Clinical trial NCT03558061
Conditions: Wet Age-related Macular Degeneration
Sponsor: Alkahest, Inc.
Start date: 2018-04-04; Completion date: 2018-11-18
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the therapeutic effects and safety of 800 mg ALK4290 administered daily over a 6-week dosing period in newly diagnosed patients with wet age-related macular degeneration (wAMD).

Detailed description:
This study is designed to evaluate the therapeutic effects and safety of oral ALK4290 administered at 800 mg daily over a 6-week dosing period in newly diagnosed (treatment naïve) patients with wAMD. The study agent will be orally self-administered. All subjects will receive the study agent, ALK4290. This study does not contain a placebo.

Arms: arm 1: ALK4290 800 mg daily
Interventions: intervention 1: ALK4290
Intervention descriptions: intervention 1: ALK4290 400 mg tablet twice a day

Protocol documents:
Prot_000.pdf: 
Study Title A Single Arm Open-Label Study to Evaluate the Therapeutic Effects and 
Safety of a 6-Week Treatment Regimen of ALK4290 in Patients with 
Newly Diagnosed Wet Age-Related Macular Degeneration (wAMD) 
NCT Number NCT03558061 
Document Description Protocol (Version 3.0) 
Document Date 15 May 2018 
 


 
Protocol ALK4290-201 
 
 
V3.0_15MAY2018 
 
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CONFIDENTIAL/PROPRIETARY  
 
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A Single Arm Open-Label Study to Evaluate the Therapeutic Effects and Safety of a                    
6-Week Treatment Regimen of ALK4290 in Patients with Newly Diagnosed Wet Age-Related 
Macular Degeneration (wAMD) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Number: 
ALK4290-201 
Clinical Phase: 
2 
Sponsor: 
Alkahest, Inc.  
75 Shoreway Road, Suite D 
San Carlos, CA 94070 
Investigational Drug: 
ALK4290 
Indication: 
Wet Age-Related Macular Degeneration (wAMD) 
Authorized Representative: 
 
75 Shoreway Road, Suite D 
San Carlos, CA 94070 
 
Principal Investigator: 
 
Version Number: 
V3.0 
Version Date: 
15MAY2018 
 
 
CONFIDENTIAL STATEMENT 
The information contained in this document and all information provided as related to this clinical study are 
the confidential and proprietary information of the sponsor and except as may be required by federal, state, or 
local laws or regulations may not be disclosed to others without prior written permission of the sponsor.  The 
principal investigator may, however, disclose such information to supervised individuals working on the 
clinical study, provided such individuals agree to maintain the confidentiality of such information. 
 


 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ........................................................................................................................................................ 2 
LIST OF ABBREVIATIONS ................................................................................................................................................. 6 
PROTOCOL APPROVAL PAGE .......................................................................................................................................... 8 
STATEMENT OF COMPLIANCE ........................................................................................................................................ 9 
PROTOCOL SUMMARY .................................................................................................................................................... 10 
SCHEMATIC OF STUDY DESIGN ................................................................................................................................... 12 
1 
KEY ROLES ................................................................................................................................................................. 13 
1.1 
AUTHORIZED REPRESENTATIVE (SIGNATORY) / RESPONSIBLE PARTY ........................................... 13 
1.2 
STUDY ORGANIZATION .................................................................................................................................. 13 
2 
INTRODUCTION ........................................................................................................................................................ 13 
2.1 
BACKGROUND INFORMATION ...................................................................................................................... 13 
2.2 
RATIONALE ........................................................................................................................................................ 14 
2.3 
POTENTIAL RISKS AND BENEFITS ............................................................................................................... 15 
2.3.1 
KNOWN POTENTIAL RISKS .................................................................................................................... 15 
2.3.2 
KNOWN POTENTIAL BENEFITS ............................................................................................................. 15 
3 
OBJECTIVES AND PURPOSE ................................................................................................................................... 16 
4 
STUDY DESIGN AND ENDPOINTS ......................................................................................................................... 16 
4.1 
DESCRIPTION OF THE STUDY DESIGN ........................................................................................................ 16 
4.2 
STUDY ENDPOINTS .......................................................................................................................................... 16 
5 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................................................................... 17 
5.1 
INCLUSION CRITERIA ...................................................................................................................................... 17 
5.2 
EXCLUSION CRITERIA ..................................................................................................................................... 17 
5.3 
SUBJECT WITHDRAWAL OR TERMINATION .............................................................................................. 19 
5.3.1 
REASONS FOR WITHDRAWAL OR TERMINATION ............................................................................ 19 
5.3.2 
HANDLING OF PARTICPANT WITHDRAWALS OR TERMINATION ................................................ 19 
5.4 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ...................................................................... 19 
6 
TREATMENTS ............................................................................................................................................................ 20 
6.1 
STUDY AGENT DESCRIPTION ........................................................................................................................ 20 
6.1.1 
ACQUISITION ............................................................................................................................................. 20 


 
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6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING .................................................... 20 
6.1.3 
PRODUCT STORAGE AND STABILITY ................................................................................................. 20 
6.1.4 
DOSING AND ADMINISTRATION .......................................................................................................... 20 
6.2 
STUDY AGENT ACCOUNTABILITY ............................................................................................................... 21 
6.3 
CONCOMITANT MEDICATIONS AND TREATMENTS ................................................................................ 21 
6.4 
PROHIBITED TREATMENTS, MEDICATIONS, AND PROCEDURES ......................................................... 21 
7 
VARIABLES AND THEIR ASSESSMENT ............................................................................................................... 22 
7.1 
THERAPEUTIC EFFECT .................................................................................................................................... 22 
7.2 
SAFETY AND EXPLORATORY OUTCOMES ................................................................................................. 22 
7.2.1 
ASSESSMENT OF ADVERSE EVENTS ................................................................................................... 22 
7.2.2 
SAFETY LABORATORY EVALUATIONS .............................................................................................. 26 
7.2.3 
ELECTROCARDIOGRAM ......................................................................................................................... 26 
7.2.4 
VITAL SIGNS AND PHYSICAL EXAMINATION ................................................................................... 27 
7.2.5 
OTHER OPHTHALMIC EXPLORATORY ENDPOINTS AND EVALUATIONS .................................. 27 
7.2.6 
STUDY AGENT CONCENTRATION AND PHARMACOKINETICS ..................................................... 28 
7.2.7 
PHARMACOGENOMIC EVALUATIONS ................................................................................................ 28 
7.2.8 
BIOMARKERS ............................................................................................................................................ 30 
8 
INVESTIGATIONAL PLAN ....................................................................................................................................... 30 
8.1 
VISIT SCHEDULE ............................................................................................................................................... 30 
8.2 
VISIT PROCEDURES ......................................................................................................................................... 31 
8.2.1 
SCREENING AND RUN-IN PERIOD ........................................................................................................ 31 
8.2.2 
TREATMENT PERIOD ............................................................................................................................... 31 
8.2.3 
END OF TREATMENT ............................................................................................................................... 33 
8.2.4 
FOLLOW-UP VISITS .................................................................................................................................. 34 
9 
CLINICAL MONITORING ......................................................................................................................................... 35 
10 
STATISTICAL CONSIDERATIONS ...................................................................................................................... 35 
10.1 
STATISTICAL DESIGN MODEL AND ANALYTICAL PLANS ..................................................................... 35 
10.2 
STATISTICAL HYPOTHESES ........................................................................................................................... 35 
10.3 
ANALYSIS DATASETS ..................................................................................................................................... 36 
10.4 
PLANNED ANALYSES ...................................................................................................................................... 36 
10.4.1 
ANALYSIS OF THE PRIMARY ENDPOINT ............................................................................................ 36 


 
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10.4.2 
ANALYSIS OF THE SECONDARY ENPOINT ......................................................................................... 36 
10.4.3 
EXPLORATORY ANALYSES .................................................................................................................... 37 
10.4.4 
PLANNED INTERIM ANALYSES ............................................................................................................. 37 
10.5 
SAMPLE SIZE ..................................................................................................................................................... 37 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................................................. 37 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................................ 38 
12.1 
ETHICAL STANDARD ....................................................................................................................................... 38 
12.2 
INSTITUTIONAL REVIEW BOARD ................................................................................................................. 38 
12.3 
INFORMED CONSENT PROCESS .................................................................................................................... 38 
12.3.1 
CONSENT FORMS ...................................................................................................................................... 38 
12.3.2 
CONSENT PROCEDURES AND DOCUMENTATION ............................................................................ 38 
12.4 
DATA CONFIDENTIALITY ............................................................................................................................... 39 
12.5 
FUTURE USE OF STORED SPECIMENS ......................................................................................................... 39 
12.6 
EXPEDITED REPORTING OF ADVERSE EVENTS........................................................................................ 40 
13 
DATA HANDLING AND RECORD KEEPING ..................................................................................................... 40 
13.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 40 
13.1.1 
INVESTIGATOR RESPONSIBILITIES ..................................................................................................... 40 
13.1.2 
STUDY FILES .............................................................................................................................................. 40 
13.2 
STUDY RECORDS RETENTION ....................................................................................................................... 41 
13.3 
PROTOCOL DEVIATIONS AND VIOLATIONS .............................................................................................. 41 
13.4 
PUBLICATION AND DATA SHARING POLICY ............................................................................................ 42 
13.5 
COMPLETION OF TRIAL .................................................................................................................................. 42 
14 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY ............................................................ 42 
15 
SCHEDULE OF EVENTS ....................................................................................................................................... 44 
15.1 
SCHEDULE OF EVENTS TABLE ...................................................................................................................... 44 
16 
REFERENCES ......................................................................................................................................................... 45 
16.1 
PUBLISHED REFERENCES ............................................................................................................................... 45 
16.2 
UNPUBLISHED REFERENCES ......................................................................................................................... 46 
17 
APPENDICES .......................................................................................................................................................... 47 
17.1 
CLINICAL EVALUATION OF LIVER INJURY ............................................................................................... 47 
17.1.1 
INTRODUCTION ........................................................................................................................................ 47 


 
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17.1.2 
PROCEDURES ............................................................................................................................................. 47 
17.2 
PHARMACOKINETIC, BIOMARKER, AND PHARMACOGENOMIC SAMPLING .................................... 48 
17.2.1 
TABLE OF PHARMACOKINETIC (PK), BIOMARKER, AND PHARMACOGENOMIC (PGX) 
SAMPLING .................................................................................................................................................................. 48 
17.3 
PHARMACOKINETIC MEASURES AND EVALUATION ............................................................................. 49 
17.3.1 
TIMING OF PHARMACOKINETIC BLOOD SAMPLING ...................................................................... 49 
17.3.2 
PHARMACOKINETIC SAMPLE HANDLING AND SHIPMENT ........................................................... 49 
17.3.3 
PHARMACOKINETIC DATA EVALUATION ......................................................................................... 49 
17.3.4 
HANDLING OF MISSING DATA .............................................................................................................. 50 
17.4 
 ................................................................. 51 
17.4.1 
 ......................................................... 51 
17.5 
COCKCROFT-GAULT FORMULA ................................................................................................................... 52 
18 
REVISION HISTORY .............................................................................................................................................. 53 
 
 
 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALT 
Alanine Amino Transferase 
AM 
Ante Meridiem 
AMD 
Age-Related Macular Degeneration 
Anti-VEGF 
Anti-Vascular Endothelial Growth Factor 
AP 
Alkaline Phosphatase 
aPTT 
Activated Partial Thromboplastin Time 
ARM 
Age-Related Maculopathy 
ARMS2 
Age-Related Maculopathy Susceptibility 2 AST 
AST 
Aspartate Amino Transferase 
AUC 
Area under the Curve 
BCVA 
Best Corrected Visual Acuity 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
 
 
 
 
CCR3 
C-C Chemokine Receptor Type 3 
 
 
CK 
Creatinine Kinase 
CK-MB 
Creatinine Kinase-MB Test 
Cmax 
Maximum Plasma Concentration 
CMP 
Clinical Monitoring Plan 
CNV 
Choroidal Neovascularization 
CNVM 
Choroidal Neovascular Membranes 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRT 
Central Retinal Thickness 
CST 
Central Subfield Thickness 
CTCAE 
Common Terminology Criteria for Adverse Events 
CSR 
Clinical Study Report 
CYP 
Cytochrome P450 
DILI 
Drug Induced Liver Injury 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic Acid 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
ESC 
Eosinophil Shape Change 
ETDRS 
Early Treatment Diabetic Retinopathy Study  
FA 
Fluorescein Angiography 
FU 
Follow-up 


 
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GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HCV 
Hepatitis C Virus Test 
HEV 
Hepatitis E Virus Test 
HPLC-MS/MS 
High Performance Liquid Chromatography, Tandem Mass Spectrometry  
ICH 
International Conference of Harmonization 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
INR 
International Normalized Ratio 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRF 
Intraretinal Fluid 
ISF 
Investigator Site File 
IVT 
Intravitreal 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Drug Regulatory Activities  
NOA 
Not Analyzed 
NOP 
No Peak Detectable 
NOR 
No Valid Result 
NOS 
No Sample Available 
OCT 
Optical Coherence Tomography 
PED 
Pigment Epithelial Detachment 
P-gp 
Permeability Glycoprotein 
pH 
Potential of Hydrogen 
PK 
Pharmacokinetics 
PP 
Polypropylene 
PT 
Prothrombin Time 
QRS 
QRS Interval on ECG 
QT 
QT Interval on ECG 
RBC 
Red Blood Cell Count 
RNA 
Ribonucleic Acid 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SAP 
Statistical Analytical Plan 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SRF 
Subretinal Fluid 
Tdp 
Torsade de Pointes 
ULN 
Upper Limit of Normal 
VA 
Visual Acuity 
VCA 
Vascularized Composite Allotransplantation 
VEGF 
Vascular Endothelial Growth Factor 
wAMD 
wet Age-Related Macular Degeneration 
WBC 
White Blood Cell Count 
YAG 
Yttrium Aluminum Garnet 


 
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PROTOCOL APPROVAL PAGE 
 
 
 
Study Title: 
A Single Arm Open-Label Study to Evaluate the Therapeutic Effects and 
Safety of a 6-Week Treatment Regimen of ALK4290 in Patients with 
Newly Diagnosed Wet Age-Related Macular Degeneration (wAMD) 
Protocol Number: 
ALK4290-201 
Version/Date:  
V3.0_15MAY2018 
Sponsor Name and 
Address: 
 
Alkahest, Inc. 
75 Shoreway Road, Suite D 
San Carlos, CA 94070 
 
 
 
I, the undersigned, have read and approve this protocol and agree on its content. It is confirmed that the information and 
guidance given in this protocol complies with scientific principles, the guidelines of Good Clinical Practice, the Declaration 
of Helsinki in the latest relevant version, and applicable legal and regulatory requirements.  
 
 
 
 
 
Approved by: 
 
  
 
 
 
  
Sponsor Representative (print) 
 Signature  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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STATEMENT OF COMPLIANCE 
 
Protocol Title: 
A Single Arm Open-Label Study to Evaluate the Therapeutic Effects and Safety of a 6-Week 
Treatment Regimen of ALK4290 in Patients with Newly Diagnosed Wet Age-Related 
Macular Degeneration (wAMD) 
Protocol Number: 
ALK4290-201 
Protocol Version V3.0_15MAY2018 
 
 
By my signature, I have thoroughly read this study protocol and have understood the requirements as well as the 
conditions of this study protocol.  I agree to the following points: 
• 
To perform the clinical study according to this protocol and all applicable laws and regulations including, but not 
limited to, current and relevant versions of the European Medicines Agency (EMA) regulations, the local 
(Polish/Hungarian) Drug Laws, the International Conference on Harmonization - Good Clinical Practice 
guideline (ICH-GCP), and the ethical principles that have their origins in the Declaration of Helsinki.  
• 
Not to implement deviations from or changes to the protocol or protocol amendments without agreement from 
the sponsor and prior submission to and written approval (where required) from the Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC), except when necessary to eliminate an immediate hazard to the 
subjects, or for administrative aspects of the study (where permitted by all applicable regulatory requirements).  
• 
To record accurately all required data on the electronic case report forms (eCRFs). 
• 
To provide direct access to source data/documents (source document verification). 
• 
To use all study material only as specified in this protocol. 
• 
To report within 24 hours any adverse event that is serious, whether it is considered treatment-related or not. 
• 
To instruct and train all delegates in my institution who will take over tasks within this clinical study.  
• 
To onsite monitoring of all source documents by Alkahest, Inc. or designee and to on-site inspection of source 
documents by appropriate regulatory authorities, including but not limited to the EMA, local governing 
regulatory bodies, and IRB/IEC inspectors. 
 
 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
Print Name 
 
 


 
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PROTOCOL SUMMARY 
 
 
Title: 
A Single Arm Open-Label Study to Evaluate the Therapeutic Effects and Safety 
of a 6-Week Treatment Regimen of ALK4290 in Patients with Newly Diagnosed 
Wet Age-Related Macular Degeneration (wAMD) 
 
Précis:  
This study is designed to evaluate the therapeutic effects and safety of oral 
ALK4290 administered at 800 mg daily over a 6-week dosing period in newly 
diagnosed (treatment naïve) subjects with wAMD.  The study agent will be self-
administered orally.  Training on study agent administration will be conducted 
prior to initial study agent administration (at Visit 2) under the supervision of 
study personnel.  All study agent administrations at the study site will be done 
under the direct supervision of the study personnel for documentation of precise 
administration times.    
 
All subjects will undergo a screening visit, baseline/treatment visit(s), an end of 
study/early termination visit, and follow-up visits, as applicable. Visits will 
include safety and tolerability assessments, best corrected visual acuity (BCVA) 
as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) 
testing method, and morphological evaluations utilizing spectral domain optical 
coherence tomography (SD-OCT) and fundus photography/fluorescein 
angiography (FA).  For a complete listing of study events, please see Section 
15.1, Schedule of Events Table.  
 
Objectives: 
The primary objective of the study is to investigate the potential therapeutic 
effects of a 6-week, twice daily oral dosing regimen of ALK4290 on BCVA in 
newly diagnosed (treatment naïve) subjects with wAMD as measured by 
ETDRS.  As a secondary objective, the study will assess the safety of the 
proposed dosing regimen.  The exploratory objectives are to investigate the 
potential pharmacokinetic and ocular morphological effects related to twice daily 
treatment of ALK4290 in newly diagnosed subjects with wAMD by measuring 
changes in concentrations of ALK4290 in plasma at various time points as well 
as central subfield thickness (CST), intraretinal fluid (IRF), subretinal fluid 
(SRF), and pigment epithelial detachment (PED) identified by SD-OCT and 
fundus photography/FA. Additionally, pharmacogenomic and biomarker 
evaluations will be conducted on blood and plasma samples. 
 
