Effects of Antiplatelet and Antioxidant Agents on Drusen Progression: A Pilot, Prospective Cohort Study
Phase: PHASE3
Conditions: Dry Age-related Macular Degeneration
Sponsor: Navamindradhiraj University

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Proposal 
The Institutional Review Board of the Faculty of Medicine Vajira Hospital 
        
1.   Study title 
Effects of antiplatelet and antioxidant agents on drusen progression: A pilot, prospective 
cohort study 
 
2. Principal Investigator 
 
     2.1   Name    
Yolradee Winuntamalakul, MD. 
 
 
       Position 
Ophthalmology resident 
 
 
       Department Department of ophthalmology, Faculty of medicine, Vajira 
hospital 
 
 
      Phone number +662-2443874, +668-51283362 
 
 
      E-mail:  
yolradee.win@nmu.ac.th 
 
 
 
 
 
 
2.2   Name   
Yodpong Chantarasorn, MD. 
 
 
       Position 
Associate Professor 
 
 
       Department Department of ophthalmology, Faculty of medicine, Vajira 
hospital 
 
 
      Phone number +662-2443874, +668-91036633 
 
 
      E-mail:  
yodpong@nmu.ac.th  
 
 
 
3. Co-investigator 
 
None 
 
4. Background and Rationale 
Age-related macular degeneration (AMD) is one of the leading causes of blindness in the 
elderly. The incidence of AMD is 8.69% worldwide (1) and 6.8%–7.38% in Asia (1, 2). AMD is 
classified as dry AMD/non-neovascular AMD or wet AMD/neovascular AMD. 
Drusen, a small yellowish spot, is a hallmark of AMD. Early stages of AMD will present 
only drusen and asymptomatic, progressing to retinal pigmented epithelium (RPE) 
abnormalities later, and progressing to geographic atrophy in late/advanced or advanced 
stages of AMD (3, 4). 

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AMD is caused by a variety of mechanisms, including genetic factors, waste product 
accumulation in the RPE, which causes mitochondrial function abnormalities, resulting in RPE 
destruction and cell death. Furthermore, reactive oxygen species in the retina caused by 
inflammation and cell death promote RPE dysfunction and death as a vitreous cycle (3-5). 
Also, from choriocapillaris vascular ischemia (6). 
 
The progression of disease from the early stages to the advanced stages is 5–6.6 years 
(7, 8) and causes irreversible visual loss. In age-related eye disease studies (AREDS), antioxidant 
supplements consist of vitamin C, vitamin E, zinc, copper, lutein, and zeaxanthin. According 
to the study, supplements can reduce the risk of progression to advanced AMD by 25% in 
Category 3 and 4 (9, 10). Because there is no specific treatment for AMD other than slowing 
the rate of progression, several studies are required to discover AMD treatment. 
 
Antiplatelet drugs can reduce rate of progression to geographic atrophy by reducing 
choriocapillaris ischemia (11) and do not increase the rate of bleeding when compared to no 
medication (11, 12).  
 
Some studies showed that antioxidants such as N-acetylcysteine, vitamin C, and 
vitamin E can protect RPE from oxidative stress and decrease cell death by reducing reactive 
oxygen species (9, 10, 13-15). In addition, drusen decreased and no geographic atrophy was 
observed in a dry AMD patient who took daily supplements (16). Therefore, antioxidants such 
as N-acetylcysteine may have benefits in dry AMD with minor side effects (17-19). 
The aim of this clinical trial is to evaluate the effect of low doses of antiplatelet 
medications (aspirin 81 mg/day or clopidogrel 75 mg/day) with or without a combination of 
antioxidants (N-acetylcysteine 600 mg/day) in a dry AMD patient with large drusen. 
 
5. Propose 
5.1 Primary Objective  
To evaluate dry AMD progression in participants with large drusen by drusen volume 
analysis. 
Participants will divide in to three groups. 
• Participants who were already taking low dose antiplatelet medications (aspirin 81 
mg/day or clopidogrel 75 mg/day). 
• Participants who take the antiplatelet drug mentioned above in addition to the 
antioxidant (N-acetylcysteine 600 mg/day) prescribed by the investigator. 
• Participants does not use any medications. 

