Conditions: Non-infectious Uveitis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
In this study, PP-001 is assessed for safety and efficacy in patients diagnosed with non-infectious chronic uveitis. PP-001 is a novel small molecule that inhibits a specific enzyme (Dihydroorotate Dehydrogenase) and has shown pre-clinical efficacy in treatment of non-infectious uveitis. PP-001 will be administered to participants as a single intravitreal injection in ascending doses.

Detailed description:
This study assesses safety and efficacy of PP-001 after intravitreal injection in patients diagnosed with non-infectious chronic uveitis. PP-001 is a novel small molecule inhibitor of Dihydroorotate Dehydrogenase (DHODH) and has shown pre-clinical efficacy in treatment of non-infectious uveitis. PP-001 is to offer a local treatment alternative to corticosteroids with the objective to reduce or possibly replace steroid intake of non-infectious uveitis patients. In the current study, PP-001 will be injected in ascending doses into the vitreous body of the eye of study participants who suffer from non-infectious uveitis. Participants will be monitored for safety and efficacy evaluation of the study drug.

Arms:
arm 1: Single intravitreal injection of 3 up to 4 doses of PP-001

Interventions: intervention 1: PP-001
Intervention descriptions: intervention 1: Drug - no placebo

Protocol document:
Prot_000.pdf: 
Panoptes Pharma GesmbH 
Clinical Protocol PP-001-1001 
Version 3.1_GER 03 November 2017 
Page 1 of 54 
Confidential Information 
 
 
 
Clinical Trial Protocol No. PP-001-1001 
 
A safety study of intravitreal PP-001 in patients with chronic, non-infectious 
uveitis having chronic inflammation 
EudraCT Number 2016-000412-15 
 
 
 
 
Version Date:  
03. November 2017 
Version Status: 
3.1_GER 
 
 
 
 
 
 
The information contained herein is the property of Panoptes Pharma GesmbH and may not be 
produced, published, or disclosed to others without written authorization of Panoptes Pharma 
GesmbH.


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Version 3.1_GER 03 November 2017 
Page 2 of 54 
Confidential Information 
A safety study of intravitreal PP-001 in patients with chronic, non-infectious uveitis having 
chronic inflammation 
(Protocol PP-001-1001) 
 
SPONSOR RELATED CONTACT DETAILS 
 
Sponsor: 
Panoptes Pharma Gesmbh 
Reisnerstrasse 34/1 
1030 Vienna 
Austria 
Sponsor’s Study Managers: 
Dr. Franz Obermayr 
Tel: +436648557369 
Franz.Obermayr@panoptes-pharma.com 
 
Sponsor’s Medical Representative: 
Prof. Dr. Johannes Gobertus Meran 
Tel: +436648557369 
 
CRO’s Project Manager 
Verena Köpke 
Sourcia GmbH Lochhamerstrasse 31 
82152 Martinsried 
Germany 
M:   +49 (0)151 744 03195 
verena.koepke@sourcia.eu 
 
 
 


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Version 3.1_GER 03 November 2017 
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Confidential Information 
PROTOCOL APPROVAL FORM 
SUBMISSION OF PROTOCOL PP-001-1001 
 
Title: A safety study of intravitreal PP-001 in patients with chronic, non-infectious uveitis 
having chronic inflammation 
(Protocol PP-001-1001) 
 
03. November 2017 
NAME 
TITLE 
DATE 
03. November 2017 
Dr. Franz Obermayr 
CEO, Panoptes 
Pharma 
 
 
 
 Signature 
 
 
 
 


Panoptes Pharma GesmbH 
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Version 3.1_GER 03 November 2017 
Page 4 of 54 
Confidential Information 
INVESTIGATOR SIGNATURE PAGE 
A safety study of intravitreal PP-001 in patients with chronic, non-infectious uveitis having 
chronic inflammation 
(Protocol PP-001-1001) 
In conducting this clinical study, I agree to be responsible for: 
• Ensuring that the clinical investigation is conducted according to the World Medical 
Association Declaration of Helsinki (revised version of Edinburgh, Scotland, 2000, Note of 
Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002), the 
guidelines of International Conference on Harmonization (ICH) Good Clinical Practice 
(CPMP/ICH/135/95), and other applicable local and national laws and requirements 
• Protecting the rights, safety, and welfare of patients under my care 
• Maintaining control of the drugs under investigation 
I also agree to conduct the study as detailed in the protocol and in accordance with Panoptes 
Pharma GesmbH guidelines and all applicable government regulations. These guidelines and 
regulations include, but are not limited to: 
• Permission to allow Panoptes Pharma GesmbH and regulatory agencies, to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner, which ensures 
patient confidentiality. If I am notified that this study is to be inspected by a regulatory 
agency, I will notify Panoptes Pharma GesmbH as soon as possible thereafter (no later than 
1 week) 
• Submission of the proposed clinical investigation, including the protocol, the informed 
consent documents, and any other patient materials required for study conduct, to a duly 
constituted Independent Ethics Committee (IEC) 
• Obtaining written informed consent only after ensuring that the patient, or his/her legal 
representative, is competent to make the decision, understands what is contained in the 
informed consent document, and is consenting voluntarily. Written informed consent will be 
obtained prior to administration of study drug or any non-routine study-related procedures; 
the document contains all the essential elements of consent and has been previously approved 
by the sponsor and IEC. Reference of written informed consent will be provided in source 
documentation 
• Submission of any protocol amendment to the IEC. If the protocol amendment change(s) 
increase risk to the study population, full IEC written approval must be obtained prior to 
implementation. For changes that do not involve increased risk or affect the validity of the 
investigation or the patient's rights, prior IEC approval may be obtained by expedited review 
• Adherence to the study protocol. Documentation and explanation of individual post-
enrolment protocol deviations will be recorded in the source documentation at the site and be 
provided to Panoptes Pharma GesmbH 
• Notification to Panoptes Pharma GesmbH of all serious adverse events (SAEs), regardless of 
relationship to study drug, as specified in the protocol. Notification to the IEC of SAEs as 
specified in the protocol and per additional guidelines as provided by the IEC 


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• Notification to IEC of all unanticipated problems within the timeframe provided by the IEC. 
For the purposes of this study, unanticipated problems are defined as any incident, 
experience, or patient outcome that meets all of the following criteria: (1) unexpected; (2) 
related or possibly related to participation in the study; (3) and suggests that the research 
places patients or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known 
• Provision of adequate study oversight by personally conducting or supervising the 
investigation, including, but not limited to: allotting sufficient time to properly conduct and 
complete the study within the agreed upon time period; having available an adequate number 
of qualified staff and adequate facilities for the expected duration of the study and to conduct 
the study properly and safely; and ensuring that all persons assisting with the study are 
adequately informed about the protocol and the investigational product(s) and are capable of 
performing their study-related duties and functions. Qualifications of individuals assigned 
responsibility for the administration of the investigational product will be compliant with 
state and local law or national regulations, as applicable 
• Submission of timely progress reports to the IEC and Panoptes Pharma GesmbH at 
appropriate intervals not to exceed 1 year and submission of a final report to the IEC within 
the timeframe set by the IEC, but not later than 3 months after the completion or termination 
of the clinical investigation 
• Maintenance of accurate source records from which case report forms are completed as well 
as drug accountability records that show the receipt and disposition (on an overall and per 
patient basis) of all study drug(s) shipped to the Investigator by Panoptes Pharma GesmbH 
In addition, I agree to provide all the information requested in the electronic case report form 
(eCRF) presented to me by Panoptes Pharma GesmbH by carefully following the completion 
guidelines provided as part of the eCRF. 
If I opt to terminate my participation in the study, the foregoing shall equally apply. 
Prof. Dr. Stephan Thurau 
Augenklinik der Ludwig-Maximilians-Universität 
(LMU) 
Klinikum der Universität München 
Campus Innenstadt 
Mathildenstr. 8 
D-80336 München 
Prof. Dr. Stephan Thurau 
 
 
 
 
 
Investigator’s Signature 
 
 


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SYNOPSIS 
Study Title: A safety study of intravitreal PP-001 in patients with chronic, non-infectious uveitis 
having chronic inflammation 
Study Objectives: 
Primary Objective 
• To assess the safety and tolerability of ascending doses of PP-001 in patients with chronic, 
non-infectious uveitis when administered as a single intravitreal injection of 0.3 µg, 0.6 µg and 
1.2 µg with the option of an addition cohort with a dose of 2.1 µg PP-001 
Secondary Objectives 
• To assess the improvement of inflammation in patients with chronic, non-infectious uveitis 
after ascending doses of PP-001 when administered as a single intravitreal injection of 0.3 µg, 
0.6 µg and 1.2 µg with the option of an addition cohort with a dose of 2.1 µg PP-001 
• To evaluate the pharmacokinetics of PP-001 in patients with chronic, non-infectious uveitis 
when administered as a single intravitreal injection of 0.3 µg, 0.6 µg and 1.2 µg with the option 
of an addition cohort with a dose of 2.1 µg PP-001 
Study Population: 
Inclusion Criteria 
1. Male or female patients without childbearing potential older than 18 years of age who have 
diagnosis of chronic posterior uveitis, intermediate uveitis or panuveitis. 
2. Good general state of health (mentally and physically). Laboratory parameters and vital 
signs of patients must be within the normal ranges and patients must not have a diagnosis 
of any acute or chronic illness except uveitis. 
3. A signed and dated written informed consent form. 
4. A signed and dated written data protection consent form. 
5. Male patients must ensure that one highly effective method combined with an acceptable 
method of contraception is used for the entire duration of the study, from first dose up to 
the study follow-up visit, and refrain from fathering a child in the 3 months following the 
last study drug administration. Male patients must agree with their female partners prior to 
screening to use the above specified methods of contraception while receiving protocol-
specified medication, and for 3 months after stopping the medication. Female patients must 
be of non-childbearing potential. The definition of non-childbearing potential includes the 
following: 
• Surgically sterile (e.g., hysterectomy with or without oophorectomy; fallopian 
tube ligation; endometrial ablation), at least 30 days prior to signature of the 
Informed Consent form 
• At least 3 years post-menopause (i.e., 4 years post last menstrual period), or 
menopause confirmed by follicle-stimulating hormone (FSH) testing.  


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6. Have diagnosis of chronic posterior uveitis, intermediate uveitis or panuveitis (as defined 
by the Standardization of Uveitis Nomenclature Working Group [Jabs et al., 2005]) in at 
least one eye. For patients with panuveitis, the anterior component of inflammation must 
be less than the posterior component. The investigator to his best knowledge must rule out 
any suspected masquerade syndrome or infection prior to study entry. 
7. Have chronic, posterior uveitis, intermediate uveitis or panuveitis requiring treatment 
8. Have media clarity, pupillary dilation and patient cooperation sufficient for adequate 
visualization of the optic nerve in the study eye. 
9. Have been receiving an adequate therapy of e.g. systemic corticosteroid treatment or 
immunosuppressive therapy (e.g. azathioprine, methotrexate, cyclosporine, 
mycophenolate, tacrolimus) or any combination thereof. Any systemic therapy at study 
start should be continued throughout the study. 
10. Best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity of 10 
letters or better (approximately 1/35 or 0.032) but equal or less than 50 letters 
(approximately 20/100 or 0.2) in the study eye. 
11. Best-corrected ETDRS visual acuity of 50 letters or better in the fellow eye (approximately 
20/100 or 0.2) 
 
Exclusion Criteria 
1. Patients in whom media opacities (cornea, anterior or posterior synechia, cataract, vitreous 
haze and others) of either eye preclude investigation and documentation of the posterior 
pole and intravenous fluorescein angiography, or optical coherence tomography evaluation 
in the study eye. 
2. Patients receiving any local biologicals. 
3. Treatment with cyclophosphamide or chlorambucil. 
4. Intravitreal injections (including but not limited to anti-vascular endothelial growth factors) 
60 days prior to the baseline. 
5. Posterior subtenon's injection or orbital floor injection of steroids 90 days prior to Baseline. 
6. Any implantable corticosteroid-eluting device (Ozurdex, Iluvien, Retisert, triamcinolone 
intravitreal implant, fluocinolone intravitreal implant) in the study eye, with the following 
exceptions: 
• If the device had been removed more than 90 days prior to Day 0 of this study, the 
eye will be eligible for PP-001-1001. 
• If Ozurdex had been implanted 6 months before Day 0 of this study, the eye will 
be eligible for PP-001-1001. 
• If Iluvien or Retisert had been implanted 3 years before Day 0 of this study, the 
eye will be eligible for PP-001-1001. 
7. Intraocular surgery within 90 days prior to Day 0 in the study eye. 
8. Capsulotomy within 30 days prior to Day 0 in the study eye. 
9. History of vitreoretinal surgery or scleral buckling within 90 days prior to Day 0 in the 
study eye. 
10. Any ocular surgery (including cataract extraction or capsulotomy) of the study eye 
anticipated within the first 60 days following Day 0. 
11. Intraocular pressure (IOP) ≥25 mmHg in the study eye (glaucoma patients maintained on 
no more than one topical medication with IOP <25 mmHg are allowed to participate). 
12. Ocular hypotonia (IOP less than 6 mmHg). 


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13. Pupillary dilation inadequate for quality fundus photography in the study eye. 
14. Aphakia or anterior chamber lens in the study eye. 
15. Visible scleral thinning, scleral ectasia or keratoconus in the study eye. 
16. Presence of any ocular malignancy. 
17. Ocular or periocular infection in either eye or the use of systemic antibiotics. 
18. Participation in other investigational drug or device clinical trials within 90 days prior to 
Day 0, or planning to participate in other investigational drug or device clinical trials 
within 180 days following Day 0. This includes both ocular and non-ocular clinical trials. 
19. Female patients who are of childbearing potential or who are pregnant.  
20. Use of any anticoagulant or thrombocyte aggregation inhibiting agent (marcumar, 
warfarin, heparin, enoxaparin, apixaban, rivaroxaban, pentosanpolysulfate, dabigatran, 
aspirin, and others) less than 14 days prior to injection visit (Day 0). 
21. Known allergy or hypersensitivity to the study medication, any component of the delivery 
vehicle, any corticosteroids or any diagnostic agents used during the study (e.g., 
fluorescein, dilation drops, antibiotic drops, povidone). 
22. Patients with diagnosis of any acute or chronic systemic illness other than uveitis  
Duration of Study: Total duration of study for each patient will be 8 weeks or less (from 
screening to last follow-up). 
Drug Products: PP-001 will be supplied as a sterile concentrate solution in a 2 ml vial and will 
be diluted according to dose as specified in the pharmacy manual. 
Study Drug Assignment: Patients will be dosed in ascending order with 0.3, 0.6, 1.2 or 2.1 µg 
PP-001 depending on the cohort to which they are assigned. 
Duration of Treatment: Patients will receive a single dose of PP-001. 
Study Drug Administration: PP-001 will be administered as a single intravitreal injection, 
which will be performed under sterile conditions in an operating room setting. For safety reasons 
an emergency pars plana vitrectomy aiming at removal of injected drug will be available in case 
of a severe adverse event including, but not limited to, acute loss of visual acuity or acute 
inflammatory or toxic response to injection. It is therefore mandatory for patients to remain in 
the hospital for at least 4 hours after the injection procedure.  
Blinding: This is an open-label study. 
Study Design: This prospective, multi-centre, open-label, non-randomized, consecutive study 
will be conducted in accordance with the European Union (EU) Clinical Trial Directive 
2001/20/EC and 2005/28/EC, The Medicines for Human Use (Clinical Trials) Regulations 2004 
and current amendments, the Declaration of Helsinki (revised version of Edinburgh, Scotland 
2000), Good Manufacturing Practice (GMP), Good Clinical Practice (GCP) and the current 
national regulations and guidelines, approved by both the local ethics committee and regulatory 
authority. Eighteen patients older than 18 years of age will be enrolled and receive a single 
intravitreal injection of PP-001. Patients must have chronic, posterior uveitis, intermediate 
uveitis or panuveitis requiring treatment and have been receiving an adequate therapy of e.g. 
systemic corticosteroid treatment or immunosuppressive therapy (e.g. azathioprine, 
methotrexate, cyclosporine, mycophenolate, tacrolimus) or any combination thereof. Any 
systemic therapy at study start should be continued throughout the study. Patients must have 
best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity of 10 letters 


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or better (approximately 1/35 or 0.032) but equal or less than 50 letters (approximately 20/100 or 
0.2) in the study eye.  
The study will involve eight inpatient visits (Screening, Baseline, the day of injection [Day 0] 
and Days 2, 7, 14, 21 and 28) and telephone calls on Day 1 and on Day 40. 
Patients will be divided into three cohorts of four patients. Patients will receive the following 
treatments administered as a single intravitreal injection: 
• Cohort 1 will receive 0.3 µg of PP-001 
• Cohort 2 will receive 0.6 µg of PP-001 
• Cohort 3 will receive 1.2 µg of PP-001 
The patients within a cohort will be dosed consecutively with a minimum time interval of 7 days 
between the start of injection of the previous patient and start of injection of the next patient. The 
results from each dosing day will be reviewed before progressing with the subsequent dosing 
day. The next cohort will only commence with dosing after the previous cohort has completed all 
study sessions up to Day 28 and no safety issues have been identified after being reviewed by the 
safety data management board (SDMB).  
After 12 patients have been treated in the three cohorts and after all patients have finished the 
last follow up an interim analysis by the SDMB will be conducted to identify potential safety 
issues and to determine the highest tolerable dose. If no safety issue can be identified, then a 
fourth, higher dose will be given to a cohort of four patients (Cohort 4). The dose for a potential 
Cohort 4 will be 2.1 µg of PP-001. 
If safety issues are identified in any of Cohorts 2, 3 or 4, two additional patients will receive the 
next lower dose. 
Statistical Considerations: 
• Sample Size: Eighteen patients will be enrolled in the study. No power calculations will be 
performed and the sample size is based on the requirements of the study design.  
• Treatment Comparison of Interest: a comparison will be made between the cohorts with 
regard to safety tolerability and efficacy. 
Interim Analysis: the results from each dosing day of the first cohort will be reviewed before 
progressing with the subsequent dosing day. Dosing of the next cohort will only commence after 
the previous cohort has completed all study sessions up to Day 28 and no safety issues have been 
identified after being reviewed by the SDMB. 
Analysis Populations 
• Intent-to-treat (ITT) Analysis Set: all patients regardless of whether or not the patient 
received study drug 
• Per-protocol Analysis Set: all ITT Analysis Set patients who have no major protocol 
deviations, and who complete the study up to the end of the post-study assessments 
• Safety Analysis Set: all patients who receive any amount of study drug. All safety analyses 
will be conducted in this population 


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• Pharmacokinetic Analysis Set: all patients who receive any amount of study drug will be 
included in the formal analysis of pharmacokinetic parameters providing they have at least 
one evaluable pharmacokinetic sample 
Variables for Analysis: 
Primary 
• Safety parameters (i.e., changes in clinical signs and symptoms from ophthalmic exam, and 
AEs) 
Secondary 
• Improvement of inflammation or of any other parameter determined at the ophthalmic 
examination following the injection of PP-001 
• The concentration of PP-001 in plasma at Screening, 4 h ± 1 h after dosing and on Day 2 
Safety analysis 
The incidence of treatment-emergent adverse events (TEAEs), SAEs, deaths and 
discontinuations of study drug due to an AE or SAE will be summarized by System Organ Class 
and Preferred Term according to the Medical Dictionary for Regulatory Activities, by 
relationship to study drug, and by severity. The incidence of potentially clinically significant 
vital signs will be summarized. 
Pharmacokinetic analysis 
The concentration of PP-001 in plasma will be measured in blood samples taken at Screening, 
4 h ± 1 h after dosing and on Day 2. 


