Oral Memantine for the Treatment of

Glaucoma
Design and Results of 2 Randomized, Placebo-Controlled,
Phase 3 Studies
Robert N. Weinreb, MD,1 Jeffrey M. Liebmann, MD,2 George A. Cioffi, MD,2
Ivan Goldberg, MBBS, FRANZCO,3 James D. Brandt, MD,4 Chris A. Johnson, PhD, DSc,5
Linda M. Zangwill, PhD,1 Susan Schneider, MD,6 Hanh Badger, PharmD,6 Marina Bejanian, PhD6

Purpose: To evaluate the effectiveness and safety of oral memantine as a potential neuroprotective agent in
open-angle glaucoma (OAG) at risk for progression.
Design: Two randomized, double-masked, placebo-controlled, parallel-group, multicenter, 48-month studies
identically designed, initiated 1 year apart, and completed in 2006. Protocol amendments included a 1-year
extension (first study) and change in primary endpoint and analysis (second study).
Participants: Patients (2298 total) with bilateral OAG; glaucomatous optic disc damage and visual field loss
in 1 eye; glaucomatous optic disc damage and/or visual field loss in the contralateral eye (at screening), topically
treated or untreated intraocular pressure (IOP) of 21 mmHg or less (at baseline); and at risk of glaucomatous
progression (per prespecified criteria).
Methods: Patients were randomized 3:2:2 to receive memantine 20 mg, memantine 10 mg, or placebo
tablets daily. Glaucomatous progression was assessed in the intent-to-treat population by full-threshold standard
automated perimetry (SAP), frequency doubling technology (FDT), and stereoscopic optic disc photographs,
standardized by quality control assessment at centralized reading centers. Safety evaluations included adverse
events (AEs), best-corrected visual acuity, biomicroscopy, IOP, and ophthalmoscopy. Efficacy data from each
study were analyzed per protocol. Pooled analyses of efficacy and safety data were also performed.
Main Outcome Measures: The predefined primary efficacy measure was glaucomatous visual field pro-
gression, as measured by SAP. Additional efficacy measures included glaucomatous progression of visual field
(FDT) and optic nerve damage (stereoscopic optic disc photographs).
Results: The proportion of patients who completed the studies was similar among groups (80%e83%).
Compared with placebo, daily treatment with memantine 10 mg or 20 mg for 48 months did not delay glau-
comatous progression significantly in the individual studies and pooled analyses. The pooled risk reduction ratio
(95% confidence interval) assessed by SAP was
0.13 (
0.40, 0.09) and
0.17 (
0.46, 0.07) for memantine 10
mg and 20 mg, respectively. Results were similar per FDT and stereoscopic optic disc photographs. The most
common AEs leading to treatment discontinuations were dizziness, headache, fatigue, and nausea.
Conclusions: With technologies available when the studies were conducted, daily treatment with mem-
antine over 48 months was not shown to prevent glaucomatous progression in this patient
population. Ophthalmology 2018;125:1874-1885 ª 2018 by the American Academy of Ophthalmology. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Supplemental material available at www.aaojournal.org.

Open-angle glaucoma (OAG) is an irreversible, chronic,
progressive, multifactorial optic neuropathy characterized
by progressive retinal ganglion cell death and functional
optic nerve damage.1 Management of OAG currently relies
on pharmacologic and surgical treatments aiming to lower
intraocular pressure (IOP), a key risk factor.1e3 However,
lowering IOP does not always prevent disease progression.
In each of the major National Institutes of Health-sponsored
clinical trials of glaucoma or ocular hypertension, lowering
IOP did reduce the number of patients reaching a glaucoma
endpoint but a large number of patients continued to wor-
sen.4e7 Thus, there is an unmet need for alternative treat-
ment strategies that could be used alone or in conjunction
with IOP-lowering therapy.
Because glaucoma is a neurodegenerative disease, patients
could benefit from neuroprotective therapies that would

1874 ª 2018 by the American Academy of Ophthalmology https://doi.org/10.1016/j.ophtha.2018.06.017