Endpoints: 
Primary Endpoint:  
• Mean change in BCVA letter score as measured by the ETDRS testing 
method 
 
Secondary Endpoint: 
• 
Safety as assessed by incidence, seriousness, and severity of adverse events 
 
Exploratory Endpoints: 
• Changes in concentrations of ALK4290 in plasma at various time points 
• Changes in CST, IRF, SRF, and PED as measured by SD-OCT and fundus 


 
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photography/FA 
• Evaluation of pharmacogenomic characteristics and biomarkers in blood and 
plasma samples  
 
Population: 
Approximately 30 subjects, 50 years of age or older, with a diagnosis of wAMD 
who are treatment naïve 
 
Phase: 
2 
 
Number of Sites: 
TBD 
Description of 
Study Agent: 
ALK4290: A small molecule antagonist of the human C-C chemokine receptor 
type 3 (CCR3) 
 
Study Duration: 
10 months  
 
Participant 
Duration: 
10 weeks (6-week treatment plus 4-week follow-up) 
 
 


 
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SCHEMATIC OF STUDY DESIGN 
 
 
 
 


 
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1 
KEY ROLES 
 
1.1 
AUTHORIZED REPRESENTATIVE (SIGNATORY) / RESPONSIBLE PARTY 
  
 
Alkahest, Inc.  
75 Shoreway Road, Suite D  
San Carlos, CA 94070  
 
 
 
1.2 
STUDY ORGANIZATION 
 
The name and contact information of the responsible party and individuals involved with the study (e.g., 
investigator(s), sponsor’s medical expert and study monitor, sponsor’s representative(s), laboratories, steering 
committees, and oversight committees [including independent ethics committees (IECs) and Institutional Review 
Boards (IRBs)], as applicable) will be maintained by the sponsor, or their designee, and provided to the investigator. 
 
2 
INTRODUCTION 
2.1 
BACKGROUND INFORMATION 
Age-related macular degeneration (AMD) is the most common degenerative disease of the macula and the leading 
cause of irreversible blindness in the industrialized world in adults over 50, with a global prevalence of 170 million 
(Pennington 2016, Wong 2014).  It is estimated that globally 196 million people will have AMD in 2020, increasing to 
288 million in 2040 (Wong 2014).  Approximately 10% of individuals aged 65 to 74 years and 30% of individuals 
aged 75 to 85 years show signs of AMD (Friedman 2004).   
Early stage AMD, also termed age-related maculopathy (ARM), is associated with the accumulation of drusen and 
disturbances of the retinal pigment epithelium (RPE) (van Leeuwen 2003).  Drusen are biochemical by-products of 
photoreceptor cells that accumulate in the Bruch’s membrane and are categorized based on their visual appearance 
(Bird 2010). Morphology, number, and location of drusen relative to the macula are indicative of disease progression 
(Jager 2008, van Leeuwen 2003).  Epidemiological studies suggest that oxidative stress is associated with both the 
incidence and the progression of AMD.  Growing evidence indicates that AMD is downstream of a chronic 
inflammatory condition wherein activation of the immune system plays an important role (Buschini 2015).  Metabolic 
products accumulate in the extracellular space between Bruch’s membrane and the RPE, activating the complement 
system with a significant increase in oxidative stress, similar to what happens in atherosclerosis or Alzheimer’s disease 
(Buschini 2015). 
Clinically, advanced AMD is categorized into the non-exudative dry or atrophic form and the exudative wet or 
neovascular form.  Advanced dry AMD is characterized by drusen and geographic atrophy extending to the center of 
the macula (Jager 2008).  Exudative or wet AMD (wAMD), the more aggressive and debilitating form of advanced 
AMD, arises from the growth of abnormal blood vessels from the choroid into the normally avascular sub-RPE and 
subretinal regions (choroidal neovascularization (CNV)). Fluid accumulation in the sub-RPE spaces, derived from the 
abnormal choriocapillaris changes and growth under the RPE or retina causing serum and blood accumulation into 
subretinal spaces, leads to retinal thickening, mostly at the macular area.  Involvement of the fovea by choroidal 
neovascular membrane (CNVM) growth, edema, and hemorrhage may profoundly impair visual acuity (VA) and loss 
of vision can be precipitous (Pennington 2016, Jager 2008).  In the presence of active CNV, patients may also 


 
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experience pigment epithelial detachment (PED), a pathological process in which the retinal pigment epithelium 
separates from the underlying Bruch’s membrane due to the presence of blood, SRF and/or IRF (Pepple 2011).  PEDs 
are important markers of disease severity, risk for progression, and vision loss, and are seen in up to 62% of eyes with 
advanced wAMD (Coscas 2007).  Although wAMD represents only 10 to 15% of the overall prevalence of age-related 
macular AMD, it is responsible for more than 80% of cases of severe visual loss or legal blindness resulting from 
AMD (Ferris 1984). 
Currently, blockade of vascular endothelial growth factor, a potent proangiogenic messenger, is the basis of available 
therapies for wAMD (Riaz 2017, Ambati 2012).  Intravitreally administered anti-vascular endothelial growth factor 
(anti-VEGF) therapies include Lucentis® (ranibizumab)(Brown 2006, Rosenfeld 2006), Avastin® 
(bevacizumab)(Martin 2011)(typically used as an off-label drug to treat wAMD), and Eylea® (aflibercept) (Heier 
2012).  These agents have become the standard of care, and have led to significant improvements in lesion 
morphology, reduction of the vascular leakage, and, as a consequence, improvement in central vision.  However, 
intravitreal (IVT) injections carry a risk to patients and a burden to both patients and caretakers.  Firstly, there is the 
potential for serious risk associated with each IVT injection procedure, including endophthalmitis, retinal detachments, 
traumatic cataract, and increased intra-ocular pressure (IOP) (Falavarjani 2013). Secondly, monthly treatment and 
monitoring, which might continue for a patient’s lifetime, is a substantial burden to patients, ophthalmologists, and the 
healthcare system, given the expense of the biologicals used to treat wAMD.  
A clear unmet medical need exists to reduce the frequency of IVT injections (or eliminate them altogether), and 
extensive efforts have been undertaken to lower the injection frequency of anti-VEGF agents in wAMD (Freund 2015). 
The second major aspect of the unmet medical need concerns further improvement in maintenance therapy and 
incremental visual acuity gains over current therapies.  To address these unmet clinical needs, the oral therapeutic 
ALK4290 was developed. 
2.2 
RATIONALE 
 
Alkahest study ALK4290-201 will evaluate 400 mg of ALK4290 administered orally twice a day for a total dose of 
800 mg. ALK4290 is a highly specific and potent small molecule antagonist of the human C-C chemokine receptor 
type 3 (CCR3). The CCR3/eotaxin axis is a key chemotactic factor for eosinophils, mast cells, and, in the context of 
wAMD, endothelial cells.  Inhibiting CCR3 interrupts endothelial cell migration, thereby reducing the morphological 
changes (e.g., central retinal thickness (CRT), edema, and blood leakage) attributed to pathologic CNV (Nagai 2015). 
The anticipated clinical results from an orally administered CCR3 antagonist therapy would be to maintain or, 
potentially, improve visual acuity, enhance quality of life, and reduce the need for IVT injections. 
 
Although a significant amount of preclinical data exists for CCR3 blockade in wAMD, there is no published clinical 
data supporting the therapeutic use of CCR3 in wAMD (Nagai 2015, Wang 2016, Wang 2011)(for further details and 
information, see the 
 for ALK4290). This study is designed to demonstrate a therapeutic effect 
of ALK4290 on BCVA in wAMD subjects.  Without treatment, patients with wAMD lose an average of 10 ETDRS 
letters within 1 year and eventually most patients become legally blind. The current standard of care for wAMD is IVT 
anti-VEGF therapy which usually maintains and improves BCVA.  Despite anti-VEGF therapy, one sixth of patients 
progress to blindness. In addition, IVT injections are burdensome and expensive for patients and the healthcare system, 
and may be associated with serious adverse events (e.g., endophthalmitis, retinal detachment, traumatic cataract, and 
IOP). High concentrations of anti-VEGF may have deleterious long-term consequences for the integrity of the retina 
and the RPE.   
Hence, an equally effective oral maintenance treatment, or an oral treatment that provides incremental improvement in 


 
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BCVA compared to anti-VEGF therapy, would be considered a substantial medical advance. The aim of this 6-week 
trial is to investigate whether orally administered ALK4290 has the potential to maintain or increase BCVA as 
measured by ETDRS.  If a favorable effect on BCVA is observed, this study would potentially provide the basis for a 
longer-term evaluation of the effects of ALK4290 to further assess functional and morphological benefits. 
2.3 
POTENTIAL RISKS AND BENEFITS 
 
2.3.1 
KNOWN POTENTIAL RISKS 
 
 
 
 
 
 
 
 
 
 
 
 
  ALK4290 was considered safe and well tolerated by the subjects with wAMD in the trial.  Potential 
risks associated with the study design include those related to the study procedures and methodology, most notably 
the potential risks associated with FA including allergic reactions and renal/ thyroid complications. 
 
Potential risks associated with the study design include those related to the study procedures and methodology. 
Potential risks associated with FA include allergic reactions and renal/ thyroid complications. Potential risks 
associated with study methodology include the delayed initiation of a known effective therapy - IVT anti-VEGF 
therapy and a risk of irreversible loss of visual acuity. Although well controlled prospective studies that quantify 
the risk of delaying anti-VEGF therapy in wAMD do not exist, retrospective studies have shown a trend towards 
worse visual acuity outcomes. For example, for patients in which the delay in treatment was 21 weeks or more 
(compared to a delay of 7 weeks or less) the odds ratio for worsening vision after treatment was 2.62 995% CI 
1.20, 5.68), indicating a 2.6-fold increase in the likelihood of adverse response to treatment (Lim 2012).  A 
retrospective study evaluating the short-term progression of wAMD and the impact of unintentional delays in the 
initiation of anti-VEGF therapy, ranging from 2 to 108 days, showed no correlation between time to therapy 
initiation and deterioration of patient VA at 3 months and 1 year (Munk 2012). 
 
2.3.2 
KNOWN POTENTIAL BENEFITS 
 
The primary aim of this study is to determine if inhibition of CCR3 with ALK4290 has beneficial functional 
effects related to BCVA as measured by ETDRS.  An equally effective oral maintenance treatment, or an oral 
treatment that provides incremental improvement in BCVA, compared to anti-VEGF therapy would be 
considered a substantial medical advance. A specific aim of the current study is to investigate whether orally 
administered ALK4290 has the potential to improve BCVA.  If a favorable effect is observed, this study could 
potentially provide the basis for longer term studies to evaluate BCVA as well as associated beneficial 
morphological endpoints. 


 
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Hence, the current risk benefit supports administration in modest subject numbers up to an exposure of 6 weeks 
in duration to further investigate therapeutic effects, safety, pharmacokinetics, and morphological outcomes 
related to treatment with ALK4290 in subjects with wAMD.  
 
3 
OBJECTIVES AND PURPOSE 
The primary objective of this study is to investigate the potential therapeutic effects of a 6-week, twice daily oral 
dosing regimen of ALK4290 on BCVA in newly diagnosed subjects with wAMD who are treatment naïve (i.e., no 
previous treatment in the study eye).  Secondarily, this study aims to assess the safety of the study agent.  Exploratory 
objectives include measuring changes in concentrations of ALK4290 in plasma at various time points as well as CST, 
IRF, SRT, and PED identified by SD-OCT and fundus photography/FA. Additionally, pharmacogenomic and 
biomarker evaluations will be conducted on blood and plasma samples. 
 
4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
This will be a single arm, open-label, study to evaluate the therapeutic effects and safety of a 6-week treatment regimen 
of ALK4290 in subjects with newly diagnosed (treatment naïve) wAMD.  
This study enrolls newly diagnosed subjects with CNV secondary to AMD.  At every visit, safety and tolerability 
assessments will occur.  At specified visits, BCVA will be measured by ETDRS and morphological evaluations will be 
conducted utilizing SD-OCT and fundus photography/FA.  For a complete listing of study events, please see Section 
15.1, Schedule of Events Table. 
 
The overall duration of the study is approximately 10 months from study initiation (i.e., first subject enrolled) to study 
completion (i.e., last subject last visit) with a targeted recruitment of 30 subjects over the accrual period.  The subject 
participation period is 10 weeks (6-week treatment plus 4-week follow-up), unless prematurely discontinued. 
 
4.2 
STUDY ENDPOINTS 
 
The endpoints in this study pertain to the therapeutic efficacy, safety, and pharmacokinetic/pharmacodynamic effects 
of a total daily dosage of 800 mg of ALK4290 administered orally twice a day as 400 mg tablets for 6 weeks. 
Primary Endpoint: 
• 
Mean changes in BCVA as measured by the ETDRS testing method (see Section 7.1)(Ferris 1982) 
 
 
 


 
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Secondary Endpoint: 
• 
Safety as assessed by incidence, seriousness, and severity of adverse events 
 
Exploratory Endpoints:  
• 
Changes in concentrations of ALK4290 in plasma at various time points 
• 
Changes in CST, IRF, SRF, and PED as measured by SD-OCT and fundus photography/FA 
• 
Evaluation of pharmacogenomic characteristics and biomarkers in blood and plasma samples 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible for inclusion, all subjects must meet the following criteria: 
• 
Men and women with newly diagnosed active CNV secondary to AMD, diagnosed by a retinal specialist with 
all the following characteristics and ophthalmic inclusion criteria applied to the study eye: 
• 
No prior treatment for wAMD in the study eye and no current or planned concomitant intravitreal anti-
VEGF treatment in the fellow eye 
• 
CST ≥ 250 microns on SD-OCT (exclusive of subretinal pigment epithelial fluid, inclusive of SRF) 
• 
Presence of SRF and/or IRF on SD-OCT 
• 
Any active CNV with subfoveal leakage as determined by FA 
• 
Total lesion size not greater than 12 disc areas on FA 
• 
If present, subretinal hemorrhage must comprise < 50% of the total lesion area on FA 
• 
No subfoveal fibrosis or atrophy on FA 
• 
BCVA letter score, as measured by ETDRS in the study eye, between 70 and 24 letters, inclusive, at 
screening 
• 
Patients 50 years of age or older at screening visit 1 
• 
Body mass index (BMI) between18 and ≤ 40 at screening visit 1 
• 
Hungary: Female subjects must not be pregnant or breastfeeding. Women of childbearing potential and men 
must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in the study, she should inform her treating physician immediately. 
Poland: Female subjects must not be pregnant or breastfeeding. Women of childbearing potential must have 
a negative serum pregnancy test at screening/visit 1, the first treatment visit, and the last treatment visit. 
Women of childbearing potential and men must agree to use highly effective contraception (Clinical Trial 
Facilitation Group 2014) prior to study entry. A woman is considered of childbearing potential following 
menarche and until becoming postmenopausal (no menses for at least 2 years without an alternative cause). 
Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in the 
study, she should inform her treating physician immediately. 
• 
Signed informed consent consistent with ICH-GCP guidelines and local legislation prior to participation in 
the trial, which includes medication washout and restrictions 
 
5.2 
EXCLUSION CRITERIA 
A subject will not be eligible for inclusion if any of the following criteria apply: 
• 
Previous participation in any studies of investigational drugs within 1 month preceding screening visit (Visit 
1) 


 
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• 
Any form of macular degeneration that is not age-related (e.g., Best’s disease, Stargardt’s disease, Sorsby’s 
disease, etc.) 
• 
Additional eye disease in the study eye that could compromise BCVA (i.e., uncontrolled glaucoma (intra-
ocular pressure > 24) with visual field loss, clinically significant diabetic maculopathy, history of ischemic 
optic neuropathy or retinal vascular occlusion, vitreomacular traction, monocular vision, or genetic disorders 
such as retinitis pigmentosa; high myopia > 8 diopters) 
• 
The presence of polypoidal choroidal vasculopathy (PCV) or retinal angiomatous proliferation (RAP) in the 
study eye  
• 
Anterior segment and vitreous abnormalities in the study eye that would preclude adequate observation with 
fundus photography/FA or SD-OCT 
• 
Intraocular surgery in the study eye within 3 months prior to screening 
• 
Aphakia or total absence of the posterior capsule (yttrium aluminum garnet (YAG) laser capsulotomy 
permitted, a minimum of 1 month prior to enrollment) in the study eye 
• 
Known allergy to fluorescein sodium for injection in FA 
• 
Current or planned use of medications known to be toxic to the retina, lens, or optic nerve (e.g. 
desferoximine, chloroquine/hydrochloroquine, chlorpromazine, phenothiazines, tamoxifen, nicotinic acid, 
and ethambutol) 
• 
Medical history or condition:  
• 
Uncontrolled diabetes mellitus, with hemoglobin A1c (HbA1c) > 8% 
• 
Myocardial infarction or stroke within 12 months of screening 
• 
Active bleeding disorder 
• 
Concomitant use of warfarin or anticoagulation therapy 
• 
Major surgery within 1 month of screening or planned within the study period 
• 
Hepatic impairment 
• 
Uncontrolled hypertension  
• 
Positive screening for Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) 
• 
 
   
• 
 
• 
Use of systemic steroids (>10 mg prednisone or equivalent/day) within 14 days of first dose of study agent 
or known diseases which could require the use of systemic steroids within the study period 
• 
Use of intravitreal steroids: 
• 
Dexamethasone (Ozurdex) or triamcinolone within 6 months prior to screening  
• 
Flucinolon (Retisert or Iluvien) within 48 months prior to screening 
• 
Patients with a clinically relevant abnormal screening hematology, blood chemistry, or urinalysis, if the 
abnormality defines a significant disease as defined in other exclusion criteria (e.g., aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) greater than 2.0-fold the upper limit of normal at 
screening; total bilirubin (TB) or prothrombin time (INR) > 1.5 times the upper limit of normal at 
screening). Laboratory testing may be repeated once during the screening phase  
• 
Patients with impaired renal function defined as calculated glomerular filtration rate (GFR) < 30 mL/min 
• 
Significant alcohol or drug abuse within past 2 years 
• 
Based on ECG reading, patients with a risk of prolonged QT interval effects including: 
• 
A marked baseline prolongation of QTc (using Bazett’s formula: ≥ 430 ms in men and ≥ 450 ms 
in women) with confirmation on a repeat ECG) 
• 
A history of additional risk factors for Torsade de Pointes (TdP) (e.g., heart failure, hypokalemia, 
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• 
The use of concomitant medications known to prolong the QT/QTc interval 
• 
Significant disease or other medical conditions (as determined by medical history, examination, and clinical 
investigations at screening) that may, in the opinion of the investigator, result in the any of the following: 
• 
Put the patient at risk because of participation in the study 
• 
Influence the results of the study 
• 
Cause concern regarding the patient’s ability to participate in the study 
• 
Patients with malignancy for which the patient has undergone resection, radiation or chemotherapy within 
past 5 years. Patients with treated basal cell carcinoma or fully cured squamous cell carcinoma are allowed 
 
5.3 
SUBJECT WITHDRAWAL OR TERMINATION 
 
5.3.1 
REASONS FOR WITHDRAWAL OR TERMINATION 
 
 
 
A subject will be withdrawn from the study for the following medical or administrative reasons: 
• 
Occurrence of an AE that represents an unacceptable risk to the subject and when continued 
participation in the investigational study is not warranted, in the judgment of the investigator, 
sponsor, or medical monitor. The investigator must follow the subject until the AE resolves or is 
stable 
• 
Treatment with a prohibited concomitant medication other than the use of appropriate 
medications for the treatment of AEs under direction of the investigator 
• 
Subject noncompliance, defined as refusal or inability to adhere to the trial schedule or 
procedures 
• 
At the request of the subject or the subject’s legally authorized representative (e.g., subject 
withdraws consent), investigator, sponsor or regulatory authority 
• 
Pregnancy 
 
5.3.2 
HANDLING OF PARTICPANT WITHDRAWALS OR TERMINATION 
 
 
 
Approximately 30 subjects will be enrolled in the study.  Subjects will be encouraged to complete the study and all 
assessments. However, subjects may voluntarily withdraw at any time, and the investigator may discontinue 
individual subjects from the study at any time.  For subjects who withdraw consent from the study, no study 
procedures will be done thereafter.  For those that withdraw from receiving the study agent, follow-up visits and 
the safety phone follow-up are to occur as per the protocol. Excluding cases of medical emergency, but prior to the 
discontinuation of a subject from the clinical study for disease worsening, the study investigator should discuss 
each case of discontinuation with the sponsor and/or the medial monitor. 
 
