Clinical trial NCT04722991
Conditions: Diabetic Retinopathy
Keywords: Non-proliferative Diabetic Retinopathy
Sponsor: Bayer
Start date: 2021-03-17; Completion date: 2024-04-22
Enrollment: 109 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 2 study is conducted to investigate the safety and efficacy of runcaciguat in the treatment of diabetic retinopathy. To assess efficacy, the retinal morphology will be investigated by 7-field color fundus photography for central assessment of the diabetic retinopathy severity score, or DRSS. Two-step DRSS improvement at 24 weeks of treatment will be the primary efficacy endpoint. DRSS assessments are repeated after completion of 48 weeks of treatment. In addition, vision threatening complications will be recorded throughout the study and assessed as secondary efficacy endpoint.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Runcaciguat (BAY1101042) intervention 2: Placebo
Intervention descriptions: intervention 1: Oral dose of runcaciguat intervention 2: Oral dose of matching placebo

Protocol documents:
Prot_002.pdf: 
 
Document Type: 
Clinical Study Protocol 
Official Title: 
A Phase 2 randomized, placebo-controlled, double-masked proof-
of-concept study to investigate the efficacy and safety of 
runcaciguat (BAY 1101042) in patients with moderately severe to 
severe non-proliferative diabetic retinopathy 
NCT Number: 
NCT04722991 
Document Date: 
09-Feb-2023 
 


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Title page
Protocol title: 
A Phase 2 randomized, placebo-controlled, double-masked proof-of-concept study to 
investigate the efficacy and safety of runcaciguat (BAY 1101042) in patients with moderately 
severe to severe non-proliferative diabetic retinopathy
Protocol number:
20739
Protocol Version:
5.0
Amendment Number:
4
Compound number: BAY 1101042 / Runcaciguat
Brief title:
Non-proliferative diabetic retinopathy treated with runcaciguat
Study phase:
2
Acronym:
NEON-NPDR
Sponsor name and legal registered address:
Non-US:
Bayer AG, 51368 Leverkusen, Germany 
US territory:
Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, 
P.O. Box 915, Whippany, NJ 07981-0915, USA
Regulatory agency identifier number(s):
IND:
149136
EudraCT: 2020-002333-15
Approval date: 
09 FEB 2023
Medical Monitor name and contact information will be provided separately.
Name:
Role:
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the sponsor’s medically responsible person is filed in the TMF and is available on 
request.
Confidential
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation.  Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD


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Protocol amendment summary of changes table
Document history
Document
Date
Applicable documents
Amendment 4
09 FEB 2023
Clinical study protocol
Amendment 3
04 NOV 2021
Master Protocol
Protocol Part A
Protocol Part B
Amendment 2
13 JAN 2021
Master Protocol
Protocol Part A
Protocol Part B
Amendment 1
23 NOV 2020
Master Protocol
Protocol Part A
Protocol Part B
Original protocol
24 AUG 2020
Master Protocol
Protocol Part A
Protocol Part B
Amendment 4 (09 FEB 2023)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall rationale for Amendment 4: 
A description of changes and a brief rationale is outlined in the table at the end of this section.  
An overview is given below.
Clarification of dose-titration instructions
Clear blood pressure limits were added to the titration instructions to provide more precise 
guidance on when to maintain and not increase the dose. This amendment is expected to 
improve participant’s safety and to result in more consistent titration decisions across sites.
In addition, two dose reductions are now permissible instead of a single dose reduction.
This change is considered substantial as it has effects on participant’s safety.
Primary endpoint after 48 weeks instead of after 24 weeks of treatment
2-step DRSS improvement is the main efficacy endpoint in this clinical study. Assessments 
are planned after 12, 24, and 48 weeks of treatment. The assessment after 24 weeks was 
initially defined as the primary endpoint. However, information was received from other 
clinical trials in non-proliferative diabetic retinopathy, that achieving 2-step DRSS 
improvement in a sufficient number of study participants may take longer than 24 weeks for 
most drugs not administered by intravitreal injection (e.g. ROBIN trial NCT03238963, 
discussed in (Boyer et al. 2021). To provide sufficient time for the treatment effect, the 
primary assessment of this endpoint is moved to 48 weeks of treatment. Up to the date of this 
amendment, on-treatment DRSS assessments were not transferred from the central reading 
center into the study database, they were not seen by the sponsor nor by the independent data 
monitoring committee, in agreement with study procedures. No interim assessment was 
performed until now. Thus, no efficacy data from the present study were reviewed and the 
decision for this amendment was solely driven by general considerations triggered by 


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information received from other clinical trials in diabetic retinopathy. Based on these 
considerations, a power adjustment is not deemed necessary.
This change to the primary endpoint assessment is considered substantial.
A full overview of changes is provided in the two tables below.


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Key changes in study design and other substantial changes
Section # 
and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Section 1.2 Schema
Section 3 Objectives and 
endpoints
Section 4.1 Overall design
Section 4.2 Scientific rationale 
for study design
Section 4.4 End-of-study 
definition
Section 8 Study assessments 
and procedures
Section 9.1 Statistical 
hypotheses
Section 9.4.2 Primary endpoint
Section 9.4.3.1 Efficacy
The primary DRSS assessment was 
moved to 48 weeks of treatment.
Information was received from other 
clinical trials in non-proliferative diabetic 
retinopathy, that achieving 2-step DRSS 
improvement in a sufficient number of 
study participants may take longer than 
24 weeks for most drugs not administered 
by intravitreal injection (e.g. ROBIN trial 
NCT03238963, discussed in (Boyer et al. 
2021). To increase the probability of a 
successful clinical trial, the primary 
assessment of this endpoint is moved to 
48 weeks of treatment
Section 2.3.1 Risk assessment Safety information from CONCORD 
study was updated.
Update of new information included in the 
IB
Section 6.5.1 Intra-individual 
dose-titration decisions
Minimum treatment interruption in 
case of pertinent adverse event 
extended to 48 hours.
Correction and extension of minimum 
temporary discontinuation interval
Section 4.1.2 Part 2 – Proof of 
concept
Section 8.4 Pharmocokinetics
Section 9.5 Interim analysis
No interim analysis is planned. DMC 
oversight will continue as planned.
With the primary endpoint moved to the 
end of the treatment period, the interim 
assessment is no longer deemed useful.
Section 6.5.1 Intra-individual 
dose-titration decisions 
Section 7.1.3 Re-challenge / 
re-start of study intervention
The dose-titrations instruction was 
specified by providing minimum 
blood pressure requirements for 
dose titration.
This amendment is expected to 
improve participant’s safety and to 
result in more consistent titration 
decisions across sites.
(substantial amendment)
Section 6.5.1 Intra-individual 
dose-titration decisions 
Up to two (instead of only one) dose 
reductions are permissible
Allowing only a single dose reduction 
and imposing permanent treatment 
discontinuation in case a single dose 
reduction does not sufficiently improve 
tolerability may result in undue early 
treatment discontinuations and reduce 
the power of the clinical trial
Section 7.1.1 Permanent 
discontinuation
If study intervention is permanently 
discontinued, an End-of-Treatment 
visit should be performed in line 
with Visit 15. The participant 
remains in the study for continued 
assessment of study outcomes 
following the visit schedule in 
section 1.3.
Clarification of the visit schedule for 
study intervention permanent 
discontinuation


