Conditions: Diabetic Retinopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 79
Healthy volunteers: no

Brief summary:
The main objective is to evaluate ocular and systemic safety and tolerability of BI 1467335 as well as whether BI 1467335 monotherapy has a potential to improve retinal lesions in patients with moderately severe Non-proliferative diabetic retinopathy (NPDR) (DRSS level 47) or severe Non-proliferative diabetic retinopathy (NPDR) (DRSS level 53), without Center-involved diabetic macular edema (CI-DME)

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BI 1467335 intervention 2: Placebo
Intervention descriptions: intervention 1: Once daily intervention 2: Once daily

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (15.0) / Saved on: 20 Nov. 2017
Clinical Trial Protocol
TITLE PAGE
Document Number:
c14141887-05
EudraCT No.:
2016-002971-91
BI Trial No.:
1386.12
BI Investigational 
Medicinal Product:
BI 1467335
Title:
A Randomized, double-masked, placebo-controlled exploratory 
study to evaluate safety, tolerability, pharmacodynamics and 
pharmacokinetics of Orally administered BI 1467335 for 12 
weeks with a 12 week follow up period in patients with Non-
proliferative diabetic retinopathy without center-involved
diabetic macular edema (ROBIN study)
Lay Title:
A study that tests BI 1467335 in patients with diabetic eye 
disease (diabetic retinopathy). It looks at the way BI 1467335 is 
taken up, the effects it has, and how well it is tolerated.
Clinical Phase:
IIa
Trial Clinical 
Monitor:
Phone
Fax 
Coordinating 
Investigator:
Phone:
Fax:
Status:
Final Protocol / Revised Protocol (based on global amendment 4)
Version and Date:
Version:
Date: 
5.0
11 Apr 2019
Page 1 of 93
Proprietary confidential information.
2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Finished product name
Not applicable
Active ingredient name:
BI 1467335
Protocol date
02 Jun 2017
Revision date
11 Apr 2019
Trial number
1386.12
Title of trial:
A Randomized, double-masked, placebo-controlled exploratory study to evaluate 
safety, tolerability, pharmacodynamics and pharmacokinetics of Orally 
administered BI 1467335 for 12 weeks with a 12 week follow up period in patients 
with Non-proliferative diabetic retinopathy without center-involved diabetic 
macular edema (ROBIN study)
Coordinating 
Investigator:
Phone:
Fax:
Trial site(s):
Multi-center trial
Clinical phase:
IIa
Trial rationale:
This study is designed to assess the safety and tolerability of the oral compound BI 
1467335 and to investigate the changes in DR lesion morphology. An oral 
medication capable to treat the moderate/severe stages of NPDR could fill an 
important gap in which patients with NPDR could receive treatment and thereby 
their disease progression could be slowed or even reversed. 
Trial objective(s):
The primary objective is to evaluate safety and tolerability of 12 weeks treatment of 
oral BI 1467335 compared to placebo in patients with moderately severe to severe 
non-proliferative diabetic retinopathy (NPDR) without center-involved diabetic 
macular edema (CI-DME) and secondary to explore the efficacy of BI 1467335 on 
improvement of diabetic retinopathy.
Trial design:
Placebo-controlled, double-masked, randomized, parallel design comparison of two 
groups over 12 weeks of treatment with 12 weeks of follow-up.
Number of patients 
randomized: 
100
Number of patients on 
each treatment:
50
Diagnosis:
Patients with moderately severe or severe NPDR, i.e. Diabetic Retinopathy Severity 
Scale (DRSS) level 47 or 53 without CI-DME.


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Main in- and exclusion 
criteria
Male or female patients; of legal age
Diagnosis of diabetes mellitus Type 1 or Type 2 
Non-proliferative diabetic retinopathy (NPDR) without CI-DME in the study eye at 
screening with NPDR level 47 or level 53, as determined by the Central reading 
center (CRC) by using the DRSS 
Best corrected visual acuity Early Treatment Diabetic Retinopathy Study (ETDRS)
letter score ≥ 70 letters in the study eye at screening
No evidence of active neovascularization of the iris or angle neovascularization in 
the study eye
No prior pan-retinal photocoagulation in the study eye 
No history of Diabetic macular edema (DME) or DR treatment with macular laser 
within 3 months prior to screening, or intraocular injections of medication within 6
months prior to screening, and no more than 4 prior intraocular injections at any 
time in the past in the study eye
Test product:
BI 1467335 film-coated tablets
dose:
10 mg daily (two 5 mg  tablets q.d.)
mode of 
administration:
p.o.
Comparator products:
Placebo film-coated tablets
dose:
Not applicable
mode of 
administration:
p.o.
Duration of treatment:
12 weeks of treatment with 12 weeks follow-up
Endpoints:
Primary endpoint is the proportion of patients with ocular adverse events according 
to Common Terminology Criteria for Adverse Events (CTCAE) over the on-
treatment period (over 24 weeks).
Secondary endpoints are the proportion of patients with at least 2 steps 
improvement in the study eye on the DRSS at week 12 compared to baseline, and
the proportion of patients with adverse events (according to CTCAE) other than 
ocular adverse events over the on-treatment period (over 24 weeks)
Safety criteria:
Adverse event reporting, vital signs, 12-lead electrocardiogram (ECG) and standard 
safety laboratory parameters.
Statistical methods:
The randomization will be stratified by the severity level of the disease under study 
as assessed by DRSS, i.e. levels 47 or 53.
Endpoints related to proportion of patients with improvement in DRSS will be 
summarized descriptively and will be analyzed using logistic regression adjusting 
for baseline visual acuity if sufficient numbers of events are observed.. 
 
 
All other endpoints will be analyzed using descriptive statistics.


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FLOW CHART
Tests and Procedures
Screening 23
Treatment Period 1
Follow-up period
Visit
1 21
2a
Base-
line
2b
Phone 
Visit
3
4a
4b
Phone 
Visit
EOT 2
FU1
FU2
FU3
Week 
1
4
8
12
16
20
24
Day 
-28 to -3 3
1
8
29
57
83
85
EOT19
+28
EOT19
+56
EOT19
+84
Time window for visits
(days)
±1 
±3
±3
±1
+6
±6 
±6
±6
Informed consent 
signed 4
X 21
Informed consent for 
biobanking 5
X
Demographics
X
Medical history/baseline 
conditions
X
Substance use 22
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
All AEs/SAEs/
AESIs 20,24
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
Vital signs 6
X
X
X
X
X
X
X
X
Height 
X
Body weight 
X
X
X
X
Pregnancy testing 7
XS
  XU
  XU
  XU
XU
XU
XU
XU
Resting ECG 8
X
X
X
X
X
X
X
X
Ophthalmological
exams: 9
Visual acuity (BCVA)
X
X
X
X
X
X
X
X
Color fundus 
photography (for 
DRSS evaluation) 10
X 21
X
X
X
X
X
X
X
 
Gonioscopy
X
In-/Exclusion criteria
X
X
IRT call 11
X
X
X
X
X
Trial medication
administration at site
X
X
X
X
Dispense trial medication
X
X
X
Collection of trial 
medication, check of 
medication compliance
X
X
X
Dispense trial medication
diary 12
X
X
X


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Tests and Procedures
Screening 23
Treatment Period 1
Follow-up period
Visit
1 21
2a
Base-
line
2b
Phone 
Visit
3
4a
4b
Phone 
Visit
EOT 2
FU1
FU2
FU3
Collection / check of trial 
medication diary
X
X
X
Reminder to the patient13
X
X
Laboratory tests:
Chemistry, hematology, 
urinalysis
X
X
X
X
X
X
X
X
Infection testing 18 
X
 
  
  
  
  
  
Study completion 17
X
BCVA = Best corrected visual acuity; DRSS = Diabetic Retinopathy Severity Scale; EOT = End of Treatment; 
ECG = electrocardiography; FU = Follow Up; IRT = Interactive Response Technology; OCT-A = 
; XS =serum testing; XU= 
urine testing; = preferentially at this particular visit but also possible at later visits.
1 The medication will be administered once daily, beginning on Day 1 (Visit 2a). Scheduled last day of trial 
medication intake is Visit EOT where the trial medication will be administered at the site from the kit that the 
patient returns to the site, unless patient discontinues prematurely for safety reasons or withdraws consent.
2 This Visit has also to be completed for patients who are withdrawn or who have discontinued the trial early: in 
case of early discontinuation, visit EOT will be completed as soon as possible after the last trial medication 
intake instead of the next planned treatment period visit, and the visits FU1, FU2 and FU3 should be 
performed 4, 8 and 12 weeks after the last trial medication intake, respectively. If patient discontinues 
prematurely for safety reasons or withdraws consent, trial medication administration and PK collection will 
not be performed at EOT Visit. Please refer to Section 6.2.3.
3 The screening period should be kept as short as possible, but the minimum time interval between Screening 
and Randomization is necessary to allow for receipt of confirmation from the central imaging reading center, 
laboratory and ECG results.
4 Prior to any study related procedure; may also be done at an extra visit up to 2 weeks before Visit 1. Re-
consenting may become necessary when new relevant information becomes available and should be conducted 
according to the sponsor’s instructions. Note: Collection of adverse events and other study requirements begin 
at the time patient signs informed consent.
5 Serum/plasma and DNA biobanking is optional. To allow the collection of additional blood samples for 
serum/plasma and DNA biobanking a separate informed consent must be obtained. 
6 Vital signs (to be performed prior to blood collection) include: pulse rate, arterial systolic and diastolic blood 
pressure and respiratory rate (Section 5.2.2).
7 Pregnancy testing: at screening serum pregnancy test is done (XS), and at the other visits as a reflex when urine 
testing (XU) is positive.
8 At screening and follow-up visits 12-lead ECGs should preferentially be performed prior to blood sampling. 
During the treatment period, ECG should be performed approximately 60 min after trial medication intake. At 
visits 3 and 4a the ECG may be performed later at that day. ECGs will be recorded after the patients have 
rested for at least 5 minutes in a supine position. Please refer to Section 5.2.4.


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9
 
 
 
 
 
10The DRSS evaluation is performed by the independent central imaging reading center.
11At visits 2a (randomization call), 3 and 4a, the respective IMP kit number has to be allocated to the patient via 
IRT. At Visit EOT the IRT call is performed to close out the patient (Termination of medication).
12All patients will complete a trial medication diary during the treatment phase to document medication intake 
and treatment compliance. The diary will be dispensed to the patients and collected and reviewed by site-staff 
at the following visits. Please refer to Section 6.2.2.
13Site staff will call the patient in advance to the Visit 2 and EOT visit to remind of trial medication intake and 
time recording on the day before the visit. Please also refer to Section 6.2.2. 
 
 
 
 
 
17Study completion of patient participation also needs to be indicated in the eCRF if the patient withdraws 
prematurely following randomization (see Section 3.3.4).
18QuantiFERON® TB test and HBsAg test 
19If the last day of trial medication intake is different from the EOT visit, the date of the last day of trial 
medication intake will be used for calculation of the FU visit dates
20After the individual patient’s end of the trial the investigator should report only any occurrence of cancer, 
related SAEs and related AESIs of which the investigator may become aware of and only via the SAE form, 
please see section 5.2.6.2.1.
21Screening visit should be performed in two visits. After Informed consent is obtained, fundus photography 
should be performed and sent to central reading service. If patient is eligible based on the DRSS grading, the 
patient should return to complete the rest of the screening. In case of scheduling difficulty for certain patients, 
screening can be performed in one visit. If screening is done as one visit, fundus photography should be 
performed in line with other ophthalmological examinations.
22Alcohol, caffeine and tobacco at screening, Alcohol and caffeine at other visits.
23 Refer to Section 6.2.1 for re-screening and re-test.
24 For all ocular AEs (marked as Ocular Event in the CRFs), ocular symptoms present at the time of the event 
must be reported on the Ocular Symptoms CRF page, including red and/or dry eye, eye pain, flashing lights, 
floaters, photophobia and watering eyes.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................10
1.
INTRODUCTION...............................................................................................13
1.1
MEDICAL BACKGROUND.............................................................................13
1.2
DRUG PROFILE................................................................................................15
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................18
1.4
BENEFIT - RISK ASSESSMENT.....................................................................19
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........22
2.1.1
Main objectives....................................................................................................22
2.1.2
Primary endpoint................................................................................................22
2.1.3
Secondary endpoints...........................................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................24
3.3
SELECTION OF TRIAL POPULATION .......................................................25
3.3.1
Main diagnosis for trial entry ............................................................................25
3.3.1.1
Study eye criteria ..................................................................................................26
3.3.2
Inclusion criteria .................................................................................................26
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Withdrawal of patients from therapy or assessments .....................................28
3.3.4.1
Withdrawal from trial treatment ...........................................................................29
3.3.4.2
Withdrawal of consent for trial participation........................................................29
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................30
4.
TREATMENTS...................................................................................................31
4.1
INVESTIGATIONAL TREATMENTS ...........................................................31
4.1.1
Identity of the Investigational Medicinal Products..........................................31
4.1.2
Selection of doses in the trial and dose modifications......................................31
4.1.3
Method of assigning patients to treatment groups...........................................31
4.1.4
Drug assignment and administration of doses for each patient......................32
4.1.4.1
Trial medication administration at the study site..................................................32
4.1.4.2
Trial medication administration at days without site visits...................................33
4.1.5
Masking (blinding) and procedures for unmasking ........................................33


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4.1.5.1
Masking.................................................................................................................33
4.1.5.2
Unmasking and breaking the code........................................................................33
4.1.6
Packaging, labelling, and re-supply...................................................................34
4.1.7
Storage conditions...............................................................................................34
4.1.8
Drug accountability.............................................................................................34
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................35
4.2.1
Other treatments and emergency procedures..................................................35
4.2.2
Restrictions, warnings and precautions............................................................35
4.2.2.1
Restrictions regarding concomitant treatment ......................................................35
4.2.2.2
Precautions on diet and life style ..........................................................................37
4.2.2.3
Contraception requirements..................................................................................37
4.2.2.4
Restrictions regarding gamete donation................................................................37
4.3
TREATMENT COMPLIANCE........................................................................37
5.
ASSESSMENTS..................................................................................................39
5.1
ASSESSMENT OF EFFICACY........................................................................39
5.2
ASSESSMENT OF SAFETY.............................................................................40
5.2.1
Physical examination ..........................................................................................40
5.2.1.1
Body weight/height...............................................................................................40
5.2.2
Vital signs.............................................................................................................40
5.2.3
Safety laboratory parameters ............................................................................41
5.2.4
Electrocardiogram ..............................................................................................43
5.2.6
Assessment of adverse events.............................................................................44
5.2.6.1
Definitions of AEs ................................................................................................44
5.2.6.2
Adverse event collection and reporting ................................................................47
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................48
5.6
OTHER ASSESSMENTS...................................................................................52
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................52
6.
INVESTIGATIONAL PLAN.............................................................................53
6.1
VISIT SCHEDULE.............................................................................................53
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................53
6.2.1
Screening and run-in period(s)..........................................................................54
6.2.2
Treatment period(s)............................................................................................55


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6.2.3
Follow up period and trial completion..............................................................57
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................58
7.1
STATISTICAL DESIGN - MODEL.................................................................58
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................58
7.3
PLANNED ANALYSES.....................................................................................58
7.3.1
Primary endpoint analyses.................................................................................58
7.3.2
Secondary endpoint analyses .............................................................................59
7.3.4
Safety analyses.....................................................................................................60
7.4
INTERIM ANALYSES ......................................................................................61
7.5
HANDLING OF MISSING DATA ...................................................................61
7.6
RANDOMISATION ...........................................................................................61
7.7
DETERMINATION OF SAMPLE SIZE .........................................................61
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........63
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................63
8.2
DATA QUALITY ASSURANCE ......................................................................64
8.3
RECORDS...........................................................................................................64
8.3.1
Source documents ...............................................................................................64
8.3.2
Direct access to source data and documents.....................................................65
8.3.3
Storage period of records ...................................................................................65
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................66
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........66
8.6
TRIAL MILESTONES.......................................................................................66
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................67
9.
REFERENCES....................................................................................................68
9.1
PUBLISHED REFERENCES............................................................................68
9.2
UNPUBLISHED REFERENCES......................................................................71
10.
APPENDICES.....................................................................................................72
 
 
10.3
THE DIABETIC RETINOPATHY SEVERITY SCALE (DRSS).................74
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................76
11.1
GLOBAL AMENDMENT 1 ..............................................................................76
11.2
GLOBAL AMENDMENT 2 ..............................................................................81
11.3
GLOBAL AMENDMENT 3 ..............................................................................85
11.4
GLOBAL AMENDMENT 4 ..............................................................................91


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine transaminase, SGPT
AMP
Auxiliary medicinal product
AST
Aspartate transaminase, SGOT
(s)AOC3
(Soluble) Amine oxidase copper-containing 3
AUC
Area under the curve
BCVA
Best Corrected Visual Acuity
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
CA
Competent authority
CI-DME
Center-involved diabetic macular edema
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CML
Clinical Monitor Local
CNV
Choroidal neovascularization
CRA
Clinical Research Associate
CRC
Central reading center
CRO
Clinical Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome P450 protein
DILI
Drug-induced liver injury
DM
Diabetes mellitus
DME
Diabetic macular edema
DR
Diabetic retinopathy
DRSS
Diabetic Retinopathy Severity Scale
ECG
Electrocardiography
eCRF
Electronic case report form
EDC
Electronic data capturing
EDTA
Ethylenediaminetetraacetic acid
eGFR
Estimated glomerular filtration rate
EOT
End of treatment
ERG
Electroretinography
ETDRS
Early Treatment Diabetic Retinopathy Study
EudraCT
European clinical trials database
FAS
Full Analysis Set
FU
Follow-up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HbA1c
Glycosylated hemoglobin
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure


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ICF
Informed Consent Form
IEC
Independent Ethics Committee
IOP
Intraocular pressure
IRB
Institutional Review Board
IRMA
Intraretinal microvascular abnormalities
IRT
Interactive Response Technology
ISF
Investigator Site File
IVT
Intravitreal treatment
LC-MS/MS
Liquid chromatography tandem mass spectrometry
M
Metabolite(s)
MAO-B
Monoamine oxidase B
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effect Model for Repeated Measures
MRD
Multiple raising dose
NOA
Not analyzed
NOAEL
No Observed Adverse Effect Level
NOR
No valid result
NOS
No sample available
NPDR
Non-proliferative diabetic retinopathy
OIR
Oxygen induced retinopathy
OPU
Operative Unit
PD
Pharmacodynamic
PDR
Proliferative diabetic retinopathy
p.o.
per os (oral)
PRP
Panretinal photocoagulation
q.d.
quaque die (once a day)
QT
Sum of QRS complex, ST segment and T wave on ECG
QTc(V, F)
Heart-rate corrected QT interval (V=using Van de Water’s formula, 
F=using Fridericia's formula)
REP
Residual Effect Period
RIMA
Reversible inhibitor of MAO-A
PTM
Planned time
SAE
Serious Adverse Event
SOP
Standard operating procedure
SRD
Single raising dose
SSAO
Semicarbazide-sensitive amine oxidase
STZ
Streptozotocin
SUSAR
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
VA
Visual acuity


