Conditions: Macular Edema
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 105
Healthy volunteers: no

Brief summary:
This is a proof of mechanism trial to explore the effect of BI 1026706 on the central retinal thickness and to evaluate safety and tolerability of BI 1026706 administered orally for 12 weeks in patients with mild vision impairment due to center-involved DME

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BI 1026706 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_001.pdf: 
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03441881-03
EudraCT No.:
2015-003529-33
BI Trial No.:
1320.22
BI Investigational 
Product:
BI 1026706
Title:
A randomized, double-masked, placebo-controlled exploratory 
study to evaluate pharmacodynamics, safety and tolerability of 
orally administered BI 1026706 for 12 weeks in patients with 
mild visual impairment due to center-involved diabetic macular
edema (DME)
Brief Title:
Safety and effect on central retinal thickness of BI 1026706 in 
patients with diabetic macular edema
Clinical Phase:
II a
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol
Version and Date:
Version 2.0
Date: 07 Mar 2016
Page 1 of 65
Proprietary confidential information.
2016 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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BI Trial No.: 1320.22
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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim
Name of finished product:
-
Name of active ingredient:
BI 1026706
Protocol date:
16 Dec 2015
Trial number:
1320.22
Revision date:
07 Mar 2016
Title of trial:
Randomized, double-masked, placebo-controlled exploratory study 
to evaluate pharmacodynamics, safety and tolerability of orally 
administered BI 1026706 for 12 weeks in patients with visual 
impairment due to center-involved diabetic macular edema (DME)
Coordinating
Investigator:
Phone: 
Fax: 
Trial site(s):
Multi-centre trial
Clinical phase:
Phase IIa
Objective(s):
To investigate pharmacodynamics, safety and tolerability of oral 
BI 1026706 in patients with diabetic macular edema (DME).
Methodology:
Randomized, double-masked, placebo-controlled, parallel design 
comparison of BI 1026706 versus placebo group over 12 weeks.
No. of patients: 
total entered:
100
each treatment:
50
Diagnosis:
Patients with vision impairment due to center-involved DME 
Main criteria
for inclusion:
Main Inclusion criteria:

Age 18 years

Male or female of non-childbearing potential

Diabetes mellitus type 1 or type 2 with stable antidiabetic 
medication (stable medication defined as: no change in oral 
antidiabetic medication and/or no initiation of intensive 


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Trial Protocol
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001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Name of company:
Boehringer Ingelheim
Name of finished product:
-
Name of active ingredient:
BI 1026706
Protocol date:
16 Dec 2015
Trial number:
1320.22
Revision date:
07 Mar 2016
insulin treatment within 3 months prior to randomization or 
plans to do so in the next 4 months)

Center-involved DME with central subfield thickness (CSFT)
300 µm on SD-OCT in the study eye, confirmed by CRC

Best corrected visual acuity ETDRS letter score in the study 
eye ≤ 84 and 70.
Main Exclusion criteria:

Macular edema considered to be due to other causes than 
DME 

Additional eye disease in the study eye that, in the opinion of 
the Investigator, might affect macular edema or could 
compromise or alter visual acuity during the course of the 
study 

Anterior segment and vitreous abnormalities in the study eye 
that would compromise the adequate assessment of the visual 
acuity or an adequate examination of the posterior pole

Intraocular surgery in the study eye within 4 months prior to 
randomization or planned intraocular surgery, including 
cataract, during the study period

Proliferative diabetic retinopathy or iris neovascularisation in 
the study eye

Aphakia in the study eye

Any indication that requires immediate treatment with anti-
VEGF or with laser photocoagulation during the study period 
as per Investigator’s judgment 

History of prior laser photocoagulation or other surgical, 
intravitreal or peribulbar treatment in the study eye within 4 
months prior to randomization, either for DME or an ocular 
condition other than DME

History of fluocinolone acetonide intravitreal implant in the 
study eye


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Name of company:
Boehringer Ingelheim
Name of finished product:
-
Name of active ingredient:
BI 1026706
Protocol date:
16 Dec 2015
Trial number:
1320.22
Revision date:
07 Mar 2016

Application of intraocular corticosteroids in the study eye 
within 2 years prior to randomization in phakic eyes or 9 
months in pseudophakic eyes 

Systemic anti-VEGF or pro-VEGF treatment within 4 months 
prior to randomization

Patients with a clinically relevant abnormal screening 
haematology, blood chemistry, or urinalysis

Renal impairment with estimated CrCL (as calculated by 
Cockcroft-Gault equation) < 30 mL/min at screening

Myocardial infarction or unstable angina pectoris within 3 
months before randomization.
Test product(s):
BI 1026706 film-coated tablet
dose:
100 mg twice daily (b.i.d.); total daily dose 200 mg
mode of 
administration:
p.o. 
Comparator 
products:
Placebo film-coated tablet
dose:
Not applicable
mode of 
administration:
p.o.
Duration of 
treatment:
12 weeks (84 days)
Endpoint
The primary endpoint is the change from baseline in central subfield
thickness (CSFT) in DME patients at week 12 as assessed by 
Spectral-Domain Optical Coherence Tomography (SD-OCT).
Safety criteria:
Adverse events, visual acuity, vital signs (blood pressure, pulse rate), 
physical examination, weight, 12-lead ECG and clinical laboratory 
parameters.
Statistical methods: For the primary endpoint, change from baseline in CSFT at 12 
weeks, restricted maximum likelihood estimation based on mixed-


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Name of company:
Boehringer Ingelheim
Name of finished product:
-
Name of active ingredient:
BI 1026706
Protocol date:
16 Dec 2015
Trial number:
1320.22
Revision date:
07 Mar 2016
effect model for repeated measures (MMRM) analysis will be used
to obtain adjusted means for the treatment effects. This model will
include treatment and week as discrete fixed effects, baseline CSFT
as continuous fixed effects, as well as the interaction between week
and treatment and the interaction between week and baseline CSFT.
All other endpoints will be analysed via MMRM or descriptive 
statistics.


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FLOW CHART
Investigations/Tests and 
Procedures
Screening 
Period
Randomized Treatment Period
Follow-up 
Period
Visit
1
2a
2b
Phone
Visit
3
4
5/EOT 1
6/End of 
Study 2
Study Week
1
4
8
12
16
 
Informed consent
X
Review of in-/exclusion criteria
X
X
Demographics
X
Medical history / baseline 
conditions
X
Adverse events
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
Body height
X
Body weight
X
X
X
X
Vital signs (BP, PR)
X
X
X
X
X
X
12 lead-ECG
X
X
X
X
X
X
Safety dipstick urine test
X
X
X
X
X
X
Safety laboratory blood tests 4
X
X
X
X
X
X
PK blood sampling 5
X
X
X
X
Pharmacogenetic (PGx) blood
sample for genotyping 6
X
Informed consent DNA banking7
X

DNA banking blood sample 
  X 7

Biomarker blood sampling
X
X
Ophthalmological exams: 8
Slit lamp
X
X
X
X
X
X
SD-OCT
X
X
X
X
X
X
Ocular tonometry
X
X
Collect/check study drug diary
X
X
X
Collection of study drug /
Drug accountability check
X
X
X
Compliance check
X
X
X
IRT Randomization call
X
Dispense study drug kits
X
X
X
Dispense study drug diary
X
X
X
Administration of study drugs at 
site
X
X
X
Study completion 9
X
BP = blood pressure; EOT = End of treatment; IRT = Interactive Response Technology; PR = pulse rate.


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................13
1.1
MEDICAL BACKGROUND.............................................................................13
1.2.1
Toxicology............................................................................................................15
1.2.2
Clinical Studies....................................................................................................15
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....16
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................16
2.2
TRIAL OBJECTIVES........................................................................................16
2.3
BENEFIT - RISK ASSESSMENT.....................................................................17
2.3.1
The risks of the study procedures......................................................................17
2.3.2
Drug related risks................................................................................................18
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................19
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................19
3.1.1
Administrative structure of the trial .................................................................19
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................20
3.3
SELECTION OF TRIAL POPULATION .......................................................21
3.3.1
Main diagnosis for trial entry ............................................................................21
3.3.1.1
Study eye criteria ..................................................................................................21
3.3.2
Inclusion criteria .................................................................................................22
3.3.3
Exclusion criteria ................................................................................................22
3.3.4
Removal of patients from therapy or assessments...........................................25
3.3.4.1
Removal of individual patients .............................................................................25
3.3.4.2
Discontinuation of the trial by the sponsor...........................................................25
4.
TREATMENTS...................................................................................................26
4.1
TREATMENTS TO BE ADMINISTERED.....................................................26
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........26
4.1.2
Method of assigning patients to treatment groups...........................................26
4.1.4
Drug assignment and administration of doses for each patient......................27
4.1.4.1
Study medication administration at the study site ................................................27
4.1.4.2
Study medication administration at home.............................................................27


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4.1.4.3
Returning of study medication after home administration....................................28
4.1.5
Masking and procedures for Unmasking..........................................................28
4.1.5.1
Masking.................................................................................................................28
4.1.5.2
Unmasking and breaking the code........................................................................29
4.1.6
Packaging, labelling, and re-supply...................................................................29
4.1.7
Storage conditions...............................................................................................29
4.1.8
Drug accountability.............................................................................................29
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
TREATMENT.....................................................................................................30
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....30
4.2.2
Restrictions ..........................................................................................................30
4.2.2.1
Restrictions regarding concomitant treatment ......................................................30
4.2.2.2
Restrictions on diet and life style..........................................................................32
4.2.2.3
Restrictions regarding women of childbearing potential, pregnancy and 
breastfeeding.........................................................................................................32
4.3
TREATMENT COMPLIANCE........................................................................32
5.
VARIABLES AND THEIR ASSESSMENT ....................................................33
5.1
TRIAL ENDPOINTS..........................................................................................33
5.1.1
Primary Endpoint ...............................................................................................33
5.1.2
Secondary Endpoints:.........................................................................................33
5.2
ASSESSMENT OF EFFICACY........................................................................33
5.3
ASSESSMENT OF SAFETY.............................................................................34
5.3.1
Physical examination ..........................................................................................34
5.3.2
Vital Signs............................................................................................................34
5.3.3
Ophthalmological examinations ........................................................................35
5.3.4
Safety laboratory parameters ............................................................................35
5.3.4.1
Safety laboratory parameters obtained from blood...............................................35
5.3.4.2
Safety laboratory parameters obtained from urine................................................38
5.3.5
Electrocardiogram (ECG)..................................................................................38
5.3.6
Assessment of adverse events.............................................................................38
5.3.6.1
Definitions of adverse events................................................................................38
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................46
6.
INVESTIGATIONAL PLAN.............................................................................47
6.1
VISIT SCHEDULE.............................................................................................47


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................47
6.2.1
Screening period..................................................................................................47
6.2.2
Treatment period ................................................................................................48
6.2.3
End of treatment and Follow-up period ...........................................................49
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................51
7.1
STATISTICAL DESIGN - MODEL.................................................................51
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................51
7.3
PLANNED ANALYSES.....................................................................................51
7.3.1
Primary endpoint analyses.................................................................................52
7.3.2
Secondary endpoint analyses .............................................................................52
7.3.4
Safety analyses.....................................................................................................53
7.4
INTERIM ANALYSES ......................................................................................54
7.5
HANDLING OF MISSING DATA ...................................................................54
7.6
RANDOMIZATION...........................................................................................54
7.7
DETERMINATION OF SAMPLE SIZE .........................................................54
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........56
8.1
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...........................................................................................................56
8.2
DATA QUALITY ASSURANCE ......................................................................56
8.3
RECORDS...........................................................................................................57
8.3.1
Source documents ...............................................................................................57
8.3.2
Direct access to source data and documents.....................................................57
8.3.3
Storage period of records ...................................................................................57
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................57
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........58
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................58
8.6
TRIAL MILESTONES.......................................................................................58
9.
REFERENCES....................................................................................................60
9.1
PUBLISHED REFERENCES............................................................................60
9.2
UNPUBLISHED REFERENCES......................................................................61
10.
APPENDICES.....................................................................................................62
10.1
PHARMACOKINETIC ANALYSES...............................................................62
10.2
TIME AND VISIT SCHEDULE FOR PK, SAFETY AND BIOMARKER 
BLOOD SAMPLING..........................................................................................62
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................64


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ABBREVIATIONS
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse Event
AESI
Adverse Event of Special Interest
AUC
Area under the curve
b.i.d.
bis in die (twice daily dosing)
BCRP
Breast Cancer Resistance Protein
BP
Blood Pressure
CA
Competent Authority
CI
Confidence Interval
Cmax
Peak plasma concentration
Cmin
Minimum plasma concentration
CML
Local Clinical Monitor 
Cpre
Pre-dose trough concentration 
CRA
Clinical Research Associate
CRC
Central Reading Center
CrCL
Creatinine Clearance
CRF
Case Report Form
CRO
Contract Research Organisation 
CSFT
Central subfield foveal thickness
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CTX
Carboxy-terminal collagen crosslinks
CYP
cytochrome P 450
DDI
Drug-drug interaction
DILI
Drug Induced Liver Injury
DM
Diabetes mellitus
DME
Diabetic Macular Edema
DR
Diabetic retinopathy
eCRF
Electronic Case Report Form
EOT
End of Treatment
ETDRS
Early Treatment Diabetic Retinopathy Study
EudraCT
European Clinical Trials Database
 