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Section # 
and Name
Description of Change
Brief Rationale
Section 7.1.1 Permanent 
discontinuation
Withdrawal from trial is no longer 
mandatory, in case of vision 
threatening complication or 
progression to PDR, but to be 
decided case by case by the 
investigator.
There is no safety concern with 
continuing treatment after a vision 
threatening complication.  Continued 
treatment may be beneficial. Therefore, 
treatment discontinuation is not 
mandatory in general but to be 
considered case by case by the 
investigator.
Clarifications and corrections (non-substantial)
Section # 
and Name
Description of Change
Brief Rationale
Section 1.3 Schedule of 
activities (SoA)
Footnotes were added to clarify the 
timepoints for safety, blood 
sampling and ophthalmology 
examinations. 
Clarification of sequence of activities
Section 1.3 Schedule of 
activities (SoA) 
Administer study intervention (after 
blood draws) was removed at Visit 
15 EoT. Dispensation of urine 
pregnancy test was added at Visit 
12. 7-field color fundus 
photography (DRSS) was removed 
at Visit 8.
Corrections of mistakes:
Assessing DRSS assessment after 
8 weeks of treatment in addition to after 
12 weeks of treatment cannot be 
expected to provide relevant additional 
data.  
Section 7.1.2 Temporary 
discontinuation
If the re-assessed laboratory result 
indicates a decrease in eGFR 
<40% from baseline, study 
intervention may be re-started at 
the same dose as before this 
temporary discontinuation, in line 
with section 7.1.3.  
Clarification on re-starting study 
intervention


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Table of contents
Title page................................................................................................................................... 1
Protocol amendment summary of changes table................................................................... 2
Table of contents....................................................................................................................... 6
Table of tables........................................................................................................................... 8
Table of figures......................................................................................................................... 9
1.
Protocol summary ........................................................................................................... 10
1.1
Synopsis ......................................................................................................................... 10
1.2
Schema........................................................................................................................... 13
1.3
Schedule of activities (SoA) .......................................................................................... 14
2.
Introduction ..................................................................................................................... 16
2.1
Study rationale ............................................................................................................... 17
2.2
Background.................................................................................................................... 18
2.2.1
Disease background......................................................................................... 18
2.2.2
The role of soluble guanylyl cyclase in diabetic retinopathy .......................... 18
2.2.3
Runcaciguat ..................................................................................................... 20
2.3
Benefit/risk assessment.................................................................................................. 20
2.3.1
Risk assessment ............................................................................................... 21
2.3.2
Benefit assessment........................................................................................... 26
3.
Objectives and endpoints................................................................................................ 27
4.
Study design..................................................................................................................... 28
4.1
Overall design ................................................................................................................ 28
4.1.1
Part 1 – PK/PD................................................................................................. 28
4.1.2
Part 2 – Proof of concept ................................................................................. 29
4.2
Scientific rationale for study design............................................................................... 29
4.3
Justification for dose...................................................................................................... 30
4.4
End-of-study definition.................................................................................................. 33
5.
Study population ............................................................................................................. 33
5.1
Inclusion criteria ............................................................................................................ 33
5.2
Exclusion criteria ........................................................................................................... 34
5.3
Lifestyle considerations ................................................................................................. 36
5.4
Screen failures................................................................................................................ 36
5.5
Criteria for temporarily delaying randomization / study intervention administration... 37
5.6
Selection of the study eye .............................................................................................. 37
6.
Study intervention(s) and concomitant therapy........................................................... 37
6.1
Study interventions administered................................................................................... 37
6.1.1
Study interventions .......................................................................................... 37
6.1.2
Medical devices ............................................................................................... 38
6.2
Preparation / handling / storage / accountability............................................................ 39
6.3
Measures to minimize bias: Randomization and masking............................................. 39
6.4
Study intervention compliance ...................................................................................... 40
6.5
Dose modification.......................................................................................................... 41
6.5.1
Intra-individual dose-titration decisions.......................................................... 41
6.5.2
Stopping rules (study level)............................................................................. 41


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6.6
Continued access to study intervention after the end of the study................................. 42
6.7
Treatment of overdose ................................................................................................... 42
6.8
Concomitant therapy...................................................................................................... 43
7.
Discontinuation of study intervention and participant discontinuation/withdrawal 44
7.1
Discontinuation of study intervention............................................................................ 44
7.1.1
Permanent discontinuation............................................................................... 44
7.1.2
Temporary discontinuation.............................................................................. 45
7.1.3
Re-challenge / re-start of study intervention.................................................... 45
7.2
Participant discontinuation / withdrawal from the study ............................................... 46
7.3
Lost to follow up............................................................................................................ 46
8.
Study assessments and procedures ................................................................................ 47
8.1
Efficacy assessments...................................................................................................... 48
8.1.1
Ophthalmology assessments............................................................................ 48
8.1.1.1
Color fundus photography (CFP) ................................................... 48
8.1.1.2
Best corrected visual acuity (BCVA) ............................................. 49
8.1.1.3
Fluorescein angiography (FA)........................................................ 49
8.1.1.4
Optical coherence tomography (OCT) ........................................... 49
8.1.1.5
Optical coherence tomography angiography (OCT-A) .................. 49
8.1.1.6
Slit lamp biomicroscopy (anterior and posterior segment)............. 50
8.1.1.7
Tonometry (intraocular pressure (IOP) measurement)................... 50
8.1.2
Vision-threatening complications.................................................................... 50
8.1.3
Albuminuria..................................................................................................... 51
8.1.4
Visual function questionnaire (VFQ-25)......................................................... 51
8.2
Safety assessments......................................................................................................... 51
8.2.1
Physical examination....................................................................................... 51
8.2.2
Vital signs ........................................................................................................ 51
8.2.3
Electrocardiograms.......................................................................................... 52
8.2.4
Clinical safety laboratory assessments ............................................................ 52
8.2.5
Pregnancy testing............................................................................................. 53
8.3
Adverse events (AEs), serious adverse events (SAEs) and other safety reporting........ 54
8.3.1
Time period and frequency for collecting AE and SAE information.............. 54
8.3.2
Method of detecting AEs and SAEs ................................................................ 54
8.3.3
Follow-up of AEs and SAEs............................................................................ 55
8.3.4
Regulatory reporting requirements for SAEs .................................................. 55
8.3.5
Pregnancy......................................................................................................... 55
8.3.6
Adverse events of special interest (AESI)....................................................... 56
8.4
Pharmacokinetics ........................................................................................................... 56
8.5
Genetics.......................................................................................................................... 57
8.6
Biomarkers..................................................................................................................... 58
8.6.1
Laboratory biomarkers..................................................................................... 58
8.6.2
Ambulatory blood pressure monitoring (ABPM) – only in Part 1 .................. 59
8.7
Immunogenicity assessments......................................................................................... 59
8.8
Health economics........................................................................................................... 59
9.
Statistical considerations ................................................................................................ 59
9.1
Statistical hypotheses..................................................................................................... 59
9.2
Sample size determination ............................................................................................. 60
9.3
Analysis sets................................................................................................................... 61
9.4
Statistical analyses ......................................................................................................... 61