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VAP-1
Vascular adhesion protein-1
VEGF
Vascular endothelial growth factor
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
Boehringer Ingelheim (BI) is developing BI 1467335, an oral, small-molecule inhibitor of 
amine oxidase copper-containing 3 (AOC3) also known as vascular adhesion protein-1 
(VAP-1) and semicarbazide-sensitive amine oxidase (SSAO) for the indication non-
proliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema 
(CI-DME).
1.1
MEDICAL BACKGROUND
Diabetes mellitus (DM) denotes a heterogeneous group of disease which share common 
elements of hyperglycemia due to lack of insulin (Type 1) or glucose intolerance due to 
insulin deficiency, impaired effectiveness of insulin action, or both (Type 2). The chronic 
hyperglycaemia of diabetes is associated with long-term damage, dysfunction and failure of 
various organs, foremost the eyes, kidneys, nerves, heart, and blood vessels.
In 2015, about 415 million people suffered from diabetes worldwide (of which 95% had Type 
2 diabetes), and this number is predicted to increase to 642 million patients by the year 2040
with particularly large increases in prevalence observed in the developing world [R16-4703]. 
Duration of diabetes is a major risk factor associated to the development of diabetic 
retinopathy (DR). In the USA, the prevalence rate of DR is estimated at 28.5% of the patients 
with diabetes aged 40 and older [R16-3206, R12-1768]. Worldwide prevalence is estimated 
at 34.6%. Approximately 10% (range between 5-15%) of the patients with diabetes also 
suffer from diabetic macular edema (DME). DME is the leading cause of visual loss in the 
diabetic population. It affects central vision and can lead to decline in vision ranging from 
slight visual blurring to blindness, substantially affecting independence and quality of life. In 
about 20-25% of the patients with DME, vision is impaired to a level of 20/40 or worse.
The molecular mechanisms by which diabetes leads to DR and DME includes possible roles 
for hyperglycemia-induced oxidative stress, polyol pathway activation, and production of 
advanced glycation end products [R17-0333]. However, the exact mechanism is unclear. At 
the early phase of the disease the patient might be asymptomatic and the retina appear to be 
normal on clinical routine examination, however, on more detailed testing, the retinal 
thickness is reduced due to neuronal loss, and the color vision and contrast sensitivity are all 
abnormal. In the NPDR stages, the vascular retina begins to become abnormal, the vascular 
wall becomes weaker, and small microaneurysms are formed (this is mild NPDR). These 
microaneurysms start to leak fluid into the retina, leading to the formation of exudates and 
further dysfunction of the retinal neurons. Some of retinal blood vessels start to become 
occluded and localised hypoxia endure. Vascular sluggish leads to venous changes and 
haemorrhages, whilst hypoxia induces new vessel formation, initially in form of intraretinal 
microvascular abnormalities (IRMA) (this is moderate or severe NPDR) and eventually 
neovascularisation outside the retina (proliferative diabetic retinopathy, PDR). 
Patients with NPDR without center-involved DME (CI-DME) are in general not displaying 
visual impairment. Visual impairment usually occurs with the development of CI-DME. It is 
important to distinguish DME and CI-DME in terms of treatment, as the latter is usually 
treated with anti-vascular endothelial growth factor (anti-VEGF). While DME is known to 


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occur at any point during the course of DR, it is associated with the degree of diabetic 
retinopathy that is present: Visual function is usually assessed by testing visual acuity (VA) 
using specialized reading charts (e.g. the Early Treatment Diabetic Retinopathy Study 
(ETDRS) chart and Snellen acuity chart). The term best corrected visual acuity (BCVA) 
means the best possible vision achieved by the patient after corrective prescription glasses are 
used. Snellen acuity chart is commonly used in optician shop for prescription glasses, 
however, ETDRS chart is becoming the gold standard for clinical trial (e.g. the ETDRS 
visual acuity score of 85 or Snellen 20/20 representing normal vision).
As vision is still good in patients with NPDR without CI-DME, the usual standard of care is 
currently observation until either CI-DME or PDR develops. Upon onset of CI-DME, 
intravitreal injection with anti-VEGF therapy is indicated, such as aflibercept (Eylea®) or 
ranibizumab (Lucentis®). Patients who progress to PDR without DME are indicated for 
panretinal photocoagulation (PRP), which is associated with an initial vision loss but better 
long-term effects on vision compared to no treatment. Therefore, it is recommended to 
initiate PRP only in specific cases with severe or very severe NPDR [R17-0368].
Ranibizumab (Lucentis®) was recently approved by the FDA for treatment of DR with and 
without DME. Aflibercept is indicated for treatment of DR is in patients who have CI-DME.
Few trials are currently investigating treatment options for patients with NPDR who do not 
have CI-DME. One trial is the EUROCONDOR study, which investigates the effects of 
somatostatin and brimonidine (neuroprotective agents) on patients with mild NPDR or 
absence of DR (i.e. less than level 20 on the severity scale) where anti-VEGF and laser 
therapy are not indicated. The preliminary results showed topical treatment with somatostatin 
and brimonidine seems not useful for preventing the development of neurodegeneration, at 
least in a period of 2 years of follow-up. Topical treatment with somatostatin and brimonidine 
is effective in arresting the progression of neurodegeneration after excluding patients in the 
low quartile of IT values (best retinal function). That is, in those patients in whom some 
degree of neurodegeneration is already present. Somatostatin has a positive effect in 
microvascular disease by arresting or maintaining the number of microaneurysms in 
comparison with placebo [R17-1803].
Another ongoing study (recruitment started in January 2016) is Protocol W from the Diabetic 
Retinopathy Clinical Research Network, [ClinicalTrials.gov identifier: NCT02634333] which 
will investigate the effect of aflibercept vs placebo on the progression of patients with 
moderate to severe NPDR (no CI-DME) to PDR or onset of CI-DME. Estimated time of 
completion of the first primary endpoint (i.e. progression of disease) is 2020.
Lastly, the Panorama study in patients with moderate to severe NPDR without CI-DME has 
also started in 2016 [ClinicalTrials.gov identifier: NCT02718326]. The primary endpoint is 
2-step improvement in Diabetic Retinopathy Severity Scale (DRSS) at 6 and 12 months. 
As patients with NPDR without CI-DME generally still have good vision, their disease may 
go unnoticed in regions with limited check up by ophthalmologists. Retinal camera is now 
commonly used for screening of diabetic patients, and identification of these patients is now 
common in developed nations. Furthermore, it is expected that smartphones with specialized 


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lenses can image the retina, which will allow easier detection of DR in the coming years. 
Normally, NPDR patients will progress to proliferative stages of the disease or onset of CI-
DME, triggering treatment with PRP, intravitreal injections with anti-VEGF therapies and/or 
focal/grid photocoagulation therapy [P12-13318]. Anti-VEGF injections are invasive and 
expensive, and more importantly patients need frequent monitoring and multiple visit to the 
retinal specialists. On average, patients with CI-DME need 9 to 10 injections in the first 12 
months of treatment [R15-5225]. Laser treatment for PDR, especially PRP, is associated with 
risks of developing retinal side effects, including peripheral and central visual field loss, and 
mild visual loss. Furthermore, despite these treatments, many patients would still have 
bleeding inside the eye leading to visual loss from a few days to a few months, and about 
15% of patients required surgical removal of the blood, risking significant visual loss [R17-
0293]. 
Therefore, there is a great need for medications, in particular for patients with NPDR without 
CI-DME, which are non-invasive such as an oral compound, which will slow progression or 
even reverse the retinal damage. A 2-step improvement of DRSS was shown to be possible 
by monthly injection of anti-VEGF agents in patients with moderate or severe NPDR as well 
as CI-DME [R17-0367]. The study was aimed to treat CI-DME, but the improvement of the 
retinopathy was a bonus. The FDA approved the anti-VEGF agents as a treatment of diabetic 
retinopathy in patients with CI-DME.
The moderately severe / severe NPDR without CI-DME group is considered to be the most 
appropriate target group. Patients with CI-DME and / or PDR, would normally be treated 
with anti-VEGF agents and / or PRP laser. In patients with milder NPDR, it is more difficult 
to get improvement due to the ceiling effect. 
Treatment with an oral AOC3 inhibitor is anticipated to become first-line therapy for patients 
with moderate / severe NPDR without CI-DME. There are current studies using anti-VEGF 
agents to treat these target patients using 2 steps improvement of DRSS as an endpoint.
1.2
DRUG PROFILE
AOC3 is a glycosylated trans-membrane protein with oxidative activity towards primary 
amines [R15-6139]. It is mainly expressed on endothelial cells, smooth muscle cells and 
adipocytes [R15-5788]. In the eye, AOC3 immunoreactivity can be found in the arteries of 
the optic nerve, retina and choroid [R17-1787]. Under inflammatory conditions, the protein is 
exposed at the extracellular membrane of endothelial cells towards the lumen of the vessels, 
where immune cells can recognize and bind to the extracellular part of the enzyme, which 
leads to e.g. reduced rolling velocity of neutrophils on the endothelium [R15-2803]. The 
enzymatic activity is essential for the support of immune cell transmigration towards the 
interstitium. Besides the membrane-bound form, a soluble form of AOC3 (sAOC3) can be 
found in plasma as well as in the vitreous. The sAOC3 consists mainly of the extracellular 
enzymatic domain of AOC3. Shedding from the membrane is catalyzed by metallo-
proteinases, which are increased under endothelial stress and inflammation [R15-5787]. 
Elevated levels of sAOC3 can be found in patients suffering from diabetes, atherosclerosis, 
myocardial infarction and nonalcoholic steatohepatitis. Especially in proliferative diabetic 


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retinopathy, soluble AOC3 is elevated in plasma as well as in the vitreous of patients [R15-
5787]. 
In preclinical studies, it was shown that AOC3 is involved in the migration of lymphocytes, 
granulocytes, leukocytes and macrophages to the site of inflammation [R15-6045; R15-6047; 
R15-6048; R15-5654]. Inhibition of AOC3 by an antibody or small molecule reduced 
inflammation in a variety of disease models [R15-1863; R15-6059; R15-1868; R15-6056; 
R15-6058]. In support of the role of AOC3 as a mediator of inflammation, AOC3-deficient 
mice have impaired rolling and transmigration of leukocytes and reduced recruitment of 
granulocytes to sites of inflammation [R15-6045; R15-2803]. 
Several literature experiments with AOC3 enzyme inhibitors in pre-clinical models of 
diabetes induced vascular permeability and diabetic retinopathy have been published. A 
model of streptozotocin (STZ) induced diabetes exhibited increased plasma sAOC3 levels as 
well as retinal vascular permeability as measured by fluorescein extravasation [R15-1862]. 
Treatment of rats with reversible AOC3 inhibitors reduced the vascular permeability in a 
dose dependent manner. In a model of laser-induced choroidal neovascularization (CNV), 
treatment with AOC3 inhibitor reduced macrophage infiltration in the lesions as well as the 
lesion size in a dose dependent manner [R16-5320]. Further, the pathological 
neoangiogenesis could be reduced in an oxygen induced retinopathy (OIR) mouse model by 
the treatment with reversible AOC3 inhibitors [R17-1786].
The observed effects of BI 1467335 on models of ocular diseases argue for an improvement 
of neuronal function and prevention of pathologic neoangiogenesis by AOC3 inhibition. 
The data therefore argue for the treatment of patients with NPDR and progression to PDR 
with BI 1467335 for the prevention of loss of visual acuity due to neuronal dysfunction and 
neovascularization.
 


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For a more detailed description of the BI 1467335 profile please refer to the current
Investigator’s Brochure (IB) which is included in the Investigator Site File (ISF).
1.3
RATIONALE FOR PERFORMING THE TRIAL
The current standard of care for patients with NPDR without DME is mostly observation 
until the disease progresses significantly, while the treatment options in these advanced 
stages are either aggressive (laser treatment) and can damage the retina, or they are costly and 
invasive (anti-VEGF injection therapy). Therefore, there is a large unmet medical need for:


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
Drugs affecting disease progression and/or addressing the neurodegenerative aspects of 
NPDR and PDR, thereby delaying the complications associated to progression to/of PDR, 
or progression to CI-DME and thereby delaying or preventing the need for intravitreal 
injections/focal photocoagulation or PRP

Improved/non-invasive route of administration (i.e. orals, topicals)

Treatment options for patients refractory to anti-VEGF

Safer treatment options (i.e. no damage to chorioretinal structures)
Thus an oral medication capable to treat the moderate/severe stages of NPDR could fill an 
important gap in which patients with NPDR could receive treatment and thereby their disease 
progression could be slowed or even reversed. 
This study is designed to assess the safety and tolerability of the oral compound BI 1467335 
and to investigate the changes in DR lesion morphology as assessed by the DRSS and visual 
acuity.
1.4
BENEFIT - RISK ASSESSMENT
BI 1467335 has not been previously investigated in patients with NPDR or other ocular 
diseases, and the sponsor is not aware of any clinical studies on the effects of orally 
administered AOC3 inhibitors in patients with NPDR. Although NPDR without CI-DME is 
currently only observed until either CI-DME or PDR develops, a safe and easy to administer 
compound to slow further disease progression would be beneficial to avoid invasive 
treatments in advanced stages. Treatments such as intravitreal injections require multiple 
injections over time and come with procedural risks, such as endophthalmitis, vitreous 
hemorrhage, retinal detachment, traumatic cataract, and increased intraocular pressure (IOP). 


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Planned treatment is 12 weeks with 10 mg q.d. The 10 mg dose was selected based on the 
available data and currently available PK and toxicology data support the administration of 
BI 1467335 for 12 weeks. The planned 12 week treatment duration is considered sufficient to 
observe potential impact of BI 1467335 in patients with NPDR without CI-DME.
This study also includes a 12-week follow-up observation period after stopping the trial 
medication. While, based on its half-life, BI 1467335 is expected to be eliminated from the 
blood much earlier, the 12-week follow-up was chosen due to irreversible binding of the 
BI 1467335 to its target. This 12-week follow-up would allow observation of any prolonged 
effects of BI 1467335. 
This is a newly developed drug at an early stage of testing and therefore an individual benefit 
cannot be guaranteed. As with any new drug, unknown or unexpected adverse events may 
occur. Patients enrolled in this study will have a 50% chance of receiving placebo or 
receiving the active drug. It is not known whether there will be any benefit on objective 
parameters such as the level of severity determined by the DRSS or on clinical symptoms 
such as visual acuity for those patients following 12 weeks of treatment with BI 1467335. 
This is a trial of short duration, and the assignment to the placebo arm is not associated with a 
higher risk to the patient due to slow progression of the NPDR. However, both patients on 
active drug as well as patients on placebo may receive rescue treatment according to local 
clinical standard of care if their visual acuity worsens significantly or if a clinically 
significant progression of NPDR is detected during the trial (please also refer to Section 
4.2.1).
While individual patients may benefit through study procedures (monthly assessment of 
disease severity, safety monitoring), they may also contribute to a better understanding of the 
underlying disease, disease management, or better drug development in the future. 
Ophthalmological exams used in this study are non-invasive and are standard procedures 
used in ophthalmological practice and will be used in this study according to usual medical 
practice. Some of the examinations, like BCVA, are used commonly even in healthy people 
for visual correction, 
 
 


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will be excluded from further examinations (see Section 3.3.4).
Some of the examinations require pupil dilatation, which may lead to temporary light 
sensitivity and impaired vision. This is frequently done with ophthalmological exams and 
ophthalmological clinics should have sufficient experience for handling this (patient 
instructions, disposable eye coverings, etc.).
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.2.6.1.4, adverse events of special interest.
Continuous safety monitoring will be performed in regular Medical Quality Review Meetings 
according to the sponsor’s Standard operating procedures (SOPs) (please refer to Section
8.7).


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective is to evaluate ocular and systemic safety and tolerability of BI 1467335 as 
well as whether BI 1467335 monotherapy has a potential to improve retinal lesions in 
patients with moderately severe NPDR (DRSS level 47) or severe NPDR (DRSS level 53), 
without CI-DME. 
2.1.2
Primary endpoint
Ocular safety of BI 1467335 as assessed by the proportion of patients with any ocular 
adverse events (according to Common Terminology Criteria for Adverse Events (CTCAE)
as defined in Section 5.2.6.1.5) over the on-treatment period (over 24 weeks) (see Section 
7.3.4).
This is no safety issue.
2.1.3
Secondary endpoints
Proportion of patients with at least 2 steps improvement in the study eye on the DRSS at 
week 12 compared to baseline.
The proportion of patients with adverse events other than ocular adverse events over the 
on-treatment period (over 24 weeks) (according to CTCAE).
This is no safety issue.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The trial is a randomized, double-masked, placebo-controlled, parallel-group, multicenter 
proof of clinical principle study. Patients will be enrolled into the study once they have 
signed the informed consent form. Due to high probability of patients screen failing due to 
DRSS grading on fundus photography, screening should be performed in two parts. Fundus 
photography should be performed first, and if patients are eligible based on the fundus 
photography results, patients should return to complete the rest of the screening 
examinations. In case of scheduling difficulty for certain patients, screening can be performed 
in one visit. Patients become eligible for randomization if they have met all inclusion and 
none of the exclusion criteria. Randomized patients will take 10 mg q.d. of BI 1467335 or 
matching placebo from Day 1 to Day 85 (12 weeks). Following conclusion of a 12-week
treatment period, or upon withdrawal from trial medication, all patients will be eligible to 
receive local standard of care therapy at the discretion of the investigator. Patients will be 
followed up at three follow-up visits until twelve weeks after the End of treatment visit 
(EOT).
Figure 3.1: 1
Trial design
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A randomized, double-masked placebo-controlled design is chosen for this trial in order to 
evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of 10 mg q.d. of 
BI 1467335 in patients with moderately severe NPDR (DRSS level 47) or severe NPDR 
(DRSS level 53) without CI-DME. Because currently there is no efficacious therapy available 


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for this patient group at this stage of the disease, this trial aims to improve the level of disease 
severity at early time points in the course of the disease.
The treatment period of 12 weeks is deemed adequate to evaluate safety and tolerability, and 
is covered by currently available toxicology data.
A placebo control arm was chosen for this trial in order to compare BI 1467335 and placebo 
regarding safety and tolerability in patients with NPDR. Approximately equal numbers of 
patients will be randomized to both treatment groups. Randomization will be stratified by the 
level of disease severity (please refer to Section 7) based on DRSS levels 47 or 53 as this may 
have impact on the expected effects regarding the primary outcome.
3.3
SELECTION OF TRIAL POPULATION
A sufficient number of male and female patients with DM either type 1 or type 2 and NPDR 
without CI-DME will be screened to ensure the randomization of 100 patients from approx. 
20-25 study sites. For consistent evaluation of endpoints only prequalified study sites will 
participate, and retina images (
 fundus photography, 
 will be evaluated by 
an independent central reading center (CRC). 
It is expected that around 4-5 patients will be randomized at each study site. If enrolment is 
delayed, additional sites may be recruited. Permission to enroll more than 15 patients per site 
must be obtained from the Trial Clinical Monitor (TCM) at BI. This will only be allowed 
after a careful review of the enrolment status and of the site.
Screening of patients for this trial is competitive across all countries within the study, i.e. 
screening for the trial will stop at all sites at the same time once a sufficient number of 
patients has been screened. Investigators will be notified about screening completion and will 
then not be allowed to screen additional patients for this trial.
Re-screening and re-testing is described in Section 6.2. 
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.   
3.3.1
Main diagnosis for trial entry
Patients with NPDR without CI-DME at the Screening visit are eligible for inclusion if they 
fulfil all of the inclusion criteria (Section 3.3.2) and none of the exclusion criteria (Section 
3.3.3). Only one study eye per patient may be enrolled according to Section 3.3.1.1 (Study 
eye criteria). Ophthalmologic evidence of NPDR without CI-DME with DRSS levels 47 or
53 in the study eye needs to be confirmed by the CRC.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.


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3.3.1.1
Study eye criteria
The following procedure is to be applied for the selection of the study eye at baseline:

If only one eye meets all of the inclusion and none of the exclusion criteria, this eye will 
qualify for the study eye. The fellow eye will be examined for evaluation of safety. 