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Table 1. 
Schedule of Assessments and Procedures 
Phase 
Screening 
Baselinei i 
Pre 
injection 
Post 
injection 
Telephone 
calla 
Safety visits 
Telephone 
calla 
Day 
-14 up to 
dosing 
-7 up to 
dosing 
0 
0 
1 
2 
7 
+/-1 
14 
+/-1 
21 
+/-1 
28h 
+/-1 
40 
Electroretinography 
 
X 
 
 
 
 
 
X 
 
X 
 
Fluorescein angiogram 
X 
 
 
 
 
 
 
 
 
X 
 
Optical coherence tomography 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
Best corrected visual acuity (ETDRS)  
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
Visual field (computerized, 30°) 
 
X 
 
 
 
 
X 
 
 
X 
 
Visually evoked cortical potential 
X 
 
 
 
 
 
 
 
 
X 
 
Intraocular pressure 
X 
X 
 
Xb 
 
X 
X 
X 
X 
X 
 
Slit lamp examination c 
X 
X 
X 
Xb 
 
X 
X 
X 
X 
X 
 
Dilated fundoscopyd  
X 
X 
 
Xb 
 
X 
X 
X 
X 
X 
 
Study drug injection 
 
 
 
X 
 
 
 
 
 
 
 
Blood sampling for PK analysis 
X 
 
 
Xb,e 
 
X 
 
 
 
 
 
Corneal endothelial microscopy  
 
X 
 
 
 
 
X 
 
 
X 
 
Fundus photography 
 
X 
 
 
 
 
 
 
 
X 
 
Amsler grid 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
Medical and ophthalmic histories 
X 
X 
 
 
 
 
 
 
 
 
 
Vital signsf 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Twelve-lead electrocardiogram 
X 
 
 
 
 
 
 
 
 
X 
 
Laboratory assessments 
X 
 
 
 
 
 
 
 
 
X 
 
Patient-reported outcomesg 
 
X 
 
 
 
 
 
 
 
X 
 
Concomitant medication 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Serious medical events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ETDRS: Early Treatment of Diabetic Retinopathy Study; PK: Pharmacokinetic 
a. Standardized questions including (but not limited to): pain, blurred vision, change in visual acuity, redness of the eye 
b. Examination will be performed after administration of study drug 
c. Conjuctiva, cornea, anterior chamber including grading of cells and haze (Standardization of Uveitis Nomenclature Working Group), lens (Lens opacities 
classification system II) and vitreal haze (Standardization of Uveitis Nomenclature Working Group) 
d. Including slit lamp biomicroscopy of the fundus 
e. Day 0 blood sample will be taken 4 h ± 1 h after injection 
f. Blood pressure and heart rate 
g. National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25), SF36™ Health Survey Version 2 (SF-36v2) and EuroQol-5 Dimensions Health 
Questionnaire (EQ-5D) 
h: for visit 28 option to perform examinations to 2 consecutive days; 
i: in case screening visit and baseline visit are on the same day (-7 up to dosing), examinations scheduled for both visits need only to be performed once and may be used for 
both study visits 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AUC 
Area under the plasma concentration time curve  
BP 
Blood pressure 
CS 
Clinically significant 
Cmax 
Maximum plasma concentration 
DHODH 
Dihydroorotate dehydrogenase 
EAU 
Experimental autoimmune uveitis  
ECG 
Electrocardiogram 
eCRF 
Electronic case report form  
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
EU 
European Union 
 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
h 
Hours 
hERG 
Human ether-à-go-go-related gene  
HR 
Heart rate 
IC50 
Half-maximal inhibitory concentration 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
ITT 
Intent-to-treat  
IFN-γ 
Interferon gamma 
IL-17 
Interleukin 17 
IOP 
Intraocular pressure  
K3EDTA 
Tri-potassium ethylenediaminetetraacetic acid 
MedDRA 
Medical Dictionary for Regulatory Activities  
NCS 
Not clinically significant 
NIU 
Non-infectious uveitis 
NOAEL 
No-observed-adverse-effect-level 
NOEL 
No-observed-effect level  
OCT 
Optical coherence tomography 
OECD 
Organisation for Economic Co-operation and Development  
PP 
Per-protocol 
QA 
Quality assurance 
SAE 
Serious adverse event 
SDMB 
Safety data management board 
TEAE 
Treatment-emergent adverse event 
TNF 
Tumour necrosis factor 
 
 


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TABLE OF CONTENTS 
 
1. 
INTRODUCTION ................................................................................................................... 17 
 
Background of the Disease and Treatment Options ..................................................... 17 
 
Background on PP-001 ................................................................................................. 17 
 
Non-Clinical Development ........................................................................................... 18 
1.3.1 
Mechanism of Action and Non-Clinical Pharmacology ........................... 18 
1.3.2 
Pharmacokinetics and Product Metabolism .............................................. 18 
1.3.3 
Non-Clinical Safety and Toxicology ........................................................ 19 
 
Summary of Clinical Data ............................................................................................ 19 
2. 
STUDY OBJECTIVES ........................................................................................................... 20 
 
Primary Endpoints ........................................................................................................ 20 
 
Secondary Endpoint ...................................................................................................... 20 
3. 
STUDY DESIGN .................................................................................................................... 20 
 
Study Rationale ............................................................................................................. 21 
3.1.1 
Dose Rationale .......................................................................................... 22 
 
Potential Risks and Benefits to Human Patients ........................................................... 23 
4. 
STUDY POPULATION ......................................................................................................... 24 
 
Inclusion Criteria .......................................................................................................... 24 
 
Exclusion Criteria ......................................................................................................... 25 
5. 
STUDY DRUG ADMINISTRATION ................................................................................... 26 
 
Randomization .............................................................................................................. 26 
 
Study Drug Treatment .................................................................................................. 26 
5.2.1 
Duration of Treatment ............................................................................... 26 
5.2.2 
Post-Baseline Treatment Modifications .................................................... 27 
 
Timing of Dosing and Dose Administration ................................................................. 27 
 
Preparation of Treatment .............................................................................................. 27 
 
Blinding ........................................................................................................................ 27 
 
Unblinding of Therapy Assignments ............................................................................ 27 
 
Adherence ..................................................................................................................... 27 
 
Occupational Safety ...................................................................................................... 27 
6. 
STUDY ASSESSMENTS AND PROCEDURE .................................................................... 27 


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Surgical Procedure ........................................................................................................ 28 
 
Medical/Surgical History .............................................................................................. 28 
 
Physical Examination ................................................................................................... 28 
 
Vital Signs ..................................................................................................................... 28 
 
Twelve-Lead Electrocardiogram .................................................................................. 29 
 
Clinical Laboratory Tests .............................................................................................. 29 
 
Opthalmic Examination Procedures ............................................................................. 29 
6.7.1 
Electroretinography ................................................................................... 30 
6.7.2 
Fluorescein Angiogram ............................................................................. 30 
6.7.3 
Optical Coherence Tomography ............................................................... 30 
6.7.4 
Best Corrected Visual Acuity .................................................................... 30 
6.7.5 
Visual Field Measurement ........................................................................ 30 
6.7.6 
Visually Evoked Cortical Potential ........................................................... 30 
6.7.7 
Intraocular Pressure ................................................................................... 31 
6.7.8 
Slit Lamp Examination ............................................................................. 31 
6.7.9 
Dilated Fundoscopy .................................................................................. 31 
6.7.10 Corneal endothelial microscopy ................................................................ 31 
6.7.11 Fundus photography .................................................................................. 31 
6.7.12 Amsler grid ............................................................................................... 31 
6.7.13 Health Outcome Measures ........................................................................ 31 
 
Telephone Interview ..................................................................................................... 31 
 
Prior and Concomitant Medications ............................................................................. 32 
6.9.1 
Prior Medications ...................................................................................... 32 
6.9.2 
Concomitant Medication ........................................................................... 32 
 Prohibited Medications ................................................................................................. 32 
 Non-Pharmacologic Treatments and Procedures .......................................................... 32 
 Sample Collection for Pharmacokinetic Analysis ........................................................ 32 
6.12.1 Plasma Sample Collection ......................................................................... 32 
6.12.2 Assay Methodology .................................................................................. 33 
 Total Blood Volume Collected ..................................................................................... 33 
 Discontinuation from Treatment or Study .................................................................... 33 
6.14.1 Discontinuation from Study ...................................................................... 33 
6.14.2 Individual Stopping Criteria ...................................................................... 34 
6.14.3 Study Stopping Criteria ............................................................................. 34 
6.14.4 Lost to Follow-up ...................................................................................... 34 


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 Premature Termination of the Trial .............................................................................. 34 
 Contraceptive measures ................................................................................................ 35 
7. 
ADVERSE EVENTS .............................................................................................................. 36 
 
Assessment of Severity (Intensity) ............................................................................... 37 
 
Assessment of Relationship to Study Drug .................................................................. 37 
 
Serious Adverse Events ................................................................................................ 37 
 
Other Reportable Events ............................................................................................... 38 
8. 
DRUG SUPPLIES .................................................................................................................. 39 
 
PP-001 ........................................................................................................................... 39 
8.1.1 
Packaging and Labelling ........................................................................... 39 
8.1.2 
Storage of Study Drugs ............................................................................. 40 
8.1.3 
Product Accountability .............................................................................. 40 
9. 
STATISTICAL ANALYSIS ................................................................................................... 40 
 
Treatment Comparison of Interest ................................................................................ 40 
 
Sample Size Determination .......................................................................................... 40 
 
Analysis Populations ..................................................................................................... 41 
9.3.1 
Intent-to-Treat Analysis Set ...................................................................... 41 
9.3.2 
Per-protocol Analysis Set .......................................................................... 41 
9.3.3 
Safety Analysis Set ................................................................................... 41 
9.3.4 
Pharmacokinetic Analysis Set ................................................................... 41 
 
Criteria for Evaluation .................................................................................................. 41 
9.4.1 
Safety Analysis Variables ......................................................................... 41 
9.4.2 
Pharmacokinetic Analysis Variables ......................................................... 41 
9.4.3 
Efficacy Analysis Variables ...................................................................... 41 
 
Demographic and Baseline Characteristics .................................................................. 41 
 
Safety Analysis ............................................................................................................. 42 
 
Pharmacokinetic Analyses ............................................................................................ 42 
 
Efficacy analysis ........................................................................................................... 42 
 
Handling of Missing Data ............................................................................................. 42 
 Interim Analysis ............................................................................................................ 42 
10. STUDY MONITORING ......................................................................................................... 43 
 Clinical Monitoring ....................................................................................................... 43 
 Safety Data Monitoring Board ...................................................................................... 43 


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11. INDEPENDENT ETHICS COMMITTEE APPROVAL ....................................................... 43 
12. ETHICAL CONDUCT OF THE STUDY .............................................................................. 43 
13. INFORMED CONSENT ........................................................................................................ 44 
14. QUALITY ASSURANCE/QUALITY CONTROL ............................................................... 44 
15. DATA HANDLING AND RECORD KEEPING ................................................................... 44 
 Data Handling ............................................................................................................... 44 
 Patient Confidentiality .................................................................................................. 45 
 Computer Systems ........................................................................................................ 45 
 Data Entry ..................................................................................................................... 45 
 Data Validation ............................................................................................................. 46 
 Record Keeping ............................................................................................................ 46 
16. Facilities .................................................................................................................................. 46 
17. TERMINATION OF STUDY ................................................................................................. 47 
18. FINANCING AND INSURANCE ......................................................................................... 47 
19. PUBLICATION POLICY ....................................................................................................... 47 
20. LIST OF REFERENCES ........................................................................................................ 49 
21. APPENDICES ......................................................................................................................... 50 
 Appendix 1: Clinical Laboratory Tests ......................................................................... 50 
 Appendix 2: Values of Potential Clinical Concern ....................................................... 51 
 Appendix 3: ECG Values of Potential Clinical Concern .............................................. 52 
 Appendix 4: Investigator Signature Page ..................................................................... 53 
 
 
 


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1. 
INTRODUCTION 
 
Background of the Disease and Treatment Options 
PP-001 is indicated for the treatment of non-infectious uveitis (NIU). Uveitis is a chronic or 
relapsing intra-ocular inflammatory disease that affects the uvea (composed of the iris, choroid 
and ciliary body), retina, vitreous body, optic nerve head, retinal pigment epithelium and the 
anterior chamber, but may also involve adjacent structures, including the sclera or cornea 
[Barisani-Asenbauer et al., 2012; Barry et al., 2014]. 
The integrity and transparency of the ocular media (aqueous, lens and vitreous) and ocular tissue 
(iris, ciliary body, retina, pigment epithelium and choroid) are critical for optimal visual function 
because they refract, transmit, regulate and sense light. Any distortion of the visual axis by 
inflammatory processes within the eye can adversely affect vision [Caspi, 2008]. Uveitis is a 
disease with symptoms ranging from temporary effects, including discomfort, pain or blurring of 
vision, to permanent defects in visual acuity and visual field due to irreversible tissue damage 
and even blindness. Visual impairment may result from direct damage to any ocular structure 
(e.g., cataracts, glaucoma, macular oedema [Barry et al., 2014]). 
Uveitis can be caused by infections or by autoimmune disease. Non-infectious uveitis covers all 
uveitis cases, which are considered to be of autoimmune or autoinflammatory origin including 
systemic immunological disease-associated uveitis. It also includes acute and chronic uveitis, as 
well as relapsing forms, and may occur at any location in the eye. 
In NIU, T-cells (Th1 and Th17) become autoreactive towards ocular antigens like retinal-soluble 
antigen or interphotoreceptor retinoid-binding protein and this leads to a substantial immune 
response. Once activated, T helper cells secrete many different cytokines, of which interferon 
gamma (IFN-γ) and interleukin 17 (IL-17) are the hallmarks of Th1 and Th17 cells, respectively. 
This results in the recruitment of neutrophils and other leukocytes as well as lymphocytes from 
the peripheral blood to the eye. Subsequent tissue destruction is mediated by non-specific 
activation of immune cells.  
The main treatment strategies for NIU involve the suppression of local inflammation. Treatments 
range from topical therapy (commonly corticosteroid eye drops) to systemic immunosuppression 
with either corticosteroids or steroid-sparing immunomodulatory therapeutic agents [Barry et al., 
2014]. Topical medication is generally only used to treat uveitis that affects the anterior part of 
the eye (i.e. anterior chamber). Patients suffering from intermediate and/or posterior uveitis (i.e. 
that which affects the vitreous body and retina/choroid) are routinely treated with high doses of 
systemic corticosteroids. Dosing of corticosteroids depends on the timeframe and severity of 
inflammation. Usually, the initial treatment includes high-dose corticosteroids, which is then 
slowly tapered according to disease activity. The ultimate expected therapeutic role of PP-001 
will be as a steroid-sparing agent and allow steroid doses to be tapered quickly. Due to its 
underlying mode of action, PP-001 is suitable for the treatment of NIU only. 
 
Background on PP-001 
PP-001 has the molecular formula C19H8F7NO4S and a molecular weight of 479.3 g/mol. PP-001 
is a third generation small molecule inhibitor of dihydroorotate dehydrogenase (DHODH) and 
has a half-maximal inhibitory concentration (IC50) of DHODH of less than 4 nM. By inhibiting 


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DHODH, the expression of IL-17 and IFN-γ is suppressed. Independently, highly proliferating T 
cells are inhibited. PP-001 thereby specifically targets the underlying cause of uveitis. 
PP-001 is 150-fold more potent than the orally administered small-molecule DHOHD inhibitor, 
leflunomide (IC50 DHODH, 650 nM). Leflunomide (Arava®) and its active metabolite 
teroflunomide (Aubagio®) are approved for the treatment of rheumatoid arthritis and multiple 
sclerosis, respectively. PP-001 is structurally and mechanistically distinct from leflunomide. The 
hepatic metabolization of leflunomide to teriflunomide leads to the off-target inhibition of 
protein kinases and is responsible for its side effect profile [Herrmann et al., 2000]. 
PP-001 drug substance is a small, synthetic molecule. The drug product is formulated as 1 mg/ml 
sterile concentrate formulation in 2 ml glass vials (PP-001 concentrate for intravitreal injection). 
Buffer and tonicity agents are added as excipients. Prior to administration, the PP-001 
concentrate solution is diluted with sterile aqueous sucrose solution to the final dosing solution 
(PP-001 solution for intravitreal injection). 
 
Non-Clinical Development 
1.3.1 Mechanism of Action and Non-Clinical Pharmacology 
Proof of concept for PP-001 in the treatment of non-infectious uveitis was established in a rat 
experimental autoimmune uveitis (EAU) model following oral and intravitreal administration of 
PP-001. In these studies, PP-001 was shown to be effective in prevention and treatment of 
experimentally induced autoimmune uveitis. Treatment with PP-001 at an oral dose level of 
25 mg/kg significantly reduced the number of relapses and their intensity when compared to 
control. The determined ocular exposures (AUC) at the oral efficacious dose level of 25 mg/kg in 
rat were 1.27 µg·h/g and 4.8 µg·h/g for vitreous and retina, respectively. Intravitreally dosed 
PP-001 (3 µg/eye) reduced the number of relapses per eye by 50% when compared to control. 
Inhibition of the human ether-à-go-go-related gene (hERG) channel by PP-001 was not indicated 
when tested at concentrations well above the intended human exposure. The 14-day intravenous 
repeated dose toxicity study in rats did not show evidence for adverse effects on safety 
pharmacology parameter at the highest dose tested (1 mg/kg body weight). PP-001 is intended 
for intravitreal use with no need of systemic availability of the drug. The systemic exposure in 
humans is expected to be below the minimal biologically active concentration of 958 ng/ml for 
T-cells and 58–265 ng/ml for evaluated cytokines. Thus, no stand-alone in vivo safety 
pharmacology studies were conducted.  
1.3.2 Pharmacokinetics and Product Metabolism 
Pharmacokinetic and metabolic parameters have been evaluated in several in vitro and in vivo 
experiments in various species.  
PP-001 exhibited strong in vitro plasma protein binding properties with bound fraction levels of 
>99.9%. PP-001 exhibited high metabolic stability after incubation with human liver 
microsomes. Inhibition potential towards human Cytochrome P450 enzymes was detected but 
considered insignificant due to low systemic PP-001 exposure after intravitreal administration. 


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Following intravitreal administration of 60 to 250 µg PP-001 per animal, systemic exposure in 
the low ng/ml range was detected. Systemic exposure at efficacious human doses (0.6–1 µg/eye) 
is expected to be even lower. The half-life of PP-001 after intravitreal injection in rabbits was 
between 12 and 21 hours in ocular tissues and between 5 and 6 hours in peripheral blood. PP-001 
does not elicit ocular melanin binding properties as shown in an in vivo ocular distribution study 
that compared pigmented rats with albino rats. 
1.3.3 Non-Clinical Safety and Toxicology 
Non-clinical safety and toxicology studies included acute (intravitreal) and repeated dose 
(intravenous) toxicity testing in rabbits and rats, and in vitro genotoxicity testing in bacterial and 
mammalian cells. All pivotal non-clinical studies were conducted in a country that is a member 
of the Organisation for Economic Co-operation and Development (OECD) Mutual Acceptance 
of Data program in accordance with the OECD Test Guidelines and Principles of Good 
Laboratory Practice (GLP) and respective ICH and Committee for Medicinal Products for 
Human Use guidance. 
When PP-001 was given via the systemic route the no-observed-effect level (NOEL) in a 14-day 
repeated dose toxicity study in rats was 1 mg/kg body weight, which was the highest dose tested. 
In this study, the detected systemic exposure was several hundred fold higher than the expected 
exposures after intravitreal therapeutic doses in humans and thus provides an adequate safety 
margin with respect to systemic toxicity.  
In an ocular extended single dose toxicity study conducted in rabbits (12 eyes dosed in 6 
animals), intravitreal injection of PP-001 was shown to be safe with a no-observed-adverse-
effect-level (NOAEL) of 10 µg/eye over an observation period of 15 days. Higher doses (20 and 
30 µg/eye) resulted in adverse changes in retina (retina detachment and retinal tear, focal 
exudation etc.), choroid (vessel enlargement, choroidal exudates) and vitreous (floaters). There 
was no test item related intraocular pressure (IOP) abnormality or any other finding in body 
weight change, food and water consumption and clinical pathology in any dose group observed 
during the course of the study. Toxicokinetic analysis of blood plasma after dosing with 30 µg in 
each eye established that maximum plasma concentration (43.5 ng/ml) was reached at 4 h post 
dosing and PP-001 was not detectable after 8 h post dosing. There was no test item related 
intraocular pressure (IOP) abnormality or any other finding in body weight change, food and 
water consumption and clinical pathology in any dose group observed during the course of the 
study 
PP-001 did not show genotoxic potential in S. typhimurium tester strains and a mouse lymphoma 
assay. No phototoxic risk is indicated since PP-001 does not absorb light at relevant 
wavelengths. 
 
Summary of Clinical Data 
This is a first time in human study therefore no clinical data is available. 
 