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5.2 Secondary Objectives 
 5.2.1 Best-corrected visual acuity/BCVA of participants by groups in 6.1 
 5.2.2 Rate of progression to geographic atrophy or neovascular AMD  
 
 
5.2.3 Side effects and safety 
 
6.  Framework 
 
               
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.  Material and Method  
 
7.1 Study Design 
Prospective interventional cohort study 
 
7.2 Study Population 
Participants with dry AMD or non-neovascular AMD who have large will be divided into 
three groups.  
1. Participants who were already taking low dose antiplatelet medications (aspirin 81 
mg/day or clopidogrel 75 mg/day). 
Aspirin 81 mg/d or 
Clopidogrel 75 mg/d  
Participants with large drusen in dry AMD 
Divided into 3 groups 
Rate of Geographic atrophy or 
neovascular AMD development 
BCVA 
Drusen volume 
analysis 
Side effects 
No medication 
Aspirin 81 mg/d or Clopidogrel 
75 mg/d combined with N-
acetylcysteine 600 mg/d 

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2. Participants who take the antiplatelet drug mentioned above in addition to the 
antioxidant (N-acetylcysteine 600 mg/day) prescribed by the investigator. 
3. Participants does not use any medications. 
Participants must take medication for at least 12 months. Antiplatelet drugs are 
medications that patients take to treat their underlying condition, such as aspirin 81 
mg/day or clopidogrel 75 mg/day. Participants using antiplatelet medications will be 
randomly assigned to receive N-acetylcysteine or not. 
 
 
7.3 Inclusion, exclusion criteria and Criteria for discontinuation 
Inclusion criteria 
1. Dry AMD with at least 1 large drusen. According to the AREDS study, large drusen 
have a size of more than 125 micron.(21) 
2. Patients can evaluate SD-OCT (Spectral domain optical coherence tomography), 
OCT angiography, and best-corrected visual acuity. 
3. Age range: 50-85 years 
4. Patients who have previously used antiplatelet drugs. 
 
Exclusion criteria  
1. Patient with advanced AMD, such as geographic atrophy, neovascular complications 
(choroidal neovascularization) 
2. Patient with additional retinal diseases that affect visual acuity, e.g., retinal 
detachment, diabetic macular edema. 
3. Patient with a history of intravitreal anti-VEGF injection or macular laser. 
4. Patient using SSRIs, SNRIs, azole, NSAIDs, dual antiplatelet, anticoagulant 
medications. 
 
Criteria for discontinuation 
1. Participants who cannot tolerate the side effects of N-acetylcysteine. However, the 
side effects of N-acetylcysteine are mild, such as heartburn, nausea, and vomiting.(17, 22) 
2. Participants need to stop antiplatelet drugs prescribed by their doctor. 
3. Participants cannot evaluate their BCVA or undergo SD-OCT or OCT angiography. 
 
 

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7.4  Sample size 
Previous study showed drusen volume accumulation before the advanced stage was 
0.264 ± 0.013 mm3 per year (23). The AREDS formula can reduce progression to the 
advanced AMD by 4% each year. The researchers believe that using antiplatelet 
medication alone or in combination with antioxidants will decrease progression by 10%, 
or 0.211 mm3. 
 𝑁= 
(𝑍1−𝛼
2
+𝑍1−𝛽)2𝜎2
(𝜇−𝜇0)2
 
 
reference value (𝜇0) = 26.4 
mean (𝜇) = 21.1 
standard deviation (𝜎) = 13 
alpha (𝛼) = 0.05 
beta (𝛽) = 0.2 
Estimated sample size: 
            N = 48 
Sample size = 48 eyes per group. Some participants lost 20% throughout the follow-
up period. As a result, the sample size is 174 eyes (58 eyes per group).  
 
7.5  Variables 
Independent Variable – 3 medications groups 1. Aspirin 81 mg per day or 
Clopidogrel 75 mg per day 2. Aspirin 81 mg per day or Clopidogrel 75 mg per day 
combined with N-acetylcysteine 600 mg (NAC-long, Temmler Pharma, Marburg, 
Germany) per day 
Dependent variable - Drusen volume analysis, rate progression to geographic 
atrophy or neovascular AMD, and BCVA 
 
7.8  Methodology 
 
1. Application for ethic review  
2. Select dry AMD participants based on inclusion and exclusion criteria. Participants 
sign an informed consent form. 
 3. Participants will be divided into three groups.  