This is an open access article under the CC BY-NC-ND license ISSN 0161-6420/18
(http://creativecommons.org/licenses/by-nc-nd/4.0/). Published by Elsevier Inc.
 Weinreb et al 
Oral Memantine in Glaucoma
prevent or slow retinal ganglion cell loss.8 Preclinical studies
have shown that elevated levels of the excitatory amino acid
glutamate are toxic to mammalian retinal ganglion cells and
neurons, and that the resulting damage is mediated by
overstimulation (or excitotoxicity) of the N-methyl-D-
aspartate (NMDA) receptor, which in turn leads to an
excess of intracellular calcium and cell death.9e12 In addi-
tion, increased levels of glutamate and glutamine (metabolic
precursor) and decreased levels of the glutamate transporter
EAAT-1 have been reported in the vitreous13 and retinal
mounts,14 respectively, of patients with glaucoma (compared
with healthy individuals), suggesting an association between
the excessive release of glutamate in the retina, neuronal cell
death, and glaucoma.15,16
Memantine is an uncompetitive NMDA receptor antago-
nist17 that binds preferentially to NMDA receptor-operated
cation channels; it is an open-channeleblocking NMDA
antagonist and thus binds only to channels that have been
activated by glutamate binding to the receptor. Because
memantine has a low to moderate affinity for the receptor and
its inhibitory effect exhibits strong dependence on membrane
voltage,17,18 it effectively blocks excessive glutamatergic ac-
tivity at concentrations that do not affect normal neurotrans-
mission. Memantine can inhibit overstimulation of the NMDA
receptor and potentially provide neuroprotection by preventing
excessive calcium influx. In support of this mechanism, results
from preclinical studies have shown that memantine reduces
excitotoxicity in animal models of glaucoma.19e23
Oral memantine was first offered for marketing by Merz
& Co in 1982 and is currently approved in several countries
for the treatment of moderate to severe Alzheimer’s and
Parkinson’s diseases, 2 other age-related neurodegenerative
pathologic conditions. The 2 phase 3 studies presented
herein evaluated the effectiveness and safety of oral mem-
antine administered daily in doses of either 10 mg or 20 mg,
compared with placebo, in patients with chronic OAG who
were at risk of disease progression. The clinical hypotheses
evaluated were (1) treatment with at least 1 daily dose of
oral memantine would result in either significantly fewer
patients exhibiting glaucomatous progression or significant
delays in progression, as measured by changes in visual
fields using standard automated perimetry (SAP), and (2)
memantine has a favorable safety profile.
Methods
Study Design
Two randomized, double-masked, placebo-controlled, parallel-group,
multicenter, 48-month, identically designed studies (Clinical-
Trials.gov identifiers, NCT00141882 and NCT00168350; registered
on August 31, 2005, and September 9, 2005, respectively) were
initiated 1 year apart and conducted in accordance with the tenets of
the Declaration of Helsinki, the International Conference on Har-
monisation Guidelines for Good Clinical Practice, and all privacy
requirements applicable at the time. Institutional review board or
ethics committee approval was obtained, and all patients provided
written informed consent before any study-related procedure or
changes in treatment, as well as other locally required documentation
of consent. Although the first study was extended by 1 year, this article
presents the 4-year data from both studies. Because there were no
specific guidelines that could be used to develop the study protocol,
scientific advice on the study design and endpoints was provided by
the Committee for Medicinal Products for Human Use and agreed
upon by the United States Food and Drug Administration.
Study Population and Treatment
Patients diagnosed with bilateral OAG were eligible for enrollment
in the study if they met predetermined criteria of patients at risk of
glaucomatous progression (Table 1). Notably, patients were
excluded if they had any ocular pathology in either eye that
could have interfered with the ability to obtain visual field
assessments, or any condition or situation that could have
confounded the study results. Patients with mild chronic
blepharitis, cataract, age-related macular degeneration, or back-
ground diabetic retinopathy could be enrolled at the investigator’s
discretion. No washout of topical IOP-lowering medications was
required before initiation of study treatment.
At the baseline visit, unique patient numbers were assigned in
ascending, consecutive order (without omission or reuse). An
automated system was then used to randomize eligible patients to
memantine 20 mg, memantine 10 mg, or placebo tablets daily in an
uneven double-masked allocation of 3:2:2, respectively. This site-
specific randomization scheme was based on phase 2 study results
showing that the patient discontinuation rate was higher in the 20-mg
memantine group than in the 10-mg memantine and placebo groups.
Although a 30-mg daily dose was deemed safe and tolerable in 2
short-term (12 weeks) phase 2 studies (with dizziness, coordina-
tion abnormality, headache, and nausea being most frequently re-
ported as adverse events [AEs]; unpublished data [The first phase 2
study was conducted between October 1997 and December 1997,
while the second was conducted between February 1998 and June
1998] Allergan plc), it was thought that a 20-mg dose would be
tolerated better for chronic use by most patients, consistent with the
recommended dose in moderate to severe Alzheimer’s disease.
Study tablets (identical in appearance) were provided in 1-week
blister cards marked with the order of use to allow dose escalation
(if applicable) from 5 mg to 10 mg or 20 mg per day (Fig S1,
available at www.aaojournal.org). Dosing began on a Monday
(day 0), preferably between 5:00 PM and 9:00 PM (especially if
dizziness occurred), but could be changed to the morning
(6:00
10:00 AM) based on the occurrence of AEs (e.g., insomnia).
If treatment was discontinued before month 48 because of
glaucomatous progression (confirmed by the reading center),
nonadherence to treatment, AEs, or other reasons (determined by
the investigator), the patient remained in the study and attended
the remaining study visits. Data handling for those patients is
described in “Outcome Measures and Statistical Analyses” below.
Assessments
Twenty visits were scheduled over 48 months (Table S1, available at
www.aaojournal.org). Efficacy evaluations included glaucomatous
visual field progression by SAP (using a Humphrey field analyzer
[HFA] 24-2 full threshold program) and frequency doubling
technology (FDT), as well as progression of glaucomatous optic
nerve damage based on stereoscopic optic disc photographs. All
visual field evaluations (i.e., qualification of disease status for
study entry and progression) based on SAP and FDT findings
were standardized by undergoing quality control assessment at a
centralized visual field reading center (Devers Eye Institute/
Discoveries in Sight, Portland, Oregon). Specifically, after
confirmation of acceptability of the baseline visual fields for each
patient (before treatment initiation), the visual field reading center
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Table 1. Eligibility Criteria

Key Inclusion and Exclusion Criteria

Key inclusion criteria

 Topically treated or untreated IOP 21 mmHg in each eye at baseline (laser or filtering surgery performed >3 months before screening was
acceptable)
 Experience with SAP visual field tests before the screening visit (i.e., 2 tests during the past 2 yrs using the Humphrey perimeter with a 30-2 or 24-2
full-threshold algorithm, the full-threshold versions of FastPac or Swedish interactive threshold algorithm standard, or the equivalent on the Octopus
perimeter)
 Presence at the screening visit of typical glaucomatous optic disc damage and glaucomatous visual field loss in 1 eye, and either glaucomatous optic
disc damage or visual field loss, or both, in the contralateral eye, as confirmed by the visual field reading center (Devers Eye Institute/Discoveries in
Sight, Portland, Oregon) and optic disc reading center (Hamilton Glaucoma Center, University of California San Diego, La Jolla, California)
 Patient is at risk of glaucomatous progression, as determined by the documented presence of optic disc hemorrhage within 12 mos of the screening
visit in either eye, OR 2 of the following risk factors:
e Vertical cup-to-disc ratio 0.8 in one or both eyes
e Mean deviation in visual field worse than
10 dB in either eye (verified by the reading center)
e Pseudoexfoliation in either eye
e Age >70 yrs
e Family history (parent or sibling) of glaucoma
e Black African racial origin
e Systemic hypertension requiring medical treatment
e Migraine (defined by the International Headache Society24) with or without aura, Raynaud’s syndrome, or both
 BCVA of 20/32 or better (Snellen equivalent on the ETDRS chart) in each eye
Key exclusion criteria