If both eyes in an individual patient meet all of the inclusion criteria and none of the 
exclusion criteria, the eye with the higher (=worse) DRSS level at screening will qualify 
for the study eye.
o
If both eyes show the same DRSS level, the eye with the worse BCVA letter score 
(as assessed by ETDRS chart at screening) will qualify for the study eye; 
o
If both eyes show the same DRSS level and the same BCVA letter score, the eye 
with the clearer lens will qualify for the study eye;
o
If both eyes show exactly the same conditions mentioned above, the left eye will 
be selected to be the study eye.
3.3.2
Inclusion criteria
1. Of legal age (according to local legislation, usually ≥ 18 years) at screening
2. Male or female patients. Women of childbearing potential (WOCBP)1 must be ready and 
able to use two methods of contraception with at least one of them being a highly 
effective method of birth control per ICH M3 (R2) that result in a low failure rate of less 
than 1% per year when used consistently and correctly. A list of contraception methods 
meeting these criteria is provided in the patient information.
3. Diagnosis of diabetes mellitus (type 1 or type 2):
-
Documented diabetes by American Diabetes Association (ADA) and/or World Health 
Organization criteria
4. Glycosylated hemoglobin (HbA1c) ≤12% at screening
5. Non-proliferative diabetic retinopathy (NPDR) without center-involved diabetic macular 
edema (CI-DME) in the study eye at screening with NPDR level 47 or level 53, as 
determined by the CRC by using the DR severity scale (DRSS) 
6. Best corrected visual acuity ETDRS letter score ≥ 70 letters in the study eye at screening
7. Media clarity, pupillary dilation and individual cooperation sufficient for adequate retinal 
examination including fundus photographs 
8. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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3.3.3
Exclusion criteria
1. Cataract surgery performed within 6 months prior to screening or planned during the trial
in the study eye; or any additional eye disease in the study eye that, in the opinion of the 
investigator, could compromise or alter visual acuity during the course of the study (e.g. 
vein occlusion, uncontrolled intraocular pressure (IOP) >24 mmHg on optimal medical 
treatment, glaucoma with visual field loss, uveitis or other ocular inflammatory disease, 
vitreomacular traction, monocular vision, history of ischemic optic neuropathy, or genetic 
disorders such as retinitis pigmentosa) 
2. Active center-involved DME (CI-DME) on clinical examination and OCT central 
subfield thickness in the study eye above 300 µm as measured by Optovue OCT or above 
320 µm as measured by Heidelberg OCT.
3. Anterior segment and vitreous abnormalities in the study eye that would compromise the 
adequate assessment of the best corrected visual acuity or an adequate examination of the 
posterior pole
4. Evidence of neovascularization on clinical examination including active 
neovascularization of the iris (small iris tufts are not an exclusion) or angle 
neovascularization in the study eye, ruled out by gonioscopy (documented in the last 4 
weeks before screening or performed at screening)
5. Prior pan-retinal photocoagulation (defined as ≥ 100 burns placed previously outside of 
the posterior pole) in the study eye
6. Treatment of either CI-DME or DR with macular laser within 3 months prior to 
screening, or intraocular injections of medication within 6 months prior to screening, and 
no more than 4 prior intraocular injections in the study eye at any time in the past 
7. Patients treated with MAO inhibitors or drugs that may have potential side effects due to 
MAO inhibition, as described in Section 4.2.2.1.
8. Current or planned, during the trial, use of medications known to be toxic to the retina, 
lens or optic nerve, or cause vision loss (see Section 4.2.2.1) 
9. Patients who must or wish to continue the intake of other restricted medications (see 
Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the 
trial
10. Estimated Glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 calculated by Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at screening, or where 
the investigator expects filtration rate is likely to drop below 60 mL/min/1.73m2 during 
the trial
11. Alanine transaminase (ALT) or aspartate transaminase (AST) greater than 2.0-fold the 
upper limit of normal, or total bilirubin > 1.5x upper limit of normal. 
12. Uncontrolled arterial hypertension defined as a single measurement of systolic blood 
pressure >180 mmHg, or two consecutive measurements of systolic blood pressure
> 160 mmHg and/or diastolic blood pressure >100 mmHg on optimal medical regimen at 
screening. If blood pressure is brought to ≤160/100 mmHg by antihypertensive treatment
until randomization, individual can become eligible.


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13. Wolff-Parkinson-White Syndrome, baseline QTcF > 450 ms (Fridericia's formula), family 
history of long QT, or on medication prolonging QT time at screening or planned 
initiation during the trial
14. Diagnosis of a serious or unstable systemic or eye disease and other conditions that, in the 
clinical judgment of the investigator, are likely to interfere with the analyses of safety and 
efficacy in this study. Patients with an expected life expectancy of less than 2 years are 
also excluded.
15. Active known or suspected chronic or relevant acute infections, such as HIV (Human 
Immunodeficiency Virus)\viral hepatitis, or tuberculosis. QuantiFERON® TB test and 
HBs Ag test will be performed during screening. Patients with a positive test result may 
participate in the study if further work up (according to local practice/guidelines) 
establishes conclusively that the patient has no evidence of active infection.
16. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ 
carcinoma of uterine cervix.
17. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
them an unreliable study participant or unlikely to complete the trial
18. Known hypersensitivity to any component of the trial drug and/or allergy to fluorescein 
dye 
19. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to randomization or planned during the trial, e.g. hip replacement
20. Currently enrolled in another investigational drug trial, or less than 30 days or 5 times 
half-life of the investigational drug, whichever is longer, since ending another 
investigational drug trial from the screening visit in this trial or receiving other 
investigational treatment(s); patients participating in a purely observational trial will not 
be excluded.
21. Previous randomization in this trial
22. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
23. Any other clinical condition that, in the opinion of the investigator, would jeopardize 
patient safety while participating in this clinical trial.
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different implications, please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the randomized patients in the trial: if possible on
treatment, or at least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to randomization, as well as the
explanation of the consequences of withdrawal. 


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The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and Electronic Case Report Form (eCRF). If the 
reason for discontinuation is death, this should be reported on the SAE form as well, 
regardless of causal relationship.
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision

The patient needs to take concomitant drugs that interfere with the investigational product
(see Section 4.2.2.1)

The patient can no longer be treated with trial medication for other medical reasons (such 
as eye surgery, adverse events, other diseases, or pregnancy)

Worsening of the disease that requires eye treatment or procedures prohibited in the trial
(see Section 4.2.2.1)

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to stick to the trial requirements in the future.

Patient develops QTcF > 500 ms or change from Visit 1 > 60 ms.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart and Sections 6.2.2. and 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the eCRF. These data will be included in the trial database and reported.
If a patient becomes pregnant during a trial, study drug must be stopped and patient will 
follow the same procedure for early treatment discontinuation as outlined above. After the 
last study follow-up visit, the patient will be followed up until birth or otherwise termination 
of the pregnancy. Patient’s data will be collected and reported in the clinical trial report until 
last patient last visit and any events thereafter, including outcome of the pregnancy, will be 
reported in the BI Pharmacovigilance database.
If patient develops clinically significant adverse reaction, judged by the investigator, related 
to FA procedure, further FA will not be performed for that patient. Patient may continue in 
the study based on the investigator’s assessment.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow up on safety cannot occur.


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If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between treatment withdrawal and withdrawal of 
consent for trial participation and explain the options for continued follow up after 
withdrawal from trial treatment, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Test product
Substance:
BI 1467335
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim 
Unit strength:
5 mg
Posology
2 tablets once daily
Route of administration:
Oral
Table 4.1.1: 2
Comparator product
Substance:
Placebo to match BI 1467335
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim 
Unit strength:
Not applicable
Posology
2 tablets once daily
Route of administration:
Oral
4.1.2
Selection of doses in the trial and dose modifications
The pre-clinical data suggests that AOC3 inhibition of 90% or higher is sufficient to translate 
into a clinical effect on retinal pathology in DR. 
 
 
 
 
Thus, 10 mg is a sufficiently high dose to test the potential clinical effect in this exploratory 
study.
4.1.3
Method of assigning patients to treatment groups
All treatments will be double-masked as to be indistinguishable for the patient as well as for 
the investigator. After assessment of all inclusion and exclusion criteria, each eligible patient 


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will be randomized at Visit 2a to receive BI 1467335 or placebo in a 1:1 ratio according to a 
randomization plan. The assignment will occur in a masked fashion via Interactive Response 
Technology (IRT). To facilitate the use of the IRT, the investigator will receive all necessary 
instructions. 
Note that the medication number is different from the patient number. Site personnel will 
enter the medication number in the eCRF.
4.1.4
Drug assignment and administration of doses for each patient
IRT will allocate medication kit numbers at Visit 2a, 3 and 4a. The medication number will 
be different at each visit. At each visit, the medication box with corresponding medication 
number must be dispensed to the patient. The amount of trial medication dispensed and 
returned will be recorded on drug accountability forms.
The first trial medication dose at Visit 2a is given to the patient by the site staff at the 
investigational site, and trial medication is then dispensed to the patient for home 
administration (please refer to Section 4.1.4.2). 
The medication will be administered once daily, beginning on Day 1 (Visit 2a) until the day 
of EOT Visit (Day 85 according to the visit schedule), unless patient discontinues 
prematurely. All treatments will consist of two tablets (BI 1467335 or placebo) to be taken 
orally approximately at the same time each day. This will not be changed during the entire 
study treatment period (Visit 2a to EOT).
4.1.4.1
Trial medication administration at the study site
At Visits 2a, 3, 4a and EOT the administration of trial medication is done at the study site 
under the supervision of the investigator or qualified site staff. Two tablets of the trial drug
will be administered with a glass of water after predose blood sampling. The actual visit date 
and time of trial drug administration at the visit will be recorded in the eCRF at each visit. 
At Visits 2a, 3 and 4a, new trial medication boxes will be used for administration of the 
morning dose at the clinical site and will be dispensed for home administration. At EOT visit 
trial medication will be taken from the box that the patient returns to the site.
Patients who erroneously take the morning dose of trial medication before coming to the 
clinic at visits 3 and EOT (with scheduled PK samples) should have the visit rescheduled as 
soon as possible, ideally on the following day.
The site staff will instruct and remind the patients:

how to fill in the trial medication diary and to bring the diary to the next visit

not to take their trial medication at the morning of the next visit as they will be dosed 
while at the sites after blood samples are taken (as described in Section 6.2.2)

to bring all trial medication blisters within the box (regardless of whether empty or not) 
back to the investigational site


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4.1.4.2
Trial medication administration at days without site visits
At home, trial medication will be self-administered by the patients. Patients are to be 
instructed to take the tablets orally with water in the morning at approximately the same time 
every day. Medication can be taken with or without food. Patients will record the 
administration dates and times of all doses with the help of a trial drug diary as outlined in the 
Flow Chart and in Section 6.2.2.
If a dose is missed by more than 8 hours, that dose should be skipped and the next dose 
should be taken as scheduled. No double doses should be taken and dose reductions are not 
permitted.
In case medication runs out (or is lost) at home, the patient will go to the site for an additional 
visit in order to be provided with replacement medication. If a reserve trial medication is 
needed, the investigator or authorized site staff will assign reserve trial medication via the 
IRT system.
Patients should be instructed to bring all unused drug and empty study blisters to the study 
site at every visit during the treatment period.
4.1.5
Masking (blinding) and procedures for unmasking
4.1.5.1
Masking
Patients, investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-masked trial will remain masked with regard to the randomized
treatment assignments until after database lock with the exceptions noted below. Please refer 
to Section 4.1.5.2 for rules of breaking the code for patients in emergency situations.
The randomization code will be kept secret by Clinical Trial Support up to database lock. The 
randomization codes will be provided to bioanalytics prior to last patient out to allow for the
exclusion from the analyses of PK samples taken from placebo patients and to a member of 
the team conducting the interim PK/PD analysis. Bioanalytics will not disclose the 
randomization code or the results of their measurements until the trial is officially unmasked.
If a planned interim PK/PD analysis is conducted, access to unmasked data required to 
conduct the planned interim PK/PD analysis will be restricted to members of the trial and 
project teams who are not directly involved with study conduct. The logistical aspects of 
conducting the interim PK /PD analysis, and the plan to access interim results will be 
described in the Interim Analysis Logistics Plan and Results Access Plan.
4.1.5.2
Unmasking and breaking the code
Emergency unmasking will be available to the investigator / pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unmasking must be 


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documented in the source documents and/or appropriate eCRF page along with the date and 
the initials of the person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomization code for individual patients during trial conduct. The access to the 
code will only be given to authorized Pharmacovigilance representatives and not be shared 
further. 
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated Contract research 
organization (CRO). They will be packaged and labelled in accordance with the principles of 
Good Manufacturing Practice (GMP). Re-supply to the sites will be managed via an IRT 
system, which will also monitor expiry dates of supplies available at the sites.
All trial medication will be contained in medication boxes identified with the trial number 
and medication number. Each medication box will contain sufficient BI 1467335 tablets or 
matching placebo for 28 days treatment plus 7 days reserve.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the process outlined in 
the ISF should be followed.
4.1.8
Drug accountability
The investigator, pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (IRB) / ethics 
committee 

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal investigator

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the Principal investigator,

Availability of Form FDA 1572 (if applicable)
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 


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The investigator, pharmacist or investigational drug storage manager must maintain records 
of the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the sponsor or warehouse / drug distribution center or alternative disposal of 
unused products. If applicable, the sponsor or warehouse / drug distribution center will 
maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the Clinical Trial 
Protocol (CTP) and reconcile all investigational products received from the sponsor. At the 
time of return to the sponsor or appointed CRO, the investigator / pharmacist / investigational 
drug storage manager must verify that all unused or partially used drug supplies have been 
returned by the clinical trial patient and that no remaining supplies are in the investigator’s 
possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
As per judgment of the investigator, administration of local standard of care treatment such as 
Intravitreal Treatment (IVT) or peribulbar injections, or laser or other surgical treatment is 
allowed in clinically significant worsening of the disease, and should be considered in the 
event of vision loss of ≥5 letters.
After the end of treatment with trial medication (EOT Visit), standard of care therapy is at the 
discretion of the investigator. Standard of care therapy is, for the purpose of the present trial, 
considered a non-investigational medical treatment.
 
 Only products that 
have marketing authorization in the country must be used and administered according to local 
requirements.  Documentation about administration must be available in source documents 
and will be recorded in ISF. Any side effects of intravenous fluorescein dye will be described 
in the Patient Information. 
4.2.2
Restrictions, warnings and precautions
4.2.2.1
Restrictions regarding concomitant treatment
The following medications are prohibited 5 weeks prior to BI 1467335 dosing and during 
study participation. In addition BI 1467335 should be discontinued for at least 14 days prior 
to starting a chronic treatment with these same agents:

Antidepressants
o
Tricyclic antidepressants such as butriptyline, clomipramine, imipramine, 
trimipramine, desipramine, dibenzepin, lofepramine, maprotiline, nortriptyline, 
amitriptyline, amitriptylinoxide, amoxapine,demexiptiline, dimetacrine, dosulepin, 


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doxepin, fluacizine, imipraminoxide, melitracen, metapramine, nitroxazepine, 
noxiptiline, pipofezine, propizepine, quinupramine, amineptine, iprindole, 
opipramol, tianeptine
o
Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, fluvoxamine, 
sertraline, citalopram, escitalopram and paroxetine
o
Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, 
duloxetine, atomoxetine, desvenlafaxine, levomilnacipran, milnacipran, 
sibutramine

MAO Inhibitors
o
Nonselective MAO-A/MAO-B inhibitors such as isocarboxazid, nialamide, 
phenelzine, hydracarbazine and tranylcypromine.
o
Selective MAO-A inhibitors such as bifemelane, moclobemide, pirlindole, and 
toloxatone.
o
Selective MAO-B inhibitors such as rasagiline, selegiline and safinamide.
The following medications are prohibited 2 weeks prior to BI 1467335 dosing and during 
study participation:

Meperidine

Tramadol

Methadone

Propoxyphene

Dextromethorphan

Cyclobenzaprine

Sympathomimetic medications including nasal, oral and ophthalmic decongestants and 
cold remedies

Bupropion, triptans (almotriptan, rizatriptan, sumatriptan, zolmitriptan, oxitriptan), 
linezolide, tedizolid, methylene blue, lithium and pethidine
The following drugs are prohibited during the entire duration of the trial:

Drugs that may affect the retina or the optic nerve, such as quinolones, thioridazine, 
deferoxamine, ethambutol or vigabatrin: at the time of screening and during the trial.

Amidarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens 
(excluding oral contraception), anabolic steroids and valproic acid and any medication 
which prolongs QT time

Initiation of intensive insulin therapy (switch from regular injections to pump) 
Anti-VEGF injection treatment with aflibercept (Eylea®) or ranibizumab (Lucentis®) in the 
study eye is not allowed to be given in addition to the trial drug. Use of bevacizumab 
(Avastin®) is not allowed in either the study eye or in the fellow eye, in addition to the trial 
drug. If the prohibited anti-VEGF intravitreal treatment has to be started during the study 
prior to the scheduled end of treatment visit, trial medication has to be stopped and the EOT 
visit has to be performed.
If patients are taking medication that is a Cytochrome P450 protein (CYP) 2D6 substrate, 
then the patients should be monitored for possible side effects that may result from potential 


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drug interaction between such medication and trial medication. A list with medication 
examples will be provided in the ISF.
4.2.2.2
Precautions on diet and life style
Patients should be advised to avoid the consumption of large amounts of tyramine-rich food 
while taking BI 1467335, such as: 

Aged cheese

Aged meats

Soybean products (Soy sauce)

Red wine

Beer

Yeast products

St John’s Wort

Pickled herring

Sauerkraut (fermented cabbage)

Tryptophan supplements
There are no other restrictions on diet, exercise, alcohol consumption or smoking except that 
the patient’s usual habits, including smoking habits and caffeine intake, should be within 
acceptable daily amounts and not be drastically changed throughout the study conduct. All 
patients should be on a stable diet and exercise (life style) regimen according to standard of 
care throughout the study. Assessing the restrictions on diet and life style of study patients is 
left to the investigator.
4.2.2.3
Contraception requirements
Women of childbearing potential (WOCBP) must use, during the whole trial, two methods of 
contraception with at least one of them being a highly effective method of birth control per 
ICH M3 (R2) that results in a low failure rate of less than 1% per year when used consistently 
and correctly, as described in the patient information.
4.2.2.4
Restrictions regarding gamete donation 
Gamete donation must not be performed within 3 months after the end of treatment.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on tablet counts, treatment compliance will be calculated as shown in the formula 
below. Compliance will be verified by the Clinical Research Associate (CRA) authorised by 
the sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
     Number of tablets which should have been taken
as directed by the investigator


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If the treatment compliance is not between 80-120%, site staff will explain to the patient the 
importance of treatment compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
For the endpoints, baseline is defined as the value at Visit 2a; if not measured at Visit 2a then 
baseline is the value at Visit 1. All ophthalmologic examinations will be performed on both 
eyes, as described below. 
Centrally collected ophthalmological data (color fundus photography, 
will be transferred from the CRC to the sponsor’s database. The 
local measurement data will remain at the study sites as source documents.
If clinically significant worsening is observed in the assessments of efficacy during the study,
it will be reported as adverse events in the eCRF and on the SAE form if applicable (please 
also refer to Section 5.2.6.1.1).
Color Fundus Photography
Seven-field or modified 4-field digital fundus photographs will be obtained from both eyes 
by a qualified person according to the imaging manual to collect all data for the assessment of 
the ETDRS Diabetic Retinopathy Severity Scale (DRSS). The images will be sent to the 
independent CRC who performs the grading on the basis of the DRSS. This scale evaluates 
retinal hemorrhages, venous beading and IRMA and divides diabetic retinopathy into 13 
levels; this scale can be used to describe overall severity of the retinopathy and change in 
severity over time. In addition, severity of retinopathy in this eye could be assessed as a risk 
factor by using this grading system [R17-1872]. 


