretation of data.  Black 
ink is required to ensure clarity of reproduced CRF copies.  When making changes or corrections, cross 
out the original entry with a single line, and initial and date the change.  DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID ON THE ORIGINAL. 
 
6.6           STUDY DRUG ACCOUNTABILITY 
The Investigator is responsible for the control and distribution of study drug. 
All partially used or empty containers should be disposed of at the study site according to institutional 
standard operating procedure.  
 
6.7           DISCLOSURE OF DATA 
Subject medical information obtained by this study is confidential, and disclosure to third parties other 
than those noted below is prohibited. 
Upon the subject’s permission, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. 
Data generated by this study must be available for inspection upon request by representatives of the 
U.S. FDA, national and local health authorities, the drug manufacturer and the IRB/EC for each study 
site, if appropriate. 
 
6.8           RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents pertaining to the conduct 
of this study and the distribution of investigational drug, including CRFs, consent forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator for 2 years after 

26 
 
the investigation is discontinued and the U.S. FDA and the applicable national and local health 
authorities are notified. 
 
7.               PAYMENTS, REMUNERATIONS AND COSTS TO PARTICIPANTS 
7.1  
PAYMENT AND REMUNERATION 
There is no compensation for participants for this protocol.  
 
7.2             COSTS 
There are no costs for study procedures or study drug to participants. 
 
8.    
REFERENCES 
1. 
Yu, D.Y., et al., Intraretinal oxygen levels before and after photoreceptor loss in the RCS rat. 
Invest Ophthalmol Vis Sci, 2000. 41(12): p. 3999-4006. 
2. 
Usui, S., et al., NADPH oxidase plays a central role in cone cell death in retinitis 
pigmentosa. J Neurochem, 2009. 110(3): p. 1028-37. 
3. 
Komeima, K., et al., Blockade of neuronal nitric oxide synthase reduces cone cell death in a 
model of retinitis pigmentosa. Free Radic Biol Med, 2008. 45(6): p. 905-12. 
4. 
Davies, S.M., et al., Measurements of protein carbonyls, ortho- and meta-tyrosine and 
oxidative phosphorylation complex activity in mitochondria from young and old rats. Free 
Radic Biol Med, 2001. 31(2): p. 181-90. 
5. 
Levine, R.L., Carbonyl modified proteins in cellular regulation, aging, and disease. Free 
Radic Biol Med, 2002. 32(9): p. 790-6. 
6. 
Buss, H., et al., Protein carbonyl measurement by a sensitive ELISA method. Free Radic Biol 
Med, 1997. 23(3): p. 361-6. 
7. 
Shen, J., et al., Oxidative damage is a potential cause of cone cell death in retinitis 
pigmentosa. J Cell Physiol, 2005. 203(3): p. 457-64. 
8. 
Komeima, K., et al., Antioxidants reduce cone cell death in a model of retinitis pigmentosa. 
Proc Natl Acad Sci U S A, 2006. 103(30): p. 11300-5. 
9. 
Komeima, K., B.S. Rogers, and P.A. Campochiaro, Antioxidants slow photoreceptor cell 
death in mouse models of retinitis pigmentosa. J Cell Physiol, 2007. 213(3): p. 809-15. 
10. 
Usui, S., et al., Increased expression of catalase and superoxide dismutase 2 reduces cone 
cell death in retinitis pigmentosa. Mol Ther, 2009. 17(5): p. 778-86. 
11. 
Usui, S., et al., Overexpression of SOD in retina: need for increase in H2O2-detoxifying 
enzyme in same cellular compartment. Free Radic Biol Med, 2011. 51(7): p. 1347-54. 
12. 
Campochiaro, P.A., et al., Is There Excess Oxidative Stress and Damage in Eyes of Patients 
with Retinitis Pigmentosa? Antioxid Redox Signal, 2015. 23(7): p. 643-8. 
13. 
Lee, S.Y., et al., N-Acetylcysteine promotes long-term survival of cones in a model of retinitis 
pigmentosa. J Cell Physiol, 2011. 226(7): p. 1843-9. 
14. 
Tse, H.N., et al., High-dose N-acetylcysteinine in stable COPD: the 1-year, double-blind, 
randomized, placebo-controlled HIACE study. Chest, 2013. 144(1): p. 106-118. 
15. 
Zheng, J.P., et al., Twice daily N-acetylcysteine 600 mg for exacerbations of chronic 
obstructive pulmonary disease (PANTHEON): a randomized, double-blind placebo-
controlled trial. Lancet, 2014. 2(3): p. 187-194. 

27 
 
16. 
Demedts, M., et al., High-dose acetylcysteine in idiopathic pulmonary fibrosis. N. Engl. J. 
Med., 2005. 353(21): p. 2229-2242. 
17. 
Smilkstein, M.J., et al., Efficacy of oral N-acetylcysteine in the treatment of acetominophen 
overdose. Analysis of the national multicenter study (1976-1985). N. Eng. J. Med., 1988. 
319: p. 1557-1562. 
18. 
Pendyala, L. and P.J. Creaven, Pharmacokinetic and pharmacodynamic studies of N-
acetylcysteine, a potential chemopreventive agent during a phase I trial. Cancer Epidemiol. 
Biomark. Prevention, 1995. 4: p. 245-251. 
19. 
Miller, L.F. and B.H. Rumack, Clinical safety of high oral doses of acetylcysteine. Semin. 
Oncol., 1983. 10 (Suppl 1): p. 76-85. 
20. 
Oldham, J.M., et al., TOLLIP, MUC5B, and the response to N-acetylcysteine among 
individuals with idiopathic pulmonary fibrosis. Amer. J. Resp. Crit. Care Med., 2015. 
192(12): p. 1475-1482. 
 
 

28 
 
Appendix A 
Schedule of Activities for Subjects with RP  
Protocol Activities  
BL 
28+
7d 
56+
7d 
84+7
d 
112+
7d 
140+
7d 
168+
7d 
196+
7d 
224+
7d 
252+
7d 
Screening 
Day1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History/ Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BCVA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Funduscopic Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Paracentesis (study eye) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Draw for RNA & DNA samples 
X 
 
 
 
 
 
 
 
 
 
 
Blood Draw for serum bilirubin levels 
X 
 
 
 
 
 
 
 
 
 
 
Blood Draw for measurement of oxidative markers 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
Blood Draw for measurement of plasma NAC 
levels (before administration of oral NAC and 1 & 
2 hours after administration – 2 hour draw 
optional) 
 
X 
 
 
X 
 
 
X 
 
 
 
MP1 microperimetry 
X 
X 
 
 
 
 
 
 
 
 
 

29 
 
MAIA microperimetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SD-OCT 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Fundus autofluorescence 
X 
 
 
 
 
 
 
X 
 
 
 
Ultrawide angle fundus photo 
X 
 
X 
 
 
 
Treatment with  NAC  
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X