The subject withdrawal criterion below should be used to assess worsening or disease progression.  In such cases, a 
documented assessment by the principle investigator is required, and subjects with clinically significant disease 
progression should be considered for withdrawal from the study and subsequent initiation of standard of care: 
• 
A BCVA loss of ≥ 5 letters from baseline 
• 
New macular subretinal hemorrhage 
• 
Investigator discretion based on acute worsening of underlying disease or substantial risk to further 
participation in the study 
 
5.4 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
 
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both parties will arrange discontinuation procedures and notify the appropriate regulatory authority(ies), IRBs, and 
IECs.  In terminating the study, the sponsor and the investigator will continue to protect the subjects’ privacy and 
identity as required by relevant statues and regulations. 
 
Alkahest, Inc. has the right to terminate a study site from participating in the study at any time. Reasons for study or 
site termination may include, but are not limited to: 
• 
Unsatisfactory subject enrollment (i.e., < 2 subjects enrolled within a 6-month period) 
• 
Unacceptable protocol deviations/violations as assessed by the medical monitor 
• 
Inaccurate or incomplete data entry and recording 
• 
Investigational site non-compliance with ICH/GCP 
• 
Unacceptable emergent safety profile 
 
6 
TREATMENTS 
6.1 
STUDY AGENT DESCRIPTION 
 
 
6.1.1 
ACQUISITION 
 
The study agent will be manufactured, labeled, packaged, and distributed by Alkahest, Inc.  
 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
 
  
 The subjects will be provided with 1 bottle at 
each treatment visit so that the time windows between visits (see Section 15.1, Schedule of Events Table) will be 
covered.  The study agent will be delivered to the sites immediately prior to site activation and thereafter upon 
request. The product will be labeled for investigational use according to the relevant regulatory requirements for 
clinical studies.   
 
For further details and information on ALK4290, including packaging and labeling, see the 
 
   
 
6.1.3 
PRODUCT STORAGE AND STABILITY 
 
  A 
temperature log must be maintained to make certain the study agent is stored at the correct temperature.  If the 
storage conditions are found to be outside the specified range, the site must immediately notify the sponsor or 
designee. 
 
6.1.4 
DOSING AND ADMINISTRATION 
 
The study agent will be self-administered orally twice daily for a total daily dose of 800 mg.  Training on study 
agent administration will be conducted prior to initial study agent administration (at Visit 2) under the supervision 
of study personnel.  All study agent administrations at the study site will be done under the direct supervision of 
the study personnel for documentation of precise administration times.   
 


 
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6.2 
STUDY AGENT ACCOUNTABILITY 
 
The investigator and/or pharmacist will receive the study agent delivered by the sponsor when the following 
requirements are fulfilled: 
• 
Approval of the study protocol and Informed Consent by the IRB or IEC 
• 
Availability of a signed and dated clinical trial contract between the sponsor and the investigational site 
• 
Approval/notification of the appropriate regulatory authority 
• 
Availability of the curriculum vitae of the principal investigator 
• 
Availability of a signed and dated clinical trial protocol or immediately imminent signing of the clinical trial 
protocol 
 
The investigator and/or pharmacist must maintain records of the study agent’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused study agent.   
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and the unique code 
numbers assigned to the study agent and trial subjects.  The investigator/pharmacist will maintain records that 
document adequately that the subjects were provided the doses specified by the protocol and reconcile all study agent 
received from the sponsor.  At the time of final study agent reconciliation, the investigator/pharmacist must verify 
that all unused or partially used portion of study agent have been returned by the clinical trial subject and that no 
remaining study agent is retained by the investigator. 
Accountability records must be maintained and readily available for inspection by representatives of Alkahest, Inc. or 
their designee and are open to inspection by regulatory authorities at any time.  The accounts of any study agent 
accidentally wasted or intentionally disposed of must be maintained.  
The disposal of used, partially used, or wasted study agent materials must be performed in accordance with the 
institution’s drug disposal policy. At study initiation, the clinical study monitor will evaluate the site’s standard 
operating procedure for study drug disposal/destruction to ensure it complies with study requirements.  At the end of 
the study, following final study agent reconciliation by the monitor, the study site will be instructed by the sponsor to 
return or destroy all unused study agent supplies, including empty containers. A copy of the institution’s drug 
disposal policy should be maintained or referenced in the ISF. 
 
6.3 
CONCOMITANT MEDICATIONS AND TREATMENTS 
 
 
All prescription, over-the-counter, and non-prescription medications (including herbal therapies and supplements) must 
be documented in the source documents and electronic Case Report Forms (eCRFs).  All subjects should be maintained 
on the same medications at the same dosage and administration throughout the entire study period, as medically 
feasible, with no introduction of new chronic therapies. Any changes in medications should be documented in the 
eCRF with reason for change (e.g., adverse event, etc.). 
 
6.4 
PROHIBITED TREATMENTS, MEDICATIONS, AND PROCEDURES 
 
 
 
 
No other interventional therapy for wAMD is concomitantly allowed. 


 
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The use of oral corticosteroids or high potency topical steroids (e.g. with systemic exposure) are restricted during the 
screening and treatment period of the study. The use of inhaled corticosteroids will be allowed if stably treated for 4 
weeks prior to screening without a dose adjustment and not anticipated to require a dose adjustment during the study 
treatment period.  The use of low potency topical corticosteroids (other than those intended for ocular application) will 
be allowed. 
Primarily, no changes in concomitant therapy will be allowed except for treatments permitted according to Section 6.3 
above.  However, in case of adverse events in need of treatment, symptomatic therapy according to the judgement of 
the investigator will be permitted. All concomitant therapies and/or rescue therapies will be recorded on the appropriate 
pages of the eCRF. 
 
Subjects should be advised to avoid alcoholic beverages from 48 hours 
before study agent administration and until the end-of-study examination.  
 
7 
VARIABLES AND THEIR ASSESSMENT 
 
For the following endpoints, baseline is the value from Visit 2 and if not measured at Visit 2, then is the value from 
Visit 1.  Detailed information on the methodology used with the following will be included in a Statistical Analytical 
Plan (SAP). 
 
7.1 
THERAPEUTIC EFFECT 
 
BCVA will be assessed using ETDRS charts at 4 meters initial testing distance. The trained technician measuring the 
BCVA using ETDRS should be the same throughout the study period. A detailed manual for performing refractions 
and measuring BCVA using the ETDRS testing method will be provided to investigators. 
 
7.2 
SAFETY AND EXPLORATORY OUTCOMES 
 
Safety will be assessed by the incidence and intensity of adverse events (AEs) (see Section 7.2.1). Changes in 
laboratory test results, vital signs, ECG, physical examination, and/or ocular morphologic investigations will be 
recorded as AEs/serious adverse events (SAEs) in the eCRF if they are judged clinically relevant by the investigator. 
 
7.2.1 
ASSESSMENT OF ADVERSE EVENTS 
 
7.2.1.1  
Terminology for Use for Adverse Event Descriptions  
 
When reporting an adverse event, the event description should use the best matching terminology describing the 
event as found in the Common Terminology Criteria for Adverse Events (CTCAE v4.03).  If an available CTCAE 
term fits the event well, no additional descriptors may be needed.  However, necessary descriptions should be 
added in order to clarify the event or to place it in an appropriate context.  The adverse event name should ideally 
be 1-3 words in length with additional description provided elsewhere on the adverse event report.  A copy of the 
CTCAE is provided in the ISF.  Standardized terms from the CTCAE will be used by the sponsor and the Contract 
Research Organization (CRO) to categorize events for reporting to regulatory authorities using the Medical 
Dictionary for Regulatory Activities (MedDRA, v. 20.1).  In most cases, the CTCAE terms match MedDRA 
coding terminology.  If an appropriate term matching the adverse event cannot be found in the CTCAE and the 


 
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preferred MedDRA term is unknown, the AE description should include a diagnosis, sign, or symptom with 
additional information to facilitate subsequent categorization into MedDRA coding terms. 
 
7.2.1.2  
Definition of Adverse Events 
 
7.2.1.2.1 Adverse Event  
 
An AE is defined in the ICH E2D as “any unfavorable or unintended sign, symptom, or disease temporarily 
associated with the use of a medicinal product whether or not considered related to the product.”  Progression or 
worsening of the medical condition under study, by itself, does not necessarily constitute an adverse event unless 
the change can be reasonably attributed to an action of the study agent and not only to its lack of efficacy. Simply 
defining an adverse event does not imply a causal relationship; relatedness to the study agent is defined in Section 
7.2.1.2.4. 
 
7.2.1.2.2 Serious Adverse Event  
 
An SAE is defined for this protocol as any AE that meets one or more of the following criteria: 
 
A. A death (CTCAE Grade 5 event) occurring during the study, whether or not considered treatment-related; 
B. A life-threatening event (CTCAE Grade 4); 
C. An event requiring inpatient hospitalization or prolonged hospitalization due to the adverse event; 
D. An adverse event resulting in a significant, persistent, or permanent change, impairment, damage or 
disruption in the participant’s body function or structure, physical activities or quality of life; 
E. An event that otherwise required a medical or surgical intervention to preclude permanent impairment or 
damage (excluding unrelated elective or cosmetic procedures). 
 
7.2.1.2.3 Grading Severity of Adverse Events 
 
 
The investigator must grade the severity of all reported adverse events into one of the following five (5) categories:  
• 
Grade 1 (Mild) 
• 
Grade 2 (Moderate) 
• 
Grade 3 (Severe) 
• 
Grade 4 (Life-Threatening) 
• 
Grade 5 (Death) 
 
The standardized CTCAE severity grading scales for the specific type of adverse event reported must be used 
when a matching CTCAE term is available.  The highest severity grade experienced for the event should be 
reported.  The initial severity grading may be updated in follow-up reports if the maximum grade changes to a 
higher level.  The CTCAE grading scale should be used according the following guidelines. 
 
 
Grade 1 (Mild) 
 
Transient (< 48 hours) or mild discomforts, no or minimal medical therapy or intervention required, 
hospitalization not necessary, no or little limitation in normal activities, nonprescription or single-use 
prescription therapy may be employed to relieve symptoms (e.g., aspirin for simple headache, acetaminophen 
with codeine for post-surgical pain).  Mild adverse events may be listed as expected consequences of the 


 
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therapy for any given protocol, and standard supportive measures for such an expected event do not necessarily 
elevate the event to a higher grade. 
 
Grade 2 (Moderate) 
 
Mild to moderate limitation in activity, some assistance may be needed; possibly none but usually minimal 
intervention/therapy required, hospitalization possible. 
 
Grade 3 (Severe) 
 
Marked limitation in activity, some assistance usually required; medical intervention/therapy required; 
hospitalization possible or likely. 
 
Grade 4 (Life-Threatening) 
 
Extreme limitation in activity, significant and immediate assistance required; significant medical/therapy 
intervention required to prevent loss of life; hospitalization, emergency treatment or hospice care probable. This 
grade is used when the subject was, in the view of the investigator, at substantial risk of dying at the time of the 
adverse event or it was suspected that use or continued use of the study agent would have resulted in the 
subject’s death. 
 
Grade 5 (Death) 
 
Death related to AE. 
 
7.2.1.2.4 Relatedness of Study Agent to Adverse Event 
 
 
The investigator (or an authorized study physician) or sponsor must submit an attribution for the relatedness of the 
reported AE to the study agent. The attribution should take into account both the temporal association and any 
known physical, physiological, or toxicological information regarding the study agent that could reasonably infer 
causality.  The three attribution categories are: 
  
• 
Definite - Clearly related to the study agent.  An adverse event that follows a temporal sequence from 
administration of the study agent; follows a known response pattern to study agent; and, when appropriate 
to the protocol, is confirmed by improvement after stopping the study agent (positive rechallenge; and by 
reappearance of the reaction after repeat exposure (positive rechallenge)); and cannot be reasonably 
explained by known characteristics of the subject’s clinical state or by other therapies. 
• 
Possibly - May be related to the study agent.  An adverse event that follows a reasonable temporal 
sequence from administration of study agent and follows a known response pattern to the study agent, but 
could have been produced by the subject' clinical state or by other therapies. 
• 
Unrelated - Clearly NOT related to the study agent.  An adverse event that does not follow a reasonable 
temporal sequence after administration of the study agent and most likely is explained by the subject’s 
clinical disease state or by other therapies.  In addition, a negative rechallenge to the study agent would 
support an unrelated relationship. 
 
 


 
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7.2.1.2.5 Worsening of Underlying Disease and/or Other Pre-Existing Conditions  
 
Worsening of the underlying disease and/or of other pre-existing conditions will be recorded as an AE/SAE in the 
eCRF. 
 
7.2.1.2.6 Changes in Safety Evaluations  
 
Changes in vital signs, ECG, physical examination, laboratory test results, and ophthalmic evaluations will be 
recorded as an AE/SAE in the eCRF if they are judged clinically relevant by the investigator. 
 
7.2.1.2.7 Adverse Events of Special Interest 
 
 
The following are considered adverse events of special interest (AESI): 
 
• 
Hepatic injury defined by the following alterations of liver parameters:  
For subjects with normal liver function at baseline an elevation of AST and/or ALT ≥ 3-fold ULN 
combined with an elevation of total bilirubin ≥ 2-fold upper limit of normal (ULN) measured in the 
same blood draw sample. Subjects showing these lab abnormalities need to be followed up according 
to Section 17.1.2. 
• 
Abrupt decrease (> 15 letters lost from baseline) of BCVA  
• 
QTc prolongation (> +50 ms from baseline and > 450 ms) 
 
Protocol-specific AESIs are to be reported in an expedited manner similar to SAEs even if they do not meet any of 
the criteria for an SAE (see Section 7.2.1.2.2). 
 
7.2.1.3  
Adverse Event and Serious Adverse Event Reporting 
 
All AEs, serious and non-serious, occurring during the course of the clinical trial (i.e., from signing the 
informed consent through the follow-up period) will be collected, documented, and reported to the sponsor by 
the investigator on the appropriate eCRF and SAE reporting forms.  
 
For each AE, the investigator will provide the onset date, end date, seriousness, grade, relatedness, treatment 
required, outcome, and action taken with the study agent. The investigator will determine the grade as defined 
in Section 7.2.1.2.3 and the causal relationship to the study agent (relatedness) as defined in Section 7.2.1.2.4. 
 
The investigator must report the following events immediately (within 24 hours or the next business day 
whichever is shorter) to the sponsor or designee (refer to the Lab Manual/ISF for specific instructions): SAEs 
and non-serious AEs relevant to the reported SAE and protocol-specified AESI. 
 
The investigator does not need to actively monitor subjects for adverse events once the clinical trial has ended. 
However, if the investigator becomes aware of an SAE(s) that occurred after the subject has completed the 
clinical trial, it should be reported by the investigator to the sponsor if considered relevant by the investigator. 
 
Any AE occurring during the study must be documented in the subject’s medical records and as an AE in the 
eCRF.  Any SAE occurring during the study must be documented in the subject’s medical records and as an 
SAE in the eCRF. 
 


 
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A separate SAE report should be used for each SAE.  However, if at the time of initial reporting, multiple 
SAEs are present that are temporally and/or clinically related, they may be reported on the same SAE report. 
 
The investigator should attempt to establish a diagnosis of the event (that meets the definition of an AE or 
SAE) based on signs, symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs or symptoms.  The diagnosis will become the 
basis for the verbatim term as reported by the investigator.  If no diagnosis is known and clinical signs and 
symptoms are not present, the abnormal finding should be recorded. 
 
The investigator will take all appropriate and necessary therapeutic measures required for resolution of the 
AE.  Any medication necessary for the treatment of an AE must be recorded on the concomitant medication 
case report form.   
 
The SAE report(s) should be completed as thoroughly as possible and signed by the investigator or his/her 
designee before transmittal to the sponsor or designee (e.g., study CRO).  It is very important that the 
investigator provide his/her assessment of relatedness to the study agent as well as an applicable diagnosis at 
the time of the initial SAE report. 
 
7.2.2 
SAFETY LABORATORY EVALUATIONS 
 
Blood samples and urine must be collected at every visit.  Safety laboratory examinations will include 
hematology, biochemistry, coagulation and qualitative urine analysis. 
• 
Hematology: hemoglobin, red blood cell count (RBC), white blood cell count (WBC) with 
differential, platelets 
• 
Biochemistry: glucose, sodium, potassium, calcium, inorganic phosphate, creatinine, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), lactate 
dehydrogenase (LDH), total bilirubin (if elevated provide direct bilirubin), urea, total protein, 
albumin, uric acid 
• 
Coagulation: activated partial thromboplastic time (aPTT), prothrombin time (PT)/international 
normalized ration (INR) 
• 
Urine: potential of hydrogen (pH), glucose, erythrocytes, leukocytes, protein, nitrite 
 
Glomerular filtration rate (GFR) will be estimated by the Cockroft Gault Formula utilizing serum creatinine 
(see Section 17.5).  All safety laboratory measurements will be performed by a central laboratory.  
Investigators will get guidance and instructions on laboratory sampling and processing through a separate Lab 
Manual provided by the central laboratory. 
 
The investigator is responsible for determining and documenting if out of range laboratory values are 
clinically significant or not.  All clinically significant values will be recorded as AEs in the eCRF and 
followed until resolution.  Once resolved, the appropriate eCRF page(s) will be updated.  
 
7.2.3 
ELECTROCARDIOGRAM 
 
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a computerized 
electrocardiograph. The ECGs will be recorded for a 10-second duration after the subjects have rested for at 
least 5 minutes in a supine position (see Section 15.1, Schedule of Events Table, for time points). ECGs will 
be stored in the subject’s medical records. ECGs may be repeated for quality reasons and the repeat ECG will 


 
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be used for analysis. Additional ECGs may be collected by the investigator for safety reasons. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) in the eCRF.  
 