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Visual Acuity measured by ETDRS letter charts
Best corrected visual acuity (BCVA) will be determined by using the ETDRS visual acuity 
chart starting at a test distance of 4 meters. The BCVA score is the number of letters read 
correctly by the patient. The assessment will be performed by a trained person under 
specified conditions regarding examination room and equipment.
 
 
5.2
ASSESSMENT OF SAFETY
For the standardized evaluation of ocular safety parameters a complete eye examination will 
be performed at every visit (please refer to Section 5.2.5.1) next to efficacy parameters 
(Section 5.1). In addition, the patients will be asked for symptoms that may have occurred 
since the last study visit, according to Common Terminology Criteria for Adverse Events 
(CTCAE, see also Section 5.2.6).
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular system,
abdomen, extremities, and skin. In addition, further physical examination should be 
performed if clarification of an AE is necessary. The results must be included in the source 
documents available at the site.
5.2.1.1
Body weight/height
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart. The scale used to capture body weight for each patient should remain consistent 
during the trial. In order to get comparable body weight values, it should be performed in the 
following way: Shoes and coat/jacket should be taken off and pockets should be emptied of 
heavy objects (i.e. keys, coins etc.).
5.2.2
Vital signs
Arterial systolic and diastolic blood pressure, respiratory rate (frequency /min) and pulse rate 
(palpation of the pulse) will be measured after the patient has rested for at least 5 minutes in 
the sitting position. Measurement of vital signs should precede blood sampling to avoid the 
impact of blood sampling on the vital measurements. The measured vital signs will be 
documented in the source documents and recorded in the eCRF. 


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5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. The following lab 
parameters will not be determined at each study visit:

HbA1c: at Visit 1 (screening), Visit 2a (baseline) and EOT only

Hepatitis B Surface Antigen (qualitative) at Visit 1 (screening) only 

QuantiFERON®-TB at Visit 1 (screening) only
Laboratory samples will be collected by the trial site at the time points indicated in the Flow 
Chart. All analyses will be performed by a central laboratory. 
Reference ranges, instructions regarding sample collection, details about sample handling/ 
processing and sample shipping are provided in the Laboratory Manual in the ISF. The 
central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as baseline conditions (at screening) or Adverse 
Events (after start of screening; please also refer to Section 5.2.6.1.1).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4 and the DILI Checklist provided in the ISF). The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling. The central laboratory will transfer the results of the analysis to the sponsor.
Urine parameters will be performed by the central laboratory. The urine sediment 
examination will only be done if the urine dipstick analysis is abnormal. 
Urine pregnancy tests will be performed by the site staff.
Table 5.2.3: 1 
Safety laboratory parameters
Hematology
Hematocrit (Hct)
Hemoglobin (Hb)
MCV (mean corpuscular volume)
MCH (mean corpuscular hemoglobin)
MCHC (Mean Cellular hemoglobin 
Concentration)
Red Blood Cell Distribution Width (RDW)
Red Blood Cell Count (RBC) / Erythrocytes
White Blood Cell Count (WBC) / 
Leukocytes
Platelet Count / Thrombocytes
Differential Automatic (relative and 
absolute count):
Neutrophils, Eosinophils, Basophils,
Monocytes, Lymphocytes
Coagulation
Activated Partial Thromboplastin Time (aPTT)
Prothrombin Time (INR) 
Fibrinogen


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Table 5.2.3: 1
Safety laboratory parameters (cont.)
Clinical chemistry
Albumin
Alkaline phosphatase
ALT (alanine transaminase, SGPT)
AST (aspartate transaminase, SGOT)
-GT (gamma-glutamyl transferase)
Bicarbonate
Bilirubin Total
Bilirubin Direct, if total is elevated
Bilirubin Indirect, if total is elevated
Calcium
Chloride
Creatinine
hsC-reactive protein 
Creatine kinase (CK)
CK-MB, troponin I (reflex tests, only if CK 
is elevated)
eGFR1
Glucose
Ferritin
HbA1c (only at V1, V2a and EOT)
Plasma Free fatty acids
Lactate dehydrogenase (LDH)
Lipase
Magnesium
Phosphate
Potassium
Protein total
Sodium
Urea (BUN)
LDL/HDL and total cholesterol
Triglycerides
Pregnancy Test
ß-HCG Urine Pregnancy test2
Serum Pregnancy test3
Infection testing
Hepatitis B Surface Antigen (qualitative) (only at V1)
QuantiFERON®-TB (only at V1)
Urinalysis (dipstick 
test); albumin content
Urine Nitrite
Urine Protein, semiquantitative
Albuminuria quantitatively, only if Urine protein is abnormal:
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/ Erythrocytes
Urine WBC/ Leukocytes
Urine pH
Urine creatinine
Urine Sediment 
(microscopic 
examination, only if 
urine analysis is 
abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epith Cells
Urine Sediment RBC/ Erythrocytes
Urine Sediment WBC/ Leucocytes
1. 
Estimated Glomerular filtration rate as assessed by the CKD-EPI formula (2009).
2. 
Urine pregnancy test performed on-site at all dosing visits (predose) as well as EOT and FU (only for female patients 
of childbearing potential).
3. 
Serum pregnancy test at screening as well as confirmation of positive urine pregnancy test (only for female patients of 
childbearing potential).


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5.2.4
Electrocardiogram
A centralized ECG assessment will be used for this study. Three ECGs are to be recorded as 
12-lead ECGs by a qualified person at the visits outlined in the Flow Chart approximately 60 
min after trial drug intake using equipment provided by a central ECG vendor. All ECGs will 
be printed locally and evaluated by the investigator or a designee; in addition, there is a 
central cardiologist over-read. 
ECGs will be recorded for a10-second duration after the patients have rested for at least 5 
minutes in a supine position. Six limb leads, as specified by Einthoven (I, II and III) and 
Goldberger (aVR, aVL, aVF), and six pre-cordial leads (V1–V6), according to Wilson, will 
be used. ECGs will be recorded but records may be repeated for quality reasons and the 
repeated recording will be used for analysis. If necessary, additional ECGs may be recorded 
for safety reasons. Information about the details of ECG collection will be provided in the 
ISF.
All three ECGs at screening (used as baseline before the first drug administration), and only 
the first of the three replicate ECGs at a remaining time points will be evaluated (signed, 
dated and commented upon) by the treating physician/ investigator. The remaining second 
and third replicate ECGs will be printed and kept together with other medical records of the 
patient for additional analyses if required at a later time point.
All ECGs recorded during trial conduct including the baseline ECG will also be transmitted
to a vendor for central evaluation and stored at an external central ECG database. Only the
first of the three replicate ECGs at a single assessment time will be centrally evaluated and 
transferred to the sponsor. The results of the centralized evaluation will be sent from the ECG 
core lab to the sponsor according to a pre-specified data transmission agreement. The 
remaining second and third replicate ECGs will only be stored at the ECG vendor for 
additional analyses if required at a later time point
The ECG at the screening visit is regarded as baseline. Clinically significant abnormal 
findings will be reported either as baseline condition (if identified at the screening visit) or 
otherwise as AEs and will be followed up and/or treated locally until normal or stable 
condition. In addition to the AE reports from the investigators, quantitative data (interval 
lengths) as well as qualitative findings (indicators for arrhythmia, conduction disturbances 
etc.) will be collected and will be transferred from the ECG reading center to the sponsor.
In the event of any clinical cardiac symptoms (e.g. suspicion of heart rhythm disorders or 
cardiac ischemia) during the trial, an additional ECG will be recorded at the investigator´s 
discretion. The ECG recordings will be transmitted to a vendor for central evaluation and 
stored at an external central ECG database. The electronic versions of the ECGs are regarded 
as source data.
The results of central reading will be reported to the site. ECGs and the corresponding reports 
will be evaluated (signed, dated and commented upon) by the treating physician/investigator 
and stored locally. 


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The central reader’s evaluation of the tracing is considered the official reading for the trial. In 
case of discrepancies between investigator and central reading, the central evaluation will be 
valid.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 


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
Changes in vital signs, ECG, physical examination, ophthalmological examination and 
laboratory test results, if they are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused 
death if more severe;
-
requires inpatient hospitalization, or 
-
requires prolongation of existing hospitalization,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect, or
-
is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgment which may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization or development of dependency or abuse. 
5.2.6.1.3
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of further AEs, which by their nature, can always be considered to be 
“serious” even though they may not have met the criteria of an SAE as defined above.
The latest list of “Always Serious AEs” can be found in the Electronic Data Capturing (EDC)
system. These events should always be reported as SAEs and as described in 5.2.6.2, 
subsections “AE Collection” and “AE reporting to sponsor and timelines”.
5.2.6.1.4
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.


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The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold Upper Limit of Normal (ULN) combined with 
an elevation of total bilirubin >2 fold ULN measured in the same blood draw sample, 
and/or

aminotransferase (ALT and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the RDC.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analyzed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of adverse events should be classified and recorded in the eCRF
according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 
dated 14 June 2010 [R10-4848].
5.2.6.1.6
Causal relationship of AEs
Medical judgments should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative etiologies that could explain the event (e.g. pre-existing or 
concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 


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drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). Of note, this 
criterion may not be applicable to events whose time course is prolonged despite
removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate eCRF(s) by the 
investigator:

From signing the informed consent onwards through the treatment period and the residual 
effect period (REP: period after last dose with measurable drug levels and/or 
pharmacodynamic effects still likely to be present) until the individual patient’s end of 
trial: 
o
all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: 
o
the investigator does not need to actively monitor the patient for new AEs but 
should only report any occurrence of cancer and related SAEs and related AESIs 
of which the investigator may become aware of by any means of communication, 
e.g. phone call. Those AEs should however, not be reported in the eCRF.
The REP in this study is considered as the entire FU period from last dose administration of 
trial medication until individual patient’s end of trial. All AEs that occurred through the 
treatment phase until the end of the Follow-up period will be considered as on-treatment (see 
Section 7.3.4). 
5.2.6.2.2
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.


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5.2.6.2.3
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication and any possible interactions between the trial medication 
and the AMP (intravenous fluorescein dye).
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been assessed as “chronic” or “stable”, or no further 
information can be obtained.
The results must be included in the source documents available at the site.
5.2.6.2.4
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS


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Further details on collection, handling, storage and shipment of biomarker samples will be 
provided in the laboratory manual in the ISF.


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Any leftover samples will be stored and used for not yet specified explorative investigations. 
These samples will be stored for up to three years after the CTR has been signed and may be 
used for not yet specified biomarker analyses to enable further characterization of metabolic 
diseases and their progress, as well as method development and evaluation. Results of these 
assessments will not be part of the CTR.


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5.6
OTHER ASSESSMENTS
Not applicable
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor patients’ safety and to determine pharmacodynamic and 
pharmacokinetic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of an orally administered drug, 
and are widely used in clinical trials. The pharmacokinetic parameters and measurements 
outlined in Section 5.3 are generally used for assessments of drug exposure.
The treatment with BI 1467335 is aiming to improve or stabilize retinal pathology. Therefore, 
a standard method that captures changes in retinal lesions is used for diagnostic purposes as 
well as to determine pharmacodynamic effects. The ophthalmological assessments are widely 
used for the assessment of the retina and other compartments of the eye.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits should be initiated preferentially in the morning starting before 9:00 a.m. On 
scheduled site visits, patients should be instructed to avoid intake of the daily dose of the trial
medication at home prior to visiting the site, as they will be dosed at the study site.
All drug administration at the study site will be done under the direct supervision of the study 
personnel for documentation of precise administration times.
All patient visits should be scheduled according to the Flow Chart. In the event that visits are 
missed or delayed beyond the time window, the delayed visit should be scheduled as soon as 
possible and documented with the actual date and the reason for the delayed visit. Subsequent 
visits should follow the original visit schedule.
If the reason for removal of a patient from the treatment is an adverse event or an abnormal 
laboratory test result, the patient must be followed until complete resolution or stabilization
of the event or until follow-up is agreed adequate by the investigator and BI Clinical Monitor.
Patients should make all efforts to complete the study, which includes the Visit EOT and all
follow-up visits FU1, FU2 and FU3. The procedures to be conducted at each visit are 
provided in the Flow Chart and are further described below.
Regarding removal of patients, please refer to Section 3.3.4.
Order of ophthalmological assessments
For adequate evaluation of the eye fundus it is necessary to dilate the pupil with mydriatic 
medication according to local standard (please also refer to Section 4.2.1).

Before pupil dilation, the following assessments have to be performed: BCVA

After pupil dilation, the following assessments will be performed: color fundus 
photography 

 and slit lamp examination are independent of the dilation.

Ocular tonometry and gonioscopy (at the screening visit only, if needed per Section 3.3.3
exclusion criterion #4) should be performed after imaging. Goniscopy can also be 
performed before dilation, if preferred by the investigator.
 
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart and in the
Appendix 10.2. Additional details regarding visit procedures are provided below.


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6.2.1
Screening and run-in period(s)
Informed Consent prior to trial participation
All patients must sign an Informed Consent consistent with ICH-GCP guidelines prior to any 
study specific procedures. Please refer to Section 8.1 for details.
Screening Period
The Screening period, i.e. the phase before the first administration of the trial drug, starts at
Visit 1. The Screening period may be as long as 28 days but should be kept as short as 
possible. The minimum time interval between Visit 1 and Visit 2a is 3 days to allow receipt 
of the results of the central imaging reading, safety laboratory and ECG.
Screening visit should be performed in two visits. After Informed consent is obtained, fundus 
photography should be performed and sent to central reading service. If patient is eligible 
based on the DRSS grading, the patient should return to complete the rest of the screening. In 
case of scheduling difficulty for certain patients, screening can be performed in one visit. If 
screening is done as one visit, fundus photography should be performed in line with other 
ophthalmological examinations.
 
 
Demographics and Baseline Conditions
Information on race will be collected because certain ethnic groups are at higher risk for DR; 
this demographic information is also required for the calculation of eGFR (CKD-EPI 
formula). 
The following baseline conditions will be specifically asked for: type of DM, arterial 
hypertension, metabolic syndrome and the level of DR in both eyes (as provided by the CRC). 
In addition, information will be collected in the eCRF for relevant chronic diseases, current 
observable conditions and other relevant conditions (as per investigators judgment) which 
may not be necessarily manifest at the day of examination, e.g., because therapy is given.
Medical History
Information on DR risk factors and factors that may influence AOC3 inhibition will be 
collected in the eCRF, such as duration of DM, history of arterial hypertension, history of 
hyperlipidemia, caffeine and alcohol consumption and tobacco use. Furthermore, any 
previous therapy of DR will be recorded.
In order to collect previous medical reports to keep records of exact dates/diagnoses of 
relevant medical history or prior medication, up to three documented attempts at different 
days should be made to get the reports before medical history data will be used.
Level of DR 
Images (fundus photographs, angiograms and OCT) have to be sent to the CRC for 
assessment, see Section 3.3.2. 


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Re-Screening
Patients who do not fulfil all of the eligibility criteria for a reason that later resolves and all 
eligibility criteria can be met, can be re-screened up to one time. Patients can also be re-
screened if they screen failed due to inclusion/exclusion criteria that has been changed in the 
current version of the protocol. For rescreening, patient must be registered in IRT, which will
then provide new patient number, and patient must sign a new ICF. 
 
 
 
Re-testing
Screening evaluations may be repeated once during the screening phase.
IRT
All patients who are screened must be registered with IRT. If the patient results in a screen 
failure, patient must be recorded as screen failure in IRT as soon as possible and within the 
28-day screening period. Details of IRT procedures can be found in the IRT Manual filed in 
the ISF.
6.2.2
Treatment period(s)
General remarks
As soon as eligibility of enrolled patients is confirmed, patients may enter the study and Visit 
2a can be conducted including randomization via IRT. 
IRT should not be called in advance of Visit 2a until eligibility is fully confirmed, as 
randomization of a patient cannot be reserved.
Unscheduled visits will be possible at the discretion of the investigator at any time in order to 
check the safety of the patient including a potential worsening of ocular function or to
perform safety laboratory assessments.
 
At every site visit during the treatment period (Visits 2a – EOT) patients are asked about their 
alcohol and caffeine consumption and information is recorded in the eCRF.
 
 
 


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Trial drug diary
The patients will be instructed to complete trial drug diaries during the treatment phase to 
document date and clock time of drug intake at home between the on-site visits. If the trial 
drug was not administered as planned, the reason should be provided in the diary by the 
patient. 
A new diary will be dispensed to the patients at every visit during the treatment period and 
will be collected at the following visit by the site (please refer to the Flow Chart). Selected 
entries, i.e. drug administration dates and times from the 3 days prior to each visit, will be 
entered in the eCRF by the site.
Visit 2a (Randomization)
At the start of Visit 2a it should be ensured that all Visit 1 procedures have been successfully 
completed within the past 28 days and eligibility has been confirmed including confirmation 
of eligibility by the CRC.
Trial medication is administered after predose blood collection.
 
 
 
 
Trial drug kits will be dispensed for home administration, and a trial drug diary will be 
dispensed to the patients.
Visit 2b (Phone Visit)
This interim phone call will be performed one week after randomization in order to collect 
AEs, changes in concomitant therapy, and to check handling of the trial drug diary. Patients 
should be reminded not to take medication in the morning prior to the next visit. 
Visits 3 and 4a:
At these visits the trial drug diary will be checked and dates and times of drug administration 
at the 3 days prior to the visits will be recorded in the eCRF. Unused trial medication, as well 
as empty blisters and packaging, will be collected. 
Visit 4b (Phone Visit)
This interim phone call will be performed in advance to the EOT visit in order to collect AEs, 
changes in concomitant therapy, and to check handling of the trial drug diary. Patients should 
be reminded not to take medication in the morning prior to the EOT visit.
End of Treatment (EOT) Visit:
For patients who complete treatment as scheduled, the day of the EOT Visit is the last day of 
treatment where trial drug will be administered at the site from the kit that the patient returns 
to the site. 
The overall duration of the anticipated treatment period (Randomization to EOT) should not 
be less than 84 days; therefore the EOT visit is scheduled at Day 85 with a time interval of up 
to +6 days at maximum. 


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If the trial drug intake needs to be permanently stopped during the treatment period for any
reason prior to the scheduled EOT visit, including that patients are not willing to continue 
trial drug intake any longer, the EOT visit will be completed instead of the planned treatment 
period visit as soon as possible after trial drug discontinuation. In this case the patient should 
be asked to further attend to the follow-up visits and assessments until the end of the trial 
unless they withdraw consent to participate in the trial. It is important to distinguish between 
premature trial drug discontinuation, i.e. early discontinuation, and complete withdrawal of 
consent to participate in further study procedures. 
Withdrawal of consent
If a patient is not willing to continue in the trial prior to the end of the trial, Visit EOT should 
be scheduled and completed instead of the planned treatment period visit as soon as possible. 
Also one follow-up visit (FU1) should be performed to assess for safety.
If the patient refuses to participate at an EOT Visit and withdraws consent for any reason 
(without the need to justify the decision), the trial completion page of the eCRF has to be 
filled in.
All unused trial medication will be collected and trial drug diary will be checked by the site. 
If patient discontinues prematurely for safety reasons or withdraws consent, trial medication
administration 
will not be performed at EOT Visit.
6.2.3
Follow up period and trial completion
For all patients who had at least one dose of trial medication the follow-up visits FU1, FU2 
and FU3 will be performed according to the Flow Chart 4, 8 and 12 weeks after the last 
intake of trial drug, respectively. If the last day of trial drug intake is different from the EOT 
visit, the date of the last day of trial drug intake will be used for calculation of the FU visit 
dates. 
Should it be not possible for the patient to attend a follow up visit at the study site, a visit out 
of time window should be performed as soon as possible; if a visit at the site is not possible at 
all, at least a phone contact should occur at the scheduled visit time point.
In case that standard of care DR treatment is administered at these visits, this has to be 
documented in the eCRF.
The FU3 visit is the final visit and the Study completion page in the eCRF has to be entered.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
The trial is a randomized, double-masked, placebo-controlled, parallel-group, multicenter 
proof of clinical principle study. The primary objective is to evaluate the safety and 
tolerability of BI 1467335 and to explore the mechanism of BI 1467335 in the treatment of 
patients with moderately severe NPDR (DRSS level 47) or severe NPDR (DRSS level 53),
without CI-DME.
BI 1467335 will be compared to placebo. The primary endpoint is occurrence of ocular 
adverse events.
The randomization will be stratified by the severity level of the disease under study as 
assessed by DRSS, i.e. level 47 or 53.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No confirmatory hypothesis testing is planned. This study is considered exploratory.
7.3
PLANNED ANALYSES
The analysis populations are defined below. Patients will be analyzed according to 
randomized treatment, unless otherwise specified. Important protocol violations and the 
handling of patients with such violations will be described in the TSAP.
Treated Set (TS)
The Treated Set will consist of all patients who were treated with at least one dose of trial 
drug (BI 1467335 or placebo).
Full Analysis Set (FAS)
The FAS will consist of all the patients who were randomized, treated with at least one dose 
of BI 1467335/placebo and have baseline and one on-treatment DRSS assessment.
 