FAS
Full Analysis Set
FU
Follow Up
5-HT2B
5-Hydroxytryptamine 2B
GCP
Good Clinical Practice
GI
Gastrointestinal
HV
Healthy Volunteer
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IOP
Intraocular Pressure


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IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IVT
intravitreal
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed-effect model for repeated measures
MRD
Multiple Rising Dose
NOAEL
No Observed Adverse Effect Level
NSAID
Nonsteroidal anti-inflammatory drugs 
PD
Pharmacodynamics
P-gp
permeability glycoprotein
PGx
Pharmakogenetics
P1NP
procollagen type I N-terminal propeptide
PK
Pharmacokinetics
p.o.
per os (oral)
PoCM
Proof of clinical mechanism
PR
Pulse Rate
PTM
Planned Time
RDC
Remote Data Capture
REML
Restricted Maximum Likelihood Estimation
REP
Residual effect period, after the last dose of medication with 
measureable drug levels or pharmacodynamic effects still likely to be 
present
RPED
Retinal pigment epithelium detachment 
SAE
Serious Adverse Event
SD-OCT
Spectral-domain Optical Coherence Tomography
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SRD
Single rising dose
TCM
Trial Clinical Monitor
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal 
VEGF
Vascular Endothelial Growth Factor


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1.
INTRODUCTION
BI 1026706 is a 
 proposed by Boehringer Ingelheim 
(BI) for the treatment of diabetic macular edema (DME), an ocular complication of diabetes 
mellitus (DM). DME is the most common cause of moderate to severe vision loss in diabetic 
patients, substantially affecting independence and quality of life.
1.1
MEDICAL BACKGROUND
DME is the leading cause of vision loss in persons aged 20 to 74 years and the leading cause 
of blindness in diabetic patients. The disease affects central vision and can lead to decline in 
vision ranging from slight visual blurring to blindness. DME develops in approximately 20% 
of diabetic patients within 15 years following the diagnosis of diabetes. About 8.7 million 
patients suffer from DME worldwide, with about 50% of those having early stages of vision
impairment in line with the targeted patient population (R15-1951).
The exact pathogenesis of DME is only incompletely understood. The disease is 
characterized by intraretinal and subretinal accumulations of fluid due to the leakage of 
intraretinal fluid from perifoveal abnormal retinal capillaries or microaneurysms. Increased 
vasopermeability occurs as a result of breakdown of the blood-retinal barrier (BRB) due to 
many factors. DME is not a condition that develops independently from other diabetic 
findings. Rather, it is closely associated with the degree of diabetic retinopathy (DR) that is 
present, and the duration and type of diabetes that the patient has (R15-5250).
Recent evidence indicates that DR is a neurovascular disease of the retina. There is a strong 
relationship between the development of DR and chronic hyperglycaemia which triggers a 
sequence of events causing vascular endothelial dysfunction (R15-5221), but the pathology 
extends beyond a pure microvasculopathy and includes oxidative stress and inflammatory 
mechanisms, such as increased nitric oxide (NO) production and release of pro-inflammatory 
cytokines (R15-5222, P08-12095). Both oxidative stress and inflammation result in up-
regulation of cytokines, chemokines and growth factors like vascular endothelial growth 
factor (VEGF), which are associated with deleterious effects on vascular and neuronal cells 
and increase of retinal capillary permeability and subsequent retinal edema (R15-5246). 
Until 2010, the standard of care for treating clinically significant macular edema was 
focal/grid laser photocoagulation, reducing the risk of vision loss and increasing the 
possibility of vision gain compared with no treatment. From 2010, pharmacotherapy in the 
form of anti-VEGF agents administered by intravitreal injections has proven to be superior to 
focal/grid laser photocoagulation in decreasing the risk of vision loss and increasing the 
possibility of vision gain. This led to approval of ranibizumab (Lucentis®) in 2010 for the 
indication DME, and of aflibercept (Eylea®) in 2014. In addition, bevacizumab (Avastin®), an 
anti-VEGF agent indicated for the treatment of certain metastatic cancers but not for DME, is 
frequently used as off-label treatment due to its similar efficacy outcomes and reduced costs
(R15-5248). 
Anti-VEGF treatment is characterized by a fast onset of action. After the first injection, about 
half-maximal efficacy was observed, on average, with a mean improvement in visual acuity


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of about 12 letters compared to baseline, as measured by ETDRS letter charts. It was 
demonstrated that DME patients with a mild vision loss at baseline (i.e., ETDRS best 
corrected visual acuity (BCVA) of 78 to 69 letters) have shown a mean gain of about 8 letters 
with an average of 9 intravitreal (IVT) injections after a treatment period of 52 weeks. In 
patients with more severe vision loss with a baseline vision worse than 69 letters a more 
prominent mean gain of 14 to 19 letters with a similar number of injections was observed
(R15-5225). 
Regarding the safety profile, rare but serious adverse reactions are related to the injection 
procedure including endophthalmitis, rhegmatogenous retinal detachment and iatrogenic 
traumatic cataract. Increases in intraocular pressure (IOP) have been noted both pre- and 
post-IVT treatment, as well as sustained elevations in IOP (R15-5524). In addition, there is a 
potential risk of arterial thromboembolic events following intravitreal use of VEGF 
inhibitors. Based on these safety concerns mostly related to the invasive injection procedure 
initiation of anti-VEGF treatment would be preferable deferred to more advanced disease 
stages (i.e., BCVA < 69 letters, approximate Snellen equivalent ≤ 20/40). So far, there are no 
other drugs that have been shown to be equally effective (R15-5223). This leaves treatment 
opportunities for an easy to administer and safer, such as an oral compound to treat early 
stages and intervene earlier in the progressive course of DME in order to preserve vision in 
patients with mild vision impairment due to center-involved DME, characterized by vision 
loss of up to 15 letters, i.e. ETDRS visual acuity ranging from 84 to 70 letters (approximate 
Snellen equivalent < 20/20 and 20/40).
 
 
 
 
 
 
 
 
 
 
 


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1.2.1
Toxicology
Repeat–dose toxicity studies in rat and cynomolgus monkeys (maximum feasible dose of 
1000 mg/kg) with daily oral administration for up to 13 weeks have revealed no adverse 
findings or toxicological target organs with clinical relevance. No Observed Adverse Effect 
Levels (NOAEL) were 1000 mg/kg/day in cynomolgus monkeys, and in the 13-week rat 
study 400 mg/kg in males and 250 mg/kg in females. However, adverse findings in rats were 
considered to be not relevant for humans when BI 1026706 is administered as tablets. Based 
on the revised human therapeutic dose of 25–100 mg b.i.d., corresponding safety margins 
(AUC0-24h and Cmax based) derived from the 13-week studies are 32or higher.
1.2.2
Clinical Studies
The clinical studies completed so far involve the single rising dose (SRD) study in healthy 
volunteers (HV) and the MRD study in HVs and patients with osteoarthritis. Overall, these 
phase I trials evaluating safety, tolerability and PK of BI 1026706 demonstrated that the 
compound was safe and well tolerated with no unexpected safety signal. 
When administered as tablet, BI 1026706 exposure increased dose-proportionally up to 100 
mg and less than dose-proportional at higher doses (200 and 400 mg). Food had a minimal 
impact on AUC and Cmax of BI 1026706 following administration of a 100 mg dose 
suggesting that tablets could be administered with or without food in upcoming patient trials.
For a more detailed description of the drug profile refer to the current Investigator’s Brochure
(IB) (c03035551-01) which is included in the Investigator Site File (ISF).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
By inhibiting 
a reduction of the edema at the fovea region of patients with DME is 
expected, resulting in reduction of the abnormal increase of the central retina thickness and, 
finally, improvement of the central vision. An oral medication capable to treat patients with 
center-involved DME with mild vision loss could fill the gap in which all patients with DME 
could be treated properly without the risk of possible complications of current treatment 
options. Therefore, the target population for BI 1026706 is seen in patients with center-
involved DME and as first-line therapy before anti-VEGF treatment initiation.
This phase 2a study is designed to demonstrate a beneficial effect of oral BI 1026706 on 
retinal lesion morphology for clinical proof of mechanism (PoCM). Therefore, this study will 
investigate the change in central subfield thickness (CSFT) after 12 weeks of treatment, 
 
. This study is also conducted 
as a safety and tolerability trial. The duration of treatment in the current trial is longer than 
that of previous phase I trials and it will therefore serve as a bridging trial between the 
previous phase I MRD study of 12 days duration performed in healthy volunteers and in 
patients with osteoarthritis and the planned phase IIb study of 52 week duration in patients 
with DME. 
2.2
TRIAL OBJECTIVES
The primary objective of the current PoCM study is to explore the mechanistic of BI 1026706
in the treatment of patients with mild vision impairment due to center-involved DME and to 
evaluate safety and tolerability of BI 1026706 administered orally twice daily for 12 weeks.
 
Concentrations of BI 1026706 in plasma will be determined to allow for exploratory 
pharmacokinetics (PK)/pharmacodynamic (PD) correlations to efficacy parameters. 
 
Also, safety assessed throughout the study will provide key information regarding the 
appropriateness of using BI 1026706 as a long-term treatment in DME by extending exposure 
to 12 weeks in the current study.
 
 
 


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2.3
BENEFIT - RISK ASSESSMENT
BI 1026706 has not been previously investigated in patients with DME or other ocular 
diseases, and the sponsor is not aware of any clinical studies on the effects of orally 
administered 
 in patients with DME. Although DME may be successfully 
treated in most patients using IVT injections with anti-VEGF biologics, not all patients 
respond adequately and there is room for additional efficacy. Intravitreal treatment requires
multiple injections over time and the procedure carries the risk of endophthalmitis, vitreous 
hemorrhage, retinal detachment, traumatic cataract, and increased intraocular pressure (IOP). 
An equally effective oral therapy would be considered an attractive medical advance. 
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 
CSFT or on clinical symptoms such as vision impairment related to DME for those patients 
following 12 weeks of treatment with BI 1026706. 
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 DME is detected during the trial 
(please also refer to Section 4.2.1). Beyond close monitoring of DME symptoms, lesion 
morphology, clinical laboratory parameters and clinical evaluations there is no specific 
benefit for these patients. However, the inclusion of a placebo group is essential for the 
evaluation of the safety and tolerability of BI 1026706 in DME which have not been studied 
so far.
Given the high unmet need for an effective oral treatment for DME, good clinical tolerability 
of BI 1026706 coupled with a favorable risk/ benefit ratio supports the conduct of this study.
Early pharmacokinetic and safety evaluations of orally administered BI 1026706 
demonstrated that treatment was well tolerated at potentially relevant levels and support 
further clinical development. Safety will be monitored (as described in Section 5.3) at each 
clinic visit. This study will therefore provide insight into the safety profile of BI 1026706 in 
the target population over a longer treatment period of 12 weeks to allow bridging to further
studies with longer treatment duration. 
The risk of inclusion patients with DME is acceptable based on the data and trial results 
mentioned in Section 2.3.2 below. The patients participating in this study will be exposed to

the risks of the study procedures

the known risks related to exposure to the investigational product

unknown risks that might be related to exposure to the investigational product.
2.3.1
The risks of the study procedures
SD-OCT is an established medical imaging technique that uses eye-safe near-infrared light 
without damage to the tissue.
 
 Other study 
procedures such as routine ocular examinations, 
, electrocardiography 
(ECG) recording, blood pressure measurements or collection of blood are unlikely to cause 
any adverse events.


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2.3.2
Drug related risks
BI 1026706 was overall well tolerated at all dose levels (both oral solution and tablet 
formulation) in the three single dose studies 1320.1, 1320.3, and 1320.13 and in the MRD
study 1320.2 in which it was administered for up to 12 days. However, some gastrointestinal 
effects were observed in subjects treated with high doses (200 or 300 mg q.d.) of oral solution 
in the MRD study, most likely due to the amount of excipients in the final solution. In this 
study, a solid tablet formulation will be used.
Based on in-vitro data, BI 1026706 exposure may be affected by inhibition or induction of 
cytochrome P 450 (CYP) 3A4 and permeability glycoprotein 1 (P-gp). The potential of 
BI 1026706 as a perpetrator of drug-drug interactions (DDI) is expected to be low. A DDI
trial (1320.20) to evaluate the impact of CYP 3A4 and P-gp inhibition on the 
pharmacokinetics of BI 1026706 is ongoing. Specific medication exclusion criteria will 
ensure that the DDI risk is minimized (see Section 4.2.2).
Data obtained in the SRD and the MRD trials suggest that renal excretion of unchanged drug 
is a minor elimination pathway in humans with relative fractions of unchanged drug <4% and 
<3.5%, respectively (values expressed as GeoMean). Therefore, no accumulation of 
BI 1026706 is expected in patients with mild to moderate renal insufficiency.
 
