Stop Retinal Ganglion Cell Dysfunction Study
Phase: PHASE3
Conditions: Glaucoma
Sponsor: University of Miami

1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STOP RETINAL GANGLION CELL 
DYSFUNCTION STUDY 
(STOP-RGCD) 
 
 
 
 
 
 
Manual of Procedures 
 
Version 0.8 
10/30/15 
 
 
 
 
 
 
 
 
 
 
 
 
 

2 
 
Table of Contents 
 
 
1. 
Introduction 
1.1 
Background and Significance 
1.2 
Objective 
1.3 
References 
 
2. 
Study Design 
2.1 
Inclusion Criteria 
2.2 
Exclusion Criteria 
2.3 
Patient Stratification 
2.4 
Randomization 
2.5 
Analysis and Sample Size Calculations 
2.6 
Masking 
2.7 
Timetable for the Study 
 
3. 
Clinical Procedures 
3.1 
Visual Acuity 
3.2 
Slit Lamp Biomicroscopy 
3.3 
Tonometry 
3.4 
Motility Evaluation 
3.5 
Gonioscopy 
3.6 
Ophthalmoscopy 
3.7 
Corneal Thickness Measurement 
3.8 
Perimetry 
3.9 
Optical Coherence Tomography 
3.10 Standard Seated Position PERG Measurement 
3.11 Head Down Tilt PERG Measurement 
3.12 Disc Photos 
 
4. 
Prescription of types of Pressure Lowering Medical therapy  
4.1 
Introduction 
 
5. 
Policy Matters 
5.1 
Patient Consent 
5.2 
Publication and Presentation Policy 
5.3 
Ancillary Studies Policy 
5.4 
Policy of Confidentiality 
5.5 
Authorship Policy 
 
6. 
Clinical Centers Procedures 
6.1 
Qualifying Assessment 
6.2 
Assignment of Patient Identification Number 
6.3 
Randomization Procedure 

3 
 
6.4 
Schedule of Visits 
 
7. 
Statistical Coordinating Center Procedures 
7.1 
Data Management 
7.2 
Data Security 
7.3 
Data Forms 

4 
 
1. 
Introduction 
 
 
1.1 
Background and Significance 
 
1.2 
Objective 
 
1.3 
References 
 

5 
 
1.1 
Background and Significance 
 
 
Glaucoma causes progressive damage and death of retinal ganglion cells 
(RGCs) resulting in blindness. The prevalence of the disease will rise to a 
projected 3 million Americans by 2020. A central yet unresolved issue in 
glaucoma is determining, in individual subjects, the onset of the disease. This is 
defined as the stage at which retinal ganglion cells (RGC) have lost their 
autoregulatory ability in response to a chronically stressful biomechanical, 
vascular or molecular environment, and become increasingly dysfunctional over 
time until they die and are eliminated from the neuronal pool. Were the duration 
of the stage of RGC dysfunction preceding death known, then it would represent 
the ideal time window for initiating therapeutic strategies to prevent cell death 
and visual loss.  
Recent studies pioneered by our group in human and mouse models of 
glaucoma showed that RGC dysfunction, measured with the Pattern Electro-
retinogram (PERG), can be restored after intraocular pressure (IOP) lowering.1-6 
In addition, RGC dysfunction may be induced in susceptible eyes of mice and 
human in association with temporary IOP elevation during head-down body tilt 
(HDT). 4, 6, 7 Further, our group has demonstrated that patients with substantially 
lowered PERG amplitude in Standard Seated Position (SSP) undergo more rapid 
Retinal Nerve Fiber Layer (RNFL) thinning than do patients with normal PERG. 8 
If RGC function is modifiable in response to IOP modulation, then this 
represents both a rationale for treatment and a target to change the natural 
history of the disease.  
 
 
1.2 
Objective 
 
 
The principal objective of this study is to prospectively follow glaucoma suspects 
(GS) with depressed PERG amplitude, either in SSP or upon HDT, who have 
been randomized either to observation or to receive either pressure lowering 
medicines and compare them with respect to longitudinal RNFL thinning from 
baseline. Further objectives include confirmation of previously published and 
unpublished findings suggesting that: pressure lowering medicines improve 
PERG amplitude in eyes with depressed SSP PERG amplitude; 3 substantially 
depressed SSP PERG amplitude is a risk factor for more rapid RNFL thinning in 
eyes not receiving pressure lowering medications; 8 and that delayed PERG 
phase upon HDT in combination with hemodynamic measurements is predictive 
of RNFL thinning in eyes not receiving pressure lowering medications. 
 
 

6 
 
1.3 
References 
 
 
1 Ventura LM, Porciatti V. Restoration of retinal ganglion cell function in 
early glaucoma after intraocular pressure reduction: a pilot study. 
Ophthalmology 2005;112:20-27. 
2 Sehi M, Grewal DS, Goodkin ML, Greenfield DS. Reversal of retinal 
ganglion cell dysfunction after surgical reduction of intraocular pressure. 
Ophthalmology 2010;117:2329-2336. 
3 Ventura LM, Feuer WJ, Porciatti V. Progressive loss of retinal ganglion 
cell function is hindered with IOP-lowering treatment in early glaucoma. 
Invest Ophthalmol Vis Sci 2012;53:659-663.  
4 Nagaraju M, Saleh M, Porciatti V. IOP-Dependent Retinal Ganglion Cell 
Dysfunction in Glaucomatous DBA/2J Mice. Invest Ophthalmol Vis Sci 
2007;48:4573-4579. 
5 Porciatti V, Nagaraju M. Head-up tilt lowers IOP and improves RGC 
dysfunction in glaucomatous DBA/2J mice. Exp Eye Res 2010;90:452-
460. 
6 Porciatti V, Ventura LM. Adaptive changes of inner retina function in 
response to sustained pattern stimulation. Vision Res 2009;49:505-513. 
7 Ventura LM, Golubev I, Lee W, et al. Head-down posture induces PERG 
alterations in early glaucoma. J Glaucoma 2013;22:255-264.  
8 Banitt MR, Ventura LM, Feuer WJ, et al. Progressive loss of retinal 
ganglion cell function precedes structural loss by several years in 
glaucoma suspects. Invest Ophthalmol Vis Sci 2013;54:2346-2352. 
 