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- Participants who were already taking low dose antiplatelet medications (aspirin 
81 mg/day or clopidogrel 75 mg/day). 
 
 
 
- Participants who take the antiplatelet drug mentioned above in addition to the 
antioxidant (N-acetylcysteine 600 mg/day) prescribed by the investigator. 
 
 
 
- Participants does not use any medications. 
Participants must take medication for at least 12 months. Antiplatelet drugs are 
medications that patients take to treat their underlying condition, such as aspirin 81 
mg/day or clopidogrel 75 mg/day. Participants using antiplatelet medications will be 
randomly assigned to receive N-acetylcysteine or not. 
4. The date the medication receipt is day 1. Participants must follow up every three 
months for a total of twelve months. Participants will examine BCVA, take a fundus 
photo, SD-OCT, and OCT angiography, and evaluate side effects from medication and 
compliance. 
 
 
7.9 Statistical analysis               
1. Quantitative data is drusen volume analysis, rate of progression to geographic 
atrophy or neovascular AMD, using ANOVA test; multiple regression analysis by 
confounder adjustment, pairwise comparison, and linear mixed modal analysis. A p-value 
of < 0.05 was considered statistically significant. 
2. Qualitative Data is side effect from medications.  
 
8.  Reference  
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related macular degeneration and disease burden projection for 2020 and 2040: a systematic 
review and meta-analysis. The Lancet Global Health. 2014;2(2):e106-e16. 
2. Kawasaki R, Yasuda M, Song SJ, Chen S-J, Jonas JB, Wang JJ, et al. The prevalence of age-
related macular degeneration in Asians: a systematic review and meta-analysis. 
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3. Ambati J, Fowler BJ. Mechanisms of age-related macular degeneration. Neuron. 
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4. Buschini E, Piras A, Nuzzi R, Vercelli A. Age related macular degeneration and drusen: 
neuroinflammation in the retina. Progress in neurobiology. 2011;95(1):14-25. 

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5. Deng Y, Qiao L, Du M, Qu C, Wan L, Li J, et al. Age-related macular degeneration: 
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Informed Consent Form 
 
 
 
 
 
 
 
         Date…………………………………….. 
 
I, ....................................................................................................., Age .......................... years old, 
Adress ........................................................................................, Province ...................................................., 
City ................................................, Postal code .........................., Phone number ......................................... 
Hereby, declare my intention that I consent to be a participant of the research project effects of 
Antiplatelet and Antioxidant Agents on Drusen Progression: A Pilot, Prospective Cohort Study. I have 
received the Participant Information Sheet, read through and understood all the details. I have been 
informed of the details of the research objectives, details of the process steps that the participant must 
perform, duration of the participation, benefits and risks that will occur of the participation, 
preventive and corrective measures, compensation to be received, and expenses that I must be 
responsible for (if any). Also, the principal investigator has already given explanation and completely 
answered all my queries. 
I acknowledge that I have the right to receive additional information on both benefits and 
harms from participating this research and be able to withdraw or cease my participation any time 
without any impact on my study in the future. I also consent the researcher to use my personal data 
for the research and present the research results as an overview only. 
Should there be any unusual symptoms, sick feeling and/or impact on my mental occurred 
during participating in the research, I shall promptly inform the researcher. 
Should I have any queries regarding the research procedure or there be any undesirable side 
effects incurred from participating in the research, I shall be able to contact Dr. Yolradee 
Winuntamalakul, phone number +6685-1283362. 
If I am not treated as stated in the Participant Information Sheet, I shall be able to contact the 
chairman of the Institutional Review Board of the Faculty of Medicine Vajira Hospital, 
Navamindradhiraj university, phone number + 662-2443843. 
I have thoroughly read and fully understood the contents. Therefore, I give my consent to 
participate in the research voluntarily and willingly. I have signed this Informed Consent Form. 
 
 

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contents to the participant until understands. I give my consent to participate in the research using 
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