7.3.1
Primary endpoint analyses
No primary efficacy endpoint has been defined for this study.
For analyses of the primary safety endpoint “proportion of patients with ocular adverse 
events” over the on-treatment period please refer to Section 7.3.4.


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7.3.2
Secondary endpoint analyses
The proportion of patients with at least 2 steps improvement from baseline on the DRSS
(Table 10.3: 1) in the study eye at week 12 will be summarized as the frequency and 
percentage of patients. Logistic regression analyses adjusted for treatment and baseline visual 
acuity may be performed if a sufficient number of events is observed. Baseline measurements 
are defined in Section 5.1. The odds ratio and corresponding 95% confidence interval will be 
presented along with the p-value. The analysis will be performed on the FAS. 
For analyses of the secondary safety endpoint “proportion of patients with adverse events
other than ocular adverse events” over the on-treatment period, refer to Section 7.3.4.


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7.3.4
Safety analyses
All findings noticed at ophthalmological examinations and/or clinically relevant symptoms 
(according to the judgment of the investigator) which are reported by the patients will be 
recorded as ocular adverse events according to the CTCAE classification. All adverse events 
will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
Standard BI summary tables and listings will be produced. Consistent with the REP definition 
in Section 5.2.6.2.1, all adverse events with an onset between start of treatment and last 
follow up visit will be assigned to the on-treatment period for evaluation. Measurements 
(such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to treatments 
(see Section 4.1) based on the actual treatment at the planned time of the measurement or on 
the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements planned or AEs recorded prior to first intake of trial medication will be 
assigned to 'screening' and those between first trial medication intake until the last follow up
visit will be assigned to the treatment period. These assignments including the corresponding 
time intervals will be defined in detail in the TSAP.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and last follow up 
visit. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at the database lock. This also includes 
the primary endpoint.
Laboratory data will be analyzed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarized. 
Treatment groups will be compared descriptively with regard to distribution parameters as 
well as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values.
Clinically relevant ECG findings will be reported as baseline conditions or AEs. Quantitative 
and qualitative ECG data from the ECG reading center will be reported descriptively.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.


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7.4
INTERIM ANALYSES
 
 
 
 
 
During the conduct of the interim analysis, access to unmasked data will be restricted to 
members of the trial and project teams not directly involved with study conduct. The results
of the interim analysis will not be used to make any adaptions of this trial, like sample size 
adjustments.
For steps to maintain blinding during the interim analysis see Section 4.1.5.1.  
7.5
HANDLING OF MISSING DATA
For the analyses of efficacy endpoints, if a patient misses a visit, the missing data will not be 
imputed and only on-treatment data will be included. 
Additional details on the handling of missing data, including sensitivity analyses of the 
efficacy endpoints and any imputation rules for further endpoints will be specified in the 
TSAP prior to unmasking. No imputation is planned for the analysis of AEs, laboratory data 
or vital signs. Rules for handling missing data are outlined in BI SOPs.
7.6
RANDOMISATION
BI will arrange for the randomization and the packaging and labelling of trial medication. 
The randomization list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the CTR. Access to the codes will be 
controlled and documented. Procedural aspects of assigning patients to treatment groups and 
controlling the randomization code are provided in Section 4.1.3 and Section 4.1.5.
7.7
DETERMINATION OF SAMPLE SIZE
The primary endpoint for the trial is occurrence of ocular adverse events. 


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As this is an exploratory study, no formal sample size calculation has been applied. It is 
expected that using 50 patients per group will be sufficient to detect clinically relevant signals 
for ocular events between active treatment and placebo.
Additionally, with DRSS data from 100 patients the probability of seeing at least 2 steps 
improvement in the study eye on the DRSS at week 12 compared to baseline in 2 patients is 
approximately 80%, assuming a response rate of 6% on active treatment and 0% response on 
placebo.
Figure 7.7: 1
Probabilities for seeing different amount of patients with 2 step 
improvement in DRSS assuming different success rates.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI SOPs, the EU regulation 536/2014 and other 
relevant regulations. Investigators and site staff must adhere to these principles.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor with regard 
to publication of the results of this trial are described in the investigator contract. As a rule, 
no trial results should be published prior to finalization of the CTR.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / Independent Ethics Committee (IEC) and competent 
authority (CA) according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative
The patient must be given sufficient time to consider participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator must sign (or 
place a seal on) and date the informed consent form. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
informed consent.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
eCRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see Section 8.3.2). The investigator must ensure that all patient identifiers 
(e.g. patient’s name, initials, address, phone number, social security number) have properly 
been removed or redacted from any copy of the patients’ source documents before sending 
them to the sponsor.


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If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the eCRF, data must be derived from source documents, for example:
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)
Dates of patient’s visits, including dispensing of trial medication
Medical history (including trial indication and concomitant diseases, if applicable)
Medication history
Adverse events and outcome events (onset date (mandatory), and end date (if available))
Serious adverse events (onset date (mandatory), and end date (if available))
Concomitant therapy (start date, changes)
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it)
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all eCRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).


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Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below and in Section 5.4.1. 
Patient privacy will be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the World Health 
Organization GCP handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Out”). The “Last Patient Drug Discontinuation” (LPDD) date is defined as 
the date on which the last patient at an individual trial site ends trial medication (as scheduled 
per protocol or prematurely). Individual investigators will be notified of SUSARs occurring 
with the trial medication until 30 days after LPDD at their site. Early termination of the 
trial is defined as the premature termination of the trial due to any reason before the end of 
the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.


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The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by BI.
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
- manage the trial in accordance with applicable regulations and internal SOPs
- direct the clinical trial team in the preparation, conduct, and reporting of the trial
- ensure appropriate training and information of Local Clinical Monitors (CML), CRAs, and 
investigators of participating countries
The organization of the trial in the participating countries will be performed by the respective 
local or regional BI-organization (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a CRO with which the responsibilities and tasks will have 
been agreed and a written contract filed before initiation of the clinical trial.
Individual and aggregated safety data will be reviewed in a masked fashion by members of 
the BI trial team in Medical Quality Review Meetings at regular intervals to determine the 
safety profile according to the sponsor’s SOPs. 
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organize, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, a central imaging reading center, a central ECG service provider 
and an IRT vendor will be used in this trial. Details will be provided in the respective 
manuals, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P12-13318
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Kozousek V, Lam WC, Maberley DAL. Canadian Ophthalmological 
Society evidence-based clinical practice guidelines for the management of 
diabetic retinopathy. Can J Ophthalmol 2012;47(2)(Suppl 1):S1-S30
R10-4848
Common terminology criteria for adverse events (CTCAE): version 4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010). 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
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R12-1768
Yau JWY, et al, Meta-Analysis for Eye Disease (Meta-Eye) Study Group. 
Global prevalence and major risk factors of diabetic retinopathy. Diabetes 
Care 2012;35:556-564.
R15-1862
Inoue T, Morita M, Tojo T, Yoshihara K, Nagashima A, Morimoto A, et al.  
Synthesis and SAR study of new thiazole derivatives as vascular adhesion 
protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema. 
Bioorg Med Chem 2013;21(5):1219-1233.
R15-1863 
Inoue T, Morita M, Tojo T, Nagashima A, Moritomo A, Miyake H. Novel
1H-imidazol-2-amine derivatives as potent and orally active vascular 
adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema 
treatment. Bioorg Med Chem 2013;21(13):3873-3881.
R15-1868 
Foot JS, Deodhar M, Turner CI, Yin P, Dam EM van, Silva DG, et al. The 
discovery and development of selective 3-fluoro-4-aryloxyallylamine 
inhibitors of the amine oxidase activity of semicarbazide-sensitive amine 
oxidase/vascular adhesion protein-1 (SSAO/VAP-1). Bioorg Med Chem 
Lett 2012;22(12):3935-3940.
R15-2803 
Stolen CM, Marttila-Ichihara F, Koskinen K, Yegutkin GG, Turja R, Bono 
P, et al. Absence of the endothelial oxidase AOC3 leads to abnormal 
leukocyte traffic in vivo. Immunity 2005;22(1):105-115.
R15-5225
Diabetic Retinopathy Clinical Research Network. Aflibercept, 
bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 
2015;372(13):1193-1203.


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R15-5654 
Koskinen K, Vainio PJ, Smith DJ, Pihlavisto M, Yla-Herttula S, Jalkanen S, 
et al. Granulocyte transmigration through the endothelium is regulated by 
the oxidase activity of vascular adhesion protein-1 (VAP-1). Blood 
2004;103(9):3388-3395.
R15-5787
Murata M, Noda K, Fukuhara J, Kanda A, Kase S, Saito W, et al. Soluble 
vascular adhesion protein-1 accumulates in proliferative diabetic 
retinopathy. Invest Ophthalmol Vis Sci 2012;53(7):4055-4062.
R15-5788
Weston CJ, Adams DH. Hepatic consequences of vascular adhesion 
protein-1 expression. J Neural Transm 2011;118:1055-1064.
R15-6045 
Marttila-Ichihara F, Smith DJ, Stolen C, Yegutkin GG, Elima K, Mercier N,  
et al. Vascular amine oxidases are needed for leukocyte extravasation into 
inflamed joints in vivo. Arthritis Rheum 2006;54(9):2852-2862.
R15-6047 
Salter-Cid LM, Wang E, O’Rourke AM, Miller A, Gao H, Huang L, et al. 
Anti-inflammatory effects of inhibiting the amine oxidase activity of 
semicarbazide-sensitive amine oxidase. J Pharmacol Exp Ther 
2005;315(2):553-562.
R15-6048 
Xu HL, Salter-Cid L, Linnik MD, Wang EY, Paisansathan C, Pelligrino 
DA. Vascular adhesion protein-1 plays an important role in postischemic 
inflammation and neuropathology in diabetic, estrogen-treated 
ovariectomized female rats subjected to transient forebrain ischemia. J 
Pharmacol Exp Ther 2006;317(1):19-29.
R15-6056 
O’Rourke AM, Wang EY, Miller A, Podar EM, Scheyhing K, Huang L, et 
al. Anti-inflammatory effects of LJP 1586 [Z-3-fluoro-2-(4-
methoxybenzyl)allylamine hydrochloride], an amine-based inhibitor of 
semicarbazide-sensitive amine oxidase activity. J Pharmacol Exp Ther 
2008;324(2):867-875.
R15-6058 
Merinen M, Irjala H, Salmi M, Jaakkola I, Hanninen A, Jalkanen S. 
Vascular adhesion protein-1 is involved in both acute and chronic 
inflammation in the mouse. Am J Pathol 2005;166(3):793-800.
R15-6059 
Lee WY, Salmi M, Kelly MM, Jalkanen S, Kubes P. Therapeutic advantage 
of anti-VAP-1over anti-α4 integrin antibody in concanavalin A-induced 
hepatitis. Hepatology 2013;58(4):1413-1423.
R15-6139
Lyles GA. Mammalian plasma and tissue-bound semicarbazide sensitive 
amine oxidase: biochemical, pharmacological and toxicological aspects. Int 
J Biochem Cell Biol 1996;28(3):259-274.


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R16-3206
Centers for Disease Control and Prevention (CDC). National diabetes 
statistics report: estimates of diabetes and its burden in the United States, 
2014. https://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-
report-web.pdf (access date: 14 July 2016); Atlanta: U.S. Department of 
Health and Human Services; 2014.
R16-4703
International Diabetes Federation (IDF). IDF diabetes atlas.  
http://www.diabetesatlas.org/ (access date: 29 September 2016); 7th ed. 
Brussels: International Diabetes Federation (IDF); 2015.
R16-5320
Yoshikawa N, Noda K, Ozawa Y, Tsubota K, Mashima Y, Ishida S. 
Blockade of vascular adhesion protein-1 attenuates choroidal 
neovascularization. Mol Vision 2012;18:593-600.
R17-0293
Writing Committee for the Diabetic Retinopathy Clinical Research 
Network. Panretinal photocoagulation vs intravitreous ranibizumab for 
proliferative diabetic retinopathy: a randomized clinical trial. JAMA 
2015;314(20):2137-2146.
R17-0333
Roy S, Kern TS, Song B, Stuebe C. Mechanistic insights into pathological  
changes in the diabetic retina: implications for targeting diabetic  
retinopathy. Am J Pathol 2017;187(1):9-19.
R17-0367
Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al, 
RIDE and RISE Research Group. Long-term outcomes of ranibizumab 
therapy for diabetic macular edema: the 36-month results from two phase 
III trials: RISE and RIDE. Ophthalmology (Rochester) 2013;120(10): 2013-
2022.
R17-0368
Diabetic retinopathy guidelines (December 2012) (update to Section 14.3.4 
in July 2013 in accordance with 'College Statement on Intravitreal 
Injections').
http://www.academia.edu/9407834/The_Royal_College_of_Ophthalmologi
sts_Diabetic_Retinopathy_Guidelines (access date: 1 February 2017); 
London: Royal College of Ophthalmologists; 2013.
R17-1786
Mashima Y, Kurono N, Yoshikawa N, inventors, R-Tech Ueno, applicant. 
Composition for ophthalmic disease associated with hypoxia or ischemia 
(European patent application, EP 2 599 498 A1, date of publication: 
05.06.2013, application number: 13157478.2). European Patent Office; 
2013.
R17-1787
Almulki L, Noda K, Nakao S, Hisatomi T, Thomas KL, Hafezi-Moghadam 
A. Localization of vascular adhesion protein-1 (VAP-1) in the human eye. 
Exp Eye Res 2010;90:26-32.


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R17-1803
Final report summary - EUROCONDOR (European Consortium for the 
Early Treatment of Diabetic Retinopathy) (last updated on 2016-10-07).  
http://cordis.europa.eu/result/rcn/189871_en.html (access date: 18 May 
2017); European Union, European Commission; 2016.
R17-1872
Analysis dataset from the four year adolescent retinopathy paper.  
https://www.niddkrepository.org/studies/edic/4-year-adolescent/ (access 
date: 18 May 2017); National Institute of Diabetes and Digestive and 
Kidney Diseases (NIDDK); 2007.
9.2
UNPUBLISHED REFERENCES
c04751792-04
BI 1467335 Investigator's Brochure Version No. 4. 27 March 2017.
c09036683-01
Single ascending dose and multiple ascending dose Phase 1 study of PXS-
4728A administered orally in healthy adult males. PXS-4728A-101. 13 Nov 
2015.
n00254459
Effects of BI 1467335 on retinal function in the STZ-induced diabetic rat 
model
n00252630
Efficacy of AOC3 inhibitor BI 1467335 in a mouse model of oxygen 
induced retinopathy (OIR)
n00257993
In vitro inhibition of MAO-A and MAO-B catalyzed kynuramine
deamination by BI 1467335. 31 Aug 2017.
n00259383
Irreversible in vitro inhibition of MAO-B catalyzed kynuramine
deamination by BI 1467335. 01 December 2017. 


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10.3
THE DIABETIC RETINOPATHY SEVERITY SCALE (DRSS)
The DRSS from the Early Treatment Diabetic Retinopathy Study (ETDRS) will be used for 
the assessment of the level of DR by the Central Reading Center [R17-1872]. 
Table 10.3: 1
The DRSS for individual eye
Level
Severity
Definition
10
No retinopathy
Diabetic retinopathy absent
20
Very mild NPDR
Microaneurysms only
35
Mild NPDR
Hard exudates, cotton-wool spots, and/or mild retinal 
hemorrhages
43
Moderate NPDR
43A Retinal hemorrhages moderate (>photograph 1) in four 
quadrants or severe (≥photograph 2A) in one quadrant
43B Mild IRMA (<photograph 8A) in one to three quadrants
47
Moderate NPDR
47A Both level 43 characteristics
47B Mild IRMA in four quadrants
47C Severe retinal hemorrhages in two to three quadrants
47D Venous beading in one quadrant
53
Severe NPDR
53A ≥2 level 47 characteristics
53B Severe retinal hemorrhages in four quadrants
53C Moderate to severe IRMA (≥photograph 8A) in at least one 
quadrant
53D Venous beading in at least two quadrants
53E ≥2 level 53A-D characteristics
61
Mild PDR
New vessels elsewhere < 0.5 disc area in one or more quadrants
65
Moderate PDR
65A New vessels elsewhere ≥ 0.5 disc area in one or more 
quadrants
65B New vessels disc <photograph 10A 
71, 75
High-risk PDR
New vessels disc ≥photograph 10A, or New vessels disc 
<photograph 10A or New vessels elsewhere ≥0.5 disc area plus 
vitreous hemorrhage or preretinal hemorrhage, or vitreous 
hemorrhage or preretinal hemorrhage obscuring ≥1 disc area
81, 85
Advanced PDR
Fundus partially obscured by vitreous hemorrhage and either new 
vessels not gradable or retina detached at the center of the macula


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
18 Jan 2018
EudraCT number
EU number
2016-002971-91
BI Trial number
1386.12
BI Investigational Product(s)
BI 1467335
Title of protocol
A randomized, double-masked, placebo-controlled 
exploratory study to evaluate safety, tolerability, 
pharmacodynamics and pharmacokinetics of orally 
administered BI 1467335 for 12 weeks with a 12 
week follow up period in patients with non-
proliferative diabetic retinopathy without center-
involved diabetic macular edema
To be implemented only after approval of the IRB / IEC / Competent 
Authorities

To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval

Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only

Section to be changed
TITLE PAGE
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
Study title was updated to add ROBIN study name
Rationale for change
ROBIN was selected as a study name
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Statistical methods
7.3.2
Secondary endpoint analyses
Description of change
Added descriptive analysis of secondary efficacy 
endpoint.
Rationale for change
Add alternate secondary efficacy analysis since too 
few events may be observed in a study of this size 
to allow adequate statistical modelling.
Section to be changed
1.4
BENEFIT - RISK ASSESSMENT
3.3.4.1 Withdrawal from trial treatment
Description of change
 
 


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Rationale for change
Request from Health authorities
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS 
3.3.2
Inclusion criteria
Description of change
Removal of upper age limit in IN#1
Rationale for change
Request from Health authorities
Section to be changed
3.3.2
Inclusion criteria
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Removal of diabetic treatment restrictions from 
IN#3
Removal of restriction of starting new insulin 
therapy from section 4.2.2.1
Rationale for change
Request from Health authorities
Section to be changed
3.3.2
Inclusion criteria
Description of change
Changing HbA1c inclusion criteria ion IN #4 from 
10% to 12%
Rationale for change
To allow inclusion of additional patients since 
diabetic treatment restriction was removed
Section to be changed
3.3.3
Exclusion criteria
Description of change
Addition of cataract surgery exclusion criteria  in 
EX#1
Rationale for change
Request from Health authorities
Section to be changed
3.3.3
Exclusion criteria
Description of change
Addition ‘suspected’ infections as exclusion 
criteria in EX#15
Rationale for change
Request from Health authorities
Section to be changed
3.3.4.1 Withdrawal from trial treatment
Description of change
Additional criteria for patient withdrawal based on 
change in QTc
Rationale for change
Request from Health authorities
Section to be changed
6.2.1
Screening and run-in period(s)
Description of change
The following sentence was added in the Re-
Screening paragraph:
Patients can also be re-screened if they screen 
failed due to inclusion/exclusion criteria that has 
been changed in the current version of the protocol.
Rationale for change
To allow re-screening of patients due to change in 
inclusion/exclusion criteria.