 
 
 
 
Although rare, a potential for drug-induced liver injury 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 5.3.6.1.
Females will only be included in this trial if they are of non-childbearing potential.
Overall BI 1026706 showed an acceptable safety profile supporting a parallel-design in Phase 
IIa. For further details, please refer to the IB (c03035551-01).


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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 mechanism study. Patients will be enrolled into the study once they have signed the 
informed consent form. Patients become eligible for randomization if they have met all 
inclusion and none of the exclusion criteria. Entered patients will take 100 mg b.i.d. of 
BI 1026706 or placebo from Day 1 to Day 84 (12 weeks). Following conclusion of a 12 week 
treatment period, or upon withdrawal from study medication, all patients will be eligible to 
receive standard of care therapy at the discretion of the Investigator. Patients will be followed 
up at the End of Study Visit four weeks after the End of treatment Visit 5/EOT. 
The 12 weeks treatment design is described in Figure 3.1: 1.
Figure 3.1: 1
Study Design
3.1.1
Administrative structure of the trial
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to 


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-
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,
-
order the materials as needed for the trial, 
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information
can be found in the ISF.
A Coordinating Investigator will be nominated and will be responsible to coordinate 
Investigators at different centres participating in this multicentre trial. Tasks and 
responsibilities will be defined in a contract. Relevant documentation on the participating 
(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in ISF.
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 pharmacodynamics, safety, tolerability and PK of 100 mg b.i.d. of BI 1026706 in 
patients with mild vision loss due to center-involved DME. Because an efficacious therapy is 
available for patients with DME who experience at least moderate visual loss (defined as a 15 
or more letter score decrease in visual acuity), this trial aims to treat DME patients with only 
mild vision loss in order to stabilize or even improve central macular edema early in the 
course of the disorder where it is a reasonable alternative to observe disease progression with 
the possibility of initiation of rescue treatment at any time during the study.
The study is a short clinical proof of mechanism trial, and given a rather slow progression of 
DME the duration of the study is considered sufficient to assess the primary outcome of 
change from baseline in comparison to placebo by SD-OCT in lesion morphology (R15-
5225). The chosen primary outcome is objective with minimal time related effects expected 
and is therefore appropriate. 
A placebo control arm was chosen for this trial in order to compare BI 1026706 and placebo 
regarding safety and tolerability in patients with DME, which is another important aim of the 
trial. The treatment period of 12 weeks is deemed adequate to evaluate safety and tolerability, 
and is covered by currently available 13 weeks toxicology data.
Approximately equal numbers of patients will be randomized to both treatment groups. 
Randomization will be stratified by previous treatment for DME into treatment naïve versus 
previously treated patients as this may have impact on the expected effects regarding the 
primary outcome.
There is the possibility of rescue treatment according to standard of care interventions in the 
case of significant worsening of clinical and PD parameters at all times during the study for 
both treatment arms, BI 1026706 and placebo. 


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3.3
SELECTION OF TRIAL POPULATION
A sufficient number of male and female patients with DM either type 1 or type 2 and center-
involved DME with mild vision loss will be screened to ensure the randomization of 100 
patients from around 44 study sites. The reason for conducting the study with many sites lies 
with the expected enrolment rate which might be low, as patients are only mildly affected and 
pure observation is a reasonable option before starting standard intravitreal injection therapy.
To take account of the consistent evaluation of endpoints at all sites only prequalified study 
sites will participate, and SD-OCT images will be evaluated by an independent central 
reading center (CRC).
It is expected that around 2-3 patients will be randomised at each study site. If enrolment is
delayed, additional sites may be recruited. Permission to enrol more than 15 patients per site
must be obtained from the 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 study is competitive across all countries within the study, i.e.
screening for the study will stop at all sites when it is anticipated that a sufficient number of
patients have been screened to yield the desired number of patients randomised to trial
treatment. Investigators will be notified when sufficient patients have been screened and
when screening is complete, and will not be allowed to recruit additional patients for the
study. Patients who have completed Visit 1 procedures prior to notification of the termination 
of recruitment will be allowed to continue in the study, if they meet all entry criteria and they 
are able to follow the visit schedule specified in this Clinical Trial Protocol (CTP).
A screening 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.
3.3.1
Main diagnosis for trial entry
Patients with vision loss due to center-involved DME at the Screening visit are eligible for 
inclusion if they fulfil all of the inclusion criteria and none of the exclusion criteria. Only one 
study eye per subject may be enrolled. Ophthalmologic evidence of center-involved DME 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 in- and exclusion criteria.
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 exclusion criteria, this eye will qualify 
for the study eye;
o If both eyes in an individual patient meet all of the inclusion criteria and none of the 
exclusion criteria, the eye with the larger CSF thickness (CSFT) will qualify for the study 


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eye; the fellow eye will be examined only for safety reasons and will be not enrolled into 
the analysis of the primary endpoint;
If both eligible eyes show the same size of CSFT, the eye with the worse BCVA letter 
score as assessed by ETDRS chart will qualify for the study eye; 
If both eligible eyes show the same size of CSFT and the same BCVA letter score, the 
eye with the clearer lens will qualify for the study eye;
If both eyes show exactly the same conditions mentioned before, the investigator 
together with the patient may decide which eye will be selected as the study eye.
3.3.2
Inclusion criteria
1.
Age ≥ 18 years
2.
Male patients or female patients of non-childbearing potential 1
3.
Diagnosis of DM (type 1 or type 2) as evidenced by one of the following:
-
Current regular use of insulin for the treatment of diabetes
-
Current regular use of oral anti-hyperglycaemia agents for the treatment of diabetes
-
Documented diabetes by American Diabetes Association (ADA) and/or World Health 
Organization criteria
4.
Retinal thickening due to DME involving the center of the macula in the study eye as 
confirmed by the Investigator on clinical exam
5.
DME confirmed on SD-OCT with CSFT 300 µm in the study eye at screening, 
confirmed by CRC
6.
Best corrected visual acuity ETDRS letter score in the study eye ≤ 84 and 70 at 
screening
7.
Media clarity, pupillary dilation and individual cooperation sufficient for adequate SD-
OCT and fundus photographs
8.
Signed and dated written informed consent consistent with GCP and local legislation 
prior to admission to the trial. Medication washout and medication restrictions are 
allowed only after signed informed consent is obtained.
3.3.3
Exclusion criteria
1.
Macular edema considered to be due to other causes than DME in the study eye.
An eye should not be considered eligible if:
-
The macular edema is considered to be related to ocular surgery, such as cataract 
extraction, or
-
Clinical examination and/or SD-OCT suggest that vitreoretinal interface abnormalities 
are contributing to the macular edema, such as a taut posterior hyaloid or epiretinal 
membrane
2.
Additional eye disease in the study eye that, in the opinion of the Investigator, might 
affect macular edema or could compromise or alter visual acuity during the course of the 
study (e.g., vein occlusion, uncontrolled intraocular pressure (IOP) >24 mmHg on 
                                                
1 Women of non-childbearing potential are defined as:
- postmenopausal (12 months with no menses without an alternative medical cause) or
- permanently sterilized (defined as hysterectomy, bilateral oophorectomy or bilateral salpingectomy).


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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) 
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.
An ocular condition is present in the study eye such that, in the opinion of the 
Investigator, any visual acuity loss would not improve from resolution of macular edema, 
e.g., foveal atrophy, dense subfoveal hard exudates, pigment abnormalities or fibrosis
5.
Intraocular surgery in the study eye within 4 months prior to randomization or planned 
intraocular surgery, including cataract, during the study period
6.
History of yttrium aluminium garnet (YAG) laser capsulotomy performed in the study 
eye within 2 months prior to randomization
7.
Proliferative diabetic retinopathy or iris neovascularisation (including the anterior 
chamber angle, ruled out by gonioscopy) in the study eye
8.
Aphakia in the study eye
9.
Any indication that requires immediate treatment or for which treatment is expected in 
the study eye with anti-VEGF or with laser photocoagulation during the course of the 
study, as per Investigator’s judgment 
10. History of prior laser photocoagulation or other surgical, intravitreal or peribulbar 
treatment in the study eye within 4 months prior to randomization, either for DME or an 
ocular condition other than DME
11. History of fluocinolone acetonide intravitreal implant in the study eye
12. Application of intraocular corticosteroids in the study eye within 2 years prior to 
randomization in phakic eyes or 9 months in pseudophakic eyes
13. History of topical steroid or nonsteroidal anti-inflammatory drugs (NSAID) treatment in 
the study eye within 30 days prior to randomization
14. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization
15. Use of systemic steroids >10 mg prednisone equivalent/day within 4 weeks prior to 
randomization or known diseases which could require the use of such systemic steroids 
within the study period
16. Current or planned, during the study period, use of medications known to be toxic to the 
retina, lens or optic nerve 
17. Initiation of intensive insulin treatment (multiple daily injections or a pump) within 3 
months prior to randomization or plans to do so in the next 4 months
18. Change in oral antidiabetic medication within 3 months prior to randomization
19. Patients with a clinically relevant abnormal screening haematology, blood chemistry, or 
urinalysis, if the abnormality defines a significant disease as defined in other exclusion 
criteria; AST or ALT greater than 2.0-fold the upper limit of normal; Patients with total 
bilirubin (TB) or INR> 1.5x upper limit of normal.  Laboratory testing may be repeated 
once during the screening phase
20. Renal impairment with estimated creatinine clearance (CrCL; as calculated by 
Cockcroft-Gault equation) < 30 mL/min at screening, or where Investigator expects 
CrCL is likely to drop below 30 ml/min during the course of the study
21. Myocardial infarction or unstable angina pectoris within 3 months before randomization


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22. Uncontrolled arterial hypertension defined as a single measurement of systolic >180 
mmHg, two consecutive measurements of systolic >160 mmHg, or diastolic >100mmHg 
on optimal medical regimen. If blood pressure is brought ≤160/100 mmHg by 
antihypertensive treatment, individual can become eligible
23. Significant disease or other medical conditions* as determined by medical history, 
examination and clinical investigations at screening that may, in the opinion of the 
Investigator, result in any of the following:
-
Put the patient at risk because of participation in the study, 
-
Influence the results of the study, 
-
Cause concern regarding the patient’s ability to participate in the study. 
*e.g. cardiac, gastro-intestinal, hepatic, renal, metabolic, dermatologic, neurological, 
haematological, oncological and psychiatric; history of relevant orthostatic hypotension, 
fainting spells or blackouts; current chronic or relevant acute infections including 
external ocular infections in the study eye such as significant blepharitis, chalazion or 
conjunctivitis; patients with malignancy for which the patient has undergone resection, 
radiation or chemotherapy within past 5 years. Patients with treated basal cell carcinoma 
or fully cured squamous cell carcinoma are allowed
24. Patients with a history of and/or active significant alcohol or drug abuse, as assessed by 
the Investigator
25. Known allergy to any component of the study drug
26. Women of childbearing potential or who are nursing
27. Male patients who do not agree to minimize the risk of female partners becoming 
pregnant from the first dosing day until 3 months after the trial medication treatment has 
finished 1
28. Patients who have participated in another investigational trial within the last 30 days 
preceding randomization with any drug that has not received regulatory approval or are 
participating in another trial (patients participating in a purely observational trial will not 
be excluded)
29. Previous randomization in this trial.
                                                
1 Male patients who have sexual intercourse with women of childbearing potential will be instructed and must 
agree to use at least one of the following acceptable forms of effective contraception:
- Established use of oral, injected or implanted hormonal methods of contraception by the female partner of the 
male patient
- Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female partner of the male 
patient
- Use of barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/suppository
- Sterilization of the male patient (with the appropriate post-vasectomy documentation of the absence of sperm 
in the ejaculate).


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3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient is to be withdrawn from study treatment if:

The patient withdraws consent for study treatment or study participation, without the need 
to justify the decision.

The patient needs to take concomitant drugs that interfere with the investigational product 
in the clinical judgement of the Investigator (please refer to Section 4.2.2).