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2. 
STUDY OBJECTIVES 
Primary Objective 
• 
To assess the safety and tolerability of ascending doses of PP-001 in patients with chronic, 
non-infectious uveitis when administered as a single intravitreal injection of 0.3 µg, 0.6 µg 
and 1.2 µg with the option of an addition cohort with a dose of 2.1 µg PP-001 
Secondary Objectives 
• To assess the improvement of inflammation in patients with chronic, non-infectious 
uveitis after ascending doses of PP-001 when administered as a single intravitreal 
injection of 0.3 µg, 0.6 µg and 1.2 µg with the option of an addition cohort with a dose 
of 2.1 µg PP-001 
• To evaluate the pharmacokinetics of PP-001 in patients with chronic, non-infectious 
uveitis when administered as a single intravitreal injection of 0.3 µg, 0.6 µg and 1.2 µg 
with the option of an addition cohort with a dose of 2.1 µg PP-001 
 
Primary Endpoints 
• Safety parameters (i.e., changes in clinical signs and symptoms from ophthalmic exam, and 
AEs) 
 
Secondary Endpoint 
• Improvement of inflammation or of any other parameter determined at the ophthalmic 
examination following the injection of PP-001 
• The concentration of PP-001 in plasma at Screening, 4 h ± 1 h after dosing and on 
Day 2 
3. 
STUDY DESIGN 
This prospective, multi-centre, open-label, non-randomized, consecutive study will be conducted 
in accordance with the European Union (EU) Clinical Trial Directive 2001/20/EC and 
2005/28/EC, The Medicines for Human Use (Clinical Trials) Regulations 2004 and current 
amendments, the Declaration of Helsinki (revised version of Edinburgh, Scotland 2000), Good 
Manufacturing Practice (GMP), Good Clinical Practice (GCP) and the current national 
regulations and guidelines, approved by both the local ethics committee and regulatory authority. 
Eighteen patients older than 18 years of age will be enrolled and receive a single intravitreal 
injection of PP-001. Patients must have chronic, posterior uveitis, intermediate uveitis or 
panuveitis requiring treatment and have been receiving an adequate therapy of e.g. systemic 
corticosteroid treatment or immunosuppressive therapy (e.g. azathioprine, methotrexate, 
cyclosporine, mycophenolate, tacrolimus) or any combination thereof. Any systemic therapy at 
study start should be continued throughout the study. Patients must have best-corrected Early 
Treatment Diabetic Retinopathy Study (ETDRS) visual acuity of 10 letters or better 


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(approximately 1/35 or 0.032) but equal or less than 50 letters (approximately 20/100 or 0.2) in 
the study eye.  
Patients must give written consent for the study before any study assessments are performed. 
Screening assessments will be performed 8–14 days before dosing. Baseline assessments will be 
performed no more than 7 days before injection. The study will involve eight study visits 
(Screening, Baseline, the day of injection (Day 0) and Days 2, 7, 14, 21 and 28) and telephone 
calls on Day 1 and Day 40.  
Patients will be divided into three cohorts of four patients. Patients will receive the following 
treatments administered as a single intravitreal injection: 
• Cohort 1 will receive 0.3 µg of PP-001 
• Cohort 2 will receive 0.6 µg of PP-001 
• Cohort 3 will receive 1.2 µg of PP-001 
The patients within a cohort will be dosed consecutively with a minimum time interval of 7 days 
between the dosing of the previous patient and the dosing of the next patient. The results from 
each dosing day will be reviewed before progressing towards the subsequent dosing day. The 
next cohort will only receive PP-001 after the previous cohort has completed all study sessions 
up to Day 28 and no safety issues have been identified after reviewed by the Safety data 
management board (SDMB). 
After 12 patients have been treated in the three cohorts and after all patients have finished the 
last follow up an interim analysis by the SDMB will be conducted to identify potential safety 
issues and to determine the highest tolerable dose. If no safety issue can be identified, then a 
fourth, higher dose will be given to a cohort of four patients (Cohort 4). The dose for a potential 
Cohort 4 will be 2.1 µg of PP-001. 
If safety issues are identified in any of Cohorts 2, 3 or 4, two additional patients will receive the 
next lower dose.  
Safety will be assessed by monitoring vital signs and recording of AEs (see Section 7). Safety 
procedures will be performed by the Investigator or suitably qualified individuals designated by 
the Investigator. 
Pharmacokinetic sampling will take place at Screening, 4 h ± 1 h after injection and on Day 2.  
Efficacy will be evaluated by ophthalmic examination. 
An overview of the schedule of assessments/procedures is presented in Table 1. 
 
Study Rationale 
PP-001 is proposed for development as an intravitreal injection for the treatment of NIU. This 
first time in human study will investigate the safety, tolerability and efficacy of single ascending 
doses of PP-001 using intravitreal injection in male and female patients. The study population 
will comprise patients with NIU and an otherwise good state of health to ensure homogeneity. 
Patients with chronic posterior uveitis, intermediate uveitis or panuveitis, for whom maximal 
medical treatment failed or who are unable to tolerate medical treatment because of adverse 
ocular or systemic effects will be included in this study. The data generated in this study will 


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support the progression of a well-tolerated dose of PP-001, administered by intravitreal injection 
in patients with NIU.  
3.1.1 Dose Rationale 
PP-001 will be developed for the treatment of non-infectious posterior uveitis. 
For evaluation of a safe human starting dose, a calculation based on a mg/kg basis is not 
considered appropriate for intravitreally administered drugs. However, in the EU there is no 
applicable guidance available in this regard and thus, reference is made to the Food and Drug 
Administration’s Note for Guidance Estimating the Maximum Safe Starting Dose in Initial 
Clinical Trials [Food and Drug Administration, 2005]. For PP-001, the starting dose was 
evaluated by normalization the compartmental volumes and concentrations of the therapeutic 
doses between rabbits and humans. Using the different volumes for vitreous humour (rabbit and 
human) the NOAEL dose of 10 µg/eye in rabbits would therefore correspond to a human dose of 
26.7 µg/eye.  
Since this study will involve patients data on the minimum efficacious dose of PP-001 and its 
exposure in vitreous and retinal tissues (which are both considered the main target tissues) are 
considered. More importantly, this calculation provides an additional safety margin compared to 
a simple normalization based on differences in the size of eyes (rabbit vs. human) and is to be 
preferred because of the steep dose-toxicity curve that was observed in the intravitreal toxicity 
study in rabbits. 
An oral dose of 25 mg/kg was shown to be efficacious in the EAU rat model. This dose level led 
to an ocular AUC of 1.27 µg·h/g and 4.8 µg·h/g for vitreous and retina in pigmented animals, 
respectively. Exposure of vitreous and retina have been determined after intravitreal injection of 
various doses of PP-001 into pigmented rabbit eyes. By applying a linear extrapolation it was 
calculated that an efficacious dose of approximately 0.25–0.36 µg/eye in rabbits corresponds to 
an efficacious retinal AUC of 4.8 µg·h/g, whereas a dose of 0.20–0.27 µg per rabbit eye is 
needed to reach an efficacious vitreous AUC of 1.27 µg·h/g (see Table 2).  
Considering the higher vitreous volume of the human eye, a dose of 0.54 to 0.96 µg/eye is 
expected to achieve efficacious exposure in the human vitreous and retina, respectively. 
 
Table 2 
Calculated Human Efficacious Exposure and Dose 
Species 
Vitreous 
humour 
[ml] 
Efficacious dose 
based on exposure 
in retina 
Efficacious 
retinal AUC 
(µg·h/g) 
Efficacious dose 
based on vitreous 
Exposure 
Efficacious 
vitreous AUC 
(µg·h/g) 
Rat 
0.056 
25 mg/kg 
 
25 mg/kg 
 
Rabbit 
1.5 
0.25–0.36* µg/eye 
4.8 
0.20–0.27* µg/eye 
1.27 
Human 
4 
0.67–0.96** µg/eye 
 
0.54–0.73** µg/eye 
 
AUC: Area under the plasma concentration time curve 


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* Calculated efficacious dose based on PK study in rabbits; values are calculated by dividing the applied intravitreal 
dose/eye by obtained the AUC from time 0 to time t in pigmented rabbits (see Section 1.3.2) multiplied by the 
efficacious AUC in pigmented rats (see Section 1.3.2); ** Calculated efficacious human dose using the vitreous 
volume difference between rabbit and human. 
 
It must be noted that the calculation above is only an estimation. Due to inter-individual 
variations in the volume of vitreous humour, an even lower starting dose of 0.3 µg/eye is 
proposed for this first time in human study. 
With a starting dose of 0.3 µg/eye an appropriate safety margin of 86 is provided as depicted 
below in Table 3. 
 
Table 3 
Safety Margin Calculation of Human Starting Dose  
Species 
Vitreous 
Humour 
[ml] 
Dose 
[µg/eye/patient] 
Proposed 
Starting Dose 
[µg/eye/patient] 
Safety Margin* 
Rabbit 
1.5 
10 
 
 
Human 
4 
26.7* 
0.3 
>86** 
* Calculated human equivalent dose based on normalization of compartment volumes of the vitreous. 
** Safety margin to calculated human equivalent dose. 
 
In conclusion, the proposed starting dose of 0.3 µg/eye provides an adequate safety margin for 
clinical study PP-001-1001 with respect to local and systemic toxicity. Plasma levels following a 
single intravitreal dose of 0.3 µg/eye will lead to a negligibly low plasma exposure of PP-001 (if 
present at all) and thus no systemic toxicity is expected. Regarding local effects observed in the 
eye the starting dose provides a safety margin >86-fold compared to the calculated human 
equivalent dose derived from an extended single dose study in rabbits, where 10 µg/eye was 
considered to be the NOAEL. 
Consecutive dosing and careful monitoring using state of the art methodology will provide 
additional safety level. 
 
Potential Risks and Benefits to Human Patients 
PP-001 is a novel chemical molecule to inhibit a known enzyme called DHODH, a known drug 
target for systemic treatment of rheumatoid arthritis, psoriatic arthritis and multiple sclerosis. 
PP-001 is a novel inhibitor of DHODH and has the potential to deliver a new treatment for 
patients with severe non-infectious uveitis. Currently patients suffering from intermediate and/or 
the posterior uveitis (i.e., the vitreous body and retina/choroid are affected) are routinely treated 
with systemic corticosteroids with well known side effects. The future expected therapeutic role 
of PP-001 will be as a steroid-sparing agent that will allow steroid doses to be tapered quickly or 
even replaced.  
In this proposed study the safety and tolerability of single doses of intravitreally administered 
PP-001 will be evaluated. Based on the preclinical pharmacokinetics the ocular half-life is 


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expected to be less than 20 h and the systemic exposure is expected to be below the biological 
activity and close to or below the limit of detection of the applied bioanalytical method 
(10 ng/ml). Due to the local treatment (intravitreal injection) and the preclinical data on plasma 
exposure of PP-001 it is unlikely that there will be any systemic exposure of PP-001 in human 
and therefore no systemic effects of PP-001 are expected. 
This study will identify the tolerated doses at expected efficacious ocular exposures and will 
serve as the basis for further studies long term acting PP-001. 
The inclusion and exclusion criteria restrict access to the study to severely affected patients with 
severely compromised visual acuity 
At this stage of development, toxicity of PP-001 in human eyes cannot be ruled out but the risk is 
considered low based on the safety factor calculated using preclinical data. Considering the 
expected low systemic exposure of PP-001, potential systemic side effects known from other 
DHODH inhibitors are not expected. In order to minimize this risk, the first patient will receive 
the lowest dose, which is approximately 90 times less than the established safe concentration in 
preclinical studies. The next patient will only receive an injection after a safety gap of 7 days and 
review of all data by the SDMB. The next highest dose will only be administered after the safety 
of the lower dose has been established. 
The procedure of an injection into an inflamed eye has been established in other approved types 
of uveitis treatment such as Ozurdex and Retisert, in Phase III studies with sirolimus and the off-
label use of intraocular triamcinolone. These studies have not shown any significant risks 
associated with eye injections. Concerns have been raised over the application of small crystals 
into the eye because of the potential to induce an autoinflammatory reaction. The type and 
structure of the preparation used in this study should reduce this risk.  
Study PP-001-1001 will provide valuable data on the safety, tolerance and pharmacokinetic 
profile of PP-001 after single dosing in patients with severe uveitis, which will help to define the 
dose for future studies. 
In conclusion, based on the currently available safety data, PP-001 has an acceptable benefit/risk 
profile in patients at doses in the estimated therapeutic range of 0.3–1.2 (2.1) µg/eye, and at the 
same time might reduce some of the inflammatory indices in patients with severe uveitis who 
have no treatment alternative. 
4. 
STUDY POPULATION 
 
Inclusion Criteria 
1. Male or female patients of non child bearing potential older than 18years of age who have 
diagnosis of chronic posterior uveitis, intermediate uveitis or panuveitis. 
2. Good state of health (mentally and physically). Laboratory parameters and vital signs of 
patients must be within the normal ranges and patients must not have a diagnosis of any 
acute or chronic illness except uveitis. 
3. A signed and dated written informed consent form. 
4. A signed and dated written data protection consent form. 


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5. Male patients must ensure that one highly effective method combined with an acceptable 
method of contraception is used for the entire duration of the study, from first dose up to 
the study follow-up visit, and refrain from fathering a child in the 3 months following the 
last study drug administration. Male patients must agree with their female partners prior to 
screening to use the above specified methods of contraception while receiving protocol-
specified medication, and for 3 months after stopping the medication. Female patients must 
be of non-childbearing potential. The definition of non-childbearing potential includes the 
following: 
• Surgically sterile (e.g., hysterectomy with or without oophorectomy; fallopian 
tube ligation; endometrial ablation), at least 30 days prior to signature of the 
Informed Consent form 
• At least 3 years post-menopause (i.e., 4 years post last menstrual period), or 
menopause confirmed by follicle-stimulating hormone (FSH) testing.  
6. Have diagnosis of chronic posterior uveitis, intermediate uveitis or panuveitis (as defined 
by the Standardization of Uveitis Nomenclature Working Group working group [Jabs et 
al., 2005]) in at least one eye. For patients with panuveitis, the anterior component of 
inflammation must be less than the posterior component. The investigator to his best 
knowledge must rule out any suspected masquerade syndrome or infection prior to study 
entry. 
7. Have chronic uveitis, posterior, intermediate uveitis or panuveitis requiring treatment. 
8. Have media clarity, pupillary dilation and patient cooperation sufficient for adequate 
visualization of the optic nerve in the study eye. 
9. Have been receiving an adequate therapy of e.g. systemic corticosteroid treatment or 
immunosuppressive therapy (e.g. azathioprine, methotrexate, cyclosporine, 
mycophenolate, tacrolimus) or any combination thereof. Any systemic therapy at study 
start should be continued throughout the study. 
10. Best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity of 10 
letters or better (approximately 1/35 or 0.032) but equal or less than 50 letters 
(approximately 20/100 or 0.2) in the study eye. 
11. Best-corrected ETDRS visual acuity of 50 letters or better in the fellow eye (approximately 
20/100 or 0.2). 
 
Exclusion Criteria 
1. Patients in whom media opacities (cornea, anterior or posterior synechia, cataract, vitreous 
haze and others) of either eye preclude investigation and documentation of the posterior 
pole and intravenous fluorescein angiography, or optical coherence tomography evaluation 
in the study eye. 
2. Patients receiving any local. 
3. Treatment with cyclophosphamide or chlorambucil. 
4. Intravitreal injections (including but not limited to anti-vascular endothelial growth factors) 
60 days prior to the baseline. 
5. Posterior subtenon's injection or orbital floor injection of steroids 90 days prior to Baseline. 
6. Any implantable corticosteroid-eluting device (Ozurdex, Iluvien, Retisert, triamcinolone 
intravitreal implant, fluocinolone intravitreal implant) in the study eye, with the following 
exceptions: 


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• If the device had been removed more than 90 days prior to Day 0 of this study, the 
eye will be eligible for PP-001-1001. 
• If Ozurdex had been implanted 6 months before Day 0 of this study, the eye will 
be eligible for PP-001-1001. 
• If Iluvien or Retisert had been implanted 3 years before Day 0 of this study, the 
eye will be eligible for PP-001-1001. 
7. Intraocular surgery within 90 days prior to Day 0 in the study eye. 
8. Capsulotomy within 30 days prior to Day 0 in the study eye. 
9. History of vitreoretinal surgery or scleral buckling within 90 days prior to Day 0 in the 
study eye. 
10. Any ocular surgery (including cataract extraction or capsulotomy) of the study eye 
anticipated within the first 60 days following Day 0. 
11. Intraocular pressure ≥25 mmHg in the study eye (glaucoma patients maintained on no 
more than one topical medication with IOP <25 mmHg are allowed to participate). 
12. Ocular hypotonia (IOP less than 6 mmHg). 
13. Pupillary dilation inadequate for quality fundus photography in the study eye. 
14. Aphakia or anterior chamber lens in the study eye. 
15. Visible scleral thinning, scleral ectasia or keratoconus in the study eye. 
16. Presence of any ocular malignancy. 
17. Ocular or periocular infection in either eye or the use of systemic antibiotics. 
18. Participation in other investigational drug or device clinical trials within 90 days prior to 
Day 0, or planning to participate in other investigational drug or device clinical trials 
within 180 days following Day 0. This includes both ocular and non-ocular clinical trials. 
19. Female patients who are of childbearing potential or who are pregnant.  
20. Use of any anticoagulant or thrombocyte aggregation inhibiting agent (marcumar, 
warfarin, heparin, enoxaparin, apixaban, rivaroxaban, pentosanpolysulfate, dabigatran, 
aspirin and others) less than 14 days prior to injection visit (Day 0). 
21. Known allergy or hypersensitivity to the study medication, any component of the delivery 
vehicle, any corticosteroids or any diagnostic agents used during the study (e.g., 
fluorescein, dilation drops, antibiotic drops and povidone). 
22. Patients with diagnosis of any acute or chronic systemic illness other than uveitis.  
5. 
STUDY DRUG ADMINISTRATION 
See Section 8 for a complete description of study drugs. Instructions for the preparation of the 
study drugs will be provided in a Pharmacy Manual. 
 
Randomization 
This is a non-randomized study. Patients will be assigned to the next available cohort as they are 
recruited to the study. 
 
Study Drug Treatment 
5.2.1 Duration of Treatment 
Patients will receive a single intraocular dose of PP-001. 


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5.2.2 Post-Baseline Treatment Modifications 
The results from each dosing day will be reviewed before progressing with the subsequent 
dosing day. Dosing in the next cohort will only commence with dosing after the previous cohort 
has completed all study sessions up to day 28 and no safety issues have been identified after 
being reviewed by the SDMB. 
 
Timing of Dosing and Dose Administration 
The study drug will be administered on Day 0 following the completion of all pre-dose 
procedures. 
 
Preparation of Treatment 
A Pharmacy Manual will be provided to investigative sites with additional details on preparation 
of study drug material. 
 
Blinding 
This is an open-label study. 
 
Unblinding of Therapy Assignments 
As this is an open-label study, unblinding will not be required. 
 
Adherence 
Throughout the study, hospital staff or study personnel will administer all doses of study drug. 
The date, start and stop time of each dose will be recorded in the electronic case report form 
(eCRF). 
 
Occupational Safety 
PP-001 is not expected to pose any occupational safety risk to site staff under normal conditions 
of use and administration. 
A Material Safety Data Sheet describing occupational hazards and recommended handling 
precautions either will be provided to the Investigator, where this is required by local laws, or is 
available upon request from Panoptes Pharma GesmbH. 
In line with good handling of chemical products, precautions are to be taken to avoid skin and 
eye contact. In the case of unintentional occupational exposure, any signs or symptoms should be 
treated appropriately and the Sponsor notified. 
6. 
STUDY ASSESSMENTS AND PROCEDURE 
A schedule of study procedures is presented in Table 1. Patients meeting the eligibility criteria 
listed in Section 4 may be enrolled in the study after the nature and purpose of the protocol have 


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been explained and written informed consent to participate has been voluntarily given. Study 
personnel must complete all screening procedures after informed consent is signed and before 
the first dose of study drug. Note: assessments performed as part of routine standard of care 
before consent may be used to satisfy study screening requirements; however, no study-specific 
procedures may be performed before informed consent is given. 
The time and day on which PP-001 is administered will be regarded as 0 h on Day 0. The 
Investigator should make every effort to perform procedures at the scheduled times and to record 
the actual time of the procedures, where appropriate, in the patient's eCRF. 
For patients who are screened (i.e., those with signed written informed consent) but do not meet 
the screening criteria, the reason for screening failure will be recorded. 
 
Surgical Procedure 
The study treatment procedure must be performed only by the qualified Investigator in an 
operating room, surgical suite, or in an office setting using sterile technique. The study 
medication kit should be readily available during the procedure. The final diluted PP-001 
solution will be injected at the required dose at a volume of 100 µL (see Section 8). For safety 
reasons, an emergency pars plana vitrectomy aiming at removal of injected drug will be available 
in case of a severe adverse event including, but limited to, acute loss of visual acuity or acute 
inflammatory or toxic response to injection. It is therefore mandatory for patients to remain in 
the hospital for at least 4 hours after the injection procedure.  
 
Medical/Surgical History 
A medical and surgical history will be taken at Screening. All medical history findings that have 
been present/active within 5 years before enrolment will be entered into the eCRF regardless of 
clinical relevance or presence at study start. Medical history findings that have not been present 
within the 5 years before enrolment will be recorded if deemed clinically relevant to the conduct 
of the study by the Investigator. The medical history should include drug allergy history and past 
and present smoking status. 
 
Physical Examination 
A complete physical examination will be performed by the Investigator at Screening. At the time 
points specified in Table 1, subsequent directed physical examinations will be performed 
according to standard institutional practices and must be documented in source documents. 
Body weight and height will be measured at Screening only. 
 
Vital Signs 
Vital signs (heart rate [HR] and blood pressure [BP]) will be recorded at time points specified in 
Table 1. Blood pressure and HR will be assessed according to standard practice at the clinical sites. 
Study personnel will record vital sign measurements in the eCRF. 


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Vital signs measurements are to be repeated if clinically significant changes or machine errors 
occur. Out of range BP and HR will be repeated at the Investigator’s discretion. Semi-supine BP 
and HR will be measured more frequently if warranted by the clinical condition of the patient. 
 