 History of epilepsy or significant psychiatric disease, including schizophrenia, bipolar disorder, or major depression
 Clinical determination of impaired renal function
 Dizziness or lightheadedness within 1 week before the baseline visit
 Use of >2 topical (or any oral) IOP-lowering products at the baseline visit
 Any glaucoma other than chronic POAG, LTG (not defined in the protocol), pigmentary glaucoma, or pseudoexfoliative glaucoma
 Any ocular pathology in either eye that may have interfered with the ability to obtain visual field, disc imaging, or accurate IOP readings
 Any situation or condition that, in the investigator’s opinion, may have confounded the study results (e.g., interfered with visual function) or
interfered significantly with participation in the study
 Refractive error such that the spherical equivalent was worse than þ5 or
5 D, or the cylinder value was worse than þ3 or
3 D (before conversion
to spherical equivalent)
 Any active ocular disease other than OAG (e.g., uveitis, ocular infections, keratoconus, or severe dry eye) or the inability to dilate the pupils to at
least 4 mm (with medication, if necessary)
 Laser or any other intraocular surgery within 3 months before the screening visit (with a total exclusion for refractive surgery)
 Visual field mean deviation worse than
22 dB in either eye (verified by the reading center)
 Women who were pregnant, nursing, planning a pregnancy, or not using contraception

BCVA ¼ best-corrected visual acuity; D ¼ diopter; dB ¼ decibels; ETDRS ¼ Early Treatment Diabetic Retinopathy Study; IOP ¼ intraocular pressure;
LTG ¼ low-tension glaucoma; OAG ¼ open-angle glaucoma; POAG ¼ primary open-angle glaucoma; SAP ¼ standard automated perimetry.

received and evaluated all visual field tests obtained from both eyes
at all visits (scheduled or unscheduled). Similarly, stereoscopic optic
disc photographs (including those obtained at the screening visit)
were obtained by certified photographers, and progression was
graded by independent, certified graders at a centralized optic disc
reading center (Hamilton Glaucoma Center, University of
California San Diego, La Jolla, California).
Detection of progression of glaucomatous visual fields by SAP
used the procedure outlined by Chauhan et al25 and was based on
the glaucoma change probability26 originally described by Heijl
et al26 and available on HFA using the STATPAC2 program
(Carl Zeiss Meditech, Dublin, CA). Baseline visual field values
(established by averaging data obtained at screening and baseline
for each visual field location of each eye) and total deviation
probability maps (showing the difference between patient-specific
values and age-specific normal values) obtained for each visual
field location at each prespecified postbaseline visit (Table S1)
were recorded. The change from baseline (total deviation) was
then determined for each location; a reduction greater than the
5% probability level at a single visual field location indicated a
significant change from baseline for that location, based on
testeretest results for glaucoma patients and sensitivity for indi-
vidual visual field locations. Progression was declared if the same 5
or more visual field locations demonstrated significant reductions
from baseline (P < 0.05) in a confirmatory visual field obtained
within 8 weeks. Although there is still no gold standard to define
visual field progression, this procedure was found to yield 92.2%
sensitivity to detect the earliest change in glaucomatous visual field
loss, and 97.2% specificity to correctly identify glaucomatous vi-
sual fields that have not undergone progressive change (Johnson
CA, Cioffi GA, personal communication, 1999; based on longi-
tudinal data from 203 glaucoma patients with 10 visual fields
obtained over >5 years and verified by computer simulations).
Glaucomatous visual field progression by FDT was measured
by certified technicians using the Humphrey Zeiss/Welch Allyn
system (Carl Zeiss, Oberkochen, Germany) with full-threshold N-
30 procedure (FDT software version 2.6 or higher) according to
standardized instructions. Threshold (measured in decibels [dB])
and total deviation of 19 test points per eye were recorded, along
with fixation, false-positive and false-negative errors. All results,
including abnormal and unreliable ones, were sent to the reading
center, which developed an FDT glaucoma change probability