7.2.4 
VITAL SIGNS AND PHYSICAL EXAMINATION 
 
7.2.4.1  
Vital Signs 
 
 
Vital signs (blood pressure, pulse rate and respirations) and temperature will be recorded according to Section 
15.1, Schedule of Events Table.  
 
7.2.4.2  
Physical Examination  
 
A general physical examination including height (measured only at screening) and weight will be performed 
according to the time points in Section 15.1, Schedule of Events Table.  Whenever possible, the same health care 
practitioner should perform this examination.   
 
7.2.5 
OTHER OPHTHALMIC EXPLORATORY ENDPOINTS AND EVALUATIONS 
 
The ophthalmic endpoints described below as being evaluated over time will be measured in an exploratory 
manner to investigate the extent, onset, and duration of action without specific inferential testing at any time point. 
The same is valid for endpoints described as change from baseline. 
• 
CST as measured by SD-OCT, absolute and as change from baseline 
• 
Presence and height of IRF by SD-OCT over time, absolute and as change from baseline 
• 
Presence and height of SRF by SD-OCT over time, absolute and as change from baseline 
• 
Presence and height of PED by SD-OCT over time, absolute and as change from baseline 
• 
Neovascular leakage as demonstrated by fundus photography/FA, absolute and as change from 
baseline 
• 
Vascular area measured by SD-OCT and fundus photography/FA, absolute and as change from 
baseline 
 
7.2.5.1  
Optical Coherence Tomography 
 
 
The retinal layers and thickness can be visualized and measured by OCT. The study eye will be investigated by a 
trained person using only specified OCT equipment.  A detailed manual for OCT image acquisition and data 
transmission will be provided in the ISF. The reported CST will be exclusive of the sub-RPE layer fluid. 
 
7.2.5.2  
Fundus Photography/Fluorescein Angiography 
 
 
The retinal vasculature of the study eye will be evaluated and imaged by fundus photography/FA. A detailed 
manual for fundus photography/FA will be provided in the ISF. 
 
7.2.5.3  
Slit Lamp and Intraocular Pressure Measurement 
 
 
The slit lamp examination is to be performed in both eyes. The anterior and posterior segment of the eye should be 
assessed. The results will be entered in the eCRF.  IOP will be measured using applanation Goldmann tonometry in 
both eyes during each visit.  The results will also be entered in the eCRF. 
 


 
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7.2.6 
STUDY AGENT CONCENTRATION AND PHARMACOKINETICS 
  
Plasma concentration measurements of ALK4290 will be collected to assess systemic exposure to the study agent.  
For sampling time points and further details, please refer to Section 17.3.  
 
7.2.6.1  
Pharmacokinetic Endpoints 
 
 
As far as feasible, the following pharmacokinetic parameters will be derived by noncompartmental methods:  
• 
Cmax   
Maximum concentration of ALK4290 in plasma after single dose 
• 
tmax   
Time of Cmax relative to last dosing 
• 
tmax,ss   
Time of Cmax,ss relative to last dosing 
• 
Cpre,ss,N  
Pre-dose concentration of ALK4290 in plasma immediately before administration  
                       of the Nth dose 
In addition, the average pre-dose concentration in plasma at steady state will be calculated as the geometric 
mean of Cpre,ss,N values. 
 
7.2.6.2  
Methods of Sample Collections 
 
 
For quantification of ALK4290 plasma concentrations and for biomarker investigations (see Section 7.2.8), 
one blood sample of approximately 6 mL per sampling time point (see Section 17.2.1, Table of 
Pharmacokinetic, Biomarker, and Pharmacogenomic Sampling) will be taken from an antecubital or forearm 
vein into a potassium ethylenediaminetetraacetic acid (EDTA)-anticoagulant blood drawing tube. 
The EDTA-anticoagulated blood samples will be centrifuged to collect plasma. For pharmacokinetic samples 
only, the obtained plasma will be split into 2 aliquots and stored in polypropylene tubes. At the selected time 
points with additional biomarker determinations, 5 instead of 2 aliquots of at least 0.5 mL plasma each will be 
prepared from the blood sample. The time from blood collection until the transfer of plasma aliquots into the 
freezer should not exceed 60 minutes, with interim sample storage on wet ice whenever possible. Samples will 
be positioned upright and will be frozen at approximately -20°C or below until shipment.  These aliquots will 
be processed by the central laboratory. Details of plasma collection, sample handling, and shipment 
instructions will be provided in the Lab Manual/ISF. 
 
7.2.6.3  
Analytical Determinations 
 
 
Concentrations of ALK4290 and metabolites (if feasible) in plasma samples will be determined by a validated 
high performance liquid chromatography, tandem mass spectrometry (HPLC-MS/MS) assay.  Leftover 
samples will be used for exploratory biomarker assessment (see Section 7.2.8). 
 
 
7.2.7 
PHARMACOGENOMIC EVALUATIONS 
  
Pharmacogenetic analysis of prespecified genes is mandatory and a prerequisite for participation in this study. 
 
 


 
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• 
 
 
 
 
 
 
 
 
 
 
Prespecified analyses will be performed at the end of the trial and the data will be part of the report. All 
remaining samples will be destroyed after the end of the trial. 
 
• 
 
 
 
 
7.2.7.1  
Methods and Timing of Sample Collection 
One blood sample of 3 mL blood for prespecified pharmacogenomic testing will be obtained at Visit 2 in a 
potassium EDTA-anticoagulant blood drawing tube.
 
 For additional information, 
see Section 17.2.1, Table of Pharmacokinetic, Biomarker, and Pharmacogenomic Sampling and in the Lab 
Manual/ISF. 
The PAXgene Blood DNA tubes and EDTA containing blood sampling tubes can be stored and shipped at 
room temperature within 14 days. If a longer storage and shipment period for PAXgene Blood DNA tubes is 
necessary, these blood samples should be stored at a temperature of -20°C or below. Once frozen, thawing of 
the samples should be avoided. 
 
7.2.7.2  
Analytical Determinations 
 
 
DNA will be extracted from blood samples according to standard molecular genetics methods and analyzed by 
standard genotyping and gene expression technologies. 
 
Detailed instructions for pharmacogenomic sampling, handling and shipment of samples are provided in the 
Lab Manual/ISF.  
 
 
 
 
 


 
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7.2.8 
BIOMARKERS 
 
Measurement of biomarkers is exploratory. 
 
 
 After completion of the study, 
leftover samples may be used for further methodological and/or other, non-genetic biomarker investigations either 
by the sponsor, or designee. The study samples will be discarded after completion of the additional investigations, 
but not later than 3 years after the final study report has been archived. 
 
7.2.8.1  
Method of Sample Collection 
For quantification of ALK4290 plasma concentrations (see Section 7.2.6) and for biomarker investigations, 
one blood sample of approximately 6 mL per sampling time point (see Section 17.2.1, Table of 
Pharmacokinetic, Biomarker, and Pharmacogenomic Sampling and Section 15.1 Schedule of Events Table) 
will be taken from an antecubital or forearm vein into a potassium EDTA-anticoagulant blood drawing tube. 
The EDTA-anticoagulated blood samples will be centrifuged to collect plasma. For pharmacokinetic studies 
only, the obtained plasma will be split into 2 aliquots and stored in polypropylene tubes. At the selected time 
points with additional biomarker determinations, 5 instead of 2 aliquots of at least 0.5 mL plasma each will be 
prepared from the blood sample. The time from blood collection until the transfer of plasma aliquots into the 
freezer should not exceed 60 minutes, with interim sample storage on wet ice whenever possible. Samples will 
be positioned upright and will be frozen at approximately -20°C or below until shipment.  These aliquots will 
be collected by the central laboratory.  Details of plasma collection, sample handling, and shipment 
instructions will be given in the Lab Manual in the ISF.   
 
7.2.8.1  
Analytical Determinations 
The exploratory biomarker measurements will be conducted either at the sponsor’s labs or at external CROs 
using appropriate methodology (e.g., immunoassays, multiplex technology).  A Lab Manual/ISF will describe 
the handling of the samples.  
 
8 
INVESTIGATIONAL PLAN 
8.1 
VISIT SCHEDULE 
 
All study agent administrations at the study site will be done under the direct supervision of the study personnel for 
documentation of precise administration times.  In case a visit is delayed beyond the window detailed in Section 
15.1, Schedule of Events Table, the delayed visit should be scheduled as soon as possible and documented with the 
actual date and the reason for the delayed visit.  The next visit, should still take place at the time it was originally 
scheduled in this treatment course.  Any delays in visit dates, outside of the defined criteria in the Schedule of 
Events Table, will be reported as a protocol deviation. 
 
 


 
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8.2 
VISIT PROCEDURES 
 
The investigations as outlined in Section 15.1, Schedule of Events Table will be performed at the respective visits 
as described in detail in the following sections. 
 
8.2.1 
SCREENING AND RUN-IN PERIOD 
The screening period (Visit 1), i.e. the phase after informed consent and before the first administration of the study 
agent, may be as long as 6 days (day -7 to -2).  However, a pretrial fundus photography/FA examination performed 
within 14 days prior to Visit 1 can be used as the screening ophthalmologic examination.  In special cases where it 
is not logistically possible to meet the protocol defined screening period, the screening can be extended by an 
additional 7 days (day -14) without repeating the screening assessment.   
The medical history and medication history within 3 months prior to Visit 1, as well as baseline condition of the 
subject, will be captured in the eCRF. 
 
8.2.1.1  
Visit 1 
 
At Visit 1, the following procedures and assessments are performed: 
 
• 
Signing of all applicable Informed Consents 
• 
Potential study subject eligibility based on all study-specific inclusion and exclusion criteria (see 
Sections 5.1 and 5.2)  
• 
Demographics and medical history 
• 
All ophthalmological evaluations: BCVA, SD-OCT, fundus photography/FA, slit lamp, and IOP (see 
Sections 7.1 and 7.2.5) 
• 
Vital signs, physical examination, safety laboratory tests, Poland only: serum pregnancy test (in women 
of childbearing potential), and 12-lead ECG (see Sections 7.2.2, 7.2.3 and 7.2.4) 
• 
Review of concomitant medications (see Sections 6.3 and 6.4) 
• 
AE reporting and evaluation according to Section 7.2.1  
 
 
8.2.2 
TREATMENT PERIOD 
 
All ophthalmic examinations and other assessments will be performed before intake of the study agent on the 
respective day.  The examinations of each visit are specified in Section 15.1, Schedule of Events Table.  In 
addition, please see Section 17.2.1, Table of Pharmacokinetic, Biomarker and Pharmacogenomic Sampling for 
detailed information regarding these evaluations.  
 
8.2.2.1  
Visit 2 
 
At Visit 2, the following procedures and assessments are performed: 
 
• 
Pharmacokinetic and biomarker samples are taken (see Sections 7.2.6 and 7.2.8) 


 
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• 
Pharmacogenomic samples are taken (see Section 7.2.7) 
• 
Specified ophthalmological assessments: BCVA, SD-OCT, slit lamp, and IOP 
• 
Vital signs, physical examination, safety laboratory tests, and Poland only: serum pregnancy test (in 
women of childbearing potential) 
• 
Review of concomitant medications 
• 
AE reporting and evaluation 
• 
Study agent administration training and study agent dispensing/administration 
• 
Study agent accountability 
 
8.2.2.2  
Visit 3 
 
At Visit 3, the following procedures and assessments are performed: 
 
• 
Pharmacokinetic samples are taken 
• 
Specified ophthalmological assessments: BCVA, SD-OCT, slit lamp, and IOP 
• 
Vital signs, safety laboratory tests, and 12-lead ECG 
• 
Review of concomitant medications 
• 
AE reporting and evaluation 
• 
Study agent dispensing/administration 
• 
Study agent accountability  
 
8.2.2.3  
Visit 4 
 
At Visit 4, the following procedures and assessments are performed: 
 
• 
Pharmacokinetic samples are taken  
• 
Specified ophthalmological assessments: BCVA, SD-OCT, slit lamp, and IOP  
• 
Vital signs, physical examination and safety laboratory tests  
• 
Review of concomitant medications 
• 
AE reporting and evaluation 
• 
Study agent dispensing/administration 
• 
Study agent accountability  
 
8.2.2.4  
Visit 5 
 
At Visit 5, the following procedures and assessments are performed: 
 
• 
Pharmacokinetic samples are taken  
• 
Specified ophthalmological assessments: BCVA, SD-OCT, slit lamp, and IOP  
• 
Vital signs and safety laboratory tests  
• 
Review of concomitant medications 


 
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• 
AE reporting and evaluation 
• 
Study agent dispensing/administration 
• 
Study agent accountability   
 
8.2.2.5  
Visit 6 
 
At Visit 6, the following procedures and assessments are performed: 
 
• 
Pharmacokinetic and biomarker samples are taken  
• 
Specified ophthalmological assessments: BCVA, SD-OCT, slit lamp, and IOP  
• 
Vital signs, physical examination, safety laboratory tests, and 12-lead ECG  
• 
Review of concomitant medications 
• 
AE reporting and evaluation 
• 
Study agent dispensing/administration 
• 
Study agent accountability   
 
8.2.2.6  
Visit 7 
 
At Visit 7, the following procedures and assessments are performed: 
 
• 
Pharmacokinetic samples are taken  
• 
Specified ophthalmological assessments: BCVA, SD-OCT, slit lamp, and IOP  
• 
Vital signs and safety laboratory tests  
• 
Review of concomitant medications 
• 
AE reporting and evaluation 
• 
Study agent dispensing/administration 
• 
Study agent accountability  
 
 
8.2.3 
END OF TREATMENT 
All end of treatment (EOT) study-related procedures will be conducted at the conclusion of 6 weeks of treatment 
on Day 43 ±1.  However, for subjects who withdraw consent from the study, no study procedures will be done 
thereafter.  For subjects that withdraw from the study agent, EOT procedures and follow up visits are to occur as 
per the protocol. Excluding cases of medical emergency, but prior to the discontinuation of a subject from the 
clinical study for disease worsening, the study investigator should discuss each case of discontinuation with the 
sponsor. 
 
8.2.3.1  
Visit 8 
 
At Visit 8, the following procedures and assessments are performed: 
 


 
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• 
Pharmacokinetic and biomarker samples are taken 
• 
All ophthalmological assessments: BCVA, SD-OCT, fundus photography/FA, slit lamp, and IOP 
• 
Vital signs, physical examination, safety laboratory tests, Poland only: serum pregnancy test (in women 
of childbearing potential), and 12-lead ECG 
• 
Review of concomitant medications 
• 
AE reporting and evaluation  
 
 
8.2.4 
FOLLOW-UP VISITS 
 
Follow-up visits will be performed after Visit 8 for all subjects who had at least one dose of trial treatment.  
Follow-up visits will not be performed if: 
 
• 
The subject is lost to follow-up 
• 
The subject withdraws consent from the study 
• 
The investigator and sponsor agree not to pursue further follow-up visits with the subject 
• 
The subject dies 
 
In these cases, the trial completion page of the eCRF must be filled out.  
 
8.2.4.1  
Visit 9 
 
At Visit 9, the following procedures and assessments are performed: 
 
• 
Pharmacokinetic and biomarker samples are taken 
• 
Specified ophthalmological assessments: BCVA, SD-OCT, slit lamp, and IOP  
• 
Vital signs and safety laboratory tests 
• 
Review of concomitant medications 
• 
AE reporting and evaluation  
 
8.2.4.2  
Visit 10 
 
At Visit 10, the following procedures and assessments are performed: 
 
• 
Specified ophthalmological assessments: BCVA, SD-OCT, slit lamp, and IOP 
• 
Vital signs, physical examination, and safety laboratory tests 
• 
Review of current medications 
• 
AE reporting and evaluation 
 
8.2.4.3  
Safety Follow-up: Documented Phone Call 
 
At Day 71 (28 days after end of treatment), the following assessments are performed by phone: 


 
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• 
Review of current medications 
• 
AE reporting and evaluation  
 
In addition, the Trial Completion page must be finalized and entered in the eCRF.   
9 
CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, that 
the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with 
the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirement(s). 
 
• 
Monitoring for this study will be performed by the study CRO in accordance with the Clinical Monitoring Plan 
(CMP). 
• 
A mix of on-site and centralized risk-based monitoring will be performed to ensure the safety of clinical 
subjects and the accuracy and completeness of study data.  
• 
The sponsor will be provided with copies of monitoring reports per the timelines specified within the CMP. 
• 
Details of clinical site monitoring tasks and scope are documented in the study’s CMP. The CMP describes 
in detail who will conduct monitoring, at what frequency monitoring will be done, at what level of detail 
monitoring will be performed, and the distribution of monitoring reports. 
• 
Independent audits may be conducted by the sponsor in accordance with the Clinical Quality Oversight Plan 
to ensure monitoring practices are performed consistently across all participating sites and that monitors are 
following the CMP. 
 
10 
STATISTICAL CONSIDERATIONS 
10.1 
STATISTICAL DESIGN MODEL AND ANALYTICAL PLANS 
The therapeutic effect of the treatment will be investigated in one single group of subjects, with no control group. 
The observed mean effect will be compared with 0 as reference value.  Overall baseline and demographic data will 
be summarized using descriptive statistics.  
Subject disposition (e.g., the number of subjects enrolled, completed, and discontinued) will be summarized and 
medical history data will be listed. Prior and concomitant medications taken from screening and during the study 
will be categorized by World Health Organization (WHO) classification for therapeutic class and drug name, listed 
and summarized by number and percentage of subjects.   
Final analyses are not limited to the summaries described herein.  Analytical details and assumptions will be fully 
presented in the SAP. 
 
10.2 
STATISTICAL HYPOTHESES 
The null and alternative hypothesis for change from baseline in BCVA letter score as measured by ETDRS testing 
method are:  
 
H0: Change from baseline in BCVA letter score = 0 
 
H1: Change from baseline in BCVA letter score ≠ 0 with α1= 0.20 
 


 
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10.3 
ANALYSIS DATASETS 
 
Four analysis datasets are possible however, analyses may not necessarily be conducted with all four: 
 
• Intention-to-Treat (ITT) Dataset: all enrolled subjects 
• Safety Dataset: all subjects who received at least 1 dose of the study agent  
• Evaluable Dataset:  all subjects who complete at least 3 weeks of treatment during the 6-week 
treatment period 
• Per Protocol Dataset:  a subset of the Evaluable Dataset comprised of subjects who have no major 
protocol violations 
 
The presentation of baseline characteristics will be based on the ITT dataset.  All safety analyses will be performed for 
the Safety Dataset.  Analyses of the primary and exploratory endpoints will focus on the Evaluable and/or Per Protocol 
Datasets. 
 
10.4 
PLANNED ANALYSES  
 
10.4.1 
ANALYSIS OF THE PRIMARY ENDPOINT 
 
The therapeutic effect of the treatment will be investigated in one single group of subjects, with no control group. 
The changes from baseline in BCVA will be compared with 0 as reference value.  The study is not designed to 
detect significant changes in BCVA over time.  However, using available data, including changes in BCVA from 
baseline, descriptive summarization will be developed.  Of particular interest will be the within-subject changes 
in BCVA from baseline and their distribution around a null value of zero.   
 