Twelve-Lead Electrocardiogram 
Triplicate 12-lead electrocardiograms (ECGs) will be performed within a 5-minute interval at the 
time points outlined in Table 1. 
The patient should be stabilized in a supine position for 5 minutes before recording the ECG at 
Screening. The ECG recordings should allow a full assessment of QT intervals. Machine-read 
values for QTc/QTcF will be evaluated for determination of eligibility at Screening. If the 
quality of the ECG is insufficient then it must be repeated. All ECG data must be reviewed by 
the attending physician and any findings of clinical significance found following Screening will 
be recorded as AEs in the eCRF. In addition, advice may be sought from appropriate 
cardiologists, if necessary. All ECGs will be made available to the Sponsor for review and might 
be sent to a Cardiac Core Laboratory for further evaluation.   
 
Clinical Laboratory Tests 
Safety laboratory tests will be performed at the time points specified in Table 1 and sent to a 
local laboratory. Additional tests may be performed at the discretion of the Investigator if 
deemed clinically appropriate. If required, samples may be sent to a central laboratory for 
confirmation of local results. 
A full list of the clinical laboratory tests that will be performed and analyzed is presented in 
Section 21.1. 
Any safety laboratory results outside the normal range will be repeated at the discretion of the 
Investigator and will be evaluated by the Investigator or designee as “clinically significant (CS)” 
or “not clinically significant (NCS).” Any CS value should be repeated as necessary and 
followed until resolution. 
 
Opthalmic Examination Procedures 
Detailed ophthalmic examination will be used to evaluate screening criteria, determine efficacy 
and as a safety measure. All procedures should be performed at the times outlined in Table 1. 
The primary efficacy variable is vitreous haze. The ophthalmologist will grade vitreous haze by 
viewing the optic disc and posterior retina using an indirect ophthalmoscope set to large beam 
and mid power illumination with a 20-diopter lens. Low ambient lighting and the same indirect 
ophthalmoscope should be used whenever possible. The scale is based on the following unit 
scale categorized as follows: 
0 
No inflammation 
+0.5 
Trace inflammation (slight blurring of the optic disc margins and/or 
loss of the NFL reflex) 
+1 
Mild blurring of retinal vessels and optic nerve 


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+1.5 
Optic nerve head and posterior retinal view obscuration greater than 
+1, but less than +2 
+2 
Moderate blurring of optic nerve head 
+3 
Marked blurring of optic nerve head 
+4 
Optic nerve head not visible 
 
6.7.1 Electroretinography 
Patients will receive anaesthetic drops and the patient’s eyelids will be kept open with a 
speculum. An electrode is gently placed on each eye and an additional electrode is placed on the 
skin to provide a ground. Electrical signals produced by the retina in response to light will be 
measured with the electrodes. 
6.7.2 Fluorescein Angiogram 
Fluoroscein angiograms will be used to assess blood flow in the retina and choroid. Dilation eye 
drops will be given to patients, who will then place their chin on a chin rest and forehead against 
a support bar. Images of the retina, papilla, macular region and the choroid will be taken. 
6.7.3 Optical Coherence Tomography 
Three-dimensional images of the eye will be generated using optical coherence tomography 
(OCT). OTC is a laser-based, non-invasive, diagnostic system providing high-resolution images 
of the retina and retinal thickness. Optical coherence tomography will be performed in the study 
eye only. High-resolution cross-sectional images will be examined for physiological 
abnormalities. 
6.7.4 Best Corrected Visual Acuity 
Best corrected visual acuity will be measured in both eyes using an ETDRS chart. Patients will 
be asked to read the smallest letters they can from a chart. 
6.7.5 Visual Field Measurement 
Computerised 30° visual field measurement will be conducted. 
6.7.6 Visually Evoked Cortical Potential 
The electrical response of the primary visual cortex to a visual stimulus will be measured. Three 
electrodes will be placed on the scalp. One electrode will measure the response, another 
electrode will be placed at a reference location, typically on the forehead or top of the head. The 
third electrode will be placed on the patient’s ear for grounding. These electrodes will be 
connected to a visual electrodiagnostic test system. 


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6.7.7 Intraocular Pressure 
Intraocular pressure will be measured using Goldman contact tonometry. 
6.7.8 Slit Lamp Examination 
A slit lamp will be used to examine the conjuctiva, cornea, anterior chamber including grading of 
cells and haze (classified according to Standardization of Uveitis Nomenclature Working Group 
criteria), lens (classified according to Lens opacities classification system II) and vitreal haze 
(classified according to Standardization of Uveitis Nomenclature Working Group). 
6.7.9 Dilated Fundoscopy 
Visualization of the fundus will be carried out as part of an eye exam by dilating the patient’s 
pupils. This procedure will include slit lamp biomicroscopy of the fundus. 
6.7.10 Corneal endothelial microscopy 
The corneal endothelial layer will be assessed by microscopic evaluation of the cornea.  
6.7.11 Fundus photography 
The eye, retina, retinal vasculature, optic disc, macula and posterior pole will be photographed 
using a retinal camera. Vitreous haze will also be documented. 
6.7.12 Amsler grid 
To test for macular degeneration, patients will be asked to look at an Amsler grid and wear their 
reading glasses. With one eye covered, patients will be asked to state if any of the lines appear 
wavy, blurred or distorted, whether there are missing or dark areas in the grid. The test will be 
repeated for both eyes. 
6.7.13 Health Outcome Measures 
Patient-reported outcomes will be assessed using the National Eye Institute Visual Functioning 
Questionnaire 25 (VFQ-25), SF36™ Health Survey Version 2 (SF-36v2) and EuroQol-5 
Dimensions Health Questionnaire (EQ-5D). For additional information on these outcome 
measures, refer to the Procedure Manual. 
 
Telephone Interview 
A telephone interview will take place on Day 1 to evaluate the safety of PP-001. Standardized 
questions will be used and will include (but not be limited to) assessment of pain, blurred vision, 
change in visual acuity and eye redness. 


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Prior and Concomitant Medications 
Prior and concomitant medications that will be recorded include prescription medications, 
dietary supplements/vitamins and over-the-counter medications. Topical medications will be 
recorded only if used as treatment for an AE. The minimum requirement is that drug name, 
indication and the start and stop dates of administration are to be recorded. 
6.9.1 Prior Medications 
A medication history will be taken at Screening. All medications taken within 1 week before  
Day 0 will be entered into the eCRF. 
6.9.2 Concomitant Medication 
All concomitant medications taken during the study will be recorded in the patient's eCRF. 
 
Prohibited Medications 
The following medications are prohibited: 
• Local biologicals  
• Cyclophosphamide or chlorambucil 
• Immunosuppressive, immunomodulatory or steroid treatment for any other disease 
than uveitis 
• Any anticoagulant or thrombocyte aggregation inhibiting agent (marcumar, warfarin, 
heparin, enoxaparin, apixaban, rivaroxaban, pentosanpolysulfate, dabigatran, aspirin 
and others) 
• Any systemic antibiotic treatment 
 
Non-Pharmacologic Treatments and Procedures 
Non-pharmacologic treatments and procedures (e.g., diagnostic) that occur during the study will 
be entered into the eCRF, including the date and reason for the treatment/procedure. 
 
Sample Collection for Pharmacokinetic Analysis 
6.12.1 Plasma Sample Collection 
Blood samples for pharmacokinetic analysis of PP-001 in plasma following intraocular dosing 
will be collected at Screening, 4 h ± 1 h after dosing and on Day 2. 
Blood samples will be collected from a vein in the opposite arm from the arm in which infusion 
is given into tubes containing K3EDTA, as a coating, and immediately chilled on crushed ice. 
Plasma will be separated by centrifugation at approximately 2,000g for approximately 10 
minutes at approximately +4 °C and transferred in equal aliquots (at least 300 µl) to 3 
polypropylene screw top cryo vials labeled with the following: PP-001-1001, subject number, 


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date of dosing, nominal sampling time, aliquot ID (e.g. A, B, C). Promptly following 
centrifugation, plasma specimens will be immediately frozen and stored at approximately -20 °C 
or cooler until transported for analysis. The total time period from blood withdrawal to storage of 
plasma at approximately -20 °C should not exceed 60 minutes. The primary samples (aliquot A) 
should be transferred to the A&M analytical laboratory on dry ice. 
6.12.2 Assay Methodology 
Pharmacokinetic samples will be analyzed for the concentration of PP-001 using a validated 
liquid chromatography-tandem mass spectrometry method at the bioanalytical laboratory. 
 
Total Blood Volume Collected 
Patients will have approximately 20 mL of blood collected for safety and pharmacokinetic 
evaluations during the study. 
 
Discontinuation from Treatment or Study 
Patients are free to withdraw from the study at any time for any reason. Patients may be 
withdrawn from the study at the discretion of the Principal Investigator or Sub-Investigator at 
any time. Once a patient has been withdrawn from the study, they may not be re-entered. Patients 
who withdraw or who are withdrawn from the study will not be replaced. If a patient is 
discontinued from treatment or from the study, the reason for discontinuation will be collected in 
the eCRF. 
If a patient is prematurely withdrawn from study drug treatment, the Investigator should make 
every effort to retain the patient in the study and perform all procedures scheduled for the 
follow-up. Any patient withdrawn from treatment due to an AE, serious AE (SAE) or clinically 
significant safety value will be evaluated by the Investigator, or a monitoring physician, and will 
be treated and/or followed up until the symptoms or values have either resolved or are assessed 
as stable by the Investigator. 
6.14.1 Discontinuation from Study 
A patient may be discontinued prematurely from the study for the following reasons: 
• Withdrawal by patient (specify the reason in the eCRF) 
• Lost to follow-up 
• Death 
• Physician decision (i.e., assessment that it is not in the patient’s best interest to 
continue, or another reason; specify the reason in the eCRF) 
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6.14.2 Individual Stopping Criteria 
If an individual Patient meets one or more of the following criteria, the SDMB and Investigator 
will discuss whether the patient should be withdrawn from the study or dosing, or postponed 
until the criterion is no longer met: 
• Patient develops a concurrent illness, condition or procedural complication that would 
interfere with the patient’s continued participation 
• Patient experiences a study drug-related SAE as determined by the Investigator 
Patients may also be withdrawn from the study at any time at the discretion of the Investigator 
for other safety or tolerability reasons, or for behavioural or administrative reasons. 
A patient may also withdraw from the study at any time at their own request. 
If a patient is prematurely withdrawn from study treatment, the Investigator should make every 
effort to retain the patient in the study and to perform all procedures scheduled for the follow-up 
visit. Any patient withdrawn from treatment due to an AE, SAE or clinically significant 
abnormal laboratory test value will be evaluated by the Investigator, or a monitoring physician, 
and will be treated and/or followed up until the symptoms or values have either resolved or are 
assessed as stable by the Investigator. 
6.14.3 Study Stopping Criteria 
Dosing of further patients will be stopped if the following criterion is observed: 
• A moderate or severe AE classified as being possibly, probably or definitively study-
drug related or potential major safety concerns as identified by the Investigator after 
consultation with the SDMB are reported in more than 50% of patients in the same 
cohort.  
Dosing will be stopped or the dose decreased if: 
• One patient on any dosing day shows a possibly, probably or definitively study-drug-
related SAE judged by the Investigator after consultation with the SDMB or other 
potential major safety concerns are identified by the Investigator in agreement with the 
SDMB. 
6.14.4 Lost to Follow-up 
If a patient does not report to the study site for a scheduled visit, study personnel will make four 
contact attempts: three telephone contact attempts and, if these are unsuccessful, a certified letter 
will be sent to the patient. The patient will be considered lost to follow-up if (1) upon receipt of 
delivery confirmation of the certified letter the patient does not contact the site or (2) the certified 
letter is returned as undeliverable within 7 days. 
 
Premature Termination of the Trial  
In the event of any SAE, which, in the investigator’s opinion, justifies termination of the trial, 
dosing will be stopped and the sponsor will be informed immediately. The sponsor and 


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investigator reserve the right to terminate this trial should serious or severe AEs or any other 
safety issue occur during the trial. If the trial is terminated prematurely, the investigator will 
return all eCRFs to the sponsor, and the sponsor or investigator, as appropriate, will provide a 
written statement of the reasons for termination. The sponsor will ensure that the relevant 
regulatory agencies and main research ethics committees are notified. 
 
Contraceptive measures 
Female patients of childbearing potential are not allowed to participate in this study. The 
definition of non-childbearing potential includes the following: 
• Surgically sterile (e.g., hysterectomy with or without oophorectomy; fallopian 
tube ligation; endometrial ablation), at least 30 days prior to signature of the 
Informed Consent form 
• At least 3 years post-menopause (i.e., 4 years post last menstrual period), or 
menopause confirmed by follicle-stimulating hormone (FSH) testing.  
Fertile men need to adhere to contraceptive measures in accordance with the “Recommendations 
related to contraception and pregnancy testing in clinical trials, September 2014” of the Clinical 
Trials Facilitation Group. 
Male patients must ensure that one highly effective method of contraception combined with an 
acceptable method of contraception is used for the entire duration of the study, from first dose up 
to the study follow-up visit, and must refrain from fathering a child in the 3 months following the 
last study drug administration. Male patients must agree with their female partners prior to 
screening to use the above specified methods of contraception while receiving protocol-specified 
medication, and for 3 months after stopping the medication. 
Highly effective methods of birth control are defined as those that result in a low failure (i.e., 
< 1 % per year) when used consistently and correctly, such as:  
- combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, transdermal) 
- progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable)  
- intrauterine device  
- intrauterine hormone-releasing system  
- bilateral tubal occlusion 
- vasectomised partner 
- sexual abstinence 
Acceptable birth control methods are defined as those that result in a failure rate of more than 
1% per year and include: 
- progestogen-only hormonal contraception, where inhibition of ovulation is not the primary 
mode of action 
- male or female condom with or without spermicide 
- cap, diaphragm or sponge with spermicide; 
 
Periodic abstinence and withdrawal are not acceptable methods of contraception. Female 
partners of male patients must be informed by their male partners about the need to use one 


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highly effective methods of birth control combined with an acceptable method of birth control as 
defined above. 
7. 
ADVERSE EVENTS 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not related to the investigational medicinal product. 
Any pre-existing conditions or signs and/or symptoms present in a patient before the start of the 
study (i.e., before informed consent) should be recorded as medical/surgical history. Any 
medical occurrences that are new or worsened from the time of informed consent and up to and 
including the final visit must be reported as AEs or SAEs. All AEs and SAEs must be recorded 
irrespective of whether they are considered drug-related. 
Patients will be monitored throughout the study for adverse reactions to the study medications 
and/or procedures at each study visit. Questions will be posed in a non-leading manner so as not 
to bias the response. In addition to questioning at specific time points, patients will be 
encouraged to report any AEs spontaneously. Any patient with an AE, SAE or clinically 
significant abnormal laboratory test value will be evaluated by the Investigator, or a monitoring 
physician, and will be treated and/or followed up until the symptoms or values have resolved or 
are assessed as stable by the Investigator. A physician, either at the Investigative site or at a 
nearby hospital emergency room, will administer treatment of any SAEs. Where appropriate, 
medical tests and examinations may be performed to ensure that an AE has fully resolved. 
Adverse events will be monitored throughout the study from the time a patient is consented 
through the final follow-up visit; SAEs are to be collected from the time of consent through to 
the follow-up visit. Whenever possible, a specific disease or syndrome rather than individual 
associated signs and symptoms should be identified by the Investigator and recorded on the 
patient's eCRF. However, if an observed or reported sign or symptom is not considered a 
component of a specific disease or syndrome by the Investigator, it should be recorded as a 
separate AE on the patient's eCRF. 
Each AE or SAE reported will be assessed for severity and the date and time of onset (if 
available), time relationship to dosing, duration and outcome of each event will be noted. 
Laboratory abnormalities are not considered AEs unless they are associated with clinical signs 
and symptoms or require medical intervention. Clinically significant abnormal clinical laboratory 
findings or other abnormal assessments that are associated with the disease being studied, unless 
judged by the Investigator as more severe than expected for the patient’s condition, or that are 
present or detected at the start of the study and do not worsen, will not be reported as AEs or 
SAEs. 
The Investigator will exercise medical and scientific judgment in deciding whether an abnormal 
clinical laboratory finding or other abnormal assessment is clinically significant. 


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Assessment of Severity (Intensity) 
The following definitions for rating severity (intensity) will be used: 
Mild:  
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate:  
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but the 
patient is still able to function. 
Severe: 
The type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
 
Assessment of Relationship to Study Drug 
The Investigator will use his/her clinical judgment to explain each AE and determine its 
relationship, if any, to study drug treatment. Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors and the temporal relationship of the 
event to the study drug will be considered and investigated. The Investigator will also consult the 
Investigator’s Brochure in the determination of his/her assessment. Causality should be assessed 
using the following categories: 
Not Related  
The event could readily be explained by factors not involving the study 
drug and a temporal relationship with the study drug did not exist. 
Possibly Related  
There was some temporal relationship between the event and the 
administration of the study drug and the event was unlikely to be explained 
by the patient’s medical condition or other therapies. 
Probably Related  
The temporal relationship between the event and the administration of the 
study drug was suggestive, and the event was less likely to be explained by 
the patient’s medical condition or other therapies. 
Definitely Related  The event followed a reasonable temporal sequence from administration of 
the study drug, followed a known or suspected response pattern to the 
study drug, was confirmed by improvement upon stopping the study drug 
(dechallenge) and reappeared upon repeated exposure (rechallenge). (Note: 
this is not to be construed as requiring re-exposure of the patient, however, 
a category of definitely related can only be used when recurrence was 
observed). 
 
Serious Adverse Events 
An SAE is any untoward medical occurrence that: 
• Results in death 
• Is life-threatening 
• Results in persistent or significant disability/incapacity 


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• Requires in patient hospitalization or prolongation of existing hospitalization 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
NOTE: medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These should also be considered serious. Examples of such events are invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of drug dependency or drug abuse. 
All SAEs for patients occurring from the time of informed consent through to the follow-up visit 
must be reported to Panoptes Pharma GesmbH or their representative within 24 h of the 
knowledge of the occurrence (this refers to any AE that meets one or more of the aforementioned 
serious criteria). Reporting is done by completing the SAE form electronically in the eCRF 
system for the study.  
The SAE form should be completed in as much detail as possible but a lack of complete 
information should not delay the reporting of the SAE.  
There may be situations when an SAE has occurred and the Investigator has minimal information 
to include in the initial report to Panoptes Pharma GesmbH. However, it is very important that 
the Investigator always makes an assessment of causality for every event prior to transmission of 
the SAE report form to Panoptes Pharma GesmbH. The Investigator may change his/her opinion 
of causality in light of follow-up information, amending the SAE report form accordingly. The 
causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
The Investigator will provide the assessment of causality as per instructions on the SAE form in 
the CRF. 
If an SAE occurs during this study, the following (Sponsor) personnel should be contacted: 
Dr. Franz Obermayr: 
Phone (office and after-hours):  
+43 664 8557369 
 
Other Reportable Events 
Certain events that occur in the absence of an AE should be reported to the Sponsor as Other 
Reportable Events. These include the following: 
• Pregnancy exposure (female partners of male patient becomes pregnant while taking 
study drug) 
• Although pregnancy is not technically an AE, all pregnancies must be followed to 
conclusion to determine their outcome. This information is important for both 
drug safety and public health concerns. It is the responsibility of the Investigator 
or designee to report any pregnancy in a patient that occurs during this study to 
Panoptes Pharma GesmbH or their representative. 


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• Accidental exposure (someone other than the study patient was exposed to study drug) 
• Overdose (patient received more than the prescribed dose of study drug within a given 
timeframe) 
• Other medication errors that potentially place patients at a greater risk of harm than 
was previously known or recognized (e.g., study drug was administered by an incorrect 
route) 
8. 
DRUG SUPPLIES 
 
PP-001 
The active substance being investigated in this study is PP-001. Physicochemical properties are 
presented in the PP-001 Investigator’s Brochure. 
The drug product for intraocular administration is supplied by the Sponsor as a 1 mg/ml 
concentrate solution (PP-001 concentrate for intravitreal injection). Together with the 
concentrate solution, a sterile sucrose solution for dilution will be provided. A description of the 
unit formula of the concentrate formulation is provided in the PP-001 Investigator’s Brochure. 
Preparations with different concentrations of active pharmaceutical ingredient will be 
administered in order to achieve the desired dose escalation. The highest administered dose of 
PP -001 in the planned trial will be 2.1 µg and the lowest dose will be 0.3 µg. The corresponding 
dilution ratios for dilution of the PP-001 concentrate solution (1 mg/mL) with the dilution liquid 
in the hospital pharmacy are presented in Table 4. 
Table 4 
Dilution of the Investigational Medicinal Product in the Hospital Pharmacy 
Dilution 
1 : 47 
1 : 82.5 
1 : 165 
1 : 330 
Concentration after dilution, mg/mL 
0.021 
0.012 
0.006 
0.003 
Volume of PP-001 concentrate for 
intravitreal injection (1 mg/mL) to be 
diluted with 33 mL of the dilution 
liquid, mL 
0.7 
0.4 
0.2 
0.1 
PP-001 dose (per 0.1 mL injected 
solution), µg 
2.1 
1.2 
0.6 
0.3 
 
A defined volume of the concentrate solution (0.1 – 0.7 mL of PP 001 concentrate for intravitreal 
injection [1 mg/mL]) will be added directly into the bottle containing exactly 33 mL of the 
dilution liquid and mixed in order to obtain the dosing solution with the desired PP-001 
concentration.  
The final PP-001 dosing solutions will always be injected at a volume of 100 µL. 
8.1.1 Packaging and Labelling 
Study drugs will be packaged and labelled in accordance with the applicable regulatory authority 
requirements. 