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Oral Memantine in Glaucoma
program (similar to that for the HFA) to determine the progression
status of each test point of each eye at all postbaseline visits, based
on testeretest results from healthy controls (18
85 years of age)
and glaucoma patients with various amounts of visual field dam-
age. Specifically, total deviation probability maps were obtained
for each visual field location and compared with baseline values (as
described above). Values that indicated a change from baseline that
was more than the 95% confidence limits (based on location and
sensitivity) were considered significant changes (P < 0.05) from
baseline. Glaucomatous progression of an eye was declared if 2
adjacent test locations exhibited significant reductions in sensitivity
(P < 0.05) from baseline on the FDT glaucoma change probability
analysis. Time to glaucomatous field progression for each patient
was the time when the first progression event was found in either
eye at any postbaseline visit. No confirmation test was required for
this efficacy measure.
In addition to the methods described above, the visual field
readers performed clinical assessment of all visual fields (SAP and
FDT) to verify that the pattern and shape of visual field loss was
consistent with glaucomatous damage and was not typical of
pathologic characteristics in other locations in the visual pathways
(e.g., cataract, macular disease, retinal degenerations, other optic
neuropathies, and chiasmal or postchiasmal disorders).
Progression of glaucomatous optic nerve damage on stereo-
scopic optic disc photographs was assessed by 2 graders who
compared baseline photographs with photographs taken at each
prespecified follow-up visit (Table S1) but were masked to the
temporal sequence of the photographs to determine whether there
was a change in disc excavation/cupping, rim thinning, or retinal
nerve fiber layer defect between the baseline photograph and
each follow-up visit photograph; if they disagreed, a third grader
adjudicated. If photograph quality was deemed unacceptable, a
new set was obtained within 4 weeks. The photographic sequence
then was unmasked (after grading and adjudicating were com-
plete), consistent with the procedure described in the Ocular Hy-
pertension Treatment Study.27
Safety evaluations included AEs, as well as vital signs, clinical
laboratory evaluations, best-corrected visual acuity, slit-lamp bio-
microscopy (without pupil dilation), IOP (measured by standard
Goldmann applanation tonometry after the biomicroscopic exam-
ination was completed), and ophthalmoscopy (with pupil dilation)
on predetermined visits (Table S1).
Outcome Measures and Statistical Analyses
The prespecified primary efficacy measure was progression of vi-
sual field loss, as assessed using HFA (24-2 full threshold SAP
program) and verified by the visual field reading center. The key
secondary efficacy measures were progression of glaucomatous
findings based on FDT visual field data and stereoscopic optic disc
photographs (verified by the visual field reading center and optic
disc reading center, respectively).
Efficacy analyses were performed using the intent-to-treat
population (i.e., all randomized patients), based on the treatment
to which patients were randomized. Patients who stayed in the
study and attended the remaining study visits after discontinuing
treatment were included in those analyses. A survival analysis
based on the KaplaneMeier method and life table method was also
carried out, from which the time to an event was estimated. Sta-
tistical significance was assessed using the nonparametric log-rank
test or Cox proportional hazards model as appropriate. Key effi-
cacy analyses were repeated using data obtained during treatment.
Safety analyses included all randomized patients who received at
least 1 dose of study medication (as treated), using data obtained
during treatment, that is, data from patients on treatment and up to
30 days after the last dose.
Post hoc analyses of the first study that excluded the subgroup
of patients with low-tension glaucoma (LTG; not defined per
protocol) were performed because of the considerable number of
such patients and because LTG may involve different mechanisms
(compared with non-LTG).28 Based on these and other findings of
the first study, the second study (NCT00168350) protocol and
analysis plan were amended before unmasking that study. The
primary efficacy measure was changed to the cumulative
probability of developing progression by month 48 using FDT
(as verified by the reading center). The primary population was
changed to all randomized patients during treatment who did not
have LTG at baseline, and comparison between memantine 20
mg and placebo was considered primary. The cumulative
probability of developing progression by month 48 was based on
the life table method.
For each study, a sample size of approximately 1050 patients
was to be enrolled to have an estimated 233 patients per treatment
group complete the 48-month visit, or confirmed progression of
glaucoma (20%) by HFA 24-2 perimetry (primary efficacy var-
iable) while on study treatment, based on the following assump-
tions: an estimated dropout rate of 45% in the 20-mg memantine
group versus 25% in the 10-mg memantine and placebo groups
(based on unpublished phase 2 study results suggesting a higher
rate of discontinuation with memantine 20 mg over 12 weeks); a 2-
sided log-rank test with an a of 0.05 for equality of survival curves
of time to progression; and 85%, 92%, and 96% power to detect a
difference of 10%, 12.5%, and 15%, respectively, among the
memantine and placebo groups. The nQuery Advisor software
version 1.0 (Statistical Solutions Ltd, Boston, MA) was used for
the computation.
After the studies were completed, data were pooled and sum-
marized with descriptive statistics, frequency tables, and listings.
Categorical variables were analyzed using the Wilcoxon rank-sum
test (ordinal) and Fisher exact test, Pearson chi-square test, or
Cochran-Mantel-Haenszel method (nominal), incorporating the
investigator site effect (to account for potential intersite variability)
where applicable. Continuous variables were tested for statistical
significance using the analysis of variance. Within-group changes
from baseline at each follow-up visit were analyzed using the
Wilcoxon signed-rank test (categorical variables) and paired t test
(continuous variables). For the primary analysis, a statistical
adjustment for multiple between-group comparisons was made
using Hochberg’s procedure to control for an overall type-I error
rate of 5%. All analyses were generated using SAS software
version 9.1 (SAS Institute, Inc., Cary, NC); P values less than 0.05
were considered statistically significant.
Although only pooled analyses of the demographics, baseline
characteristics, and safety data for the overall population are
presented herein, the efficacy results of each individual study are
presented to support the change in primary endpoint during the
course of the drug development program, along with the corre-
sponding pooled analyses performed after completion of the studies.
Results
Demographics and Baseline Characteristics
In the 2 phase 3 studies, a total of 2298 patients (first study,
n ¼ 1119; second study, n ¼ 1179) from 126 centers met the
eligibility criteria and were randomized (intent-to-treat population).
Notably, the proportion of patients who completed each 48-month
study was similar in the memantine 20-mg (80%), memantine
10-mg (83%), and placebo (83%) groups (Fig 1). The proportions
of patients who discontinued study treatment because of AEs were
numerically (but not statistically) higher in the memantine groups
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 Ophthalmology Volume 125, Number 12, December 2018

Figure 1. Flowchart showing patient disposition. aClinicalTrials.gov identifiers, NCT00141882 and NCT00168350. bAnalyzed per protocol. cAnalyzed post
hoc. dAnalyzed per amended protocol. eIncluded both low-tension glaucoma (LTG) and non-LTG patients. Patients could have discontinued treatment.
f
Glaucoma progression. gIncluded protocol violations, concomitant therapy, administrative reasons (i.e., lost to follow-up, relocation, and personal reasons),
and others. ITT ¼ intent-to-treat.

than in the placebo group, consistent with the overall proportions
of patients who discontinued treatment (Fig 1).
Pooled patient demographics and baseline characteristics were
similar among treatment groups and were consistent with those of
patients with glaucoma in general (Table 2). Of note, approximately
25% of patients had LTG (per investigator assessment). Overall,
89% of patients had a vertical cup-to-disc ratio 0.8, along with
another risk factor such as visual field mean deviation worse than
10
dB, family history, or systemic hypertension requiring medical treat-
ment (Table 3). Topical IOP-lowering therapy used at study entry
included brimonidine, brinzolamide, latanoprost, betaxolol, dorzola-
mide, timolol, fixed-combination dorzolamide plus timolol, levobu-
nolol, unoprostone, carteolol, travoprost, fixed-combination
brimonidine plus timolol, and fixed-combination latanoprost plus
timolol. Prior glaucoma surgery included trabeculectomy, trephine
surgery, argon laser trabeculoplasty, and iridectomy.

Table 2. Patient Demographics and Baseline Characteristics (Intent-to-Treat Population)*

Memantine 20 mg (n [ 974) Memantine 10 mg (n [ 664) Placebo (n [ 660)

Age, yrs
Mean (SD) 65.0 (9.9) 64.9 (9.9) 65.1 (9.4)
Range 18e81 26e82 28e81
Sex, no. (%)
Female 566 (58) 341 (51) 353 (53)
Male 408 (42) 323 (49) 307 (47)
Race, no. (%)
Black African 141 (14) 97 (15) 93 (14)
Other 833 (86) 567 (85) 567 (86)
Glaucoma diagnosis, no. (%)
Chronic POAG 705 (72) 476 (72) 479 (73)
LTGy 241 (25) 169 (25) 160 (24)
Pigmentary glaucoma 37 (4) 17 (3) 22 (3)
Pseudoexfoliative glaucoma 43 (4) 21 (3) 22 (3)
Central corneal thickness (SD), mm 53939 53738 54036
Mean IOP (SD), mmHg
Right eye 14.6 (3.2) 14.5 (3.3) 14.5 (3.5)
Left eye 14.6 (3.2) 14.4 (3.2) 14.7 (3.3)
Mean vertical cup-to-disc ratio (SD) 0.80 (0.11) 0.80 (0.11) 0.79 (0.12)

IOP ¼ intraocular pressure; LTG ¼ low-tension glaucoma; POAG ¼ primary open-angle glaucoma; SD ¼ standard deviation.
*ClinicalTrials.gov identifiers, NCT00141882 and NCT00168350.
y
Per investigator assessment; no specific criteria were defined in the protocol.