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9.4.1
General considerations..................................................................................... 61
9.4.2
Primary endpoint.............................................................................................. 62
9.4.3
Secondary endpoint(s) ..................................................................................... 62
9.4.3.1
Efficacy........................................................................................... 62
9.4.3.2
Safety .............................................................................................. 63
9.4.4
Other efficacy analyses.................................................................................... 63
9.4.5
Other safety analysis........................................................................................ 63
9.4.6
Other analysis .................................................................................................. 64
9.5
Interim analysis.............................................................................................................. 64
10. Supporting documentation and operational considerations ....................................... 65
10.1
Appendix 1: Regulatory, ethical, and study oversight considerations........................... 65
10.1.1
Regulatory and ethical considerations............................................................. 65
10.1.2
Financial disclosure ......................................................................................... 65
10.1.3
Informed consent process ................................................................................ 66
10.1.4
Data protection................................................................................................. 66
10.1.5
Committees structure....................................................................................... 67
10.1.5.1
Central reading centers ................................................................... 67
10.1.5.2
Steering committee ......................................................................... 67
10.1.5.3
Data monitoring committee (DMC) ............................................... 67
10.1.5.4
Safety assessment group ................................................................. 67
10.1.6
Dissemination of clinical study data................................................................ 67
10.1.7
Data quality assurance ..................................................................................... 68
10.1.8
Source documents............................................................................................ 68
10.1.9
Study and site start and closure........................................................................ 69
10.1.10 Publication policy............................................................................................ 70
10.2
Appendix 2:  Clinical laboratory tests ........................................................................... 70
10.3
Appendix 3:  AEs and SAEs: Definitions and procedures for recording, evaluating, 
follow-up, and reporting ................................................................................................ 72
10.3.1
Definition of AE .............................................................................................. 72
10.3.2
Definition of SAE............................................................................................ 73
10.3.3
Recording and follow-up of AE and/or SAE................................................... 74
10.3.4
Reporting of SAEs........................................................................................... 75
10.4
Appendix 4:  Contraceptive guidance and collection of pregnancy information .......... 76
10.5
Appendix 5:  Liver safety: Suggested actions and follow-up assessments.................... 78
10.6
Appendix 6:  Standardized meal.................................................................................... 80
10.7
Appendix 7: Abbreviations............................................................................................ 81
10.8
Appendix 8: Protocol amendment history ..................................................................... 82
10.8.1
Amendment 4................................................................................................... 82
10.8.2
Amendment 3................................................................................................... 82
10.8.3
Amendment 2................................................................................................... 91
10.8.4
Amendment 1................................................................................................... 91
11. References ........................................................................................................................ 93
Table of tables
Table 1-1
Study objectives and endpoints ............................................................................. 11
Table 1-2
Schedule of activities:  Part 1 – Screening (Visit 1) and titration phase (Visits 2 to 
6)............................................................................................................................ 14


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Table 1-3
Schedule of activities:  Part 2 - Screening (Visit 1) and titration phase (Visits 2 to 
6)............................................................................................................................ 15
Table 1-4
Schedule of activities:  Parts 1 and 2 - Visits 7 to 16............................................ 16
Table 2-1
Placebo-corrected change in blood pressure and heart rate from baseline after 
once-daily runcaciguat administration over 7 days (ANCOVA, pre-dose adjusted, 
90%CI) .................................................................................................................. 22
Table 2-2
Risk assessment for the study intervention runcaciguat........................................ 24
Table 3-1
Study objectives and endpoints ............................................................................. 27
Table 4-1
Overall study plan.................................................................................................. 28
Table 4-2
CONCORD Study 18748 (CKD): Simulated median outcome in % of treated 
patients [90% CI]................................................................................................... 32
Table 4-3
PK/PD relationship in animal models of CKD and DR Model estimates of EC50 
with 90% CI........................................................................................................... 32
Table 6-1
Study interventions................................................................................................ 38
Table 6-2
Level of masking – Part 1 and 2............................................................................ 39
Table 6-3
List of prohibited medications............................................................................... 43
Table 8-1
ETDRS final retinopathy severity scale (for individual eyes)............................... 48
Table 9-1
Planned sample size............................................................................................... 60
Table 9-2
Analysis sets .......................................................................................................... 61
Table 10-1 Protocol-required laboratory tests ......................................................................... 71
Table 10-2 Highly effective contraception methods................................................................ 77
Table 10-3 Liver-safety-related monitoring and discontinuation criteria................................ 79
Table 10-4 Laboratory examinations for workup of liver safety findings............................... 80
Table of figures
Figure 1–1 Schematic study design ......................................................................................... 13
Figure 2–1 The role of sGC activator in diabetic retinopathy ................................................. 19
Figure 2–2 sGC stimulators and activators target different redox states of the enzyme ......... 20


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1.
Protocol summary
1.1
Synopsis
Protocol title:
A Phase 2 randomized, placebo-controlled, double-masked proof-of-concept study to 
investigate the efficacy and safety of runcaciguat (BAY 1101042) in patients with moderately 
severe to severe non-proliferative diabetic retinopathy 
Brief title:  Non-proliferative diabetic retinopathy treated with runcaciguat
Overall study plan:
Study 20739 is a Phase 2 proof-of-concept study that includes a subpart with PK/PD 
assessments (Part 1). Part 1 enrolls a subset of patients at a more intense investigation in 
specific study sites. Part 2 is the main PoC part, to be conducted in ophthalmology sites, that 
enrolls the majority of participants. PoC will be based on the evaluation of outcomes in 
participants from both parts.
Rationale:
Results from previous Phase 1 studies in healthy as well as renally impaired patients as well 
as a phase 2 study with patients with chronic kidney disease have demonstrated that 
runcaciguat given as modified-release oral tablets was well tolerated and support the start of 
further studies in patients. 
Due to the mode of action of sGC activators, and based on preclinical data, it is assumed that 
sGC activators, administered to NPDR patients, can positively influence retinal perfusion and 
thereby improve fundus morphology and reduce the progression of retinal ischemia and 
vision-threatening later stages like PDR and/or DME.
The present study is to be conducted to obtain information on sGC activators by investigating 
1. whether runcaciguat improves the diabetic retinopathy score in patients with 
moderately severe to severe NPDR
and to
2. explore the pharmacokinetic - pharmacodynamic relationship of runcaciguat on retinal 
perfusion
The results are intended to provide useful information to improve the design of clinical studies 
with subsequent sGC activators, for example by supporting the choice of the appropriate dose 
and treatment duration. 


