Clinical trial NCT03584724
Conditions: Uveitis
Keywords: HLA-B27 relapses curcumin
Sponsor: Eye Pharma
Start date: 2018-12-19; Completion date: 2020-12-30
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to explore the efficacy of Norflo Oro in the treatment of relapsing autoimmune uveitis (RAU), measured as a long term reduction of the frequency and the severity of relapses, in patients with HLA-B27 associated uveitis, under conditions of routine medical practice. The reduction of the mean number of relapses per patient between the year before study treatment and the study period will also be assessed.

Detailed description:
The secondary objective of this study will be: (i) evaluation of the improvement of side effects due to HLA-B27 associated uveitis such as intraocular pressure (IOP), cystoid macular edema, keratophaty and synechia (ii) evaluation of the improvement in uveitis-related symptoms: BCVA and symptoms measured by VAS, like ocular pain, photophobia, floaters and blurred vision; (iii) evaluation of cell damage and inflammation reduction in patients with HLA-B27 associated uveitis; (iv) evaluation of the patients' attitude towards the study treatment and also the evaluation of the safety profile of the study product.

Arms: arm 1: The study subject will take the entire content of one packet of Norflo (each box contains 30 packets) with meal twice per day for one year. The study subject will be evaluated in a total of three visits. arm 2: The study subject will take the entire content of one packet of Placebo (each box contains 30 packets) with meal twice per day for one year. The study subject will be evaluated in a total of three visits.
Interventions: intervention 1: Norflo Oro intervention 2: Placebo for Norflo Oro
Intervention descriptions: intervention 1: Norflo Oro is highly bioavailable curcumin complexed into phytosomes intervention 2: Placebo consist of look-alike single foil pouches without active ingredient of Norflo.

Protocol documents:
Prot_000.pdf: 
Protocol Code NORFLO-ORO-16 
Confidential 
Version 1.6 
Version Date: 10 Oct 2019 
Page 1 of 67 
Clinical Development 
NORFLO® ORO 
NCT03584724
Study protocol 
Assessment of the anti-inflammatory effects of NORFLO® ORO in 
acute relapses of HLA-B27 associated autoimmune uveitis: a 
multicenter randomized, placebo-controlled, double-blind clinical 
study. 
Document type: 
Study Protocol 
Version number:  
1.6 
Development phase: 
not applicable (food supplement) 
Release date:  
10 – October - 2019 
Property of Eye Pharma S.p.A. 
Confidential 
May not be used, published, or otherwise disclosed 


Protocol Code NORFLO-ORO-16 
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Page 2 of 67 
SPONSOR’S  SIGNATURE FOR APPROVAL 
Clinical Research Protocol 
Assessment of the anti-inflammatory effects of NORFLO® ORO in acute relapses of HLA-
B27-associated autoimmune uveitis: a multicenter randomized, placebo-controlled, double-
blind clinical study. 
Protocol Number: 
NORFLO-ORO-16 
Version Date: 
Version n. 1.6, version date 10-Oct-2019 
Investigational Product: NORFLO® ORO (curcumin-phospholipid 600mg) 
Sponsor: 
Eye Pharma SpA  
Via Borghero 9  
16148 Genoa Italia 
Coordinating Principal 
Investigator: 
Name:  Pia Allegri 
Telephone: +39 0185 683678 
Fax: +39 0185 683728  
E-mail: pallegri@asl4.liguria.it
Coordinating Center: 
S.S. Uveitis Center, Rapallo Hospital, Genoa- Italy 
_____________________________
_______________ 
Giuseppe Campora         
Date 
C.E.O.
Eye Pharma S.p.A. 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time. The information in this document may 
not be disclosed unless law or regulations require such disclosure. Subject to the foregoing, this 
information may be disclosed only to those persons involved in the study who have a need to know, with 
the obligation not to further disseminate this information.   


Protocol Code NORFLO-ORO-16 
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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and providing 
Eye Pharma SpA with complete and timely information, as outlined in the protocol.  It is 
understood that all information pertaining to the study will be held strictly confidential and 
that this confidentiality requirement applies to all study staff at this site. I require and I will 
get written informed consent from each study participant before starting any procedure. 
I am aware that my electronic signature or manual, or that of a co-investigator, on a Case 
Report Form indicates that the data contained on that form has been reviewed and approved 
by the person who affixes the signature. 
Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures 
required to carry out the study in accordance with accepted GCP principles and to abide by 
the terms of this protocol. 
 
Protocol Number:  NORFLO-ORO-16  
Protocol Date: 10-Oct-2019 
 
Protocol Title:  Assessment of the anti-inflammatory effects of NORFLO® ORO in acute 
relapses of HLA-B27-associated autoimmune uveitis: a multicenter randomized, placebo-
controlled, double-blind clinical trial. 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
 
 
Site Name 
 
Address 
 
 
 
Phone Number 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS………………………………………………………………………………………………………………………….7 
PROTOCOL SYNOPSYS.............…………………………………………………………………………………………………………………9 
1. 
BACKGROUND .............................................................................................................................. 15 
 
OVERVIEW ............................................................................................................................................. 15 
 
DISEASE PATHOPHYSIOLOGY ...................................................................................................................... 15 
 
OVERVIEW OF NORFLO® ORO ................................................................................................................. 21 
 
OVERVIEW OF NON-CLINICAL STUDIES ........................................................................................................ 22 
 
OVERVIEW OF CLINICAL STUDIES ................................................................................................................ 23 
2 
STUDY RATIONALE ............................................................................................................................ 25 
3 
STUDY OBJECTIVES ........................................................................................................................... 28 
 
PRIMARY OBJECTIVE .......................................................................................................................... 28 
 
SECONDARY OBJECTIVES ........................................................................................................................... 28 
4 
STUDY DESIGN .................................................................................................................................. 28 
 
STUDY OVERVIEW ................................................................................................................................... 28 
5 
CRITERIA FOR EVALUATION ................................................................................................... 29 
 
PRIMARY EFFICACY ENDPOINT ........................................................................................................... 29 
 
SECONDARY EFFICACY ENDPOINTS .................................................................................................... 30 
 
SAFETY EVALUATIONS ....................................................................................................................... 30 
6 
SUBJECT SELECTION ................................................................................................................. 30 
 
STUDY POPULATION ........................................................................................................................... 31 
 
INCLUSION CRITERIA .......................................................................................................................... 31 
 
EXCLUSION CRITERIA ......................................................................................................................... 31 
7 
CONCURRENT MEDICATIONS .................................................................................................. 32 
 
ALLOWED MEDICATIONS AND TREATMENTS ...................................................................................... 32 
 
PROHIBITED MEDICATIONS AND TREATMENTS ................................................................................... 32 
8 
ENROLLMENT, TREATMENT ASSIGNMENT AND BLINDING ............................................ 32 
 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS .............................................................. 32 
 
BLINDING ............................................................................................................................................ 32 
 
FORMULATION OF TEST AND CONTROL PRODUCTS ............................................................................ 33 
 
Formulation of Test Product .................................................................................................... 33 
 
Formulation of Control Product ............................................................................................... 34 
 
Packaging and Labeling ........................................................................................................... 34 
 
SUPPLY OF STUDY PRODUCTS AT THE SITE ......................................................................................... 34 
 
Dosage/Dosage Regimen .......................................................................................................... 34 
 
Dispensing ................................................................................................................................ 35 
 
SUPPLY OF STUDY PRODUCT AT THE SITE ........................................................................................... 35 
 
Storage ...................................................................................................................................... 35 
 
STUDY PRODUCT ACCOUNTABILITY ................................................................................................... 35 
 
MEASURES OF TREATMENT COMPLIANCE ........................................................................................... 35 
9 
STUDY PROCEDURES AND GUIDELINES ................................................................................ 36 
 
CLINICAL ASSESSMENTS ............................................................................................................................ 36 


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Demographics ........................................................................................................................... 36 
 
Concomitant Medications ......................................................................................................... 36 
 
Medical History ......................................................................................................................... 36 
 
Physical Examination ................................................................................................................ 36 
 
Urine dipstick specific pregnancy test ....................................................................................... 37 
 
Adverse Events .......................................................................................................................... 37 
 
Vital Signs ................................................................................................................................. 37 
 
OPHTHALMOLOGICAL EXAMS GUIDE ............................................................................................................ 37 
 
BCVA ......................................................................................................................................... 37 
 
Laser Flare Photometry ............................................................................................................. 37 
 
OCT ........................................................................................................................................... 38 
 
Slit lamp .................................................................................................................................... 39 
 
Goldmann tonometry ............................................................................................................... 39 
10 
EVALUATIONS BY VISIT ............................................................................................................ 40 
 
VISIT 1 (T0) ..................................................................................................................................... 40 
 
VISIT 2 (T1, 6 MONTHS ± 10 DAYS) ................................................................................................. 40 
 
VISIT 3 – END OF STUDY (T2, 12 MONTHS ± 10 DAYS) .................................................................... 41 
 
ADDITIONAL UNSCHEDULED VISITS IN CASE OF RELAPSE ............................................................. 41 
 
EARLY WITHDRAWAL VISIT .......................................................................................................... 42 
11 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS ................................................... 42 
 
EARLY DISCONTINUATION OF STUDY DRUG .................................................................................. 42 
 
REPLACEMENT OF SUBJECTS ................................................................................................................. 43 
12 
PROTOCOL VIOLATIONS........................................................................................................... 43 
13 
ADVERSE EVENTS REPORTING AND DOCUMENTATION .................................................................... 43 
 
OVERVIEW ........................................................................................................................................ 43 
 
AE SEVERITY ..................................................................................................................................... 44 
 
ABNORMAL TEST FINDINGS ................................................................................................................... 45 
 
EVENTS TO BE REPORTED...................................................................................................................... 45 
 
All adverse Events ................................................................................................................ 45 
 
Adverse Events requiring immediate Notification ............................................................... 45 
 
INVESTIGATOR RESPONSIBILITIES ........................................................................................................... 47 
 
EVALUATION OF CAUSALITY .................................................................................................................. 47 
14 
STATISTICAL METHODS AND CONSIDERATIONS ............................................................... 47 
 
DATA SETS ANALYZED ......................................................................................................................... 48 
 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...................................................................................... 48 
 
ANALYSIS OF PRIMARY ENDPOINT ................................................................................................. 48 
 
ANALYSIS OF SECONDARY ENDPOINTS .......................................................................................... 49 
 
SAFETY EVALUATIONS ................................................................................................................... 49 
 
INTERIM ANALYSIS ........................................................................................................................ 50 
 
SAMPLE SIZE .................................................................................................................................. 50 
15 
DATA COLLECTION, RETENTION AND MONITORING ......................................................................... 50 
 
DATA COLLECTION INSTRUMENTS .......................................................................................................... 50 
 
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS .................................................................... 52 
 
MONITORING .................................................................................................................................... 52 
 
RECORD MAINTENANCE AND RETENTION ................................................................................................. 52 
16 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ................................... 53 


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SUBJECT CONFIDENTIALITY ................................................................................................................... 53 
 
INSTITUTIONAL REVIEW BOARDS (IRB) AND INDEPENDENT ETHICS COMMITTEES (IEC) .................................... 53 
 
STUDY CONDUCT ................................................................................................................................ 54 
 
PARTICIPANT INFORMATION AND INFORMED CONSENT .............................................................................. 54 
 
MODIFICATION OF THE INFORMATION AND CONSENT FORM ....................................................................... 54 
17 
OWNER OF THE RESULTS – PUBLICATION POLICY ............................................................................. 55 
 
INVESTIGATOR RESPONSIBILITIES ........................................................................................................... 55 
18 
REFERENCES ...................................................................................................................................... 56 
 
 
LIST OF APPENDICES 
APPENDIX 1 - RECOMMENDED DATA COLLECTION SCHEDULE ...................................................................... 59 
APPENDIX 2 - OPHTALMOLOGICA EXAMS GUIDE ........................................................................................... 60 
 
 
 


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List of Abbreviations 
 
AE 
Adverse event 
AAU 
Acute anterior uveitis 
AC 
Anterior chamber 
ACE 
Angiotensin converting enzyme 
AIFA 
Italian Medicine Agency 
ANA 
Antinuclear autoantibodies 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under curve 
BCVA 
Best corrected visual acuity 
COX-2 
Cyclooxygenase-2  
CRF 
Case report form 
CRP 
C-reactive protein 
C3 
C4 
Complement component 3 
Complement component 4 
CME 
Cystoid macular edema  
DMC 
Data Monitoring Committee 
DSMB 
Data and Safety Monitoring Board 
ENA 
Extractable nuclear antigens 
ERUPR 
Endoplasmic reticulum unfolded protein response  
ESR 
Erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
FB 
Fibrinogen 
GGT 
Gamma-Glutamyltransferase 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HLA 
Human Leukocyte Antigen  
HSV 
Herpes simplex virus  
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulins 
IL-8 
Interleukin -8  
iNOS 
Inducible nitric oxide synthase 
IRB 
Institutional Review Board 


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MCP 
Monocyte chemoattractant protein  
MHC 
Major histocompatibility complex 
NKR 
Natural killer receptors  
OCT 
Optical coherence tomography  
RF 
Rheumatoid factor 
PI 
Principal investigator 
RAU 
Recurrent anterior uveitis  
SAE 
Serious adverse event 
SUN  
Standardization of Uveitis Nomenclature 
TNF-α 
Tumor necrosis factor-alpha 
UAR 
Relapsing autoimmune uveitis  
VZV 
Varicella-zoster virus 
 


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Protocol Synopsis 
 
TITLE 
Assessment of the anti-inflammatory effects of NORFLO® ORO in 
acute relapses of HLA-B27-associated autoimmune uveitis: a 
multicenter randomized, placebo-controlled, double-blind clinical 
study. 
 
SPONSOR 
Eye Pharma SpA, via Borghero 9, 16148 - Genoa (GE) Italy  
Telephone: +39 010 513188 – Fax: +39 010 3071430 
 
NUMBER OF SITES 
4  
 
RATIONALE 
In our previous study, Allegri et al. have shown how the treatment with 
NorFlo® (curcumin-phospholipid (Meriva® 600mg)) 2 tablets daily in 
128 patients in combination with conventional therapy is capable of 
reducing the relapses in patients with recurrent anterior uveitis (RAU) 
by 88%.  The enrolled subjects suffered from uveitis of different 
etiologies, among which were found three main different etiological 
groups: herpetic uveitis, autoimmune inflammatory ocular disease and 
various origin anterior uveitis. Among these three groups, the most 
sensitive patients to the treatment were autoimmune RAU (n=56). 
These extraordinary results lay the groundwork for further investigating 
the effectiveness of curcumin-phospholipids in autoimmune HLA-
B27-associated uveitis, which represents the most common type of 
uveitis (75% of total uveitis). NORFLO® ORO aims at obtaining an 
anti-inflammatory effect that is synergistic to conventional therapy to 
counteract the occurrence of secondary symptoms (as cystoid macular 
edema) of HLA-B27-associated uveitis. 
 