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2 
Study Design 
 
 
2.1 
Inclusion Criteria 
 
2.2 
Exclusion Criteria 
 
2.3 
Patient Stratification 
 
2.4 
Analysis and Sample Size Calculations 
 
2.5 
Randomization 
 
2.6 
Masking  
 
2.7 
Timetable for the Study 
 
 
 
2.1 
Inclusion Criteria 
 
 
All of the criteria listed below must be present in the study eye in order for the 
patient to be eligible for enrollment in the study. 
 
a. 
Age 18 to 85 years, inclusive 
 
b. 
Refractive errors within -5 to +3 diopters 
 
c. 
Best corrected visual acuity (BCVA) better than or equal to 20/30 (Snellen) 
 
d. 
Normal standard automated perimetry (SAP) according to the Ocular 
Hypertension Treatment Study (OHTS) criteria15 (reliability < 15% on all 
indices, normality > 5% on all global indices in two consecutive sessions 6 
months apart) 
 
e. 
Glaucoma Suspect Status defined as one or more of the following: 
 
- 
Glaucomatous optic disc appearance (vertical cup-to-disc ratio [C/D] 
≥0.5 
- 
Cup disc ratio asymmetry ≥0.2 
- 
Localized thinning of the disc 
- 
Presence or history of splinter disc hemorrhage 
- 
Moderately increased IOP (>21 to <28 mm Hg). 
- 
Family history of vision loss for glaucoma 

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2.2 
Exclusion Criteria 
 
 
If any of the following exclusion criteria are present in the study eye, the patient 
may not be entered into the study. 
a. Age-related macular degeneration 
b. Diabetes 
c. Parkinson’s disease 
d. Multiple sclerosis 
e. Unwilling or unable to give consent, unwilling to accept randomization, or 
unable to return for scheduled protocol visits. 
f. Pregnant or nursing women. 
g. Currently using prescribed pressure lowering medicines and unwilling to 
be withdrawn from them. 
h. An OHTS risk score high enough in the judgment of the ophthalmologist or 
optometrist managing the patient to recommend pressure lowering 
medicine to the patient and not randomization. 
i. An OCT abnormal enough in a pattern consistent with glaucoma. 
 
 
2.3 
Stratification of patients 
 
 
 
Definition: Abnormal SSP PERG amplitude is defined as ≤60% of age specific 
normal. The logarithm of age specific normal PERG amplitude is obtained from 
the regression equation published by Ventura et al (IOVS 2006; 47:3904-11) 
 
 
log expected normal amplitude = 0.612 – 0.374 × log (age in years). 
 
Definition: Susceptible to HDT is defined in the following way.  
a. The effect of HDT on PERG Phase (EPP) is calculated as: 
 
 
EPP = 3.433 * (PhaseHDT – PhaseSSP) – 308.465 × PhaseHDT ÷ PhaseSSP 
 
where each phase variable is expressed as percent of age specific 
normal. The age specific normal phase is obtained from the regression 
equation (Ventura et al) = 1.99 – 0.0027 × age. 
 
b. The effect of HDT on hemodynamic variables (EHV) is calculated from 
measurements of Systolic Brachial Pressure (SBrP) and Ocular Perfusion 
Pressure (OPP). 
 
EHV = 24.815 × (SBrPHDT ÷ SBPSSP) + OPPSSP 
 

9 
 
c. These two variables are substituted into the logistic equation 
 
Probability = exp(EPP+EHV) ÷ (1 + exp(EPP+EHV)) 
 
 
A probability so obtained which is > 0.3 is considered susceptible.  
 
Patients eligible for inclusion in the study will be stratified into one of three groups 
based on the results of PERG testing at baseline.  
 
1. Patients with abnormal baseline SSP PERG in one or both eyes (average 
of two measurements in different sessions) will be included in stratum 1, 
abnormal PERG (GS-A). Patients in this stratum will be randomized to 
observation or pressure lowering medicines. 
 
2. Patients with neither eye abnormal by SSP PERG but demonstrated 
susceptible to HDT in one or both eyes – average of two measurements - 
will be included in stratum 2, HDT susceptible (GS-S). Patients in this 
stratum will be randomized to observation or pressure lowering medicines. 
 
3. Patients with both eyes neither abnormal nor susceptible will be included 
in stratum 3 (GS-N). Patients in this stratum will be observed and not 
offered randomization. 
 
 
2.4 
Randomization  
 
 
After a patient has been placed in their study stratum, the Biostatistics Center will 
issue them a study ID number. The Biostatistics Center will provide patients in 
strata 1 or 2 (GS-A, GS-S) with their randomized treatment assignment to 
observation or pressure lowering medicines. Randomization will be performed 
with in each stratum in a permuted variable block fashion to ensure approximate 
balance of treatment assignments within strata.  
 
 
2.5 
Analysis and Sample Size Calculations 
 
 
Percentages of patients with RNFL thinning after four years of follow up will be 
compared between the observation and pressure lowering medicine groups. 
RNFL thinning is defined as a decrease in average RNFL of 4.0µm (Budenz, 
(Invest Ophthalmol Vis Sci. 2010;51:5724 –5730)). 
 
Preliminary data suggest that about 40% of untreated patients in stratum 1 (GS-
A) will have incident RNFL thinning, while about 60% of untreated patients in 

10 
 
stratum 2 (GS-S) will have incident RNFL thinning. These data also suggest that 
about 15% of patients in stratum 3 (GS-N) will have incident RNFL thinning.  
 
If pressure lowering medicines reduce the risk of RNFL thinning in patients in 
strata 1 and 2 to 15%, then about 32 patients in each randomized treatment 
group would provide 80% power. 42 patients in each randomized treatment 
group would provide 90% power.  
 
If pressure lowering medicines do not reduce the risk of thinning to 15% but only 
to half the risk in the untreated patients, then 66 patients in each group would 
provide 80% power. 
 
These calculations assume separate independent un-corrected significance tests 
in each stratum. If pressure lowering medicines had similar effects in each 
stratum, a pooled analysis would have substantially more power. 
 
 
 
2.6 
Masking 
 
 
Neither the investigator nor the patient is masked as to which treatment the 
patient receives. 
 
