Acute Changes in Optic Nerve Head (ONH) and Macular Blood Flow After Caffeine Consumption in Glaucoma Patients and Healthy Subjects: A Quantitative Optic Coherence Tomography Angiography (OCTA) Study
Phase: NA
Conditions: Glaucoma, Primary Open Angle
Sponsor: Wills Eye

840 Walnut Street 
Philadelphia, PA 19107 
215-928-3000 
1-877-AT-WILLS 
www.willseye.org 
 
                                                                                                                                 
 
 
 
 
 
 
 
 
 
 
 
Acute Changes in Optic Nerve Head (ONH) and Macular Blood Flow after Caffeine Consumption in 
Glaucoma Patients and Healthy Subjects: A Quantitative Optical Coherence Tomography Angiography 
(OCTA) Study 
 
Principal Investigator:  M. Reza Razeghinejad, MD 
 
NCT03675412 
IRB# 18-729 
 
 
Study Protocol 
April 25, 2019 
 
 
 
 
 
 
 
 
 
 
 
 

Study Protocol 
 
Protocol Title 
Acute Changes in Optic Nerve Head (ONH) and Macular Blood Flow after Caffeine Consumption in 
Glaucoma Patients and Healthy Subjects: A Quantitative Optical Coherence Tomography Angiography 
(OCTA) Study 
 
Principal Investigator:  M Reza Razeghinejad, MD 
Co-Investigators:  Melih Ustaoglu, MD; Sapna Sinha, MD; Carina T. Sanvicente, MD; Marlene R Moster, 
MD; Michael J. Pro, MD; Elizabeth Dale, MD; Daniel Lee, MD; Johnathan S. Myers, MD; L. Jay Katz, MD; 
Scott J. Fudemberg, MD; Anand V Mantravadi, MD 
Department: Glaucoma Service   
Phone Number:  215-928-7023 
 
Objectives 
The primary objective of this study is to assess the acute changes in peripapillary and macular blood flow 
after an intake of oral caffeine in glaucoma patients and healthy subjects, by using optical coherence 
tomography angiography (OCTA).   
 
Hypothesis 
Ingestion of caffeine in glaucoma patients and healthy subjects may decrease peripapillary and macular 
blood flow. 
 
Background and Significance 

Caffeine is the most widely consumed drinking nutrient in the world; it is naturally included in coffee, tea 
and cocoa beans.1,2 Although caffeine is naturally or synthetically found in many dietary sources (energy 
drinks, soda-type beverages, juice, chewing gums, candy, etc.), it is mostly linked to coffee consumption 
since it is the most commonly ingested beverage worldwide.1,3-5 Daily consumption of coffee varies among 
nations, for example, an average daily intake of caffeine of about 180 mg/day is reported in the United 
States4,6, and 260 mg/day in Japan.1,7 It is known that a regular cup of coffee (236 mL) contains 
approximately 135 – 150 mg of caffeine and a daily intake of about 200 mg/day is considered moderate.5,8  
 
Caffeine works by binding to adenosine receptors of the central and peripheral nervous systems, heart 
and blood vessels.1 It affects various organs and its effect on the vascular system can be explained by two 
possible mechanisms: binding to the vascular smooth muscle receptors and leading to vasoconstriction or 
increasing the intracellular calcium concentration which leads to increased nitric oxide synthesis and 
vasodilatation.9,10 It decreases ocular blood flow due to vasoconstruction.11-14 In a recent study, a 
significantly decrease in choroidal thickness after 200 mg oral caffeine intake was observed.11 In other 
studies, decrease in retinal blood flow in healthy volunteers was demonstrated by using blue field 
simulation technique12, laser speckle tissue circulation analyzer14 and OCTA13. 
 