10.4.2 
ANALYSIS OF THE SECONDARY ENPOINT 
 
Safety will be assessed for the following endpoints: 
• Incidence, seriousness, and severity of adverse events 
• Changes from baseline in clinical laboratory values 
• Changes from baseline in physical examination 
• Changes from baseline in vital signs 
All treated subjects (i.e., all subjects who received at least 1 dose of the study agent) will be included in the safety 
evaluation.  Safety analyses will be descriptive in nature and will be based on accepted standards. 
 
Tabulations of frequencies/proportions will be used for the evaluation of categorical (qualitative) data, and 
tabulations of descriptive statistics will be used to analyze continuous (quantitative) data. 
 
 
 
 


 
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10.4.3 
EXPLORATORY ANALYSES 
 
Observed values as well as changes from baseline in CST, IRF, SRF, and PED as measured by SD-OCT and 
fundus photography/FA will be summarized using descriptive statistics.  Pharmacokinetic, biomarker, and 
pharmacogenomic analyses will be carried out using an exploratory approach to investigate the potential influence 
on the therapeutic response of ALK4290.   
 
 
10.4.4 
PLANNED INTERIM ANALYSES 
Continuous data monitoring will be performed. One interim analysis will be performed when 2/3 of all entered 
subjects have reached Day 15 (Visit 4). It will include only the primary and a subset of the secondary 
endpoints, (i.e., mean change in BCVA as measured by ETDRS and the accumulated AE information). 
Recruitment into the trial will be stopped if the interim analysis shows relevant safety problems with 
ALK4290.  No formal futility analysis will be conducted. 
 
10.5 
SAMPLE SIZE 
 
A total of 30 subjects will be enrolled in the study with the intent of obtaining ~25 evaluable subjects who have 
completed at least 3 weeks of treatment and evaluations through Visit 4.  Subjects who discontinue prior to Visit 4 
may be replaced.  Subjects who withdraw or are withdrawn during screening will be replaced.  The study is not 
powered for detecting statistically significant differences in therapeutic parameters in subjects with wAMD receiving 
ALK4290.  However, the proposed sample size may be sufficient to identify trends in the effects of ALK4290 and in 
the relationship between dose and response. 
 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
 
Each participating site will maintain appropriate medical and research records for this trial, in compliance with  
ICH E6 R2 and regulatory and institutional requirements for the protection of confidentiality of participants. Each site 
will permit authorized representatives of regulatory agencies, the IRB/IEC, the sponsor, or the sponsor’s 
representatives to examine (and when permitted by applicable law, to copy) clinical records for the purposes of quality 
assurance reviews, audits, and evaluation of the study safety, progress, and data validity.  
 
Source data are all information, original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial. Examples of these original documents and data records 
include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, participant’s 
memory aids or evaluation checklists, pharmacy dispensing records, recorded audio tapes of counseling sessions, 
recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and participant files and 
records kept at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical trial.  
 
It is not acceptable for the eCRF to be the only record of a subject’s participation in the study. This is to ensure 
that anyone who would access the medical record has adequate knowledge that the subject is participating in a 
clinical trial.  Source document templates will be developed for this study. 
 
 


 
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12 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 
ETHICAL STANDARD 
 
The study will be conducted in compliance with the protocol, the principles laid down in the Declaration of Helsinki, 
and in accordance with the ICH Harmonized Tripartite Guideline for GCP. 
 
12.2 
INSTITUTIONAL REVIEW BOARD 
 
This protocol and any accompanying material to be provided to the subject (such as advertisements, subject 
information sheets, or descriptions of the study used to obtain informed consent) will be submitted by the investigator 
to an IRB or IEC.  Approval from the IRB/IEC must be obtained before starting the study and should be documented in 
a letter to the investigator specifying the protocol number, protocol version, documents reviewed, and date on which 
the committee met and granted the approval.  
 
All changes to the consent form will be IRB approved; a determination will be made regarding whether previously 
consented participants need to be re-consented. 
 
Any modifications or amendment to the protocol must also be submitted to the IRB/IEC for approval prior to 
implementation. 
 
12.3 
INFORMED CONSENT PROCESS 
 
12.3.1 
CONSENT FORMS 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the participant and 
written documentation of informed consent is required prior to any invasive study procedures.  
 
12.3.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
It is the responsibility of the investigator or designee to obtain written informed consent from each subject 
participating in this study and/or their legally authorized representative after adequate explanation of the aims, 
methods, objectives, and potential hazards of the study and prior to undertaking any study-related procedures. 
 
Subjects should have the opportunity to discuss the study with their family members or other advisors and the time 
to consider participation in the trial carefully. The participants may withdraw consent at any time throughout the 
course of the trial. The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study. 
 
The investigator or designee must utilize an IRB/IEC-approved consent form that contains the elements required 
by ICH GCP and applicable regulatory requirements for documenting written informed consent.  Each informed 
consent will be appropriately signed and dated by the subject and/or their legally authorized representative and the 
person obtaining consent.  A copy of the signed consent form will be provided to the subject and/or their legally 
authorized representative.  By signing the informed consent form, all parties agree they will complete the 
evaluations required by the study, unless they withdraw voluntarily or are terminated from the study for any 
reason. 
 


 
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Investigators will be expected to maintain a screening log of all potential study candidates that includes limited 
information about the potential candidate (e.g., date of screening).  
 
All subjects who provide consent will be assigned a unique study number.  This number will be used to identify the 
subject throughout the clinical study and must be used on all study documentation related to the study subject.  
Once a number is assigned to a subject, that number will remain with that study subject and will not be reused. 
 
If an individual’s medical chart or results of diagnostic tests performed as part of an individual’s regular 
medical care are going to be used for screening, written informed consent must be obtained prior to review of 
that information. 
 
12.4 
DATA CONFIDENTIALITY  
Subject confidentiality is held in strict trust by the participating investigators, their staff, the sponsor and their agents. 
This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical 
information relating to participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB/IEC or government 
regulatory agencies may inspect documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit the study monitor access to such records. 
 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their identities are protected 
from unauthorized parties. Only subject initials and an identification code (i.e., not names) should be recorded on non-
local lab samples, requisitions and any documents submitted to the CRO, sponsor and/or IRB/IEC.  The investigator 
must keep a subject log showing codes, names, and addresses for all subjects screened and for all subjects enrolled in 
the trial. The study participant’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as 
dictated by local IRB/IEC and Institutional regulations. 
 
12.5 
FUTURE USE OF STORED SPECIMENS 
 
With the subject’s (or the subject’s legally authorized representative’s) approval and as approved by local IRB/IECs, 
de-identified biological samples may be stored at Alkahest, or designee, for future use. These samples could be used 
for research and to improve treatment. Alkahest will also be provided with a code-link that will allow linking the 
biological specimens with the specific data from each subject, maintaining the masking of the identity of the study 
subject. 
 
During the conduct of the study, an individual subject can choose to withdraw consent to have biological specimens 
stored for future research. However, withdrawal of consent for biospecimen storage will not be possible after the study 
is completed. 
 
When the study is completed, access to study data and/or samples will be managed by Alkahest.  
 


 
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12.6 
EXPEDITED REPORTING OF ADVERSE EVENTS 
 
Expedited reporting of serious adverse events to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the ISF. 
 
 
13 
DATA HANDLING AND RECORD KEEPING 
13.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, and timeliness of the data 
reported. 
 
Source documents provide evidence for the existence of the subject and substantiate the integrity of the data 
collected. Source documents are filed at the investigator’s site.  Data entered in the eCRFs that are transcribed 
from source documents must be consistent with the source documents or the discrepancies must be explained. All 
source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. Black or 
blue ink is required to ensure clarity of reproduced copies. When making changes or corrections, cross out the 
original entry with a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE 
CORRECTION FLUID OR TAPE ON THE ORIGINAL. The investigator may need to request previous medical 
records or transfer records, depending on the trial; also, current medical records must be available. 
 
For each subject who receives the study agent, the eCRF must be completed in a timely manner.  The investigator 
will review and approve the eCRF for each study subject after all data have been entered, the eCRFs have been 
source document verified, and all queries have been resolved. This also applies to records for those subjects who 
fail to complete the study.  If a subject withdraws from the study, the reason must be noted on the eCRF.  If a 
subject is withdrawn from the study because of an AE, thorough efforts should be made to clearly document the 
outcome. 
 
All data collection and recordkeeping procedures must be compliant with applicable ICH GCP. 
 
13.1.1 
INVESTIGATOR RESPONSIBILITIES 
 
The investigator will comply with the protocol (which has been approved/given favorable opinion by an IRB/IEC), 
ICH GCP, and applicable regulatory requirements. The investigator is ultimately responsible for the conduct of all 
aspects of the study at the study site and verifies by signature the integrity of all data transmitted to the sponsor. 
The term “investigator” as used in this protocol as well as in other study documents, refers to the investigator or 
authorized study personnel that the investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the investigator’s signature is 
specifically required. 
 
13.1.2 
STUDY FILES 
 
The investigator must maintain adequate and accurate records to enable the conduct of the study to be fully 
documented and the study data to be subsequently verified.  These documents should be classified into two 
separate categories (although not limited to) the following: (1) investigator’s study file, and (2) subject clinical 


 
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source documents. 
 
The investigator’s study file will contain the protocol/amendments, eCRF, IRB/IEC approval with correspondence, 
informed consents, drug records, staff curriculum vitae and authorization forms, and other appropriate documents 
and study-specific manuals (e.g., Lab Manual). 
 
Subject clinical source documents would include (although are not limited to) the following: subject hospital/clinic 
records, physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, radiologic imaging, X-
ray, pathology and special assessment reports, consultant letters, screening and enrollment log, etc. 
 
13.2 
STUDY RECORDS RETENTION 
 
All clinical study documents must be retained by the investigator until two years after the study is discontinued and 
regulatory authorities have been notified.  Before the investigator destroys any material related to the clinical study, 
he/she must obtain approval in writing from the sponsor. 
 
The investigator should keep a file where the full name and address of the subject and all signed informed consents are 
included for at least 15 years after completion of the trial. Any original study-related information that permits 
verification of inclusion and exclusion criteria, including clinical history, a copy of all data collection logs, and 
documents on the use of the study agent, must be stored for as long a time period as permitted by the center.  
Should the investigator wish to move study records to another location, arrangements must be made to store these in 
sealed containers so that they can be returned sealed to the investigator in case of a regulatory audit. Where source 
documents are required for the continued care of the Subject, appropriate copies should be made for storage outside of 
the site. 
 
13.3 
PROTOCOL DEVIATIONS AND VIOLATIONS 
 
A protocol deviation is any noncompliance with the clinical trial protocol or with GCP. The noncompliance may be 
either on the part of the subject, the investigator, or the study site staff. When deviations occur, corrective actions 
are to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
Violations are instances of protocol noncompliance that have the potential to affect the safety of subjects.   
 
Protocol Deviations are instances of protocol noncompliance that DO NOT have the potential to affect the safety of 
subjects.  Protocol Deviations do not require review by the medical monitor. 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. Violations are instances of protocol noncompliance 
that DO have the potential to affect the safety of subjects.  Violations are a subset of Protocol 
Deviations. 
 
All instances of protocol noncompliance will be logged and tracked by the site and CRO.  Periodic review of Protocol 
Deviations will inform assessment of site performance. 


 
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It is the responsibility of the site to use continuous vigilance to identify and report deviations promptly to the study 
CRO and/or sponsor. All deviations must be addressed in study source documents. Protocol deviations must be sent to 
the local IRB/IEC per their guidelines. The site investigator/study staff is responsible for knowing and adhering to their 
IRB/IEC requirements. 
 
13.4 
PUBLICATION AND DATA SHARING POLICY 
 
Any formal presentation or publication of data collected as a direct or indirect result of this trial will be considered as a 
joint publication by the investigator(s) and the sponsor. In the case of multicenter studies, it is mandatory that the first 
publication be made based on the totality of data obtained from all centers, analyzed as stipulated in the protocol, and 
presented and interpreted as documented in the final Clinical Study Report. The resulting publication will name 
investigators according to the policy of the chosen journal. Where it is not permitted for all investigators to be included 
as authors, the publication will name all investigators within the publication. 
 
Individual investigators may publish data arising from their own subjects. The investigator will provide the sponsor 
with copies of written publications (including abstracts and posters) at least 60 days in advance of submission. This 
review is to permit the sponsor to review the communication for accuracy (thus avoiding potential discrepancies with 
submissions to regulatory authorities), to verify that confidential information is not inadvertently divulged (including 
patent protection), to allow adequate input or supplementary information that may not have been available to the 
investigator, and to allow establishment of co-authorship. 
 
Investigators participating in multicenter studies must agree not to engage in presentations based on data gathered 
individually or by a subgroup of centers before publication of the first main publication, unless this has been agreed 
otherwise by all other investigators and the sponsor. However, in the event that no publication of the overall results has 
been submitted after approval of the Clinical Study Report, investigators may publish results of one or more center’s 
subjects to the same review as outlined above. The sponsor will circulate proposed multicenter publications to all 
investigators for review. 
 
Data will be reviewed by all participating investigators prior to publication. The study sponsor will have 60 days to 
review all definitive publications, such as manuscripts and book chapters, and a minimum of 30 days to review all 
abstracts. 
 
Sponsor reserves final approval and editing rights for all publications or abstracts that consider aggregated data from 
more than one individual site. 
 
13.5 
COMPLETION OF TRIAL 
 
The EMA/competent authority in each participating EU member state needs to be notified about the end of the trial 
(last subject out) or early termination of the trial. 
 
14 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST POLICY 
 
A separate financial disclosure agreement will be made between each principle investigator and Alkahest, Inc. or its 
authorized representative before the study agent is shipped.  Each investigator will notify Alkahest, Inc. or its 
authorized representative of any relevant changes during the conduct of the study and for 1 year after the study has 


 
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been completed.  Alkahest and the study CRO will evaluate any disclosed conflicts of interest and will establish a 
mechanism for their management. 
 


 
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15 
SCHEDULE OF EVENTS 
15.1 
SCHEDULE OF EVENTS TABLE 
 
 
Screening 
Treatment Period 
Follow-Up 
Visit Number 
Day 
Time Window (days) 
1 
-7 to -2 
2 
1 
3 
8 
±1 
4 
15 
±1 
5 
22 
±1 
6 
29 
±1 
7 
36 
±1 
8/EOT7 
43 
±1 
9/FU 
50 
±1 
10/FU 
57 
±1 
Phone/FU 
71 
±1 
Informed Consent1 
X 
Informed Consent for 
Pharmacogenomics2 
X 
 
 
 
Demographics 
X 
Medical history 
X 
Inclusion/exclusion criteria3 
X 
X 
Physical examination 
     X 
X 
 
X 
 
X 
 
X7 
 
X 
 
Vital signs (seated) 
X 
X 
X 
X 
X 
X 
X 
X7 
X 
X 
 
Laboratory tests 
X 
X 
X 
X 
X 
X 
X 
X7 
X 
X 
 
Pregnancy test (as applicable)9 
X 
X 
 
 
 
 
 
X 
 
 
 
12-lead ECG 
X 
 
X 
 
 
X 
 
X7 
 
 
 
SD-OCT 
X 
X 
X 
X 
X 
X 
X 
X7 
X 
X 
 
Fundus photography/FA 
X 
 
 
 
X7 
 
 
Visual acuity 
X 
X 
X 
X 
X 
X 
     X 
X7 
X 
X 
 
Slit lamp 
X 
X 
X 
X 
X 
X 
X 
X7 
X 
X 
 
IOP 
X 
X 
X 
X 
X 
X 
X 
X7 
X 
X 
 
Administration of study agent4 
 
X 
X 
X 
X 
X 
X 
X7 
 
Dispense study agent 
 
X 
X 
X 
X 
X 
X 
 
 
Study agent accountability 
X 
X 
X 
X 
X 
X 
X7 
 
 
 
Pharmacokinetics blood sample (for 
plasma extraction)  
X5 
X6 
X6 
X6 
X6 
X6 
X5,7 
X 
 
 
Biomarker plasma aliquots 
 
X5 
 
 
 
X5 
 
X5,7 
X5 
 
 
Pharmacogenomics blood sample 
 
 
X2 
Adverse events8 
X 
X 
X 
X 
X 
X 
X 
X7 
X 
X 
X 
Concomitant/current medications8 
X 
X 
X 
X 
X 
X 
X 
X7 
X 
X 
X 
Trial completion 
 
 
 
 
 
 
 
 
X 
1. All subjects must sign an informed consent consistent with ICH-GCP guidelines prior to any trial related procedures, which includes medication washouts 
and restrictions.  
2. Informed consents must be obtained for pharmacogenomic sampling 
. Pharmacogenomics sampling will be performed at 
enrollment/baseline (Visit 2). 
 
 
3. A preliminary check of inclusion/exclusion criteria will be performed at screening (Visit 1) after obtaining informed consents. 
4. Study agent will be self-administered in the clinic under supervision of study personnel during every visit of the treatment period (Visits 2-8) following all 
safety and ophthalmic assessments.  Training on study agent administration will be conducted prior to the initial study agent administration at Visit 2.   
5. A pre-dose pharmacokinetic (PK) blood sample will be taken to be centrifuged for collection of plasma samples. Biomarker plasma aliquots will be 
obtained from the pharmacokinetic (PK) samples.  At Visit 2 only, four post-dose pharmacokinetic blood samples will be taken. 
6. A pre-dose PK blood sample will be taken to be centrifuged for collection of plasma samples. 
7. End of Treatment (EOT) visit (Visit 8): all study related procedures will be conducted at the conclusion of 6 weeks of treatment on Day 43 ±1. Withdrawal 
of consent is allowed at any time. For subjects who withdraw consent from the study, no study procedures will be done thereafter. For those that withdraw 
from the study agent, follow-up visits are to occur as per the protocol. Excluding cases of medical emergency, but prior to the discontinuation of a subject 
from the clinical study for disease worsening, the study investigator should discuss each case of discontinuation with the sponsor. 
8. Adverse events and concomitant medications will be assessed at every study visit as well as recorded at any unscheduled subject contact (e.g., unscheduled  
phone calls, etc.).  Following completion of study agent treatment (Visits 2-8), all current medications will be assessed in the follow-up period. 
9. Pregnancy test required in Poland only per Inclusion Criteria. 


 
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16 
REFERENCES 
16.1 
PUBLISHED REFERENCES 
 
Ambati J, Fowler BJ. Mechanisms of age-related macular degeneration. Neuron. 2012;75:26-39. 
 
Bird AC.  Therapeutic targets in age-related macular disease.  J Clin Investig. 2010;120:3033-3041. 
 
Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al. Ranibizumab versus verteporfin for 
neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444. 
 
Buschini E, Fea AM, Lavia CA, Nassisi M, Pignata G, Zola M, et al. Recent developments in the management of dry 
age-related macular degeneration. Clin Opthalmol. 2015;9:563-574. 
 