 
2.7 
Timetable for the Study 
 
 
• Year 1: Validate new PERG instrument, including normal control 
values. Complete baseline measurements, place patients into study 
strata and randomize GS-A and GS-S patients 
 
• Year 2-4: Collect follow up visit data, monitor for pressure lowering 
in those patients randomized to receive pressure lowering therapy 
 
• Year 5: Collect final follow up visit data and perform analyses 

11 
 
3. 
Clinical Procedures 
 
 
3.1 
Visual Acuity 
 
3.2 
Slit Lamp Biomicroscopy 
 
3.3 
Tonometry 
 
3.4 
Gonioscopy 
 
3.5 
Ophthalmoscopy 
 
3.6 
Corneal Thickness 
 
3.7 
Perimetry 
 
3.8 
Optical Coherence Tomography 
 
3.9 
SSP PERG evaluation 
 
3.10 HDT PERG evaluation 
 
3.11 Disc Photos 
 
 
 
3.1 
Visual Acuity  
 
 
Visual acuity is measured before pupil dilation, tonometry, gonioscopy, or any 
other technique that could affect vision.  Refraction is performed prior to formal 
measurement of visual acuity by either technique at the Qualifying Assessment 
and at the annual follow-up visits.  Snellen visual acuity is measured at the 
Qualifying Assessment and at every follow-up visit.   
 
Subjective Refraction: 
 
Subjective refraction must be performed at the Qualifying Assessment and at the 
annual follow-up visits in order to determine best-corrected visual acuity.  It is 
permissible to use a phoropter to determine best-corrected Snellen visual acuity.  
However, trial frames are required for testing best-corrected  visual acuity.  The 
trial frame is placed and adjusted on the patient’s face so that the lens cells are 
parallel to the anterior plane of the orbits and centered in front of the pupil. 
 

12 
 
The left eye is occluded first.  An approximate beginning refraction may be 
determined by retinoscopy, automated refraction, or a subjective refraction from 
a prior visit.  The sphere is refined first.  The cylinder is then refined, first the axis 
followed by the power.  Finally, the sphere is rechecked.  If a phoropter was used 
in the subjective refraction, the refraction is placed in a trial frame and the sphere 
is refined prior to visual acuity testing.  The right eye is then occluded, and the 
procedure is repeated for the left eye. 
 
If the patient wears contact lenses and has glasses also, he or she is instructed 
not to wear the contact lenses on the day of the Qualifying Assessment.  In the 
event that the patient either has no glasses or has forgotten the instructions and 
reported for the Qualifying Assessment wearing contact lenses, the contact 
lenses are removed and at least thirty minutes allowed to elapse before 
subjective refraction and visual acuity testing is performed. 
 
 
 
Snellen Visual Acuity: 
 
Snellen visual acuity may be measured using any standard visual acuity chart.  
The same type of chart must be used throughout the duration of the study.  
Snellen visual acuity is measured during the Qualifying Assessment and at all 
follow-up visits.  Standardized refraction is performed prior to Snellen visual 
acuity testing at the Qualifying Assessment and annual follow-up examinations. 
 
 
 
3.2 
Slit Lamp Biomicroscopy 
 
 
Examination of the anterior segment using slit lamp biomicroscopy is performed 
at the Qualifying Assessment to document the status of the eye, and at all follow-
up examinations to detect any changes in the conjunctiva, cornea, anterior 
chamber, iris, and lens that may be attributable to the disease or treatment. Slit 
lamp biomicroscopy may be performed with any commercially available 
instrument, and it is used in a standard fashion starting anteriorly and working 
posteriorly.  Standardizing opacities is difficult, but it is expected that subjective 
grading by the optometrist or glaucoma specialist is relatively reproducible.  
Pseudophakic eyes with uncomplicated cataract extraction are included in the 
study. Aphakic eyes are excluded from the study. 
 
 
 
 
 
 

13 
 
3.3 
Tonometry 
 
 
Goldmann applanation tonometry is used to measure the intraocular pressure, 
except when irregular corneal astigmatism, corneal scarring, or corneal edema 
precludes accurate readings.  The intraocular pressure is measured prior to 
pupillary dilation.  Whenever possible, the intraocular pressure should be 
checked at the same time of the day as the Qualifying Assessment to minimize 
the effect of diurnal fluctuation of intraocular pressure. 
 
Goldmann Applanation Tonometry: 
 
The calibration of the Goldmann applanation tonometer is checked every 3 
months, as described in the Haag-Streit Goldmann Applanation Tonometer 
Operator’s Manual.  Clean the prism according to your institutional infection 
control policy.  The right eye is always tested first.  Following instillation of a drop 
of 0.5% proparacaine, a fluorescein strip is placed near the lateral canthus in the 
lower conjunctival sac.  Once the lacrimal fluid has been sufficiently colored, the 
fluorescein strip is removed.  Alternatively, one drop of premixed fluorescein and 
anesthetic may be instilled.  The patient’s head is properly positioned in the chin 
rest and against the forehead rest without leaning forward or straining.  Any tight-
fitting neckwear is loosened.  The patient is asked to look straight ahead at a 
distant object or fixation target.  If it is necessary to hold the eyelids open, the 
investigator holds the eyelids open against the orbital rim taking care not to apply 
any pressure on the globe.  The patient is instructed not to hold his or her breath.  
If corneal astigmatism is greater than 3.0 diopters, the prism is rotated so that the 
axis of the minus cylinder on the prism graduation corresponds to the red mark 
on the prism holder.  The investigator looks through the slit lamp and gently 
brings the tip of the prism in contact with the center of the cornea.  The mires 
should be well focused, centered horizontally, and positioned vertically so that 
they are of equal circumference above and below the horizontal dividing line.  If 
the mires are narrower than approximately one tenth their diameter, the 
investigator instills additional fluorescein.  The investigator adjusts the measuring 
drum until the inner borders of the two mires just touch each other.  If pulsation is 
present, the measuring drum is adjusted until the mires separate a given 
distance during systole and overlap the same distance during diastole.  The 
investigator removes the prism from the cornea and repeats the procedure in the 
right eye until two successive measurements are within 1 mm Hg.  The 
investigator records the last two successive measurements.  After testing of the 
right eye is complete, testing of the left eye follows the same technique. 
 