Optical coherence tomography angiography (OCTA) is a novel imaging tool that separates moving scatters 
from static background tissue to create three-dimensional angiograms15 by assessing the change in the 
OCT signal caused by flowing blood cells.16 This new technology enables a fast and non-invasive angiogram 
scan.16,17 Numerous studies have validated the use of the OCTA in the evaluation of various diseases of 
the retina, choroid, and optic nerve by evaluation of the  total blood flow and microvasculature structure. 
18-25   
 

The correlation of IOP changes after caffeine intake was evaluated and a transient increase in IOP of 
approximately 1 - 2 mmHg within two hours were reported in previous studies26-28. Although an associated 
transient IOP elevation has been reported with caffeine, it is not considered as a risk factor for glaucoma.26 
In the present study, we aim to evaluate the optic nerve head and macular blood flow changes by using 
OCTA in glaucoma patients at different stages and healthy subjects before and after ingestion of 200 mg 
caffeine tablet.  
 
Methods: 
Study Design 
Interventional Prospective Clinical Trial  
 
Inclusion and Exclusion Criteria 
Inclusion criteria: 
Age 18-90 
 
Glaucoma patients  
 
Healthy subjects 
Exclusion Criteria: 
 
Diseases, ophthalmic or systemic, that are likely to affect the OCTA test results. 
 
More than moderate grade cataract 
 
Nystagmus  
 
Inability to fixate for OCTA scan 
 
Macular degeneration other than mild drusen or pigmentary changes 
 
Diabetic retinopathy  
 
Neovascular glaucoma 

 
Current macular edema 
 
Prior laser treatment to the retina 
 
Inflammatory retinopathy or choroidopathy 
 
Keratoconus or other corneal ectasia 
 
Corneal scarring in central 4 mm 
 
Non-glaucoma optic neuropathies: ischemic and traumatic optic neuropathy, optic 
atrophy 
 
Rheumatologic diseases with vascular involvement: rheumatoid arthritis, systemic lupus 
erythematosus, 
 
Raynaud’s phenomena 
 
Pregnant and lactating women 
 
Patients with mental illness (schizophrenia, bipolar disorder, anxiety symptoms) 
 
Alcohol addiction 
 
Pre-existing bladder symptoms 
 
Pre-existing cardiac disease 
 
Pre-existing sleep disorder 
 
Refractive spherical diopter >5 or cylinder > 3. 
 
Subjects who would develop a possible tolerance to caffeine (subjects drinking more than 
one cup of coffee per day) 
 
Number of Patients to Enroll 
 
20 patients with early stage primary open angle glaucoma  
 
20 patients with moderate stage primary angle glaucoma 

 
20 patients with advanced stage primary angle glaucoma 
 
20 healthy subjects without glaucoma 
 
Study Timeline 
 
Patient enrollment will begin after IRB approval.  We plan to complete enrollment and data acquisition 
within 1 year of IRB approval. 
 
Study Data and Outcome Measures 
All included patients will undergo a baseline examination involving case history. Measurement of best 
corrected visual acuity, visual field examination, corneal pachymetry, Axial length, and examination of the 
anterior and posterior segments of the eye. 
The IOP, systolic and diastolic blood pressure, and heart rate will be checked before, and one hour and 
two hours after caffeine ingestion. The severity of glaucomatous damage was classified into early, 
moderate and severe stage according to Hodapp-Parrish-Anderson criteria.29  
Macular and peripapillary blood flow index, vessel density, areas of capillary dropout or non-perfusion 
detected by OCT angiography will be assessed before, one hour and two hours after the  ingestion of 
caffeine tablet.  
 
Procedures Involved 
Qualifying patients presenting to the Wills Eye Hospital Glaucoma Service will be asked for enrollment. 
Informed consent will be obtained from all participants. Subjects will undergo a comprehensive eye 
examination including Humphrey visual field and ocular biometry in both eyes. Scans will be obtained with 
the Avanti AngioVue HD OCTA (Optovue, Inc, Fremont, CA, USA), before and, one hour and two hours 
after a 200 mg caffeine tablet ingestion.  All eyes will undergo imaging using the standard 4.5 mm HD Disc 

scan protocol and the 6mm HD Retina scan protocol. In addition, a regular ONH structural scan (along 
with a 3D-Disc baseline scan) and a regular GCC structural scan will be acquired which provide comparison 
to normative database of the device to characterize the RNFL and GCC thickness status of the study eyes. 
Arterial blood pressure, heart rate and IOP will also be measured before and, one and two hours after the 
200 mg caffeine tablet ingestion. 
 