Clinical Trial Facilitation Group.  Recommendations related to contraception and pregnancy testing in clinical trials. 
Version 2014-09-15:1-13. 
 
Coscas F, Coscas G, Souied E, Tick S, Soubrane G. Optical coherence tomography identification of occult choroidal 
neovascularization in age-related macular degeneration. Am J Ophthalmol. 2007;144:592-599. 
 
Falavarjani KG, Nguyen QD.  Adverse events and complications associated with intravitreal injection of anti-VEGF 
agents: review of the literature. Eye. 2013;27:787-794. 
 
Ferris FL, Fine SL, Hyman L.  Age-related macular degeneration and blindness due to neovascular maculopathy.  Arch 
Opthalmol. 1984;102:1640-1642. 
 
Ferris FL, Kasoff A, Bresnick GH, Bailey I.  New visual acuity charts for clinical research. Am J Ophthalmol. 
1982;94:91-96. 
 
Freund KB, Korobelnik JF, Devenyl R, Framme C, Galic J, Herbert E, et al. Treat-and-extend regimes with anti-VEGF 
agents in retinal diseases.  Retina. 2015;35:1489-1506. 
 
Friedman DS, O’Colmain BJ, Munoz B, Tomany SC, McCarty C, de Jong P, et al. Prevalence of age-related macular 
degeneration in the United States. Arch Ophthalmol 2004;122:564-572. 
 
Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, et al.  Intravitreal aflibercept (VEGF Trap-
Eye) in wet age-related macular degeneration.  Ophthalmology. 2012;119:2537-2548. 
 
Jager RD, Mieler WF, Miller JW.  Age-related macular degeneration.  N Engl J Med. 2008;358:2606-2617. 
 
Lim JH, Wickremasinghe SS, Xie J, Chauhan DS, Baird PN, Robman LD, et al.  Delay to treatment and visual 
outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. Am J 
Ophthalmol. 2012;153:678-686. 
 
Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular 
age-related macular degeneration. N Engl J Med. 2011;364:1897-1908. 
 


 
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Munk M, Kiss C, Sulzbacher F, Eisenkӧlbl, Sacu S, Kalcher K, et al. Short-term progression of wet AMD and 
correlation with 1-year treatment results. Acta Ophthalmol. 2012;90:e420-427. 
 
Nagai N, Ju M, Izumi-Nagai K, Robbie SJ, Bainbridge JW, Gale DC, et al. Novel CCR3 antagonists are effective 
mono- and combination inhibitors of choroidal neovascular growth and vascular permeability. Am J Pathol. 
2015;185:2534-2549. 
 
Pennington KL, DeAngelis MM. Epidemiology of age-related macular degeneration (AMD): associations with 
cardiovascular disease phenotypes and lipid factors. Eye Vis. 2016;3:1-20.  
 
Pepple K, Mruthyunjaya P. Retinal pigment epithelial detachments in age-related macular degeneration: classification 
and therapeutic options. Semin Ophthalmol. 2011;26:198-208. 
 
Riaz M, Baird PN. Recent advances and future directions for the pharmacogenetic basis of anti-VEGF treatment 
response in neovascular age-related macular degeneration. Neural Regen Res. 2017;12:584-585. 
 
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab for neovascular 
age-related macular degeneration. N Engl J Med. 2006;355:1419-1431. 
 
van Leeuwen R, Klaver CC, Vingerling JR, Hofman A, de Jong P. The risk and natural course of age-related 
maculopathy. Arch Ophthalmol. 2003;121:519-526.  
  
Wang H, Han X, Gambhir D, Becker S, Kunz E, Liu AJ, et al.  Retinal inhibition of CCR3 induces retinal cell death in 
a murine model of choroidal neovascularization.  PLoS One. 2016;11(6):e0157748. 
 
Wang J, Wittchen ES, Jiang Y, Ambati B, Grossniklaus HE, Hartnett ME.  Upregulation of CCRS by age-related 
stresses promotes choroidal endothelial cell migration via VEGF-dependent and -independent signaling.  Invest 
Ophthalmol Vis Sci. 2011;52:8271-8277. 
 
Wong WL, Su X, Li X, Mong C, Cheung CMG, Klein R, et al. Global prevalence of age-related macular degeneration 
and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 
2014;2:e106-116. 
 
16.2 
UNPUBLISHED REFERENCES 
 
 
 
 
 
 
 
 
 


 
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17 
APPENDICES 
17.1 
CLINICAL EVALUATION OF LIVER INJURY 
 
17.1.1 
INTRODUCTION 
 
Alterations of liver laboratory parameters, as described in Section 7.2.1.1.7 (protocol-specified AESI), are to be 
further evaluated using the procedures described below. 
 
17.1.2 
PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17.1.2.1  Clinical Chemistry 
• 
Obtain an alkaline phosphatase, albumin, PT or INR, creatinine kinase (CK), creatinine kinase MB test 
(CK-MB,) ceruloplasmin, α-1 antitrypsin, transferrin amylase, lipase, fasting glucose, cholesterol, 
triglycerides 
 
17.1.2.2  Serology 
• 
Obtain a hepatitis A (anti-immunoglobulin M(IgM), anti-IGM)), hepatitis B (hepatitis B antigen, anti-HBs, 
DNA), hepatitis C (anti-hepatitis C virus (HCV), ribonucleic acid (RNA) if anti-HCV positive), hepatitis D 
(anti-IgM, anti-immunoglobulin G (IgG)), hepatitis E (anti-hepatitis E virus (HEV), anti-HEV IgM, RNA 
if anti-HEV IgM positive), anti-smooth muscle antibody (titer), anti-nuclear antibody (titer), anti-liver-


 
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kidney microsomes (LKM) antibody, antimitochondrial antibody, Epstein Barr virus (vascularized 
composite allotransplantation (VCA) IgG, VCA IgM), cytomegalovirus (IgG, IgM), herpes simplex virus 
(IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), toxoplasmosis (IgG, IgM) 
17.1.2.3  Hormones 
• 
Thyroid-stimulating hormone 
 
17.1.2.4  Hematology 
• 
Thrombocytes, eosinophils 
 
17.1.2.5  Ultrasound 
• 
Provide an abdominal ultrasound to rule out biliary tract, pancreatic, or intrahepatic pathology (e.g., bile 
duct stones or neoplasm) 
 
17.1.2.6  Observation/Repeat Testing 
• 
Initiate close observation of subjects by repeat testing of ALT, AST, and total bilirubin (with fractionation 
by total and direct) at least weekly until the laboratory ALT and/or AST abnormalities stabilize or return to 
normal, then according to the protocol. Depending on further laboratory changes, additional parameters 
identified e.g. by reflex testing will be followed up based on medical judgment and GCP. 
 
17.2 
PHARMACOKINETIC, BIOMARKER, AND PHARMACOGENOMIC SAMPLING 
 
17.2.1 
TABLE OF PHARMACOKINETIC (PK), BIOMARKER, AND PHARMACOGENOMIC (PGX) 
SAMPLING 
 
Visit 
Day 
Time Point 
Time for 
Database Setup 
PK 
Blood 
Extra Biomarker Aliquot 
from PK Blood Sample 
PGX 
Blood 
2 
1 
Prior to (i.e., within 15 min before study 
agent administration) 
-0:15 h 
X 
X 
X 
0:00 
0:00 h 
Study agent administration 
0:15 ± 5 minutes 
0:15 h 
X 
0:30 ± 5 minutes 
0:30 h 
X 
1:30 ± 20 minutes 
1:30 h 
X 
X 
3:00 or later (preferably at the end of 
all visit procedures) 
3:00 h 
X 
3 
8 (±1) 
-00:15 min (i.e., within 15 min before 
study agent administration) 
167:45 h 
X 


 
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4 
15 (±1) 
-00:15 min (i.e., within 15 min before 
study agent administration) 
335:45 h 
X 
 
5 
22 (±1) 
-00:15 min (i.e., within 15 min before 
study agent administration) 
503:45 h 
X 
6 
29 (±1) 
-00:15 min (i.e., within 15 min before 
study agent administration) 
671:45 h 
X 
X 
7 
36 (±1) 
-00:15 min (i.e., within 15 min before 
study agent administration) 
839:45 h 
X 
 
8 
43 (±1) 
-00:15 min (i.e within 15 min before 
study agent administration) 
1,007:45 h 
X 
X 
9 
50 (±1) 
Any time during visit – preferably at  
the end of all visit procedures 
1,179:00 h 
X 
X 
 
 
17.3 
PHARMACOKINETIC MEASURES AND EVALUATION 
 
17.3.1 
TIMING OF PHARMACOKINETIC BLOOD SAMPLING 
For the time schedules of pharmacokinetic blood samples, please refer to Section 17.2.1.  PK samples will be taken 
from all subjects at Visits 2-9.   
 
17.3.2 
PHARMACOKINETIC SAMPLE HANDLING AND SHIPMENT 
Methods of pharmacokinetic sample collection are described in Section 7.2.6.2.  Further instructions for sampling 
procedures, and for handling, storage and shipment of the samples will be provided in the Lab Manual in the ISF.   
 
17.3.3 
PHARMACOKINETIC DATA EVALUATION 
For pharmacokinetic analysis and displays, concentrations will be presented in the same format as reported in the 
bioanalytical report.  Only concentrations within the validated concentration range and actual sampling times will 
be used for the calculation of pharmacokinetic parameters. 
Noncompartmental pharmacokinetic analyses of the plasma concentration-time data will be performed using a 
validated software program and for this purpose the actual sampling time for pre-dose samples will be set to zero. 
Plasma concentrations will be plotted graphically versus time for all subjects as listed in the plasma concentration-
time tables. For the presentation of mean profiles, the arithmetic and geometric mean and the planned blood 
sampling times will be used. 
Individual tmax(,ss) values will be directly determined from the plasma concentration time profiles of each subject.  
The following descriptive statistics will be calculated for concentration data and PK parameters: N, arithmetic 
mean, standard deviation, minimum, median, maximum, 10th, 25th, 75th, and 90th percentiles, arithmetic coefficient 
of variation, geometric mean, and geometric coefficient of variation.  Individual concentration values/PK 
parameters may be excluded from calculation of descriptive statistics and graphical displays, e.g. due to relevant 


 
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deviation of actual versus planned sampling time.  Such data however will be listed associated with an appropriate 
flag.   
17.3.4 
HANDLING OF MISSING DATA 
In the noncompartmental analysis, concentration data identified with NOS, NOR, and NOA will not be considered. 
BLQ and NOP values in the lag phase will be set to zero.  The lag phase is defined as the period between time zero 
and the first timepoint with a concentration above the quantification limit. All other BLQ and/or NOP values of the 
profile will be ignored.  Every effort will be made to include all concentration data in an analysis. If not possible, a 
case to case decision is required whether the value should be excluded. 
Descriptive statistics of concentrations will be calculated only when at least 2/3 of the individuals have 
concentrations within the validated concentration range. The overall sample size to decide whether the '2/3' rule is 
fulfilled will be based on the total number of samples intended to be drawn for that time point (i.e., BLQ, NOR, 
NOS, NOA, NOP are included).  Descriptive statistics of parameters are calculated only when at least 2/3 of the 
individual parameter estimates of a certain parameter are available. 
 
 


 
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17.4 
LIST OF 
 
 
The table included in Section 10.4.1 presents a list of drugs 
 
 
17.4.1 
 
 
 


 
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17.5 
COCKCROFT-GAULT FORMULA 
Glomerular filtration rate (GFR) may be estimated based on the commonly used and accepted formula, the Cockcroft-
Gault formula:  
 
Units: GFR [ml/min], age [years], weight [kg], serum creatinine [mg/dl], FS is a correction Factor for Sex: in males FS = 
1, in females FS = 0.85 
 
 
 


 
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18 
REVISION HISTORY 
8 
REVISION HISTORY 
18.1 
SUMMARY OF CHANGES  
 
Protocol Version 3.0 dated 15MAY2018 
Replaces: Protocol Version 1.0 dated 27OCT2017 [Hungary] 
Replaces: Protocol Version 2.0 dated 19MAR2018 [Poland] 
 
The following table describes changes from Version 1.0 (dated 27OCT2017 [Hungary]) and Version 2.0 
(dated 19MAR2018 [Poland]) with justifications provided. In Version 3.0, the two former country-specific 
protocols were combined into a single protocol for global standardization and compliance.  
 
Section 
Description 
Country 
Justification 
Title Page 
Change of 
Authorized 
Representative 
• Hungary 
• Poland 
Due to staffing assignment changes within Alkahest, the 
Authorized Representative has been changed from
 
 
Throughout 
The exploratory 
endpoint of central 
retinal thickness 
(CRT) was changed 
to central subfield 
thickness (CST) 
• Hungary 
• Poland 
• 
Measurement of central retinal thickness (CRT) includes 
multiple subfields and must be performed by a central 
reader, which was not utilized in this study. 
• 
Determination of central subfield thickness (CST) is a 
specific measurement of retinal thickness that is limited 
to a circular area of diameter of 1 mm from the center 
point of the retina that can be measured by investigators 
without the need for a central reader. 
Throughout 
Minor changes to 
grammar and 
formatting 
• Hungary 
• Poland 
Grammar and formatting standardization. 
Throughout 
Where appropriate, 
updated “patient” to 
“subject” 
Hungary 
• 
A “patient” becomes a “subject” following study 
enrollment. 
• 
Updated terminology for clarity and standardization. 
List of 
Abbreviations 
• Added “CST: 
Central Subfield 
Thickness” 
• Removed “OPU: 
Operative Unit” 
• Hungary 
• Poland 
• 
Abbreviation added to accommodate clarified 
exploratory endpoint measurement. 
• 
Abbreviation removed – not required in Protocol. 
1.1 
Change of 
Authorized 
Representative 
(Signatory) / 
Responsible Party 
• Hungary 
• Poland 
Due to staffing assignment changes within Alkahest, the 
Authorized Representative (Signatory) / Responsible Party 
has been changed from 
 
 
The email address has also been updated to reflect 
this change. 
5.1 
Inclusion Criteria in 
bullet 1/sub-bullet 2: 
Changed “Central 
• Hungary 
• Poland 
Standardized nomenclature to align with clarified 
abbreviation. 


 
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subfield retinal 
thickness to CST” 
5.1 
• Inclusion Criteria 
in bullet 5 revised 
to include 
requirements 
related to 
pregnancy and 
pregnancy testing 
for Hungary and 
Poland 
• The requirements 
have not changed 
in either country 
from V1.0/V2.0 to 
V3.0 other than 
being combined to 
create a single 
protocol.    
• Hungary 
• Poland 
Bullet 5 now includes the following country-specific 
requirements: 
• Hungary: Female subjects must not be pregnant or 
breastfeeding. Women of childbearing potential and men 
must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study 
entry. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in the 
study, she should inform her treating physician 
immediately 
• Poland: Female subjects must not be pregnant or 
breastfeeding. Women of childbearing potential must 
have a negative serum pregnancy test at screening/visit 1, 
the first treatment visit, and the last treatment visit. 
Women of childbearing potential and men must agree to 
use highly effective contraception (Clinical Trial 
Facilitation Group 2014) prior to study entry. A woman is 
considered of childbearing potential following menarche 
and until becoming postmenopausal (no menses for at 
least 2 years without an alternative cause). Should a 
woman become pregnant or suspect she is pregnant while 
she or her partner is participating in the study, she should 
inform her treating physician immediately. 
 
7.2.1.2.4 
Revised number of 
categories of 
relatedness 
Hungary 
Previous version incorrectly stated there were four categories 
of relatedness which has been revised to state there are three 
categories of relatedness. 
7.2.5.1 
Removed the 
following sentence: 
“As a further 
endpoint, the total 
retinal thickness, 
inclusive of the sub-
RPE layer, will be 
measured.” 
• Hungary 
• Poland 
Measurement of total retinal thickness includes multiple 
subfields and must be performed by a central reader, which 
was not utilized in this study. 
8.2.1.1 
Serum pregnancy test 
required in Poland 
only added to bullet 5 
Hungary 
Per request from the Polish Department of Clinical Trials for 
Medicinal Products, added the following: “Poland only: 
serum pregnancy test (in women of childbearing potential).” 
8.2.1.1 
Serum pregnancy test 
required in Poland 
only 
Poland 
Added “Poland only:” to indicate that serum pregnancy 
testing is not required in Hungary.  
8.2.2.1 
Serum pregnancy test 
required in Poland 
only added to bullet 4 
Hungary 
Per request from the Polish Department of Clinical Trials for 
Medicinal Products, added the following: “Poland only: 
serum pregnancy test (in women of childbearing potential).” 


 
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8.2.2.1 
Serum pregnancy test 
required in Poland 
only 
Poland 
Added “Poland only:” to indicate that serum pregnancy 
testing is not required in Hungary. 
8.2.3.1 
Serum pregnancy test 
required in Poland 
only added to bullet 3 
Hungary 
Per request from the Polish Department of Clinical Trials for 
Medicinal Products, added the following: “Poland only: 
serum pregnancy test (in women of childbearing potential).” 
8.2.3.1 
Serum pregnancy test 
required in Poland 
only 
Poland 
Added “Poland only:” to indicate that serum pregnancy 
testing is not required in Hungary. 
10.2 
• H0 updated to 
“Change from 
baseline in BCVA 
letter score = 0” 
was previously 
“Change from 
baseline in BCVA 
letter score > 0” 
• H1 updated to 
“Change from 
baseline in BCVA 
letter score ≠ 0 
with α1= 0.20” 
was previously 
“Change from 
baseline in BCVA 
letter score < 0 
with α1= 0.025” 
• Hungary 
• Poland 
Statistical analyses updated to two-sided alpha between 0.05 
and 0.20 versus one-sided approach used in previous 
version. 
15.1 
Removed superscript 
“5” from 
“Pharmacokinetics 
blood sample (for 
plasma extraction)” 
at Visit 9 
• Hungary 
• Poland 
No treatment is administered at Visit 9. Thus, the sample 
can be performed at any time during visit – preferably at the 
end of all visit procedures. 
15.1 
Pregnancy test 
screening/visit 1, first 
treatment visit, and 
final treatment visit 
for subjects in Poland 
Hungary 
Per request from the Polish Department of Clinical Trials for 
Medicinal Products, added pregnancy test (as applicable per 
Inclusion Criteria in Poland) at screening/visit 1, first 
treatment visit, and final treatment visit. 
15.1 
Added superscript 
“9” and footnote to 
Pregnancy test 
indicating it is 
required in Poland 
only 
• Hungary 
• Poland 
Superscript/footnote required to indicate this test is required 
in Poland only. 
16.1 
Added reference to 
define “highly 
effective” 
Hungary 
Clinical Trial Facilitation Group.  Recommendations related 
to contraception and pregnancy testing in clinical trials. 
Version 2014-09-15:1-13. 