STUDY DESIGN 
This is a multicenter, randomized, double-blind, placebo-controlled 
study. 
 
PRIMARY 
OBJECTIVE 
To explore the efficacy of NORFLO® ORO in reducing the number and 
severity of relapses, when compared to placebo. The reduction of the 
mean number of relapses per patient between the year before study 
treatment and the study period will also be assessed. 


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SECONDARY 
OBJECTIVES 
- 
To evaluate the improvement of side effects due to HLA-B27-
associated uveitis such as glaucoma, cystoid macular edema, 
keratopathy and synechia. 
- 
To evaluate the improvement in uveitis-related symptoms. 
- 
To evaluate cell damage and inflammation reduction in patients 
with HLA-B27-associated uveitis. 
- 
To evaluate the patients’ attitude towards the study treatment. 
- 
To evaluate the safety profile of the study product. 
NUMBER OF 
SUBJECTS 
60  
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria:  
1. Subjects ≥ 18 years of age at baseline Visit. 
2. HLA-B27 positive related uveitis (acute alternating non 
granulomatous uveitis); the uveitis shall not be in acute phase at 
the time of enrolment and at least 8 weeks must have elapsed after 
the resolution of the last uveitis attack. 
3. Subjects with at least one autoimmune uveitis relapse (UAR) in the 
last year. 
4. Written informed consent obtained from subject or subject’s legal 
representative and ability for the subject to comply with the 
requirements of the study. 
 
Exclusion Criteria: 
1. Presence of a condition or abnormality that in the opinion of the 
investigator would compromise the safety of the patient or the 
quality of the data collected. 
2. Subjects that have received systemic therapy for uveitis with anti-
inflammatory, immunosuppressive or biological drugs in the 30 
days before study start.  
3. Subjects with an anticipated need for systemic anti-inflammatory, 
immunosuppressive or biological drugs during the 12 months of 
the study. 
4. Subjects who received an intravitreal, peribulbar, sub-tenon, 
periocular injection in the previous 6 months.  
5. Subjects that are receiving long-term treatment with systemic anti-
inflammatory, immunosuppressive or biological drugs for other 
diseases different from uveitis. 
6. Women who are taking hormonal contraceptives. 


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7. Subjects that have taken supplements and nutraceuticals in the 
last 30 days prior to baseline visit. Use of supplements and 
nutraceuticals will not be admitted during the study. 
8. Subjects for whom baseline LFM and other evaluations cannot 
be accurately performed. 
9. Women who are pregnant or breast-feeding. 
TEST PRODUCT, 
DOSE AND ROUTE 
OF 
ADMINISTRATION 
NORFLO® ORO at 2 single foil pouches per day (equal to 3.49 g of 
product).The product will be administered orally every day for 12 
months. The administration will take place each day in two separate 
doses before meals (lunch and dinner). 
 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
PLACEBO at 2 single foil pouches per day (equal to 3.49 g of product).  
The product will be administered orally every day for 12 months. The 
administration will take place each day in two separate doses before 
meals (lunch and dinner). 
 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will participate in the study for up to 12 months.  
Treatment duration:  12 months   
Visits: Baseline Visit (Visit 1 - T0), Visit 2 (T1, 6 months), Visit 3 (T2, 
12 months).   
 
The screening will be done in the same day of the baseline visit. 
 
After the first 3 months of treatment subjects will be contacted by phone 
by the study staff, to assess the correct study product intake. 
 
The enrolment period will be 3 months, therefore the total duration of 
the study is expected to be about 15 months.  
   


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CONCOMITANT 
MEDICATIONS 
Allowed: 
In case of relapse the following treatments will be allowed:  
- 
any midriatic topical therapy  
- 
any traditional topical therapy recommended for the treatment of 
relapsing autoimmune uveitis. 
In the case of relapse with LFM values are > 100 ph/ms despite 
treatment with topical therapy, or in any case the LFM values result to 
be > 100 ph/ms, then a systemic therapy is recommended and the 
subject has to be dropped-out from the study and treated according to 
the best medical judgement. 
Prohibited: 
Supplements and nutraceuticals; systemic therapies for uveitis with 
anti-inflammatory, immunosuppressive, biological drugs; hormonal 
contraceptives; long-term treatment with systemic anti-inflammatory, 
immunosuppressive or biological drugs for other diseases different 
from uveitis. 
Systemic therapies with anti-inflammatory, immunosuppressive drugs 
are allowed for reasons different from uveitis and in any case for 
periods not exceeding 15-30 days. 
 
EFFICACY 
EVALUATIONS 
A clinical assessment and diagnosis will be performed on each patient 
enrolled in the study. 
 
PRIMARY ENDPOINT 
Mean number per patient and severity of relapses reduction in the 
NORFLO® ORO treatment group when compared to the placebo group. 
The reduction of the mean number of relapses per patient between the 
year before treatment and the study period within each treatment group 
will also be assessed. The two endpoints will be assessed in a 
hierarchical order. 
Cell damage and inflammation reduction, as assessed by Laser Flare 
Meter in the NORFLO® ORO treatment group when compared to the 
placebo group. 


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SECONDARY 
ENDPOINTS 
The improvement of side effects due to HLA-B27-associated uveitis, 
such as intraocular pressure (IOP) by Goldmann applanation 
tonometry, cystoid macular edema (central foveal thickness – central 1 
mm subfield thickness) by optical coherence tomography (OCT) 
Spectralis® 
(Heidelberg 
Egineering, 
Heidelberg 
Germany), 
keratopathy, evaluated by fluorescein staining of the cornea, and 
synechia assessed by photographic slit lamp (anterior chamber 
photographs will be retained), in the NORFLO® ORO treatment group 
when compared to placebo group. 
The improvement in uveitis-related symptoms (BCVA, ocular pain, 
photophobia, floaters and blurred vision measured by VAS). 
Patients’ attitude towards NORFLO® ORO treatment compared to 
placebo, through the Quick Questionnaire. 
SAFETY 
EVALUATIONS 
Incidence of adverse events in the NORFLO® ORO treatment group 
compared to placebo group. 
Use of concomitant medication. 
Changes in vital signs. 
STATISTICS 
Primary Analysis  
Mean and standard deviation will be used to describe the number of 
relapses per patient. The mean number of relapses per patient will be 
compared between the treatment groups using Student’s t-test. 
ANOVA will be used to adjust for predictive/confounding variables. 
In addition, a generalized linear mixed model (GLMM) will be used to 
assess the effects of the treatment on reducing the number of relapses. 
The average and the maximum intensity will be compared between 
treatment groups using Student’s t-test. ANOVA will be used to include 
predictive/confounding variables in the model.  
The mean number of relapses per patient observed during the study will 
be compared to the mean number of relapses reported during the 
previous year within each treatment group using paired t-test or 
ANOVA, to eventually adjust for predictive/confounding variables. 
The two endpoints will be assessed in a hierarchical order. 
 
Secondary Analysis 
The incidence of side effects associated HLA-B27-associated uveitis, 
such as IOP, cystoid macular edema, keratopathy and synechia, will be 
compared between treatment groups using logistic regression. 
The changes in BCVA and symptoms measured by VAS will be 
compared between treatment groups using ANCOVA, with the baseline 
level included in the model.  


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The level of cell damage and inflammation will be assessed through 
Laser Flare Meter. The difference between treatment groups will be 
compared using ANCOVA, with the baseline level included in the 
model.  
Each information collected through the Quick questionnaire will be 
compared between the two treatment groups using chi-square test. 
 
Safety Analysis 
Adverse event will be coded using the last updated version of the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary to 
give a preferred term (PT) and a system/organ class term (SOC) for 
each. Adverse events will be tabulated by treatment group. Tables will 
include the number of patients who experienced at least one AE, of 
study product-related AEs (defined as definitely, probably, possibly, or 
unrelated), of serious AEs, and the number of patients withdrawn due 
to AE, summarized by treatment arm. Comparisons between treatment 
arms will be performed using chi-square test. Concomitant medications 
will be summarized by treatment using descriptive statistics and they 
will be listed. Vital signs will be summarized by treatment using 
descriptive statistics for absolute values and change from baseline. 
Compliance to the study treatment will be assessed through the patient 
diary and checked versus the used and unused study product containers 
given back by the patients. 
Rationale for Number 
of Subjects 
With a statistical power of 80%, a significance level (alpha) of 5% and 
a common SD of 0.7, 46 patients are needed to observe a difference of 
0.6 relapses/patients between the two treatment groups (2 
relapses/patient in the NORFLO® ORO treatment group vs. 2.6 in the 
placebo treatment group). To take into account a potential dropout rate 
of 20% over 1 years, 60 patients will be recruited. A second primary 
endpoint, i.e. the reduction of mean number of relapses between the 
year before treatment and the study period, will be examined. These 
two endpoints will be assessed in a hierarchical order. 
 
 
 
 
 


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1. BACKGROUND 
 
 Overview 
The first human leukocyte antigen (HLA) haplotype association with inflammatory diseases 
was discovered in 1972 and it correlated the HLA-B27 haplotype with severity and 
susceptibility to ankylosing spondylitis. Ankylosing spondylitis remains one of the strongest 
known disease associated with HLA-B27. Since then, more than 100 disease associations 
have been demonstrated, including many ocular diseases and systemic diseases with specific 
ocular manifestations1. These diseases also include reactive arthritis (previously referred to 
as Reiter’s syndrome), inflammatory bowel disease, and psoriatic arthritis.  
In ophthalmology, HLA associations are strongest in diseases of the uvea. Of patients with 
uveitis, 19-88% have the HLA-B27 phenotype, depending upon the study population cited. 
Acute anterior uveitis (AAU) may occur as a distinct clinical entity or in conjunction with a 
group of autoimmune rheumatic diseases called seronegative spondyloarthropathies2. By 
definition, patients with these diseases have a negative rheumatoid factor, hence the term 
seronegative 3-4.   
An HLA disease association is defined as a statistically increased frequency of the HLA 
haplotype in individuals with the disease compared to the frequency in individuals without 
the disease. This is expressed as a relative risk. For example, HLA-B27 appears in 80-90% 
of patients with ankylosing spondylitis. Expressed as a relative risk, an HLA-B27 positive 
individual is approximately 87 times more susceptible to developing ankylosing spondylitis 
compared to the general population. 
 Disease Pathophysiology 
The HLA system is genetically encoded in humans by the 
major histocompatibility complex (MHC), which is found 
on chromosome 6, and plays a determining role in 
immunity and in self-recognition (autoimmunity) in 
virtually all cells and tissues, with the exception of 
erythrocytes5.   
Three classes of gene products are encoded within the 
small region of the major histocompatibility complex 
(MHC). Class I MHC molecules include HLA-A, HLA-B, 
or HLA-C (Figure 1) and serve as the antigen-presenting 
platform for CD8 or cytotoxic T cells. Class I molecules 
are present on all nucleated cells. Class II MHC molecules, 
the HLA-D region, serve as the antigen-presenting cells for 
CD4 or helper T cells.  Macrophages and dendritic cells are the important class II antigen-
Figure 1- The HLAB gene is located on 
the short (p) arm of chromosome 6 at 
the position 21.3 


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presenting cells. Class I and class II molecules allow antigen presentation to the specific T-
cell 
receptor 
via 
specific 
structural 
grooves 
in 
their 
tertiary 
structure. 
Autoimmune/inflammatory conditions can occur if mutations in the groove-binding site of 
class I and II molecules occur, leading to inappropriate binding to self-peptides or certain 
environmental peptides.  
The actual role of HLA-B27 in triggering an inflammatory response causing diseases is still 
not precisely known. The molecular mimicry is the oldest theory, in which an autoimmune 
response is mounted initially against a peptide derived from an infectious agent and is 
subsequently directed against self-peptides due to epitopic similarities resulting in biding 
affinity to HLA-B27. At least two self-peptides have been identified in patients with 
ankylosing spondylitis, which supports this hypothesis.  
A second theory, referred to as the HLA-B27 misfolding hypothesis, is based on a peculiar 
biochemical property of the HLA-B27 molecule. Unfolded HLA-B27 proteins accumulate 
in the endoplasmic reticulum (ER) and trigger a proinflammatory stress response that is 
called the endoplasmic reticulum unfolded protein response (ERUPR). As a result, 
interleukin 23 (IL-23) is released, activating a proinflammatory response via interleukin-17-
secreting Th17 T lymphocytes.  
Another potential pathological mechanism of HLA-B27 is called the HLA-B27 heavy chain 
homodimer hypothesis. It is suggested that B27 heavy chains dimerize and accumulate in the 
endoplasmic reticulum. In turn, this initiates the proinflammatory ERUPR. In addition, B27 
heavy chains and dimers can bind to other regulatory immune receptors such as the natural 
killer receptors (NKRs). This in turn recruites proinflammatory leukocytes and triggers the 
production of proinflammatory mediators.  
Alternative theories claim the T-cell antigen as the susceptibility factor or other innate system 
etiological mechanisms that are unrelated to HLA. Finally, HLA-B27 may simply represent 
a marker locus, closely linked to the yet unidentified immune response gene that is truly 
responsible for the inflammatory response6.  
Several hypotheses to explain the association of AAU and HLA-B27 have been tested in 
animal models. Many cases of uveitis or reactive arthritis follow gram-negative bacillary 
dysentery or chlamydial infection. These gram-negative organisms include Shigella, 
Salmonella, Klebsiella, and Yersinia species. Similarities in the gram-negative cell wall 
lipopolysaccharide present in these microbes may explain their immunogenicity. Animal 
experiments with rodents that have been genetically altered to express human HLA-B27 
molecules show that bacterial infection of the gut predisposes the animals to arthritis and to 
a reactive arthritis–like syndrome. In addition, chronic intracellular chlamydial joint or eye 
infection might stimulate, via the HLA-B27 molecule, a CD8 T cell effector mechanism that 
was activated to kill the infected cells but that also indirectly injures the eye7.  