 
PT100: 
 
The PT100 (Reichert) is portable, non contact tonometer that is used to compare 
IOP between SSP and HDT position. The patient is positioned in either sitting 

14 
 
position or HDT position and instructed to fix on a distant object. Tight-fitting 
neckwear is loosened, and the patient is instructed not to hold his or her breath.  
The operator used the instrument as an ophthalmoscope and aims the light 
beam toward the patient’s pupil. PT100 visual indicators guide the operator to 
correct alignment position. Once alignment is achieved the PT100 automatically 
takes an IOP measurement, that is perceived by the patient as an light air puff on 
the cornea. Three sequential measurements are required, and the instrument 
automatically calculates the average and the SD. The right eye is always tested 
first. 
 
 
3.4 
Gonioscopy 
 
 
Gonioscopy is performed with the patient sitting at the slit lamp using either a 
Zeiss type four-mirror gonioprism or Goldmann single- or three-mirror lens.  An 
examination of the anterior chamber angle for neovascularization is performed 
under high magnification for the purpose of excluding eyes with 
neovascularization from the study. 
 
 
3.5 
Ophthalmoscopy 
 
 
A dilated fundus examination is performed at the Qualifying Assessment to 
determine the status of the retina and optic nerve, and at all one-year follow-up 
examinations to detect any changes.  After pupil dilation with appropriate 
mydriatics, the optic nerve and posterior pole are examined at the slit lamp using 
a Hruby lens, fundus contact lens, or Volk 90 diopter, 78 diopter, or 60 diopter 
lens.  A head-mounted indirect ophthalmoscope and hand held condensing lens 
(20 diopter or 28 diopter Nikon aspheric lens) is used to evaluate the retinal 
periphery. At the Qualifying Assessment, particular attention is paid for signs of 
macular degeneration that represent an exclusion criterion. 
 
 
3.6 
Corneal Thickness Measurement 
 
 
Central corneal thickness is measured with ultrasound pachymetry at the first 
baseline exam.  The right eye is tested first.  A drop of 0.5% proparacaine is 
instilled for anesthesia.  The patient is asked to look straight ahead at a distant 
object or fixation target.  The pachymeter probe is lined up with the center of the 
pupil and slowly advanced until it contacts the cornea.  The probe is withdrawn 
when an audible signal is made indicating that a measurement has been 

15 
 
recorded.  The patient is instructed to blink.  The procedure is repeated to obtain 
three separate readings, and the investigator records the measurements.  After 
testing of the right eye is complete, the same technique is applied to testing of 
the left eye. 
 
 
3.7 
Perimetry 
 
 
Quantitative automated perimetry is performed using the Humphrey Field 
Analyzer .  Visual field testing is performed before tonometry, gonioscopy, or any 
other technique that could affect vision.   
 
A 24-2 threshold test is performed in all patients using a size III white stimulus.  
Visual field testing may be performed with the Swedish Interactive Thresholding 
Algorithm (SITA) or full threshold strategy, but the same testing strategy must be 
used throughout the duration of the study.  The pupil diameter should be 3 mm or 
greater before visual field testing is undertaken, and this may require 
pharmacologic dilation.  Standardized refraction is performed to determine the 
patient’s distance refraction and best-corrected visual acuity prior to visual field 
testing.  The age appropriate plus lens is added to the distance refraction.  
Patient education is provided, and the instrument is set up for the test.  The 
technician should monitor the patient during testing.  Visual fields are performed 
preoperatively (within one month of enrollment in the study) and annually 
thereafter.  Copies of all visual fields are faxed to the Statistical Coordinating 
Center for evaluation. 
 
 
3.8 
Optical Coherence Tomography  
 
 
Quantitative image analysis of the retinal nerve fiber layer (RNFL) and Ganglion 
Cell (GCA) is performed with Zeiss-Cirrus according to the protocol of (Mwanza 
et al, Ophthalmology 2012, 119:1151-1158). Cirrus HD-OCT is used to acquire 1 
macular (Macular Cube 200×200 protocol) and 1 optic disc (Optic Disc Cube 
200×200 protocol) scan in each qualifying eye after pupil dilation with tropicamide 
1% and phenylephrine 2.5%. Only good-quality scans, defined as scans with 
signal strength ≥6, without RNFL discontinuity or misalignment, involuntary 
saccade or blinking artifacts, and absence of algorithm segmentation failure on 
careful visual inspection, are used for analysis. Peripapillary RNFL thickness 
analysis includes the average, superior, and inferior quadrant thicknesses. 
Parameters from the ONH analysis include the rim area, cup-to-disc area ratio, 
and vertical cup-to-disc diameter ratio, which were measured automatically by 
the Cirrus internal ONH analysis algorithm. The GCA algorithm detects and 
measures the thickness of the macular GCIPL within a 14.13-mm2 elliptical 

16 
 
annulus area centered on the fovea. The following GCIPL thickness 
measurements are analyzed: average, minimum, and sectoral (superior, 
superonasal, inferonasal, inferior, inferotemporal, and superotemporal). 
 
 
 
3.9 
Standard Seated Position (SSP) PERG 
 
 
This study uses a PERG protocol optimized for glaucoma detection, which does 
not require topical anesthesia or pupil dilation; the recording electrodes are non-
corneal (PERGLA, ref. Porciatti&Ventura Ophthalmology 2004, 111:161-168). 
Surface gelled cup electrodes (Grass, 9 mm diameter) are taped around the eyes 
with Blender surgical tape after a small patch of skin (~1 squared centimeter) on 
both lower eyelids, temples, and forehead is cleansed with disposable skin prep 
pads (Dynarex). Appropriate lenses for the viewing distance (30 cm) are 
mounted on a trial frame (Oculus), and the visual acuity for near is tested. This 
should be Jager J1 or better. Subjects look at the center of visual display pattern 
of moving black and white bars with both eyes for about 3 min, during which they 
can blink freely. PERG signal from both eyes are automatically recorded and 
measured for their amplitude, phase and intratest variability.  
 