Data analysis 
OCT Analysis 
Acceptable images should have clear and sharp focus artifacts free (e.g., motion lines), without motion 
artifact (identified by horizontal misalignment of vessel segments on en face images), and Scan Quality of 
6 or higher.  The scans will be evaluated for vessel density, vessel length per unit area, flow index, foveal 
avascular zone area. Capillary dropout will also be recorded, if present. 
 
Statistical Analysis 
Continuous variables will be gathered for all groups using the following statistics: the mean, standard 
deviation, minimum, maximum, median, first quartile, and third quartile values. The frequency and 
percentages will be reported for the categorical measures. Subgroup analysis will be performed to 
determine differences in blood flow related to the diagnosis, IOP change and ocular perfusion pressure. 
 
Confidentiality 
Every effort will be made to protect the confidentiality of the data of the participants.  All data will be de-
identified and the assigned ID number will be used to track individual participants. 
 
References 
 

1. 
Temple JL, Bernard C, Lipshultz SE, Czachor JD, Westphal JA, Mestre MA. The Safety of Ingested 
Caffeine: A Comprehensive Review. Frontiers in psychiatry. 2017;8:80. 
2. 
Nehlig A. Are we dependent upon coffee and caffeine? A review on human and animal data. 
Neuroscience and biobehavioral reviews. Mar 1999;23(4):563-576. 
3. 
Jiwani AZ, Rhee DJ, Brauner SC, et al. Effects of caffeinated coffee consumption on intraocular 
pressure, ocular perfusion pressure, and ocular pulse amplitude: a randomized controlled trial. 
Eye (London, England). Aug 2012;26(8):1122-1130. 
4. 
Mitchell DC, Knight CA, Hockenberry J, Teplansky R, Hartman TJ. Beverage caffeine intakes in the 
U.S. Food and chemical toxicology : an international journal published for the British Industrial 
Biological Research Association. Jan 2014;63:136-142. 
5. 
Gilbert RM. Caffeine consumption. Progress in clinical and biological research. 1984;158:185-
213. 
6. 
Fulgoni IIIVL, Keast DR, Lieberman HR. Trends in intake and sources of caffeine in the diets of US 
adults: 2001–2010. The American journal of clinical nutrition. 2015;101(5):1081-1087. 
7. 
Yamada M, Sasaki S, Murakami K, et al. Estimation of caffeine intake in Japanese adults using 16 
d weighed diet records based on a food composition database newly developed for Japanese 
populations. Public health nutrition. May 2010;13(5):663-672. 
8. 
Chandra P, Gaur A, Varma S. Effect of caffeine on the intraocular pressure in patients with 
primary open angle glaucoma. Clinical ophthalmology (Auckland, N.Z.). 2011;5:1623-1629. 
9. 
Sumpio BE, Riley JT, Dardik A. Cells in focus: endothelial cell. The international journal of 
biochemistry & cell biology. Dec 2002;34(12):1508-1512. 
10. 
Echeverri D, Montes FR, Cabrera M, Galan A, Prieto A. Caffeine's Vascular Mechanisms of Action. 
International journal of vascular medicine. 2010;2010:834060. 
11. 
Dervisogullari MS, Totan Y, Yuce A, Kulak AE. Acute effects of caffeine on choroidal thickness 
and ocular pulse amplitude. Cutaneous and ocular toxicology. Dec 2016;35(4):281-286. 
12. 
Lotfi K, Grunwald JE. The effect of caffeine on the human macular circulation. Investigative 
ophthalmology & visual science. Nov 1991;32(12):3028-3032. 
13. 
Karti O, Zengin MO, Kerci SG, Ayhan Z, Kusbeci T. ACUTE EFFECT OF CAFFEINE ON MACULAR 
MICROCIRCULATION IN HEALTHY SUBJECTS: An Optical Coherence Tomography Angiography 
Study. Retina. Feb 2 2018. 
14. 
Okuno T, Sugiyama T, Tominaga M, Kojima S, Ikeda T. Effects of caffeine on microcirculation of 
the human ocular fundus. Japanese journal of ophthalmology. Mar-Apr 2002;46(2):170-176. 
15. 
Wang RK, Jacques SL, Ma Z, Hurst S, Hanson SR, Gruber A. Three dimensional optical 
angiography. Optics express. Apr 02 2007;15(7):4083-4097. 
16. 
Gao SS, Jia Y, Zhang M, et al. Optical Coherence Tomography Angiography. Investigative 
ophthalmology & visual science. Jul 01 2016;57(9):Oct27-36. 
17. 
Scripsema NK, Garcia PM, Bavier RD, et al. Optical Coherence Tomography Angiography Analysis 
of Perfused Peripapillary Capillaries in Primary Open-Angle Glaucoma and Normal-Tension 
Glaucoma. Investigative ophthalmology & visual science. Jul 01 2016;57(9):Oct611-oct620. 
18. 
Bonini Filho MA, de Carlo TE, Ferrara D, et al. Association of Choroidal Neovascularization and 
Central Serous Chorioretinopathy With Optical Coherence Tomography Angiography. JAMA 
Ophthalmol. Aug 2015;133(8):899-906. 
19. 
Liu L, Jia Y, Takusagawa HL, et al. Optical Coherence Tomography Angiography of the 
Peripapillary Retina in Glaucoma. JAMA ophthalmology. Sep 2015;133(9):1045-1052. 
20. 
Nobre Cardoso J, Keane PA, Sim DA, et al. Systematic Evaluation of Optical Coherence 
Tomography Angiography in Retinal Vein Occlusion. American journal of ophthalmology. Mar 
2016;163:93-107.e106. 