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Clinical Features 
The sequence of HLA-B27 has been known since 1985. The antigen consists of at least 100 
subtypes. Some HLA-B27 subtypes are associated with other HLA-B27 inflammatory 
diseases such as anterior uveitis. The HLA-B27 antigen is present in only 1.4-8% of the 
general population (higher in certain Native American groups and Scandinavians). Of 
patients with acute anterior uveitis, up to 50-60% of patients are HLA-B27 positive. Both 
racial background and country of origin affect the rate of incidence of HLA-B27 associated 
acute anterior uveitis (AAU). In specific, the frequency of HLA-B27 anterior uveitis is lowest 
in blacks, intermediate in Asians, and highest in whites8.  
HLA-B27 associated AAU is the most frequent type of endogenous uveitis and it accounts 
for 18-32% of all anterior uveitis cases in western countries and for 6-13% of all anterior 
uveitis cases in Asia. The relatively lower frequency of AAU in Asia is related to the lower 
frequency of HLA-B27 found in this population. As mentioned, there are varying global 
patterns of HLA-B27 associated AAU that may be attributed to different genetic factors, such 
as HLA-B27 polymorphisms and non-MHC genes. These geographic variations may also 
exist because of yet unidentified pathogenic environmental factors. 
Studies indicate that HLA-B27 associated uveitis is a distinct clinical entity characterized by 
a male predominance and frequent association with seronegative arthritic syndromes, such 
as ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and inflammatory bowel 
disease9.  
The first episode of HLA-B27 associated AAU most commonly occurs in patients aged 20-
40 years, whereas onset of HLA-B27-negative AAU occurs a decade later. Of patients with 
AAU, at least 50-60% are HLA-B27 positive. The first AAU episode is generally a benign 
non granulomatous unilateral disease presenting as a classic triad of pain, redness, and 
photophobia. Corneal manifestations may include fine keratic precipitates and fibrin on the 
endothelium. Corneal edema may develop due to endothelial decompensation. Band 
keratopathy, characterized by an accumulation of calcium in the corneal epithelium, may be 
seen in chronic uveitis. The anterior chamber of the eye shows cells and flare, which appears 
as a haze upon slit lamp examination, and which reflects 
protein accumulation in the anterior chamber of the eye 
due to the breakdown of the blood-aqueous barrier. In 
severe inflammation, fibrinous exudate in the anterior 
chamber of the eye may cause apposition of the iris to 
the lens or anterior vitreous, preventing aqueous from 
flowing and occluding the pupil, causing iris bombe as 
depicted in Figure 2. The fibrinous exudate may be 
mistaken for endogenous endophthalmitis, cataract, or 
hypopyon. In some cases, a hypopyon leukocytic 
 
Figure 2 – Clinical signs of acute 
anterior uveitis (AAU). 


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exudate may be seen, and, rarely, even a spontaneous hyphema may occurs as a result of 
severely dilated iris vessels. 
Pigment dispersion, pupillary miosis, and iris nodules may be noted, and synechiae, both 
anterior and posterior, can occur. Posterior segment involvement is relatively rare, but 
cystoid macular edema, disc edema, pars plana exudates, or choroiditis may be seen. 
Intraocular pressure often is low, secondary to decreased aqueous production with 
inflammation of the ciliary body and trabecular meshwork10. Intraocular pressure also may 
be high if inflammatory cells and debris clog the trabecular meshwork, particularly in patients 
with a preexisting poor aqueous outflow facility.  
Uveitis may precede the diagnosis of spondyloarthritis and be the first manifestation. 
However, there is not trend between uveitis and spondyloarthritis i.e. a joint inflammation is 
not always associated with an ocular inflammation or viceversa. 
Different clinical forms may be present: 
- Patient has uveitis and HLA-B27 + but not ankylosing. 
- Patient has ankylosing, uveitis and HLA-B27 -. 
- Patient has ankylosing HLA-B27 + and concomitant exacerbations or not. 
 
Diagnosis 
A careful history and physical examination usually helps distinguish between the uveitic 
entities associated with a systemic disease and with HLA-B27 from those that are not 
associated with HLA-B27. Disease entities causing AAU are varied and include traumatic 
iritis, postcataract extraction iritis, juvenile rheumatoid arthritis, herpetic infection (both 
herpes simplex and herpes zoster), syphilis, sarcoidosis, Fuchs heterochromic iridocyclitis, 
glaucomatocyclitic crisis, Behcet disease, and low-grade endophthalmitis11.  
The diagnosis of HLA-B27 associated anterior uveitis is clinical. However, blood chemistry 
and diagnostic tests are necessary for a differential diagnosis: 
- 
HLA-B27 typing. The role of HLA-B27 testing in patients with unilateral AAU is 
important in the differential diagnosis. The lack of HLA-B27 antigen in unilateral AAU 
may be a clue for the clinician to search for other specific uveitis entities and other 
systemic diseases. It also may be useful in determining the prognosis of AAU, as AAU 
associated with HLA-B27, even in the absence of a systemic disease, is less favorable 
when compared with that of patients who are HLA-B27 negative.  
- 
Inflammatory markers: ESR, CRP and fibrinogen, C3 and C4. 


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- 
Radiographs of sacroiliac joints to identify sclerosis and narrowing of the joint space, 
which is followed by ligamentous ossification, and osteoporosis. Both sacroiliac joints 
usually are involved, but signs may first appear on one side. Ankylosing spondylitis may 
first present to an ophthalmologist in the form of AAU. A family history or symptoms of 
back problems and a positive HLA-B27 are highly suggestive of the diagnosis.  
- 
ACE, total IgG and IgM HSV-1 and VZV, ANA , ENA, anti-DNA. 
 
Treatment 
Medical management of AAU includes topical or systemic corticosteroids and topical 
cycloplegics. Periocular corticosteroid injections are extremely useful in acute, recalcitrant, 
or noncompliant cases, particularly when posterior segment involvement occurs. 
Immunosuppressive therapy may be necessary in refractory cases or in those patients with 
corticosteroid-induced adverse effects. The primary goal of the treatment is to eliminate all 
cells, thereby minimizing complications including cataracts, cystoid macular edema, 
hypotony or glaucoma.  
Cycloplegics help relieve photophobia, secondary to ciliary spasm, and prevent/break 
synechiae formation. Corticosteroids are the mainstay of uveitis therapy, but they should be 
used prudently due to their adverse effects. The treatment goal is to use the minimum amount 
of corticosteroids necessary to control inflammation and to prevent complications. 
Aggressive initial therapy may hasten recovery and limit the duration of therapy. 
Prednisolone acetate 1% given every hour is strongly recommended for acute presentations. 
Usually, 2-3 weeks treatment at maximal frequency is sufficient to completely eliminate all 
cells. Always discontinue corticosteroids by tapering the dose is recommended. 
Corticosteroids may be administered by 4 routes, including topical, periocular, intraocular 
(intravitreal), and systemic. Topical therapy is used in anterior uveitis. The dosing varies 
from hourly to once daily. Occasionally, severe inflammation may not respond and may 
require periocular, intraocular, or systemic corticosteroids treatment, especially if the 
posterior segment is involved. Periocular corticosteroids are usually given as depot injections 
in the sub-Tenon space. Intravitreal corticosteroids by injection or by implantation of a 
sustained released device have been shown to be useful in the treatment of both chronic 
uveitis and uveitic cystoid macular edema.  
Systemic corticosteroids can be administered orally or intravenously. These are especially 
beneficial when the systemic disease requires therapy as well. More potent 
immunosuppression may be required in patients with vision-threatening inflammation 
interfering with activities of daily living, lack of response to corticosteroid treatment, and 
intolerance of corticosteroids12.  


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The role of the rheumatologist in the management of AAU is important in identifying 
underlying systemic diseases that may be present and in monitoring subsequent 
immunosuppressive therapy.  Current therapies for uveitis remain nonspecific in their mode 
of action, and there have a number of adverse effects, as already mentioned. Owing to this, 
future novel therapeutic approaches should target the specific mechanisms underlying the 
immune response and will include utilization of compounds that target cytokines, 
chemokines, cell adhesion molecules, and T-cell subsets.  
 
Complications 
AAU generally runs a short course of a few days to weeks and up to 3 months, with a 
tendency to recur in the same eye, especially in individuals who are HLA-B27 positive. 
Complications of AAU include: 
- 
Posterior subcapsular cataracts 
- 
Open and close angle glaucoma  
- 
Keratopathy (Figure 5) 
- 
Posterior synechiae (Figure 3) 
- 
Cystoid macular edema and retinal vasculitis (Figure 4). 
 
 
 
 
 
 
 
 
The prognosis of HLA-B27 associated anterior uveitis, either with or without systemic 
disease, is less favorable when compared with patients who are HLA-B27 negative with 
idiopathic anterior uveitis. Despite the potential for sequelae, the overall prognosis is good13. 
Classic AAU resolves completely when promptly and aggressively treated. Undertreated or 
Figure 4 - Cystoid macular edema. 
Figure 3 - Posterior subcapsular 
cataracts 
Figure 5 - Keratopathy. 


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misdiagnosed cases may progress to chronic iridocyclitis due to permanent damage of the 
blood-aqueous barrier. 
 
 
 Overview of NORFLO® ORO  
NORFLO® ORO is based on curcumin-phospholipids complex that contributes to the anti-
inflammatory and the anti-edema effects. 
Curcumin is the yellow pigment of Turmeric (Curcuma longa L.), the most popular spice of 
the Indian cuisine and a major ingredient of curry powders. In the Western diet, turmeric is 
mainly used as a food additive to color dairy products. Because of the different use (spice vs. 
food additive), the dietary intake of curcumin in the Western diet is negligible, but it can 
reach as much as 150 mg/day in the Indian diet 14. 
Turmeric has a long history of medicinal use in India, and because it may be beneficial for 
many conditions, turmeric is a veritable panacea. Modern cellular studies on curcumin have 
validated most of its indications in traditional medicine, even expanding the potential of 
curcumin to genetic diseases associated with Caucasians15. Curcumin shows strong anti-
oxidative and anti-inflammatory effects. In the past two decades, over 8000 articles have 
demonstrated the molecular basis of curcumin antioxidant, anti-inflammatory, antibacterial, 
anti-apoptosis and anticancer properties. As a result, curcumin has emerged as a master 
switch of inflammation, with both a direct and a genomic activity on regulation of 
proinflammatory enzymes, inflammatory transcription factors and inflammatory cytokines16. 
Over 100 clinical trials have focused on unravelling the role and the benefits of curcumin in 
various chronic diseases, including diabetes and cancers, as well as autoimmune, 
cardiovascular, neurological and psychological diseases. 
 
Curcumin modulates the inflammatory response by down-regulating the activity of 
cyclooxygenase-2 (COX-2), lipoxygenase and inducible nitric oxide synthase (iNOS) 
enzymes; inhibits the production of inflammatory cytokines such as tumor necrosis factor-
alpha (TNF-a), interleukin (IL) -1, -2, -6, -8, and -12, monocyte chemoattractant protein 
(MCP) and migration inhibitory protein; down-regulates mitogen-activated and Janus 
kinases17-18. 
 
Curcumin, just like most dietary phenolics, is sparingly soluble both in water and in organic 
solvents, but has polar groups (two phenolic hydroxyl and one enolic hydroxyl) that can 
interact via hydrogen bindings and polar interactions with complementary group, like the 
polar heads of phospholipids. Phosphatidylcholine has a highly polarized head, the negative 
charge of a phosphate group and the positive charge of the choline ammonium group. 
Therefore, the phosphatidylcholine head can complex a variety of poorly soluble phenolics, 
including curcumin. Phenolic like curcumin show a high affinity for biological membranes. 
Once formulated with phospholipids, curcumin is embedded into their lipidic matrix that 


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shields it from hydrolytic degradation. The rapid exchange of phospholipids between 
biological membranes and extracellular fluids, allows shuttling curcumin from the 
phospholipid carrier into the biological membranes, increasing curcumin uptake by cells.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NORFLO® ORO contains a patented formulation of curcumin and phosphatidylcholine 
enriched soy lecithin (Phytosome – Meriva®) 19. Curcumin and phosphatidylcholine form a 
non-covalent adduct when mixed in a 1:2 weight ratio. Further, two parts of microcrystalline 
cellulose are added to improve flowability of the powder. The overall content of curcumin is 
around 20% and its bioavailability is increased 20-21. Phytosome® has been shown to increase 
the hydrolytic stability of curcumin and to increase the oral absorption of curcumin by over 
20 folds. 
By embedding curcumin into the hydrophobic domains of phospholipids, curcumin is 
shielded from water-triggered degradation while, at the same time, the rapid exchange of 
phospholipids between biological membranes and the extracellular fluids can shuttle 
curcumin into biological membranes, boosting its cellular uptake (Figure 6). The improved 
oral bioavailability of curcumin as Phytosome® has been confirmed by human 
pharmacokinetic studies. Clinical efficacy of Phytosome® in the treatment of inflammatory 
conditions has been proven at dosages significantly lower than those of unformulated 
curcumin 22 confirming its higher bioavailability (Figure 7). 
 
 
Overview of Non-Clinical Studies 
 
Phytosome® 
Meriva® 
Curcumin 
Phospholipids 
Intestinal barrier 
Figure 6 - Schematic of the release 
mechanism of curcumin phospholipid 
complexes (Phytosome – Meriva) in the gut.
Figure 7 - Human pharmacokinetic study. Meriva 
has shown a bioavailability of about 30 times higher 
than standard curcumin (Reference) 


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Meriva®
 
has shown an improved bioavailability compared to uncomplexed curcumin in rats. 
Male Wistar rats received 340 mg/kg of either unformulated curcumin or curcumin 
formulated with phosphatidylcholine (Meriva®) by oral gavage. Rats were euthanized 15, 30, 
60 and 120 minutes post administration of the compounds. Plasma, intestinal mucosa and 
liver were analyzed for the presence of curcumin and metabolites using HPLC with UV 
detection. Identity of curcumin and metabolites was verified by negative ion electrospray 
liquid chromatography/tandem mass spectrometry. Peak plasma levels and area under the 
plasma concentration time curve (AUC) values for parent curcumin after administration of 
Meriva® were fivefold higher than the AUC of unformulated curcumin. Similarly, liver levels 
of curcumin were higher after administration of Meriva® compared to unformulated 
curcumin. The results suggest that curcumin formulated with phosphatidylcholine provides 
higher systemic levels of parent agent than unformulated curcumin. The improved 
bioavailability does not translated into an increased toxicity. Just like curcumin, the acute 
oral toxicity of Meriva ® in rats is higher than 2 g/Kg23.  
Colorectal tumor-bearing mice with oxaliplatin-resistant cells were treated with Meriva® 
alone and in combination with oxaliplatin. Oxaliplatin-resistant HCT116 p53wt and p53(-/-) 
cell lines were generated and the effects of oxaliplatin in combination with curcumin on 
resistance- and proliferation-associated proteins investigated. Eighty nude mice were 
implanted with HCT116 p53wt colorectal cancer cells before randomization into the 
following treatment groups: control, Meriva only, oxaliplatin only, Meriva® + oxaliplatin. 
Meriva® in combination with oxaliplatin was able to decrease the proliferative capacity of 
oxaliplatin-resistant p53wt and p53 (-/-) cell lines more effectively than oxaliplatin alone. 
Meriva® in combination with oxaliplatin also decreased expression of markers associated 
with cell proliferation. After 21 days of treatment in the xenograft model, the order of 
treatment efficacy was Meriva® + oxaliplatin > Meriva® > oxaliplatin > control. The decrease 
in tumor volume when compared to vehicle-treated animals was 53, 35 and 16%, 
respectively. Meriva® did not adversely affect the DNA-platinating ability of oxaliplatin. On 
the other hand, curcumin enhanced the cytotoxicity of oxaliplatin in models of oxaliplatin 
resistance in vitro. In vivo, Meriva greatly enhanced oxaliplatin efficacy, without affecting 
the mode of action of oxaliplatin. Therefore, addition of formulated curcumin to oxaliplatin-
based chemotherapy regimens has the potential for clinical benefit in colorectal cancer24. 
 