3.10 Head Down Tilt (HDT) PERG 
 
IOP (Reichert PT100), automatic systemic blood pressure and heart rate (Vital 
Signs, Welch-Allyn), and PERG are first recorded with the subjects seated in 
SSP (Baseline). Subjects are then asked to recline on an electronically 
adjustable tilting bed (Skytron Elite 5001), which includes a foam-molded neck 
and shoulder restrainer to help the subject to maintain a comfortable position and 
prevent sliding in HDT (-10 deg) position. To record HDT-PERG, the PERG 
instrument is incorporated in a balanced, adjustable frame to align the stimulus 
with the subject’s gaze. The frame includes a quick release handle to 
immediately move away the instrument from the subject’s face for safety 
reasons. IOP, systemic blood pressure, and heart rate are measured again in the 
tilted position approximately 7 minutes after baseline readings. 
 
 
 
3.11 Disc Photos 
 
 
 
Digital optic disk stereo photographs will be obtained at the qualifying visit and at 
every annual follow up visit.  
 

17 
 
 
4. 
Pressure Lowering Medical Therapy 
 
4.1 
Introduction 
 
4.2 
Goal of pressure lowering medical therapy 
 
4.3 
Medications to reduce eye pressure 
 
 
 
4.1 
Introduction 
 
 
The principal study intervention is lowering of intraocular pressure in the group 
randomized to receive this therapy. 
 
 
4.2 
Goal of pressure lowering therapy 
 
 
The goal is 20% reduction in intraocular pressure from the average of the 
Baseline IOP, hereafter called treatment baseline. The 20% reduction is not 
necessary if IOP ≤ 15 mm Hg. Medical therapy is changed and/or added until 
both goals are met or until the participant is receiving maximum tolerated topical 
medical therapy. Participants not meeting treatment goals despite maximum 
tolerated topical medical therapy continue to be followed in the trial.  
 
4.3 
Medications to reduce eye pressure 
 
─Prostaglandin analogs include Xalatan®, Lumigan®, and Travatan Z®, and 
they work by increasing the outflow of fluid from the eye. Side effects are 
possible changes in eye color and eyelid skin, stinging, blurred vision, eye 
redness, itching, burning. 
─Beta blockers such as timolol are the second most often used class of 
medication and work by decreasing production of fluid.: side effects are low blood 
pressure, reduced pulse rate, fatigue, shortness of breath; rarely: reduced libido, 
depression. 
─Carbonic anhydrase inhibitors (CAIs) reduce eye pressure by decreasing the 
production of intraocular fluid. These are available as eye drops (Trusopt®, 
Azopt™) as well as pills [Diamox® (acetazolamide) and Neptazane® 
(methazolamide)].Side effect of eye drops are stinging, burning, eye discomfort. 

18 
 
Side effects of pills are: tingling hands and feet, stomach upset, memory 
problems, depression, frequent urination. 
─Combined medications can offer an alternative for patients who need more than 
one type of medication: side effects may include any of the side effects of the 
drug types they contain. 
 
 
5 Study Organization 
 
5.1 
Introduction 
 
5.2 
Clinical Centers 
 
5.3 
Statistical Coordinating Center 
 
5.4 
Safety and Data Monitoring Plan 
 
5.5 
Steering Committee 
 
 
 
 
Introduction 
 
 
This single center randomized trial of glaucoma suspects is organized as follows: 
 
• Project Chairman (Vittorio Porciatti, DSc) 
 
• Clinical Center (John McSoley, OD, Steven Gedde, MD, Luis Vazquez 
MD, Pedro Monsalve, MD, Giacinto Triolo, MD) 
 
• Biostatistics Center (William Feuer, MS, Joyce Shiffman, MS) 
 
Since the patients being treated do not have manifest glaucoma at baseline and 
risks of treatment are well understood and minimal, no Safety and Data 
Monitoring Committee was created. However, a Safety and Data Monitoring Plan 
is created (details in section 5.5). 
 
 
5.1 
Project Chairman 
 
 

19 
 
Dr Porciatti, the project chairman, is responsible for ensuring that PERG 
measurements are completed for each patient and, with the study’s clinical 
coordinator, ensuring integrity of data collection and entry. He is also responsible 
for obtaining approval for the study and consent form from the local Institutional 
Review Board. 
 
 
5.2 
Clinical Center 
 
 
Clinical center personnel include  
 
• A fulltime clinical coordinator (Marlene Colon) who is responsible for  
- 
Patient scheduling 
- 
Patient flow in the clinic (ie from ophthalmic examining room to 
locations of testing for visual field, OCT, photography, PERG),  
- 
Ensuring completeness of study forms (ie data collection),  
- 
Data entry. 
 
• Treating optometrist (John McSoley) and ophthalmologists (Steven Gedde 
and Luis Vazquez) whose responsibilities include:  
- 
Assessing the eligibility of patients for the Stop-RGCD Study. 
- 
Enrolling patients in the study through informed consent. 
- 
Managing each patient in accordance with the randomized treatment 
assignment. 
- 
Examining patients using the techniques and schedules established for 
the study. 
- 
To work with the clinical coordinator to complete the proper forms and 
obtain visual fields, OCT scans, and optic disc photos at the 
appropriate follow-up visits. 
- 
To promote patient satisfaction and commitment to the trial. 
 
• Research Fellows (Pedro Monsalve, MD, Giacinto Triolo, MD) whose 
responsibilities include: 
• Recording PERG in SSP and during HDT  
• Measuring IOP in SSP and during HDT 
• Measuring Blood Pressure in SSP and during HDT 
• To work with the study coordinator to complete the proper forms and data 
entry in the Access database. 
 
 
5.3 
Biostatistics Center 
 
 
 

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The study statistician for the Stop-RGCD study, William J Feuer and Ms. Joyce 
Schiffman, has the following responsibilities: 
 
• Creation of the variable permuted block randomization lists for the GS-
A and GS-S strata. 
• Running interim edit checks of study data. 
• Performing data analyses and preparing manuscripts with the project 
chairman. 
• Ensuring security of patient data transmitted to the biostatistics center. 
 