21. 
Rispoli M, Savastano MC, Lumbroso B. CAPILLARY NETWORK ANOMALIES IN BRANCH RETINAL 
VEIN OCCLUSION ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. Retina (Philadelphia, 
Pa.). Nov 2015;35(11):2332-2338. 
22. 
Jia Y, Bailey ST, Hwang TS, McClintic SM, Gao SS. Quantitative optical coherence tomography 
angiography of vascular abnormalities in the living human eye. May 05 2015;112(18):E2395-
2402. 
23. 
Hwang TS, Jia Y, Gao SS, et al. OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FEATURES OF 
DIABETIC RETINOPATHY. Retina (Philadelphia, Pa.). Nov 2015;35(11):2371-2376. 
24. 
Jia Y, Bailey ST, Wilson DJ, et al. Quantitative optical coherence tomography angiography of 
choroidal neovascularization in age-related macular degeneration. Ophthalmology. Jul 
2014;121(7):1435-1444. 
25. 
Wang X, Jia Y, Spain R, et al. Optical coherence tomography angiography of optic nerve head and 
parafovea in multiple sclerosis. The British journal of ophthalmology. Oct 2014;98(10):1368-
1373. 
26. 
Kang JH, Willett WC, Rosner BA, Hankinson SE, Pasquale LR. Caffeine consumption and the risk 
of primary open-angle glaucoma: a prospective cohort study. Investigative ophthalmology & 
visual science. May 2008;49(5):1924-1931. 
27. 
Higginbotham EJ, Kilimanjaro HA, Wilensky JT, Batenhorst RL, Hermann D. The effect of caffeine 
on intraocular pressure in glaucoma patients. Ophthalmology. May 1989;96(5):624-626. 
28. 
Ajayi OB, Ukwade MT. Caffeine and intraocular pressure in a Nigerian population. Journal of 
glaucoma. Feb 2001;10(1):25-31. 
29. 
Hodapp E, Parrish II RK, Anderson DR. Clinical decisions in glaucoma. St. Louis: CV Mosby co; 
1993. 
 
 
6/27/18; 12/13/18; rev. 4/25/19