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8.1.2 Storage of Study Drugs 
Access to all study drugs must be restricted to designated study personnel throughout the study. 
PP-001 will be stored between 15 and 25°C. 
8.1.3 Product Accountability 
The Investigator is responsible for study medication accountability, reconciliation and record 
maintenance. In accordance with all applicable regulatory requirements, the Investigator or 
designated study site personnel must maintain study drug accountability records throughout the 
course of the study. This person(s) will document the amount of study drug received from the 
supplier, the amounts dispensed to patients as well as lot numbers and expiration/retest date of 
study medications. 
At the conclusion of the study, any unused study drug will either be returned to a 
Sponsor-designated recipient or destroyed at the site after discussion with the Sponsor. If no 
supplies remain, this will be recorded in the drug accountability section of the final monitoring 
report. 
All unused study drug provided by the Sponsor will be retained for purposes of drug 
accountability. In addition, empty and partially used vials of PP-001 will be retained by the 
pharmacy for the purposes of drug accountability. Every effort will be made to retain used 
containers of PP-001 in the pharmacy for the purposes of drug accountability. 
A member of the Sponsor’s clinical operations staff (or designee) will check the supplies storage, 
dispensing procedures and records at regular intervals throughout the study. 
9. 
STATISTICAL ANALYSIS 
Statistical analyses of the primary and secondary outcomes will be conducted as outlined below. 
Descriptive statistics, including the numbers and percentages for categorical variables, and the 
numbers, means, standard deviations, medians, minimums, and maximums for continuous 
variables will be provided. Additional statistical analyses, other than those described in this 
section, may be performed if deemed appropriate. A description of the statistical analysis 
performed on the study data will be outlined in the Statistical Analysis Plan. 
 
Treatment Comparison of Interest 
The relationship between safety and efficacy results and exposure to PP-001 will be investigated. 
 
Sample Size Determination 
Eighteen patients will be enrolled in the study. No power calculations will be performed and the 
sample size is based on the requirements of the study design. 


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Analysis Populations 
9.3.1 Intent-to-Treat Analysis Set 
The Intent-to-treat (ITT) Analysis Set will consist of all patients regardless of whether or not the 
patient received study drug. 
9.3.2 Per-protocol Analysis Set 
The Per-protocol (PP) Analysis Set will consist of all ITT Analysis Set patients who have no 
major protocol deviations and who complete the study up to the end of the post-study 
assessments. 
9.3.3 Safety Analysis Set 
The Safety Analysis Set will consist of all randomized patients who receive any amount of study 
drug. All safety analyses will be conducted in this population. 
9.3.4 Pharmacokinetic Analysis Set 
All patients who receive any amount of study drug will be included in the formal analysis of 
pharmacokinetic parameters providing they have at least one evaluable pharmacokinetic sample. 
 
Criteria for Evaluation 
9.4.1 Safety Analysis Variables 
Safety and tolerability of PP-001 as measured by treatment-emergent AEs (TEAEs) and vital 
signs. 
9.4.2 Pharmacokinetic Analysis Variables 
The concentration of PP-001 in plasma at Screening, 4 h ± 1 h after dosing and on Day 2. 
9.4.3 Efficacy Analysis Variables 
The improvement of inflammation – or any other parameter – as shown by ophthalmic 
examination. 
 
Demographic and Baseline Characteristics 
Enrolment, protocol deviations and discontinuations from the study drug and the study will be 
summarized. Demographics (age, race, ethnicity and sex), medical and surgical history and study 
drug administration will also be summarized by treatment group. 


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Safety Analysis 
Safety will be evaluated in the Safety Analysis Set by presenting summaries of AEs and vital 
signs. 
Summary tables will be provided for all TEAEs. A treatment-emergent AE is defined as an AE 
with a start date and time on or after the first dose of study drug. Adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA®). The number and 
percentage of patients with TEAEs will be tabulated by system organ class and MedDRA 
Preferred Term for each treatment group and by severity and relationship to treatment. 
Adverse events leading to premature discontinuation from the study drug and serious TEAEs 
will be presented either in a table or a listing. 
Descriptive statistics of vital signs and the change from baseline for each scheduled evaluation 
will be summarized at each study visit and the worst overall post-baseline value will be provided. 
The number and percent of patients with treatment-emergent values with potential clinical 
significance will be tabulated. 
 
Pharmacokinetic Analyses 
The concentration of PP-001 in plasma will be measured in blood samples taken at Screening, 
4 h ± 1 h after dosing and on Day 2. 
 
Efficacy analysis 
All efficacy endpoints will be presented in terms of descriptive statistics. 
The relationship between the change from baseline of an efficacy endpoint and exposure to 
PP-001 will be investigated. 
 
Handling of Missing Data 
Missing values will not be imputed. 
 
Interim Analysis 
The results from each dosing day of the first cohort will be reviewed before progressing with the 
subsequent dosing day. The next cohort will only commence with dosing after the previous 
cohort has completed all study sessions up to day 28 and no safety issues have been identified 
after being reviewed by the SDMB. 
After a total of 12 patients have been treated in the three cohorts and after all patients have 
finished the last follow-up, an interim analysis by the SDMB will be conducted to identify 
potential safety issues and to determine the highest tolerable dose. If no safety issue can be 
identified, then a fourth dose with a higher amount of PP-001 will be given to Cohort 4 
comprising of four patients. The dose for a potential Cohort 4 will be defined after completion of 
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If safety issues have been identified in any of Cohorts 2 to 4, then two additional patients will 
receive the next lower dose.  
10. 
STUDY MONITORING 
 
Clinical Monitoring 
All aspects of the study will be carefully monitored by the Sponsor’s authorized individuals, 
acting as agents of the sponsor with respect to current GCP and Standard Operating Procedures 
for compliance with applicable government regulations. These individuals will have access to all 
records necessary to ensure integrity of the data and will periodically review the progress of the 
study with the Principal Investigator. 
Frequent communication between the study site and the Sponsor is essential to ensure that the 
patient safety is monitored adequately. The Investigator will make safety assessments on an 
ongoing basis. The Sponsor’s medical monitor will review safety information from all study sites 
as it becomes available throughout the study. 
 
Safety Data Monitoring Board 
Safety will be assessed by monitoring the results of the ophthalmic examinations and AEs 
throughout the study. Risk assessments will be made by the SDMB after each cohort in written 
form and throughout the study based on the above. For details please refer to SDMB policy. 
11. 
INDEPENDENT ETHICS COMMITTEE APPROVAL 
The Principal Investigator agrees to provide the Independent Ethics Committee (IEC) with all 
appropriate material, including a copy of the informed consent. The study will not be initiated 
until the Investigator obtains written approval of the research plan (protocol) and the informed 
consent document from the appropriate IEC and copies of these documents are received by 
Panoptes Pharma GesmbH. 
It is the Investigator’s responsibility to obtain IEC approval for all subsequent major changes to 
the protocol, in compliance with local law. Appropriate reports on the progress of this study will 
be made by the Investigator to the IEC and Sponsor in accordance with applicable government 
regulations and in agreement with policy established by the Sponsor. 
12. 
ETHICAL CONDUCT OF THE STUDY 
This clinical study will be conducted in compliance with this Protocol, will be conducted in 
accordance with the EU Clinical Trial Directive 2001/20/EC and 2005/28/EC, The Medicines for 
Human Use (Clinical Trials) Regulations 2004 and current amendments, the Declaration of 
Helsinki (revised version of Edinburgh, Scotland 2000), Good Manufacturing Practice (GMP), 
GCP and the current national regulations and guidelines, approved by both the local ethics 
committee and regulatory authority.  


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13. 
INFORMED CONSENT 
The International Conference on Harmonization (ICH) has issued guidelines to provide 
protection for human patients in clinical investigations. The ICH Tripartite Guideline for GCP 
establishes the general requirements for informed consent. 
A properly executed, written informed consent in compliance with the terms of these guidelines 
shall be obtained from each patient before entering the study, or before performing any unusual 
or non-routine procedure in relation to the study. The purpose of the study, procedures to be 
carried out, and potential hazards will be described to each potential patient in non-technical 
terms. Patients (or their legally authorized representative) will be required to read, voluntarily 
sign, and date an informed consent form summarizing the discussion at Screening, and will be 
assured that they may withdraw from the study at any time without jeopardizing their medical 
care. 
Patients will sign and date one copy of the informed consent form, which will be photocopied. 
The copy will be retained by the patient and the original will be retained on file by the 
Investigator. 
The consent form must be approved by the appropriate IEC and Sponsor before study initiation 
at a study site. Any subsequent changes to the approved informed consent form must be 
reviewed and approved by the appropriate IEC and Sponsor before implementation. 
14. 
QUALITY ASSURANCE/QUALITY CONTROL 
Standard Operating Procedures belonging to Panoptes Pharma GesmbH or designee(s) will be 
adhered to for all activities relevant to the quality of the study and are routinely monitored by the 
Quality Assurance (QA) Division. 
Data will undergo quality control checks before clinical database lock. Sponsor-designated, 
independent monitors will be responsible for monitoring the study and its data within the eCRFs. 
A QA audit of this study may be conducted by the Sponsor or Sponsor’s designee. The QA 
auditor will have access to all medical records, the Investigator’s study-related files and 
correspondence and information in the informed consent documentation of this study. 
An inspection of this study may be conducted by a regulatory agency. The Investigator agrees to 
contact the Sponsor as soon as possible, but not later than within 1 week, upon notification of an 
inspection by a regulatory agency. The Investigator agrees to allow the Inspector direct access to 
all relevant documents and to allocate his/her time and that of study site personnel to the 
Inspector to discuss findings in any relevant issues. The Investigator will allow Sponsor 
personnel to be present as an observer during a regulatory inspection, if requested. 
15. 
DATA HANDLING AND RECORD KEEPING 
 
Data Handling 
Data will be recorded at sites using eCRFs and reviewed by the Sponsor or designee during 
monitoring visits. The recorded data in the eCRF system will be verified with source documents. 
All corrections or changes made to any study data must be appropriately tracked in an audit trail 


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in the eCRF system. The eCRFs will be considered complete when all missing, incorrect, and/or 
inconsistent data have been accounted for. Data collected at baseline will only be entered into the 
eCRF if the patient is eligible for study participation following review of the data by the 
Investigator or designee. 
Adverse events, concomitant medication data and clinical observations will be in the patients’ 
hospital notes, or recorded on source data forms, and will be transferred into the eCRF after 
assessment by the Investigator or designee. 
Data produced by automatic devices with original print-outs (e.g., BP measurements) will be 
included in the source documentation. Any results outside the normal range should be designated 
by the Investigator or designee as “clinically significant” or “not clinically significant”. 
 
Patient Confidentiality 
The Investigator and his/her staff will be required to manage patient data collected for the study in 
accordance with applicable laws and regulations on personal data protection. 
Data collected during this study may be used to support the development, registration, or 
marketing of PP-001. Panoptes Pharma GesmbH will control all data collected during the study, 
and will abide by the EU Directive on Data Privacy concerning the processing and use of 
patients’ personal data. For the purpose of data privacy legislation, Panoptes Pharma GesmbH 
will be the data controller. 
After patients have consented to take part in the study their medical records and the data 
collected during the study will be reviewed by Panoptes Pharma GesmbH or its representatives. 
These records and data may, in addition, be reviewed by the following: independent auditors 
who validate the data on behalf of Panoptes Pharma GesmbH; third parties with whom Panoptes 
Pharma GesmbH may develop, register, or market PP-001; national or local regulatory 
authorities and the IECs that gave approval for this study to proceed. 
Patients will be known by a unique number; however, their date of birth can also be collected if 
not in contradiction with any requirements (e.g., from IECs) and used to assist Panoptes Pharma 
GesmbH to verify the accuracy of the data, for example, that the laboratory results are assigned 
to the correct patient. The results of this study may be recorded and transferred to and used in 
other countries throughout the world, which may not afford the same level of protection that 
applies within the EU. The purpose of any such transfer would be to support regulatory 
submissions in other countries. 
 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
 
Data Entry 
Data must be recorded using the eCRF system as the study is in progress. All study site 
personnel must log into the system using their secure user name and password in order to enter, 


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review, or correct study data. These procedures must comply with EU Directives 2001/20/EC 
and 2005/28/EC for EU sites. All passwords will be strictly confidential.  
 
Data Validation 
Validation checks programmed within the eCRF system as well as supplemental validation 
performed via review of the downloaded data will be applied to the data in order to ensure 
accurate, consistent and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator who signed the 
protocol. 
 
Record Keeping 
Raw data generated in connection with this study as well as an original copy of the final clinical 
study report, will be retained in archive until at least 5 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 5 years have elapsed since the formal discontinuation of 
clinical development of PP-001. These documents will be retained for a longer period if required 
by the applicable regulatory requirements or by an agreement with the Sponsor. It is the 
responsibility of the Sponsor to inform the Investigator/Institution as to when these documents 
no longer need to be retained. 
As required under European Directive 2005/28/EC, Article 17, all ‘essential documents’ (as 
described in the ICH GCP Guidelines) must be retained by Panoptes Pharma GesmbH and the 
Investigator for at least 5 years after the completion of the clinical study. Therefore, all studies, 
independent of where they were conducted in the world, must follow this requirement in the 
event a submission is ever made in the EU. These documents may be retained for a longer 
period; however, if required by the applicable regulatory requirements or by an agreement with 
Panoptes Pharma GesmbH. It is the responsibility of Panoptes Pharma GesmbH to inform the 
Investigator as to when these documents no longer need to be retained. The Investigator must 
obtain written permission from Panoptes Pharma GesmbH before the destruction of any study 
document. 
These records must be made available at reasonable times for inspection and duplication, if 
required, by national or foreign Regulatory Authorities in accordance with regulatory 
requirements. 
16. 
FACILITIES 
This study will be performed in up to twelve sites in Europe. 
  
The following analytical laboratory will perform the determination of PP-001 in plasma: 
A&M GmbH 
Kopernikusstrasse 25 
50126 Bergheim 
Germany 


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Managing directors: Dr Axel Römer, Dr Tobias Klaassen 
Phone: +49-2271-4787-0 
Fax: +49-2271-4787-44 
 
17. 
TERMINATION OF STUDY 
The Sponsor reserves the right to discontinue this study at any time. However the safety of the 
patients will never be compromised and treated patients will always get at least all schedules 
follow up visits. 
18. 
FINANCING AND INSURANCE 
The costs necessary to perform the study will be agreed with each Investigator and will be 
documented in a separate financial agreement that will be signed by the Investigator and 
Panoptes Pharma GesmbH, before the start of the study.  
The Investigator will be required to disclose any financial arrangement whereby the value of the 
compensation for conducting the study could be influenced by the results or outcome of the 
study. The following information will be collected: any significant payments of other sorts from 
Panoptes Pharma GesmbH, (e.g., money to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria); any proprietary interest in PP-001; 
any significant equity interest in Panoptes Pharma GesmbH as defined in 21 CFR 54 2(b). 
In consideration of participation in the study, Panoptes Pharma GesmbH will pay the Investigator 
or nominated payee the sums set out in the payment schedule attached to the Investigator 
agreement. 
19. 
PUBLICATION POLICY 
It is intended that the results of the study may be published as scientific literature. Results may 
also be used in submissions to Regulatory Authorities. The following conditions are to protect 
commercial confidential materials (e.g., patents, etc.), not to restrict publication. 
All information concerning PP-001 (such as patent applications, formulae, manufacturing 
processes, basic scientific data, or formulation information supplied to the Investigator by 
Panoptes Pharma GesmbH and not previously published) is considered confidential by Panoptes 
Pharma GesmbH and shall remain the sole property of Panoptes Pharma GesmbH. The 
Investigator agrees not to use it for other purposes without written consent from Panoptes 
Pharma GesmbH. 
It is understood by the Investigator that Panoptes Pharma GesmbH will use the information 
developed in this clinical study in connection with the development of PP-001 and, therefore, 
may be disclosed as required to other Panoptes Pharma GesmbH Investigators or any appropriate 
international Regulatory Authorities. In order to allow for the use of information derived from 
this clinical study, the Investigator understands that he/she has an obligation to provide Panoptes 
Pharma GesmbH with complete test results and all data developed during this study. 
Before submitting the results of this study for publication or presentation, the Investigator will 
allow Panoptes Pharma GesmbH at least 30 days in which to review and comment upon the 


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publication manuscript (or presentation materials). Panoptes Pharma GesmbH agrees that before 
it publishes any results of this study, it shall provide the Investigators at least 30 days for full 
review of the publication manuscript. In accordance with generally recognized principles of 
scientific collaboration, co-authorship with any Panoptes Pharma GesmbH personnel will be 
discussed and mutually agreed upon before submission of a manuscript to a publisher. 
All manuscripts, abstracts or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by Panoptes Pharma GesmbH in advance of 
submission. The review is aimed at protecting Panoptes Pharma GesmbH's proprietary 
information existing either at the date of the commencement of the study or generated during the 
study. 
The detailed obligations regarding the publication of any data shall be set out in the agreement 
between each Investigator and Panoptes Pharma GesmbH. 
 
 


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20. 
LIST OF REFERENCES 
Barisani-Asenbauer T, Maca SM, Mejdoubi L, Emminger W, Machold K, Auer H. Uveitis-a rare 
disease often associated with systemic diseases and infections-a systematic review of 2619 
patients. Orphanet J Rare Dis 2012;7:57. 
Barry RJ, Nguyen QD, Lee RW, Murray PI, Denniston AK. Pharmacotherapy for uveitis: current 
management and emerging therapy. Clin Ophthalmol 2014;8:1891–1911. 
Caspi R. Autoimmunity in the immune privileged eye: pathogenic and regulatory T cells. 
Immunol Res 2008;42;41–50. 
Food and Drug Administration. Note for Guidance Estimating the Maximum Safe Starting Dose 
in Initial Clinical Trials. 2005. 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM078932.pdf [Accessed 08 February 
2016] 
Herrmann M, Schleyerbach R, Kirschbaum BJ. Leflunomide: an immunomodulatory drug for the 
treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology 
2000;47:273–289. 
Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) 
Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of 
the First International Workshop. Am J Ophthalmol 2005;140:509–516. 
 