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy).
Patients who drop out prior to randomization will be considered screening failures. They will 
be recorded as screening failures in the electronic Case Report Form (eCRF) and no further 
follow-up is required. The data will be included in the trial database and will be reported.
Patients who discontinue or withdraw from the study after randomization (Visit 2a) will be 
considered as “early discontinuations” and the reason for premature discontinuation must be
recorded in the eCRFs. For patients stopping the treatment prematurely before end of week 
12, all investigations according to Visit 5/EOT should be done as soon as possible after 
stopping the study drug. The End of study Visit (Visit 6) will be performed 28 days after 
Visit 5/EOT in all patients, as outlined in the Flow Chart and Section 6.2.3. The data will be 
included in the trial database and will be reported.
Patients who withdraw or discontinue from the trial after randomization will not be replaced.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim 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 CTP, or the contract disturbing 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
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product(s) and comparator product(s)
Table 4.1.1: 1
Test product (active drug):
Substance:
BI 1026706
Pharmaceutical formulation:
Film-coated tablets (Formulation B1)
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG,
Birkendorfer Str. 65, 88397 Biberach
Germany
Unit strength:
100 mg
Posology
Twice daily
Route of administration:
oral
Table 4.1.1: 2
Comparator product (placebo):
Substance:
Placebo to match BI 1026706
Pharmaceutical formulation:
Film-coated tablets (Formulation B1)
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG,
Birkendorfer Str. 65, 88397 Biberach
Germany
Unit strength:
Placebo to match 100 mg
Posology
Twice daily
Route of administration:
oral
4.1.2
Method of assigning patients to treatment groups
During randomisation visit (Visit 2a) and after the patient’s eligibility has been reconfirmed, 
the treatment will be assigned via Interactive Response Technology (IRT). To facilitate the 
use of the IRT, the Investigator will receive all necessary instructions.


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4.1.4
Drug assignment and administration of doses for each patient
At Visit 2a (Day 1) eligible patients will be randomized to one of 2 double-masked oral
treatment groups (BI 1026706 100 mg b.i.d. or placebo matching to the active drug b.i.d., 
ratio 1:1) using an IRT system. The medication will be administered twice daily, beginning 
on Day 1 (Visit 2a) until in the evening of the day before Visit 5/EOT (Day 84 according to 
the visit schedule). 
Trial medication is dispensed every month at regularly scheduled study visits (i.e., Visit 2a –
4). The first study medication dose at Visit 2a is given to the patient by the site staff at the 
investigational site, and trial medication boxes are then dispensed to the patient for home 
administration (please refer to Section 4.1.4.2). Study drug kits will contain enough supply to 
last until the next visit plus some overage. The assigned medication numbers must be entered 
in the eCRF.
4.1.4.1
Study medication administration at the study site
At Visits 2a, 3 and 4 during the treatment period, the administration of study medication is 
under the supervision of the Investigator or qualified site staff. One tablet (BI 1026706 or 
placebo) will be administered with or without a glass of water. At Visit 3 and 4, new study
medication boxes will be used for administration of the morning dose at the clinical site after
blood sampling (please refer to Appendix 10.2 for details) and will be dispensed for home 
administration.
4.1.4.2
Study medication administration at home 
At home, tablets (BI 1026706 or placebo) will be self-administered by the patients.
Patients should be instructed to take their study medication twice daily: one tablet each 
morning and one tablet each evening, at the same time every day, with or without a glass of 
water. 
To ensure a dose interval of about 12 hours, the medication should be taken every day 
approximately at the same time between 07:00 and 11:00 a.m. / 07:00 and 11:00 p.m.


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If trial medication is not taken at the site, patients will be requested to document the time 
points of each administration in their study medication diary. If the study drug was not 
administered as planned, the reason should be provided in the diary by the patient. A new 
diary will be dispensed at every visit during the treatment phase and will be collected at the 
following visit by the site (please refer to the Flow Chart).
No double doses should be taken, and dose reductions are not permitted.
If a scheduled dose is missed by:
less than 6 hours after the scheduled dose time, the patient must take the missed dose and 
take all remaining doses at scheduled time. The error must be logged in the Medication 
diary and reported to the study doctor at the next study visit.
six (6) hours or more after the scheduled dose time, the patient must skip the missed dose 
and take the next scheduled dose; subsequent doses must be taken at the scheduled time 
according to the CTP. The error must be logged in the Medication diary and reported to 
the study doctor at the next study visit.
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.
The site staff will instruct and remind the patients prior to the next visit
- how to fill in the study medication diary and to bring the diary to the next visit
- not to take their study 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 study medication blisters within the box (regardless of whether empty or not) 
back to the investigational site.
4.1.4.3
Returning of study medication after home administration 
During on-site Visits 3, 4 and 5/EOT, the returned trial medication kits and the patient’s diary 
have to be collected and assessed to determine whether the patient took the medication 
correctly and the times and dates are filled in. Any discrepancy has to be documented by the 
Investigator. Regarding calculation of treatment compliance please refer to Section 4.3.
4.1.5
Masking and procedures for Unmasking
4.1.5.1
Masking
Masking in this trial is double blind, i.e. 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.
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 pharmacokinetic (PK) samples taken from placebo 


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patients. Bioanalytics will not disclose the randomization code or the results of their 
measurements until the trial is officially unblinded.
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 
documented in the source documents and/or appropriate CRF page along with the date and 
the initials of the person who broke the code.
4.1.6
Packaging, labelling, and re-supply
The trial medication (BI 1026706, placebo) will be provided by the Department of 
Pharmaceutical Development of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, 
Germany. 
The clinical trial supply consists of boxes (treatment kits) labelled with the trial identification 
and medication kit numbers. Each box will contain 5 blisters, each containing 14 tablets of 
BI 1026706 or Placebo matching BI 1026706. 
The boxes will be labelled according to the country regulatory requirements. 
Supply and re-supply will be managed by the IRT system. 
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.
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 trial protocol by the IRB / ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of 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.
The Investigator and/or pharmacist and/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 alternative disposal of unused products. 
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 


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document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor or appointed contract research organisation (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
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
As per judgment of the Investigator, administration of local standard of care treatment such 
as IVT or peribulbar injections, or laser or other surgical treatment of DME like anti-VEGF, 
intravitreal or peribulbar corticosteroids or focal/grid macular photocoagulation is allowed in 
clinically significant worsening of the disease, and may be considered in the event of vision 
loss of ≥5 letters or in the event of CSFT increase of ≥10% as compared to the previous visit 
confirmed by the CRC.
After the end of treatment with study medication (Visit 5/EOT), 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. 
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
An overview of restricted medications is provided in Table 4.2.2.1: 1 with examples of 
individual drugs. However, it remains the Investigators’ responsibility to exclude any drugs 
that are described as potent and moderate CYP/P-gp inhibitors/inducers or sensitive 
substrates of the given CYP enzymes/P-gp/ Breast Cancer Resistance Protein (BRCP) with a 
narrow therapeutic window that are not present in the footnotes of Table 4.2.2.1: 1.
Table 4.2.2.1: 1 
Restricted medication
Class
Instruction / Explanation
Investigational drugs
Not permitted, see exclusion criterion number 27
Systemic anti-VEGF or pro-VEGF 
treatment
Not permitted 4 months prior to first trial drug administration (Day 1, 
Visit 2a) and during the trial
Oral corticosteroids >10 mg 
prednisone equivalent/day or high 
potency topical steroids with 
systemic exposure 1
Not permitted 4 weeks prior to first trial drug administration (Day 1, 
Visit 2a) and during the trial (including combinations containing 
corticosteroids) 


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Table 4.2.2.1: 1 
Restricted medication (continued)
Class
Instruction / Explanation
Drugs that may affect macular 
edema, such as glitazones, 
latanoprost, niacin (vitamin B3)
Not permitted 4 weeks prior to first trial drug administration (Day 1, 
Visit 2a) and during the trial
Drugs that may affect the retina or 
optic nerve, such as quinolones, 
thioridazine, deferoxamine, 
ethambutol, vigabatrin
Not permitted during the trial
Potent and moderate CYP3A4 
inhibitors 2
Not permitted 4 weeks prior to first trial drug administration (Day 1, 
Visit 2a) and during the trial
Potent and moderate CYP3A4 
inducers 2
Potent and moderate P-gp inhibitors 
(drugs causing > 2-fold increase in 
AUC of sensitive substrate) 2
Potent and moderate P-gp inducers 
(drugs causing > 50% decrease in 
AUC or 50% increase in clearance of 
sensitive substrate) 2
Sensitive CYP3A4, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, P-gp 
and Breast Cancer Resistance Protein 
(BCRP) substrates with a narrow 
therapeutic window 3
Not permitted 4 weeks prior to first trial drug administration (Day 1, 
Visit 2a) and during the trial
1 Use of less than or equal to 10 mg prednisone equivalent per day is allowed if taken as stable medication for at least 4 
weeks prior to randomization. 
2 Examples for CYP3A4/P-gp inhibitors/inducers: aprepitant, avasimibe, boceprevir, bosentan, carbamazepine, casopitant, 
cimetidine, clarithromycin, cobicistat, conivaptan, crizotinib, cyclosporine , ciprofloxacin, diltiazem, dronedarone, 
efavirenz, enzalutamide, erythromycin, etravirine, fluconazole, genistein, , imatinib, indinavir, itraconazole, ketoconazole, 
lapatinib, ledipasvir, lersivirine, lomitapide, lopinavir, mibefradil, mitotane, nafcilin, nefazodone, netupitant, 
phenobarbital, phenytoin, posaconazole, quinidine, rifabutin, rifampin, ritonavir, saquinavir, semagacestat, talviraline, 
telaprevir, telithromycin, thioridazine, tofisopam, troleandromycin, valspodar, verapamil, voriconazole. Grapefruit juice 
and Hypericum perforatum (St. John's Wort) are not allowed 5 days prior to randomization and during the trial.
3 Examples for substrates: CYP3A4: alfentanil, astemizole, cisapride, cyclosporine, diergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus; CYP2C8: paclitaxel; CYP2C9: warfarin, phenytoin; CYP2C19: S-mephenytoin; 
P-gp: digoxin; BCRP: methotrexate.
All concomitant medication has to be assessed by the Investigator as to whether it is a 
moderate or strong inducer or inhibitor of CYP3A4 or P-gp based on the summary of product 
characteristics (SPC), if applicable. Specific questions of eligibility based on this criterion 
should be clarified by the clinical monitor prior to inclusion.
Systemic corticosteroids: Use of less than or equal to10 mg prednisone equivalent per day is 
allowed if taken as stable medication for at least 4 weeks prior to randomization.
At the day of the visits, patients may take their concomitant medication as usual.


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4.2.2.2
Restrictions on diet and life style
Diet and lifestyle restrictions before and after administration of trial medication:
Citrus fruits, in particular grapefruits and Seville oranges (sour or bitter oranges), and their 
juices as well as products containing St. John's Wort (Hypericum perforatum) are not 
permitted 5 days prior to the first trial drug administration (Day 1, Visit 2a) and until the end 
of the treatment period (Visit 5/EOT).
Because blood concentrations of lipids will be determined one time during the study at 
baseline, patients need to have fasted overnight before Visit 2a until blood collection.
Safety blood markers of 
on Visits 2a, 5/EOT and 6/End of Study will be 
taken in the morning together with other blood parameters, prior to administration of trial 
medication (if applicable). The 
 samples at subsequent visits should be taken as 
close as possible to the time of day as the sample taken on Day 1 (Visit 2a). Please refer to 
Appendix 10.2 for further details.
There are no restrictions concerning food and liquid intake, therefore BI 1026706 may be 
taken with or without food. 
4.2.2.3
Restrictions regarding women of childbearing potential, pregnancy and 
breastfeeding
Female patients will only be included in this trial if they are of non-childbearing potential and 
are not pregnant or breastfeeding (see also Section 3.3).
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on counts, treatment compliance will be calculated as the number of capsules taken, 
divided by the number of capsules which should have been taken according to the scheduled 
period, multiplied by 100. Compliance will be verified by the on-site monitor authorised by 
the Sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
     Number of tablets which should have been taken
The patient will complete a patient diary confirming that trial medication at home has been 
taken correctly during treatment period. If the number of doses taken is not between 80-
120%, site staff will explain the patient the importance of treatment compliance.


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5.
VARIABLES AND THEIR ASSESSMENT 
5.1
TRIAL ENDPOINTS
5.1.1
Primary Endpoint 
The primary endpoint will be the change from baseline in CSFT at week 12, as measured by 
SD-OCT. Baseline CSFT is determined at Visit 2a.
5.1.2
Secondary Endpoints:
Safety and tolerability of BI 1026706 will be assessed by frequency (in percent) of adverse 
events over the treatment period.
5.2
ASSESSMENT OF EFFICACY
For the endpoints, baseline is defined as the value at Visit 2a, and if not measured at Visit 2a 
then baseline is the value at Visit 1. Examinations will be performed on both eyes, but 
efficacy will be assessed only in the study eye. The centrally collected ophthalmological data 
will be transferred from the CRC to the sponsor’s database. The local measurement data will 
remain at the study sites as source documents.
Spectral-domain Optical Coherence Tomography (SD-OCT)


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The retinal layers and thickness can be visualized and measured by OCT. The assessment
will be performed by a qualified person, and only specified OCT equipment will be used. For 
a given study participant, the same SD-OCT machine type should be used for the duration of 
the study. OCT images will be sent to an independent CRC for evaluation. A detailed 
Imaging Manual for image acquisition and data transmission will be provided.
Next to the central foveal subfield also the other subfields of the inner ring (3.0 mm diameter) 
of the SD-OCT scan will be analyzed in an exploratory manner. The measurements at Visit 
2a (Randomization visit) provide baseline values.
 