Overview of Clinical Studies 
 
The efficacy and tolerability of curcumin-complex was evaluated as an adjunctive therapy to 
traditional treatment. Curcumin-phosphatidylcholine complex (Meriva®/NorFlo) was 
administered twice a day in recurrent anterior uveitis of different etiologies. The study group 
consisted of 106 patients who completed a 12-month follow-up therapeutic period. The 
patients were divided into three main groups based on the uveitis origin: group 1 
(autoimmune uveitis), group 2 (herpetic uveitis), and group 3 (different etiologies of uveitis). 


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The primary endpoint was the evaluation of relapse frequency in all treated patients, before 
and after Meriva® treatment, followed by the number of relapses in the three etiological 
groups. The secondary endpoints were the evaluation of relapse severity and of the overall 
quality of life. The results showed that Meriva® was well tolerated and could reduce eye 
discomfort symptoms and signs after a few weeks of treatment in more than 88% of patients. 
There was also an improvement in symptoms and signs associated with relapses after 
Meriva® treatment, including improvement in ocular pain, blurring of vision, pericorneal 
hyperemia and aqueous or vitreous cells, and flare in 42% of patients. In conclusion, this is 
the first study that reports the potential therapeutic potential of curcumin and its efficacy in 
eye relapsing diseases, such as anterior uveitis, and points out that curcumin treatment may 
be beneficial also in other eye inflammatory and degenerative conditions, such as the dry 
eye, maculopathy, glaucoma, and diabetic retinopathy25.  
The improvement of diabetic microangiopathy and retinopathy was evaluated in 38 diabetic 
patients treated with Meriva®. Inclusion criteria for the study were established diabetes for 
at least 5 years and signs of retinal edema and peripheral microangiopathy. Meriva® was 
administered at the dosage of 2 tablets/day (each tablet containing 500 mg Meriva® 
corresponding to 100 mg curcumin) for a period of at least 4 weeks in addition to the standard 
management plan, while the control group (n = 39) followed the standard management plan 
alone. All subjects (treatment and controls) completed the follow-up period, there were no 
dropouts and Meriva® showed an optimal tolerability. At 4 weeks after starting the treatment, 
microcirculatory and clinical evaluations indicated an improvement of microangiopathy. In 
terms of peripheral microangiopathy, in the Meriva® supplemented group, there was a 
significant improvement in the venoarteriolar response (p<0.05) and a decrease in the score 
of peripheral edema (p<0.05), a sign typically associated with the failure of the venoarteriolar 
response. At the retinal level, high-resolution duplex scanning, used to measure retinal flow, 
showed improvements in the Meriva® supplemented patients. The evaluation of retinal 
edema (Steigerwalt’s scale) showed an improvement indicated by improved visual acuity 
(Snellen scale). There were no clinical or microcirculatory improvements in the control 
group. These preliminary observations indicate that curcumin administered in a bioavailable 
form such as Meriva®, is beneficial for the management of diabetic microangiopathy and 
retinopathy26. 
In addition to its anti-inflammatory activity, Meriva® has been anecdotally reported to 
decrease acute pain in patients with various chronic diseases. Curcumin can desensitize the 
transient receptor potential A1 (TRPA1), a nociceptor-specific ion channel, which mediates 
the analgesic effect of acetaminophen. Further curcumin can inhibit and downregulate the 
expression of cyclo-oxygenase 2 (COX-2), the selective target of nimesulide, a nonsteroidal 
anti-inflammatory agent. Building on these effects of curcumin, we carried out a pilot 
comparative study of the acute pain-relieving properties of curcumin compared to 
acetaminophen and nimesulide. At a dose of 2 g (corresponding to 400 mg of curcumin), 
Meriva® showed analgesic properties that were comparable to those of a standard dose (1 g) 


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of acetaminophen, but lower than a therapeutic (100 mg) dose of nimesulide. The analgesic 
activity of lower doses (1.5 g) of Meriva® was less satisfactory, displaying longer onset of 
activity than that of nimesulide for both doses. On the other hand, gastric tolerability of 
Meriva® was significantly better than that of nimesulide and comparable with that of 
acetaminophen. Taken together, these results suggest that the analgesic properties of 
curcumin have clinical relevance, at least at a dose of 2 g when administered in the Meriva® 
formulation. While this dose is significantly higher than that used to relieve chronic 
inflammatory conditions (1–1.2 g/day), its pain-relieving activity could benefit from the 
general downregulation of the inflammatory response induced by curcumin, considering that 
the TRPA1-mediated mechanisms of analgesia are magnified by attenuation of 
inflammation. In patients treated with Meriva, this would also translate into better control of 
acute pain, providing a rationale for the analgesic properties associated with this specific 
curcumin formulation27. 
In a three-month study, Meriva® was able to decrease joint pain and to improve joint function 
in 50 patients with osteoarthritis (OA). Since OA is a chronic condition requiring prolonged 
treatment, the long-term efficacy and safety of Meriva were investigated in a longer (eight 
months) study involving 100 patients with OA. The clinical end points were complemented 
by the biochemical evaluation of a series of inflammatory markers (interleukin [IL]-1beta, 
IL-6, soluble CD40 ligand [sCD40L], soluble vascular cell adhesion molecule (sVCAM)-1, 
and erythrocyte sedimentation rate [ESR]). Significant improvements of both the clinical end 
points and biochemical markers were observed for the Meriva treated group compared to the 
control group. These results, coupled with an excellent tolerability, suggest that Meriva® may 
be beneficial for the long-term complementary management of OA28. 
2 STUDY RATIONALE 
In a previous study, Dr. Allegri’s team has shown that treatment of 128 patients with NorFlo® 
(curcumin-phospholipids (Meriva® 600mg) 2 tablets/day) in combination with conventional 
therapy was capable of reducing the 88% of relapses in patients with recurrent anterior uveitis 
(RAU) (Figure 8).  The enrolled subjects suffered from uveitis of different etiologies. The 
three main different etiological groups of enrolled subjects were herpetic uveitis, 
autoimmune inflammatory ocular disease and various origin anterior uveitis. A few months 
after starting the treatment, a significant improvement in symptoms associated with relapse, 
like the ciliary pain, blurred vision, hyperemia and the presence of aqueous humor cells was 
observed in 42% of the treated patients. Only 8% of the patients worsened and required other 
treatments, such as sub-Tenon space injections. Among the three groups of RAU etiology, 
the patients that were most sensitive to the treatment with NorFlo® belonged to the 
autoimmune RAU etiology (n=56) 26.  
 


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Relapse of uveitis is defined as an occurrence of anterior chamber cells of grade 1+ or higher 
according to the Studies of Uveitis Nomenclature criteria. In cases in which view of the 
anterior chamber is impaired by the loss of corneal clarity, a relapse will be defined as new 
corneal findings of endothelial inflammatory deposits or edema obscuring the anterior 
chamber in the absence of other causes of corneal edema and combined with two or more of 
the following features:  conjunctival hyperemia, photophobia, decreased vision, or pain. 
 
These extraordinary results provide the rationale to further study the effectiveness of 
curcumin-phospholipids in autoimmune HLA-B27-associated uveitis, which represents the 
most common type of uveitis (75% of total uveitis). NORFLO® ORO will provide a 
synergistic anti-inflammatory effect and will counteract the occurrence of cystoid macular 
edema, which is the most serious complications associated with the HLA-B27-associated 
uveitis. We expect that treatment with NORFLO® ORO will reduce recurrence of anterior 
uveitis in patients with HLA-B27-associated uveitis by targeting trigger factors such as 
inflammation, and the side effects related to the pathology (cystoid macular edema, synechia, 
keratophathy) overall improving the quality of life of the treated patients. 
The study will be conducted by inserting a group of control patients and diagnostic 
ophthalmologic analysis, including analysis with the Kowa Laser Flare Meter instrument 
(LFM).  
The role of intraocular inflammation in the disruption of the blood-aqueous barrier leading 
to the spreading of proteins and inflammatory cells into the aqueous humor has been well 
documented. To evaluate and grade this kind of inflammatory leakage (flare) in the anterior 
chamber (AC) of the eye the Standardization of Uveitis Nomenclature (SUN) is generally 
used. Grading, which ranges between 0 and 4+, is unreliable and not useful to detect and give 
a correct measurement of AC inflammation because it relies on the subjectivity of evaluation 
and the nonlinear grading of flare at the slit-lamp, therefore subjected to high variability.  
Currently, the only system that allows to quantitatively, reproducibly and objectively 
measure intra-ocular inflammation is the Kowa Laser Flare Meter (LFM) instrument. Such 
instrument includes a photomultiplier that amplifies the intensity of the light scattered by 
Figure 8 - A) Total number of patients with relapses before (blue) and after (red) Norflo therapy. 
B) Total relapse number before (blue) and after (red) Norflo therapy. 


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small molecules (flare) or larger particles (inflammatory cells) in the aqueous humor. The 
information is then processed by a computer and the result is expressed in photon counts per 
millisecond (ph/ms).  
LFM instruments can quantify back-scattered light both from small molecules and from 
larger particles such as inflammatory cells. 
LFM measurements may be unreliable in eyes with extensive posterior synechiae or mature 
cataract due to increased background scattering of light. Seven measurements are usually 
obtained, the highest and lowest values are discarded and the mean and standard deviation 
of the remaining five readings are automatically calculated. Patients do not experience any 
pain or discomfort during measurements. Aqueous flare intensity has been found in the range 
of 2.9–3.9 ph/ms in healthy individuals between 20 and 40 years of age. Flare values have 
been found to increase slightly with age, reaching 5.0–6.5 ph/ms in subjects between 70 and 
80 years of age. Flare values < 10 ph/ms are considered normal. 
Effective management of uveitis requires a reproducible and quantitative method to 
determine and monitor intraocular inflammation. It has become evident that clinically 
meaningful changes in flare counts could be achieved both in low and high-flare situations 
because LFM allows measuring flares ranging between 3 and 1000 ph/ms on a linear scale. 
Gonzales et al. reported an inverse relationship between LFM flare and visual acuity in 
patients with uveitis. While no relationship was found between complications and anterior 
chamber cell or flare scores at the slit-lamp, a strong relationship was found between LFM 
flare and complications such as posterior synechia and macular edema, highlighting the 
importance of utilized LFM as diagnostic tool. 
 
HLA-B27-Associated Acute Anterior Uveitis 
The inflammatory pattern of acute HLA-B27-associated anterior uveitis has been evaluated 
using LFM. In a study on 44 patients presenting an acute episode of anterior uveitis, the mean 
initial flare was 160 ± 22 ph/ms (range: 11–787 ph/ms). All patients were given standard 
therapy consisting of hourly instillations of 1% prednisolone drops progressively tapered 
after 3 days according to the evolution of inflammation. A 50% and 90% flare reduction 
occurred after 2 and 8 days, respectively, under the standard therapeutic regimen used. In 15 
out of the 44 patients enrolled, an additional periocular corticosteroid injection was needed 
because of insufficient flare decrease (less than 30% of initial flare) or because of flare 
increase after 48 h. Following periocular injection of 4 mg of betamethasone, a 50% flare 
reduction occurred between 10h and 24h. The end of an episode of anterior uveitis was 
defined as a flare level below 8 ph/ms. This study demonstrates that LFM allows meticulous 
adjustment of therapy in patients with HLA-B27-associated uveitis. 
The sensitivity of LFM in monitoring anterior chamber inflammation in HLA-B27-
associated uveitis has been further evaluated in a recent study that compared LFM measured 


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values to slit-lamp grading system of aqueous cells. In this prospective masked trial, the mean 
time for a 50% reduction was 3.9 days for LFM flare and 14 days for aqueous cells. The 
mean time for a 90% reduction was 19.6 days for LFM flare and 40 days for aqueous cells. 
Based on these results, the authors concluded that LFM flare was a more sensitive parameter 
than the slit-lamp grading of cells in assessing evolution of acute anterior uveitis. Currently, 
uveitis specialists who use LFM as diagnostic instrument continue treatment until LFM flare 
returns to normal levels following an episode of HLA-B27-associated acute anterior uveitis 
29-35. 
 
3 STUDY OBJECTIVES 
 Primary Objective 
To explore the efficacy of NORFLO® ORO in RAU, measured as a long-term reduction of 
the frequency and severity of relapses, in patients with HLA-B27-associated uveitis, under 
conditions of routine medical practice. The reduction of the mean number of relapses per 
patient between the year before study treatment and the study period will also be assessed.  
 Secondary Objectives 
The secondary objectives of this study include: 
- 
the evaluation of the improvement of side effects due to HLA-B27-associated uveitis 
such as IOP, cystoid macular edema, keratopathy and synechia; 
- 
the evaluation of the improvement in uveitis-related symptoms (BCVA and symptoms 
measured by VAS like ocular pain, photophobia, floaters and blurred vision). 
- 
the evaluation of cell damage and inflammation reduction in patients with HLA-B27-
associated uveitis; 
- 
the evaluation of  the patients’ attitude towards the study treatment; 
- 
the evaluation of the safety profile of the study product. 
4 
STUDY DESIGN 
 
Study Overview 
This is a multicenter, double blind, placebo-controlled and randomized study.  This study 
will be conducted in compliance with both European and FDA requirements. 
Patients eligible for participation in this study, as part of their routine medical care, will 
receive NORFLO® ORO or placebo in addition of the conventional therapy. In the study, 
patients will be followed up to 1 year. This study will include patients with HLA-B27-
associated relapsing uveitis. Participating sites will be encouraged to enroll patients in both 


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cohorts (NORFLO® ORO or placebo), through an e-based randomization system in order to 
minimize bias in patients’ selection. 
 