 


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21. 
APPENDICES 
 
Appendix 1: Clinical Laboratory Tests  
Blood and urine samples for the following will be sent to a local laboratory for testing.   
Hematology 
• Coagulation panel (including prothrombin time with international normalized 
ratio and partial thromboplastin time)  
• Complete blood count with red blood cell indices and white blood cell 
differential 
• Reticulocyte count 
• Platelet count 
Chemistry 
• Blood urea nitrogen 
• Creatinine 
• Glucose, fasting 
• Sodium 
• Potassium 
• Chloride 
• Calcium 
• Magnesium 
• Phosphorus 
• Aspartate aminotransferase 
• Alanine aminotransferase 
• Gamma-glutamyl transpeptidase 
• Alkaline phosphatase 
• Creatinine phosphor-kinase 
• Total bilirubin 
• Direct bilirubin 
• Uric acid 
• Albumin 
• Total protein 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, and leukocyte esterase by 
dipstick 
• Microscopic examination (all samples) 
 
 
 


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Appendix 2: Values of Potential Clinical Concern 
Haematology 
Hemoglobin Males: < 12.0 or > 18.0 g/dl Females: < 10.5 or 16.1 g/dl 
Hematocrit Males < 36.0 or > 54.0% Females: < 31.0 or > 50.6% 
Leukocytes > 1 K/µl below or > 3 K/µl above the limit of the reference range 
Platelets < 80 or > 500 K/µl 
Chemistry 
Total bilirubin ≥ 1.5 times upper limit of the reference range 
AST > 2 times upper limit of the reference range 
ALT > 2 times upper limit of the reference range 
GGT > 2 times upper limit of the reference range 
Alk Phosphatase > 1.5 times upper limit of the reference range 
Creatinine > 1.8 mg/dl 
BUN > 1.5 times upper limit of the reference range 
Glucose, fasting < 60 or >126 mg/dl 
Uric acid > 11 mg/dl 
Sodium > 5 mEq/l above or below the limits of the reference range 
Potassium > 0.5 mEq/l above or below the limits of the reference range 
Calcium < 7.2 or > 12 mg/dl 
Phosphate > 0.8 mg/dl below or 1.0 mg/dl above the limits of the reference range 
Albumin > 0.5 g/dl above or below the limits of the reference range 
Total protein > 1.0 g/dl above or below the limits of the reference range 
Urinalysis 
WBC > 15/hpf 
RBC > 15/hpf 
Vital Signs 
Heart Rate Supine: < 35 or > 120 bpm Erect: < 40 or > 140 bpm 
Blood Pressure Systolic > 30 mmHg change from baseline in same posture 
Diastolic >20 mmHg change from baseline in same posture 
 
 


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Appendix 3: ECG Values of Potential Clinical Concern 
Electrocardiogram 
PR interval < 120 ms; ≥ 220 ms 
QRS interval ≥ 120 ms 
QTc interval(Bazett's) 
> 470 ms (adult females ≤ 50 yrs old) 
> 480 ms (adult females > 50 yrs old) 
> 470 ms (adult males) 
Rhythms of Potential Clinical Concern 
-Asymptomatic Marked Sinus Bradycardia (rate < 35 bpm) 
-Asymptomatic Supraventricular Couplets, Atrial Bigeminy lasting > 30 seconds 
-Asymptomatic Ventricular Couplets, Ventricular Bigeminy lasting > 30 seconds 
-Asymptomatic Type I Second Degree (Wenckebach) AV Block of > 30 seconds duration 
-Asymptomatic Frequent Premature Ventricular Complexes (PVCs) (≥ 144/24 hours) 
-Asymptomatic Frequent Premature Atrial Complexes (PACs) (≥ 240/24 hours) 
Adverse Experiences 
-Symptomatic Marked Sinus Bradycardia (rate < 40 bpm) 
-Asymptomatic Sinus Pause > 3 seconds without an escape beat 
-Asymptomatic Atrial Flutter or Fibrillation, subcategorized by ventricular response rate: 
controlled = rate < 120 bpm; rapid = rate ≥ 120 bpm 
-Asymptomatic Supraventricular Tachycardia ≥ 3 beats (rate ≥ 120 bpm) 
-Asymptomatic Nonsustained Ventricular Rhythms ≥ 3 beats, but duration of < 30 
seconds, including idioventricular rhythm (rate < 40 bpm), accelerated idioventricular 
rhythm (40 ≤ x < 100) and monomorphic/polymorphic ventricular tachycardia ≥ 100 bpm 
(such as Torsade des pointes) 
-Asymptomatic Type II Second Degree (Mobitz) AV Block 
-Asymptomatic Complete (third degree) Heart Block 
Serious Adverse Experiences 
-Sustained Ventricular Arrhythmias (> 30 seconds duration) 
-Ventricular Fibrillation 
-At the discretion of the investigator, any arrhythmia classified as an adverse experience 
 
 


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Appendix 4: Investigator Signature Page 
 
INVESTIGATOR SIGNATURE PAGE 
A safety study of intravitreal PP-001 in patients with chronic, non-infectious uveitis having 
chronic inflammation 
(Protocol PP-001-1001) 
In conducting this clinical study, I agree to be responsible for: 
• Ensuring that the clinical investigation is conducted according to the World Medical 
Association Declaration of Helsinki (revised version of Edinburgh, Scotland, 2000, Note of 
Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002), the 
guidelines of International Conference on Harmonization (ICH) Good Clinical Practice 
(CPMP/ICH/135/95), and other applicable local and national laws and requirements 
• Protecting the rights, safety, and welfare of patients under my care 
• Maintaining control of the drugs under investigation 
I also agree to conduct the study as detailed in the protocol and in accordance with Panoptes 
Pharma GesmbH guidelines and all applicable government regulations. These guidelines and 
regulations include, but are not limited to: 
• Permission to allow Panoptes Pharma GesmbH and regulatory agencies, to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner, which ensures 
patient confidentiality. If I am notified that this study is to be inspected by a regulatory 
agency, I will notify Panoptes Pharma GesmbH as soon as possible thereafter (no later than 
1 week) 
• Submission of the proposed clinical investigation, including the protocol, the informed 
consent documents, and any other patient materials required for study conduct, to a duly 
constituted Independent Ethics Committee (IEC) 
• Obtaining written informed consent only after ensuring that the patient, or his/her legal 
representative, is competent to make the decision, understands what is contained in the 
informed consent document, and is consenting voluntarily. Written informed consent will be 
obtained prior to administration of study drug or any non-routine study-related procedures; 
the document contains all the essential elements of consent and has been previously approved 
by the sponsor and IEC. Reference of written informed consent will be provided in source 
documentation 
• Submission of any protocol amendment to the IEC. If the protocol amendment change(s) 
increase risk to the study population, full IEC written approval must be obtained prior to 
implementation. For changes that do not involve increased risk or affect the validity of the 
investigation or the patient's rights, prior IEC approval may be obtained by expedited review 
• Adherence to the study protocol. Documentation and explanation of individual post-
enrolment protocol deviations will be recorded in the source documentation at the site and be 
provided to Panoptes Pharma GesmbH 


Panoptes Pharma GesmbH 
Clinical Protocol PP-001-1001 
Version 3.1_GER 03 November 2017  
Page 54 of 54 
Confidential Information 
• Notification to Panoptes Pharma GesmbH of all serious adverse events (SAEs), regardless of 
relationship to study drug, as specified in the protocol. Notification to the IEC of SAEs as 
specified in the protocol and per additional guidelines as provided by the IEC 
• Notification to IEC of all unanticipated problems within the timeframe provided by the IEC. 
For the purposes of this study, unanticipated problems are defined as any incident, 
experience, or patient outcome that meets all of the following criteria: (1) unexpected; (2) 
related or possibly related to participation in the study; (3) and suggests that the research 
places patients or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known 
• Provision of adequate study oversight by personally conducting or supervising the 
investigation, including, but not limited to: allotting sufficient time to properly conduct and 
complete the study within the agreed upon time period; having available an adequate number 
of qualified staff and adequate facilities for the expected duration of the study and to conduct 
the study properly and safely; and ensuring that all persons assisting with the study are 
adequately informed about the protocol and the investigational product(s) and are capable of 
performing their study-related duties and functions. Qualifications of individuals assigned 
responsibility for the administration of the investigational product will be compliant with 
state and local law or national regulations, as applicable 
• Submission of timely progress reports to the IEC and Panoptes Pharma GesmbH at 
appropriate intervals not to exceed 1 year and submission of a final report to the IEC within 
the timeframe set by the IEC, but not later than 3 months after the completion or termination 
of the clinical investigation 
• Maintenance of accurate source records from which case report forms are completed as well 
as drug accountability records that show the receipt and disposition (on an overall and per 
patient basis) of all study drug(s) shipped to the Investigator by Panoptes Pharma GesmbH 
In addition, I agree to provide all the information requested in the electronic case report form 
(eCRF) presented to me by Panoptes Pharma GesmbH by carefully following the completion 
guidelines provided as part of the eCRF. 
If I opt to terminate my participation in the study, the foregoing shall equally apply. 
 
 
Investigator name (print) 
 
Investigator`s signature, Date 
 
 

SAP_001.pdf: 
 
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STATISTICAL ANALYSIS PLAN 
 
PROTOCOL: PP-001-1001 
 
 
A safety study of intravitreal PP-001 in patients with chronic, non-
infectious uveitis having chronic inflammation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
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Contents 
Abbreviations ...................................................................................................................................... 5 
Revision History ................................................................................................................................. 6 
1. 
Introduction ................................................................................................................................ 7 
2. 
Study Objectives ......................................................................................................................... 7 
2.1 
Primary objective ................................................................................................................. 7 
2.2 
Secondary objectives ........................................................................................................... 7 
3. 
Study Design ............................................................................................................................... 7 
3.1 
General design and plan ....................................................................................................... 7 
3.2 
Visit Schedule and Visit Windows ...................................................................................... 8 
3.3 
Sample size justification .................................................................................................... 10 
3.4 
Randomization and blinding .............................................................................................. 10 
3.5 
Efficacy endpoints ............................................................................................................. 10 
3.5.1 
Primary endpoint ........................................................................................................ 10 
3.5.2 
Secondary efficacy endpoints ..................................................................................... 10 
3.6 
Safety endpoints ................................................................................................................. 11 
3.7 
Other endpoints .................................................................................................................. 11 
3.7.1 
PK parameters ............................................................................................................. 11 
3.7.2 
Patient Reported Outcomes ........................................................................................ 11 
4. 
Statistical Analysis ................................................................................................................... 11 
4.1 
General ............................................................................................................................... 11 
4.2 
Analysis sets ....................................................................................................................... 12 
4.2.1 
Per-Protocol Analysis Set ........................................................................................... 12 
4.2.2 
Safety Analysis Set ..................................................................................................... 12 
4.2.3 
Pharmacokinetic Analysis Set .................................................................................... 12 
4.2.4 
Incorrect treatment allocations ................................................................................... 12 
4.3 
Sub-group analyses ............................................................................................................ 13 
4.4 
Covariates .......................................................................................................................... 13 
4.5 
Pooling of sites ................................................................................................................... 13 
4.6 
Interim analyses ................................................................................................................. 13 
4.7 
Handling of missing and incomplete data .......................................................................... 13 
4.8 
Changes in the planned analysis ........................................................................................ 13 
4.9 
Data Review Meeting ........................................................................................................ 13 
4.10 
Software ......................................................................................................................... 14 
5. 
Evaluation of Demographic and Baseline Characteristics ....................................................... 14 
5.1 
Subject enrolment and disposition ..................................................................................... 14 
5.2 
Protocol violations ............................................................................................................. 14 
5.3 
Study discontinuations ....................................................................................................... 14 


 
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5.4 
Demographics and baseline characteristics ....................................................................... 15 
5.5 
Medical and ophthalmic history ......................................................................................... 15 
5.6 
Prior and concomitant medications .................................................................................... 16 
5.7 
Other baseline characteristics ............................................................................................ 16 
6. 
Evaluation of Treatment Compliance and Exposure ................................................................ 17 
6.1 
Compliance to study drug and treatment ........................................................................... 17 
6.2 
Exposure to study drug ...................................................................................................... 17 
6.3 
Evaluation of pharmacokinetics ......................................................................................... 17 
7. 
Evaluation of Efficacy .............................................................................................................. 17 
7.1 
Analysis of primary endpoint ............................................................................................. 17 
7.2 
Analysis of secondary efficacy endpoints .......................................................................... 17 
7.3 
Analysis of other efficacy endpoints .................................................................................. 19 
7.4 
Evaluation of pharmacodynamics ...................................................................................... 26 
8. 
Evaluation of Safety ................................................................................................................. 26 
8.1 
Adverse events ................................................................................................................... 26 
8.6 
Other safety evaluations ..................................................................................................... 28 
9. 
Tables, Figures and Listings ..................................................................................................... 28 
9.3 
Tables ................................................................................................................................. 29 
11. 
Appendices ............................................................................................................................ 31 
11.1 
Table shells ..................................................................................................................... 31 
11.2 
Listing shells .................................................................................................................. 31 
 


 
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Abbreviations 
ADR 
Adverse Drug Reaction 
ADaM 
Analysis Data Model 
AE  
Adverse Event  
ATC 
Anatomical Therapeutic Chemical  
BMI 
Body Mass Index 
BP 
Blood Pressure 
CI  
Confidence Interval 
CS 
Clinically Significant 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
HR 
Heart Rate 
IOP 
Intraocular Pressure 
ITT 
Intent to Treat 
MedDRA  
Medical Dictionary for Regulatory Activities 
NCS 
Not Clinically Significant 
NIU 
Non-Infectious Uveitis 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PT 
Preferred Term 
SAE(s)  
Serious Adverse Event(s)  
SAP 
Statistical Analysis Plan 
SDMB 
Safety and Data Management Board 
SDV 
Source Data Verified 
SOC 
System Organ Class  
TEAE 
Treatment-Emergent Adverse Event 
 


 
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Protocol Number: 
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Revision History 
Document 
Version 
Changes Made 
Document Date 
Draft 0.1 
Draft specification based on the following documents: 
• Study protocol Germany (Version 2.0, 29 
November 2016); 
• eCRF (Version Final 8, 15 March 2017). 
11 Apr 2017 
Draft 0.2 
Draft specification based on the following documents: 
• Study protocol Belgium (Version 1.0, 18 July 
2017); 
• Study protocol Netherlands (Version 1.0, 18 July 
2017); 
• Study protocol Austria ( Version 3.0, 24 April 
2017); 
• Study protocol Germany (Version 3.0, 24 April 
2017). 
Updates made based on sponsor feedback. 
24 Oct 2017 
Draft 0.3 
Draft specification based on the following documents: 
• Study protocols Belgium (Version 1.0, 18 July 
2017 and Version 1.1, 03 November 2017); 
• Study protocols Austria (Version 3.0, 24 April 
2017 and Version 3.1, 03 November 2017); 
• Study protocol Germany (Version 3.0, 24 April 
2017 and Version 3.1, 03 November 2017). 
• Study protocol Netherland (Version 1.1, 03 
November 2017). 
• Study protocols United Kingdom (Version 1.0, 20 
December 2017 and Version 1.1, 24 April 2017). 
Updates made based on sponsor feedback. 
12 Sep 2018 
Draft 0.4 
Updates made based on sponsor feedback. 
05 Nov 2018 
Final 1.0 
Version finalized after sponsor’s review. 
07 Nov 2018 
Draft 1.1 
Updates made based on sponsor feedback. 
20 Nov 2018 
Final 2.0 
Version finalized after sponsor’s review. 
19 Dec 2018 
Draft 2.1 
Updates made based on sponsor feedback. 
31 Jan 2020 
Final 3.0 
Version finalized after sponsor’s review. 
17 Feb 2020 
 


 
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1.  Introduction 
This document outlines the statistical methods to be implemented in the analysis of the data of 
Clinical Trial PP-001-1001. The purpose of this plan is to provide general guidelines from which 
the analysis will proceed. It contains a more technical and detailed elaboration of the principal 
features of the analysis described in the protocol. Any changes to the protocol or electronic Case 
Report Form (eCRF) may necessitate updates to the Statistical Analysis Plan (SAP). In case of 
deviations from this updated SAP, explanations will be provided in the clinical study report. 
2.  Study Objectives 
PP-001 is proposed for development of an intravitreal injection for the treatment of non-infectious 
uveitis (NIU). This first time in human study will investigate the safety, tolerability and efficacy of 
single ascending doses of PP-001 using intravitreal injection in male and female patients. The study 
population will comprise patients with NIU and an otherwise good state of health to ensure 
homogeneity. 
Patients with chronic intraocular inflammation, for whom maximal medical treatment failed or who 
are unable to tolerate medical treatment because of adverse ocular or systemic effects will be 
included in this study. The data generated in this study will support the progression of a well-
tolerated dose of PP-001, administered by intravitreal injection in patients with NIU. 
2.1 
Primary objective 
To assess the safety and tolerability of ascending doses of PP-001 in patients with chronic, non-
infectious uveitis when administered as a single intravitreal injection of 0.3 μg, 0.6 μg and 1.2 μg. 
2.2 
Secondary objectives 
• To assess the improvement of inflammation in patients with chronic, non-infectious uveitis 
after ascending doses of PP-001 when administered as a single intravitreal injection of 0.3 
μg, 0.6 μg and 1.2 μg  
 
• To evaluate the pharmacokinetics of PP-001 in patients with chronic, non-infectious uveitis 
when administered as a single intravitreal injection of 0.3 μg, 0.6 μg and 1.2 μg 
3.  Study Design 
3.1 
General design and plan  
In this prospective, multi-centre, open-label, non-randomized, consecutive study eighteen patients 
at the age of 18 or older will be enrolled and receive a single intravitreal injection of PP-001. 
Patients must have chronic, posterior uveitis, intermediate uveitis or panuveitis requiring treatment 


 
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and have been receiving an adequate therapy of e.g. systemic corticosteroid treatment or 
immunosuppressive therapy (azathioprine, methotrexate, cyclosporine, mycophenolate, tacrolimus) 
or any combination thereof. Any systemic therapy at study start should be continued throughout the 
study.  Patients must have best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) 
visual acuity of 10 letters or better (approximately 1/35 or 0.032) but equal or less than 50 letters 
(approximately 20/100 or 0.2) in the study eye for subjects enrolled under Austrian and German 
protocols, and equal or less than 70 letters (approximately 20/40 or 0.5) in the study eye for 
subjects enrolled under United Kingdom, Belgium and Netherland protocols. 
 
The study will involve eight inpatient visits (Screening, Baseline, day of injection [Day 0] and 
Days 2, 7, 14, 21 and 28) and telephone calls on Day 1 and on Day 40 for subjects enrolled under 
Austrian and German protocols and seven inpatient visits (Screening, Baseline, day of injection 
[Day 0] and Days 2, 7, 14 and 28) and telephone calls on Day 1 and on Day 40 for subjects 
enrolled under United Kingdom, Belgium and Netherland protocols. 
 
Patients will be divided into three cohorts of four patients. Patients will receive the following 
treatments administered as a single intravitreal injection: 
• Cohort 1 will receive 0.3 μg of PP-001 
• Cohort 2 will receive 0.6 μg of PP-001 
• Cohort 3 will receive 1.2 μg of PP-001 
 
The patients within a cohort will be dosed consecutively with a minimum time interval of 7 days 
between the start of injection of the previous patient and start of injection of the next patient. The 
results from each dosing day will be reviewed before progressing with the subsequent dosing day. 
The next cohort will only commence with dosing after the previous cohort has completed all study 
sessions up to Day 28 and no safety issues have been identified after being reviewed by the safety 
data management board (SDMB). 
After 12 patients have been treated in the three cohorts and after all patients have finished the last 
follow up an interim analysis by the SDMB will be conducted to identify potential safety issues and 
to determine the highest tolerable dose. If no safety issue can be identified, then a fourth, higher 
dose will be given to a cohort of four patients (Cohort 4). The dose for a potential Cohort 4 will be 
2.1 μg of PP-001. (Note: Interim analysis and dosing of a fourth cohort will not be performed). 
If safety issues are identified in any of Cohorts 2, 3 or 4, two additional patients will receive the 
next lower dose. 
 
Dosing of further patients will be stopped if the following criterion is observed: 
• A moderate or severe AE classified as being possibly, probably or definitively study drug 
related or potential major safety concerns as identified by the Investigator after consultation 
with the SDMB are reported in more than 50% of patients in the same cohort. 
Dosing will be stopped or the dose decreased if: 
• One patient on any dosing day shows a possibly, probably or definitively study-drug related 
SAE judged by the Investigator after consultation with the SDMB or other potential major 
safety concerns are identified by the Investigator in agreement with the SDMB. 
3.2 
Visit Schedule and Visit Windows 


 
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Assessments and study visits will be performed as listed in the table below: 
 
 
Phase 
Screening 
Baselinei 
Pre 
injection 
Post 
injection 
Telephone 
calla 
Safety visits 
Telephone 
calla 
Day 
-14 to -up to 
dosing 
-7 up to 
dosing 
0 
0 
1 
2 
+/
-1 
7 
+/
-1 
14 
+/-
1 
21l 
+/-1 
28h 
+/-1 
40 
Electroretinography 
 
X 
 
 
 
 
 
X 
 
X 
 
Fluorescein angiogram 
X 
 
 
 
 
 
 
 
 
X 
 
Optical coherence 
tomography 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
Best corrected visual acuity 
(ETDRS)  
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
Visual field (computerized, 
30°) 
 
X 
 
 
 
 
X 
 
 
X 
 
Visually evoked cortical 
potential 
X 
 
 
 
 
 
 
 
 
X 
 
Intraocular pressure 
X 
X 
 
Xb 
 
X 
X 
X 
X 
X 
 
Slit lamp examination c 
X 
X 
X 
Xb 
 
X 
X 
X 
X 
X 
 
Dilated fundoscopyd  
X 
X 
 
Xb 
 
X 
X 
X 
X 
X 
 
Study drug injection 
 
 
 
X 
 
 
 
 
 
 
 
Blood sampling for PK 
analysis 
X 
 
 
Xb,e 
 
X 
 
 
 
 
 
Corneal endothelial 
microscopy  
 
X 
 
 
 
 
X 
 
 
X 
 
Fundus photography 
 
X 
 
 
 
 
 
 
 
X 
 
Amsler grid 
 
X 
 
 
 
X 
X 
X 
X 
X 
 
Urine pregnancy test (only 
for Austrian protocols) m 
 
 
 
X 
 
 
 
 
 
X 
 
 
Urine pregnancy test (only 
for Belgium, United 
Kingdom and Netherland 
protocols) m 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Medical and ophthalmic 
histories 
X 
X 
 
 
 
 
 
 
 
 
 
Vital signsf 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Twelve-lead 
electrocardiogram 
X 
 
 
 
 
 
 
 
 
X 
 
Laboratory assessments 
X 
 
 
 
 
 
 
 
 
X 
 
Patient-reported outcomesg 
 
X 
 
 
 
 
 
 
 
X 
 
Concomitant medication 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Serious medical events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ETDRS: Early Treatment of Diabetic Retinopathy Study; PK: Pharmacokinetic 
a. Standardized questions including (but not limited to): pain, blurred vision, change in visual acuity, redness of the eye 
b. Examination will be performed after administration of study drug 
c. Conjuctiva, cornea, anterior chamber including grading of cells and haze (Standardization of Uveitis Nomenclature Working 
Group), lens (Lens opacities classification system II) and vitreal haze (Standardization of Uveitis Nomenclature Working Group) 
d. Including slit lamp biomicroscopy of the fundus 
e. Day 0 blood sample will be taken 4 h ± 1 h after injection 
f. Blood pressure and heart rate 
g. National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25), SF36™ Health Survey Version 2 (SF-3 v2) and EuroQol-5 
Dimensions Health Questionnaire (EQ-5D) 
h: for visit 28 option to perform examinations  to 2 consecutive days; 
i: in case screening visit and baseline visit are on the same day (-7 up to dosing), examinations scheduled for both visits need only to 
be performed once and may be used for both study visits; 
l: safety visit 21 is applicable only for subjects enrolled under Austrian and German protocols; 


 
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m: urine pregnancy test has been performed at different visits, depending on the protocol version. For subjects enrolled under 
German protocols (versions 2.0, 3.0 and 3.1) no pregnancy testing is done. 
3.3 
Sample size justification 
Eighteen patients will be enrolled in the study. No power calculations will be performed and the 
sample size is based on the requirements of the study design. 
3.4 
Randomization and blinding 
This is an open-label, non-randomized study. Patients will be assigned to the next available cohort 
as they are recruited to the study. 
3.5 
Efficacy endpoints 
3.5.1 Primary endpoint  
In this study to assess the safety and tolerability of ascending doses of PP-001, safety parameters 
(i.e., changes in clinical signs and symptoms from ophthalmic exam, and AEs), are the primary 
endpoints. Detailed ophthalmic examination will be used to determine efficacy and as a safety 
measure.  
The primary efficacy variable is the best corrected visual acuity (ETDRS) change from baseline at 
day 14 and day 28.  
 