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Objectives and endpoints:
Table 1-1
Study objectives and endpoints
Objectives
Endpoints 
Primary objective:  Efficacy
Establish the proof-of-concept for the 
efficacy of the sGC activator runcaciguat 
in the treatment of NPDR.
Primary endpoint:
DRSS improvement ≥2 steps at 48 weeks of treatment in the 
study eye
Secondary endpoints for primary objective:
Vision threatening complications at 48 weeks of treatment in the 
study eye
DRSS improvement ≥2 steps at 24 weeks of treatment in the 
study eye
Other endpoints (for primary objective):
Change in visual acuity from baseline
Change in leakage area on Fluorescein Angiography
DRSS changes from baseline in the study and fellow eye
Vision threatening complications in any eye up to 48 weeks of 
treatment
Secondary objective:  Safety 
Investigate the safety and tolerability of 
runcaciguat in patients with NPDR 
Secondary endpoints for secondary objective:
Frequency of treatment-emergent adverse events
Other endpoints (for secondary objective):
Laboratory parameters 
Vital signs
Electrocardiography 
Other objectives
Characterize pharmacodynamic effects of 
runcaciguat in patients with NPDR
Other endpoints
Central retinal thickness
HbA1c
Serum lipoproteins
Characterize pharmacokinetics of 
runcaciguat in patients with NPDR
Population pharmacokinetics 
Pre-dose (trough) plasma concentrations of runcaciguat by visit 
DRSS = Diabetic Retinopathy Severity Scale; NPDR = Non-proliferative diabetic retinopathy; 
Overall design:
This is a randomized, double-masked parallel study with two study arms enrolling N=98 
patients with non-proliferative diabetic retinopathy.  The study is conducted as a 
placebo-controlled study, for details see Section 6.3.
Total treatment duration is 48 weeks. The primary endpoint will be the number of 
participants with a ≥ 2-step improvement (reduction) in the DRSS after 48 weeks of treatment
in the study eye. 
A steering committee consisting of ophthalmologists and diabetologists (masked) is put in 
place to provide scientific and operational recommendations to the study protocol and may be 
consulted to support decisions in study conduct.  An independent Data Monitoring Committee 
is set up to provide recommendations based on unmasked review of data, if needed.
Brief summary:
This Phase 2 study is conducted to determine whether runcaciguat, administered at once daily 
oral doses of a modified-release formulation, is more effective in treating NPDR than placebo.


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The study comprises two subparts, 1 (PK/PD) and 2 (proof of concept); both subparts will be 
conducted in parallel.
To assess the efficacy, the retinal morphology will be investigated by 7-field color fundus 
photography (CFP) supported by 7 Field FA images for the assessment of the DRSS by a 
central reading center. Two-step DRSS improvement at 48 weeks of treatment will be the 
primary efficacy endpoint. Additional DRSS assessments are done after 12 and 24 weeks of 
treatment. In addition, vision-threatening complications will be recorded throughout the study 
and assessed as secondary efficacy endpoint. 
During the course of the study, 16 visits are planned, including the screening visit (Visit 1) 
and the end-of-study visit (Visit 16).  Visit intervals are weekly during the first 4 weeks, 
while the dose of runcaciguat (or placebo) is titrated to the target dose, then fortnightly for the 
next 4 weeks and then every 4 weeks up to Week 25 (Visit 12).  The subsequent visits, up to 
end of treatment in Week 49 (Visit 15), will be at 8-week intervals.  The end-of-study visit, 
Visit 16, will take place 4 weeks later. 
Number of participants:
A combined total of approximately 98 participants for Part 1 and 2 will be randomly assigned 
for an estimated total of ≥40 participants per intervention group evaluable for primary 
endpoint assessment, as defined in Section 9.2.  The estimated screen failure rate is 
approximately 50%.
Intervention groups and duration:
Participants are randomly assigned to one of two study arms.  Assignment will be masked, as 
detailed in Section 6.3. After providing informed consent, participants will be screened (Visit 
1) and within up to 4 weeks, eligible participants will be randomized and treatment will be 
initiated at Visit 2.  During the initial four weeks, treatment will be titrated to the target dose 
of 120 mg runcaciguat or matching placebo. Treatment will start at 30 mg runcaciguat or 
placebo once daily for the first week. If well tolerated, the dose will be increased to 60 mg 
runcaciguat or placebo at Visit 3 in the second week of treatment, then to 90 mg runcaciguat 
or placebo at Visit 4 in the third week of treatment, and finally to 120 mg runcaciguat or 
placebo at Visit 5. 
In case of intolerability (see Section 6.5.1) treatment may continue without up-titration or the 
dose may be reduced by one titration step.
Treatment will continue at the highest tolerated dose until completion of 48 weeks of 
treatment if tolerated, or until development of a vision threatening complication or 
development of PDR.
An end-of-study visit will be performed 4 weeks after end of treatment. This includes both 
participants who complete the planned treatment period, and participants who discontinue 
treatment early including treatment discontinuation due to vision threatening complications.
Data monitoring / Other committee:
Yes


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1.2
Schema
Figure 1–1
Schematic study design 
Placebo (Part 1 n = 6;  Part 2 n = 40)
Runcaciguat (Part 1 n = 12;  Part 2 n = 40)
Screening
Study treatment
total of 48 weeks
Follow up
4 weeks
         
Randomization
Last 
protocol-
stipulated 
procedure
Titration
4 weeks
30 mg
60 mg
90 mg
120 mg
End of 
titration
48 weeks
Primary 
endpoint


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1.3
Schedule of activities (SoA)
Table 1-2
Schedule of activities:  Part 1 – Screening (Visit 1) and titration phase (Visits 2 to 6)
Screen
Titration
Visit number
1
2
3,
4, 5
6
Study week
-1
1
2,
3, 4
5
Study day
-2
1
8, 15, 22
29
Permissible time window (days) -28 to -2 
n/a
±1
±2
Time (hours relative to dose)
pre 1-2 2-4 pre 1-22 2-4 pre 1-22 2-4
Initiation
Written informed consent
●
Allocation of screening number
●
Demographic data 
●
Medical/surgical history (general and cardiological)
●
Previous medication (medication history)
●
History on use of caffeine, alcohol, tobacco
●
Check of in-/exclusion criteria
●
●
Determination of study eye
●
Study 
intervention
Randomization
●
Dose titration decision 
●
Administration of study intervention (time 0)
●
●
●
Collection of unused study intervention
●
●
Dispensation of study intervention 
●
●
●
Safety4
Recording of AEs, concomitant medication
→
→
→
→
→
→
→
→
Physical examination, height, weight
●
Checking fasting / feeding state
●
●
●
●
Blood pressure, pulse rate 1
●
●
●2
●
●
●2
●
●
●2
●
12-lead ECG (triplicate) 1
●
●
●2
●
●
●2
●
●
●2
●
Urine pregnancy test (women)
●
●
●
Blood 
sampling3,4
Hematology, biochemistry
●
●
●
●
Hormones
●
Biomarker (plasma, serum)
●
●
●
Pharmacogenetics (optional)
●
Serum pregnancy test (women)
●
●
●
●
Pharmacokinetics
●
●2
●
●
●2
●
●
●2
●
Ophthalmology 
examinations4
(bilateral)
Visual acuity test (BCVA)
●
●
Tonometry 
●
●
●
●
Structural OCT 
●
●
●
●
Anterior and posterior segment examination
●
OCT angiography 
●
●
●
●
●
●
●
7-field color fundus photography (DRSS)
●
Fluorescein angiography (DRSS)
●
AE = adverse event; BCVA = best corrected visual acuity; DRSS = used for assessment of diabetic retinopathy severity score; 
ECG = electrocardiogram; OCT = optical coherence tomography
1
Blood pressure, pulse rate and ECG always to be measured in supine or semi-supine position after ≥5 minutes rest and 
before any blood draws
2
Minimum interval of 1 hour to prior and subsequent examinations
3
Blood sampling to be performed before fluorescein angiography, to avoid interferences with analytics
4
To be done before study intervention administration, except for Visit 7 taking place in the afternoon