5.4 
Data Safety and Monitoring Plan (DSMP) 
 
The University of Miami IRB has established that this study is of minimal risk, and 
the NIH-NEI SRG has established that a formal data safety and monitoring board 
is not required. However, a complete Data and Safety Monitoring Plan (DSMP) 
will be used.  
The individuals responsible for data safety and monitoring will be the principal 
investigator Dr. Porciatti, the clinical co-investigators Dr. Gedde MD, Luis 
Vazquez MD, the optometrist Dr McSoley OD, the research fellows Dr Monsalve 
MD and Dr Giacinto Triolo MD, the study coordinator Ms. Colon, and the 
biostatisticians William Feuer MS and Joyce Shiffman, MS. None of these 
individuals has conflict of interest. Quality control will include regular data 
verification and protocol compliance checks. The above individuals will meet 
quarterly to analyze study progress, any new issues, data entry verification, data 
safety and any protocol deviations. Throughout the study, the clinical co-
investigators will monitor the participants for adverse events. Events determined 
to be unanticipated problems involving risks to subjects or others will be reported 
by the PI to the IRB within 10 days.  Any other adverse events will be reported by 
the PI to IRB at the time of continuing review. All study staff members will be 
promptly informed about any unanticipated problems involving risks to subjects 
or others. If any protocol changes are needed, the PI will submit a modification 
request to the IRB.  Protocol changes will not be implemented prior to IRB 
approval unless necessary to eliminate apparent immediate hazards to the 
research subjects.  In such a case, the IRB will be promptly informed of the 
change following implementation (within 10 working days). 
 
 
6. 
Policy Matters 
 
 
6.1 
Patient Consent 
 
6.2 
Authorship Policy 
 
 

21 
 
6.1 
Patient Consent 
 
 
The Stop Retinal Ganglion Cell Dysfunction (Stop-RGCD) Study requires that 
written consent be obtained from each patient enrolled in the study.  The patient 
is requested to sign the consent form only after patient education is completed.  
The signed consent form is kept with the study records at the Clinical Center.  A 
copy of the signed consent is given to the patient, and a second copy is sent to 
the Biostatistics Center. 
 
 
INFORMED CONSENT FORM [We will ask for  official translation in Spanish as the 
English version is approved] 
 
BASCOM PALMER EYE INSTITUTE 
University of Miami 
CLINICAL INVESTIGATION CONSENT FORM 
 
TITLE: 
Monitoring Early Glaucoma with Pattern Electroretinogram. 
PURPOSE: 
Glaucoma causes progressive death of cells within the eye that build up the optic nerve. If 
glaucoma is not diagnosed and treated with eye drops, damage to the optic nerve can result in 
progressive loss of vision and eventually blindness. You do not have glaucoma, but have 
suspicious signs in one on both of your eyes that may indicate that you have the disease at a 
very early stage or you are at risk of developing it in the near future. It is important to check at 
regular intervals how many optic nerve fibers are present in your eye and how they are 
functioning. This is possible by means of two noninvasive techniques called pattern 
electroretinogram (PERG) and Optical Coherence Tomography (OCT). The PERG is the 
electrical response of the eye when you look at a pattern of moving stripes on a TV monitor. OCT 
yields an image of the thickness of the retina, from which we can evaluate the amount of optic 
nerve fibers. We ask you to participate in a research study which will be monitoring the number 
and the function of your optic nerve fibers over the course of four years. For the duration of the 
study, you may be asked to use eye drops to lower the intraocular pressure (IOP). This will 
enable the study to understand if eye drop medication is effective to prevent loss of optic nerve 
tissue and function over time. This study has been reviewed for its scientific merit and is 
sponsored by U.S. Government (National Institute of Health, Bethesda, MD). A total of 500 
subjects will participate in this research study. 
PROCEDURES: 
The PERG is recorded from small metallic buttons taped on the skin similarly to an 
electrocardiogram, with the difference that the electrodes are around the eyes. The only physical 

22 
 
contact you will experience is a gentle cleaning of the skin with an alcohol prep pad. During the 
test you must look with both eyes at a TV display for about 3 minutes. During the follow up period 
you may be asked to take one more PERG test lying down in a bed. This will cause a momentary 
increase of your eye pressure similar to the one that occurs during your normal sleep. This may 
help to understand whether or not your optic nerve functions normally when the pressure in your 
eye increases. For OCT evaluation, the pupil has to be dilated with drops as you did before for 
your eye exam. You have to briefly look at a mark inside the instrument one eye at a time. PERG 
and OCT will be performed during the same day of your visit with the eye doctor. If you have 
already done these tests in the past, as part of another study or as part of your standard 
treatment, the results of these tests will be obtained from your record, and be included in this 
study. 
If you are a participant in the Observation Group, you  will be monitored with PERG, OCT, and 
standard clinical examinations every six months until close of study. If you are a participant in the 
Medication Group you will be also treated with eye drop medicines. 
RISKS: 
There are certain risks and discomforts that may be associated with this research. You should be 
aware that you are at risk of developing glaucoma whether you participate in the study or not. It is 
not known whether the risk of developing glaucoma is reduced by eye drops to lower eye 
pressure; the study will attempt to answer this question. If you are include in the Medication 
Group, another risk is the development of a side effect to one of the prescribed medications:  
Prostaglandin analog (include Xalatan®, Lumigan®, and Travatan Z®,) : possible changes in eye 
color and eyelid skin, stinging, blurred vision, eye redness, itching, burning. 
Beta blockers such as timolol:  low blood pressure, reduced pulse rate, fatigue, shortness of 
breath; rarely: reduced libido, depression. 
Alpha agonists (Alphagan®P, iopidine®) : burning or stinging, fatigue, headache, drowsiness, dry 
mouth and nose, relatively higher likelihood of allergic reaction. 
Carbonic anhydrase inhibitors (CAIs) as eye drops (Trusopt®, Azopt™): stinging, burning, eye 
discomfort.  
 