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Oral Memantine in Glaucoma

Table 3. Pooled Risk Factors for Glaucomatous Progression at Baseline (Intent-to-Treat Population)*

Memantine 20 mg (n [ 974) Memantine 10 mg (n [ 664) Placebo (n [ 660)

Vertical cup-to-disc ratio 0.8 868 (89) 589 (89) 579 (88)
Visual field mean deviation <
10 dB 502 (52) 349 (53) 325 (49)
Family history 431 (44) 278 (42) 302 (46)
Systemic hypertension requiring medical treatment 405 (42) 280 (42) 259 (39)
Age >70 yrs 371 (38) 248 (37) 249 (38)
Migrainey and/or Raynaud’s syndrome 181 (19) 113 (17) 111 (17)
Optic disc hemorrhage <12 mos before screening 152 (16) 85 (13) 123 (19)
Black African racial origin 145 (15) 99 (15) 94 (14)
Pseudoexfoliation 53 (5) 29 (4) 28 (4)

dB ¼ decibels.
*ClinicalTrials.gov identifiers, NCT00141882 and NCT00168350.
y
As defined by the International Headache Society,24 with or without aura.

Efficacy
In the first study (NCT00141882), the SAP-based analysis showed
that by month 48, the cumulative probability of glaucomatous vi-
sual field progression with memantine 10 mg was statistically
significantly higher than with placebo (Fig 2A). However, in the
analyses based on FDT (Fig 2B) and stereoscopic optic disc
photographs (Fig 2C), there were no statistically significant
differences in the cumulative probability of glaucomatous visual
field progression and percentage of patients with progression of
glaucomatous optic nerve damage, respectively, between
memantine 10 mg or 20 mg and placebo groups. Interestingly,
post hoc subgroup analysis of non-LTG patients during treatment
showed a statistically significantly lower probability of glaucom-
atous visual field progression with memantine 20 mg compared
with placebo (Fig 3).
In the second study (NCT00168350), the overall results (as
prespecified per protocol) were similar to those in the first study,
except that the cumulative probability of glaucomatous visual field
progression with memantine 10 mg was statistically significantly
higher than with placebo when analyzed by FDT, not SAP (Fig 4).
After amendment of the primary efficacy outcome, the FDT-based
analysis in non-LTG patients showed that by month 48, there was a
statistically significantly higher probability of glaucomatous visual
field progression during treatment with memantine 10 mg, whereas
memantine 20 mg had no effect, compared with placebo (Fig 5A).
Analyses based on SAP (Fig 5B) and optic disc assessments
(Fig 5C) showed no statistically significant differences in the
cumulative probability of glaucomatous visual field progression
and percentage of patients with progression of glaucomatous
optic nerve damage, respectively, among the memantine (10 or
20 mg) and placebo groups.
Pooled analyses of non-LTG patients during treatment (from
both studies) also showed no statistically significant differences in
the cumulative probability of glaucomatous visual field progression
by SAP (Fig 6A) and FDT (Fig 6B), or the percentage of patients
with progression of glaucomatous optic nerve damage by
stereoscopic optic disc photographs (Fig 6C), between the
memantine 10-mg or 20-mg and placebo groups. Overall, pro-
gression of glaucomatous findings assessed by SAP, FDT, or

Figure 2. Bar graphs showing glaucoma progression at 48 months in the intent-to-treat population of the first study (NCT00141882) based on (A) standard
automated perimetry, (B) frequency doubling technology, and (C) stereoscopic optic disc assessments. The survival analysis using cumulative probability of
progression according to predefined intervals was performed per the life table method. For the primary analysis (standard automated perimetry), a statistical
adjustment for multiple between-group comparisons was made to control for an overall type-I error rate of 5%, using Hochberg’s procedure. yP < 0.05,
compared with placebo. aCrude rate, that is, number of patients whose disease progressed (as determined by the reading center) of the total number of
patients during the course of the study. The reading center confirmed progression if 1 or more of the following was observed: increased or new appearance of
excavation, neuroretinal rim thinning or notching, or retinal nerve fiber layer defect. mem ¼ memantine.

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 Ophthalmology Volume 125, Number 12, December 2018

memantine 10-mg and placebo groups (Table 4). Memantine was

Figure 3. Bar graph showing glaucoma progression at 48 months in
nonelow-tension glaucoma patients of the first study (NCT00141882)
during treatment, using the frequency doubling technology. The survival
analysis using cumulative probability of progression according to predefined
intervals was performed per the life table method. yP < 0.05, compared
with placebo. mem ¼ memantine.
well tolerated and treatment-related AEs reported by at least 5%
of patients in 1 treatment group (i.e., dizziness [P < 0.001,
between-group comparison], as well as headache, fatigue, and
insomnia [P  0.204, between-group comparisons]) were mild to
moderate in severity. The most commonly reported serious AEs
(regardless of causality) included prostate cancer, coronary artery
disease, pneumonia, chest pain, atrial fibrillation, osteoarthritis,
increased IOP, and congestive cardiac failure, of which only
prostate cancer was reported in statistically significantly more pa-
tients in the memantine 20-mg per day group, compared with the
placebo group (Table 4). Notably, there were no treatment-related
deaths during the 48-month study.
Consistent with the overall frequency of AEs, dizziness was
most frequently recorded as the cause for discontinuing study
treatment (Table 5). Headache, fatigue, balance disorder, and
pneumonia, in addition to dizziness, were reported by statistically
significantly more patients in the memantine 20-mg group than
the placebo group (P  0.042; Table 5). Notably, there was no
change from baseline that was statistically significant between
treatment groups when the following parameters were analyzed:
biomicroscopy and ophthalmoscopy findings with 1 severity
grade increase, best-corrected visual acuity, mean IOP, and
average central corneal thickness. In addition, analysis of standard
laboratory safety variables and vital signs did not reveal any
clinically significant treatment effects.