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Section to be changed
FLOW CHART, footnote #14
1.2
DRUG PROFILE
4.1.4.2 Trial medication administration at days 
without site visits
6.1
VISIT SCHEDULE
6.2.2
Treatment period(s)
 
 
Section to be changed
4.1.5.1 Masking
7.4
INTERIM ANALYSES
Description of change
Allow trial and project team members not involved 
with study conduct to be unmasked for the interim 
analysis.
Rationale for change
Allow specific trial and project team members to 
assist with interim PK/PD analysis.
Section to be changed
5.3.2
Methods of sample collection
Description of change
 
Rationale for change
Error in the protocol.
Section to be changed
Title page
Description of change
‘BI Investigational Product’ changed to ‘BI 
Investigational Medicinal Product’
Rationale for change
New sponsor protocol template
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
New Trial rationale section added
‘Objective(s)’ changed to ‘Trial objective(s)’
‘Methodology’ changed to ‘Trial design’
‘Number of patients entered’ changed to ‘Number 
of patients randomized’
Rationale for change
New sponsor protocol template
Section to be changed
FLOW CHART
Description of change
‘Adverse events’ changed to ‘All AEs/SAEs/AESIs 
21’ and corresponding footnote added
Rationale for change
New sponsor protocol template
Section to be changed
1.3
RATIONALE FOR PERFORMING THE 
TRIAL
Description of change
Some text modifications in the last paragraph


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Rationale for change
New sponsor protocol template
Section to be changed
3.3
SELECTION OF TRIAL POPULATION
Description of change
Last sentence was added
Rationale for change
New sponsor protocol template
Section to be changed
3.3.2
Inclusion criteria
Description of change
‘Full’ age changed to ‘legal’ age in IN#1
Rationale for change
New sponsor protocol template
Section to be changed
3.3.4
Withdrawal of patients from therapy or 
assessments
Description of change
Last sentence added
Rationale for change
New sponsor protocol template
Section to be changed
3.3.4.2 Withdrawal of consent for trial participation
Description of change
Last sentence modified to say: 
If a patient wants to withdraw consent, the 
investigator should be involved in the discussion 
with the patient and explain the difference …
Rationale for change
New sponsor protocol template
Section to be changed
4.1.2
Selection of doses in the trial and dose 
modifications
Description of change
Section title changed 
Rationale for change
New sponsor protocol template
Section to be changed
4.2.2.3 Contraception requirements
Description of change
Section tile changed from ‘Restrictions regarding 
women of childbearing potential’ to ‘Contraception 
requirements’
Rationale for change
New sponsor protocol template
Section to be changed
4.3
TREATMENT COMPLIANCE
Description of change
‘as directed by the investigator’ was added to the 
formula for treatment compliance
Rationale for change
New sponsor protocol template
Section to be changed
5.2.4
Electrocardiogram
Description of change
Text that ECGs shoud be performed by a qualified 
technologist’’ was added in the first paragraph.
Rationale for change
New sponsor protocol template
Section to be changed
5.2.6.1 Definitions of AEs
Description of change
Numbering of subsections was added
Rationale for change
New sponsor protocol template


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Section to be changed
5.2.6.1.1
Adverse event
Description of change
Last two paragraphs were added
Rationale for change
New sponsor protocol template
Section to be changed
5.2.6.2 Adverse event collection and reporting
Description of change
Numbering of subsections was added
Rationale for change
New sponsor protocol template
Section to be changed
5.2.6.2.1
AE Collection
Description of change
Figure 5.2.6.2:1 was deleted
Rationale for change
New sponsor protocol template
Section to be changed
5.4
ASSESSMENT OF BIOMARKER(S)
5.5
BIOBANKING
5.6
OTHER ASSESSMENTS
5.7
APPROPRIATENESS OF 
MEASUREMENTS
Description of change
Sections are renumbered without change in the text
Rationale for change
New sponsor protocol template
Section to be changed
8.
INFORMED CONSENT, TRIAL 
RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
Description of change
Last sentence in the first paragraph was added.
Rationale for change
New sponsor protocol template
Section to be changed
8.2
DATA QUALITY ASSURANCE
Description of change
First paragraph was added
Rationale for change
New sponsor protocol template


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11.2
GLOBAL AMENDMENT 2
Date of amendment
20 Mar 2018
EudraCT number
EU number
2016-002971-91
BI Trial number
1386.12
BI Investigational Product(s)
BI 1467335
Title of protocol
A Randomized, double-masked, placebo-controlled 
exploratory study to evaluate safety, tolerability, 
pharmacodynamics and pharmacokinetics of Orally 
administered BI 1467335 for 12 weeks with a 12 
week follow up period in patients with Non-
proliferative diabetic retinopathy without center-
involved diabetic macular edema (ROBIN study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities

To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
The immediate actions were implemented in the context of a Dear Investigator Letter 
dated 6 Mar 2018. IRB / IEC / Competent Authorities have been informed.
The changes due to this measure are contained in protocol sections 1.2, 2.3, 3.3.3 and 
4.2.2.

Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only

Section to be changed
1.2
DRUG PROFILE
Description of change
Non-clinical safety 
 
 
 
 
 
 
 
 
 
 
 
Section to be changed
1.4
BENEFIT - RISK ASSESSMENT
Description of change
The following text was added:


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Section to be changed
3.3.3
Exclusion criteria
Description of change
EX#7 was modified
Rationale for change
More detailed list of drugs excluded due to 
potential MAO-B inhibition was added to Section 
4.2.2.1.
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
First two paragraphs were added with additional 
restricted medications, both as exclusion criteria 
during screening and as prohibited medication 
during the trial 
Rationale for change
BI 1467335 demonstrated in vitro to be an 
irreversible inhibitor of MAO-B.
Section to be changed
4.2.2.2 Restrictions on diet and life style
Description of change
The following text was added:
Patients should avoid consuming food that contains 
very large amounts of tyramine, such as: 
• Aged cheese
• Aged meats
• Soybean products (Soy sauce)
• Red wine
• Tap (draft) beer
• St John’s Wort
• Pickled herring
• Sauerkraut (fermented cabbage)
• Tryptophan supplements
Rationale for change
BI 1467335 demonstrated in vitro to be an 
irreversible inhibitor of MAO-B.
Section to be changed
9.2
UNPUBLISHED REFERENCES
Description of change
References n00257993 and n00259383 were added.
Rationale for change
References for the new text that was added in the 


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Section 1.2
Section to be changed
3.3.3
Exclusion criteria
Description of change
IN #2 was modified to add “or Heidelberg OCT”
Rationale for change
To allow the use of Heidelberg OCT device.
Section to be changed
5.1
ASSESSMENT OF EFFICACY
Description of change
 
 
 
 
 
 
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Anti-VEGF injection treatment either in the study 
eye or in the fellow eye is not allowed to be given 
in addition to the trial drug during the trial. If anti-
VEGF intravitreal treatment …
was changed to
Anti-VEGF injection treatment with aflibercept 
(Eylea®) or ranibizumab (Lucentis®) in the study 
eye is not allowed to be given in addition to the 
trial drug during the trial. Use of bevacizumab 
(Avastin®) is not allowed in either the study eye or 
in the fellow eye. If the prohibited anti-VEGF 
intravitreal treatment …
Rationale for change
To allow treatment with aflibercept (Eylea®) or 
ranibizumab (Lucentis®) in the fellow eye during 
the trial.
Section to be changed
3.3.4.1 Withdrawal from trial treatment
Description of change
… change from baseline (Visit 2) > 60 ms.


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was changed to:
… change from Visit 1 > 60 ms.
Rationale for change
Correction in the protocol. For ECG, the baseline is 
Visit 1.
Section to be changed
4.1.5.1 Masking
Description of change
… member of the independent team in preparation 
for interim PK/PD analysis.
was changed to:
… member of the team conducting the interim 
PK/PD analysis.
Rationale for change
Correction in the protocol.
Section to be changed
4.3
TREATMENT COMPLIANCE
Description of change
If the number of doses taken is not between 80-
120%, …
was changed to:
If the treatment compliance is not between 80-
120%, …
Rationale for change
Correction in the protocol.


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11.3
GLOBAL AMENDMENT 3
Date of amendment
01 Aug 2018
EudraCT number
EU number
2016-002971-91
BI Trial number
1386.12
BI Investigational Product(s)
BI 1467335
Title of protocol
A Randomized, double-masked, placebo-controlled 
exploratory study to evaluate safety, tolerability, 
pharmacodynamics and pharmacokinetics of Orally 
administered BI 1467335 for 12 weeks with a 12 
week follow up period in patients with Non-
proliferative diabetic retinopathy without center-
involved diabetic macular edema (ROBIN study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities

To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval

Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only

Section to be changed
FLOW CHART
Description of change
Footnote 21 was added
Rationale for change
Based on the screen failures observed so far, 
majority of patients screen failed due to DRSS 
grading. Screening visit should be performed in 
two visits. Fundus photography would be 
performed first. If patient is eligible based on the 
DRSS grading, the rest of the screening will be 
performed. Splitting the screening would reduce 
burden of performing the remaining screening 
procedures for patients who fail DRSS grading. 
Section to be changed
3.1
OVERALL TRIAL DESIGN AND PLAN
Description of change
The following text was added:
Due to high probability of patients screen failing 
due to DRSS grading on fundus photography, 
screening should be performed in two parts. 
Fundus photography should be performed first, and 
if patients are eligible based on the fundus 
photography results, patients should return to 
complete the rest of the screening examinations. In 
case of scheduling difficulty for certain patients, 
screening can be performed in one visit.
Rationale for change
See above for splitting screening visit


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Section to be changed
6.2.1
Screening and run-in period(s)
Description of change
Screening Period
The following text was added:
Screening visit should be performed in two visits. 
After Informed consent is obtained, fundus 
photography should be performed and sent to 
central reading service. If patient is eligible based 
on the DRSS grading, the patient should return to 
complete the rest of the screening. In case of 
scheduling difficulty for certain patients, screening 
can be performed in one visit. If screening is done 
as one visit, fundus photography should be 
performed in line with other ophthalmological 
examinations.
Rationale for change
See above for splitting screening visit
Section to be changed
1.4
BENEFIT - RISK ASSESSMENT
Description of change
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale for change
Clarification regarding food and diet precaution


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Section to be changed
4.2.2
Restrictions
Description of change
Section title was changed to:
4.2.2
Restrictions, warnings and precautions
Rationale for change
Clarification regarding food and diet precaution
Section to be changed
4.2.2.2 Restrictions on diet and life style
Description of change
Section title was changed to:
4.2.2.2 Precautions on diet and life style
Patients should avoid consuming food that contains 
very large amounts of tyramine, such as …
was changed to:
Patients should be advised to avoid the 
consumption of large amounts of tyramine-rich 
food while taking BI 1467335, such as …

Tap (draft) beer
was changed to:

Beer

Yeast products
Rationale for change
Clarification regarding food and diet precaution
Section to be changed
ABBREVIATIONS
Description of change
Following abbreviation was added:
RIMA Reversible inhibitor of MAO-A
Rationale for change
New abbreviation in the protocol
Section to be changed
FLOW CHART footnote 8
Description of change
At visits without medication administration 12-lead 
ECG …
was changed to:
At screening and follow-up visits 12-lead ECG …
Rationale for change
Clarification
Section to be changed
FLOW CHART
Description of change
“Substance use” line and the corresponding 
footnote were added
Rationale for change
Substance use was described in the protocol and 
included in the CRFs. It was added in the FLOW 
CHART for clarity.
Section to be changed
3.3.3
Exclusion criteria
Description of change
2. Active center-involved DME (CI-DME) on 
clinical examination and OCT central subfield 
thickness above 300 µm in the study eye, as 
measured by Optovue OCT or Heidelberg OCT.


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was changed to:
2. Active center-involved DME (CI-DME) on 
clinical examination and OCT central subfield 
thickness in the study eye above 300 µm as 
measured by Optovue OCT or above 320 µm as 
measured by Heidelberg OCT.
Rationale for change
Update for Heidelberg OCT cut-off.
Section to be changed
6.2.1
Screening and run-in period(s)
Description of change
… caffeine consumption and tobacco use.
was changed to:
… caffeine and alcohol consumption and tobacco 
use.
Rationale for change
Clarification
Section to be changed
6.2.2
Treatment period(s)
Description of change
... patients are asked about their caffeine 
consumption …
was changed to:
… patients are asked about their alcohol and 
caffeine consumption …
Rationale for change
Clarification
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Several drug names were corrected
Rationale for change
Errors in the previous protocol version
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
 
Rationale for change
 
Section to be changed
4.2.2.4 Restrictions regarding gamete donation
Description of change
Section 4.2.2.4 was added
Rationale for change
 
Section to be changed
3.3.1.1 Study eye criteria
Description of change
… the eye with the higher (=worse) DRSS level at 
screening will qualify for the study eye; the fellow 
eye will not be enrolled into the analysis of the key 


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secondary endpoint.
was changed to:
… the eye with the higher (=worse) DRSS level at 
screening will qualify for the study eye;
Rationale for change
Clarification
Section to be changed
4.1.5.1 Masking
Description of change
Access to unmasked data …
was changed to:
If a planned interim PK/PD analysis is conducted, 
access to unmasked data …
Rationale for change
Clarification regarding interim analysis
Section to be changed
7.4
INTERIM ANALYSES
Description of change
An interim PK/PD analysis will be performed …
was changed to:
An interim PK/PD analysis may be performed …
Rationale for change
Clarification regarding interim analysis
Section to be changed
5.3.4
Pharmacokinetic – pharmacodynamic 
relationship
Description of change
The pharmacokinetics of BI 1467335 will be 
investigated …
was changed to:
The pharmacokinetics of BI 1467335 may be 
investigated …
… a pharmacometric PK/PD analysis will be 
performed …
was changed to:
… a pharmacometric PK/PD analysis may be 
performed …
Rationale for change
 
 
 
Rationale for change
Clarification
Section to be changed
6.2.1
Screening and run-in period(s)


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Description of change
Re-Screening
Patients who do not fulfil all of the eligibility 
criteria for a reason that later resolves and all 
eligibility criteria can be met within a 12-week 
period after initial screening visit, can be re-
screened up to one time.
was changed to:
Patients who do not fulfil all of the eligibility 
criteria for a reason that later resolves and all 
eligibility criteria can be met, can be re-screened up 
to one time.
Rationale for change
To allow more flexibility in re-screening
Section to be changed
7.3.5
Pharmacokinetic and pharmacodynamic 
analyses
Description of change
 
 
 
Rationale for change
Clarification
Section to be changed
7.5
HANDLING OF MISSING DATA
Description of change
Rules for handling missing data are outlined in the 
BI SOP mention in section 10.1.
was changed to:
Rules for handling missing data are outlined in BI 
SOP. 
Rationale for change
Clarification
Section to be changed
10.1
PHARMACOKINETIC ANALYSES
Description of change
 
 
 
Rationale for change
Clarification


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11.4
GLOBAL AMENDMENT 4
Date of amendment
11 Apr 2019
EudraCT number
EU number
2016-002971-91
BI Trial number
1386.12
BI Investigational Product(s)
BI 1467335
Title of protocol
A Randomized, double-masked, placebo-controlled 
exploratory study to evaluate safety, tolerability, 
pharmacodynamics and pharmacokinetics of Orally 
administered BI 1467335 for 12 weeks with a 12 
week follow up period in patients with Non-
proliferative diabetic retinopathy without center-
involved diabetic macular edema (ROBIN study)
Global Amendment due to urgent safety reasons

Global Amendment

Section to be changed
FLOW CHART
4.1.4.1 Trial medication administration at the study 
site
5.3.1
Assessment of pharmacokinetics
5.3.2
Methods of sample collection
6.2.2
Treatment period(s)
10.2
TIME SCHEDULE FOR BI 1467335 
PHARMACOKINETIC (PK), PK METABOLITE 
(M) AND PHARMACODYNAMIC (PD) BLOOD 
SAMPLING
Description of change
 
 
 
 
 
 
 
 
 
Section to be changed
FLOW CHART
Description of change
Footnote 23 added
Rationale for change
To clarify rescreening and retesting procedures at 
screening


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Section to be changed
FLOW CHART
Description of change
 
Rationale for change
Section to be changed
FLOW CHART
5.2.5.1 Ocular safety parameters
6.1
VISIT SCHEDULE
Description of change
Reference to Section 3.3.3 exclusion criterion #4
added to the description of gonioscopy procedure.
The flowing sentence was added to Flow chart 
footnote 9 and Section 6.1:
“Goniscopy can also be performed before dilation, 
if preferred by the investigator.”
Rationale for change
Clarification when gonioscopy should be 
performed.
Section to be changed
ABBREVIATIONS
3.3.3
Exclusion criteria
3.3.4.1 Withdrawal from trial treatment
Description of change
Specification of QTcF formula
Rationale for change
Clarification that QTcF formula is being used for 
QTc assessments
Section to be changed
3.3.3
Exclusion criteria
Description of change
EX#1 – ‘in the study eye’ added to cataract surgery 
language
Rationale for change
Clarification that exclusion related to cataract 
surgery applies to the study eye.
Section to be changed
3.3.3
Exclusion criteria
Description of change
EX#6 was changed to:
“Treatment of either CI-DME or DR, with …”
Rationale for change
Clarification
Section to be changed
FLOW CHART
 
 
 
 


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Rationale for change
To emphasize additional information collected for 
ocular events. This is not a new requirement in the 
protocol or CRFs. 
Section to be changed
6.2.1
Screening and run-in period(s)
Description of change
Laboratory testing may be repeated …
was changed to 
Screening evaluations may be repeated …
Rationale for change
Clarification that all screening evaluations can be 
repeated not just laboratory testing
Section to be changed
7.3.2
Secondary endpoint analyses
Description of change
The following sentence was deleted:
A sensitivity analysis may be performed excluding 
observations obtained after the start of rescue 
medication.
Rationale for change
Such sensitivity analysis cannot be performed since 
there is no defined rescue medication.
Section to be changed
FLOW CHART
6.2.2
Treatment period(s)
Description of change
 
 
 
 
 
 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c14141887
5.0
clinical-trial-protocol-version-5
A Randomized, double-masked, placebo-controlled exploratory study to evaluate
safety, tolerability, pharmacodynamics and pharmacokinetics of Orally administered
BI 1467335 for 12 weeks with a 12 week follow up period in patients with
Non-proliferative diabetic retinopathy without center-involved diabetic macular
edema (ROBIN study)
Author-Clinical Trial Leader
12 Apr 2019 18:12 CEST
Approval-Team Member Medicine
12 Apr 2019 20:58 CEST
Approval-Clinical Pharmacokinetics
15 Apr 2019 09:45 CEST
Author-Trial Statistician
15 Apr 2019 19:25 CEST
Approval-Therapeutic Area 
16 Apr 2019 08:27 CEST
Verification-Paper Signature
Completion
18 Apr 2019 19:18 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c14141887
5.0