Sixty subjects with HLA-B27-associated uveitis will be enrolled and they will be divided 
into 2 groups, 30 will receive the treatment and 30 the placebo, in addition to conventional 
therapy. In Italy 46 patients will be recruited. 
Each subject will receive a single dose of either placebo or NORFLO® ORO two times a day 
for 1 year. Subjects will be assigned to the treatments in a random order.  Evaluations will 
be taken at baseline (t0) and during each of the following two visits within the study (t1 6 
months, t2 12 months). 
Data from screened patients will be reviewed to determine the subject eligibility. Subjects 
who meet all inclusion criteria and none of the exclusion criteria will be enrolled in the study 
and randomized to treatment.  
The following treatment regimens will be applied: 
 NORFLO® ORO – 1.7450 gr  
 Placebo – 1.7450 gr 
Total duration of subject participation will be of about 12 months.  Total duration of the study 
is expected to be about 15 months. 
Table 1 – Dosage Regimen 
 
Dosage regimen/Each 
center  
Administration 
Duration  
NORFLO® ORO 
3.49 gr total (2 single foil 
pouches of 1,7450 g) per 
day 
Each single pouch (1,7450 
g) at main meal in a glass 
of water 
12 months 
PLACEBO 
3.49 gr total (2 single foil 
pouches of 1,7450 mg) per 
day  
Each single pouch (1,7450 
g) at main meal in a glass 
of water 
12 months 
 
5 CRITERIA FOR EVALUATION 
 Primary Efficacy Endpoint 
The primary efficacy endpoint will be the mean number and intensity of relapses per patient 
occurred during the study, from baseline to end of treatment, in patients treated with the 
NORFLO® ORO compared to patients treated with placebo. 
The reduction in relapses will be determined by a reduction of the intraocular inflammation 
through a clinical and diagnostic evaluation that includes Laser measurement of AC flare 


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with Kowa LFM 600 or LFM 700 (Normal range 2.5-7 ph/ms. Outside normal range > 10 
ph/ms). 
The reduction of the mean number of relapses per patient between the year before treatment 
and the study period within each treatment group will also be assessed. 
The reduction of cell damage and inflammation will be measured by the Laser Flare Meter, 
in patients affected by HLA-B27-associated uveitis after treatment with NORFLO® ORO, 
when compared to placebo.  
 Secondary Efficacy Endpoints 
The following secondary endpoints will be examined: 
- 
The reduction of the side effects due to HLA-B27-associated uveitis, such as IOP 
assessed by Goldmann applanation tonometry (APL), cystoid macular edema (central 
foveal thickness – central 1 mm subfield thickness), assessed by optical coherence 
tomography (OCT) Spectralis® spectralis, keratopathy, evaluated by fluorescein staining 
of the cornea (present/absent), and synechiae, assessed by photographic slit lamp 
(present/absent and if present, involving one or more quadrants; photograpsh shall be 
retained to document synechia), after treatment with NORFLO® ORO, when compared 
to placebo. 
- 
The improvement in uveitis-related symptoms (BCVA, symptoms like ocular pain, 
photophobia, floaters and blurred vision, measured by VAS) after treatment with 
NORFLO® ORO, when compared to placebo. 
- The patients’ attitude towards the treatment with NORFLO® ORO, compared to placebo, 
will be captured by means of a questionnaire (Quick Questionnaire) specifically 
developed for the study on the basis of previous experiences4,36-39. 
 
 Safety Evaluations 
The safety evaluations will include: 
- 
The incidence and typology of adverse events in the NORFLO® ORO treatment group 
compared to placebo group. 
- 
The use of concomitant medications. 
- 
The changes in vital signs. 
 
6 SUBJECT SELECTION 
 


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 Study Population 
Subjects with a diagnosis of HLA-B27-associated uveitis who meet the inclusion and 
exclusion criteria will be eligible for participation in this study.   
 Inclusion Criteria 
1. Subjects ≥ 18 years of age at baseline Visit. 
2. HLA-B27 positive related uveitis (acute alternating non granulomatous uveitis the 
uveitis shall not be in acute phase at the time of enrolment and at least 8 weeks must 
have elapsed after the resolution of the last uveitis attack. 
3. Subjects with at least one autoimmune uveitis relapse (UAR) in the last year. 
4. Written informed consent obtained from subject or subject’s legal representative and 
ability for the subject to comply with the requirements of the study. 
 
 Exclusion Criteria 
1. Presence of a condition or abnormality that in the opinion of the investigator would 
compromise the safety of the patient or the quality of the data collected. 
2. Subjects that have received systemic therapy for uveitis with anti-inflammatory, 
immunosuppressive or biological drugs in the 30 days before study start.  
3. Subjects with an anticipated need for systemic anti-inflammatory, immunosuppressive 
or biological drugs during the 12 months of the study. 
4. Subjects who received an intravitreal, peribulbar, sub-tenon, periocular injection in the 
previous 6 months.  
5. Subjects that are receiving long-term treatment with systemic anti-inflammatory, 
immunosuppressive or biological drugs for other diseases different from uveitis. 
6. Women who are taking hormonal contraceptives. 
7. Subjects that have taken supplements and nutraceuticals in the last 30 days prior to 
baseline visit. Use of supplements and nutraceuticals will not be admitted during the 
study. 
8. Subjects for whom baseline LFM and other ocular evaluations cannot be accurately 
performed. 
9. Women who are pregnant or breast-feeding. 
The study will be considered completed once the last clinical site will be closed. Participation 
in this study has no impact on the type of medical care that the patient will receive during the 
study as well as post-study participation. 
 


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7 CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies. 
 Allowed Medications and Treatments 
All topical drugs (any topical midriatic treatment and any traditional topical therapy for 
uveitis) will be admitted for the treatment of the signs and symptoms associated with HLA-
B27-associated chronic relapsing uveitis. 
In the case of relapse with LFM values are > 100 ph/ms despite treatment with topical 
therapy, or in any case the LFM values result to be > 100 ph/ms, then a systemic therapy is 
recommended and the subject has to be dropped-out from the study and treated  according to 
the best medical judgement. 
 
Prohibited Medications and Treatments 
The following medications are prohibited during the study and the administration will be 
considered a protocol violation: supplements and nutraceuticals, systemic therapies for 
uveitis (anti-inflammatory, immunosuppressive, biologicals), hormonal contraceptives, 
long-term treatment with systemic anti-inflammatory, immunosuppressive or biological 
drugs for other diseases different from uveitis. Systemic therapies with anti-inflammatory, 
immunosuppressive drugs are allowed for reasons different from uveitis and in any case for 
periods not exceeding 15-30 days. 
 
8 ENROLLMENT, TREATMENT ASSIGNMENT AND BLINDING 
 
 Method of Assigning Subjects to Treatment Groups 
Up to 60 eligible patients will be randomly assigned to NORFLO® ORO or placebo 
treatment groups in a 1:1 ratio using a stratified randomization blocks scheme. The 
patient randomization list will be generated by Latis S.r.l., using the procedure PROC PLAN 
of SAS 9.4 for Windows (SAS Institute Inc., Cary, NC, USA).  
 
 Blinding 
Due to the objectives of the study, the investigators, research staff, or patients will not know 
the treatment identity (test or control).  The following study procedures will be in place to 
ensure double-blind administration of study treatments:   
 Access to the randomization code will be strictly controlled.   


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Packaging and labeling of test and control treatments will be identical to maintain the blind.  
The study blind will be broken on completion of the clinical study and after the study 
database has been locked.  
During the study, the blind may be broken only in emergencies when knowledge of the 
patient’s treatment group is necessary for further patient management.  
The Principal investigator will receive a study treatment identification key in the form of 
sealed envelopes containing the kit number and the corresponding treatment. 
The envelope can be opened only in case of an emergency presenting the need to disclose 
the identification of the study treatment assigned to the patient, for the purpose of establishing 
the appropriate therapy. Once the code is broken for a patient, this patient shall be withdrawn 
from the study, with the completion of the final study evaluation, indicating the specific 
reason of the patient withdrawal. 
The Study Monitor must be notified immediately by the investigator of any emergency 
unblinding; the date and time, along with the reason for the unblinding, will be noted. 
Treatment codes will not be freely available to the investigator or personnel monitoring the 
study until after the study completion and database lock.  
 
 
Formulation of Test and Control Products 
 Formulation of Test Product 
NORFLO® ORO is a new formulation of Eye Pharma S.p.A., for oral administration. 
NORFLO® ORO is a yellow-colored solution that requires no reconstitution. See Table 2 for 
the formulation of NORFLO® ORO. 
 
Table 2 - Formulation and Measured pH of NORFLO® ORO and Placebo  
 
NORFLO® ORO                       g/ST 
Placebo                                   g/Kg 
Active Ingredient, 
mg/mL 
Turmeric lecithin                       0.500 g 
Turmeric - phosphatidylserine  0.100 g 
 
Other ingredient, 
mg/mL 
Erythritol                                0.2891 g 
Erythritol                          165.67 g  
 
Silicon Dioxide                      0.0175 g  
Silicon Dioxide                    4.53 g 
 
Polysorbate 20 (Tween 20)    0.0174 g 
Polysorbate 20 (Tween 20)  9.99 g 
 
Isomalt                                    0.192  g 
Isomalt                              533.30 g 


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Guar Gum                                0.300 g 
Guar Gum                         171.92 g 
 
Orange flavor                           0.100 g 
Orange flavor                      57.31 g 
 
Stevia                                       0.050 g 
Stevia                                    8.60 g 
 
Lemon flavor                           0.100 g 
Lemon flavor                      28.65 g 
 
Citric acid                                0.008 g 
Citric acid                             4.58 g 
 
Sucro ester E473                     0.006 g 
Sucro ester E473                0.006 g 
 
 
Sunset yellow  (E110)             12 g 
 
 Formulation of Control Product 
A placebo will be provided by Eye Pharma in a pack containing 30 single foil pouches ready 
for administration. The placebo composition is reported in Table 2. 
 Packaging and Labeling 
Packaging: study product and placebo will be supplied in cartons containing 30 single foil 
pouches that are enough for a month-long treatment. 
The study products will be delivered to the subjects based on the interval period between 
visits as indicated below: 
Visit 1 (baseline, t0)): each patient receives 13 kits containing 30 single foil pouches 
Visit 2 (t1, 6 months): each patient receives 18 kits containing 30 single foil pouches. 
Labeling: Each carton (kit) of study products will be labeled with the protocol number, a 
treatment number, production lot, expiration date, the name of the sponsor, and directions 
for patient use and storage.   
 
Supply of Study Products at the Site 
Eye Pharma (or designee) will ship the Study Products to the investigational sites after sites 
activation (i.e. all required regulatory documentation has been received by Eye Pharma and 
a contract has been executed). 
 Dosage/Dosage Regimen 
Study products will be administered as follows. 
Two single foil pouches per day, each with main meals, with an estimated interval of about 
8 hours between doses. A minimum interval of 4 hours between doses should be maintained. 
The treatment will last for a period of 12 months. 


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Table 3 - Dosage Regimen  
 
Dosage regimen/ 
Each center  
Administration 
Minimum 
interval 
between doses 
Duration  
NORFLO® 
ORO 
3.49 gr (2 single foil 
pouches of 1.7450 g) 
per day 
Each 
single 
pouch (1.7450 g) 
at main meal in a 
glass of water 
4 hr  
12 months 
PLACEBO 
3.49 gr (2 single foil 
pouches of 1.7450 g) 
per day  
Each 
single 
pouch (1.7450 g) 
at main meal in a 
glass of water 
4 hr 
12 months 
 
 Dispensing 
Investigator (or designee) delivers the study product to the patient at each visit. 
 Supply of Study Product at the Site 
 Storage 
Study products should be stored by the study site at controlled room temperature, 15 to 30ºC 
(59 to 86ºF). If the temperature of the study drug storage in the clinic/pharmacy exceeds or 
falls below this range, this should be reported to Eye Pharma (or designee) and captured as a 
deviation. Subjects will be instructed to store the medication in original packaging (foil pouch 
and protected from light) at room temperature.  
 Study Product Accountability 
An accurate and current accounting of the dispensing and return of study product for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study product foil pouches dispensed and returned by the subject will be recorded 
on the appropriate form. The study monitor will verify these documents throughout the 
course of the study. 
 Measures of Treatment Compliance 
Subjects will be asked to keep a patient diary noting the day and date they take the study 
product and any adverse events they experience. Subjects will be asked to bring their patient 
diary to each study visit along with all used and unused study product containers.  


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Due to non-compliance with study procedures, the investigator can withdraw subjects from 
study participation. The investigator will communicate promptly to Eye Pharma the patient 
withdrawal from the study.  
 
9 STUDY PROCEDURES AND GUIDELINES 
 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in APPENDIX 1. Data sheets on diagnostic 
ophthalmologic exams to be carried out during the study are shown in APPENDIX 2. 
Prior to conducting any study-related activities, written informed consent must be signed and 
dated by the subject or subject’s legal representative.   
 Clinical Assessments  
  Demographics  
Patient demographic and baseline characteristic data to be collected on all patients includes: 
date and place of birth, place of living, sex, race, and ethnicity (where legally possible), work 
typology.  
 Concomitant Medications 
All concomitant medications will be registered at baseline visit and their changes, if any, will 
be documented at each following visit. Dose, route, unit frequency of administration, and 
indication for administration and dates of medication will be captured. 
 Medical History 
Relevant medical history, including history of current disease and information regarding 
underlying diseases, with special attention to ocular diseases and uveitis, will be recorded at 
baseline visit (t0). 
 Physical Examination 
A physical examination will be performed by the investigator at baseline visit (t0). Qualified 
staff may complete the abbreviated physical exam at all other visits. New abnormal physical 
exam findings during the study must be documented as adverse event and will be followed 
by a physician or other qualified staff at the next scheduled visit. 
A rheumatologic evaluation will be done at screening in order to assess if the whether the 
disease also has a systemic involvement (ankylosing spondylitis) or not.  


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 Urine dipstick specific pregnancy test 
Urine dipstick specific pregnancy test will be performed at the site at baseline and at each 
following visit. The study products cannot be administered if the pregnancy test results 
positive or doubtful. 
  Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation to 
study product will be recorded on the case report form (CRF).  
  Vital Signs 
Systolic and diastolic blood pressure and heart rate will be measured at baseline and at each 
following visit. 
 Ophthalmological exams guide 
Both eyes will be evaluated at each visit. 
 BCVA 
One goal of a complete eye examination is to determine the best corrected visual acuity 
(BCVA).  Normal visual acuity is generally accepted as 20/20, although many people can 
see 20/15, and a few can see 20/10. If the eye cannot see 20/20 with a glasses or contact lens 
correction, then a refraction is required to determine the BCVA.   
The visual acuity testing protocols recommended are: 
• Distance acuity with correction (CC) if the patient needs glasses or contact lenses for the 
best distance vision.  The exception is visual acuity testing after cataract or refractive surgery, 
as these procedures will likely change the refractive status of the eye. 
• Distance acuity without correction (SC) if the patient wears no glasses or contact lenses 
(default test). 
BCVA will be measured at baseline and at each following visit.  
 