 
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contraception 
 
 
 

SAP_001.pdf: 
Study Title A Single Arm Open-Label Study to Evaluate the Therapeutic Effects and 
Safety of a 6-Week Treatment Regimen of ALK4290 in Patients with 
Newly Diagnosed Wet Age-Related Macular Degeneration (wAMD) 
NCT Number NCT03558061 
Document Description Statistical Analysis Plan (Version 1.0) 
Document Date 20 August 2018 
 


FORM.152.03 Updated 30-Aug-2016 
STATISTICAL ANALYSIS PLAN 
A Single Arm Open-Label Study to Evaluate the Therapeutic Effects and Safety 
of a 6-Week Treatment Regimen of ALK4290 in Patients with Newly Diagnosed 
Wet Age-Related Macular Degeneration (wAMD) 
Sponsor: 
 Alkahest, Inc. 
Protocol Number: 
ALK4290-201 
Author: 
 
Biostatistician 
Statistics & Data Corporation 
Date: 
20 AUG 2018 
Version: 
1.0 


Page 2 of 29 
Protocol Title 
A Single Arm Open-Label Study to Evaluate the Therapeutic Effects and Safety of a 6-Week 
Treatment Regimen of ALK4290 in Patients with Newly Diagnosed Wet Age-Related Macular 
Degeneration (wAMD) 
Protocol Number: 
ALK4290-201 
Version:  
1.0  
Date:    
20 AUG 2018 
Statistical Analysis Plan Approval 
Prepared by: 
  
Date 
Biostatistician 
Statistics & Data Corporation 
Reviewed by: 
___________ 
  
Date 
Associate Director, Biostatistics 
Statistics & Data Corporation 
Reviewed by: 
___________ 
  
Date 
Manager of Clinical Data Management 
ProTrials Research 
Approved by: 
   
Date 
Director of Clinical Operations 
Alkahest, Inc. 


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Table of Contents 
1. 
Introduction .............................................................................................................................. 7 
2. 
Study Objectives ...................................................................................................................... 7 
3. 
Study Variables ........................................................................................................................ 7 
3.1 Primary Variable ....................................................................................................................... 7 
3.2 Secondary Variable .................................................................................................................. 7 
3.3 Exploratory Variables ............................................................................................................... 7 
3.4 Statistical Hypotheses .............................................................................................................. 8 
4. 
Study Design and Procedures ................................................................................................. 8 
4.1 General Study Design .............................................................................................................. 8 
4.2 Schedule of Visits and Assessments ....................................................................................... 9 
5. 
Study Treatments ................................................................................................................... 10 
6. 
Sample Size and Power Considerations ................................................................................ 10 
7. 
Data Preparation .................................................................................................................... 10 
8. 
Analysis Sets .......................................................................................................................... 11 
8.1 Intent-to-Treat Set .................................................................................................................. 11 
8.2 Safety Set ............................................................................................................................... 11 
8.3 Evaluable Set ......................................................................................................................... 11 
8.4 Per Protocol Set ..................................................................................................................... 11 
9. 
General Statistical Considerations ......................................................................................... 11 
9.1 Missing or Inconclusive Data Handling .................................................................................. 12 
9.2 Definition of Baseline ............................................................................................................. 12 
9.3 Visit Windows and Visit Mapping ........................................................................................... 12 
9.4 Data Analysis Conventions .................................................................................................... 13 
9.5 Adjustments for Multiplicity ..................................................................................................... 13 
10. 
Disposition of Subjects ........................................................................................................... 13 
11. 
Demographic and Baseline .................................................................................................... 14 
11.1 Demographic and Vital Signs ................................................................................................. 14 
11.2 Baseline Characteristics ......................................................................................................... 14 
12. 
Medical History and Concomitant Medications ...................................................................... 14 
12.1 Medical History ....................................................................................................................... 14 
12.2 Prior and Concomitant Medications/Treatments .................................................................... 14 
13. 
Dosing Compliance and Treatment Exposure ....................................................................... 15 
13.1 Dosing Compliance ................................................................................................................ 15 


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13.2 Treatment Exposure ............................................................................................................... 15 
14. 
Analysis of the Primary Endpoint ........................................................................................... 16 
15. 
Analysis of the Secondary Endpoints .................................................................................... 17 
16. 
Safety Analyses ..................................................................................................................... 17 
16.1 Adverse Events ...................................................................................................................... 18 
16.2 Slit-Lamp Biomicroscopy Examination ................................................................................... 19 
16.3 Intraocular Pressure (IOP) ..................................................................................................... 20 
16.4 Clinical Laboratory Values ..................................................................................................... 20 
16.5 Electrocardiogram (ECG) ....................................................................................................... 21 
16.6 Vital Signs .............................................................................................................................. 21 
16.7 Physical Examination ............................................................................................................. 22 
17. 
Analysis of the Exploratory Endpoints ................................................................................... 22 
17.1 SD-OCT and Fundus Photography/Fluorescein Angiography ............................................... 22 
18. 
Interim Analyses ..................................................................................................................... 23 
19. 
Pharmacokinetic Analysis ...................................................................................................... 23 
20. 
Biomarker Analysis ................................................................................................................ 23 
21. 
Changes from Protocol-Stated Analyses ............................................................................... 23 
22. 
References ............................................................................................................................. 24 
23. 
Revision History ..................................................................................................................... 24 
24. 
Tables ..................................................................................................................................... 24 
25. 
Listings ................................................................................................................................... 26 
26. 
Figures ................................................................................................................................... 27 
27. 
Appendix 1 ............................................................................................................................. 27 
 
 
 


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List of Abbreviations 
AE 
Adverse Event 
ALT 
Alanine Amino Transferase 
AMD 
Age-Related Macular Degeneration 
AP 
Alkaline Phosphatase 
aPTT 
activated Partial Thromboplastic Time 
ARM 
Age-Related Maculopathy 
AST 
Aspartate Amino Transferase 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BLQ 
Below the Limit of Quantification 
Cmax 
Maximum Plasma Concentration 
CNV 
Choroidal Neovascularization 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CST 
Central Subfield Thickness 
DBP 
Diastolic Blood Pressure 
DVM 
Data Validation Manual 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDTA 
Early Treatment Diabetic Retinopathy Study 
EOT 
End of Treatment 
ETDRS 
Early Treatment Diabetic Retinopathy Study  
FA 
Fluorescein Angiography 
FP 
Fundus Photography 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
ICH 
International Conference of Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product (Study Agent) 
INR 
International Normalized Ratio 


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IOP 
Intraocular Pressure 
IRF 
Intraretinal Fluid 
ISF 
Investigator Site File 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Drug Regulatory Activities  
NCS 
Not Clinically Significant 
NOA 
Not Analyzed 
NOP 
No Peak Detectable 
NOR 
No Valid Result 
NOS 
No Sample Available 
OCT 
Optical Coherence Tomography 
PED 
Pigment Epithelial Detachment 
pH 
Potential of Hydrogen 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PT 
Preferred Term 
PT 
Prothrombin Time 
RBC 
Red Blood Cell Count 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SAP 
Statistical Analytical Plan 
SBP 
Systolic Blood Pressure 
SDC 
Statistics & Data Corporation 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
SRF 
Subretinal Fluid 
TEAE 
Treatment-Emergent Adverse Event 
wAMD 
Wet Age-Related Macular Degeneration 
WBC 
White Blood Cell Count 
WHO 
World Health Organization 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol ALK4290-201, Version 3.0 dated 15MAY2018 and Clarification Memorandum #1 dated 
12JUL2018. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports (CSR). 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated.  This SAP provides details of the specific statistical methods that 
will be used.  The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol.  If additional analyses are required to supplement 
the planned analyses described in this SAP they may be completed and will be identified in the CSR. 
2. Study Objectives 
The primary objective of this study is to investigate the potential therapeutic effects of a 6-week, twice 
daily oral dosing regimen of ALK4290 on best corrected visual acuity (BCVA) in newly diagnosed 
(treatment naïve) patients with Wet Age-Related Macular Degeneration (wAMD) as measured by the 
Early Treatment Diabetic Retinopathy Study (ETDRS) testing method. The secondary objectives are to 
assess the safety of the proposed dosing regimen.   
3. Study Variables 
3.1 
Primary Variable 
• 
Mean change from baseline in BCVA letter score as measured by the ETDRS testing method 
at 6-weeks 
3.2 
Secondary Variable 
• 
Safety as assessed by incidence, seriousness, and severity of adverse events (AE) 
3.3 
Exploratory Variables 
• 
Changes in concentrations of ALK4290 in plasma at various time points  
• 
Changes in central subfield thickness (CST), intraretinal fluid (IRF), subretinal fluid (SRF), and 
pigment epithelial detachment (PED) as measured by spectral domain optical coherence 
tomography (SD-OCT) and fundus photography/fundus angiography (FP/FA) 
• 
Evaluation of pharmacogenomic characteristics and biomarkers in blood and plasma samples 


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3.4 
Statistical Hypotheses 
The null and alternative hypotheses for change from baseline in BCVA letter score as measured 
by ETDRS testing method are as follows:  
H0: Mean change from baseline in BCVA letter score at 6 weeks = 0 
H1: Mean change from baseline in BCVA letter score at 6 weeks ≠ 0 
The hypothesis testing will be at a two-sided Type I error rate (α) of 0.20. Specifics of the statistical tests 
are provided in Section 14.  
4.
Study Design and Procedures
4.1 
General Study Design 
This is a single arm, open-label study to evaluate the therapeutic effects and safety of a 6-week 
treatment regimen of ALK4290 in patients with newly diagnosed (treatment naïve) wAMD. This study 
enrolls newly diagnosed patients with Choroidal Neovascularization (CNV) secondary to AMD.  All 
subjects will receive the investigational treatment ALK4290 at a daily dosage of 800 mg administered 
orally twice a day as 400 mg tablets for 6 weeks.  At every visit, safety and tolerability assessments will 
occur.  At specified visits, BCVA will be measured by the ETDRS testing method and morphological 
evaluations will be conducted utilizing SD-OCT and FP/FA.   
The study eye is defined as the eye that meets all the inclusion criteria and none of the exclusion criteria. 
If both eyes meet the inclusion and none of the exclusion criteria, the study is selected by the 
investigator, per their discretion. 
The overall duration of the study is approximately 10 months from study initiation (i.e., first subject 
enrolled) to study completion (i.e., last subject last visit) with a targeted recruitment of 30 subjects over 
the accrual period.  The subject participation period is 10 weeks (6-week treatment plus 4-week follow-
up), unless prematurely discontinued. 




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5.
Study Treatments
This is a single arm, open-label study. All subjects will receive the investigational treatment ALK4290 at
a daily dosage of 800 mg administered orally twice a day as 400 mg tablets for 6 weeks.
6.
Sample Size and Power Considerations
A total of 30 subjects will be enrolled in the study with the intent of obtaining approximately 25 evaluable
subjects who would complete at least 3 weeks of treatment and evaluations through Visit 5 (Day 22).
Subjects who discontinue prior to Day 22 may be replaced. Subjects who withdraw or are withdrawn
during screening (prior to completing V2) will be replaced. The study is not powered for detecting
statistically significant differences in therapeutic parameters in subjects with wAMD receiving ALK4290.
7.
Data Preparation
Data management procedures, including database design and selection of the data dictionary will be
performed by the Data Manager and reviewed and approved by the Sponsor.  Auto-coding of all AEs,
medical histories and concomitant medications will be performed by the IBM Clinical Development EDC
system with additional manual coding performed by the Sponsor designated medical coder.  Medical
coding will be reviewed by the GCT Medical Monitor and confirmed and approved by the Sponsor. All
reported study data will be recorded on the electronic Case Report Forms (eCRF) using IBM Clinical
Development and transferred to SDC by ProTrials.  Clinical personnel at the study site and the CRO are
responsible for ensuring that the protocol is followed and that the eCRFs are properly completed.
Additional safety lab data external to the eCRF data will be provided by Synevo to ProTrials to be 
reconciled with the EDC data and transferred separately  to SDC for analysis.  External PK data will be 
transferred from KCAS and will be analyzed by SDC as outlined in the PK plan (separate from the SAP). 
 
 
All Subject IDs will be assigned automatically within the EDC.  The Subject ID consists of 9 numbers: 
the first set of 3 numbers are specific for the protocol number (i.e., 201); the second set of 3 numbers 
are specific for the site number (i.e., 001 through 012), and the third set of 3 numbers are the subject 
specific screening number (e.g., 001, 002, etc.).   
After data are entered into EDC, data are reviewed and verified by the clinical monitoring/operations 
CRO and ProTrials Data Management. Additionally, SAE reconciliation of the Clinical Database is 
performed against the Alkahest Global Safety Database and any issues are resolved. When the 
database has been confirmed to be complete, consistent and accurate, the database will be locked 
according to ProTrials Standard Operating Procedures and study specific Data Management Plan. Any 


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changes to the database after that time can only be made with the approval of the Sponsor in 
consultation with ProTrials and SDC.  
Final analyses outlined in this document will be performed after: 
•
All data management requirements are met according to ProTrials’ Standard Operating
Procedures (SOP), including performance of edit and verification checks, documentation and
resolution of data queries, and database lock with written authorization provided by appropriate
ProTrials’ and Sponsor personnel;
•
All major protocol deviations and the Per Protocol (PP) set have been determined.
8.
Analysis Sets
The presentation of baseline characteristics will be based on the Intent-to-Treat (ITT) set.  All safety
analyses will be performed using the Safety set.  Analyses of the primary and exploratory efficacy
endpoints will focus on, but will not be limited to, the Evaluable and/or PP sets, as defined below.
8.1 
Intent-to-Treat Set 
The Intent-to-treat set includes all enrolled subjects. 
8.2 
Safety Set 
The Safety set includes all subjects who received at least 1 dose of the study agent. 
8.3 
Evaluable Set 
The Evaluable set includes all subjects who complete at least 3 weeks of treatment during the 6-week 
treatment period. 
8.4 
Per Protocol Set 
The Per Protocol set is a subset of the Evaluable set, comprised of all subjects who completed the study 
and have no major protocol violations. 
9.
General Statistical Considerations
Final data analysis will be performed by SDC after the study is completed and the database has been
cleaned and locked. One interim analysis will be performed by SDC when two-thirds of all enrolled
subjects have either completed Day 15 (Visit 4) or prematurely exited the study; at this time, a snapshot
of the database will be extracted (without formal pre-database-lock data cleaning) for inclusion in the
interim analysis. Statistical programming and analyses will be performed using SAS Version 9.4 or
higher.




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will be selected in that order. If multiple visits of the same type are equidistant from the scheduled 
window, then the earliest visit of that type will be selected.  
Subject listings will include all visits. 
9.4 
Data Analysis Conventions 
Quantitative variables will be summarized using descriptive statistics including the number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum values. Means, 
medians, and confidence intervals (CI) will be reported to two decimal places and SDs to three. 
Summaries for discrete variables will include frequency counts and percentages.  All percentages will 
be rounded to one decimal place (i.e., XX.X%).  Change from baseline will be calculated as the value 
at follow-up visit minus baseline. 
The primary efficacy analysis will be evaluated at a two-sided significance level of 0.20. All p-values will 
be rounded to four decimal places; p-values less than 0.0001 will be presented as “<0.0001”; p-values 
greater than 0.9999 will be presented as “>0.9999”. 
9.5 
Adjustments for Multiplicity 
There will be no adjustments for multiplicity for this early phase, exploratory study. 
10. Disposition of Subjects
Subject disposition will be presented in terms of the numbers and percentages of subjects who were
enrolled, treated, completed the study, and discontinued from the study.
The number and percentage of subjects discontinued from the study and the reasons for study 
discontinuation will be summarized for all enrolled subjects.  The reasons for study discontinuation that 
will be summarized include: AEs, treatment with prohibited concomitant medications, subject non-
compliance, withdrawal of consent, pregnancy, termination of study, and other. A subject listing will be 
provided that includes the date (and study day) of and reason for premature study discontinuation. 
The number and percentage of subjects with protocol deviations will be summarized for the ITT set.  A 
subject listing will be provided that includes the date of the deviation and the deviation description. 
Subject listings will be provided to list out informed consent dates, inclusion and exclusion criteria 
violations, and exclusions from the PP set. 


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11. Demographic and Baseline
11.1 
Demographic and Vital Signs 
Demographic variables collected in this study include age in years (at time of screening), sex, race, 
ethnicity, body mass index (BMI), weight, height, iris color, and study eye (OD or OS).  Subjects who 
record more than one race will be grouped into a single category denoted as ‘Multiple Race’.  
Age (years) will be summarized using continuous descriptive statistics.  Age will also be categorized as 
follows:  <65 years and ≥65 years.   
The number and percentage of subjects will be presented for age category, sex, race, ethnicity, iris color 
and study eye (OD or OS).  Percentages will be based on the total number of subjects in the ITTset.  A 
subject listing that includes all demographic variables will be provided. 
11.2 
Baseline Characteristics 
Baseline BCVA letter score as measured by the ETDRS testing method; CST, presence and height of 
IRF, SRF, and PED as measured by SD-OCT; and presence and size of CNV and leakage from CNV 
as measured by FP/FA will be included in the relevant summaries (including the demography 
summary) and listings. 
12. Medical History and Concomitant Medications
12.1 
Medical History 
Medical history will be summarized using discrete summary statistics and presented at the subject level 
by system organ class (SOC) and preferred term (PT).  If a subject reports the same PT multiple times 
within the same SOC, that PT will only be counted once within that SOC.  As with the PT, if a subject 
reports multiple conditions within the same SOC, the SOC will only be counted once.  Separate tables 
will be created for ocular and non-ocular medical history.  Medical history will be coded using MedDRA, 
Version 21.0.  The summaries will be based on the ITT set. 
Listings of relevant medical history, including prior medical history within three months prior to Visit 1 
(Screening) will be captured in the appropriate eCRF. A subject listing of reported medical history with 
start and stop dates (or ongoing) will be provided. 
12.2 
Prior and Concomitant Medications/Treatments 
At the screening Visit 1 (Day -7 to Day -2), subjects will be asked what medications they are taking, as 
well as those the subject may have taken prior to screening.  At each subsequent study visit, subjects  


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will be asked what concomitant medications they are currently taking or if there have been any changes 
to their medication since the previous visit. 
All prior and concomitant ocular and non-ocular medications will be listed using the ITT set including 
generic name, route of administration, start date, stop date, dosage, and indication. Prior and 
concomitant medications will be categorized by WHO Drug Dictionary (B3 Global March 2018 or higher) 
classification for therapeutic class and drug name. 
Counts and percentages of ocular and non-ocular concomitant medications will be summarized 
separately, and summaries will be displayed for the ITT set.  Subjects with multiple medications in the 
same WHO drug dictionary class or preferred name will be counted only once for that respective WHO 
drug dictionary class or preferred name.   
13. Dosing Compliance and Treatment Exposure
13.1 
Dosing Compliance 
A dose is considered a single 400 mg tablet.  Subjects are instructed per protocol to administer a dose 
twice daily (i.e., once in the morning and once in the evening).  Dosing compliance (% compliance) will 
be assessed by calculating the number of actual doses received and comparing that to the number of 
expected doses as follows: 
Compliance (%) = 
Number of Actual Doses Received 
x 100 
Number of Expected Doses 
The number of actual doses received will be calculated from the the number of dispensed and returned 
tablets as recorded in the eCRF.  The number of expected doses that will be used for calculating 
compliance will be calculated as {2x [date of last dose – date of first dose]} +1 for all subjects, regardless 
of study completion status. Overall compliance will also be categorized as compliant (≥75%) and non-
compliant (<75%). 
Treatment compliance (%) will be summarized for the Safety set using continuous descriptive statistics. 
The compliance categories defined above will be summarized with counts and percentages.   
A subject listing of compliance will also be produced. 
13.2 
Treatment Exposure 
Extent of exposure will be calculated in days using the following: 
Extent of Exposure (days) = [Date of last dose – Date of first dose] + 1 