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Table 1-3
Schedule of activities:  Part 2 - Screening (Visit 1) and titration phase (Visits 2 to 6)
Screen
Titration
Visit number
1
2
3
4
5
6
Study week
-1
1
2
3
4
5
Study day
-2
1
8
15
22
29
Permissible time window (days) -28 to -2 
0
±1 
±2 2
±2 2 
±2 
Initiation
Written informed consent
●
Allocation of screening number
●
Demographic data 
●
Medical/surgical history (general and cardiological)
●
Previous medication (medication history)
●
History on use of caffeine, alcohol, tobacco
●
Check of in-/exclusion criteria
●
●
Determination of study eye
●
Study 
intervention
Randomization
●
Dose titration decision by investigator
●
●
●
Administration of study intervention (time 0, after 
blood draws)
●
●
●
●
●
Collection of unused study intervention
●
●
●
●
Dispensation of study intervention 
●
●
●
●
●
Safety4
Record AEs and concomitant medication
→
→
→
→
→
→
Physical examination, height, weight
●
Blood pressure, pulse rate 1
●
●
●
●
●
●
12-lead ECG 1
●
●
●
●
●
●
Urine pregnancy test (women)
●
●
●
●
●
Blood 
sampling3,4
Hematology, biochemistry 
●
●
●
●
●
●
Hormones
●
Biomarker (plasma, serum)
●
●
●
●
●
Pharmacogenetics (optional)
●
Serum pregnancy test (women)
●
●
●
●
●
●
Pharmacokinetics (pre dose)
●
●
●
●
Ophthalmology 
examinations4
(bilateral)
Visual acuity test (BCVA)
●
●
Tonometry 
●
●
●
●
●
●
Structural OCT 
●
●
●
●
●
●
Anterior and posterior segment examination
●
OCT angiography (optional)
●
●
●
●
●
●
7-field color fundus photography (DRSS)
●
Fluorescein angiography (DRSS)
●
AE = adverse event; BCVA = best corrected visual acuity; DRSS = used for assessment of diabetic retinopathy severity score; 
ECG = electrocardiogram; OCT = optical coherence tomography
1
Blood pressure, pulse rate and ECG always to be measured in supine or semi-supine position after ≥5 minutes rest 
and before any blood draws
2
Visit windows are wider than in Part 2 due to difference in PK/PD assessments
3
Blood sampling to be performed before fluorescein angiography to avoid interferences with analytics
4
To be done pre-dose before study intervention administration, except for Visit 7 taking place in the afternoon


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Table 1-4
Schedule of activities:  Parts 1 and 2 - Visits 7 to 16
Visit number
7 1
8
9
10
11
12
13
14
15
EoT
16
EoS
Study week
7
9
13
17
21
25
33
41
49
53
Study day
43
57
85
113
141
169
225
281
337
365
Permissible time window (days)
±2 
±2 
±7 
±7 
±7 
±7 
±7
±7
±7
±7
Study 
interv.
Dispensation of study intervention
●
●
●
●
●
●
●
●
Administer study intervention (after blood draws)
●
●
●
●
●
●
●
Collection of unused study intervention
●
●
●
●
●
●
●
●
●
Safety 4
Record AEs and concomitant medication
→
→
→
→
→
→
→
→
→
→
Physical examination, weight
●
Blood pressure, pulse rate 2
●
●
●
●
●
●
●
●
●
●
12-lead ECG 2
●
●
●
●
●
●
●
Dispensation of urine pregnancy test 3
●
●
●
Blood 
sampling4,5
Hematology, biochemistry 
●
●
●
●
●
●
●
●
●
●
Biomarker samples: plasma, serum 
●
●
●
●
●
●
●
Serum pregnancy test (women)
●
●
●
●
●
●
●
●
●
●
Pharmacokinetics
●
●
●
●
●
●
Ophthalmolog 
examinations 4 
(bilateral)
Visual acuity test (BCVA)
●
●
●
●
●
●
●
Tonometry 
●
●
●
●
●
●
●
●
●
●
Structural OCT 
●
●
●
●
●
●
●
●
●
●
Anterior and posterior segment examination
●
●
●
OCT angiography (optional in Part 2)
●
●
●
●
●
●
●
●
●
●
7-field color fundus photography (DRSS)
●
●
●
Fluorescein angiography (DRSS)
●
●
AE = adverse event; BCVA = best corrected visual acuity; DRSS = used for assessment of diabetic retinopathy severity score; 
ECG = electrocardiogram; EoS = End of study; EoT = end of treatment; OCT = optical coherence tomography
1
Visit 7 should take place in the afternoon, PK and biomarker samples to be taken at 4 to 8 hours after dosing
2
Blood pressure, pulse rate and ECG always to be measured in supine or semi-supine position after ≥5 minutes rest and 
before any blood draws
3
Additional urine pregnancy test to be provided to women for use off-site 4 weeks after the respective visit
4
To be done pre-dose before study intervention administration, except for Visit 7 taking place in the afternoon
5
Blood sampling to be performed before fluorescein angiography to avoid interferences with analytics
2.
Introduction
As of amendment 3, this Section and its sub-sections were integrated from Master Protocol. 
Runcaciguat (BAY 1101042) is a representative from a new class of drugs, the soluble 
guanylate cyclase (sGC) activators.  The sponsor is developing sGC activators for the 
treatment of microangiopathies, namely chronic kidney disease (CKD) and non-proliferative 
diabetic retinopathy (NPDR).  For both indications, proof-of-concept studies are currently 
ongoing, one being the NEON-NPDR study.  
For the NPDR indication, the treatment is intended to 

Prevent progression of diabetic retinopathy and vision-threatening complications

Reverse retinal changes attributed to diabetic retinopathy

Maintain visual acuity.


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Runcaciguat will be investigated in a formulation of modified-release (MR) tablets, which 
result in peak plasma concentrations at approximately 10 hours post dose and a peak-to-trough 
concentration ratio of 2:1.  The terminal half-life of runcaciguat in plasma ranged from 
approximately 14 to 21 hours in healthy study participants.
Runcaciguat, given as MR tablets, showed vasodilatory effects at doses from 20 mg to 90 mg 
once daily without clinically relevant signs of hemodynamic intolerance.  Once-daily doses up 
to the highest investigated dose of 90 mg administered over 7 days were safe and well 
tolerated by healthy participants.  
Other indications under development for runcaciguat include chronic kidney disease.  
A clinical study in patients with chronic kidney disease (CONCORD study 18748; EudraCT: 
2019-003297-53) started in 2020 and is ongoing in parallel.  In that study, patients are treated 
with once-daily doses of runcaciguat titrated up to 120 mg.  The current recruitment status is
summarized in Section 2.3.1. 
Further information on pre-clinical and available clinical data relevant in the context of this 
study are provided and discussed in Section 2.3. Additional information is given in the most 
recent version of the IB.  
2.1
Study rationale
The clinical development of runcaciguat so far has shown that the compound is well tolerated. 
However, formulation challenges lead to an inconvenient dosing regimen and a difficult to 
manage supply chain. 
 