 Laser Flare Photometry   
 Anterior Chamber Flare Assessment and Measurement Kowa LFM 600 and 700 
The role of intra-ocular inflammation in driving disruption of blood-aqueous barrier and 
leading to the spreading of proteins and inflammatory cells into the aqueous humor has been 
previously established. The Standardization of Uveitis Nomenclature (SUV) system to 
evaluate and grade this kind of inflammatory leakage (flare) in the anterior chamber (AC) 
of the eye, ranging from 0 to 4+, is not useful or unreliable to detect and quantify AC 


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inflammation because the SUV test depends on the subjectivity of the evaluation and on the 
nonlinear grading of flare at the slit-lamp.  
Currently, the only available system to quantitatively and objectively measure (with 
reproducibility) intra-ocular inflammation is the Kowa Laser Flare Meter (LFM) instrument. 
Such instrument includes a photomultiplier that amplifies the intensity of the light scattered 
by small molecules (flare) or larger particles (inflammatory cells) in the aqueous humor. The 
information is then processed by a computer and the result is expressed in photon counts per 
millisecond (ph/ms). 
LFM instruments quantify back-scattered light both from small molecules and from larger 
particles such as inflammatory cells. Therefore, LFM measurements may be unreliable in 
eyes with extensive posterior synechiae or mature cataract due to increased background 
scattering of light. Seven measurements shall be obtained with LFM. The highest and the 
lowest LFM values are discarded and the mean and standard deviation of the remaining five 
LFM readings are automatically calculated. Patients do not experience any pain or discomfort 
during measurements. Aqueous flare intensity in the range of 2.9–3.9 ph/ms corresponds to 
healthy individuals between 20 and 40 years of age and they increase slightly with age, 
reaching 5.0–6.5 ph/ms for patients between 70 and 80 years of age.  
Effective management of uveitis requires a reproducible and quantitative method to 
determine and monitor intraocular inflammation. Clinically meaningful changes in flare 
counts can be detected both in low and high-flare values because LFM allows measuring 
flare values that range between 3 and 1000 ph/ms on a linear scale. Gonzales et al. reported 
an inverse relationship between LFM flare and visual acuity in patients with uveitis. While 
no relationship was found between complications and anterior chamber cell or flare scores 
at the slit-lamp, a strong relationship was found between LFM flare and complications such 
as posterior synechia and macular edema.Intra-ocular inflammation evaluation by the Kowa 
Laser Flare Meter examination will be done at baseline and at each following visit. 
 OCT  
Optical coherence tomography (OCT) Spectralis® (Heidelberg Egineering, Heidelberg 
Germany) is a non-invasive imaging test that uses light waves to take cross-section pictures 
of your retina, the light-sensitive tissue lining the back of the eye. 
Cross-sectional visualization is an extremely powerful tool in the identification and 
assessment of retina abnormalities. The high resolving power (10µm - Time Domain, 5µm 
– Spectral Domain) provides excellent detail for evaluating the vitreo-retinal interface, 
neurosensory retinal morphology, and the RPE-choroid complex. The ability to perform 
volumetric and retinal thickness analysis also provides a quantitative and repeatable method 
to evaluate surgical and pharmacological interventions. Individual high resolution line scans 
are a simple way to identify overt as well as very subtle retinal interface pathologies, such 
as a persistently adherent posterior hyaloid, fine epiretinal membranes, and vitreomacular 


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traction. In a procedure that is easily tolerated by most patients, well-placed line scans can 
differentiate between pseudo holes, lamellar holes and full thickness macular holes with a 
high degree of confidence. Line scans can also confirm the presence of retinal edema from 
various causes. When combined with serial thickness map or volume analysis, these different 
data sets provide a detailed picture of disease progression or therapeutic response. 
OCT Spectralis® examination will be done at baseline and at each following visit. 
 Slit lamp 
Slit-lamp biomicrography encompasses a wide spectrum of challenging photographic 
techniques for imaging structures and diseases of the anterior segment. Most photographic 
slit-lamps are equipped with two lighting sources, variable flash intensity, changeable 
magnifications, and changeable angles of illumination. Patients present a wide variety of 
disease entities that have specific textures, colors, transparency, size and depth. The slit lamp 
is a binocular microscope that provides the examiner with a stereoscopic (i.e. three-
dimensional) view of the eye. The slit lamp allows examining the eye with a beam or "slit" 
of light (versus diffuse light) whose height and width can be adjusted. The slit of light, when 
directed at an angle, accentuates the anatomic structures of the eye, allowing close inspection. 
The slit lamp provides greater magnification (10 to 25 times) and illumination than most 
handheld devices (i.e. the Wood's lamp), which is necessary to diagnose a number of 
traumatic and non-traumatic disorders. 
Slit lamp examination will be done at baseline and at each following visit. 
 Goldmann tonometry 
Tonometry is the procedure to determine the intraocular pressure (IOP), the fluid pressure 
inside the eye. IOP is an important test in the evaluation of patients at risk from glaucoma. 
[1] Most tonometers are calibrated to measure pressure in millimeters of mercury (mmHg). 
Goldmann tonometry is considered to be the gold standard and most widely accepted method 
IOP test. A special disinfected prism is mounted on the tonometer head and then placed 
against the cornea. The examiner then uses a cobalt blue filter to view two green semi circles. 
The force applied to the tonometer head is then adjusted using a dial connected to a variable 
tension spring until the inner edges of the green semicircles in the viewfinder meet. When an 
area of 3.06 mm (0.120 in) has been flattened, the opposing forces of corneal rigidity and the 
tear film are roughly approximate and cancel each other out allowing the pressure in the eye 
to be determined from the force applied.  
Intraocular pressure will be evaluated at baseline and at each following visit.  
 


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10 EVALUATIONS BY VISIT 
 Visit 1 (t0) 
1. 
Review the study with the subject (subject’s legal representative) and obtain written 
informed consent  
2. 
Assign a unique screening number to the subject 
3. 
Record subject’s demographics data 
4. 
Record subject’s medical history, including a history of uveitis, diagnosis date and 
prior uveitis treatments and the number of relapses during the previous year 
5. 
Record subject’s concomitant medications 
6. 
Perform a physical examination of the subject 
7. 
Vital signs collection 
8. 
• Urine dipstick specific pregnancy test 
9. 
Perform a rheumatologic evaluation of the subject 
10. 
Perform subject’s ophthalmic evaluation (BCVA, Slip lamp, OCT Spectralis®, LFM, 
Goldman tonometry). 
11. 
Evaluation of uveitis symptoms by VAS (ocular pain, blurry vision, floaters, 
photophobia) 
12. 
Evaluation of the patient's attitude towards the study treatment, through the Quick 
Questionnaire 
13. 
Evaluate inclusion/exclusion criteria adherence 
14. 
Randomize subject and dispense study product  
15. 
Initiate subject diary. 
 
After about 3 months of treatment the study staff will contact the patient by phone to verify 
that the study product is correctly taken. 
 
Visit 2 (t1, 6 Months ± 10 days) 
1. 
Perform subject’s ophthalmic evaluation (BCVA, Slip lamp, OCT Spectralis®,  LFM, 
Goldman tonometry) 
2. 
Evaluation of uveitis symptoms by VAS (ocular pain, blurry vision, floaters, 
photophobia) 
3. 
Perform a physical examination of the subject 
4. 
Vital signs collection 
5. 
Urine dipstick specific pregnancy test 


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6. 
Record any Adverse Event   
7. 
Review subject’s diary for Adverse Events and for dosing compliance 
8. 
Study product collection and accountability 
9. 
New diary and study product delivery 
10. 
Concomitant medications review 
11. 
Evaluation of the patient's attitude towards the study treatment, through the Quick 
Questionnaire 
 
Visit 3 – End of Study (t2, 12 Months ± 10 days) 
1. 
Perform subject’s ophthalmic evaluation (BCVA, Slip lamp, OCT Spectralis®, LFM, 
Goldman tonometry) 
2. 
Evaluation of uveitis symptoms by VAS (ocular pain, blurry vision, floaters, 
photophobia) 
 
3. 
Perform a physical examination of the subject 
4. 
Vital signs collection 
5. 
Urine dipstick specific pregnancy test 
6. 
Record any Adverse Event   
7. 
Review subject’s diary for Adverse Events and for dosing compliance 
8. 
Study product collection and accountability 
9. 
Concomitant medications review 
10. 
Evaluation of the patient's attitude towards the study treatment, through the Quick 
Questionnaire 
 Additional Unscheduled Visits in Case of Relapse 
Should a relapse occur, an unscheduled visit will be performed including a complete 
ophthalmic evaluation.  The number of cells in the AC will be determined by slit lamp, too. 
Topical or systemic treatment will be prescribed to the subject according to the severity of 
the relapse and according to the best medical judgement. 
Two following visits will be scheduled 2 and 6 weeks thereafter. During these visits a 
complete ophthalmic evaluation will be done. 
If the subject is prescribed a systemic treatment for the relapse, he/she will be withdrawn 
from the study, and treated according to the best medical judgement.  


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If only topical treatments are prescribed, the subject will be allowed to continue the study. 
Depending on the onset time of the relapse it could be necessary to delay Visit 2 or Visit 3 
around 2 months after the topical treatment conclusion.  
Should Visit 2 be delayed, the delay will be recovered by keeping the date of Visit 3 at 12 
months.  
Should Visit 3 be delayed, the delay will not be recovered.  
 
 Early Withdrawal Visit 
In the case of early withdrawal from the study, activities planned at Visit 3 will be performed, 
as far as possible.  
11 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
 Early Discontinuation of Study Drug  
A subject may be discontinued from the study treatment at any time if either the subject, 
and/or the investigator, and/or Eye Pharma feels that it is not in the subject’s best interest to 
continue the study treatment. The following is a list of possible reasons for study treatment 
discontinuation:  
 
Subject withdrawal of consent  
 
Subject is not compliant with study procedures 
 
Need for the subject to start a systemic anti-inflammatory, immunosuppressive, 
biologicals therapy for uveitis or for other pathologies 
 
Adverse event that indicated in the opinion of the investigator that it would be in the best 
interest of the subject to discontinue study treatment 
 
Pregnancy 
 
Protocol violation requiring discontinuation of study treatment 
 
Missed follow-up 
 
Eye Pharma requests early study termination 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed 
and treated by the investigator until the abnormal parameter or symptom has resolved or 
stabilized.   
All subjects who discontinue the study treatment should come in for an early discontinuation 
visit as soon as possible and then they should be encouraged to complete all remaining 
scheduled visits and procedures. 


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All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to obtain a reason for subject’s 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents. 
 Replacement of Subjects 
Only subjects dropping out the study because they are beginning systemic therapy with anti-
inflammatory, immunosuppressive, biologic drugs will be replaced.  
 
12 PROTOCOL VIOLATIONS 
A protocol violation occurs when either the subject, and/or the investigator, and/or Eye 
Pharma fails to adhere to significant protocol requirements affecting the inclusion, exclusion, 
subject safety and primary endpoint criteria.  Protocol violations for this study include, but 
are not limited to, the following: 
 Failure to meet inclusion/exclusion criteria 
 Compliance with study product regimen under 90%. 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. Eye Pharma will determine if a protocol violation will result in withdrawal of a 
subject. 
When a protocol violation occurs, it will be immediately reported by written (via e-mail) to 
and discussed with the Sponsor. The Sponsor’s evaluation results and, request of corrective 
actions will be reported to the investigator by written (via e-mail).  
 
13 ADVERSE EVENTS REPORTING AND DOCUMENTATION 
 Overview 
An Adverse Event (AE) is “Any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including for example an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product”. 
This definition includes intercurrent illnesses or injuries, exacerbation of pre-existing 
conditions, and adverse events occurring as a result of drug withdrawal, abuse, misuse or 


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overdose. Adverse events observed during all periods of the study are to be recorded, 
including adverse events occurring during a period without study product intake. This also 
includes adverse events which are reported within in the screening phase (since the patient 
has signed Informed Consent Form).  
Signs and symptoms considered as lack of efficacy and occurring during the study will not 
be recorded on the AEs Section of the CRF except on the condition that, in the investigator’s 
opinion, they are caused by any reason different from lack of efficacy of study product or 
meet the definition of serious AE. 
Clinically significant findings at screening (e.g., laboratory findings) are not considered an 
AE/SAE. 
If a clinical significant finding recorded at screening worsens (in terms of severity or 
frequency) during the study, it must be recorded as an AE/SAE. 
 
Unexpected Adverse Event 
An Unexpected Adverse Event is any experience not previously reported (in nature, severity 
or incidence) in the current package insert for the study product. 
 
 AE Severity 
The international common terminology criteria for Adverse Events should be used to assess 
and grade AE severity, including laboratory abnormalities judged to be clinically significant. 
It should be pointed out that the term “severe” is a measure of intensity and that a severe AE 
is not necessarily serious. 
Table 4 - AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the 
sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 


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   Abnormal test findings 
An abnormal test finding will be classified as an adverse effect if one or more of the following 
criteria are met: 
 The test finding is accompanied by clinical symptoms 
 The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug or other therapy (Note: 
simply repeating a test finding, in the absence of any of the other listed criteria, does not 
constitute an adverse effect.) 
 The test finding leads to a change in study dosing or exposure or discontinuation of 
subject participation in the clinical study 
 The test finding is considered an adverse effect by the investigator and /or Eye Pharma
 
 
   Events to be reported 
   All adverse Events  
All observed adverse events (serious or non-serious) and abnormal test findings, regardless 
of the treatment group, or any suspected causal relationship of adverse event to the 
investigational products will be recorded in the subjects’ case histories.  For all adverse 
events, sufficient information will be pursued and/or obtained so as to permit (1) an adequate 
determination of the outcome of the event (i.e., whether the event should be classified as a 
serious adverse event) and (2) an assessment of the casual relationship between the adverse 
event and the investigational treatment . Adverse events or abnormal test findings suspected 
to be associated with the investigational product will be followed until the event (or its 
sequelae) or the abnormal test finding resolves or stabilizes at a level acceptable to the 
sponsor-investigator. 
 Adverse Events requiring immediate Notification  
 
Serious Adverse Events (SAE) 
A serious adverse event (SAE) is any event that suggests a significant hazard, 
contraindication, side effect, or precaution, whether or not it is considered to be associated 
with the study product. A SAE is an AE that meets any of the following criteria: 
 
 
Results in death. This includes any death that occurs during the conduct of a clinical 
trial, including deaths that appear to be completely unrelated to the study products (e.g., 
car accident). 


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 
Is life-threatening. This includes any AE during which the patient is, in the view of 
the investigator, at immediate risk of death from the event as it occurs. This definition 
does not include events that may have caused death if they had occurred in a more 
severe form. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
 
Results in persistent or significant disability or incapacity. 
 
Is a congenital anomaly or birth defect. 
 
Other medical events that based upon appropriate medical judgment are thought to 
jeopardize the patient and/or require medical or surgical intervention to prevent one of 
the outcomes defining a SAE. 
 
Planned hospitalizations scheduled prior to the informed consent but performed during the 
study should not be considered (serious) AEs.  
 