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Extent of treatment exposure (days) and the total number of doses received for each subject exposed 
to IMP will be summarized with continuous descriptive statistics using the Safety set. A subject listing of 
treatment exposure will also be produced. 
14. Analysis of the Primary Endpoint
The primary endpoint is the mean change from baseline (Visit 2 / Day 1) to end of treatment (Visit 8 /
Day 43) in BCVA letter score of the study eye as measured by the ETDRS testing method using the
Evaluable set. BCVA will be measured at the beginning of every study visit and change from baseline
for each subject will be calculated as follow-up visit minus baseline visit. Quantitative summary statistics
will be used to summarize the BCVA letter score and change from baseline at each visit. A two-tailed,
one-sample t-test will be used to assess the mean change from baseline in BVCA letter score at each
visit, in which the change from baseline BCVA letter score will be compared to a reference value of zero.
The following SAS code will be used to run the one-sample t-test:
PROC TTEST H0=0 ALPHA=0.20 DATA=INDATA; 
VAR BCVA_CHG; 
RUN; 
where 
- INDATA is the name of the input dataset;
- BCVA_CHG is the change in BCVA from baseline to the follow-up visit.
A mixed model accounting for repeated measures will also be used to analyze BCVA. This model will 
include the change from baseline in BCVA letter score as the response variable and baseline BCVA 
letter score, smoking status and visit as explanatory variables for adjustment. LS means for each visit 
will be calculated along with corresponding 95% CIs and p-values. SAS code to implement this repeated 
measures mixed model is as follows: 
PROC MIXED DATA=INDATA; 
CLASS SUBJID SMOKE VISIT; 
MODEL CHG = BASELINE SMOKE VISIT / DDFM = KR SOLUTION; 
REPEATED VISIT / SUBJECT=SUBJID TYPE=UN; 
LSMEANS VISIT / CL; 
RUN; 
where 
- INDATA is the name of the input dataset sorted by SUBJID and VISIT;
- SUBJID is the subject ID number;
- SMOKE is the subject’s smoking history (Never smoked, Ex-smoker, Currently smokes);
- VISIT is the visit at which the BCVA letter score was collected;


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- CHG is the change from baseline in the BCVA letter score;
- BASELINE is the baseline BCVA letter score;
The Kenward-Roger method will be used to determine denominator degrees of freedom. An 
unstructured variance-covariance matrix will be used for the above repeated measures model. If the 
model does not converge using the unstructured matrix, the first order autoregressive structure and the 
compound symmetry structure will be employed, in that order. 
The above analyses will be repeated on the PP set as a sensitivity analysis. 
Additionally, the number of subjects with change from baseline in BCVA letter score for the following 
categories will be summarized with counts and percentages: 
•
>=15 letters;
•
>=14 and >=10 letters;
•
>=9 and >= 5 letters;
•
>=4 and >= -4 letters;
•
>= -5 and >= -9 letters;
•
>= -10 and >= -14 letters;
•
<= -15 letters.
BCVA results will also be presented in a data listing.  BCVA results in the fellow eye are not included in 
the analyses but will be included in the listings.  BCVA will also be summarized by visit using box plots. 
15. Analysis of the Secondary Endpoints
The analyses for secondary endpoints (incidence, seriousness and severity of AEs) will be discussed in
the next section as part of the safety analyses.  There is no secondary efficacy endpoint for the study.
16. Safety Analyses
Safety will be assessed for the following endpoints using the Safety set:
•
Incidence, seriousness, and severity of AEs;
•
Observed slit-lamp biomicroscopy values;
•
Observed intraocular pressure (IOP) values;
•
Changes from baseline in clinical laboratory values;
•
Changes from baseline in physical examination;
•
Changes from baseline in vital signs.
Adverse events will be presented using frequencies and percentages of subjects. 


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Other safety endpoints including slit-lamp biomicroscopy, IOP, clinical laboratory values, physical 
examination, and vital signs will be summarized using descriptive statistics. Changes or shifts from 
baseline will also be summarized where appropriate. Assessments performed by eye (study eye and 
fellow eye) will be summarized separately. No statistical inferential testing will be performed for safety 
variables. 
16.1 
Adverse Events 
AEs are defined as any untoward medical occurrence associated with the use of an IMP in humans, 
whether or not considered IMP-related. All AEs, serious and non-serious, occurring during the 
course of the clinical trial (i.e., from signing the informed consent through the follow-up period) will 
be collected, documented, and reported. All AEs that occur or worsen on or after the first use of 
IMP will be considered as treatment-emergent AEs (TEAE).  Reported AEs that begin prior to the 
first dose of IMP are classified as non-TEAEs; these will only be included in subject listings and not 
included in summary tables.  
When reporting an AE, the event description should use the best matching terminology describing the 
event as found in the Common Terminology Criteria for Adverse Events (CTCAE v4.03). Standardized 
terms from the CTCAE will be used to categorize events for reporting to regulatory authorities using the 
Medical Dictionary for Regulatory Activities (MedDRA, v. 21.0).   
The severity of all reported AEs are graded by the investigator into one of the following five (5) CTCAE 
categories:  
•
Grade 1 (Mild)
•
Grade 2 (Moderate)
•
Grade 3 (Severe)
•
Grade 4 (Life-Threatening)
•
Grade 5 (Death)
The relatedness of IMP to AE will be classified as definite, possibly, or unrelated. Documentation of AEs 
will include start date, end date, seriousness, severity, relatedness, whether or not medication was 
required, outcome, and action taken with the study agent.  
A serious adverse event (SAE) is defined for this protocol as any AE that meets one or more of the 
following criteria: 
•
A death (CTCAE Grade 5 event) occurring during the study, whether or not considered
treatment-related;
•
A life-threatening event (CTCAE Grade 4);


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•
An event requiring inpatient hospitalization or prolonged hospitalization due to the
adverse event;
•
An adverse event resulting in a significant, persistent, or permanent change, impairment,
damage or disruption in the participant’s body function or structure, physical activities or
quality of life;
•
An event that otherwise required a medical or surgical intervention to preclude
permanent impairment or damage (excluding unrelated elective or cosmetic procedures).
An AE of special interest (AESI) is defined for this protocol as any the following outcomes: 
•
Hepatic injury defined by the following alterations of liver parameters:
o
For subjects with normal liver function at baseline an elevation of aspartate
aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥ 3-fold the upper
limit of normal (ULN) combined with an elevation of total bilirubin ≥ 2-fold the ULN
measured in the same blood draw sample;
•
Abrupt decrease of BCVA (> 15 letters lost from baseline);
•
QTc interval prolongation (> +50 ms from baseline and > 450 ms).
An overall tabular summary of TEAEs will be presented that includes the number and percentage of 
subjects who experienced at least one TEAE.  These summaries will also include breakdowns of TEAEs 
further categorized as ocular or non-ocular, and within these categories as drug-related TEAEs, TEAEs 
with CTCAE Grade 3/4/5, drug-related TEAEs with CTCAE Grade 3/4/5, TEAEs with an outcome of 
death, serious TEAEs, drug-related serious TEAEs, TEAEs leading to discontinuation of IMP and drug-
related TEAEs leading to discontinuation of IMP.   
Furthermore, the number and percentage of subjects with TEAEs by SOC and PT; by SOC, PT and 
maximal severity; by SOC and PT for TEAEs; by SOC and PT for SAEs; and by SOC and PT for TEAEs 
leading to subject withdrawal will be presented. Separate summaries will be provided for ocular and 
non-ocular TEAEs (including systemic). Adverse events of special interest will also be summarized by 
SOC and PT. These summaries by SOC and PT will be at the subject level.  If a subject reports the 
same PT multiple times within the same SOC, that PT will only be counted once within that SOC.  As 
with the PT, if a subject reports multiple conditions within the same SOC, that SOC will only be counted 
once.   
All AEs (including non-TEAEs) will also be presented in subject listings. 
16.2 
Slit-Lamp Biomicroscopy Examination 
Slit-lamp biomicroscopy examinations will be conducted on both eyes at all scheduled visits.  The slit-
lamp findings will include examinations of the cornea, conjunctiva, anterior chamber, iris/pupil, lens and 


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eyelids.  Anterior chamber will be graded as +, ++, +++ or none; the other parameters will be graded as 
normal or abnormal.  Abnormal findings will be further classified as not clinically significant (NCS) or 
clinically significant (CS). All clinically significant values will be recorded as AEs in the eCRF and 
followed until resolution.  Once resolved, the AE eCRF page(s) will be updated  
Slit-lamp findings will be summarized by visit, for the study eye and fellow eye separately, using 
qualitative summary statistics (frequency counts and percentages).  Percentages will be based on the 
number of subjects with non-missing values at a given visit.  
A shift table will show changes from baseline Visit 2 (Day 1) to all observations at later study visits.  The 
data for slit-lamp biomicroscopy examinations will be presented in a listing. 
16.3 
Intraocular Pressure (IOP) 
IOP will be measured using applanation Goldmann tonometry or equivalent tonometer in both eyes at 
all scheduled visits.  IOP will be summarized for each eye (study eye and fellow eye)  by visit using 
quantitative summary statistics. The number and percentage of subjects with IOP >= 20 mmHg and the 
number and percentage of subjects with IOP >= 30 mmHg will be summarized. Results will be listed for 
both eyes at each visit. 
16.4 
Clinical Laboratory Values 
Blood samples and urine must be collected at every visit.  Safety laboratory examinations will include 
hematology, biochemistry, coagulation, and qualitative urine analysis. 
•
Serology (screening only): hepatitis A (anti-immunoglobulin M (IgM), anti-IGM)), hepatitis
B (hepatitis B antigen, anti-HBs, DNA), hepatitis C (anti-hepatitis C virus (HCV),
ribonucleic acid (RNA) if anti-HCV positive), hepatitis D (anti-IgM, anti-immunoglobulin G
(IgG)), hepatitis E (anti-hepatitis E virus (HEV), anti-HEV IgM, RNA if anti-HEV IgM
positive), anti-smooth muscle antibody (titer), anti-nuclear antibody (titer), anti-liver-
kidney microsomes (LKM) antibody, antimitochondrial antibody, Epstein Barr virus
(vascularized composite allotransplantation (VCA) IgG, VCA IgM), cytomegalovirus (IgG,
IgM), herpes simplex virus (IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM),
toxoplasmosis (IgG, IgM)
•
Hematology: hemoglobin, red blood cell count (RBC), white blood cell count (WBC) with
differential, platelets
•
Biochemistry: glucose, sodium, potassium, calcium, inorganic phosphate, creatinine,
aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline
phosphatase (AP), lactate dehydrogenase (LDH), total bilirubin (if elevated provide direct
bilirubin), urea, total protein, albumin, uric acid


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•
Coagulation: activated partial thromboplastic time (aPTT), prothrombin time
(PT)/international normalized ratio (INR)
•
Urine: potential of hydrogen (pH), glucose, erythrocytes, leukocytes, protein, nitrite and
glomerular filtration rate (GFR)
All safety laboratory measurements will be performed at all scheduled visits by a central laboratory 
(except serology which is evaluated at screening only) .  Investigators will get guidance and instructions 
on laboratory sampling and processing through a separate Lab Manual provided by the central 
laboratory. 
The investigator is responsible for determining and documenting if out of range laboratory values are 
clinically significant or not.  All clinically significant values will be recorded as AEs in the eCRF and 
followed until resolution.  Once resolved, the AE eCRF page(s) will be updated.  
Continuous biochemistry, hematology, and coagulation assessments will be summarized by visit and 
changes from baseline using quantitative summary statistics. The data for biochemistry and hematology 
will also be presented in listings. 
Serology and urinalysis will be listed with collection information, and clinically significant findings, but no 
tabular summaries will be produced.  
All laboratory values will be presented using conventional units. 
16.5 
Electrocardiogram (ECG) 
ECGs will be measured at screening Visit 1, Visit 3, Visit 6, and Visit 8/EOT, and graded as normal or 
abnormal.  Abnormal findings or changes from baseline will be further classified as not clinically 
significant (NCS) or clinically significant (CS).In the event abnormal ECG results requires additional 
follow up, ECGs may be performed at unscheduled visits or at a study visit that an ECG is not required 
per protocol.  ECG data performed outside of the protocol specified time points will be captured in the 
EDC on an “Unscheduled Visit” eCRF and mapped to the nearest scheduled visit as defined in Section 
9.3. ECG grades and shift from baseline will be summarized with counts and percentages for each visit 
for the Safety set.  All clinically significant findings will be recorded as AEs in the eCRF and followed 
until resolution.  Once resolved, the AE eCRF page(s) will be updated. A subject listing of the ECG 
results will also be produced. 
16.6 
Vital Signs 
Vital signs (blood pressure, pulse rate and respiration) and temperature will be summarized at all 
scheduled visits using descriptive statistics for the Safety set. Blood pressure includes systolic blood 


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pressure (SBP) and diastolic blood pressure (DBP). Change from baseline will also be summarized to 
each post-baseline visit. 
A subject listing of the vital signs results will also be produced. 
16.7 
Physical Examination 
A general physical examination including height (measured only at screening) and weight will be 
performed at screening Visit 1, Visit 2, Visit 4, Visit 6, Visit 8/EOT and Visit 10/FU.   
Physical examination data will be listed to indicate whether the physical examination was conducted or 
not, but no tabular summaries will be produced.  
17. Analysis of the Exploratory Endpoints
17.1 
SD-OCT and Fundus Photography/Fluorescein Angiography 
SD-OCT will be assessed at all scheduled study visits. The retinal layers and thickness will be visualized 
and measured by OCT and will be investigated by a trained person using only specified OCT equipment. 
Reported CST values will be exclusive of the sub-retinal pigment epithelial (RPE) layer fluid. 
FP/FA will be conducted on the study eye at Screening (Day -7 to -2; up to 14 days prior to Visit 1 is 
also acceptable for FP/FA) and Visit 8/EOT (Day 43±1). 
The following ophthalmic endpoints described below will be measured in an exploratory manner to 
investigate the extent, onset, and duration of action. Change from baseline in the study eye of the 
quantitative endpoints will be analyzed in a manner similar to the primary efficacy endpoint. Qualitative 
endpoints will be summarized for the study eye using counts and percentages for the Evaluable and PP 
sets. Subject listings will also be provided for these endpoints and will include collected data for the 
fellow eye. 
•
CST (μm) measured by SD-OCT, absolute and change from baseline
-
CST in the study eye will also be summarized for each scheduled visit using box plots.
•
Presence and maximum height (microns) of IRF by SD-OCT over time, absolute and
change from baseline
•
Presence and maximum height (microns) of SRF by SD-OCT over time, absolute and
change from baseline
•
Presence and maximum height (microns) of PED by SD-OCT over time, absolute and
change from baseline
-
Collected in EDC as RPE detachments and maximum height of the detachments are
collected when present.


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-
Maximum height of PED in the study eye will also be summarized for each scheduled
visit using box plots.
•
Presence and size (number of disc areas) of CNV measured by SD-OCT and FP/FA,
absolute and as change from baseline.
•
Presence and size (number of disc areas) of CNV leakage as demonstrated by FP/FA,
absolute and as change from baseline
The following ophthalmic endpoints will be captured in EDC as part of standard SD-OCT and FP/FA 
assessments. These endpoints will not be summarized (except for macular volume, which will be 
summarized for the study eye at scheduled visits using box plots) but will be presented in subject 
listings. 
•
Macular Volume (mm3) as measured by SD-OCT
•
Presence of Intraretinal Cystoid Spaces as measured by SD-OCT
•
Presence of Lesion in the CNV (including size of the lesion) as measured by FP/FA
•
Presence of RPE atrophy as measured by FP/FA
•
Presence of Hemorrhage in the PED (including area of the hemorrhage) as measured by
FP/FA
•
Presence of Disciform Scar/Retinal Fibrosis as measured by FP/FA
18. Interim Analyses
Continuous data monitoring will be performed. One interim analysis will be performed when two-
thirds of all entered subjects have reached Day 15 (Visit 4). The interim analysis will include only a
subset of the secondary endpoint (i.e., accumulated AE information).
Recruitment into the trial will be stopped if the interim analysis shows relevant safety problems with 
ALK4290.  No formal futility analysis will be conducted. 
19. Pharmacokinetic Analysis
A separate PK plan will be created to describe details pertinent to the analysis of collected PK data.
20. Biomarker Analysis
A separate biomarker plan will be created to describe details pertinent to the exploratory analysis of
collected biomarker data.
21. Changes from Protocol-Stated Analyses
Not applicable.










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Assessment Type 
Start Date 
End Date 
Medical History 
If only day is missing then impute 
day as the first of the month (‘01’). 
If missing day and month then 
impute the first of the year 
(‘01JAN’). 
If only day is missing then impute 
day as the last day of the month 
(‘31’ for months 01, 03, 05 ,07, 08, 
10, 12; ‘30’ for months 04, 06, 09, 
11; ‘29’ for month 02 if a leap year; 
‘28’ for month 02 if not a leap year). 
If missing day and month then 
impute the last of the year 
(‘31DEC’). 
Prior and Concomitant 
Medications 
If only day is missing and the month 
and year are the same as the date 
of IMP initiation, then impute day as 
the day of IMP initiation. 
If only day is missing and month 
and year are not the same as the 
date of IMP initiation, then impute 
the first day of the month (‘01’). 
If missing day and month and the 
year is the same as the date of IMP 
initiation, then impute day and 
month as the day and month of IMP 
initiation. 
If missing day and month and the 
year is not the same as the date of 
IMP initiation, then impute day and 
month as the first of the year 
(‘01JAN’). 
If only day is missing then impute 
day as the last day of the month 
(‘31’ for months 01, 03, 05 ,07, 08, 
10, 12; ‘30’ for months 04, 06, 09, 
11; ‘29’ for month 02 if a leap year; 
‘28’ for month 02 if not a leap year). 
If missing day and month then 
impute the last of the year 
(‘31DEC’). 


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Adverse Events 
Patial start dates for AEs will not be 
collected. 
Completely missing start dates for 
AEs will be imputed as the first 
dose date unless the corresponding 
end date indicates the AE could 
have start earlier, in which case the 
missing date will be imputed as 
01Jan of the same year as the end 
date. 
Patial end dates for AEs will not be 
collected. 
Completely missing end dates for 
AEs will not be imputed.