Combined medications can offer an alternative for patients who need more than one type of 
medication: side effects may include any of the side effects of the drug types they contain. 
. 
For the PERG, the only significant risk to you is a small chance of a rash to the cleansing agent 
for skin electrodes, which should go away without treatment. For OCT, there is a rare risk to you 
of an allergic reaction to the drops used to dilate your pupils. The risk is even lower if you did not 
have any reaction during your previous eye exams. In case of an allergic reaction, your eye 

23 
 
doctor will immediately treat it. If you had previous problems with pupil dilation, you may wish to 
speak to your eye doctor about the option of doing this additional test. 
BENEFITS: 
There is no benefit to you in participating in this study. 
COSTS: 
PERG testing will be provided at no expense to you. OCT, visual fields, and  eye drops 
medications will be billed to your insurance and, just as for visual fields, may require authorization 
before OCT is performed. You should be aware that you may be expected to travel and park at 
your own expense to and from our facility. PERG and OCT testing will be scheduled on the same 
day as your visit to the doctor. 
ALTERNATIVES: 
You have the alternative not to participate in this study 
COMPENSATION for INJURY: 
Although risks are unlikely, if injury should occur, treatment will in most cases be available. If you 
have insurance, your insurance company may or may not pay for these costs. If you do not have 
insurance, or if your insurance company refuses to pay, you will be expected to pay. Funds to 
compensate for pain, expenses, lost wages and other damages caused by injury are not routinely 
available. 
CONFIDENTIALITY: 
Your consent to participate in this study includes consent for the investigator and her assistants to 
review all your medical records as may be necessary for the purpose of the study. The 
investigator and his assistants will consider your records confidential to the extent permitted by 
law. Your records and results will not be identified as pertaining to you in any publication without 
your expressed permission. The U.S. Department of Health and Human Services (DHHS) or the 
Food and Drug Administration (FDA) may request to review and obtain copies of your research 
records. Your records may also be reviewed for audit purposes by authorized University of Miami 
employees or other agents who will be bound by the same provisions of confidentiality. 
RIGHT TO WITHDRAW: 
Your participation is voluntary. You have the right to withdraw or refuse to participate. Your 
withdrawal or lack of participation will not prejudice your future care. The principal investigator 
can remove you from the study without your consent either because of your failure to follow the 
study, if he/she feels it is in your best interest medically, or for administrative reasons.  
OTHER PERTINENT INFORMATION: 
The principal investigator will answer any questions you may have regarding the investigation. If 
you have any questions about your rights as a research subject you should contact the Human 
Subjects Research Office at (305) 243-3195, Fax (305) 243-3328 
 
__________________ _______________ 

24 
 
Signature of subject Date 
___________________________ _________________ 
Signature of witness Date 
_______________________________ _________________ 
Signature of Person Obtaining Consent Date 
_______________________________ 
Print Name of Person Obtaining Consent 
Principal Investigator’s Name: Vittorio Porciatti, Dsc 
Telephone Number: Day_305-326-6050;  Night_ Cell: 786-543-1766 
 
 
 
 
6.2 
Authorship Policy 
 
 
Authorship of Stop-RGCD will be determined at the discretion of the project 
chairman. 
 
 
 
Clinical Center Procedures 
 
 
7.1 
Qualifying Assessment 
 
7.2 
Assignment of Patient Identification Number 
 
7.3 
Randomization Procedure 
 
7.4 
Schedule of Visits 
 
 
 
7.1 
Qualifying Assessment 
 
 
The Qualifying Assessment establishes whether the patient satisfies Stop-RGCD 
Study eligibility criteria.  If the patient appears to be eligible for the study, the 
Clinical Center completes the Qualifying Assessment Form and faxes it to the 
Statistical Coordinating Center, along with a copy of the consent form.  Informed 
consent is an eligibility criterion because it is an agreement by the patient to be 
randomized and complete follow-up in their treatment group.  The SCC reviews 
each of the inclusion and exclusion criteria to ensure that the patient is eligible.  It 
is vital to the scientific validity of the study that every eligible patient be 
offered enrollment. 

25 
 
 
 
7.2 
Assignment of Patient Identification Number 
 
 
Any patient who is confirmed by the Statistical Coordinating Center to meet the 
eligibility criteria and is enrolled in the study is assigned a patient identification 
number.     
 
7.3 
Randomization Procedure 
 
 
Randomization takes place at the time the patient is enrolled in the study.  After 
patient eligibility is confirmed and a patient identification number is provided, the 
Statistical Coordinating Center assigns treatment by saying, “Treatment” or “No 
Treatment”.  The Clinical Center then repeats the assigned treatment.  The 
treatment/no treatment date is the study entry date, and the dates for all follow-
up visits are computed from this date. 
 
The randomization schedule is constructed using a computer pseudo-random 
number generator.  The allocation ratio is equal between the two treatment 
groups.  The randomization is blocked by clinic and study stratum using a 
scheme with small variable blocks.  This procedure ensures that there is an 
equal number of patients in each treatment group even early in the trial, and that 
the CC is not able to predict the next treatment assignment. 
 
 
7.4 
Schedule of Visits 
 
 
All study investigators must be familiar with the schedule of visits to ensure that 
required data is collected and that future visits are scheduled within the 
appropriate time windows.  The need for continued follow-up and timely visits 
should be stressed to the patient during the informed consent process and 
throughout the study.  An appointment schedule is generated for each patient by 
the Statistical Coordinating Center and sent to the patient’s Clinical Center.  
Table 1 summarizes the required data at each of the scheduled visits.  

26 
 
 
 
Year of Study 
 
Year 2 
Year 3 
Year 4 
Year 5 
Year 5 
Study Visit Baseline 1 
Baseline 2 
Month 
6 
FUp Yr 
1 
FUp Yr 
2 
FUp Yr 
3 
FUp Yr 
4 
FUp Yr 
4 
repeat 
Medical History 
x 
  
  
  
  
  
  
 
Ocular History 
x 
  
  
  
  
  
  
 
Refraction 
x 
x 
x 
x 
x 
 
Visual Acuity 
x 
x 
x 
x 
x 
x 
 
Visual Field 
x 
(x) If not 
done on the 
first visit 
x 
x 
x 
x 
 
PERG 
x 
x 
x 
x 
x 
x 
x 
Eye Examination 
x 
  
x 
x 
x 
x 
x 
x 
IOP 
x 
x 
x 
x 
x 
x 
x 
 
Corneal Thickness 
x 
  
  
  
  
  
  
 
Gonioscopy 
x 
  
  
  
  
  
  
 