stereoscopic optic disc photographs did not reveal a consistent

protective effect of memantine, and the primary endpoint was not
met in either study or in the pooled analysis.
Safety and Tolerability
Dizziness was the most frequently reported AE (regardless of
causality) in the pooled analysis. Considering all AEs reported by
at least 5% of patients during treatment in any group, dizziness was
also the only AE reported by statistically significantly more pa-
tients in the memantine 20-mg treatment group, compared with the
Discussion
These phase 3 studies were designed to test whether treat-
ment with oral memantine (10 or 20 mg) would result in
either significantly fewer patients exhibiting glaucomatous
progression or significant delays in progression, and thus
whether memantine would provide any neuroprotective ef-
fect at these doses. However, based on 24-2 SAP, FDT, and
optic disc photograph assessments, long-term daily treat-
ment with memantine did not slow or prevent progression of
visual field deterioration or glaucomatous optic nerve

Figure 4. Bar graphs showing glaucoma progression at 48 months in the intent-to-treat population of the second study (NCT00141882) based on (A)
standard automated perimetry, (B) frequency doubling technology, and (C) stereoscopic optic disc assessments (per protocol). The survival analysis using
cumulative probability of progression according to predefined intervals was performed per the life table method. For the primary analysis (standard automated
perimetry), a statistical adjustment for multiple between-group comparisons was made to control for an overall type-I error rate of 5%, using Hochberg’s
procedure. yP < 0.05, compared with placebo. aCrude rate, that is, number of patients whose disease progressed (as determined by the reading center) of the
total number of patients during the course of the study. The reading center confirmed progression if 1 or more of the following was observed: increased or
new appearance of excavation, neuroretinal rim thinning or notching, or retinal nerve fiber layer defect. mem ¼ memantine.

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 Weinreb et al 
Oral Memantine in Glaucoma

Figure 5. Bar graphs showing glaucoma progression at 48 months in nonelow-tension glaucoma patients of the second study (NCT00168350) during
treatment, using (A) frequency doubling technology, (B) standard automated perimetry, and (C) stereoscopic optic disc assessments (per protocol
amendment). The survival analysis using cumulative probability of progression according to predefined intervals was performed per the life table method.
y
P < 0.05, compared with placebo and memantine (mem) 20 mg. aCrude rate, that is, number of patients whose disease progressed (as determined by the
reading center) of the total number of patients during the course of the study. The reading center confirmed progression if 1 or more of the following was
observed: increased or new appearance of excavation, neuroretinal rim thinning or notching, or retinal nerve fiber layer defect. mem ¼ memantine.

damage in this population of patients with glaucoma at risk
of progression. Although there were differences between the
20-mg and 10-mg dose groups versus placebo using
different endpoints in each study, overall, there were no
consistent or clinically meaningful outcomes. In addition,
pooled results of visual field and optic disc analyses
revealed no consistent or beneficial effects of memantine.
Overall, the safety profile of memantine was mostly
consistent with published information.29e36 Regarding the
increased incidence of prostate cancer, additional analyses
were performed using relevant data from all male patients
(including possible confounding factors), but an extensive
investigation of these data in conjunction with preclinical
and postmarketing information could not explain the
increased frequency of prostate cancer in the 20-mg treat-
ment group. The finding was thus considered a spurious
result.
Despite not meeting the primary endpoint, these large,
randomized, double-masked, placebo-controlled, 4-year
studies provide valuable insights regarding the selection of
the study population and their risk factors, as well as the
methodologies for future development of neuroprotective
agents in glaucoma. For example, it is possible that initiating
memantine treatment earlier in the course of disease or in a
population defined by more restrictive progression risk
factors (e.g., age) may have produced different effects.
Similarly, central corneal thickness, presence of disc hem-
orrhage, and type of topical IOP-lowering medications used

Figure 6. Bar graphs showing glaucoma progression at 48 months in the pooled analysis of nonelow-tension glaucoma patients during treatment based on
(A) standard automated perimetry, (B) frequency doubling technology, and (C) stereoscopic optic disc assessments. The survival analysis using cumulative
probability of progression according to predefined intervals was performed per the life table method. aCrude rate, that is, number of patients whose disease
progressed (as determined by the reading center) of the total number of patients during the course of the study. The reading center confirmed progression if
1 or more of the following was observed: increased or new appearance of excavation, neuroretinal rim thinning or notching, or retinal nerve fiber layer
defect. CI ¼ confidence interval; mem ¼ memantine; RR ¼ risk reduction.

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 Ophthalmology Volume 125, Number 12, December 2018

Table 4. Adverse Events Reported by 5% or More of Patients During Treatment in Any Group and Serious Adverse Events Reported by
1% or More of Patients During Treatment in Any Group*

Memantine 20 mg (n [ 934)y Memantine 10 mg (n [ 648)y Placebo (n [ 640)y P Valuez