3.5.2 Secondary efficacy endpoints 
• Improvement of inflammation or of any other parameter determined at the ophthalmic 
examination following the injection of PP-001: 
 
o Vitreous haze, as graded by the ophthalmologist during Slit Lamp examination 
(classified according to Standardization of Uveitis Nomenclature Working Group). 
The scale is based on the following unit scale categorized as follows: 
 
0 
No inflammation 
+0.5 Trace inflammation 
+1 
Mild blurring of retinal vessels and optic nerve 
+1.5 Optic nerve head and posterior retinal view obscuration greater than +1, 
but less than +2 
+2 
Moderate blurring of optic nerve head 
+3 
Marked blurring of optic nerve head 
+4 
Optic nerve head not visible 
 
o Electroretinography 
o Fluorescein angiogram 


 
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o Optical coherence tomography 
o Visual field (computerized, 30°) 
o Visually evoked cortical potential 
o Intraocular pressure 
o Slit lamp examination 
o Dilated fundoscopy 
o Corneal endothelial microscopy 
o Fundus photography 
o Amsler grid 
3.6 
Safety endpoints 
The safety endpoints are the following:  
• Adverse Events (AEs);  
• Vital Signs (blood pressure, heart rate);  
• Electrocardiogram (ECG); 
• Laboratory parameters (hematology, biochemistry and urinalysis). 
3.7 
Other endpoints 
The other endpoints are the following: 
3.7.1 PK parameters 
The concentration of PP-001 in plasma at Screening, 4 h ± 1 h after dosing and on Day 2. 
3.7.2 Patient Reported Outcomes 
Patient-reported outcomes will be assessed by using the following questionnaire:  
• Visual Functioning Questionnaire 25 (VFQ-25); 
• SF36™ Health Survey Version 2 (SF-36v2); 
• EuroQol-5 Dimensions Health Questionnaire (EQ-5D). 
4.  Statistical Analysis 
4.1 
General 
Descriptive statistics will be provided for all variables in the summary tables by cohorts (PP-001 
0.3 μg, 0.6 μg and 1.2 μg) according to the type of variable summarized.  
Quantitative variables will be summarised by using n, arithmetic mean, SD, median and range 
(minimum and maximum).  
Categorical variables will be summarised by using frequency distributions and percentages. 
 


 
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Analysis will be performed on the treated eye only assuming that a patient is treated on one eye 
only.  
 
The baseline used in the analysis for each variable is reported in the table below: 
 
Endpoint 
Baseline 
Electroretinography 
Baseline (Day -7 up to dosing) 
Fluorescein angiogram 
Screening (Day -14 up to dosing) 
Optical coherence tomography 
Baseline (Day -7 up to dosing) 
ETDRS 
Baseline (Day -7 up to dosing) 
Visual field 
Baseline (Day -7 up to dosing) 
Visually evoked cortical potential 
Screening (Day -14 up to dosing) 
Intraocular pressure 
Baseline (Day -7 up to dosing) 
Slit lamp examination 
Baseline (Day -7 up to dosing) 
Dilated fundoscopy 
Baseline (Day -7 up to dosing) 
Corneal endothelial microscopy 
Baseline (Day -7 up to dosing) 
Fundus photography 
Baseline (Day -7 up to dosing) 
Amsler grid 
Baseline (Day -7 up to dosing) 
Patient-reported outcomes 
Baseline (Day -7 up to dosing) 
Vital signs 
Baseline (Day -7 up to dosing) 
Laboratory assessments 
Screening (Day -14 up to dosing) 
 
All endpoints data collected in the eCRF will be presented in the listings. PK endpoints will be 
listed as well. 
 
No multiplicity adjustment will be implemented. 
4.2 
Analysis sets 
4.2.1 Per-Protocol Analysis Set 
The PP set will include all Safety Set patients who have no major protocol deviations, and who 
complete the study up to the end of the post-study assessments (including telephone call days). 
4.2.2 Safety Analysis Set 
The Safety set will include all patients who receive at least one injection of study drug. All analyses 
will be conducted in this population. 
4.2.3 Pharmacokinetic Analysis Set 
The PK set will include all Safety Set patients who have at least one evaluable pharmacokinetic 
sample. 
4.2.4 Incorrect treatment allocations 


 
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Not applicable. 
4.3 
Sub-group analyses 
 
Not foreseen. 
4.4 
Covariates 
 
Not foreseen. 
4.5 
Pooling of sites 
 
Not foreseen. 
4.6 
Interim analyses 
No interim analyses will be performed. 
4.7 
Handling of missing and incomplete data 
Missing values will not be imputed. The number of patients with missing data will be presented 
under the “Missing” category, if present. 
Only the non-missing values will be evaluated for computing summary statistics. 
4.8 
Changes in the planned analysis 
The following change was implemented in this SAP with respect to the analyses planned in the 
protocol: 
• As agreed with the Sponsor, the Intent-to-Treat Analysis set will not be used for the 
analysis and only the Safety set will be used for the primary analysis instead. Moreover, 
also the Per Protocol set definition have been updated accordingly. 
• As agreed with the Sponsor, vitreous haze will not be considered as the primary endpoint 
but as secondary endpoint and the best corrected visual acuity (ETDRS) change from 
baseline at day 14 and day 28 will be considered as the primary endpoint instead. 
• Any reference to dose 2.1 μg treatment group (cohort 4) has been removed from the 
analysis since it has been decided to close the study at cohort 3.  
• No interim analyses will be performed. 
4.9 
Data Review Meeting 


 
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Major protocol violations will be identified by the Sponsor and provided to CROS NT in order to 
create the PP set.     
4.10 Software 
All statistical analyses and data processing will be performed using Statistical Analysis Systems 
(SAS®) Software (release 9.4) on a Windows 7 operating system. 
5.  Evaluation of Demographic and Baseline Characteristics 
5.1 
Subject enrolment and disposition 
Statistical analysis 
Disposition of patients will be presented by cohort and overall for all the patients.. 
The number of patients included in each of the Safety, PP and PK sets will be summarised for each 
cohort.  
5.2 
Protocol violations 
Definitions and data conventions 
All the protocol violations will be discussed case by case by the clinical team and the list of major 
and minor violators will be provided to CROS NT. 
 
Statistical analysis 
Major and minor protocol violations will be listed only. 
5.3 
 Study discontinuations 
Definitions and data conventions 
Date of first study drug intake 
The date of first study drug intake is assumed to be the date of the 1st injection at Day 0. 
 
Completer/discontinued Patient 
A Patient will be considered a completer if the answer to the question “Did the subject complete 
the study?” is equal to “Yes”. 
 
A Patient will be considered as discontinued if the answer to the question “Did the subject 
complete the study?” is equal to “No”. 
 
Statistical analysis 
Patients who discontinued from the study prematurely will also be presented with a breakdown of 
the reasons for discontinuation by cohort and overall for the Safety set.  


 
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5.4 
Demographics and baseline characteristics 
Definitions and data conventions 
Age 
If the date of birth is not missing, age will be calculated using the following rules: 
• 
If month of screening date is greater than month of date of birth or (month of screening date 
is equal to month of date of birth and day of screening date is greater than or equal to day of date of 
birth), then: 
 
Age (years) = year (screening date) – year (date of birth) 
 
• 
Otherwise:  
 
Age (years) = year (screening date) – year (date of birth) - 1 
 
In order to determinate the age of patient, the following rules will be applied for the partial date of 
birth: 
• 
if only the day is missing, the 15th of the month will be assumed; 
• 
if the day and the month are missing, 30th June will be assumed. 
 
Body Mass Index (BMI) (kg/m2) 
BMI will be calculated using the following formula:  
(
)
( )
2
m
height 
kg
t 
Body weigh
 
 
BMI =
 
Statistical analysis 
The baseline demographic characteristics will be summarised for the single cohorts and overall by 
means of descriptive statistics. 
 
The following characteristics will be provided for the Safety set: 
• 
Age (years) 
• 
Sex (male/female) 
• 
Ethnicity (Hispanic or Latino/ Not Hispanic or Latino) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or other Pacific Islander) 
• 
Weight (kg) 
• 
Height (cm) 
• 
BMI (kg/m2) 
• 
Smoking Status (Non-smoker, Ex-smoker, Current smoker) 
5.5 
Medical and ophthalmic history 
Definitions and data conventions 
Past disease 


 
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A disease is considered as past disease if it is not ongoing at screening visit (“ongoing” box is not 
ticked). 
 
Concomitant disease 
A disease is considered as concomitant disease if it is ongoing at screening visit (“ongoing” box is 
ticked). 
 
Statistical analysis 
Past disease and concomitant diseases will be coded using Medical Dictionary for regulatory 
activities (MedDRA) dictionary (version 19.0) and frequency distributions and percentages will be 
summarised by sequence for the Safety set by System Organ Class (SOC) and Preferred Term (PT). 
Counts will be given for both SOC and PT by subject. Subjects experiencing more than one 
past/concomitant disease event will be counted only once within each SOC and PT. 
5.6 
Prior and concomitant medications 
Definitions and data conventions 
The following categories of medications will be identified: 
• previous medication (stop date ≤ date of first study medication intake); 
• concomitant medication (stop date > date of first study medication intake or stop date 
ongoing/missing). 
 
In case of missing or incomplete dates/times not directly allowing allocation to any of the two 
categories of medications, a worst-case allocation will be done according to the available parts of 
the start and the end dates. The medication will be allocated to the first category allowed by the 
available data, according to the following order: 
• concomitant medication; 
• previous medication. 
 
Statistical analysis 
Previous and Concomitant medications 
Medications will be coded using WHO Drug Dictionary (WHO-DD), version 2016Q1 (1st Quarter 
of 2016), and the following Anatomical Therapeutic Chemical Classification (ATC) codes: 
• Anatomical Main Group (ATC 1st level code); 
• Chemical subgroup (ATC 4th level code); 
• Preferred name.  
Previous and concomitant medications will be summarized separately for Safety set by anatomical 
main group, chemical subgroup and preferred name by cohort. 
Subjects experiencing more than one previous (or concomitant) medication within the same 
anatomical main group, chemical subgroup and preferred name will be counted only once. 
5.7 
Other baseline characteristics 
Not foreseen.  


 
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6.  Evaluation of Treatment Compliance and Exposure 
6.1 
Compliance to study drug and treatment 
Not foreseen. 
6.2 
Exposure to study drug 
 
Not foreseen. 
6.3 
Evaluation of pharmacokinetics  
The concentration of PP-001 in plasma will be measured in blood samples taken at Screening, 
4 h ± 1 h after dosing and on Day 2. Analysis will be performed on the PK set.  
 
7.  Evaluation of Efficacy 
All efficacy endpoints will be presented in terms of descriptive statistics by cohort for the Safety 
set. 
7.1 
Analysis of primary endpoint 
Definitions and data conventions 
 
The primary efficacy variable is the best corrected visual acuity (ETDRS) change from baseline at 
day 14 and day 28. 
 
Primary efficacy analysis  
Analysis will be performed on Safety and PP sets. 
The best corrected visual acuity (ETDRS)will be summarized by visits and cohort together with the 
change from baseline at each post-baseline visit by means of descriptive statistics.  
7.2 
Analysis of secondary efficacy endpoints 
Definitions and data conventions 
 
The following detailed ophthalmic examination will be used to determine efficacy: 
 
Vitreous haze 
• as graded by the ophthalmologist during Slit Lamp examination (classified according to 
Standardization of Uveitis Nomenclature Working Group) 
Electroretinography 
• Investigator’s assessment 


 
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Fluorescein Angiogram 
• Investigator’s assessment 
• Hypofluorescence 
• Hyperfluorescence 
Optical Coherence Tomography 
• Retinal thickness 
• Cystoid spaces 
• Subretinal Fluid 
• Vitreoretinal interface abnormalities 
Visual Field Measurement 
• Mean deviation 
• Pattern standard deviation 
• Short-term fluctuation 
• Corrected pattern standard deviation 
• Investigator’s assessment 
Visually Evoked Cortical Potential 
• Investigator’s assessment 
Intraocular Pressure 
• mmHg 
• Investigator’s assessment 
Slit Lamp Examination 
• Lid 
• Conjunctiva 
• Cornea 
• Anterior chamber 
• Iris 
• Lens 
• Macula 
• Optic nerve 
• Vitreous haze 
Dilated Fundoscopy 
• Retinal Oedema 
• Infiltration 
• Vasculitis 
• Retinal Ischemia 
• Epiretinal Gliosis 
• Vascular occlusion 
• Hyperpigmentation 
• Hypopigmentation 
• Choroid Atropy 
Corneal endothelial microscopy 
• Average cell area 
• Cell density 
• Investigator’s assessment 


 
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Fundus photography 
• Investigator’s assessment 
Amsler grid 
• Investigator’s assessment 
 
Statistical analysis 
Descriptive statistics will be presented by visit and for each cohort on the Safety set.  
7.3 
Analysis of other efficacy endpoints 
Definitions and data conventions 
 
 
National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25) 
Visual functioning is assessed using the 25-item NEI-VFQ.  The questionnaire contains 25 vision-
targeted questions (grouped into 11 subscales) plus one single-item question related to general 
health (Question 1).  The responses to the 25 vision-related questions are used to generate 12 
subscale scores, and 11 of them are then averaged to produce an overall composite score to be used 
for analysis.  Averaging the subscale scores gives equal weight to each subscale, whereas averaging 
the scores of the individual questions would give more weight to the subscales containing more 
questions. 
 
The three-step process for deriving the overall NEI-VFQ composite score is explained in the VFQ-
25 Manual “The National Eye Institute 25-Item Visual Function Questionnaire (VFQ-25)” 
(Version 2000), and the details of the algorithm are given below. 
 
Step 1 
 
The categorical responses to the survey are assigned numeric values as dictated by the design of the 
questionnaire, which is available online from the National Eye Institute (2000). 
 
The numeric values are then re-coded to a scale between 0 and 100; such that a higher score 
represents better eye functioning.  The re-coding rules are given in the table below. 
 
Question Numbers 
Original Response Category(a) 
Re-coded Value 
1 
1 
2 
3 
3.5 
4 
0 
25 
50 
75 
100 
3, 4, 15c(b), 17, 18, 19 
1 
2 
3 
4 
5 
100 
75 
50 
25 
0 
2 
1 
2 
3 
4 
0 
20 
40 
60 


 
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Question Numbers 
Original Response Category(a) 
Re-coded Value 
5 
6 
80 
100 
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 
16, 16a 
1 
2 
3 
4 
5 
6 
100 
75 
50 
25 
0 
* 
20, 21, 22, 23, 24, 25 
1 
2 
3 
3.5 
4 
0 
25 
50 
75 
100 
(a) Pre-coded response choices as printed in the questionnaire. 
 
(b) Question 15c has 4 responses levels (1 to 4), but is expanded to 5 levels using Question 15b: 
 
 
If 15b = 1, then 15c should be recoded to 0. 
 
 
If 15b = 2, then 15c should be recoded to missing. 
 
 
If 15b = 3, then 15c should be recoded to missing. 
 
* 
Response choice 6 indicates that the person does not perform the activity because of non-vision related problems.  
 
If this choice is selected, the item is coded as missing. 
 
Step 2 
 
The re-coded scores are grouped into 12 categories as shown in the table below, and the mean of 
the non-missing values in each category represents the subscale score for that category. 
 
Scale 
Number of Questions 
Question Numbers to be 
Averaged for Subscale Score 
(after re-coding) 
General Health 
1 
1 
General Vision 
1 
2 
Ocular Pain 
2 
4, 19 
Near Activities 
3 
5, 6, 7 
Distance Activities 
3 
8, 9, 14 
Vision-Specific: 
 
 
 
Social Functioning 
2 
11, 13 
 
Mental Health 
4 
3, 21, 22, 25 
 
Role Difficulties 
2 
17, 18 
 
Dependency 
3 
20, 23, 24 
Driving 
3 
15c, 16, 16a 
Color Vision 
1 
12 
Peripheral Vision 
1 
10 
 
Step 3 
 
The overall composite score is calculated as the mean of 11 subscale scores that were derived in 
Step 2, excluding the “General Health” subscale score. If not all subscale scores are calculated due 
to missing values, the mean of the available subscale scores will be taken. 
 
SF36™ Health Survey Version 2 (SF-36v2)  


 
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The SF-36 is a multi-purpose, short-form health survey with only 36 questions yielding 8 health 
domain scales and 2 psychometrically based physical and mental component summary measures. 
The standard form of the SF-36v2 will be used. The question number 2 will not be used to score 
any of the 8 health domain scales or 2 summary measures because it is not applicable. 
 
The 8 health domain scales are referred to as the ‘Physical Functioning (PF)’, ‘Role- Physical 
(RP)’, ‘Bodily Pain (BP)’, ‘General Health (GH)’, ‘Vitality (VT)’, ‘Social Functioning (SF)’, 
‘Role-Emotional (RE)’, and ‘Mental Health (MH)’ scales. The 2 summary measures are referred to 
as the physical component score (PCS) and mental component score (MCS). 
 
The methods of SF-36v2 scoring, handling of missing values, z- and T-score transformations are 
provided below. 
 
Each item on the 36-item short-form health survey will be answered by the patients (on scales of 1 
to 3, 1 to 5, or 1 to 6). Some of those answers will then be re-coded so that across all questions, a 
higher score will indicate a better health state. Questions 3a-3j, ,9a, 9d, 9e, 9h, 11b, 11d will be 
scored as recorded; the other questions will have the scores transformed as shown in the  
Table 1. 
 
The raw score for the following 8 scales will be calculated by summing the scores (either original 
or re-coded depending on the question) for the set of questions listed in Table 2 if all of the 
questions within that scale are answered. If < 50% of the questions within a scale is answered, then 
the raw score will not be calculated. 
 
Table 1 
SF-36v2: Re-code 
Question 
Original code and re-code response 
Question number: 1 
    Original response 
5 
4 
3 
2 
1 
 
    Re-coded response 
5 
4.4 
3.4 
2 
1 
 
Questions numbers:  6 
    Original response 
1 
2 
3 
4 
5 
 
    Re-coded response 
5 
4 
3 
2 
1 
 
Questions numbers: 4a-4d, 5a-5c, 9b, 9c, 9f, 9g, 9i, 10, 11a, 11c 
    Original response 
5 
4 
3 
2 
1 
 
    Re-coded response 
1 
2 
3 
4 
5 
 
Question number:  7 
    Original response 
1 
2 
3 
4 
5 
6 
    Re-coded response 
6 
5.4 
4.2 
3.1 
2.2 
1 
Question number:  8 (if question number 7 is answered) 
    Original response to #8 
1 
1 
2 
3 
4 
5 
    Original response to #7 
1 
2-6 
1-6 
1-6 
1-6 
1-6 
    Re-coded response 
6 
5 
4 
3 
2 
1 


 
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SF-36v2: Re-code 
Question 
Original code and re-code response 
Question number:  8 (if question number 7 is NOT answered) 
    Original response 
1 
2 
3 
4 
5 
 
    Re-coded response 
6 
4.75 
3.5 
2.25 
1 
 
 
 
Table 2  
SF-36v2: Scales 
Scales 
Questions 
Physical functioning (PF) 
3a to 3j 
Role – physical (RP) 
4a to 4d 
Bodily pain (BP) 
7, 8 
General health (GH) 
1, 11a to 11d 
Vitality (VT) 
9a, 9e, 9g, 9i 
Social functioning (SF) 
6, 10 
Role - emotional (RE) 
5a to 5c 
Mental health (MH) 
9b, 9c, 9d, 9f, 9h 
 
 
If ≥ 50% but not all of the questions are answered on a domain, first the non-missing questions are 
recoded (if necessary) and then summed. An average score is calculated for those non-missing 
scores and that average score is filled in as the score to be used for the value of the missing 
questions. The raw score is then calculated as the sum of all the question scores. For example, for 
the VT scale, if questions 9a, 9e, and 9g are answered but question 9i is missing, the algorithm will 
proceed as shown in Table 3 from left to right: 
 
Table 3 
 
SF-36v2: Algorithm for unanswered questions 
Question Patient 
recorded 
response 
Response 
after re-
coding 
 
Average is 
filled in for 
missing 
responses 
 
9a 
1 
5 
Average of non-
missing scores = 
(5+3+5)/3 = 
4.33333. 
5 
Raw score = 
5+3+5+4.3333… 
= 17.33333… 
9e 
3 
3 
3 
9g 
5 
5 
5 
9i 
Missing 
Missing 
4.33333… 
 
 
After the raw score is calculated, the raw score is then converted into a transformed scale score (on 
a scale of 0 to 100) using the following transformation: 


 
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The transformed scale scores will then be standardised using the following formula for the z-score 
transformation: 
 
 
 
For example, a VT total raw score of 17.33333 would be transformed as follows: 
 
 
 
As shown in Table 4, the lowest possible VT score equals 4 and the possible VT total raw score 
range equals 16. This transformation converts the lowest and highest possible raw scores to 0 and 
100, respectively. Scores between these values represent the percentage of the total possible score 
achieved. 
 