 
 
 
 
 
 
 
5.3
ASSESSMENT OF SAFETY
Changes in physical examination, vital signs, safety-related findings detected in 
ophthalmologic examinations, safety laboratory parameters and ECG will be recorded as 
(S)AEs in the eCRF if they are judged clinically relevant by the Investigator.
5.3.1
Physical examination
A physical examination including height (measured only at Screening), body weight and 
assessment of the head/neck, skin, upper and lower extremities, thorax, abdomen and nervous 
system will be carried out by a physician according to the Flow Chart. In addition, further 
physical examination should be performed if clarification of an AE is necessary. Height/body 
weight and all clinically significant findings at screening will be documented in the source 
documents and recorded in the eCRF as baseline conditions.
New findings or worsening of screening conditions at follow-up physical examinations that 
are, in the opinion of the Investigator, clinically significant or meet other adverse event 
criteria defined in Section 5.3.5 will be reported as adverse events (AEs).
5.3.2
Vital Signs
Systolic and diastolic blood pressure (BP) and pulse rate (PR) will be measured after the 
patient has rested for at least 5 min in the sitting position. The measured vital signs will be 
documented in the source documents and recorded in the eCRF.


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5.3.3
Ophthalmological examinations
All ophthalmological assessments will be performed for ocular safety in both eyes. Safety-
related findings (clinically relevant changes during the study) will be entered in the eCRF as 
AEs.
The following ophthalmological examinations will be assessed in both eyes in a descriptive 
way as indicated in the Flow Chart; the results will be entered in the eCRF:
Slit lamp: The anterior and posterior segment of the eye should be assessed according to 
local procedure. Evaluation of the posterior pole may be performed by slit lamp evaluation 
or by indirect ophthalmoscopy, according to local procedures.
Ocular tonometry: Goldmann applanation tonometry is the preferred method to measure 
the intraocular pressure (IOP) in both eyes. Tonometry will be performed as the final 
ophthalmological exam at the visit days in order to avoid influence of the applanation on 
other ocular assessments.
5.3.4
Safety laboratory parameters
Detailed instructions for laboratory safety blood and urine sampling, handling and shipment 
of samples will be provided in the ISF/laboratory manual.
5.3.4.1
Safety laboratory parameters obtained from blood
The laboratory parameters to be determined in this study are listed in Table 5.3.4.1: 1 and 
will be performed by a central laboratory. Coagulation parameters will be collected at two 
visits together with other safety blood parameters. The respective reference ranges will be 
provided in the ISF. Regarding timing of sampling of safety blood markers please refer to the 
Flow Chart, Appendix 10.2 and to Section 6.2.
 
 
Additional instructions for biomarker sampling, handling and shipment of samples are 
provided 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 adverse events (please refer to Section 5.3.6).
In case the criteria for hepatic injury defined in Section 5.3.6 (protocol-specified adverse 
events of special interest) are fulfilled, a number of additional measures will be performed
(please refer to Section 5.3.6 and 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.


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Table 5.3.4.1: 1
Blood samples will be collected for the following tests in accordance 
with the visit Flow Chart and Appendix 10.2:
Category
Test name
Chemistry
AST (GOT)
ALT (GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Creatinine
Creatinine clearance (CrCL)1
Albumin
Sodium
Potassium
Calcium
Magnesium
Chloride
Inorganic phosphate
Bicarbonate
Bilirubin Total
Bilirubin Direct, if total is elevated
Bilirubin Indirect, if total is elevated
Protein, Total
Uric Acid
Glucose, non-fasting (fasting only at Visit 2a)
1Creatinine Clearance according to the Cockcroft-Gault formula


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Table 5.3.4.1: 1
Blood samples will be collected for the following tests in accordance 
with the visit Flow Chart and Appendix 10.2 (continued):
Category
Test name
Chemistry
HbA1c (only at Visit 2a and Visit 5/EOT)
Total cholesterol (only at Visit 2a)
LDL cholesterol (only at Visit 2a)
HDL cholesterol (only at Visit 2a)
Triglycerides (only at Visit 2a)
Coagulation
Activated Partial Thromboplastin Time (=aPTT) (at 
Visits 2a and 5/EOT)
Prothrombin time (Quick and INR) (at Visits 2a and 
5/EOT)
Haematology
Haematocrit (Hct)
Haemoglobin (Hb)
Red Blood Cell Count/ Erythrocytes
MCV (mean corpuscular volume)
MCH (mean corpuscular haemoglobin)
MCHC (Mean Cellular haemoglobin Concentration)
Reticulocyte Count
White Blood Cells / Leukocytes
Platelet Count/ Thrombocytes
Diff. automatic (manual if 
diff. automatic is abnormal)
- Neutrophils 
- Eosinophils 
- Basophils
- Monocytes
- Lymphocytes 
Urinalysis (Stix)
Urine Nitrite
Urine Protein, semiquantitative; 
     -> if abnormal, albuminuria will be determined 
quantitatively
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/ Erythrocytes
Urine WBC/ Leukocytes
Urine pH
Urine creatinine


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Table 5.3.4.1: 1
Blood samples will be collected for the following tests in accordance 
with the visit Flow Chart and Appendix 10.2 (continued):
Category
Test name
Albumin content and Urine-
Sediment, microscopic 
examination (both only if urine 
analysis abnormal)
Urine Albumin content
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epith Cells
Urine Sediment RBC/ Erythrocytes
Urine Sediment WBC/ Leucocytes
5.3.4.2
Safety laboratory parameters obtained from urine
Urine parameters will be performed by the central laboratory. The urine sediment 
examination will only be done if the urine dipstick analysis is abnormal. 
Clinically relevant abnormal findings as judged by the Investigator will be reported as 
adverse events (please refer to Section 5.3.6).
5.3.5
Electrocardiogram (ECG)
A centralized ECG assessment will be used for this study. All ECGs will be printed locally 
and evaluated by the Investigator or a designee; in addition, there is a central cardiologist 
over-read. 
Details of the procedure will be included in the ISF. Twelve-lead ECGs (I, II, III, aVR, aVL, 
aVF, V1-V6) will be recorded using equipment provided by a central ECG vendor. The 
ECGs will be recorded for a 10-second duration after the patient has rested for at least 5 
minutes in a supine position. Electrode placement will be performed according to the method 
of Einthoven/Goldberger (ankles and wrists). At all time-points indicated in the Flow Chart
single ECG will be recorded, but records may be repeated for quality reasons and the repeat 
ECG will be used for analysis. Additional ECGs may be collected by the Investigator for 
safety reasons. Printed ECG-records will be stored at the investigational site.
Clinically relevant abnormal findings as judged by the Investigator will be reported as 
baseline conditions at screening or as AEs during the trial. 
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 
transferred from the ECG reading centre to the Sponsor. 
5.3.6
Assessment of adverse events
5.3.6.1
Definitions of adverse events
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.


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An AE can therefore be any unfavourable 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.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and
unintended. Response in this context means that a causal relationship between a medicinal
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise
from use of the product within or outside the terms of the marketing authorization or from
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening (this 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 hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity or

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon 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.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of 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 given 
above.
The latest list of “Always Serious AEs” can be found in the RDC system. These events 
should always be reported as SAEs as described in Section 5.3.6.2.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
Worsening of the underlying disease or of other pre-existing conditions 
The following should also be recorded as an (S)AE in the eCRF and SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions and/or


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changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
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. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.6.2.
The following are considered as AESIs:

Hepatic injury defined by the following alterations of hepatic laboratory parameters: 
o 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
o Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These laboratory findings constitute a hepatic injury alert and patients showing these 
abnormalities need to be followed up according to the “DILI checklist” provided in the 
RDC-system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain etc.) without available 
laboratory results (ALT, AST, total bilirubin), the Investigator should make sure these 
parameters are analysed, 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, provided in the Investigator Site File (ISF).
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate: Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities.
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal
relationship between a suspected medicinal product and an adverse event. An adverse
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship
between a medicinal product and an occurrence is suspected.


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Medical judgment 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 aetiologies that could explain the event (e.g. preexisting 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 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 study drug treatment continues or remains
unchanged.
5.3.6.2
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate eCRF by the
Investigator:
•
From signing the informed consent onwards through the Residual Effect Period (REP) 
until individual patient’s end of study: 
- all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of study: 
- the Investigator does not need to actively monitor the patient for AEs but should only 


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report SAEs and AESIs of which the Investigator may become aware of, if considered 
relevant by the Investigator.
Figure 5.3.6.2: 1 Collection and reporting of AEs/SAEs during the study
The REP is defined as 4 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment; please see Section 7.3.4. Events which occurred after the REP will be considered 
as post-treatment events.
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.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication.
All (S)AEs, including those persisting after individual patient’s end of study must be 
followed up until they have resolved, have been sufficiently characterized, or no further 
information can be obtained.
Pregnancy
Females will only be included in this trial when they are of non-childbearing potential (please 
see Exclusion criteria). However, measures have to be defined in the event of pregnancy. 
In the unlikely event that a female subject participating in this clinical study becomes 
pregnant after having taken study medication, the Investigator must report immediately 


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(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF) and study 
medication must be stopped immediately. The Pregnancy Monitoring Form for Clinical Trials 
(Part A) should be used.
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). 
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.
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).


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5.6
APPROPRIATENESS OF MEASUREMENTS
The measurements performed in this trial are standard measurements and will be performed 
in order to monitor the pharmacodynamic endpoint as well as ocular and systemic safety 
aspects and to determine PK parameters in an appropriate way.
The primary outcome of this study is based on SD-OCT measurement which is used as a 
surrogate for pharmacological activity of BI 1026706. The treatment with BI 1026706 is 
aiming to reduce formation of edema and vascular leaking and thereby improve or stabilize 
vision. Therefore, a standard method that captures changes in edema formation is used for 
diagnostic purposes as well as to determine pharmacodynamic effect. SD-OCT is widely used 
for the assessment of the layers of the posterior pole of the eye and has proven a valuable 
measure of the central retinal thickness in DME.
 
 
 
 
 
Therefore, all measurements applied in this trial are considered by the sponsor to be 
appropriate.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The schedule for trial visits is summarised in the study Flow Chart including time windows 
for study visits. All visits are calculated from the date of randomization except for Visit 
6/End of Study which is calculated from Visit 5/End of Treatment. 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 will be planned according to the visit schedule.
In the case of medical emergencies, prior approval from the Sponsor for protocol deviations 
(e.g. visit schedule) will not be required, but the Sponsor should be notified as soon as 
possible. The relevance of any such protocol deviation will be assessed prior to analysing the 
data.
All drug administration at the study site will be done under the direct supervision of the study 
personnel for documentation of precise administration times.
Patients should make all efforts to complete the study which includes the End of Treatment 
Visit (Visit 5/EOT) and the follow-up visit 6/End of Study. The procedures to be conducted 
at each visit are provided in the Flow Chart and further described below.
Regarding removal of patients please refer to Section 3.3.4.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
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.
Visit 1 (Screening period):
The Screening period, i.e. the phase before the first administration of the trial drug, 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 2 days to allow receipt of the results of the central imaging Reading 
Center and the central laboratory.
Once DME is confirmed, a patient can be considered for eligibility; gonioscopy may be 
performed up to 1 month before study entry. 
The screening period (see Flow Chart) includes the following procedures/assessments: check 
of signed Informed Consent, demographics, review of relevant medical history/baseline 
conditions at the discretion of the Investigator, current medication and relevant medication 
history regarding eye specific interventions (e.g., injection therapies, laser) within the last 2 
years, inclusion/exclusion criteria, physical exam, body weight and height, vital signs (blood 


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pressure and pulse rate), ECG, safety laboratory tests collected according to central 
laboratory instructions, ophthalmological examinations including BCVA, slit lamp, SD-OCT, 
f
and
 ocular tonometry (intraocular 
pressure, IOP) and AE assessment since signed Informed Consent (see Section 5.3.6). 
Optional: Informed Consent for DNA banking; this separate consent can be obtained at this 
visit or at any other visit during the study.
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 anamnestic data will be used.
Images (SD-OCT, 
 have to be sent to the 
CRC for assessment immediately, see Section 3.3.2. The Randomization visit 2a should be 
performed as soon as possible after the Visit 1, when eligibility of the patient was confirmed.
Re-Screening
Patients who do not fulfil all of the eligibility criteria for a reason which later resolves and all 
eligibility criteria can be met within a 3 month period after initial visit (e.g. time since an 
exclusionary event), patients can be re-screened up to one time. Imaging of the retina (SD-
OCT, 
) does not need to be repeated at the re-screening visit if the 
corresponding criteria for inclusion of the study eye were met at the initial screening visit and
the images are not older than 28 days at the re-screening visit; otherwise new images have to 
be performed.
Patients who cannot be randomized in due time according to the Flow Chart can be re-
screened only after approval of the Sponsor.
6.2.2
Treatment period
The procedures of the visits in the treatment phase will be performed as outlined in the Flow 
Chart. 
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, as randomization of a patient cannot be reserved.
SD-OCT and BCVA as well as blood sampling will always be performed before intake of the 
trial medication on the respective day. 
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. 
At Visit 2a (Day 1), patients need to have fasted overnight before this Visit until blood 
collection. 
Visit 2a procedures include review of concomitant therapy, physical exam, body weight, vital 
signs (blood pressure and pulse rate), randomization, safety laboratory tests, PK, PGx (+ 