 
 
The Sponsor plans to run the NEON-NPDR study with runcaciguat as a PoC trial for sGC 
activators in NPDR. Although the sGC activator runcaciguat will not be further developed, the 
results from this trial will generate a general PoC for sGC activation in NPDR using a 
investigational compound that has proven its activity in nonclinical and in phase 1 clinical 
trials and that has been shown to be well tolerated.  
In addition, detailed pharmacokinetic and pharmacodynamic assessments will be performed 
on a subset of participants enrolled in Part 1.  The resulting improved PK/PD understanding 
will facilitate the translation of the results obtained with the runcaciguat to other sGC 
activators.
Therefore, this trial will be the basis for a general decision on the suitability of sGC activators
for treatment of NPDR.  In the positive case, this may optimize the development of 
subsequent sGC activators. In particular the data will facilitate the choice of the appropriate 
dose-range and the choice of the most appropriate treatment duration. This knowledge will 
result in safer and more focused clinical trials with the follow-up compound.
CCI


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2.2
Background
2.2.1
Disease background
The prevalence of diabetic retinopathy (DR) approximates 35% among people with diabetes 
worldwide (Yau et al. 2012).  Diabetic retinopathy ranks fifth among common causes for 
blindness or severe vision impairment, and the prevalence of DR-related blindness will 
increase due to increasing prevalence of diabetes (Leasher et al. 2016). 
Diabetic retinopathy is characterized by progressive changes in the retinal microvasculature 
with accompanying neuroglial damage (Santiago et al. 2018). Pathognomonic changes consist 
of microaneurysms and soft exudates, macular edema, and neovascularization.  In addition, 
other retinal cell types are affected by diabetes and may compromise or contribute to visual 
impairment.  
Predicting progression of mild- and moderate- NPDR to PDR has been evaluated at the group 
level but is still not well established at the individual level (ETDRS report number 10 1991).  
HbA1c, hypertensive status and hyperlipidemia are all factors routinely used in screening in 
many European countries (Aspelund et al. 2011, Lund et al. 2016, van der Heijden et al. 
2014), they poorly predict progression of non-proliferative retinopathy. According to Sato et 
al (Sato et al. 2001), baseline severity of diabetic retinopathy is a better predictor of clinical 
outcomes. Cunha-Vaz et al. (Cunha-Vaz et al. 2017) proposed an evolution model to PDR 
which is based on microaneurysms and retinal features, classifying patients into 3 risk 
phenotypes, disregarding HbA1c or other metabolic parameters.
Oxidative stress plays a key role in the pathogenesis of diabetic retinopathy.  Reactive oxygen 
species (ROS) are increased in the retina in diabetes, at the same time the antioxidant defense 
system is also compromised.  Increased ROS stimulate the release of pro-inflammatory cyto-
kines, promoting a chronic low-grade inflammation involving various signaling pathways.  An 
excessive production of ROS can lead to retinal endothelial cell injury, increased 
microvascular permeability, and recruitment of inflammatory cells at the site of inflammation 
(Santiago et al. 2018).
2.2.2
The role of soluble guanylyl cyclase in diabetic retinopathy
Under physiological conditions (Figure 2–1 A), endothelial (eNOS) and neuronal nitric oxide 
synthase (nNOS) are expressed by retinal cells and produce nitric oxide (NO) in small 
(nanomolar) amounts to activate the soluble forms of guanylyl cyclase (sGC).  Active sGC 
catalyzes the synthesis of cGMP from GTP.  The classical effects of the NO-sGC-cGMP axis 
are vasodilation, regulation of blood flow, inhibition of platelet aggregation and suppression 
of leukocyte adhesion and migration (Lehners et al. 2018).
Under pathological conditions, such as DR, (Figure 2–1 B), cytokine-inducible NOS (iNOS) 
is expressed.  iNOS is expressed in macrophages, microglia, glial cells, neurons, and vascular 
cells of the retina.  iNOS differs from eNOS and nNOS as it produces NO in large 
(micromolar) amounts.  Excess NO binding to superoxide results in peroxynitrite formation.  
Peroxynitrite oxidizes the sGC enzyme, which loses its heme-moiety, making it unresponsive 
to NO (Stasch et al. 2011). As a result, cGMP production is reduced and a vicious circle of 
oxidative stress within the retina is initiated that drives the progression of diabetic retinopathy 
(Förstermann 2010).


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Figure 2–1 C illustrates that the sGC activator runcaciguat (BAY 1101042) targets the nitric 
oxide-insensitive states of the sGC enzyme.  Runcaciguat binds to the unoccupied heme-
binding complex or displaces the prosthetic heme of sGC and produces an additive effect with 
NO.  In certain cases, sGC activators also protect sGC from proteasomal degradation.  This 
restores the NO-sGC-cGMP axis functions.  It improves retinal blood flow by vascular 
vasodilation through relaxation of smooth muscles, inhibits platelet aggregation and inhibited 
leukocyte adhesion.  This leads to better neurovascular unit function neurotransmission and, 
subsequently, slows the disease progression.
Figure 2–1
The role of sGC activator in diabetic retinopathy
AGE = advanced glycation endproduct; cGMP = cyclic guanosine monophosphate; DR = diabetic retinopathy; eNOS = 
endothelial nitric oxide synthase; iNOS = cytokine-inducible nitric oxide synthase; nNOS = neuronal nitric oxide synthase; 
NO = nitric oxide; ROS = reactive oxygen species; sGC = soluble guanylyl cyclase ; sGCa = soluble guanylyl cyclase A 


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Figure 2–2
sGC stimulators and activators target different redox states of the enzyme
cGMP = cyclic guanosine monophosphate; eNOS = endothelial nitric oxide synthase; GTP = guanosine triphosphate;  
NO = nitric oxide; sGC = soluble guanylyl cyclase
Source : (Stasch et al. 2015).
2.2.3
Runcaciguat
Runcaciguat is a sGC activator that improved function and retinal structure in pre-clinical DR 
models.  In patients with NPDR, runcaciguat is expected to improve retinal perfusion and 
thereby reverse changes in fundus morphology attributable to diabetic retinopathy and reduce 
the incidence of vision-threatening events and lower the risk of progression to proliferative 
diabetic retinopathy.
2.3
Benefit/risk assessment
Based on the expected low risk of study participation, discussed below in Section 2.3.1, and in 
view of the potential benefit that may result from successful development of a drug improving 
NPDR and preventing complications as discussed below in Section 2.3.2, the benefit-risk 
assessment of this study with runcaciguat is considered positive and supportive of the 
participation of patients with NPDR in this clinical trial.
Emerging safety issues affecting the benefit/risk assessment of the study will be 
communicated as soon as possible between the sponsor, all study sites and investigators and 
trial participants according to the requirements of the EMA guideline on strategies to identify 
risks for early clinical trials and including first in human studies.