SAP_001.pdf: 
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TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c30324615-01
BI Trial No.:
1386-0012
Title:
A randomized, double-masked, placebo-controlled exploratory 
study to evaluate safety, tolerability, pharmacodynamics and 
pharmacokinetics of orally administered BI 1467335 for 12 weeks 
with 12 week follow up period in patients with non-proliferative 
diabetic retinopathy without center-involved diabetic macular 
edema
Including Protocol Amendment 1 [c14141887-02], Amendment 2 
[c14141887-03], Amendment 3 [c14141887-04], and Amendment 
4 [c14141887-05]
Investigational
Product(s):
BI 1467335
Responsible trial 
statistician(s):
Email:
Date of statistical 
analysis plan:
29 JUN 2020 SIGNED
Version:
1
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2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINT(S).....................................................................................................13
5.1
PRIMARY ENDPOINT(S) ................................................................................13
5.2
SECONDARY ENDPOINT(S) ..........................................................................13
5.2.1
Key secondary endpoint(s).................................................................................13
5.2.2
Secondary endpoint(s) ........................................................................................13
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................20
6.1
TREATMENT(S)................................................................................................20
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................20
6.3
PATIENT SETS ANALYSED...........................................................................23
6.5
POOLING OF CENTRES .................................................................................24
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................25
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................25
7.
PLANNED ANALYSIS......................................................................................29
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........30
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................30
7.3
TREATMENT COMPLIANCE........................................................................31
7.4
PRIMARY ENDPOINT(S) ................................................................................31
7.5
SECONDARY ENDPOINT(S) ..........................................................................31
7.5.1
Key secondary endpoint(s).................................................................................31
7.5.2
Secondary endpoint(s) ........................................................................................31
7.7
EXTENT OF EXPOSURE.................................................................................45
7.8
SAFETY ANALYSIS..........................................................................................45
7.8.1
Adverse events.....................................................................................................45
7.8.2
Laboratory data ..................................................................................................47
7.8.3
Vital signs.............................................................................................................48
7.8.4
ECG......................................................................................................................48
7.8.5
Others...................................................................................................................49


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8.
REFERENCES....................................................................................................50
10.
HISTORY TABLE..............................................................................................54


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LIST OF TABLES
Table 5.2.2: 1 Diabetic Retinopathy Severity Score (DRSS) levels – individual eye.............13
Table 6.1: 1
Treatment descriptions.....................................................................................20
Table 6.1: 2
Trial periods .....................................................................................................20
Table 6.2: 1
Important protocol violations...........................................................................21
Table 6.3: 1
Patient sets analyzed.........................................................................................24
Table 6.7: 1
Visit intervals for efficacy endpoints ...............................................................26
Table 6.7: 2
Visit intervals for ECG, vital signs, and laboratory data .................................27
Table 6.7: 3
Visit intervals for vital signs and laboratory data for patients from sites in 
Spain only.........................................................................................................28
Table 10: 1
History table .....................................................................................................54


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
AOC3
Amine oxidase copper-containing 3
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical classification
BCVA
Best corrected visual acuity
BI
Boehringer Ingelheim
BP
Blood pressure
BRPM
Blinded report planning meeting
CARE
Clinical data Analysis and Reporting Environment
CI-DME
Center-involved diabetic macular edema
CT
Concomitant therapy
CTC
Common Terminology Criteria 
CTMS
Clinical Trial Management System
CTP
Clinical trial protocol
CTR
Clinical trial report
DBLM
Database lock meeting
DBP
Diastolic blood pressure
DR
Diabetic retinopathy
DRSS
Diabetic Retinopathy Severity Score
ECG
Electrocardiogram
ECGS
ECG analysis set
EOT
End of treatment
ETDRS
Early Treatment Diabetic Retinopathy Study
EudraCT
European clinical trials database


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Term
Definition / description
FAS
Full analysis set
FP
Fundus photography
HR
Heart rate in beats per minute
ICH
International Conference on Harmonization
iPD
Important protocol deviation
LLT
Lower level term
MedDRA
Medical Dictionary for Regulatory Affairs
Max
Maximum
Min
Minimum
MMRM
Mixed effects model for repeated measures
MQRM
Medical quality review meeting
NPDR
Non-proliferative diabetic retinopathy
OD
Oculus dexter; right eye
OS
Oculus sinister; left eye
OU
Oculus uterque, both eyes
PD
Protocol deviation
PPS
Per-protocol set
PR interval
ECG interval from onset of P wave to the beginning of QRS
PT
Preferred term
Q1
Lower Quartile
Q3
Upper Quartile
QRS complex
ECG term; combination of Q, R and S waves
QT interval
ECG interval from beginning of QRS complex to the end of the T wave
QTcB [msec]
QT interval, heart rate corrected per Bazetts formula
QTcF [msec]
QT interval, heart rate corrected per Fridericias formula
RAGe
Report Appendix Generator system


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Term
Definition / description
REP
Residual effect period
RPM
Report Planning Meeting; formerly known as BRPM
RR interval
ECG interval from peak of an R wave to the peak of the subsequent R wave
RS
Randomized set
SAE
Serious adverse event
SBP
Systolic blood pressure
SD
Standard deviation
SMQ
Standardized MedDRA query
SOC
System organ class
SS
Screened set
TMW
Trial medical writer
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing this statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol
Amendments. In particular, the TSAP is based on the planned analysis specification as
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore,
TSAP readers may consult the CTP for more background information on the study, e.g., on
study objectives, study design and population, treatments, definition of measurements and
variables, planning of sample size, randomization.
Study data will be stored in a trial database within the Medidata RAVE (BRAVE) system.
The statistical analyses will be performed within the validated working environment CARE
(Clinical data Analysis and Reporting Environment), including SASTM (current Version 9.4,
by SAS Institute Inc., Cary, NC, USA), and a number of SASTM-based tools (e.g., macros or 
the analyses of adverse event (AE) data or laboratory data; Report Appendix Generator
system (RAGe) for compilation/formatting of the clinical trial report (CTR) appendices).
 
 
 
 


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Secondary endpoint: 2-step improvement from baseline in DRSS
Version 1.0 of the CTP stated that a logistic regression model adjusted for treatment and 
baseline visual acuity will be used to analyze the secondary endpoint of the proportion of 
patients with at least a 2-step improvement from baseline in DRSS at week 12. However, in 
this Phase IIa study of 100 patients, a 2-step improvement from baseline in DRSS is likely to 
be observed in no more than 3 patients. Given the limited amount of data expected to be 
available for this endpoint, these data will be summarized as the frequency and percentage of 
patients with improvement from baseline of 2 steps or more. Logistic regression analyses 
may be performed as exploratory analyses if a sufficient number of events are observed.
The description of this secondary endpoint analysis was clarified in version 2.0 of the CTP
dated 18JAN2018.
Definition of Full Analysis Set (FAS)
The FAS definition will be generalized to include all subjects in the treated set who have a 
baseline and at least one post-baseline measurement for either DRSS or BCVA. Individual 
analyses will include only subjects with baseline and post-baseline measurements for the 
specific endpoint being analyzed.
 
 
Protocol deviations
Per “Identify and manage important protocol deviations”(001-MCS-40-413, current version
(4)), the term important protocol deviations will be used for trial reporting instead of 
important protocol violations.
 
 


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Assessment of COVID-19 Impact
Site disruption due to the COVID-19 pandemic in 2020 had the potential to impact trial visits 
for several patients prior to database lock. To assess the impact of the pandemic on this trial, 
several additional data summaries are planned. The proportion of patients completing 
treatment prior to 01MAR2020, the proportion of patients completing the trial (Week 24 or 
early discontinuation) before 01MAR2020, adverse events reported before and after 


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01MAR2020 and type of study visit completed (phone or in clinic) will be reported for 
relevant visits in the CTR.


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint of this trial is a safety endpoint. Per CTP Section 2.1.2, the primary 
endpoint is:
Ocular safety of BI 1467335 as assessed by the proportion of patients with any ocular
adverse events (according to Common Terminology Criteria for Adverse Events (CTCAE)) 
over the on-treatment period (over 24 weeks).
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
This section is not applicable as there are no key secondary endpoints in this trial.
5.2.2
Secondary endpoint(s)
As defined in CTP Section 2.1.3, the secondary endpoints of this trial are:

Improvement of at least 2 steps on the DRSS in the study eye at week 12 compared to 
baseline.

Adverse events other than ocular adverse events over the on-treatment period (over 
24 weeks), according to CTCAE.
DRSS levels for an individual eye are defined in Table 5.2.2: 1.
Table 5.2.2: 1 Diabetic Retinopathy Severity Score (DRSS) levels – individual eye
Step
DRSS
DRSS Severity
1
10
DR Absent
2
15
DR Questionable
3
20
Microaneurysm only
4
35
Mild NPDR
5
43
Moderate NPDR
6
47
Moderately Severe NPDR
7
53
Severe NPDR
8
60
PDR
1 Higher DRSS and step values indicate more severe diabetic retinopathy.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
Treatments used in this trial are described in Table 6.1:1. For basic information on treatments 
to be administered in this trial and the assignment of treatment arm, see CTP Section 4.
Table 6.1: 1
Treatment descriptions
Long Name
Short Name
Placebo
Placebo
BI 1467335 10 mg QD
10 mg QD
The trial periods defined in Table 6.1:2 will be used for analysis of trial data. 
Table 6.1: 2
Trial periods
Trial Period
Start time
Stop time
Screening
Date of informed consent
Date of first treatment 
administration (Visit 2a) – 1 
day
On-treatment (treatment 
period + residual effect 
period)
Date of first treatment 
administration (Visit 2a)
Date of individual patient’s 
end of trial participation
For this trial, the residual effect period (REP), as defined in the CTP Section 5.2.6.2, is 
considered the entire period from the date of last administration of trial medication until the 
individual patient’s end of trial date. The statistical analysis and reporting of treatment-
emergent adverse events will include all adverse events occurring or worsening during the 
on-treatment period which includes residual effect period (REP).
6.2
IMPORTANT PROTOCOL DEVIATIONS
A protocol deviation (PD) is important if it affects the rights or safety of the study subjects, or 
if it can potentially influence the primary outcome measurement(s) in a non-negligible way.
A list of important PDs (iPD) for this trial is given Table 6.2: 1. Important PDs will be 
reviewed at Medical Quality Review Meetings (MQRM) conducted periodically during the 
trial. Other iPDs identified during MQRMs, Blinded Report Planning Meetings (BRPM), or 
during review of BI CTMS issues reports may supplement this list. The decision to exclude 


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subjects with certain iPDs from analyses will be finalized at the last BRPM prior to database 
lock.
Table 6.2: 1
Important protocol violations
Category /
Code
Description
Comment
Excluded 
from
A
Entrance criteria not met
A1
Inclusion criteria not met
A1.1
Age at enrollment <18 years 
Inclusion criterion 1 not met or age 
<18 years on demographics eCRF
None
A1.2
Female patient of childbearing potential 
not using required contraception 
Inclusion criterion 2 not met
None
A1.3
No diagnosis of Type 1 or Type 2 
diabetes
Inclusion criterion 3 not met
PPS
A1.4
HbA1c > 12% at screening
Inclusion criterion 4 not met
None
A1.5
Diagnosis of NPDR without CI-DME at 
screening not met
Inclusion criterion 5 not met
PPS
A1.6
BCVA ETDRS letter score < 70 letters 
in each eye at screening
Inclusion criterion 6 not met
PPS
A1.7
Inadequate retinal examination
parameters
Inclusion criterion 7 not met
PPS
A2
Exclusion criteria met
A2.1
Additional eye disease in the study eye 
that may compromise visual acuity
Exclusion criterion 1 met
PPS
A2.2
Active CI-DME and OCT central 
subfield thickness > 300 µm in study 
eye
Exclusion criterion 2 met
PPS
A2.3
Anterior segment and vitreous 
abnormalities in the study eye
Exclusion criterion 3 met
PPS
A2.4
Evidence of neovascularization in the 
study eye
Exclusion criterion 4 met
PPS
A2.5
Prior pan-retinal photocoagulation in 
the study eye
Exclusion criterion 5 met
PPS
A2.6
History of DME or DR treatment:  
macular laser within 3 months prior to
screening, intraocular injections within 
6 months prior to screening, or >4 prior 
injections in study eye
Exclusion criterion 6 met
PPS
A2.7
Treatment with  MAO inhibitors or 
drugs with potential side effects due to 
MAO inhibition
Exclusion criterion 7 met
None
A2.8
Current or planned use of restricted 
medications
Exclusion criteria 8 or 9 met
PPS
A2.9
Glomerular filtration rate (eGFR) < 60 
mL/min/1.73m2 at screening or 
expected during trial
Exclusion criterion 10 met
None
A2.10
ALT or AST > 2x ULN or total 
bilirubin > 1.5x ULN
Exclusion criterion 11 met
None
A2.11
Excluded medical condition
Exclusion criteria 12, 13, 14, 15, 16
or 23 met
None
A2.12
Significant substance abuse
Exclusion criterion 17 met
None


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Table 6.2: 1
Important protocol violations (cont.)
Category / 
Code
Description
Comment
Excluded 
from
A2.13
Hypersensitivity to trial drug or allergy 
to fluorescein dye
Exclusion criterion 18 met
PPS
A2.14
Major surgery performed within 12 
weeks prior to randomization or 
planned during trial
Exclusion criterion 19 met
None
A2.15
Current enrollment in, or < 30 days or 5 
times half-life of the investigational 
drug since participating in, another 
investigational drug trial
Exclusion criterion 20 met
PPS
A2.16
Previous randomization in this trial
Exclusion criterion 21 met
PPS
A2.17
Women who are pregnant, nursing, or 
who plan to become pregnant during 
the trial
Exclusion criterion 22 met
None
B
Informed consent
B1
Informed consent not available/not 
done
Inclusion criterion 8 not met; 
informed consent date or signature 
missing
All
B2
Informed consent given late
Study informed consent date after 
date of any study-related procedure; 
biobanking informed consent date 
after sample collection date; or re-
consent given late.
None
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C1.1
No study medication taken
Patient randomized but no evidence 
of study medication taken
TS, FAS, 
PKS, PPS
C1.2
Incorrect trial medication taken
Incorrect medication taken for 
>20% of treatment duration or >
20% of last dose interval before 
primary endpoint assessment as 
identified after database lock by 
comparison of assigned drug kit 
number from IRT with drug kit 
number recorded in eCRF. [manual 
review]
PPS
C3
Non-compliance
C3.1
Non-compliance with trial medication 
Mean overall treatment compliance 
across treatment duration for an 
individual <80% or >120%.
PPS
C4
Medication code broken
C4.1
Medication code broken at site without 
just cause
Medication code broken for reasons
other than those documented in 
CTP Section 4.1.5.2.
[manual review]
None


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Table 6.2: 1
Important protocol violations (cont.)
Category / 
Code
Description
Comment
Excluded 
from
D
Concomitant medication
D2
Use of prohibited concomitant 
medication
Reported use of prohibited 
concomitant medications, defined 
in CTP Section 4.2.2.1[manual 
review]
PPS
F
Trial specific
F1.1
Study eye incorrectly selected.
Ophthalmologic data and/or issues 
report indicates study eye 
incorrectly selected. Incorrect study 
eye based on DRSS and BCVA will 
be flagged via SAS code. Manual 
review is needed to confirm 
protocol violations.
None
F1.2
Study eye incorrectly selected –
Confirmed
Incorrect selection of study eye 
identified in F1.1 and confirmed by 
manual review.
PPS
F2
Imaging performed by non-certified 
personnel.
Manual review of issues report 
identified non-certified personnel 
performing imaging.
PPS
F3
Imaging performed using non-certified 
equipment.
Manual review of issues report 
noted use of non-certified imaging 
equipment.
PPS
F4
BCVA/CS performed by non-certified 
personnel.
Manual review of issues report 
identified non-certified personnel 
performing BCVA/CS assessment.
PPS
F5
BCVA/CS performed using non-
certified equipment.
Manual review of issues report 
noted use of non-certified 
BVCA/CS equipment.
PPS
Note: Missing visits, evaluations, and tests will be considered missing data, not protocol deviations.
6.3
PATIENT SETS ANALYSED
The following patient analysis sets are defined for this trial:

Screened set (SS): includes all patients who sign informed consent

Randomized set (RS): includes all patients who sign informed consent, are screened 
for the trial and are randomized to trial medication, regardless of whether any trial 
medication is administered.

Treated set (TS): includes all patients who sign informed consent, are dispensed trial 
medication and are documented to have taken at least one dose of trial medication (BI 
1467335 or placebo). Safety analyses, including the analyses of the primary endpoint 
of ocular adverse events and secondary endpoint of non-ocular adverse events, and 
summaries of demographics and baseline characteristics will be based on the TS.

Full analysis set (FAS): includes all patients in the TS with non-missing baseline and 
at least one non-missing on-treatment measurement for DRSS or BVCA. Patients in 


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FAS are analyzed according to the intent-to-treat principle, i.e. patients in FAS are 
analyzed according to the trial medication assigned at randomization.

Per protocol set (PPS): includes all patients from the FAS who do not have an iPD
resulting in exclusion from the PPS.

 

ECG analysis set (ECGS): includes all subjects in TS who have at least one baseline 
and one post-baseline measurement for at least one ECG interval endpoint. 
Analyses relevant to each patient set are shown in Table 6.3: 1.
Table 6.3: 1
Patient sets analyzed
Patient set
Class of endpoint
SS
RS
TS
FAS
PPS
ECGS
Primary and secondary safety
endpoints 
X
Secondary ophthalmologic
endpoint
X
X
Further ophthalmic endpoints 
X
Safety endpoints 
X
ECG endpoints
X
Demographic/baseline 
endpoints
X
Important protocol deviations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable because center/country is not included in the statistical model.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Techniques for handling missing data are described in Section 7.5 of the CTP. Missing and 
incomplete adverse event dates will be handled according to BI standards (5). The handling 
of missing PK data and values reported as NOS, NOR, NOA or BLQ are described in Section 
10.1 of the CTP.
For efficacy analyses, missing data will not be imputed. Mixed effect models will handle 
missing data based on a likelihood methods under the “missing at random” assumption. No 
imputations of missing AEs, laboratory data or vital signs data are planned. For binary 
efficacy endpoints, patients with missing data in the study eye at the time point of interest
will be considered non-responders, i.e. failure to achieve the defined endpoint.
For ECG data, if single cardiac cycles of an ECG (out of three) are missing, the arithmetic 
mean for this single ECG will be calculated with the reduced number (1 or 2) of cycles.
For the classification of the on-treatment QTc/QT intervals into ‘no new onset’ / ‘new onset’ 
categories, a missing value is obtained only in the case that 
i.
all on-treatment values are missing, and 
ii.
the baseline value is less than or equal to 500 msec, or missing. 
If condition (i) is fulfilled but the baseline value is greater than 500 msec, this case will be 
categorized as ‘no new onset’. If baseline is missing and the maximum on-treatment QTc 
interval is greater than 450 msec (or 500 msec for QT interval, respectively), this is classified 
as a ‘new onset’ in the respective category. If baseline is missing and the maximum QTc 
interval is less than or equal to 450 msec (or 500 msec for QT interval, respectively), this will 
be categorized as ‘no new onset’. If baseline is missing, a QTc/QT interval > 500 msec at any 
time on treatment will be a notable finding.
For patients on active drug, missing plasma concentration values with ‘BLQ’ in the comment 
field will be replaced by ½ LLOQ.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study day will be calculated relative to the date of the first dose of the randomized treatment. 
The day prior to the date of the first administration of randomized treatment will be Day -1 
and the date of the first administration of randomized treatment will be Day 1. Day 0 will not 
exist.
Unless otherwise specified, baseline is defined as the last measurement collected on or prior 
to the date and time of first treatment administration. If no measurements are collected for a 
particular variable on or before the date of first treatment administration, no baseline value 
will be derived for that particular variable. Per the CTP, for the ophthalmic endpoints, 
baseline is defined as the value at Visit 2a; if not measured at Visit 2a then baseline is the 
value at Visit 1. 