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optional DNA banking sample, if Informed Consent is provided) and biomarker blood 
sampling collected according to central laboratory instructions (please also refer to Appendix 
10.2), AE assessment since last visit (see Section 5.3.6), ECG and ophthalmological 
examinations including SD-OCT, visual acuity and slit lamp. Study medication should be 
taken after blood collection and ocular assessments at the site and study drug kits will be 
dispensed for home administration. 
A trial drug diary will be provided to the patients to record the actual dates and times of drug 
administration prior to the next scheduled visit to keep records of missed drug intake and to 
take account of effects on PK trough levels.
Visit 2b (Phone Visit)
One week after randomization an interim phone call will be made at Visit 2b to collect AEs, 
changes in concomitant therapy (if any), and to check handling of the study drug diary. 
Visit 3 and 4:
At Visits 3 and 4 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 will be collected. 
Procedures to be performed at Visits 3 and 4 (see Flow Chart) include: review of concomitant 
therapy and AE assessment since last visit (see Section 5.3.6), physical examination, vital 
signs (blood pressure and pulse rate), ECG, safety laboratory tests, PK and biomarker blood 
sampling collected according to central laboratory instructions (please refer to Appendix 
10.2) and ophthalmological assessments. 
At Visit 3 (Day 29), in addition, time of breakfast on that day will be captured and also 
recorded in the eCRF.
Study medication should be taken at the end of the visits at the site from newly assigned kits, 
and then these kits together with the drug diary will be dispensed for home administration. 
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.
When circumstances prevent the proper evaluation of CSFT or visual acuity in the course of 
the study (e.g., due to recent vitreous haemorrhage), an explanation with a detailed 
description will be provided in the corresponding eCRF page.
6.2.3
End of treatment and Follow-up period
Visit 5/End of Treatment (EOT):
At the time that study drug is permanently stopped for any reason, whether this is done 
prematurely or because of reaching the end of the treatment period after 12 weeks, the Visit 
5/EOT will be completed. The time interval for the regular scheduled Visit 5/EOT is 6 days, 
i.e. Day 85+5. 


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When the Investigator decided to permanently discontinue the study medication or became 
aware that the study medication had been terminated earlier than planned, Visit 5/EOT will 
be performed as soon as possible. Subsequently, patients should come to the End of Study
Visit (Visit 6) four weeks after the premature Visit 5/EOT. 
All unused study medication will be collected and study drug diary will be checked. 
Procedures to be performed include review of concomitant therapy and AE assessment since 
last visit (see Section 5.3.6), physical examination, body weight, vital signs (blood pressure 
and pulse rate), ECG, safety laboratory tests including 
 and PK blood sampling 
(please refer to Appendix 10.2) and ophthalmological examinations according to the Flow 
Chart. 
In case that standard of care DME treatment is administered at this visit, this has to be 
documented in the eCRF. 
Visit 6/End of Study:
The Visit 6/End of Study will be performed 28 days after the Visit 5/EOT for all patients who 
had at least one dose of trial medication (see Flow Chart). 
In case that standard of care DME treatment is administered at this visit, this has to be 
documented in the eCRF. 
The Visit 6/End of Study is the final visit and the Trial completion page in the eCRF has to
be entered.
Withdrawal of consent
If a patient is not willing to continue in the trial and withdraws consent for any reason 
(without the need to justify the decision) prior to the end of the trial, Visit 5/EOT should be 
scheduled as soon as possible, and also Visit 6/End of Study should be performed to assess 
for safety.
If the patient refuses to participate at an EOT Visit, the trial completion page of the eCRF has 
to be filled in. 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a randomised, double-masked, multi-centre, placebo controlled, parallel group study. 
The primary objective is to explore the mechanism of BI 1026706 in the treatment of patients 
with visual impairment due to DME and to evaluate safety and tolerability of BI 1026706.
The superiority of BI 1026706 will be tested against placebo. The primary endpoint of the 
trial is the change from baseline in CSFT after 12 weeks of treatment. 
Restricted Maximum Likelihood Estimation (REML) based Mixed-effects Model for 
Repeated Measures (MMRM) analysis will be used to obtain adjusted means for the 
treatment effects. This model will include treatment, previous DME treatment, week and 
treatment by week interaction as fixed categorical effects. Also, baseline CSFT and baseline 
CSFT by week interaction as continuous fixed effects. An unstructured covariance matrix 
will be used to model the within-patient variation.
The randomization will be stratified by the patients’ previous DME treatment (naïve versus 
treated).
7.2
NULL AND ALTERNATIVE HYPOTHESES
The superiority of treatment with BI 1026706 to placebo will be tested for CSFT change from 
baseline at week 12 by a pairwise comparison against placebo at the α=0.05 level. The 
population used will be the Full Analysis Set (FAS).
Let MHA be the mean change from baseline in CSFT (μm) after 12 weeks in BI 1026706 group.
Let MHB be the mean change from baseline in CSFT (μm) after 12 weeks in placebo group
The primary objective hypothesis is:
H0: MHA - MHB  = 0
H1: MHA - MHB ≠ 0
The test of the null hypothesis will be supported by the 95% confidence interval (CI) for 
MHA - MHB  and the null hypothesis will be rejected if the CI excludes 0 μm.
7.3
PLANNED ANALYSES
The statistical analysis will be based on the following populations:
Treated Set (TS)


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The TS will consist of all patients who were treated with at least one dose of study drug 
(BI 1026706 or placebo).
Full Analysis Set (FAS)
The FAS will consist of all patients who were randomised, treated with at least one dose of 
BI 1026706/placebo and provided baseline and at least one post-randomization CSFT 
measurement.
Pharmacokinetic analysis Set (PKS)
The PKS will consist of all patients in the TS for whom at least one evaluable BI 1026706 
plasma concentration is available. 
7.3.1
Primary endpoint analyses
The primary analysis of the primary endpoint, change from baseline in CSFT at 12 weeks, will 
be performed on the FAS. Therefore, all randomised patients who were treated with at least 
one dose of BI 1026706/placebo, had a baseline and at least one on-treatment CSFT 
measurement will be included.
Comparisons between treatment groups for the primary endpoint will be based on a mixed
effect repeated measures model (MMRM). This model will include treatment, previous DME 
treatment, week and treatment by week interaction as fixed categorical effects. Also, baseline 
CSFT and baseline CSFT by week interaction as continuous fixed effects. An unstructured 
covariance matrix will be used to model the within-patient variation. The SAS procedure 
MIXED will be used involving the REML and the Kenward-Roger approximation for 
denominator degrees of freedom. This approach is described in Kenward and Roger (R10-
4391). Adjusted mean values as well as treatment contrasts will be presented together with 
the 95% CIs and p-values.
The statistical model will be:
CSFT change from baseline = overall mean + continuous baseline CSFT + previous DME 
treatment + treatment + week + baseline CSFT by week 
interaction + treatment by 
week interaction + random error
Baseline CSFT will be defined as the last available CSFT measurement obtained before
randomization.
Data obtained after the start of rescue medication will not be used in the primary analysis of 
the primary endpoint.
7.3.2
Secondary endpoint analyses
See Section 7.3.4.


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7.3.4
Safety analyses
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary. Standard BI summary tables and listings will be produced. All AEs with an onset 
between start of treatment and end of the REP (residual effect period), a period of 4 days after 
the last dose of trial medication, will be assigned to the treatment period for evaluation.
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 AEs will concentrate on treatment-emergent AEs. To this 
end, all AEs occurring between start of treatment and end of the REP will be considered 
‘treatment-emergent’.  The REP is defined as the time period after the last dose 
administration of trial medication when measurable drug levels or PD effects are still likely to 
be present. 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 AEs 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).
Laboratory data will be analysed 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 highlighted in the 
listings. 
Clinically relevant ECG findings will be reported as AEs. Quantitative and qualitative ECG 
data from the ECG reading centre will be reported descriptively. 
Treatment groups will be compared descriptively with regard to distribution of parameters as 
well as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values.
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
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
For the primary analysis of the primary endpoint, if a patient misses a visit, the missing data 
will not be imputed and only on-treatment data will be included. The mixed effect model will 
handle missing data based on a likelihood method under the "missing at random assumption". 
Every randomised patient with at least baseline and one on-treatment measurement will be 
included in the analysis.
Additional details on the handling of missing data, including sensitivity analyses of the 
primary endpoint and 
, will be specified in the 
TSAP prior to unmasking. No imputation is planned for the analysis of AEs, laboratory data, 
and vital signs.
7.6
RANDOMIZATION
Patients will be randomised in blocks to double-masked treatment. Approximately equal 
numbers of patients will be randomised to each treatment group. BI will arrange for the 
randomization and the packaging and labelling of study 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.
7.7
DETERMINATION OF SAMPLE SIZE
In the Diabetic Retinopathy Clinical Research Network study “Aflibercept, bevacizumab, or 
ranibizumab for diabetic macular edema” (R15-5225) the changes from baseline in CSFT at 
week 12 are estimated to be between 85 and 140 μm for the aflibercept, bevacizumab and 
ranibizumab treatments. The common standard deviations as week 12 results are not 
presented. However, standard deviations were estimated from the confidence interval bars
presented on the CSFT plots over time.


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In order to achieve 80% power and with alpha at the 5% level for a two sided test, the number 
of patients required to detect a difference in the treatments is given in the table below for a 
range of mean differences in the treatments and common standard deviations.
Table 7.7: 1
Sample Size
Mean 
difference
[µm]
Common 
standard 
deviation
[µm]
Number of 
patients per 
arm
Total sample 
size for the 
trial
20
20
14
28
30
20
7
14
40
20
5
10
20
30
29
58
30
30
14
28
40
30
8
16
20
40
51
102
30
40
23
46
40
40
14
28
It is assumed that the mean difference is 20 µm and the common standard deviation is 40 µm. 
Therefore a total sample size of 102 patients is assumed.
Calculations were performed using SAS® 9.3 proc power statistical package.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
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 Standard Operating Procedures (SOPs) and 
relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in 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 subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
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 Clinical Trial Report.
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, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (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.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
8.2
DATA QUALITY ASSURANCE
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.


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8.3
RECORDS
Electronic Case Report Forms (eCRF) 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 subject. 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 CRF must be consistent with the source data or the discrepancies must
be explained.
The current medical history of the subject 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. 
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 on-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 on-site trial-related monitoring, audits, IRB / IEC
review and regulatory inspections. Direct access must be provided to the CRF 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). The CRA and auditor may review all CRFs 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 ICH GCP.
8.3.3
Storage period of records
Trial sites: The trial sites must retain the source and essential documents (including ISF) 
according to the national or local requirements (whatever is longer) valid at the time of the 
end of the trial.
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 regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.


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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. 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 WHO 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.
8.5.1
Collection, storage and future use of biological samples and corresponding
data
Measures are in place to comply with the applicable rules for the collection, storage and
future use of biological samples from clinical trial participants and the corresponding data, in
particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analyzing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of 
biological samples and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first patient in the whole
trial (“First Patient In”).
The end of the trial is defined as the date of the last visit (Visit 6/End of study Visit, please 
refer to Section 6.2.3) of the last patient in the whole trial (“Last Patient Out”).
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).


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P08-12095
Adamis AP, Berman AJ. Immunological mechanisms in the pathogenesis of 
diabetic retinopathy. Semin Immunopathol. 2008. 30(2):65-84.
R10-4391
Kenward MG, Roger JH, The Use of baseline covariates in crossover studies. 
Biostatistics  2010. 11(1):1-17.
R15-1951
Varma R, Bressler NM, Doan QV, Gleeson M, Danese M, Bower JK, Selvin
E, Dolan C, Fine J, Coman S, Turpcu A. Prevalence of and risk factors for 
diabetic macular edema in the United States. JAMA Ophthalmol. 2014. 
132(11): 1334-1340.
R15-5221
Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM. Risks of 
progression of retinopathy and vision loss related to tight blood pressure 
control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol. 2004. 
122:1631-1640.
R15-5222
Bhagat N, Grigorian RA, Tulela A, Zarbin M. Diabetic Macular Edema: 
Pathogenesis and Treatment. Surv Ophthal. 2009. 54:1-32.
R15-5223
Arup D, McGuire PG, Sampathkumar R. Diabetic Macular Edema: 
Pathophysiology and Novel Therapeutic Targets. The Eye. 2015. 122:1375-
1394.
 
R15-5225
Wells JA, Glassman AR, Ayala AR et al. Aflibercept, Bevacizumab, or 
Ranibizumab for Diabetic Macular Edema. N Engl J Med. 2015. 372:1193-
1203.
 