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2.3.1
Risk assessment
Risks associated with study interventions – Runcaciguat
Runcaciguat was well tolerated by healthy male participants up to a single oral dose of 20 mg 
given as IR tablet.  This IR tablet resulted in maximum plasma concentrations at 
approximately 30 minutes post dose (tmax 0.5 hours).  A 30 mg IR tablet dose was not well 
tolerated based on the exaggerated vasodilative effects.  These findings were attributed to the 
fast increase in plasma concentrations, as reflected by a high peak-to-trough ratio of > 8:1.  
When administering as MR tablets with a tmax of approximately 10 hours, as planned in this 
clinical trial, mild vasodilative effects, indicated by a compensatory heart rate increase were 
observed at doses of 20 mg and above in healthy study participants. A consistent decrease of 
blood pressure was observed at doses of 50 mg and above and no signs of hemodynamic 
intolerance were apparent up to 90 mg once daily, the highest dose investigated.  Therefore, 
the MR-tablet formulation was chosen for further clinical development.  Hence, unless 
specified otherwise, any further mention of runcaciguat tablets in this document refers to the 
MR formulation.
Different drug classes introduced in clinical practice increase cGMP concentrations.  This 
group of drugs includes nitrates, phosphodiesterase inhibitors, and sGC stimulators.  Nitrates, 
in particular, have an excellent safety track record in patients with coronary heart disease.  
This is a population that includes patients with diabetes and DR, indicating that targeting 
cGMP in the patient population of this study is safe in principle.  Runcaciguat was shown to 
have vasodilatory effects in healthy subjects, with consecutive decreases in diastolic blood 
pressure and compensatory increases in heart rate.  
Concomitant treatment with other drugs acting on the NO-sGC-cGMP system has the 
potential to result in synergistic and excessive pharmacodynamic activity with the relative 
adverse effects.  Therefore, these medications must not be co-administered to the patients 
enrolled in this study. 
When runcaciguat was investigated in healthy participants at once-daily doses of 10 to 90 mg 
over 7 days, increased heart rate was observed at doses of 20 mg and higher.  Consistent 
systolic and diastolic blood pressure decreases were observed at once-daily doses of 50 mg 
and above, as shown in Table 2-1.  Overall, the effects on heart rate and blood pressure were 
higher after the first administration than after 7 days of once-daily dosing, suggestive of an 
adaptation to vasodilative effects.  Orthostatic reactions in testing standing blood pressure 
considered drug-related by the investigator, were reported after single dose only in the dose 
steps 75 and 90 mg but were not provoked on testing on the last dosing day (7 days of once 
daily dosing).  


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Table 2-1
Placebo-corrected change in blood pressure and heart rate from baseline after once-
daily runcaciguat administration over 7 days (ANCOVA, pre-dose adjusted, 90%CI)
Heart rate
(min-1)
Systolic blood pressure
(mmHg)
Diastolic blood pressure 
(mmHg)
ANCOVA
90%CI
ANCOVA
90%CI
ANCOVA
90%CI
10 mg 
1.8
-2.0 – 5.5
-2.1
-6.1 – 1.9
0.9
-2.2 – 4.0
20 mg 
4.8
1.1 – 8.5
-0.3
-4.3 – 3.7
2.5
-0.5 – 5.6
30 mg 
5.5
1.8 – 9.3
1.8
-2.2 – 5.8
0.6
-2.5 – 3.6
40 mg 
2.3
-1.4 – 6.0
2.5
-1.5 – 6.5
0.9
-2.1 – 4.0
50 mg 
4.0
1.1 – 7.0
-4.3
-7.4 – -1.1
-2.5
-4.9 – -0.0
75 mg 
2.8
-1.1 – 6.7
-5.6
-9.8 – -1.5
-2.2
-5.4 – 1.0
90 mg 
2.3
-1.5 – 6.2
-5.6
-9.8 – -1.5
-4.0
-7.2 – -0.8
Changes with 90% CI inclusive of zero (0) shown in italic
ANCOVA = analysis of covariance; CI = confidence interval
Source: PH-41225, Tables 9-4, 9-6 and 9-10
In a study investigating the effects of a single oral dose of 30 mg runcaciguat in participants of 
different age and gender in comparison with placebo, runcaciguat was well tolerated without 
clinically relevant effects on heart rate or blood pressure.
The clinical phase 2 study of runcaciguat in patients with chronic kidney disease was 
completed and final data are available (CONCORD study 18748;  EudraCT: 2019-003297-
53).  The CONCORD study was a randomized, placebo-controlled, double-masked study with 
243 patients randomized 3:1 to runcaciguat (n=184) and to placebo (n=59).  The study used 
the same titration regimen as in the present NEON-NPDR study. The treatment duration was 8 
weeks.  
Peripheral oedema, dizziness, diarrhea, headache, and hypotension occurred at an incidence of 
over 4% in participants treated with runcaciguat and at a lower incidence in placebo-treated 
participants.  They can all be plausibly explained by the mechanism of action, resulting in 
relaxation of smooth muscles and lower BP. The incidence of SAEs was similar in the 
runcaciguat and the placebo arms.  
Five cases of syncope were reported only in the runcaciguat arm, at doses of 60 mg, 90 mg, 
and 120 mg per day.  Three of the syncopes occurred after alcohol intake, in one instance in 
combination with additional sildenafil.  Another case was related to dehydration and the 
remaining case occurred in a participant who had prior hypotension and dizziness and whose 
dose was therefore not titrated beyond 60 mg.  
In the runcaciguat arm, a slight reduction in mean eGFR from baseline was observed, that 
could be explained by a transient SBP reduction.  Six cases of acute kidney injury were 
observed including one case in placebo arm. The observed incidence was higher in the 
runcaciguat arm (2.7%) than in the placebo arm (1.7%).  Except for two cases, the events 
observed from runcaciguat arm were confounded by dehydration, infection, or cardiac 
arrhythmia. All patients fully recovered.
There was no evidence for hepatic toxicity in this study in patients with chronic kidney 
disease.
Taken together, the safety data from this study indicate that runcaciguat was well tolerated.  
AEs were predominantly mild to moderate, driven by mode of action, amenable to the 
monitoring as defined for the present clinical trial, and raised no safety concern.