Adverse events reported by 5% of patients in 1 group during treatment, no. (%)
Dizziness 212 (23) 104 (16) 86 (13) < 0.001
IOP increased 142 (15) 97 (15) 112 (18) 0.372
Cataract 122 (13) 101 (16) 101 (16) 0.223
Headache 121 (13) 66 (10) 77 (12) 0.243
Hypertension 115 (12) 88 (14) 71 (11) 0.398
Fatigue 80 (9) 47 (7) 48 (8) 0.581
Visual acuity reduced 78 (8) 52 (8) 57 (9) 0.846
Dry eye 77 (8) 40 (6) 35 (6) 0.073
Nasopharyngitis 76 (8) 56 (9) 58 (9) 0.808
Sinusitis 73 (8) 46 (7) 50 (8) 0.845
Blepharitis 72 (8) 51 (8) 57 (9) 0.671
Vision blurred 71 (8) 46 (7) 46 (7) 0.917
Ocular hyperemia 66 (7) 32 (5) 45 (7) 0.182
Depression 64 (7) 35 (5) 35 (6) 0.382
Nausea 63 (7) 36 (6) 37 (6) 0.570
Insomnia 62 (7) 46 (7) 59 (9) 0.144
Eye pain 62 (7) 31 (5) 46 (7) 0.167
Upper respiratory tract infection 58 (6) 42 (7) 37 (6) 0.870
Bronchitis 54 (6) 34 (5) 38 (6) 0.850
Conjunctival hyperemia 51 (6) 40 (6) 43 (7) 0.578
Back pain 50 (5) 44 (7) 43 (7) 0.398
Influenza 50 (5) 41 (6) 35 (6) 0.688
Blood pressure increased 49 (5) 24 (4) 32 (5) 0.337
Optic disc hemorrhage 48 (5) 41 (6) 42 (7) 0.428
Constipation 48 (5) 27 (4) 30 (5) 0.668
Hypercholesterolemia 47 (5) 45 (7) 45 (7) 0.166
Drug hypersensitivity 47 (5) 44 (7) 39 (6) 0.325
Urinary tract infection 41 (4) 41 (6) 46 (7) 0.049
Arthritis 46 (5) 33 (5) 40 (6) 0.486
Arthralgia 39 (4) 29 (5) 43 (7) 0.057
Eye pruritus 41 (4) 27 (4) 41 (6) 0.111
Serious adverse events reported by 1.0% of patients in 1 group during treatment, no. (%)
Prostate cancer 17 (1.8) 6 (0.9) 3 (0.5) 0.039
Coronary artery disease 16 (1.7) 12 (1.9) 8 (1.3) 0.663
Pneumonia 12 (1.3) 8 (1.2) 6 (0.9) 0.806
Chest pain 11 (1.2) 6 (0.9) 5 (0.8) 0.723
Atrial fibrillation 9 (1.0) 6 (0.9) 5 (0.8) 0.928
Osteoarthritis 9 (1.0) 5 (0.8) 9 (1.4) 0.510
Intraocular pressure increased 6 (0.6) 3 (0.5) 7 (1.1) 0.409x
Cardiac failure congestive 5 (0.5) 8 (1.2) 5 (0.8) 0.310x

IOP ¼ intraocular pressure.

*ClinicalTrials.gov identifiers, NCT00141882 and NCT00168350.
y
Per protocol, safety analyses are based on data obtained during treatment (i.e., from patients on treatment and up to 30 days after the last dose). As a result,
40, 16, and 20 patients were excluded from the memantine 20-mg, memantine 10-mg, and placebo groups, respectively.
z
Pearson chi-square test, unless otherwise indicated.
x
Fisher exact test.

at baseline could potentially impact the response to treat-
ment, and the effects of these factors should be explored in
future studies. It is also worth considering the possibility
that the 20-mg daily dose was too low to provide adequate
neuroprotective activity and that a 30-mg dose might have
been preferable, especially if administered as 15-mg tablets
twice daily to minimize AEs.
Although the study used both functional and structural
measures of progression, additional tests (either functional
or structural) that further support the confirmation of
progression may have been valuable. Recent technological
and analytical developments for assessing structural and
functional measures of disease severity and progression
could provide much needed sensitivity, or greater speci-
ficity, and help to establish clinically applicable endpoints
that could be used in future studies of neuroprotective
agents.37e43 In addition, based on the increased sensitivity,
it may be possible to determine study outcomes in a
shorter time using these endpoints. However, early studies
exploring these novel endpoints would require confirma-
tion of effects with more classical endpoints to assess their
validity.

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Oral Memantine in Glaucoma

Table 5. Discontinuations Because of Adverse Events Reported by More than 0.5% of Patients in 1 Group During Treatment in Any
Group*

Adverse Event Memantine 20 mg (n [ 934)y Memantine 10 mg (n [ 648)y Placebo (n [ 640)y P Valuez

Dizziness 48 (5.1) 14 (2.2) 9 (1.4) < 0.001
Headache 19 (2.0) 5 (0.8) 5 (0.8) 0.036
Fatigue 15 (1.6) 3 (0.5) 4 (0.6) 0.042
Nausea 10 (1.1) 3 (0.5) 5 (0.8) 0.413
Depression 8 (0.9) 4 (0.6) 2 (0.3) 0.413x
Balance disorder 7 (0.7) 1 (0.2) 0 (0.0) 0.036x
Pneumonia 7 (0.7) 0 (0.0) 0 (0.0) 0.008x
Insomnia 6 (0.6) 2 (0.3) 4 (0.6) 0.714x
Constipation 6 (0.6) 1 (0.2) 1 (0.2) 0.274x
Asthenia 5 (0.5) 4 (0.6) 0 (0.0) 0.148x
Vertigo 5 (0.5) 4 (0.6) 2 (0.3) 0.803x
Death 4 (0.4) 4 (0.6) 3 (0.5) 0.928x
Stomach discomfort 1 (0.1) 1 (0.2) 4 (0.6) 0.161x

*ClinicalTrials.gov identifiers, NCT00141882 and NCT00168350.

y
Per protocol, safety analyses are based on data obtained during treatment (i.e., from patients on treatment and up to 30 days after the last dose). As a result,
40, 16, and 20 patients were excluded from the memantine 20-mg, memantine 10-mg, and placebo groups, respectively.
z
Pearson chi-square test, unless otherwise indicated.
x
Fisher exact test.

Limitations and challenges of the studies included the
fact that they were long-term studies with potentially con-
founding factors. For example, treatments for IOP lowering
were based on standard of care and at the discretion of
investigator, with no requirements to measure IOP at a
specific time of day per a predefined process, as is
customary in glaucoma studies of IOP-lowering medication.
The fact that LTG was not defined per protocol should also
be considered, because it may have led to variations
between centers in classification of these patients and may
have contributed to the studies outcomes. Another limita-
tion stems from the fact that patients were required to
discontinue study treatment after HFA-based progression
was declared. This would have affected the ability of other
measures to detect progression that may have occurred after
the discontinuation of study medication. However, as
evidenced by continued preclinical44e48 and clinical (clin-
icaltrials.gov identifier, NCT02862938) investigations,
neuroprotection as a treatment strategy in glaucoma remains
a viable and important concept, and methodologies,49
biomarkers,50e55 or both that allow assessment of pro-
gression over much shorter periods, with better sensitivity
to detect changes, will likely benefit future studies.
In this large population of patients with open-angle
glaucoma at risk of progression, daily treatment with
memantine for 48 months was not shown to prevent glau-
comatous progression.
Acknowledgments
The authors thank all the investigators who participated in these
studies (listed in the online supplemental material available at
www.aaojournal.org), as well as Victor Marciano (current
employee of Allergan) and Janet Cheetham, Harry Cui, Scott
Whitcup and Erik Lippa (employees of Allergan at the time the
studies were conducted) for their significant roles in data
management (V.M.), the clinical program (J.C.), statistical
analyses (H.C.), and evaluations of data and endpoints (S.W.,
E.L.), respectively. The authors also thank the numerous other
team members who provided essential support throughout the
duration of these studies.
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Footnotes and Financial Disclosures
Originally received: January 5, 2018.
Final revision: May 16, 2018.
Accepted: June 12, 2018.
Available online: August 3, 2018. Manuscript no. 2018-26.
1
Hamilton Glaucoma Center, Shiley Eye Institute and Department of
Ophthalmology, University of California San Diego, La Jolla, California.
2
Edward S. Harkness Eye Institute, Columbia University Medical Center,
New York, New York.
3
Discipline of Ophthalmology, University of Sydney and Sydney Eye
Hospital, Sydney, Australia.
4
UC Davis Eye Center, University of California, Davis, Sacramento,
California.
5
Department of Ophthalmology, University of Iowa, Iowa City, Iowa.
6
Allergan plc, Irvine, California.
Financial Disclosure(s):
The author(s) have made the following disclosure(s): R.N.W.: Consultant e
Aerie Pharmaceuticals (Irvine, California), Alcon (Fort Worth, Texas),
Allergan (Dublin, Ireland), Bausch & Lomb (Rochester, New York),
Eyenovia (Reno, Nevada), Novartis (Basel, Switzerland), Sensimed (Lau-
sanne, Switzerland), Unity (Brisbane, California), Valeant (Laval, Canada);
Financial Support e Carl Zeiss Meditec (Dublin, California), Centervue
(Padova, Italy), Genentech (San Francisco, California), Heidelberg Engi-
neering (Franklin, Massachusetts), Konan (Irvine, California), National Eye
Institute (Bethesda, Maryland), Optos (Marlborough, Massachusetts),
Optovue (Fremont, California), Tomey (Nagoya, Japan).
J.M.L.: Consultant e Aerie Pharmaceuticals, Alcon, Allergan, Bausch &
Lomb, Carl Zeiss Meditec, FORSIGHT Vision5 (Menlo Park, California),
Heidelberg Engineering, Inotek Pharmaceuticals (Lexington, Massachu-
setts), Quark Pharmaceuticals (Ness Ziona, Israel), Reichert (Depew, New
York), Sustained Nano Systems (Westhampton Beach, New York);
Financial support e Heidelberg Engineering, National Eye Institute; Equity
owner e Diopsys Corporation (Pine Brook, New Jersey), FORSIGHT
Vision5, SOLX (Waltham, Massachusetts), Sustained Nano Systems.
I.G.: Advisory board e Novartis, Allergan, Pfizer (New York, New York),
Lecturer e Mundipharma (Cambridge, United Kingdom), Financial
support e Pfizer, Novartis.
J.D.B.: Financial support e Forsight Vision Labs (Menlo Park, California);
(acquired by Allergan in 2016).
C.A.J.: Consultant e JAEB Center (Tampa, Florida), Centervue, Haag-
Streit (Köniz, Switzerland), Aerie Pharmaceuticals, Regeneron (Tarry-
town, New York), M&S Technologies (Stokie, Illinois).
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L.M.Z.: Consultant e Merck (Kenilworth, New Jersey), Optovue; Financial
support e National Eye Institute, Heidelberg Engineering, Carl Zeiss
Meditec, Topcon (Oakland, New Jersey), Optovue.
S.S.: Employee e Allergan plc (Irvine, California).
H.B.: Employee e Allergan plc (Irvine, California).
M.B.: Employee e Allergan plc (Irvine, California).
Supported by Allergan plc, Dublin, Ireland. The sponsor participated in the
design of the study, data analysis and interpretation, revision of the
manuscript for intellectual content, and decision to submit the manuscript
for publication. Writing and editorial assistance was provided to the authors
by Michele Jacob, PhD, CMPP, of Envision Pharma Group, Philadelphia,
PA, and funded by Allergan plc, Dublin, Ireland.
HUMAN SUBJECTS: Human subjects were included in this study, which
was conducted in accordance with the tenets of the Declaration of Helsinki,
the International Conference on Harmonisation guidelines for Good
Clinical Practice, and all privacy requirements applicable at the time.
Institutional Review Board/Ethics Committee approval was obtained and all
patients provided written informed consent before any study related
procedure or changes in treatment, as well as other local required docu-
mentation of consent.
No animal subjects were included in this study.
Author Contributions:
Conception and design: Weinreb, Cioffi, Johnson, Zangwill
Analysis and interpretation: Weinreb, Liebmann, Cioffi, Goldberg, Brandt,
Johnson, Schneider, Badger, Bejanian
Data collection: Weinreb, Liebmann, Cioffi, Goldberg, Brandt, Johnson,
Zangwill
Obtained funding: N/A
Overall responsibility: Weinreb, Liebmann, Cioffi, Johnson, Zangwill,
Schneider, Badger, Bejanian
Abbreviations and Acronyms:
AE ¼ adverse event; FDT ¼ frequency doubling technology;
HFA ¼ Humphrey field analyzer; IOP ¼ intraocular pressure; LTG ¼ low-
tension glaucoma; NMDA ¼ N-methyl-D-aspartate; OAG ¼ open-angle
glaucoma; SAP ¼ standard automated perimetry; SD ¼ standard deviation.
Correspondence:
Robert N. Weinreb, MD, Shiley Eye Institute, University of California San
Diego, 9415 Campus Point Drive, La Jolla, CA 92093. E-mail: rweinreb@
ucsd.edu.
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