R15-5246
Aiello LP, Bursell SE, Clermont A, Duh E. et al. Vascular Endothelial Growth 
Factor-Induced Retinal Permeability Is Mediated by Protein Kinase C In Vivo 
and Suppressed by an Orally Effective P-Isoform-Selective Inhibitor. 
Diabetes. 1997. 46:1473-1480.
 
 


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R15-5248
Do DV, Nguyen QD, Boyer D, Schmidt-Erfurth U, Brown DM, Vitti R et al. 
One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with 
diabetic macular edema. Ophtalmology. 2012. 119:1658-1665.
R15-5250
Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin 
epidemiologic study of diabetic retinopathy. III. Prevalence and risk of 
diabetic retinopathy when age at diagnosis is 30 or more years. Arch 
Ophtalmol 1984 April. 102:527-532.
R15-5524
Bressler SB, Almukhtar T, Bhorade A,  Bressler NM,  Glassman AR, et al. 
Repeated Intravitreous Ranibizumab Injections for Diabetic Macular Edema 
and the Risk of Sustained Elevation of Intraocular Pressure or the Need for 
Ocular Hypotensive Treatment. JAMA Ophtalmol. 2015. 133(5):589-597
9.2
UNPUBLISHED REFERENCES
c03035551-01
Investigator´s Brochure 
for Chronic Obstructive Pulmonary Disease. BI 1026706. 10 July 2015


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10.
APPENDICES
10.1
PHARMACOKINETIC ANALYSES
Pharmacokinetic evaluations will be performed according to the relevant Corporate Procedure 
of the Sponsor (001-MCS-36-472, current version).
Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not analyzed), 
and BLQ (below the limit of quantification), will be ignored and not replaced by zero at any time 
point (applies also to the lag phase including the predose value). Descriptive statistics of 
concentrations at specific time points will be calculated only when at least 2/3 of the individuals 
have concentrations within the validated concentration range. The overall sample size to decide 
whether the “2/3 rule” is fulfilled will be based on the total number of samples intended to be 
drawn for that time point (i.e. BLQ, NOR, NOS, and NOA are included).
10.2
TIME AND VISIT SCHEDULE FOR PK, SAFETY AND BIOMARKER
BLOOD SAMPLING
Table 10.2: 1 
Time schedule for PK, Safety laboratory including 
 
Biomarker and PGx blood sampling
Visit
Day
Sampling Time 
Point [hh:min]
CRF Time
/PTM
PK
Safety 
 
Biomarker 
sample
PGx 
1
-28 to -2
X
2a
1
Fasting blood 
collection: 1  
Prior to drug 
administration 2,
between 08:30 
a.m. and 10:30 
a.m. (±30 min)
- 1:00
X
X
X
X
0:00
0:00
First Drug administration
3
29 (±3)
Prior to drug 
administration 2, 
between 08:30 
a.m. and 10:30 
a.m. (±30 min)
- 1:00
  X 3
X
0:00
0:00
Drug administration
0:45 ± 15 min
0:45
X
2:30 ± 30 min
2:30
X
3:30 ± 30 min
3:30
X
1 Only at Day 1 (Visit 2a) blood collection will be in fasting state.
2 Drug administration is planned to occur between 07:00 and 11:00 a.m., if possible.
3 If possible, this sample is to be taken 12 hours ± 60 min after the evening drug intake on the previous day.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
04 Mar 2016
EudraCT number
2015-003529-33
BI Trial number
1320.22
BI Investigational Product(s)
BI 1026706
Title of protocol
A randomized, double-masked, placebo-controlled 
exploratory study to evaluate pharmacodynamics, 
safety and tolerability of orally administered 
BI 1026706 for 12 weeks in patients with mild 
visual impairment due to center-involved diabetic 
macular edema (DME)
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
Section 3.3.3
Description of change
Change 1: Section 3.3.3, Exclusion criteria
Added:
27. Male patients who do not agree to minimize the 
risk of female partners becoming pregnant from the 
first dosing day until 3 months after the trial 
medication treatment has finished 1
Numbers of subsequent exclusion criteria changed 
accordingly.
Change 2: Footnote 1 of Exclusion criteria
Added:
1 Male patients who have sexual intercourse with 
women of childbearing potential will be instructed 
and must agree to use at least one of the following


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acceptable forms of effective contraception:
- Established use of oral, injected or implanted 
hormonal methods of contraception by the female 
partner of the male patient
- Placement of an intrauterine device (IUD) or 
intrauterine system (IUS) by the female partner of 
the male patient
- Use of barrier methods of contraception: Condom 
or Occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository
- Sterilization of the male patient (with the 
appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate).
Rationale for change
Change 1: Section 3.3.3, Exclusion criterion 27.
Specification, to align with Subject Information
Change 2: Footnote 1 of Exclusion criteria
Specification, to align with Subject Information


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03441881
3.0
clinical-trial-protocol-version-02
A randomized, double-masked, placebo-controlled exploratory study to evaluate
pharmacodynamics, safety and tolerability of orally administered BI 1026706 for 12
weeks in patients with mild visual impairment due to center-involved diabetic
macular edema (DME)
Author-Team Member Medicine
07 Mar 2016 17:12 CET
Author-Trial Clinical Monitor
07 Mar 2016 17:14 CET
Author-Trial Statistician
07 Mar 2016 17:20 CET
Author-Trial Clinical
Pharmacokineticist
09 Mar 2016 08:58 CET
Approval-Therapeutic Area 
10 Mar 2016 10:01 CET
Verification-Paper Signature
Completion
10 Mar 2016 10:38 CET
Approval-Team Member Medicine
10 Mar 2016 14:01 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03441881
3.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c09629286-02
BI Trial No.:
1320.22
Title:
A randomized, double-masked, placebo-controlled exploratory 
study to evaluate pharmacodynamics, safety and tolerability of 
orally administered BI 1026706 for 12 weeks in patients with mild 
visual impairment due to center-involved diabetic macular edema 
(DME)
(Including protocol amendment 2 [c03441881-03])
Investigational
Product(s):
BI 1026706
Responsible trial 
statistician(s):
Tel: 
Fax:
Date of statistical 
analysis plan:
26 JUL 2017 SIGNED
Version:
Final
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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 ...................................................................................................................3
2.
LIST OF ABBREVIATIONS...............................................................................4
3.
INTRODUCTION.................................................................................................6
5.
ENDPOINTS..........................................................................................................8
5.1
PRIMARY ENDPOINT........................................................................................8
5.2
SECONDARY ENDPOINTS ...............................................................................8
6.
GENERAL ANALYSIS DEFINITIONS...........................................................10
6.1
TREATMENTS...................................................................................................10
6.2
IMPORTANT PROTOCOL VIOLATIONS....................................................11
6.3
PATIENT SETS ANALYSED ...........................................................................12
6.5
POOLING OF CENTRES..................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................14
7.
PLANNED ANALYSIS ......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........16
7.2
CONCOMITANT DISEASES AND MEDICATION......................................16
7.3
TREATMENT COMPLIANCE ........................................................................17
7.4
PRIMARY ENDPOINT......................................................................................17
7.5
SECONDARY ENDPOINTS .............................................................................17
7.5.1
Key secondary endpoint......................................................................................17
7.5.2
Other secondary endpoint ..................................................................................18
7.7
EXTENT OF EXPOSURE .................................................................................18
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse events .....................................................................................................19
7.8.2
Laboratory data...................................................................................................20
7.8.3
Vital signs.............................................................................................................20
7.8.4
ECG ......................................................................................................................21
7.8.5
Others ...................................................................................................................21
8.
REFERENCES ....................................................................................................22
10.
HISTORY TABLE..............................................................................................24


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LIST OF TABLES
Table 6.2: 1
Important protocol violations ...........................................................................11
Table 6.3: 1
Patient sets analysed .........................................................................................13
Table 6.7:1
Time windows of treatment period visits .........................................................15
Table 10: 1
History table .....................................................................................................24


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
BRPM
Blinded report planning meeting
CSFT
Central Subfield Thickness
CTC
Common Terminology Criteria
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CTX
Carboxy-Terminal Collagen Crosslinks
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DRA
Drug Regulatory Affairs
DMG
Dictionary Maintenance Group
DME
Diabetic Macular Edema
EMEA
European Agency for the Evaluation of Medicinal Products
FAS
Full analysis set
HMA
Hemorrhage/ Micro-aneurysms
ICH
International Conference on Harmonisation
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effect model for Repeated Measures
MQRM
Medical Quality Review Meeting
O*C
Oracle Clinical
PK
Pharmacokinetics
PPS
Per protocol set
PSTAT
Project Statistician
PT
Preferred term
PV
Protocol violation
Q1
Lower quartile
Q3
Upper quartile
SA
Statistical analysis


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Term
Definition / description
SD
Standard deviation
SD-OCT
Spectral-Domain Optical Coherence Tomography
SMQ
Standardised MedDRA query
SOC
System organ class
TCM
Trial Clinical Monitor
TESS
Treatment emergent signs and symptoms 
ToC
Table of contents
TMW
Trial Medical Writer
TSAP
Trial statistical analysis plan


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3.
INTRODUCTION
As per ICH E9 [3], 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 the 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.
SAS® Version 9.4 or newer version will be used for all analyses.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint will be the change from baseline in CSFT in µm at Week 12, as 
measured by SD-OCT. Baseline CSFT is determined at visit 2a. If not measured at Visit 2a, 
then baseline will be the value at Visit 1. 
5.2
SECONDARY ENDPOINTS
Safety and tolerability of BI 1026706 will be assessed by the frequency of adverse events over 
the treatment period. The definitions of adverse events can be found in the protocol section 
5.3.6.1

Serious Adverse Events (SAEs)

Drug related adverse events

Adverse events of special interest (AESIs)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For reporting purposes, all randomised patients will be classified into one of the following 
randomised treatment groups
Sort order
Treatment
Long label
Short label
01
C
BI 1026706 100mg film coated 
tablets
BI 1026706 100mg
02
D
Placebo matching BI 1026706 
100mg film coated tablets
Placebo
These will be the default labels and sort order for reporting the treatment groups.
Patients will be analysed according to the treatment groups to which they were randomised. If 
there are cases of patients receiving incorrect treatment then an ‘as treated’ analysis will be 
performed in addition. 
The following treatment periods based on actual start and stop dates of study treatment 
administration are defined:
Screening: day of informed consent to day prior to the start of randomised study medication
On-treatment: day of first administration of randomised study medication to the last day of 
study medication administration
Post-treatment: day after the last dose of randomised study medication and thereafter
For the safety analysis, post-treatment events that start up to 4 days after the last 
administration of trial medication will be assigned to randomised treatment. Adverse events 
that start on the 5th day after the last administration of trial medication will be considered 
post-treatment. 


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6.2
IMPORTANT PROTOCOL VIOLATIONS
The following table defines the different categories of important PVs. The final column 
describes which PVs will be used to exclude patients from the different patient analysis sets. 
No per protocol (PPS) analysis will be performed for this study; however patients with 
important protocol violations (IPVs) will be documented. The following list of potential IPVs 
will be used; note this is a working list and may not be finalised until the final Blinded report 
planning meeting (BRPM) prior to database lock.
Table 6.2: 1
Important protocol violations
Category /
Code
Description
Requirements
Excluded 
from
A
Entrance criteria not met
A1.1
Inclusion criteria 1, 2, or 7 not met
Inclusion criteria 1, 2, or 7 not met as 
specified in the protocol.
None
A1.2
Trial diagnosis not met
Inclusion criteria 3, 4, 5, or 6 not met as 
specified in the protocol.
None
A2
Exclusion criteria present
Exclusion criteria as specified in the protocol
present. Applies for criteria 1, 2, 5, 7, 9 – 23, 
25-29
None
B
Informed consent
B1
Informed consent not available/not 
done
Informed consent date missing; no signature 
on ICF
All
B2
Informed consent too late
Informed consent date was after Visit 1 date 
None
C
Trial medication and 
randomization
C1
Incorrect trial medication taken
Medication kit assigned not matching 
treatment patient was randomised to and/or 
not matching IVRS assignment
None


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Table 6.2: 1 (continued)
Important protocol violations
Category /
Code
Description
Example/Comment
Excluded 
from
C2
Randomisation order not followed
Patient received trial medication from 
medication kit assigned to another patient
None
C3.1
Wrong dosage schedule
Capsules (BI 1026706 or matching placebo) 
taken once daily instead of bid and/or 
incorrect daily dose taken (more or less than 
two capsules)
None
C3.2
Treatment non-compliance
Overall compliance <80% or >120%. Final 
decision to be made at BRPM.
None
C4
Medication code broken 
inappropriately
Medication code broken inappropriately -
reason for medication code break <reason>
(Manual PV)
None
D
Concomitant medication
D2
Prohibited medication taken 
concomitantly with study drug after 
randomization until End-of-
Treatment visit is completed
•
Systemic anti-VEGF or pro-VEGF 
treatment 
•
Use of systemic steroids >10mg 
prednisone equivalent/day 
•
Current or planned during the study 
period, use of medications known to 
be toxic to the retina, lens or optic 
nerve
•
plans to initiate intensive insulin 
treatment within the study period
(Manual PV)
•
Potent and moderate CYP3A4 
inhibitors
•
Potent and moderate CYP3A4 
inducers
•
Potent and moderate P-gp inhibitors
•
Potent and moderate P-gp inducers
•
Sensitive CYP3A4, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, P-gp 
and Breast Cancer Resistance Protei 
(BCRP) substrates with a narrow 
therapeutic window
None
E
Other
E1
Study eye not determined
If the study eye is not indicated in the eCRF
None
E2
Missing data
No post-baseline assessment of CSFT
None
E3
Incorrect timing
Assessment of primary endpoint CSFT not 
within the time window
None
6.3
PATIENT SETS ANALYSED
The statistical analysis will be based on the following populations:
Treated Set (TS)
The TS will consist of all patients who were treated with at least one dose of study drug 
(BI 1026706 or placebo).