Serious Adverse Event Reporting 
Study sites will document all SAEs that occur (whether or not related to the study product).  
The collection period for all SAEs will begin after the informed consent is obtained and will 
finish 2 weeks after the patient has withdrawn study participation (defined as time passed 
from the last visit). All SAE occurred in that time range must be reported to Eye Pharma 
within 24 hours of learning about its occurrence: 
Contact person for USA:  
Alice Tomei – Eye Pharma US 
Phone: 001 3052433469 
e-mail: alice.tomei@eyepharma.com 
 
Contact person for Italy:  
Lucia Degrassi – Eye Pharma S.p.A. 
Phone: +39 010 513188 
Fax: +39 010 3071430 
e-mail: lucia.degrassi@eyepharma.com 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   
The sponsor will be responsible for reporting to Competent Authorities, according to local 
laws and regulations. 


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 Investigator Responsibilities 
The Eye Pharma-investigator will promptly review documented adverse events and abnormal 
test findings to determine (1) if the abnormal test finding should be classified as an adverse 
event; (2) if there is a reasonable possibility that the adverse event was caused by the 
investigational product and (3) if the adverse event meets the criteria for a serious adverse 
event. 
If the Eye Pharma-investigator’s final determination of causality is “unknown and of 
questionable relationship to the investigational product” the adverse event will be classified 
as associated with the use of the investigational product, for reporting purposes.   
 
 Evaluation of Causality  
AE Relationship to Study Product 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 5. 
Table 5 - AE Relationship to Study Product 
Relationship 
to Product 
Comment 
Definitely 
Previously known toxicity of the agent; or an event that follows a reasonable 
temporal sequence from administration of the product; that follows a known or 
expected response pattern to the suspected product; that is confirmed by 
stopping or reducing the dosage of the product; and that is not explained by any 
other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of 
the product; that follows a known or expected response pattern to the suspected 
product; that is confirmed by stopping or reducing the dosage of the product; 
and that is unlikely to be explained by the known characteristics of the subject’s 
clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of 
the product; that follows a known or expected response pattern to that suspected 
product; but that could readily have been produced by a number of other 
factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the 
study product. 
 
14 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
issued, describing all analyses that will be performed.  The SAP will contain any 


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modifications to the analysis plan described below.  SAS 9.4 for windows (SAS Institute 
Inc., Cary, NC, USA) will be used for statistical analysis. A level of statistical significance 
(alpha) of 5% will be used to evaluate statistically significant differences between the two 
treatment groups, placebo and active treatment. 
 Data Sets Analyzed 
All eligible patients who are randomized into the study and receive at least one dose of the 
study product (the Safety Population) will be included in the safety analysis. All eligible 
patients who are randomized into the study, receive at least one dose of the study product 
and have at least a post-randomization endpoint estimate (the Intention-to-Treat Population) 
will be included in the efficacy analysis. 
 Demographic and Baseline Characteristics 
The following demographic variables collected at screening will be summarized by treatment 
group: race, gender, age, height and weight.   
 Analysis of Primary Endpoint 
The number and intensity of relapses will be assessed through instrumental analysis and 
physical examination. These endpoints will be assessed from baseline to end of treatment.  
Mean and standard deviation will be used to describe the number of relapses per patient. The 
mean number of relapses per patient will be compared between the treatment groups using 
Student’s t-test. ANOVA will be used to include predictive/confounding variables in the 
model.  
In addition, a generalized linear mixed model (GLMM) with Poisson statistical distribution 
and with the number of relapses as dependent variable will be used to assess the effects of 
the treatment on reducing the number of relapses, also including in the model other 
potentially predicting/confounding variables.  
The intensity of relapses will be scored as mild (either trace to 1+ cell OR flare ≤ 20), 
moderate (2+ to 3+ cell OR Flare > 20 and < 100) and severe (4+ cell OR Hypopyon OR 
flare ≥ 100). For each patient, the average intensity will be estimated as the mean of the 
intensity observed during each relapse. The average and the maximum intensity will be 
compared between treatment groups using Student’s t-test. ANOVA will be used to include 
predictive/confounding variables in the model. 
The mean number of relapses per patient observed during the study will be compared to the 
mean number of relapses reported the previous year within each treatment group using paired 
t-test or ANOVA, to eventually adjust for predictive/confounding variables. As group means 
can be somewhat deceptive with small number of events, the patients will be classified based 
on the number of relapses before treatment and then on the number of relapses after 
treatment. The number of patients that change class before and after treatment (for example, 
from a high number of relapses to a low number) will be described and compared between 
treatment groups.  


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The primary efficacy endpoints will be analyzed in the following hierarchical order: first, 
“the mean number and intensity of relapses during the study between treatment groups” and 
then “the reduction of mean number of relapses between the year before treatment and the 
study period”. 
The level of cell damage and inflammation will be assessed through Laser Flare Meter.  The 
difference between treatment groups will be compared using ANCOVA, with the baseline 
level included in the model.  
An analysis of the number of relapses per eye will be also considered, if appropriate.   
 
Analysis of Secondary Endpoints 
The incidence of side effects associated HLA-B27-associated uveitis, such as cystoid 
macular edema (central 1 mm subfield thickness), keratopathy and synechia, will be 
compared between treatment groups using logistic regression. In addition, the changes in 
IOP, in central 1 mm subfield thickness will be compared between treatment groups using 
ANCOVA, with the baseline level included in the model. The presence of keratopathy and 
synechiae will be compared between treatment groups using logistic regression. The number 
of quadrants involved by synechiae, when present, will be described.   
The changes in BCVA and symptoms (ocular pain, blurred vision, floaters and photophobia), 
measured by VAS, will be compared between treatment groups using ANCOVA, with the 
baseline level included in the model.  
Each information collected through the Quick questionnaire will be compared between the 
two treatment groups using chi-square test.  
 
 Safety Evaluations 
Safety and tolerability data will be summarized by treatment group.   
Clinical evaluations for safety and tolerability assessments will include monitoring AEs, vital 
signs, concomitant medications and compliance. 
Adverse event will be coded using the last updated version of the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary to give a preferred term (PT) and a system/organ 
class term (SOC) for each. Adverse events will be tabulated by treatment group. Tables will 
include the number of patients who experienced at least one AE, of study product-related 
AEs (defined as definitely, probably, possibly, or unrelated), of serious AEs, and the number 
of patients withdrawn due to AE, summarized by treatment arm. Comparisons between 
treatment arms will be performed using chi-square test. 
Concomitant medications will be summarized by treatment using descriptive statistics and 
they will be listed. 


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Vital signs will be summarized by treatment using descriptive statistics for absolute values 
and change from baseline. 
Compliance to the study treatment will be assessed through the patient diary and checked 
versus the used and unused study product containers given back by the patients.  
 Interim Analysis 
No interim analysis planned. 
 Sample Size  
In a previous study25, 275 relapses on 106 patients were observed, corresponding to a mean 
number of relapses per patient of 2.6 (Standard deviation, SD: 0.7) while in the post-
treatment group 36 relapses were registered corresponding to a mean number of relapses per 
patient of 0.34 relapses/patient. With a statistical power of 80% and a significance level 
(alpha) of 5% and a common SD of 0.7, 46 patients are needed to observe a difference of 0.6 
relapses/patients between the two treatment groups (i.e., 2 relapses/patient in the NORFLO® 
ORO treatment group vs. 2.6 in the placebo treatment group). To take into account a potential 
dropout rate of 20% over 12 months, 60 patients will be recruited. Subjects dropping out the 
study 
because 
they 
are 
beginning 
systemic 
therapy 
with 
anti-inflammatory, 
immunosuppressive, biologic drugs will be replaced. 
A second primary endpoint, i.e. the reduction of mean number of relapses between the year 
before treatment and the study period, will be examined. No formal sample size estimate is 
feasible on this endpoint, as it was not tested previously and no reasonable scenario can be 
drawn.  
As the two endpoints will be assessed in a hierarchical order (first, “the mean number and 
intensity of relapses during the study between treatment groups” and then “the reduction of 
mean number of relapses between the year before treatment and the study period”), according 
to the “Points to consider on multiplicity issues in clinical trials”, issued by the Committee 
for Proprietary Medicinal Products (CPMP - 2002), no sample size adjustment for 
multiplicity is needed.   
 
 
15  DATA COLLECTION, RETENTION AND MONITORING 
 Data Collection Instruments 
During each patient’s study visit, the study investigator or designee will collect and report 
study data in the relevant patient’s chart (source documents), documenting all significant 
observations. 
The investigator will prepare and maintain adequate and accurate source documents designed 
to record all observations and other pertinent data for each subject treated with the study 
drug.   


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Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific electronic Case Report Form (eCRF) when the 
information corresponding to that visit is available.   
Source Data include the clinical findings and observations, the laboratory and test data, and 
other information contained in Source Documents.  Source Documents are the original 
records (and certified copies of original records); including, but not limited to, hospital 
medical records, physician or office charts, physician or nursing notes, subject diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, x-rays, etc.  When applicable, information recorded on the CRF shall match the 
Source Data recorded on the Source Documents.   
Subjects will not be identified by name in the study database or in any study documents to 
be collected by Eye Pharma (or designee), but will be identified by a site number and subject 
number. 
The e-CRF used for this study will compliant with 21 CFR part 11 requirements. 
The investigator will maintain a list of all persons authorized to make entries and/or 
corrections on the CRFs. Each authorized person will be provided with a user-specific ID 
protected by a renewable password. Data entries and corrections will be made only by the 
authorized persons. The e-CRF system will record date and time of any entry and /or 
correction and the user ID of the person making the entry/correction. The system will keep 
track of all old and new values (audit trial). It is the responsibility of the investigator to ensure 
that the CRFs are properly and completely filled in. The CRFs must be completed for all 
patients who have been included in the trial. The investigator will review all CRFs and 
electronically sign and date them for each patient, verifying that the information is complete, 
true and correct. All fields on the CRF must be completed as applicable. 
Patients will be provided with paper questionnaires and diaries. Such documents will be filled 
by the patient during the study, to record data concerning symptoms, evaluation of the 
patient's attitude towards the study treatment, through the Quick Questionnaire, study 
treatment assumption.  
It is responsibility of the investigators to instruct the study participants on how to fill in the 
questionnaires and diaries in a clear way and preferably in black ball-point pen. The 
questionnaires and diaries are anonymous, the subject is identified through the study code 
assigned. At the end of the study a copy of all questionnaires and diaries will be stored in the 
Trial Center File. It is responsibility of the investigators to correctly enter the data collected 
on the questionnaires and diaries in the relevant sections of the e-CRF. The questionnaires 
and diaries will be considered source data. 
Checks to assist during the data entry and to assess the appropriateness and consistence of 
data will be developed on the e-CRF system. After e-CRF pages will be approved and 
electronically signed by the investigator, they can be reviewed both on site by the monitor 


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and remotely, by the data management staff of the sponsor or its designee. Data Clarification 
Forms (DCF) will be generated through the e-CRF system, both automatically, through edit 
checks, and manually, by CRAs and/or data managers, and the investigator will have to check 
and close them. Occasionally, paper DCF can be sent to trial sites for resolution. The 
investigator is responsible for the review and approval of all query resolutions. 
 
 Availability and Retention of Investigational Records 
The investigator must make study data accessible to the monitor, other authorized 
representatives of Eye Pharma, IRB/IEC, and Regulatory Agency inspectors upon request.  
The investigator must ensure the reliability and availability of source documents from which 
the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of minimum 5 years following 
marketing of the investigational product or for two years after centers have been notified that 
the IND has been discontinued.  There may be other circumstances for which Eye Pharma is 
required to maintain study records and, therefore, the Eye Pharma should be contacted prior 
to removing study records for any reason. 
The physician must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, and the results of any other tests or assessments. 
All information entered in the CRF must be traceable to these source documents in the 
patient’s file. The physician must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). The physician must give Eye Pharma (or 
designee) access to all relevant source documents to confirm their consistency with the CRF 
entries. 
 Monitoring 
Depending on country regulations, formal site monitoring may or may not be performed in 
this study. However, Eye Pharma (or designee) may perform informal monitoring or auditing 
occasionally and may request additional information on patients from participating 
physicians. The Eye Pharma data management or designated CRO will assure compliance 
monitoring. Monitoring activity will include reviews of the progress of the study and 
compliance with protocol, SOPs and GPP guidelines. 
 Record maintenance and retention  
The sponsor-investigator will maintain records to include: 
o IEC/IRB correspondence (including approval notifications) related to the clinical 
protocol; including copies of adverse event reports and annual or interim reports 


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o Current and past versions of the IEC/IRB-approved clinical protocol and corresponding 
IEC/IRB-approved consent form(s) and, if applicable, subject recruitment advertisements 
o Curriculum vitae (sponsor-investigator and clinical protocol sub-investigators) 
o Certificates of required training (e.g., human subject protections, Good Clinical Practice, 
etc.) for sponsor-investigator and listed sub-investigators 
o Normal value(s)/range(s) for medical/laboratory/technical procedures or tests included in 
the clinical protocol 
o Diagnostic Ophthalmic exams 
o Laboratory certification information, if applicable  
o Master randomization list  
o Signed informed consent forms (only the investigator) 
o Completed Case Report Forms, signed and dated by the investigator 
o Source Documents or certified copies of Source Documents (only the investigator) 
o Monitoring visit reports 
o Subject identification code list 
o Interim data analysis report(s), if applicable 
o Final clinical study report. 
 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number and subject number will 
identify all study subjects on the e-CRFs and other documentation submitted to the sponsor. 
Additional subject confidentiality issues (if applicable) are covered in the Clinical Study 
Agreement. 
 Institutional Review Boards (IRB) and Independent Ethics Committees 
(IEC) 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse events will be reported to the 
IRB/IEC in accordance with local regulations, with the standard operating procedures and 
policies of the IRB/IEC. The investigator will keep the IRB/IEC informed as to the progress 
of the study. The investigator will obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, consent forms, information concerning patient recruitment, payment 
or compensation procedures, or other pertinent information) will be submitted to the 
IRB/IEC. The IRB/IECs written unconditional approval of the study protocol and the 
informed consent form will be in the possession of the investigator before the study is 
initiated 


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 Study Conduct 
This clinical study will be conducted in accordance with the principles contained in the 
Declaration of Helsinki and in compliance with all international laws and regulations and 
national laws and regulations of the country in which the study is performed, as well as any 
applicable guidelines.  
 Participant Information and Informed Consent  
Informed consent will be obtained in accordance with the Declaration of Helsinki and local 
regulations. 
Eye Pharma will provide to treating physicians a proposed informed consent form that 
complies with the ICH GCP guideline and local regulatory requirements and is considered 
appropriate for this study in a separate document. Any changes to the proposed consent form 
suggested by the investigator must be agreed to by Eye Pharma before submission to the 
IRB/IEC, and a copy of the approved version must be provided to the Eye Pharma monitor 
after IRB/IEC approval. 
Any amendment to the protocol will be written by Eye Pharma.  Protocol amendments cannot 
be implemented without prior written IRB/IEC approval except as necessary to eliminate 
immediate safety hazards to patients.  A protocol amendment intended to eliminate an 
apparent immediate hazard to patients may be implemented immediately, provided the 
IRB/IEC are notified within five working days. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the study.  Information should be given in both oral and written form 
and subjects (or their legal representatives) must be given ample opportunity to inquire about 
details of the study. A copy of the signed consent form will be given to the subject or legal 
representative of the subject and the original will be maintained with the subject’s records. 
 Modification of the Information and Consent Form 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the 
patients or when the change(s) involves only logistical or administrative aspects of the study.  
Such modifications will be submitted to the IRB/IEC and written verification that the 
modification was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse events occurring during the study in accordance 
with the standard operating procedures and policies of the IRB/IEC; new information that 
may affect adversely the safety of the patients of the conduct of the study; and when the study 
has been completed. 
 