Dilated Fundus 
x 
  
x 
x 
x 
x 
x 
Ophthalmoscopy 
x 
  
x 
x 
x 
x 
x 
x 
Disc Photos 
x 
(x) If not 
done on the 
first visit 
x 
  
x 
x 
x 
x 
 
OCT 
x 
(x) If not 
done on the 
first visit 
x 
x 
x 
x 
x 
Randomization/ 
treatment onset 
 
x 
 
 
 
 
 
 

27 
 
8. 
Data Management And Security 
 
 
8.1 
Data Management 
8.2 
Data Security 
8.3 
Data Forms 
 
8.1 
Data Management 
 
 
A master log is kept of each patient enrolled in the STOP-RGCD Study.  An appointment 
schedule is made for each patient and sent to the patient’s Clinical Center.  When a data 
form is received at the Statistical Coordinating Center, it is processed for filing and data entry.  
Each form is data entered by a data entry clerk and then verified by double entry by the SCC 
Research Coordinator.  Edit checks, such as missing data and out-of-range values, will be 
clarified within the CC. 
 
The statistical package SPSS is used for data entry, management, and analysis.  Each of the 
study’s two statisticians has a personal computer and one more is dedicated to data entry.  
The Research Coordinator also has a personal computer to use for data management, study 
correspondence, reports, and manuscripts.  Each computer, except the one dedicated to data 
entry, has access to the University of Miami’s network for e-mail, Internet access, and data 
file transfer. 
 
 
8.2 
Data Security 
 
 
The paper data forms for the STOP-RGCD Study are kept in file cabinets in the Biostatistics 
facility in the McKnight Research Building.  The building is locked and access is by card key 
entry.  A security guard is present during working hours.  The computer files for the study are 
kept on computers in the same location.  These rooms are kept locked when not in use, and 
the study computer files are password-protected.  The data is backed up weekly, and monthly 
backups are stored at a remote facility.  Computer data files used for publication are saved 
and stored as separate files. 
 
 
8.3 
Data Forms 
 
 
The data forms were designed to be self-explanatory.  Their completion should not require 
reference to separate information manuals.  The data forms contain information to be 
collected at a given point in time during the study.  Information collected at another date is 
incorporated into a separate form.  Data forms are faxed to the Statistical Coordinating 
Center for data entry.  Forms will be reviewed periodically and revised as dictated by protocol 
changes.  The various data forms are provided at the end of this section.  

28 
 
BASCOM PALMER EYE INSTITUTE 
Monitoring Glaucoma Subject Data Sheet (Standard Seated Position) 
 
Visit Date 
 
  
Last Name 
 
First Name 
BP # 
 
 
Enroll Date  
 
 
Birth Date 
Gender 
1 M  2 F 
 
Ethnicity 
1 Hisp 2  non-Hisp 
 
Race 
1 C   2 AA   3 As 
4 Other 
Fam. History Glaucoma 
1 Absent   2 Present 
CCT 
OD 
 
OS 
 
 
Distance Refraction 
Sphere 
Cylinder 
 
Axis 
 
Snellen acuity 
Cataract 
 
OD 
 
 
 
/ 
 
OS 
 
 
 
/ 
 
Near Refraction 
(30cm) 
Sphere 
Cylinder 
 
Axis 
 
Jaeger acuity 
Contact lenses 
 
OD 
 
 
 
J 
 
OS 
 
 
 
J 
 
 
Severity 
Medical Treatment 
OD 
1 GS 
2 HRGS 
3 Control 
1 β-block                         2 α2-ago                     3 CAI                        4 Prost                                5 Other 
OS 
1 GS 
2 HRG 
3 Control 
1 β-block                        2 α2-ago                      3 CAI                        4 Prost                                5 Other 
 
 
IOP 
SAP Reliability 
GHT 
MD 
PSD 
OD 
 
1 Normal   2 Low 
1 WNL 2 BL 3 ONL 4 GRS 5 AHS 
 
 
OS 
 
1 Normal   2 Low 
1 WNL 2 BL 3 ONL 4 GRS 5 AHS 
 
 
 
Optic Disc 
Clinical 
Vertical C/D 
Localized Thinning 
 
Splinter Hemorrhage 
 
Disc Photos 
 
OCT today 
OD 
 
1 Absent   2 Present 
1 Absent   2 Present 
1 Not Done   2 Done 
 
1 Yes  2 No 
 
OS 
 
1 Absent   2 Present 
1 Absent   2 Present 
 
  
 
 
 
 
Notes: 
 
 
 
 
 
 
___________________________________ 
Obtained Data      (Signature) 
 
PERG 
Amplitude 
 
Phase 
 
Noise 
OD 
 
 
 
OS 
 
 
 

29 
 
BASCOM PALMER EYE INSTITUE 
Monitoring Glaucoma and Control Subject Data Sheet (Head-down Tilt procedure) 
 
Visit Date 
Last Name 
First Name 
BP # 
Birth Date 
Gender 
1 M   2 F 
Ethnicity 
1Hisp   2 non-Hisp 
Race 
1CC  2AA  3A   
4Other 
Family History 
Glaucoma 
1 Absent 
2Present 
 
Diagnosis (severity) 
Medical Treatment 
OD 
1 GS 
2 HRGS 
3 Control 
1 β-block              2 α2-ago            3 CAI                4 Prost                5 Other 
OS 
1 GS 
2 HRGS 
3 Control 
1 β-block              2 α2-ago            3 CAI                4 Prost                5 Other 
 
Distance Refraction 
Sphere 
Cylinder 
Axis 
Snellen acuity 
Cataract 
OD 
 
 
 
/ 
 
OS 
 
 
 
/ 
 
Near Refraction 
Sphere 
Cylinder 
Axis 
Jaeger acuity 
Contact lenses 
OD 
 
 
 
J 
 
OS 
 
 
 
J 
 
 
  
 
 
Notes: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature _________________________________________ 
 
 
B/P (seated) 
IOP OD 
(seated) 
IOP OS 
(seated) 
PERG 
(seated) 
Amplitude 
Phase 
Noise 
OD 
 
 
 
OS 
 
 
 
B/P (HDT) 
IOP OD      
(HDT 
IOP OS      
(HDT 
PERG     
(HDT) 
Amplitude 
Phase 
Noise 
OD 
 
 
 
OS 
 
 
 

30