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Full Analysis Set (FAS)
The FAS will consist of all patients who were randomised, treated with at least one dose of 
BI 1026706/placebo and provided baseline and at least one post-randomization CSFT 
measurement.
Pharmacokinetic Analysis Set (PKS)
The PKS will consist of all patients in the TS for whom at least one evaluable BI 1026706 
plasma concentration is available. 
Table 6.3: 1
Patient sets analysed
Patient set
Class of endpoint
TS
FAS
PKS
Primary endpoints 
primary 
analysis
Further endpoints 
X
Safety endpoints 
X
Pharmacokinetic endpoints
X
Demographic/baseline 
endpoints
X
(X)
(X) An additional FAS presentation of the demographic/baseline endpoints may be provided 
in the EoT section, if patient numbers for FAS and treated set are clearly different (i.e., a non-
negligible number of treated patients does not have post randomization data for the primary 
endpoint).
Note that the number of patients with available data for an endpoint may differ. For details, 
see section “Handling of missing data”.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
For the primary analysis of the primary endpoint, if a patient misses a visit, the missing data 
will not be imputed and only on-treatment data will be included. The mixed effect model will 
handle missing data based on a likelihood method based on the “missing at random” 


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assumption. Every randomised patient with at least baseline and one on-treatment 
measurement will be included in the analysis. 
To evaluate the impact of any missing data to the analyses of primary endpoint, multiple 
imputation will be used to handle missing data as a sensitivity analysis. All variables included 
in the analysis model will be included in the imputation model. In addition, after exploring the 
missing data mechanism and observed measurements on the blinded data, additional variables 
may be identified and added to the imputation model. 
If the data is monotone missing, a regression model will be used for imputation including 
baseline CSFT and primary endpoint at Visits 3, 4, 5 by treatment, and stratification factor 
previous DME treatment.
In the case of non-monotone missing, a Markov chain Monte Carlo (MCMC) step will be 
used to create monotone missing data in multiple datasets. The regression method will then be 
used to complete the imputation in each dataset. For each imputed complete dataset, the 
primary MMRM model described in Section 7.4 will be used for the analyses. The results will 
be pooled following the standard multiple imputation procedure.
Missing or incomplete AE dates will be imputed according to BI standards (“Handling of 
missing and incomplete AE dates”) [8]. Missing data and outliers of PK data are handled 
according to [6].
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study day will be calculated relative to the date and time of the first dose of double-masked 
randomised treatment. The day prior to the start of double-masked randomised treatment will 
be ‘Day -1’ and the start of double-masked randomised treatment will be ‘Day 1’; therefore 
‘Day 0’ will not exist. 
For efficacy analyses, baseline is defined as the latest measurement on or before the date of 
the first randomised treatment administration at Visit 2a. Therefore baseline values are 
measured at Visit 2a for 
 and endpoints assessed by SD-OCT (i.e., CSFT, 
 If Visit 2a measurement is missing, then Visit 1 will 
be used as baseline.
 
 Visit 1 measurement will 
be used as baseline as per Flow Chart. 
Planned time windows are defined in the CTP. For analyses purposes, data from 
Ophthalmological exams will be allocated to visits by means of windows with the limit 
between adjacent windows half-way between the planned dates for the visits; the middle day 
is counted to the window of the later visit. For example, Visit 2a is planned on Day 1 and 
Visit 2b is planned on Day 8. Therefore, the window of Visit 2a reaches until Day 3, the 
windows of Visit 2b starts on Day 4. If there are multiple measurement values within one 
window, 3 cases have to be distinguished: 
The following time windows are planned:
-
Pre-treatment, the lastest measurement is to be selected as baseline as described above;


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-
After study treatment start, the value closest to the nominal day will be selected for 
assessment endpoints at a particular visit and for by-visit displays. All values will be 
stored in analysis datasets;
-
For post-treatment, the lastest value in the respective window will be used .
Table 6.7:1
Time windows of treatment period visits
Window 
No.
Window label
Nominal visit
Nominal 
day
-4
Screening
VISIT 1
-28
0
Baseline
VISIT 2a
1
1
Week 1
VISIT 2b
8
4
Week 4
VISIT 3
29
8
Week 8
VISIT 4
57
12
Week 12
VISIT 5/EOT1
85
16
Week 16
VISIT 6/EOS
113
1.
Patients may stop study medication prematurely at any visit before Week 12, the nominal day and 
interval will remain missing in analysis datasets..
These windows will also be used for safety laboratory assessments. If there are multiple 
measurements within one window, the last value will be used as confirmation.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
For time to event analysis tables, the median and quartiles will be provided.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
All calculated statistics will be presented to one more decimal place than the original 
measurement accuracy of the variable being summarised. 
All p-values will be displayed to four decimal places (or “<0.0001” if appropriate).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
The following variables will be displayed in the demographics table: gender, race, age, height, 
weight, smoking and alcohol status. 
Baseline disease status will be summarised descriptively, including the best corrected visual 
acuity score, intraocular pressure measurement, and the results of the slit lamp examination.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant diseases will be coded using the current version of MedDRA coding system. 
Medications will be coded using the WHO Drug Dictionary (WHO-DD). The coding version 
number will be displayed as a footnote in the respective output. 
The diagnoses and medications will be listed. Subjects without any concomitant diagnosis or 
therapy should be marked with a “No” in the respective column. Historical anti-DME therapy 
will be summarised separately according to the ATC4 grouping.
Study eye will be listed. 
In addition, any further anti-DME therapy initiated during the course of the trial will be 
summarised in a separate table along with a summary of reasons for initiating standard of 
care.


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7.3
TREATMENT COMPLIANCE
The percentage of medication taken of study drug as reported on the compliance eCRFs will 
be summarized descriptively by visit and treatment group. Additonally, summary statistics of 
overall compliance will be presented by treatment group. Cumulative compliance per patient 
will be calculated based on weighted average of available on-treatment by visit data, weighted 
by number of days between visits (e.g., for patient who had 80% compliance at Visit 3 (Week 
4, Day 29), 100% compliance at Visit 4 (Week 8, Day 57), 100% compliance at Visit 5 (Week 
12, Day 85), the overall compliance would (29*0.8 + 28*1 + 28*1 )/85= 93.2%.
7.4
PRIMARY ENDPOINT
The primary analysis of the primary endpoint, change from baseline in CSFT at 12 weeks, 
will be performed on the FAS. Therefore, all randomised patients who were treated with at 
least one dose of BI 1026706/placebo, had a baseline and at least one on-treatment CSFT 
measurement will be included. 
Comparisons between treatment groups for the primary endpoint will be based on a mixed 
effect repeated measures model (MMRM). This model will include treatment, previous DME 
treatment, week and treatment by week interaction as fixed categorical effects. Also, baseline 
CSFT and baseline CSFT by week interaction as continuous fixed effects. An unstructured 
covariance matrix will be used to model the within-patient variation. The SAS procedure 
MIXED will be used involving the REML and the Kenward-Roger approximation for the 
denominator degrees of freedom. This approach is described in Kenward and Roger (R10-
4391). Adjusted mean values as well as treatment contrasts will be presented together with the 
95% CIs and p-values. 
The statistical model will be:
CSFT change from baseline = overall mean + continuous baseline CSFT + 
                                                 previous DME treatment + treatment + week + 
                                                baseline CSFT by week   interaction + 
                                                treatment by week interaction + random error
Baseline CSFT will be defined as the last available CSFT measurement obtained before 
randomisation. 
Data obtained after the start of rescue medication will not be used in the primary analysis of 
the primary endpoint. Waterfall plots of CSFT change from baseline will be presented. A 
sensitivity analysis using multiple imputation methods is described in Section 6.6.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.


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7.5.2
Other secondary endpoint
Secondary endpoints are safety endpoints. The analyses of safety endpoints are described in 
Section 7.8.
7.7
EXTENT OF EXPOSURE
Duration of treatment exposure (days) across the randomised treatment period will be 
calculated for each patient. The total exposure will also be summed over all patients within 
each treatment group and transformed into patient years. A standard descriptive summary of 
these data will be provided for the treated set of patients. In addition, the number and 
percentage of patients in the treatment exposure categories 0-6 weeks, >6 to 12 weeks will be 
summarised. 
Kaplan-Meier curves by treatment group showing the number of patients at risk (exposed) 
during the randomised treatment period will be produced. 


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set and performed in accordance with BI 
standards. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The format of the listings and tables will follow the BI guideline ‘Reporting of clinical trials 
and project summaries’ [1, 9]
The individual values of all subjects will be listed, sorted by treatment, subject number and 
visit. The listings will be contained in Appendix 16.2.
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of patients with AEs and NOT on the number of 
AEs.
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:
•
All AE attributes are identical (LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AE of special interest).
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence).
For further details on summarization of AE data, please refer to the guideline ‘Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries [8, 
10].
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake till last drug 
intake + 4 days will be assigned to the randomised treatment. All adverse events occurring 
before first drug intake will be assigned to ‘screening’ and all adverse events occurring after 
the residual effect period will be assigned to ‘post-treatment’ (for selected tables in 16.1.9.2 
and listings only). For details on the treatment definition, see Section 6.1.
According to ICH E3 [4], AEs classified as ‘other significant’ needs 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 haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
Meeting.
Adverse events of special interest (AESIs)


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The following are considered to be AESIs:
-
Hepatic injury defined by the following alterations of hepatic laboratory parameters:
o
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
o
Marked peak aminotransferase (ALT, and/or AST) elevations ≥ 10 fold ULN.
Depending on the number of AESIs, either a summary table by MedDRA preferred term or a 
listing will be produced. 
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarised by treatment, primary system organ class and preferred 
term. Separate tables will be provided for patients with other significant adverse events 
according to ICH E3 [4], for patients with adverse events of special interest and for patients 
with serious adverse events.
The system organ classes will be sorted alphabetically; preferred terms will be sorted by 
frequency (within system organ class).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
“Handling, Display and Analysis of Laboratory Data” [11]. The following analyses will be 
presented for all applicable laboratory parameters:

Descriptive statistics;

Frequency of patients with possible clinically significant abnormalities.
Baseline is defined by the last available measurement before study drug administration. In 
case of repeated measurements performed for the same visit the last observation will be used 
for tabulation.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.


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7.8.4
ECG
Clinically relevant ECG findings on-treatment will be reported and summarized as adverse 
events.
7.8.5
Others
For the clinical trials disclosure process (e.g. clinicaltrial.gov) special safety displays may be 
necessary, e.g. the number of non-serious Adverse Events. All required displays / ADS for the 
clinical trials disclosure process will be included in the technical TSAP, section Display Plan 
or ADS Plan as applicable.


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8.
REFERENCES
1
001-MCG-159_RD-03: “Standard table shells for inferential and descriptive End-of-
Text tables (EoT-Catalogue)”, current version; IDEA for CON.
2
001-MCG-410: "Structure, Derivation, and Documentation of Analysis Data Sets", 
current version; IDEA for CON.
3
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
4
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
5
001-MCP-090: "BI Style Guide", current version; IDEA for CON. 
6
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
7
001-MCS-50-413: "Handling of Protocol Violations in Clinical Trials and Projects",
current version; group: Study Conduct; IDEA for CON.
8
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
9
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current version; 
IDEA for CON.
10
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
11
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
15-AUG-16
None
This is the initial TSAP with the 
necessary information for trial conduct.
Final
25-JUL-17
Section 
4, 
 
 6.6, 
6.7, 7.3,
7.7, 
7.8.2.
TSAP Template 001-MCS-40-415_RD-
02 (1.0) applied;
Section 4, CSFT response added;
Section 7.1 and 7.2.
Section 6.6, sensitivity analysis 
described; handling of missing or 
incomplete AE dates updated;
Section 6.7, analyses time windows 
defined;
Section 7.3, treatment compliance 
defined; 
Section 7.7, Kaplan-Meier analyses 
removed;
Section 7.8.2, Analyses of clinical 
laboratory data specified.