When based on the 1998 US general population, the VT z-score is as follows: 
 
 
 
The lowest possible raw score, possible raw score range, mean and standard deviation for each 
scale are shown in Table 4.  
 
Table 4 
Lowest possible raw score and range, and means and standard deviations for deriving 
the z-scores for the scales of the SF-36v2 ACUTE form 
Scale 
Lowest possible 
raw score 
Possible raw 
score range 
Mean 
Standard 
deviation 
PF 
10 
20 
82.62455 
24.43176 
RP 
4 
16 
82.65109 
26.19282 
BP 
2 
10 
73.86999 
24.00884 
GH 
5 
20 
70.78372 
21.28902 
VT 
4 
16 
58.41968 
20.87823 
SF 
2 
8 
85.11568 
23.24464 
RE 
3 
12 
87.50009 
22.01216 
MH 
5 
20 
75.76034 
18.04746 
 


 
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The physical and mental component raw scores are composed of a combination of the 8 domain z-
scores and these will be calculated based on each domain scale z-score multiplied by a constant 
provided in Table 5, and then add the 8 scales together. 
To illustrate, a portion of the formula for aggregating scales when estimating an aggregate physical 
and mental component score are as follows: 
Aggregate PCS = (PF z-score x 0.42402) +  . . . + (GH z-score x -0.22069) 
Aggregate MCS = (PF z-score x –0.22999) + . . . + (MH z-score x 0.48581) 
Note: if any of the 8 domain z-score is missing the aggregate PCS and MCS will be missing. 
 
The T-scores for the 8 scale scores will be calculated by multiplying the scale z-scores by 10 and 
adding 50.  
To illustrate, a portion of the formula for transforming domain scale z-scores to T-scores: 
PF T-score = 50 + (PF z-score x 10) 
MH T-score = 50 + (MH z-score x 10) 
 
The physical and mental component T-scores will then be calculated by multiplying the component 
raw scores by 10 and adding 50. 
The formulas for computing the norm-based T-score for each component summary measure are: 
PCS T-score = 50 + (Aggregate physical component score x 10) 
MCS T-score = 50 + (Aggregate mental component score x 10) 
 
Table 5 
 SF-36v2:  Scale constants used to calculate component scores 
Scale 
Physical health 
component 
Mental health component 
PF 
0.42402 
-0.22999 
RP 
0.35119 
-0.12329 
BP 
0.31754 
-0.09731 
GH 
0.24954 
-0.01571 
VT 
0.02877 
0.23534 
SF 
-0.00753 
0.26876 
RE 
-0.19206 
0.43407 
MH 
-0.22069 
0.48581 
 
The responses to the SF-36v2 at Visit 9 (Day 28) will also be categorized as improved, 
worsened and stable based on the changes from baseline in T-score. The criteria for a MCID 
(Ware et al, 2007) will be used to assign a visit response for each score (see Table 6). The T-
scores will be based on the 1998 US general population survey as reported in Ware et al, 2007. 
At follow up visit, the criteria that will be used to assign a visit response to the changes from 
baseline will be based on the MCIDs shown in Table 6.  
 
Only patients with a non-missing score at both baseline and at Visit 9 (Day 28) will be 
considered eligible for categorization. 


 
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Table 6 
Response Categories  
 
Visit response  
Score 
Improved 
Worsened 
Stable 
PCS 
≥ + 3.1 
≤ - 3.1 
Otherwise 
MCS 
≥ + 3.8 
≤ - 3.8 
Otherwise 
PF 
≥ + 3.5 
≤ - 3.5 
Otherwise 
RP 
≥ + 3.2 
≤ - 3.2 
Otherwise 
BP 
≥ + 4.5 
≤ - 4.5 
Otherwise 
GH 
≥ + 5.7 
≤ - 5.7 
Otherwise 
VT 
≥ + 5.5 
≤ - 5.5 
Otherwise 
SF 
≥ + 5.0 
≤ - 5.0 
Otherwise 
RE 
≥ + 3.8 
≤ - 3.8 
Otherwise 
MH 
≥ + 5.5 
≤ - 5.5 
Otherwise 
 
EuroQol-5 Dimensions Health Questionnaire (EQ-5D) 
 
The EuroQol EQ-5D-5L consists of five dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) each of which is recorded on a 5 point scale (1 to 5). The 
first response choice (“no problems”) is coded as a 1; the second (“slight problems”) is coded as a 
2; the third (“moderate problems”) is coded as a 3; the forth (“severe problems”) is coded as a 4; 
the fifth (“extreme problems”) is coded as a 5 as indicated on the questionnaire. Values recorded in 
the eCRF will not be recoded.  
 
Each combination of dimensions scores for a single subject is concatenated together to form the 
Health State (e.g. a string variable ‘11233’ for the scores in mobility=1, self-care=1, usual 
activities=2, pain/discomfort=3, and anxiety/depression=3). 
 
The five dimensions will also be converted into a Health State Index on a scale of approximately 0 
to 1, where scores close to 0 represent a health state of death and a score of 1 represents full quality 
of life. The conversion between the ordinal scores to an index will be carried out using UK 
weighting and using SAS programs supplied by EUROQOL. 
 
A higher score indicates a more preferred health status. For the precision of TLFs the actual derived 
value will be used in all summary statistic calculations but will be listed to two decimal places. 
Summary statistics will be rounded based on the same decimal precisions. 
 
The final EQ-5D question (the ‘Scored Health Today’) asks respondents to rate their present health 
status on a vertical 0 to 100 visual analogue scale of 20 cm, with 0 labelled as “Worst imaginable 
health state” and 100 labelled as “Best imaginable health state.” The scale is marked in increments 
of “10,” with values labelled at each decile. 


 
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Statistical analysis 
The EuroQol-5 Questionnaire (EQ-5D-5L) Health State Index as the Scored Health, NEI-VFQ 
overall composite score and SF-36v2 scores as measured at baseline and Visit 9 (Day 28), will be 
summarised using descriptive statistics, and the change in score from the baseline visit will be 
calculated for each patient. 
7.4 
Evaluation of pharmacodynamics 
Statistical analysis 
The PK parameters will be listed only. 
8.  Evaluation of Safety 
8.1 
Adverse events 
Definitions and data conventions 
 
Pre-treatment adverse events 
An AE will be classified as pre-treatment AE if it starts before the date/time of first study 
medication intake (AE onset date/time < date/time of first study medication intake). 
 
 
Treatment-emergent adverse event (TEAE) 
An AE will be classified as a TEAE if it starts on or after the date/time of first study medication 
intake (AE onset date/time ≥ date/time of first study medication intake). 
In case of missing or incomplete dates/times not allowing a direct allocation to any of the two 
categories of AEs, a worst-case allocation will be done according to the available parts of the onset 
and the end dates/times. The AE will be allocated to the first category allowed by the available 
data, according to the following order: 
• TEAE 
• Pre-treatment. 
 
Serious adverse event (SAE) 
A SAE is an AE judged as serious. 
 
Adverse drug reaction (ADR) 
An ADR is an AE judged as “Possibly Related”, “Probably Related” or “Definitely Related”. 
 
Adverse event leading to discontinuation 
An AE leading to discontinuation is an AE with action taken equal to “Study drug withdrawn and 
/or patient withdrawn from the study”. 
 
Adverse event leading to death 
An AE leading to death is an AE with outcome equal to “Fatal”. 
 


 
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Count of adverse events 
Two AEs with the same Preferred Term (PT) and classified in the same category (pre-treatment AE 
or TEAE) will be considered as two different events when calculating the “number of events” in 
the tables.  
 
Statistical analysis 
Pre-treatment AEs and TEAEs will be presented separately. Pre-treatment AEs will be presented in 
the listings only. 
The number of treatment-emergent AEs, SAEs, ADRs, serious ADRs, severe AEs, AEs leading to 
discontinuation and AEs leading to death, and the number and the percentage of patients 
experiencing treatment-emergent AEs, SAEs, ADRs, serious ADRs, severe AEs, AEs leading to 
discontinuation and AEs leading to death will be summarised by cohort.  
AEs will be coded using the MedDRA dictionary (version 19.0). The SOCs and PTs will be used 
for tabulation. The number of AEs and the number and the percentage of patients with at least one 
AE will be presented by SOC and PT for treatment-emergent AEs, SAEs, ADRs, AEs leading to 
discontinuation and AEs leading to death by cohort.  
8.2 
Clinical laboratory evaluation 
Statistical analysis 
Hemathology, biochemistry parameters and their change from screening will be summarised by 
cohort at each available visit by means of descriptive statistics. 
Shift tables presenting the number and the percentage of patients in each bivariate category 
(screening visit versus Visit 9) with regards to Investigator’s interpretation (Normal, NCS, CS) will 
be presented by cohort for all laboratory parameters.  
Urinalysis parameters will be listed only. 
8.3 
Vital signs 
 
Statistical analysis 
Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Heart Rate (beats/min) and 
their change from baseline will be summarised by cohort at each available visit by means of 
descriptive statistics. 
8.4 
ECGs 
 
Statistical analysis 
Heart rate (beats/min), PR interval (msec), QRS Duration (msec), QTc interval (msec), QTcf 
(msec) and the Investigator’s interpretation (Normal, NCS, CS) will be listed only. 
8.5 
Physical examination 
Statistical analysis 
Physical examination will be listed only. 


 
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8.6 
Other safety evaluations 
Not foreseen. 
9.  Tables, Figures and Listings 
9.1 
Programs and tables quality control 
The statistician-programmer of the tables, listings and figures will carefully review the programs 
and will verify that no error message is highlighted in the ‘LOG’ file.  
Moreover, a second statistician-programmer will verify the internal consistency of each table by 
checking the results using different SAS programs.  
 
The following level of validation will be implemented:  
• Validation of statistical datasets: via validation of the final output (tables) 
• Validation of statistical output:  
- 
tables: independent programming, with a comparison of the results against the initial 
output; 
- 
listings: peer review. 
9.2 
Programming conventions 
All tables/figures/listings will be presented in landscape format.  
The standard font size is 9 points Arial for all tables. Listings will be presented with an 8 or 7 
points Arial.  
 
Titles will be center-aligned; footnotes will be left-aligned.  
Each table/figure/listing will have 2 titles: 
• 
The 1st title will be the table/figure/listing number with the description of the 
table/figure/listing;  
• 
The 2nd title will be a description of the study set presented in the table/figure/listing. 
Some tables will have a third title (before 2nd title) with a description of the statistical method used 
in those tables. 
 
Any footnote added to explain the table/listing/figure contents will be presented in the following 
format: 
Note 1: Percentages are calculated on the number of patients (N). 
Note 2: A serious adverse event is an .... 
Note 3: ………. 
 
The last two footnotes of each table/figure will be footers indicating: 
• 
the reference listing of the data; 
• 
the program name, the date and time of generation and the SAS® version used. 
The last footnote of each listing will be a footer indicating the program name, the date and time of 
generation and the SAS® version used. 
 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
29 of 31 
 
Protocol Number: 
PP-001-1001 
Version Final 3.0 
Document Date: 
17 Feb 2020 
 
 
Unless otherwise stated, listings will be presented by the only treatment and sorted by the patient 
number.  
 
All the listings will be based on the Safety set, except stated otherwise. 
 
The derived variables will be identified in the listings with a flag (*). 
 
In general, dates will be presented on listings in the format ddmmmyyyy (date9.) and time in the 
format hh:mm (time5.). In case of partial dates or times, missing information will be replaced by 
dashes. Numeric variables will be listed generally with the same number of decimal places as in the 
actual data. 
 
The following rules on decimal places will be considered in the listings for the derived variables (in 
the analyses approximations will not be performed): 
• 
Age (years): 0 decimal place; 
• 
BMI (kg/m2): 1 decimal place; 
• 
change from baseline: same as the variable considered. 
 
The following rules on decimal places will be considered for the results of the analyses (if the 
analyses are performed on derived variables, the level of precision of the actual data is derived 
from the previous list): 
• 
Min, max: same as actual data; 
• 
Mean and its confidence limits (unadjusted and adjusted), SD, median: actual data + 1 
decimal; 
• 
Percentage: 1 decimal place; 
• 
P-value: 3 decimal places. 
9.3 
Tables 
The list of tables is provided here below: 
 
 
TABLE 
TITLE 
TABLE 14.1.1 
SUBJECT DISPOSITION / SUMMARY OF ALL SUBJECTS 
TABLE 14.1.2.1 
PRIMARY REASONS FOR DISCONTINUATION FROM STUDY / 
SAFETY SET 
TABLE 14.1.3.1 
ANALYSIS SETS / SAFETY SET 
TABLE 14.1.4.1 
DEMOGRAPHIC CHARACTERISTICS / SAFETY SET 
TABLE 14.1.5.1 
MEDICAL AND OPHTHALMIC HISTORY: PAST DISEASES / SAFETY 
SET 
TABLE 14.1.5.2 
MEDICAL AND OPHTHALMIC HISTORY: CONCOMITANT DISEASES 
/ / SAFETY SET 
TABLE 14.1.6.1 
PREVIOUS MEDICATIONS / SAFETY SET 
TABLE 14.1.6.2 
CONCOMITANT MEDICATIONS / SAFETY SET 
TABLE 14.2.2.1 
ETDRS SCORES DURING THE STUDY AND CHANGE FROM 
BASELINE / SAFETY SET 
TABLE 14.2.2.2 
ETDRS SCORES DURING THE STUDY AND CHANGE FROM 
BASELINE / PP SET 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
30 of 31 
 
Protocol Number: 
PP-001-1001 
Version Final 3.0 
Document Date: 
17 Feb 2020 
 
 
TABLE 
TITLE 
TABLE 14.2.3.1 
SLIT LAMP EXAMINATION DURING STUDY / SAFETY SET 
TABLE 14.2.4.1 
FLUORESCEIN ANGIOGRAM, ETDRS, VISUALLY EVOKED 
CORTICAL POTENTIAL, INTRAOCULAR PRESSURE AND DILATED 
FUNDOSCOPY DURING STUDY / SAFETY SET 
TABLE 14.2.5.1 
ELECTRORETINOGRAPHY, OPTICAL COHERENCE TOMOGRAPHY, 
VISUAL FIELD, CORNEAL ENDOTHELIAL MICROSCOPY, FUNDUS 
PHOTOGRAPHY AND AMSLER GRID DURING STUDY / SAFETY SET 
TABLE 14.2.6 
PATIENT- REPORTED OUTCOMES DURING THE STUDY AND 
CHANGE FROM BASELINE / SAFETY SET 
TABLE 14.3.1.1 
SUMMARY OF TREATMENT EMERGENT ADVERSE EVENTS / 
SAFETY SET 
TABLE 14.3.1.2 
TREATMENT EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN 
CLASS AND PREFERRED TERM / SAFETY SET 
TABLE 14.3.1.3 
TREATMENT EMERGENT SERIOUS ADVERSE EVENTS BY SYSTEM 
ORGAN CLASS AND PREFERRED TERM / SAFETY SET 
TABLE 14.3.1.4 
TREATMENT EMERGENT ADVERSE DRUG REACTIONS BY 
SYSTEM ORGAN CLASS AND PREFERRED TERM / SAFETY SET 
TABLE 14.3.1.5 
TREATMENT EMERGENT ADVERSE EVENTS LEADING TO 
DISCONTINUATION BY SYSTEM ORGAN CLASS AND PREFERRED 
TERM / SAFETY SET 
TABLE 14.3.1.6 
TREATMENT EMERGENT ADVERSE EVENTS LEADING TO DEATH 
BY SYSTEM ORGAN CLASS AND PREFERRED TERM / SAFETY SET 
TABLE 14.3.2.1 
HAEMATOLOGY RESULTS DURING THE STUDY AND CHANGE 
FROM SCREENING / SAFETY SET 
TABLE 14.3.2.2 
BIOCHEMISTRY RESULTS DURING THE STUDY AND CHANGE 
FROM SCREENING / SAFETY SET 
TABLE 14.3.2.3 
HAEMATOLOGY RESULTS: SHIFTS FROM SCREENING TO VISIT9 / 
SAFETY SET 
TABLE 14.3.2.4 
BIOCHEMISTRY RESULTS: SHIFTS FROM SCREENING TO VISIT9 / 
SAFETY SET 
TABLE 14.3.3.1 
VITAL SIGNS DURING THE STUDY AND CHANGE FROM BASELINE 
/ SAFETY SET 
9.4 
Figures 
Figures not foreseen. 
9.5 
Listings 
The list of listings is provided here below: 
 
 
LISTING 
TITLE 
LISTING 16.2.1.1 
DISPOSITION OF SUBJECTS / ALL SUBJECTS 
LISTING 16.2.1.2 
STUDY TERMINATION / SAFETY SET 
LISTING 16.2.2.1 
PROTOCOL DEVIATIONS / SAFETY SET 
LISTING 16.2.2.2 
VIOLATIONS OF INCLUSION/EXCLUSION CRITERIA / SAFETY SET 
LISTING 16.2.3.1 
ANALYSIS SETS / SAFETY SET 
LISTING 16.2.4.1 
DEMOGRAPHIC CHARACTERISTICS / SAFETY SET 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
31 of 31 
 
Protocol Number: 
PP-001-1001 
Version Final 3.0 
Document Date: 
17 Feb 2020 
 
 
LISTING 
TITLE 
LISTING 16.2.4.2 
MEDICAL AND OPHTHALMIC HISTORIES / SAFETY SET 
LISTING 16.2.4.3 
 
MEDICATIONS / SAFETY SET 
LISTING 16.2.5.1 
STUDY DRUG ADMINISTRATION / SAFETY SET 
LISTING 16.2.6.1 
ETDRS / SAFETY SET 
LISTING 16.2.6.2 
SLIT LAMP EXAMINATION / SAFETY SET 
LISTING 16.2.6.3 
FLUORESCEIN ANGIOGRAM, ETDRS, VISUALLY EVOKED 
CORTICAL POTENTIAL, INTRAOCULAR PRESSURE AND DILATED 
FUNDOSCOPY / SAFETY SET 
LISTING 16.2.6.4 
ELECTRORETINOGRAPHY, OPTICAL COHERENCE TOMOGRAPHY, 
VISUAL FIELD, CORNEAL ENDOTHELIAL MICROSCOPY, FUNDUS 
PHOTOGRAPHY AND AMSLER GRID / SAFETY SET 
LISTING 16.2.6.5 
PATIENT REPORTED OUTCOMES / SAFETY SET 
LISTING 16.2.7.1 
ADVERSE EVENTS / SAFETY SET 
LISTING 16.2.8.1 
 
LABORATORY PARAMETERS: HAEMATOLOGY / SAFETY SET 
LISTING 16.2.8.2 
 
LABORATORY PARAMETERS: BIOCHEMISTRY / SAFETY SET 
LISTING 16.2.8.3 
LABORATORY PARAMETERS: URINALYSIS / SAFETY SET 
LISTING 16.2.8.4 
URINE PREGNANCY TEST / SAFETY SET 
LISTING 16.2.8.5 
 
VITAL SIGNS / SAFETY SET 
LISTING 16.2.8.6 
12-LEAD ECG RESULTS / SAFETY SET 
LISTING 16.2.8.7 
ABNORMAL PHYSICAL EXAMINATION / SAFETY SET 
LISTING 16.2.8.8 
PK / PK SET 
10.  
Literature 
• 
CROS NT Standard Operating Procedure SOP ST03/V01 “Statistical Analysis Plans”;  
• 
European Medicines Agency (EMA), International Conference on Harmonisation (ICH) E3 
Harmonised Guideline (1996) “Structure and Content of Clinical Study Reports”; 
• 
EMA, ICH E9 Harmonised Guideline (1998) “Statistical Principles for Clinical Trials”. 
11.  
Appendices  
11.1 Table shells 
See AppendixI_PP001-1001_200217(Final_3.0) 
11.2 Listing shells 
See AppendixI_PP001-1001_200217 (Final_3.0)