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To utilize all available data, including values collected between protocol-specified visit 
windows, the time intervals and descriptions shown in Table 6.7: 1 will be used in the 
analysis of safety and efficacy data with the following exceptions. Adverse events and 
concomitant medications are also collected during phone visits 2b (Study Day 8 ± 1) and 4b 
(Study Day 83 ± 1). Sites in Spain have additional mandatory visits 3c and 4c during which 
AEs, concomitant medications, vital signs and laboratory data are collected. Separate interval 
mapping will be defined in Table 6.7: 2 and Table 6.7: 3, respectively, to accommodate these 
exceptions.
If multiple values are recorded within a visit interval, the value collected closest to the 
planned visit date will be included in analyses of efficacy endpoints and vital signs data. For 
all other safety data, the worst of multiple values within an analysis window will be selected 
for analysis (see guidance for Handling, Display and Analysis of Laboratory Data (6)). Only 
one observation per time window will be selected for analysis at an on-treatment visit.  
Table 6.7: 1
Visit intervals for efficacy endpoints
Interval Definition
Visit
Planned 
day
From (day)
To (day)
Visit description
1
-28 to -3
NA
-1
Screening
2
1
1
1b
Baselinec
3
29
2
43
Week 4
4a
57
44
71
Week 8
EOT
85
72
Date of drug intake 
at EoT visit + 14
Week 12
FU1
EOT +28
Date of drug intake at 
EOT visit + 15
Date of drug intake 
in EOT visit +34
Follow-up 1
FU2
EOT +56
Date of drug intake in 
EOT visit +35
Date of drug intake 
in EOT visit +62
Follow-up 2
FU3
EOT + 84
Date of drug intake in 
EOT visit +63
Last assessment date
Follow-up 3
b Day 1 is defined as the date of first treatment administration
c Baseline data must be collected before time of study drug administration during Visit 2.


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Table 6.7: 2
Visit intervals for ECG, vital signs, and laboratory data
Interval Definition
Visit
Planned 
day
From (day)
To (day)
Visit description
1
-28 to -3
NA
-1
Screeninga
2a
1
1b (pre-dose)
1
Baselinea,c
2a
1
1 (post-dose)
14
Week 1d
3
29
15
43
Week 4
4a
57
44
71
Week 8
EOT
85
72
Date of drug intake 
in EOT visit +1
Week 12
FU1
EOT +28
Date of drug intake in 
EOT visit +2
Date of drug intake 
in EOT visit +34
Follow-up 1e
FU2
EOT +56
Date of drug intake in 
EOT visit +35
Date of drug intake 
in EOT visit +62
Follow-up 2
FU3
EOT + 84
Date of drug intake in 
EOT visit +63
Last assessment date
Follow-up 3
a Baseline ECG data are collected at screening visit. 
b Day 1 is defined as the date of first treatment administration.
c Baseline data must be collected before time of study drug administration during Visit 2.
d Only measurements collected after drug administration at Visit 2a are considered Week 1 values.
e In case of premature treatment discontinuation FU starts at +1 day after last drug admin for these values.


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Table 6.7: 3
Visit intervals for vital signs and laboratory data for patients from sites in 
Spain only
Interval Definition
Visit
Planned 
day
From (day)
To (day)
Visit description
1
-28- -3
NA
-1
Screening
2a
1
1a
1
Baselineb
2b
8
1c
11
Week 1 (Day 8)
2c
15
12
22
Week 2 (Day 15)
3
29
23
40
Week 4 (Day 29)
3c
50
41
53
Week 6 (Day 50)
4a
57
54
70
Week 8 (Day 57)
4b
83
71
84
Week 11 (Day 83)
EOT
85
85
Date of drug intake 
in EOT visit +1
Week 12 (Day 85)
FU1
Date of drug intake in 
EOT visit +2
Date of drug intake 
in EOT visit +34
Follow-up 1d
FU2
Date of drug intake in 
EOT visit +35
Date of drug intake 
in EOT visit +62
Follow-up 2
FU3
Date of drug intake in 
EOT visit +63
Last assessment date
Follow-up 3
a Day 1 is defined as the date of first treatment administration
b Baseline data must be collected before time of study drug administration during Visit 2.
c Measurements collected after drug administration at Visit 2a or at Visit 2b are considered Week 1 values.
d In case of premature treatment discontinuation FU starts at +1 day after last drug admin for these values.
There will be a centralized evaluation of 12-lead ECG recordings at the time points specified 
in Table 6.7: 2. Three triplicate ECGs will be recorded as baseline prior to the first drug 
administration. The baseline value of an ECG variable is defined as the mean of these 
baseline ECG measurements.


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7.
PLANNED ANALYSIS
Unless otherwise specified in this TSAP or related documents, the format for displaying 
analysis results will follow BI guidelines and standards.
The following descriptive statistics will be displayed in summary tables of continuous 
variables:
N
number of non-missing observations
Mean
arithmetic mean
SD
standard deviation
Min
minimum
Median 
median
Max
maximum
For tables that are provided for continuous endpoints with some extreme data values, 
summary statistics such as median, quartiles and percentiles may be preferred to mean, 
standard deviation, minimum and maximum values.
Summaries of categorical data will include tabulations of the number of observations and the 
percentages of the respective treatment arm for all possible categories. Percentages will be 
rounded to one decimal place, unless the denominator is less than 100 in all treatment 
columns, in which case integer values will be displayed. A separate category for missing 
values will be displayed only if values of a particular variable are missing for at least one 
subject.


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Individual values of data collected from all patients will be listed by treatment group, center, 
patient number and visit. These source data listings will be provided in Appendix 16.2 of the 
CTR.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive statistics are planned for this section of the report. Demographics and baseline 
characteristics will be summarized for the TS. Data will be presented for each treatment arm 
and for all treated patients combined.
The summary of demographic data will include age at time of informed consent, race, 
ethnicity and sex.
Baseline clinical characteristics summarized will include baseline disease characteristics, 
including DRSS level, BCVA score, and OCT central subfield thickness (CSFT), and 
substance use at screening.
In addition, data related to diabetic retinopathy history will be summarized separately. The 
following variables will be summarized:

Duration of diabetic retinopathy calculated as the difference between the reported 
onset date and the patient’s date of randomization;

N (%) of patients reporting a history of Type I diabetes mellitus;

Duration of diabetes mellitus Type I calculated as the difference between the reported 
onset date and the patient’s date of randomization;

N (%) of patients reporting a history of Type II diabetes mellitus;

Duration of diabetes mellitus Type II calculated as the difference between the 
reported onset date and the patient’s date of randomization;

N (%) of patients reporting a history of arterial hypertension, myocardial infarction, 
transient ischemic attacks, stroke and diabetic nephropathy.
7.2
CONCOMITANT DISEASES AND MEDICATION
Descriptive statistics will be provided for this section of the report based on the treated set.
Concomitant drug therapies (CT) and ophthalmic interventional drug therapies are coded 
according to WHO DD and will be classified according to the Anatomical Therapeutic 
Chemical (ATC) classification system. The third ATC level will be used to categorize CTs by 
therapy type. In situations where a medical product may be used for more than one equally 
important indication, there are often several classifications alternatives. As appropriate, 
patients receiving CTs with more than one possible ATC level-three category will be counted 
more than once; a footnote will clarify this possible double counting in tables. If a level three 
ATC category is not available, a lower level category may be reported. Separate summaries 
will be presented for concomitant drug therapies ongoing at baseline and concomitant drug 
therapies with start dates after date of first dose of study drug. Ophthalmic interventional 
drug therapies and general concomitant drug therapies will be summarized separately.


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Concomitant non-drug therapies will be coded using the current version of MedDRA at the 
time of database lock. Ophthalmic non-drug therapies will be presented by reported term. 
Separate summaries will be presented for concomitant non-drug therapies ongoing at baseline 
and concomitant non-drug therapies with start dates after date of first dose of study drug.
Ophthalmic non-drug therapies and general non-drug therapies will be summarized 
separately.
Concomitant medical conditions are coded similarly to AEs based on the most current 
MedDRA version at the time of database lock. A summary of concomitant conditions will be 
provided by treatment group, system organ class (SOC) and preferred term (PT).
The coding version number will be displayed as a footnote in respective outputs.
7.3
TREATMENT COMPLIANCE
Overall compliance will be calculated as the weighted average of the non-missing compliance 
values reported on the eCRF for each 28-day interval during the on-treatment period (Visits 
3, 4 and EOT). The weighted average will be calculated as the sum of the reported 
compliance values multiplied by their respective interval durations in days, divided by 100.
In the calculation of overall compliance, missing compliance values for a visit interval with 
confirmed drug administration records will be imputed as 100%. Compliance will be 
summarized by visit interval and overall.
The number and percentage of patients with non-missing overall treatment compliance of
<80%, 80%-120%, and >120% and descriptive summaries of overall compliance will be 
reported. 
7.4
PRIMARY ENDPOINT(S)
No primary efficacy endpoint is defined for this trial.
Analysis of the primary safety endpoint, i.e. proportion of patients with ocular adverse events 
over the on-treatment period, is provided in Section 7.8.
7.5
SECONDARY ENDPOINT(S)
Analyses of the secondary safety endpoint, i.e. proportion of patients with adverse events 
other than ocular adverse events over the on-treatment period, are described in Section 7.8.
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoints are defined for this trial.
7.5.2
Secondary endpoint(s)
The frequency and percentage of patients in the FAS with at least 2 steps improvement from 
baseline on the DRSS, as defined in Table 5.2.2: 1, in the study eye at week 12 will be 
summarized by treatment. Baseline DRSS is the value recorded at Visit 2a. If DRSS is not 


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measured at Visit 2a, baseline DRSS is the value recorded at Visit 1. The frequency of 
patients reporting improvement in DRSS of at least 2 steps is expected to be low. The risk 
difference and corresponding 95% confidence intervals calculated using the method of Chan 
and Zhang (7) will be reported.
In addition, a shift table showing the frequency and percentage of patients reporting each 
Week 12 DRSS by baseline DRSS value will be presented. A visual display of the percentage 
of patients experiencing no change from baseline, a one-step and two-step improvement in 
DRSS from baseline to Week 12 or one-step worsening will be created. Similar summaries
will be prepared using DRSS data collected from the non-study eye.
If a sufficient number of patients report improvement of 2 steps or more in the study eye, 
logistic regression analyses adjusted for visit, treatment and baseline visual acuity will be 
performed as exploratory analyses. The resulting odds ratios at each time point and 
corresponding 95% confidence interval will be presented, if modeling is possible.
Additionally, analyses described in this section will be repeated using the PPS instead of the 
FAS.


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7.7
EXTENT OF EXPOSURE
Basis for the assessment of treatment exposure will be the amount of trial medication and the 
duration of exposure in days calculated across the on-treatment period for each patient. 
Standard summary statistics will be displayed by treatment arm. In addition, the number and 
percentage of patients in exposure categories defined as 0 to 6 weeks, >6 to 12 weeks will be 
summarized.
7.8
SAFETY ANALYSIS
Safety analyses will be performed on the treated set (TS).
7.8.1
Adverse events
Unless otherwise specified, the analyses of AEs will be descriptive. All analyses of AEs will 
be based on the number of patients reporting an AE and not on the number of events. The 
reporting and analyses of AEs will follow the BI guideline for analyses and presentation of 
adverse event data (12). All AEs will be coded using the most current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at the time of database lock. The 
intensity of AEs will be classified according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.
For analysis, multiple AE occurrences will be collapsed into one event if all of the following 
conditions apply:

All AE attributes are identical (LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AE of special interest).

Reported occurrences are time-overlapping or time-adjacent, where time-adjacency of 
2 occurrences exists if the second occurrence started on the same day or on the day 
after the end of the first occurrence.
The analyses of AEs will be based on the concept of treatment emergent adverse events. 
Consistent with the REP definition provided in Section 6.1, all AEs with onset dates between 
the date of first treatment administration and date of last follow-up will be assigned to the 
randomized treatment. All AEs occurring before first treatment administration will be 
assigned to screening. For details on the treatment definition, see Section 6.1. 


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According to ICH E3 (13), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant adverse events with (i) ‘action taken = 
discontinuation’ or ‘action taken = reduced’, or (ii) marked hematological and other lab 
abnormalities or which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at an MQRM.
An overall summary of AEs will be presented. This summary will include the following 
event categories:

All AEs

Drug-related AEs

AEs leading to treatment discontinuation

Serious AEs (SAEs)

AESI

Highest CTC grade

Ocular AEs
The frequency and percentage of patients with AEs will be summarized by treatment, primary 
system organ class (SOC), and preferred term (PT) in each of the following tables:

All AEs

Drug-related AEs

AEs leading to treatment discontinuation

Drug-related AEs leading to treatment discontinuation

SAEs

Drug-related SAEs

AEs leading to death

AEs of special interest (AESI)

Other significant AEs according to ICH E3 (13).
Per CTP Section 5.2.6.1.4, AESIs for this trial are events of hepatic injury defined by an 
elevation of AST and/or ALT ≥ 3 fold upper limit of normal (ULN) combined with an 
elevation of bilirubin ≥ 2 fold ULN measured in the same blood draw, or aminotransferase 
(ALT and/or AST) elevations ≥ 10 fold ULN.  AEs related to these definitions will be 
summarized as AESIs.
Additionally, a table summarizing time to first AE from date of first dose of study drug will 
be presented by treatment arm, SOC and preferred term.
Primary endpoint: Ocular AEs
In additional to standard adverse event tables, separate summaries will be provided to address 
the primary endpoint and secondary safety endpoints. The frequency and percentage of 
patients reporting ocular AEs, as identified by the investigator as an ocular event on the AE 
eCRF, will be summarized by treatment, highest CTC grade, primary SOC, and PT for the 
primary endpoint analysis. The number and percentage of patients in each treatment arm 


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reporting specific ocular symptoms will be summarized and will be displayed by associated 
event in a listing. Additional summaries of serious ocular AEs, drug-related ocular AEs, 
serious drug-related ocular AEs, and ocular AEs leading to discontinuation will be provided, 
if any such events are reported. A Kaplan-Meier plot displaying time to first ocular event 
following first dose of study drug will be provided.
To assess the impact of the COVID-19 pandemic on this trial, adverse events reported after 
01MAR2020 in the subset of patients active in the trial as of 01MAR2020 will be reported 
and listed in the CTR. Overall summaries of the subset of all AEs and subset of ocular AEs 
with start dates prior to 01MAR2020 will be reported separately. In additional, frequencies of 
AEs reported during the follow-up period will be reported in the subset of patients who 
completed the trial prior to 01MAR2020 and in the subset of patients who completed the trial 
after 01MAR2020. 
Secondary endpoint: Non-ocular AEs
A separate set of the tables specified above for ocular AEs will be generated to summarize
patients reporting AEs not identified as ocular AEs. These summaries will address the 
analysis of the secondary safety endpoint. The data will be summarized by treatment, 
MedDRA primary SOC, and PT.
For further details on the summarization of AE data, refer to BI guidelines (5,12). 
7.8.2
Laboratory data
The analyses of laboratory data 
 will be descriptive in nature and will 
be based on BI standards (6).
For continuous safety laboratory parameters, standardized and normalized values will be 
derived as well as the differences from baseline. The process of standardization and 
normalization as well as standard analyses for safety laboratory data are described in the BI 
guidance for the display and analysis of laboratory data (6).
Laboratory values will be compared to their reference ranges and frequency tables will be 
provided for the number of patients within and outside the reference ranges at baseline,  the 
last measurement on treatment and the last post-treatment follow-up. Descriptive statistics 
will be provided by treatment group for baseline, on-treatment values, values collected during 
follow-up visits and for changes from baseline. Frequency tables will summarize the number 
of patients with potentially clinically significant abnormalities as defined for the XLAB 
macro.
The Estimated Glomerular filtration rate as assessed by the CKD-EPI formula is calculated 
as:
eGFR (ml/min/1.73 m²) = 141 *min(SCr/κ, 1)α *max(SCr/κ, 1)-1.209 *0.993Age 
*1.018 [if female] * 1.159 [if black]


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where SCr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for 
females and -0.411 for males, min indicates the minimum of SCr/κ or 1, and max indicates 
the maximum of SCr/κ or 1. The process of standardization and normalization as described in 
the guidance document (6) does not apply. Additionally, the shift tables for eGFR will use the 
following categories (similar to the staging of renal impairment): eGFR ≥ 90; 60-<90; 30-
<60; and<30.
Clinically relevant findings in laboratory data will be reported as AEs and will be analyzed as 
part of AE analyses.
7.8.3
Vital signs
Descriptive summaries of vital signs and body weight values over time and for the difference 
from baseline will be provided.
Clinically relevant findings in vital signs data will be reported as AEs and will be analyzed as 
part of AE analyses.
7.8.4
ECG
All evaluations of ECG data will be based on data from the ECGS. 
For quantitative endpoints, listings of individual data with notable findings flagged will be 
provided in Appendix 16.2. For patients with any notable finding in quantitative ECG 
recordings, a separate listing with corresponding time profiles will be created as an end-of-
text display.
Comments regarding the ECG recordings will be provided in a listing.
For categorical ECG endpoints, frequency tables will be provided. Findings of ECG 
abnormalities from morphological analyses will also be analyzed as categorical endpoints.
Descriptive statistics (N, mean, SD, min, median, max) will be provided for absolute values 
of QTcF, HR, QT, PR and QRS. Changes from baseline over time will also be presented for 
these values. Time profiles of mean and SD of change from baseline while on treatment will 
be displayed graphically by treatment.
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval (values log-transformed using the natural 
logarithm) will be estimated by applying the random coefficient model described in Section 
9.1.1 using all time points. A scatterplot of QTcF vs RR including the overall regression line 
will be included in the Statistical Appendix of the CTR. The resulting (fixed effect) slope 
together with two-sided 95% confidence intervals will be included in the footnote for this 
plot.


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7.8.5
Others
 
For future disclosure of trial results, specific data summaries will be included in the CTR or 
CTR appendices. Required displays will be specified in the technical TSAP. 


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
3.
001-MCS-37-473: “Performing a Pharmacometric Analysis”, current version; IDEA for 
CON.
4.
001-MCS-40-413: “Identify and Manage Important Protocol Deviations”, current 
version; IDEA for CON.
5.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON.
6.
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
7.
R15-1346: Chan ISF, Zhang Z. Test-based exact confidence intervals for the difference 
of two binomial proportions. Biometrics 55, 1202-1209, 1999.
8.
BI position paper: “Standards for Inferential Analyses; 1.1 Analyses of Continuous 
Endpoints – Parallel Group Studies”
9.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic 
Analyses of Clinical Studies”, current version; IDEA for CON.
10. 001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.
11. 001-MCG-311: “Pharmacometric Dataset Generation”, current version; IDEA for CON.
12. 001-MCG-156: "Analysis and presentation of adverse event data from clinical trials", 
current version; IDEA for CON.
13. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports,
current version
14. R10-2920: Ring A; Statistical models for heart rate correction of the QT interval. Stat
Med 29, 786-796, 2010.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1
29-JUN-2020
All
This is the final TSAP prior to DBL; 
based on initial TSAP approved 12-
SEP-2017.