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17 OWNER OF THE RESULTS – PUBLICATION POLICY 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study sponsor and participating institutions.    
 Investigator Responsibilities 
By signing the Agreement of investigator form, the investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after notifying 
the sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. Personally conduct or supervise the study. 
3. Ensure that the requirements relating to obtaining informed consent. 
4. Report to the sponsor or designee any AEs that occur in the course of the study. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study 
are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records and to make those records available for 
inspection with the sponsor (or designee). 
7. Promptly report to the IRB/IEC and the sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others). 
8. Seek IRB/IEC approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 


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B27 haplotype. Ophthalmology. 1998 Sep. 105(9):1646-51.  
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Pharmacol. 2008, 75, 787-809. 
15. Aggarwal B.B., Sung B., Pharmacological basis for the role of curcumin in chronic diseases: an age-old 
spice with modern targets. Trends Pharmacol. Sci. 2009, 30, 85-94   
16. Jurenka J.S., Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review 
of preclinical and clinical research. Altern. Med. Rev. 2009, 14, 141-153. 
17.  Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as “curecumin”: from kitchen to clinic. Biochem 
Pharmacol 2008;75:787-809 
18.  Abe Y, Hashimoto S, Horie T. Curcumin inhibition of inflammatory cytokine production by human 
peripheral blood monocytes and alveolar macrophages. Pharmacol Res 1999;39:41-47.)  


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19.  Kidd P.M., Bioavailability and activity of phytosome complexes from botanical polyphenols: the 
silymarin, curcumin, green tea, and grape seed extracts. Alt. Med. Rev. 2009, 14, 226-246. 
20. Semalty A., Semalty M., Rawat M.S.M., Franceschi F., Supramolecular phospholipids-polyphenolics 
interactions: the PHYTOSOME strategy to improve the bioavailability of phytochemicals. Fitoterapia 
2010, 81, 306-314. 
21. Giori A., Franceschi F., Phospholipid complexes of curcumin having improved bioavailability. Patent 
Application WO 2007/101551. 
22. Cuomo J, Appendino G, Dern AS, Schneider E, McKinnon TP, Brown MJ, Togni S, Dixon BM. 
Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. J Nat Prod. 
2011 Apr 25;74(4):664-9. doi: 10.1021/np1007262. Epub 2011 Mar 17. PubMed PMID: 21413691. 
23. Marczylo T.H., Verschoyle R.D., Cooke D.N., Morazzoni P., Steward W., Gescher A.J., Cancer 
Chemother. Pharmacol, 2007. 60(2), 171-177. 
 
24. Howells LM, Sale S, Sriramareddy SN, Irving GR, Jones DJ, Ottley CJ, Pearson DG, Mann CD, Manson 
MM, Berry DP, Gescher A, Steward WP, Brown K. Curcumin ameliorates oxaliplatin-induced 
chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo. Int J Cancer. 2011 Jul 
15;129(2):476-86. doi: 10.1002/ijc.25670. Epub 2010 Nov 3.  
 
25. Allegri P, Mastromarino A, Neri P. Management of chronic anterior uveitis relapses: efficacy of oral 
phospholipidic curcumin treatment. Long-term follow-up. Clin Ophthalmol. 2010 Oct 21;4:1201-6. doi: 
10.2147/OPTH.S13271.  
 
26. Steigerwalt R, Nebbioso M, Appendino G, Belcaro G, Ciammaichella G, Cornelli U, Luzzi R, Togni S, 
Dugall M, Cesarone MR, Ippolito E, Errichi BM, Ledda A,Hosoi M, Corsi M. Meriva®, a lecithinized 
curcumin delivery system, in diabetic microangiopathy and retinopathy. Panminerva Med. 2012 Dec;54(1 
Suppl 4):11-6. 
 
27. Di Pierro F, Rapacioli G, Di Maio EA, Appendino G, Franceschi F, Togni S. Comparative evaluation of 
the pain-relieving properties of a lecithinized formulation of curcumin (Meriva®), nimesulide, and 
acetaminophen. J Pain Res. 2013;6:201-5. doi: 10.2147/JPR.S42184. Epub 2013 Mar 8. 
 
28. Belcaro G, Cesarone MR, Dugall M, Pellegrini L, Ledda A, Grossi MG, Togni S,Appendino G. Efficacy 
and safety of Meriva®, a curcumin-phosphatidylcholinecomplex, during extended administration in 
osteoarthritis patients. Altern Med Rev. 2010 Dec;15(4):337-44. 
 
29. Herbort CP, Guex-Crosier Y, de Ancos E, Pittet N. Use of laser flare photometry to assess and monitor 
inflammation in uveitis. Ophthalmology 104(1), 64–71; discussion 71(1997). 
30. The clinical usefulness of laser flare photometry is shown, especially in monitoring HLA-B27-associated 
acute anterior uveitis.  
31. Wakefield D, Herbort CP, Tugal-Tutkun I, Zierhut M. Controversies in ocular inflammation and 
immunology laser flare photometry. Ocul. Immunol. Inflamm. 18(5), 334–340 (2010).  
32. Bernasconi O, Papadia M, Herbort CP. Sensitivity of laser flare photometry compared to slit-lamp cell 
evaluation in monitoring anterior chamber inflammation in uveitis. Int. Ophthalmol. 30(5), 495–500 
(2010).  
33. Tugal-Tutkun I, Herbort CP. Laser flare photometry: a noninvasive, objective, and quantitative method to 
measure intraocular inflammation. Int. Ophthalmol. 30(5), 453–464 (2010).  
34. Gonzales CA, Ladas JG, Davis JL, Feuer WJ, Holland GN. Relationships between laser flare photometry 
values and complications of uveitis. Arch. Ophthalmol. 119(12), 1763–1769 (2001). 


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35. Significant associations were found between laser flare photometry values and complications of uveitis, 
suggesting an essential role of this technology in predicting outcomes and monitoring therapy in uveitis.  
36. Tay-Kearney ML, Schwam BL, Lowder C, Dunn JP, Meisler DM, Vitale S, Jabs DA. Clinical features and 
associated systemic diseases of HLA-B27 uveitis. Am J Ophthalmol 1996;121:47-56.  
37. Onal S, Savar F, Akman M, Kazokoglu H. Vision- and health-related quality of life in patients with Behçet 
uveitis. Arch Ophthalmol 2010;128:1265-1271.  
38. Hoeksema L, Los LI. Vision-Related Quality of Life in Patients with Inactive HLA-B27-Associated-
Spectrum Anterior Uveitis. PLoS One 2016;11:e0146956. 
39. Hoeksema L, Los LI. Vision-related quality of life in herpetic anterior uveitis patients. PLoS One 
2014;9:e85224. 


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APPENDIX 1- RECOMMENDED DATA COLLECTION SCHEDULE 
 
 
VISIT 1 (T0) 
BASELINE 
VISIT 2 (T1) 
6 MONTHS (± 10 DAYS) 
VISIT 3 (T2)  
12 MONTHS (± 10 DAYS) 
Informed Consent 
X 
 
 
Demographic data 
X 
 
 
Evaluation of inclusion or exclusion criteria 
X 
 
 
Medical History 
X 
 
 
Physical examination and vital signs 
X 
X 
X 
Urine Dipstick specific pregnancy 
X 
X 
X 
Rheumatologic evaluation 
X 
 
 
Randomization 
X 
 
 
Evaluation of uveitis symptoms (by VAS) 
X 
X 
X 
Diagnostic ophthalmologic examination: 
 
 
 
    Measuring visual acuity (BCVA) 
    Slit lamp exam 
    OCT Spectralis®  
    LFM 
    IOP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quick Questionnaire 
X 
X 
X 
Dispensing of Study Product 
X 
X 
 
Counting of Returned Study Product 
 
X 
X 
Subject Diary Initiate and Delivery  
X 
X 
 
Subject Diary Review and Collection 
 
X 
X 
Concomitant Medication Review 
X 
X 
X 
Adverse Events 
 
X 
X 
A phone call will be set about 3 months after treatment start, to the purpose of evaluating that the study product is correctly taken by the subject. 


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APPENDIX 2 - OPHTALMOLOGICAL EXAMS GUIDE 
 
 
APPENDIX 2.1                 Best correct visual acuity (BCVA) 
APPENDIX 2.2                 Slit Lamp Biomicroscopy 
APPENDIX 2.3                 Goldman Tonometry 
APPENDIX 2.4                 Optical Coherent Tomography (OCT) Spectralis® 
APPENDIX 2.5                 Kowa Laser Flare-cell Meter (LFM) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Before dilatation of pupil 
2.1 Best correct visual acuity (BCVA) 
BCVA assessment by the Early Treatment Diabetic 
Retinopathy Study  
(ETDRS) Method 
 
 Retro illumination Box 
 
 Sets of 3 ETDRS charts  
                 (refraction, right eye, left eye) 
 
 
Description 
Best correct visual acuity (BCVA) will be assessed 
and graded using the ETDRS method (Ferris et al 
1982). 
As stated in the ETDRS manual of operation, if the 
subject’s visual acuity is so poor that she/he cannot 
read the largest chart letters when tested at one 
meter (i.e. the number of letters read correctly at 
one meter is zero), then the subject’s ability to count 
fingers, detect hand motion, or have light perception  
should be evaluated. 
 
EDTRS equipment (charts, light box, initial primary 
and spare light tube). 
 
Other equipment: 
 
- 
1 meter stick (non flexible) 
- 
Trial lens set (+ and – spheres, + or – cylinder, 
trial frame) 
- 
0,37 spherical lens  
- 
Jackson Cross cylinder (0,25, 0,50, 1,00, 
diopter) 
Certification:  
EDTRS site certification e-mail (from Latis) 
listing certified BCVA examiners (either during 
site visit or grandfathering process by Latis) 
and examination lane (certified by Latis or 
trained CRA) 
 
Documentation: 
BCVA worksheet (left + right eye) – ETDRS 
Example for right eye: 
 
Chart R - Refraction 
Chart 2- Left Eye (OS) 
Chart 1 - Right Eye (OD) 


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OPHTALMOLOGICAL EXAMS GUIDE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitreous 
Macula 
Optic nerve 
Choroid 
Sclera 
Iris 
Pupil 
Anterior chamber 
Cornea 
Ciliar body 
Retina 
INTERMEDIATE 
POSTERIOR 
ANTERIOR 


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OPHTALMOLOGICAL EXAM GUIDE 
2.2 Slit Lamp Biomicroscopy 
Assessment of anterior cells and 
flares. 
 
An individual subject grading 
should be performed by the same 
investigator with the same slit 
lamp 
 
 
Description 
Anterior chamber cells and flare will be assessed with slit-lamp 
Biomicroscopy and scored using the SUN working group grading 
scheme. For the determination of anterior chamber cell and flare, 
the field consists of 1x1 mm beam. 
Grading should be performed in a darkened room with the brightest 
possible slit lamp illumination, a high slit lamp magnification and a 
beam angle of 45°. 
 
Certification: NA 
 
 
 
 
Documentation: 
The SUN grading worksheet 
 
 
 
 
 
 
 
 
Documentation: 
Medical file 
 
 
 
Anterior chamber cells and flares 
Hypopyon                                                   
 (identified by slit lamp or visual examination) 
Inflammatory cells in the 
anterior chamber (Tyndall 
Phenomenon) 
Flare: exudation of proteins in the 
anterior chamber, which limits the 
visibility of the iris. 
Collection of fibrin and dense 
cellular infiltrate in the lower part of 
the anterior chamber. 


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OPHTALMOLOGICAL EXAM GUIDE 
 
 
 
 
2.3 Goldmann tonometry 
 
Intraocular pressure 
 
 
 
Description 
Goldman tonometry will be used to 
measure intraocular pressure. Intraocular 
pressure should be measured after the 
assessment of anterior chamber flare but 
prior to the installation of any dilating 
drops in addition to cycloplegics that a 
patient may already be taking.  
 
 
 
 
 
 
 
 
 
Certification: NA 
 
 
 
Documentation: 
Medical file 
(expressed in mmHg) 
 
 
 
 


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OPHTALMOLOGICAL EXAM GUIDE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AFTER dilatation of pupil 
Vitreous 
Macula 
Optic nerve 
Choroid 
Sclera 
Iris 
Pupil 
Anterior chamber 
Cornea 
Ciliar body 
Retina 
INTERMEDIATE 
POSTERIOR 
ANTERIOR 
Fundus and Posterior Pole Assessment 


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OPHTALMOLOGICAL EXAM GUIDE 
2.4 Optical Coherence Tomography (OCT) 
 
Central macular thickness 
 
 
Description 
Measurement of the central macular thickness  
OCT is an optical signal acquisition and 
processing method. It captures micrometer- 
resolution, three-dimensional images from 
within optical scattering media. It is an 
interferometric technique, typically employing 
near-infrared light, which allows it to penetrate 
into the scattering medium. 
 
 
 
 
 
 
 
 
 
 
 
 
Certification:  
 
 
 
Documentation: 
OCT report to be kept as source 
document in Patient File.  
 
 
 
 
 
Cirrus HD-OCT 
Spectralis SD-OCT 
Optovue RTvue SD-OCT 
Stratus OCT instrument 
Topscan 3D SD - 


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OPHTALMOLOGICAL EXAM GUIDE 
 
2.5 Laser Flare-cell Meter (LFM) 
 
Assessment of intraocular 
inflammation 
 
 
Description 
The laser flare-cell meter has made possible to 
determine the flare and number of cells in the 
aqueous humor quantitatively. 
LFM is a unique, precise, non-invasive, 
objective, 
quantitative 
tool 
to 
measure 
intraocular inflammation. 
 
 
 
 
 
 
Certification:  
LFM kowa 700 
 
 
Documentation: 
LFM report to be kept as source 
document in Patient File.  
 
 
 
 
 
kowa  Flare Meter Laser FML 
500-700

SAP_001.pdf: