Effect of Palmitoylethanolamide on Inner Retinal Function in Stable Glaucoma Patients. A Prospective, Randomized, Single Blind, Crossover Clinical Trial by Pattern Electroretinogram.
Phase: PHASE2
Conditions: Glaucoma
Sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia

FONDAZIONE
IRCCS POLICLINICO “SAN MATTEO”
Isttuto di Ricovero e Cura a Caratere Scientfco di dirito pubblico (D.M. 28/4/2006)
C.F. 00303490189 - P. IVA 00580590180
V.le Golgi, 19 -  27100 PAVIA
Pavia, 20/10/2014
Efect of Palmitoylethanolamide on inner retnal functon in stable glaucoma patents. A
prospectve, randomized, single blind, crossover clinical trial by patern electroretnogram.
(PEA2015)
Argomento: glaucoma therapy
PROPONENTE:  Gemma Caterina Maria Rossi
Servizio Oculistca
Email  gemma.rossi.md@gmail.com
Telefono  0382 526213

Index
1
Ratonal....................................................................................................................................................3
1
Study objectve........................................................................................................................................4
1.1
Primary objectve..............................................................................................................................4
1.2
Secondary objectves........................................................................................................................4
2
Study design and planning.......................................................................................................................4
3
Subjects....................................................................................................................................................4
4
Treatments currently available.................................................................................................................5
5
Detailed study procedures.......................................................................................................................5
5.1
Screening procedures.......................................................................................................................5
5.2
Planned assessments........................................................................................................................5
5.3
Other variables...................................................................................................................................6
6
Study defnitons and diagnostc criteria..................................................................................................7
7
Descripton of study supplement.............................................................................................................9
8
Statstcal issues.......................................................................................................................................9
9
Data management and confdentality issues..........................................................................................9
10
Ethical issues..........................................................................................................................................10
10.1
Informed consent........................................................................................................................10
10.2
Other ethical issues.....................................................................................................................10
11
Costs and fnancing................................................................................................................................10
12
Staf and dutes......................................................................................................................................10
13
Data property and publicatons..............................................................................................................11
14
References.............................................................................................................................................11
Version 1 of 20/10/2014

1
Ratonal
Glaucoma is a progressive and multfactorial neurodegeneraton involving retnal ganglion cells
(RGC) with their axons. Currently, the only approach proven to be efcient in preserving visual
functon is lowering intraocular pressure (IOP) both at inital and in advanced stages (1-4). Other
possible treatment areas have been investgated, including ocular blood fow and neuroprotecton.
There are experimental and populaton based studies indicatng that perfusion pressure may be
relevant in glaucoma but very difcult to measure (5). 
As stated this year by the European Glaucoma Society guidelines (6), neuroprotecton can be
defned as a “therapeutc approach” aiming to directly prevent, hinder and, in some cases, reverse
neuronal cell damage. Since glaucoma patents can contnue deterioratng in spite of an apparent
well controlled IOP, the need for efectve non-IOP related treatments is widely acknowledged.
Several compounds have been shown to be neuroprotectve in animal models of experimental
glaucoma, such as memantne (7) and brimonidine (8): but so far, no compound has reached a
sufcient level of evidence to be considered as a neuroprotectant in humans.
Previous studies have demonstrated that damage to RGC occurs as a primary insult followed by a
subsequent cascade of events leading to a secondary, slower, progressive injury whose fnal result
is RGC death by apoptosis; even optc nerve head blood fow abnormalites may initate this
cascade (9, 10). Gupta in 2006 reported that secondary trans-synaptc degeneraton may also
involve higher visual centers (11).
Therefore, althought IOP lowering is the major strategy for treatment of glaucoma, it is not always
efectve and enough to avoid glaucoma progression. Neuroprotecton can be considered an
additonal therapeutc strategy targetng RGCs and neurons of higher visual centers (12).
Palmitoylethanolamide (PEA) is categorized as an endocannabinoid-like molecule, it is now
available as tablet (Visimast ® 600 and 300 mg) and as eye drops (Defuxa®). It has been
demonstrated to have at least three (some) potental benefcial efects in glaucoma patents. 
In fact, the administraton of PEA enhances aqueous humor outlow facility: this efect appears to
be mediated at least partally by a SR144528-sensitve, non-CB1/CB2 receptor, the GPR55 receptor,
and the PPARα receptor, and involves p42/44 MAPK pathway. This property provide mechanistc
basis for the potental of PEA as a new therapeutc agent for the treatment of elevated IOP (13).
Some clinical studies have detected a signifcant IOP lowering efect of oral assumpton of PEA 600
mg (14, 15).
Moreover, it is able to exert direct vasorelaxaton of the (bovine) ophthalmic artery in a tme-
dependent manner via the transcripton factors PPARα suggestng a functon for them in the
physiological mechanisms of vascular regulaton (16, 17). The vasorelaxant role of
endocannabinoids raises the supply of oxygen to the retna and could prevent ischemic injury.
Finally, some studies have pointed out the role of PEA in afording protecton against neurotoxic
damage of central nervous system and eye. In vivo (on rat retna) studies have demonstrated that
PEA protects against ganglion cell death by actvaton of cannabinoids receptors (CB1 and TRPV1)
modulatng the glutamate-excitotoxicity and therefore altering the course of apoptosis (18, 19). 
Todate, endocannabinoids consttute the newest of the neuromodulators that are found in neural
and non-neural tssues throughout the body. About retna, there is general agreement that
3

cannabinoids suppress dopamine release and presynaptcally reduce transmiter release from
cones and bipolar cells (19).
1
Study objectves
Our general purpose is to evaluate the potental benefcial efects of PEA 600 mg supplementaton
on RGCs functon in subjects with glaucoma (20) by patern electroretnogram.
1.1
Primary objectve
To assess efects of PEA 600 mg a tablet a day on PERG examinaton at three months of therapy. 
1.2
Secondary objectves
To assess efects of PEA 600 mg on IOP values, if any.
To record visual acuity, visual feld, HRT, CCT, GDx and OCT (GCC) changes, if any. 
To follow QL percepton (GV and GH of NEI VFQ25)
2
Study design and planning
Monocentric, randomized, prospectve, single blind, two treatment and two period crossover
study.
We have proposed a cross-over trial to avoid or to detect the bias due to intraindividual variability
and because, from our preliminary observaton, we have noted that the efects of PEA on PERG are
completely reversible afer withdrawal, within one month.
We didn't considered a placebo treated group because the patent cannot interfer with the PERG
measurement that is objectve and totally patent-independent.
2.1
Center
Clinica Oculistca IRCCS Policlinico San Mateo Foundaton, Pavia
2.2
Study duraton
Study duraton 12 months
Enrolment period
6 months
Minimum Follow-up
 6 months
Start: January, 2015; end January, 2016
Total sample size: 40 patents
3
Subjects
3.1
Eligibility criteria
Eligibility criteria will be as follows:
-age 18 years or older
-diagnosis of primary OAG (POAG) (see Defnitons);
-controlled IOP (<18 mmHg, morning value) with any topical lowering medicaton (beta-blockers,
carbonic anhidrase inhibitors, alpha2agonists, prostaglandine analogues as monotherapy or as
4

associatve therapy; betablocker/carbonic anhidrase inhibitor, betablocker/alpha2agonist,
prostaglandine/betablocker and alpha2agonist/carbonic anhidrase inhibitor fxed combinatons as
monotherapy or in associaton);
-stable IOP<18 mmHg in the last 2 years
-stable disease in the last 2 years (no more than -1 dB/year at MD of visual feld)
-at least two reliable visual felds per year in the last 2 years
-no fltering surgery or other ocular surgery in the preceding 6 months
-writen consent to partcipate to study procedures (see Detailed study procedures) and data
utlizaton in an anonymous form
Exclusion criteria.
-ocular hypertension with normal optc nerve and visual feld
-contraindicaton to PEA
-glaucomatous scotomas within 10 degree from fxaton
-any conditon limitng the patent's ability to partcipate in the study;
-other causes of visual feld changes, such as cataract, myopic corioretnopathy, macular
diseases, retnal vascular occlusion;
3.2
Withdrawal criteria
Withdrawal criteria: patents not wishing to partcipate any longer afer signing informed consent
or any other conditon that, upon clinical judgment of the investgator, will make unacceptable
further study partcipaton for that individual patent.
4
Treatments currently available in the clini
  
cal practce
The treatment of glaucoma is based on IOP-lowering medicaton prescripton. It is well known that
IOP is not to be the only risk factor for developing or progressing the disease, but todate there is
low evidence of others systemic therapies on humans.
5
D  etailed study procedures
5.1
Screening procedures
The inclusion/exclusion criteria were verifed afer careful examinaton of patents'medical charts.
If eligible, at his/her frst clinical visit afer study start the patent will be informed of the protocol
and his/her consent required in writen form, for the use of their clinical data for scientfc
evaluatons.
5.2
Planned assessments
Baseline. Afer enrolment, all patents will undergo the following routne procedures:
complete ophthalmic examinaton
Visual acuity (VA)
Anterior segment evaluaton (anterior chamber, lens and angle)
5

IOP (Goldmann tonometry)
pachimetry (pachete 2 pachimeter) measurement
optc nerve evaluaton with indirect lens (Volk 90)
optc nerve and retnal fber evaluaton with OCT study, HRT and GDX
patern electroretnogram (PERG)
visual feld examinaton (Humphrey 24-2 sita- standard): Mean Deviaton (MD), Patern
Standard Deviaton (PSD), Glaucoma Hemifeld Test (GHT), Visual Field Index
quality of life evaluaton by general vision and general health scales of the NEI VFQ 25.
Patents will be randomized to group A (PEA 600 mg one tablet a day) or to group B (current topical
therapy) for 3 months and subsequent visit will be sheduled.
At visit 1 (V1, month 3) all patents will be submited to the following routne procedures:
complete ophthalmic examinaton
Visual acuity (VA)
Anterior segment evaluaton (anterior chamber, lens and angle)
IOP (Goldmann tonometry)
pachimetry (pachete 2 pachimeter) measurement
optc nerve evaluaton with indirect lens (Volk 90)
optc nerve and retnal fber evaluaton with OCT study, HRT and GDX
patern electroretnogram (PERG)
visual feld examinaton (Humphrey 24-2 sita- standard)
quality of life evaluaton by general vision and general health scales of the NEI VFQ 25
Patents will be crossed-over: patents of group A will be unprescribed tablets, and group B will
assume PEA 600 mg, one tablet a day, for 3 months.
Visit 2 (V2, month 6). All patents will be submited to the following routne procedures:
complete ophthalmic examinaton
Visual acuity (VA)
Anterior segment evaluaton (anterior chamber, lens and angle)
IOP (Goldmann tonometry)
pachimetry (pachete 2 pachimeter) measurement
optc nerve evaluaton with indirect lens (Volk 90)
optc nerve and retnal fber evaluaton with OCT study, HRT and GDX
patern electroretnogram (PERG)
visual feld examinaton (Humphrey 24-2 sita- standard)
quality of life evaluaton by general vision and general health scales of the NEI VFQ 25
6

Other variables
Other variables that will be collected for each subject at baseline/over tme will be: date of birth
(month/year) and sex, the following informaton will be collected: therapy (systemic and topical),
medical history (systemic and ocular, ie previous lasers/surgery).
6
Stu
  
dy defnitons and diagnostc criteria
6.1
Glaucoma diagnosis
The diagnosis of glaucoma will require: IOP >21 mmHg on at least two consecutve visits at the
tme of frst diagnosis, presence of glaucomatous optc nerve head (ONH) confrmed by an expert
fundus examinaton and at least three reliable Humphrey 24-2 full threshold visual feld tests
performed on diferent days showing a glaucomatous or suspected glaucomatous defect.
It will be performed (or confrmed, if the patent is being referred from another centre) by a senior
ophthalmologist working at the Eye Clinic of the Fondazione.
6.2
Ocular examinaton
Visual Acuity determined in Decimals unit.
Slit lamp examinaton of the anterior and posterior segment with partcular atenton to the retna
and the optc nerve aspect. 
IOP measurement (Goldmann tonometry). The MD who will measure IOP is blinded to study
procedures.
6.3
HRT and Gdx
HRT is a non-invasive procedure that scans the eye. The HRT takes 3-dimensional photographs of
the optc nerve and retna using a special laser. It starts by photographing the surface of the optc
nerve and then focuses on deeper and deeper layers before putng them all together to create the
3-dimensional image. These photographs can be used to evaluate optc, disc, retnal nerve fber
layer and retna.
The GDx nerve fber analyzers measure the retnal nerve fber layer (RNFL) thickness with a
scanning laser polarimeter based on the birefringent propertes of the RNFL. Measurement is
obtained from a band 1.75 disc diameters concentric to the disc. It projects a polarized beam of a
light into the eye. As this light passes through the NFL tssue, it changes and slow. The detectors
measure the change and convert it into thickness units that are graphically displayed. The GDx
measure modulaton around an ellipse just outside the optcs disc and ratos of the thickest points
either superiorly or inferiorly to the temporal or nasal regions.
6.4
Visual feld examinaton
The Humphrey Visual Field is a special automated procedure used to perform perimetry, a test that
measures the entre area of peripheral vision that can be seen while the eye is focused on a central
point. During this test, lights of varying intensites appear in diferent parts of the visual feld while
the patent's eye is focused on a certain spot. The percepton of these lights is charted and then
compared to results of a healthy eye at the same age of the patent in order to determine if any
damage has occurred. This procedure is performed quickly and easily in about 15 minutes, and is
efectve in diagnosing and monitoring the progress of glaucoma. Main parameters to evaluate
damage and progression or not are: mean defect and patern standard deviaton (MD and PSD,
decibels), Glaucoma hemifeld test (GHT, qualitatve descripton of the examinaton defned
7

normal, borderline, outside normal limits), and the visual feld index (VFI, a global index that
assigns a number between 1% and 100% based on an aggregate percentage of visual functon with
100% being a perfect age-adjusted visual feld). 
6.5
Optcal coherence tomography (OCT)
Optcal coherence tomography is an established medical imaging technique. It is widely used to
obtain high-resoluton images of the anterior segment of the eye and the retna, which can provide
a straightorward method of assessing axonal integrity in Glaucoma being usefull in follow-up
examinaton to detect glaucoma progression.
6.6
Patern Electroretnogram (PERG)
The PERG is an objectve and direct measure of inner retnal functon being correlated with RGCs
actvity (21, 22), which has been found to document and predict early glaucomatous changes.
There is also an indicaton that PERG may document, at pre-clinical stage, an improvement of RGCs
functon following therapeutc IOP reducton (23). therefore PERG can be considered as an early
indicator of functonal RGC changes following an interventon aimed at counteractng apoptosis.
PERG measures the functon of the retna: when light from an image enters the eye, it is converted
into electrical energy by specialized cells in the retna. These cells send electrical impulses through
the optc nerve to the brain where the image is processed. The ERG test records how well the cells
of the retna are conveying electrical impulses within the eye. In partcular the p50 wave refects
the ganglion cells vitality/actvity.
6.7
NEI VFQ 25 item
The patents’ quality of life will be examined with the Italian version of the 25 item Natonal Eye
Insttute Visual Functon Questonnaire (24). The 25 item NEI-VFQ is a vision-targeted non-disease-
specifc instrument designed to measure the impact of some ocular disorders on vision related
quality of life. Depending on the item, responses to this questonnaire pertain to the frequency or
severity of a symptom or a problem with the functoning. The NEI-VFQ scores can range from 0 to
100 with lower scores indicatng more problems or symptoms.
6.8
Single blind procedures
All the involved personal performing visual feld examinaton, optc nerve evaluaton, IOP
measurement and PERG test will be blinded to patent’s treatment period; also who will analyse
the data will be blind to the treatment group.
6.9
Adverse events
Systemic and topical advents events will be collected.
Methods for assessing and recording: patents will be asked at each visit about therapy's comfort
and side efects.
For each AE the following informaton will be recorded in the patent’s medical chart:
●
nature of adverse event
●
date and tme of occurrence and disappearance (i.e. duraton)
●
intensity: mild, moderate or severe
●
frequency: once, contnuous or intermitent
●
decision regarding study: contnuaton or withdrawal
●
relaton to the study medicaton 
8

●
measures undertaken to treat it
AEs will be treated according to the usual clinical practce. In the event of a serious adverse event
the drug will be discontnued.
7
Descripton of study supplement
See Annexes (technical descripton)
8
Statstcal issues
8.1
Elements for sample size calculatons or study power
From our preliminary observaton we noted that the mean diference in amplitude p50 between
baseline and 3-month values was 0.7 microVolt (SD 0.7), in partcular from a mean of 1.4 to a
mean of 2.1. A two-sided t-test paired achieves 87% power to infer that the mean amplitude at
baseline is 1.4 when the total sample size of a 2x2 cross-over design is 40, the mean amplitude
afer 3 months of treatment is 2.1, the standard deviaton of the period diferences for each
subject within each sequence is 0.7, and the signifcance level is 0.05.
8.2
Analysis plan primary objectve
For the primary analysis, a Anova two-sided test (or equivalent non parametric test) will be used to
compare diference between period of treatment. 
8.3
Analysis plan secondary objectves
Descriptve statstcs will be obtained for all variables assessed in the study populaton. Mean and
standard deviaton will be used for normally distributed variables, mean and interquartle range for
skewed distributons, proportons for categorical variables.
For group comparisons, Student paired t test (Wilcoxon test for skewed distributons) will be used
for quanttatve variables (ANOVA for repeated measure or Friedman for >2 groups respectvely),
and McNemar  test for categorical variables. In all cases, two-tailed tests will be applied. P-value
<0.05 will be considered signifcant. Whenever relevant, 95% confdence intervals (95%CI) will be
calculated.
Logarithmic transformaton will be applied to skewed variables, whenever relevant to achieve
normality.
Linear regression models for repeated measures will be used to take into account both eyes per
patents and trends over tme of the ophthalmological in the planned groups/subgroups
comparisons.
9
Data management and confdentality issues
All study material (protocol, CRF, completed CRF, administratve documents) will be maintained in a
safe (closed room) place site in the Glaucoma center of the Clinica Oculistca for 5 years.
9.1
Patent’s lists
The following lists will be maintained:
Enrolled patents (code-date writen consent)
Patent’s code identfcaton log (name-surname, month-year of birth, date writen consent, code)
9

9.2
Data recording
A standard case report form (CRF) has been designed, to record in writen all study details, and will
be completed by the designated personnel. Once completed, CRF will be signed by PI and
maintained in the patent's clinical chart.
Correctons will be dated, signed and justfed by PI or designated personnel.
In the patent’s medical records, study partcipaton, date of consent, assigned code and any other
relevant informaton will be recorded.
All data in the CRF will be checked for completeness, coherence, and conformity to the protocol.
Missing data will be searched for in the medical charts on a regular basis.
10 Ethical issues
The study will be conducted according to recommendatons of the Helsinki declaraton (revision
2000, Edimbourg) and to the Italian Good Clinical Practce legislaton (DM 15 Luglio 1997 and
modifcatons).
10.1 Informed consent
To be included in the study the writen consent to partecipate the study procedures is necessary.
Patents not wishing to partcipate any longer afer signing informed consent will withdrawal
consent whenever he likes.
The aim and the procedures of the study will be explained to patents during a routne follow-up
visit, with an individual speech of about half an hour. The doctor will explain also how to adhere,
the chance not to adhere or to adhere and withdrawal without any consequence on care quality.
Patents will be given tme for questons and to decide if adhere or not to the study.
10.2 Consent withdrawal
Each patent not wishing to partcipate any longer afer signing informed consent can withdraw its
consent; if the doctor will note any adverse event, the therapy will be stopped.
10.3 Insurance
An insurance is actvated at the Fondazione IRCCS Policlinico San Mateo, to cover any damage due
to the clinical study.
10.4 Potental conficts of interest
All the researchers partcipatng to the study declare that they have no potental confict of
interest.
10.5 Other ethical issues
The study design is not complex, does not interfere with routne clinical management and does not
require additonal human resources in the partcipatng centre.
11 Costs and fnancing
Medivis will supply all tablets needed for all the 40 patents for the three months of treatment.
10

12 Staf and dutes
12.1 Fondazione IRCCS Policlinico San Mateo
Unità Operatva
Nominatvo
Ruolo
Clinica Oculistca
Gemma Caterina Maria Rossi
Progetazione, Coordinamento, Arruolamento
pazient, raccolta dat
Clinica Oculistca
Marta Raimondi
Misurazione IOP (blinded)
Clinica Oculistca
Giulio Ruberto
Valutazione del PERG (blinded)
Clinica Oculistca
Patrizia Piccinini
Esecuzione PERG (blinded)
Direzione Scientfca
Carmine Tinelli, Luigia Scudeller
Analisi statstca (blinded)
13 Data property, publicatons and further studies
The proposing group will manage patents’ data and publicatons. The manufacturers of the study
drugs will not have access to the data, nor to the various drafs of the publicaton which is
expected to be writen.
The authors of the publicatons will be decided on the basis of indicatons contained in the
Uniform Requirements for Manuscripts (htp://www.icmje.org/urm_full.pdf).
Strategy of publicaton: the main manuscript resultng from this study will be submited to an
indexed journal. 
Manuscript preparaton will following the STROBE guideline: htp://www.equator-
network.org/resource-centre/library-of-health-research-reportng/reportng-guidelines/ 
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13