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Further detail on the safety data from the CONCORD study is presented in the current 
Investigator’s Brochure (Version 8.0, Section 5.3.3.2). 
In view of these results from the CONCORD study, and taking into consideration that the 
characteristics of the patient populations enrolled in the NEON-NPDR and the CONCORD 
studies are similar, it can be concluded that the weekly titration and administration of 
runcaciguat up to 8 weeks of treatment can be considered as safe also for the NEON-NPDR 
study.  
In this study, dose titrations will be confirmed by the investigator after confirmation that the 
prior dose level was well-tolerated.  These confirmations are supported by clear decision 
criteria, which are provided in Section 6.5.
The risk associated with once-daily treatment of diabetic patients with NPDR with 
runcaciguat in this study is assessed as low, considering the conservative dose titration 
regimen.  In addition, safety investigations and assessments are in place to support prompt 
reaction to any potential adverse event, in particular during the early but also during the later 
period of treatment.
Mild liver enzyme increases (reversible, without bilirubin increase) were reported in the 
single/multiple dose escalation study in two healthy participants administered once daily 
doses of 50 mg runcaciguat (Study 18747). The observed serum enzyme increases started 
prior to study drug administration, were not dose-dependent and potential alternative 
etiologies were identified (physical activity, viral infection).  As a precaution, however, study 
participants will be monitored for laboratory changes indicating potential adverse effects on 
the liver (see Sections 8.2.4 and 10.5) and relative stopping criteria are defined in 
Section 6.5.2. 
Taken together, once-daily doses up to 90 mg without initial titration were well tolerated by 
healthy study participants.  Therefore, the target dose of 120 mg, which is to be reached over a 
4-step titration spanning 4 weeks, is considered to be appropriate, as discussed in detail in 
Section 4.3 and confirmed by the experience of the CONCORD study.  Potential risks of
runcaciguat treatment and implemented mitigation activities are described in Table 2-1.


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Table 2-2
Risk assessment for the study intervention runcaciguat
Potential risk of 
clinical 
significance
Summary of data / Rationale for risk
Mitigation strategy
Hypotension, 
blood pressure 
decrease with 
compensatory 
tachycardia
Study 18747 in healthy participants:
Dose-dependent heart rate increases at 
single doses ≥20 mg interpreted as 
compensatory heart rate increase in 
response to vasodilation.
Dose-dependent decrease in diastolic and 
systolic blood pressure after single and 
multiple doses ≥50 mg
Risk communication in IB / ICF
Clinical Study design:
Individual up-titration schedule incl. 
modification/discontinuation criteria 
Monitoring of blood pressure, heart rate
Document and assess adverse events closely as 
AESI 
Liver enzyme 
elevation
Study 18747 in healthy participants:
Transient asymptomatic transaminase 
increases observed in two participants (ALT 
peak 8.6 x ULN, AST peak 3.6 x ULN, 
GLDH) without increase of bilirubin.  
Fully recovered without specific therapeutic 
intervention 
Concomitant CRP increase suggestive of 
infection as potential alternative cause 
Risk communication in IB / ICF
Clinical Study design:
Exclusion of participants with liver failure
Monitoring of liver function and definition of 
stopping criteria
Document and assess adverse events closely as 
AESI
Impairment of 
renal function
Nonclinical pharmacology
Decrease in arterial blood pressure may 
result in transient decrease in renal 
perfusion and consecutive glomerular 
filtration rate.  In rats, a transient reduction 
of urine volume, and urine electrolytes was 
observed
Risk communication in IB / ICF
Clinical Study design:
Exclusion of participants with severe renal 
impairment (eGFR < 30 mL/min) 
Monitoring of blood pressure 
Monitoring of serum chemistry for renal function 
(creatinine, eGFR), serum electrolytes
Individual dose titration
AESI = adverse event of special interest; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRP = c-reactive 
protein; eGFR = estimated glomerular filtration rate; GLDH = glutamate dehydrogenase ; IB = investigator’s brochure; 
ICF = informed consent form; ULN = upper limit of normal.
Risks associated with study procedures 
The only procedures in this study which may qualify as invasive are fluorescein angiography 
and blood draws.  
The blood volumes drawn at any visit (< 25 mL) are low and generally considered as safe.  
Fluorescein angiography is a routine diagnostic intervention in ophthalmology for patients 
with advanced DR.  The main risks of fluorescein angiography include nausea, 
hypersensitivity reactions and local reactions on the injection site that are mostly mild.  Severe 
hypersensitivity reactions are extremely rare (approximately 1 : 200,000), but have a potential 
to be fatal.  Clinical sites which examine DR patients are experienced with the use of 
fluorescein angiography and the management of adverse reactions. 
In summary, the risks associated with the study procedures can be viewed as low.


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Risks associated with assignment to the placebo arm
At present, ranibizumab and aflibercept are approved therapies for DR of any stage in the US, 
including moderate to severe NPDR.  In the EU, no pharmacologically active product is 
presently approved for treatment of NPDR.  Both ranibizumab and aflibercept are invasive 
treatment options, administered by intravitreal injection.  As NPDR is often asymptomatic, the 
inconvenience of such an invasive approach results in a low acceptance by patients and 
physicians, even in territories where it is approved.  Consequently, regular ophthalmologic 
monitoring remains the standard of care for NPDR, even where intravitreal anti-VEGF 
treatment is available.  Therefore, assignment of patients in this study with frequent 
ophthalmology examinations to the placebo arm does not represent a deviation from the 
standard of care.  
Risks associated with inclusion of women of child-bearing potential
The reproductive toxicity of runcaciguat was investigated in rats and rabbits.  In embryofetal 
development studies in both species, maternal toxicity was observed at exposures similar to 
the anticipated human exposure.  At the corresponding doses, increased rates of embryonal 
loss (resorptions) were noted in rats and malformations were observed in rabbits. 
Women of child-bearing potential may participate in this clinical study if they have a negative 
pregnancy test at screening, are not breast feeding and if they consent to use highly effective 
contraception, as specified in the inclusion and exclusion criteria (Sections 5.1 and 5.2).  If, 
despite these precautions, a female study participant becomes pregnant, study intervention 
will be permanently discontinued (Section 7.1).
With the use of highly effective contraception, i.e. methods that can achieve a failure rate of 
less than 1% per year when used consistently and correctly (CTFG 2014), together with 
regular pregnancy testing, the risk of inadvertent pregnancy in the participants is considered to 
be low.  Therefore, in line with ICH guidance M3(R2) (ICH 2009) and with the CTFG 
recommendations on contraception and pregnancy testing in clinical trials  (CTFG 2014).  
inclusion of women of child-bearing potential in this clinical study is justified.  
Risks associated with the COVID-19 pandemic situation
This clinical study is conducted as an outpatient study at sites that have procedures in place to 
minimize the risk of contagion at sites, in line with institutional and governmental guidelines 
and regulations.  In this setting, the risk of contagion attributable to study participation is 
considered similar to other activities of daily living, depending on the current local pandemic 
situation.
Diabetes and cardiovascular disease are conditions that are likely to predispose patients to a 
higher risk of severe course of infection (Ciceri et al. 2020, Robert Koch Institut 2020). On 
this basis, careful adherence to hygienic standards during study related activities is of high 
importance. 
Based on current knowledge, runcaciguat is not known to interact with the immune system.  
Therefore, there is currently no indication that incidental infection of study participants with 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) would change the individual 
risk for a severe course of infection.  Based on the mechanism of cGMP increase, treatment 
with runcaciguat may have anti-thrombogenic effects and improve perfusion of the 
microvasculature.  Whether this may result in a beneficial effect in severe courses of 


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COVID-19 is currently unknown.  Based on these considerations, a general withdrawal of 
participants intercurrently tested positive for SARS-CoV-2 does not seem to be warranted.  As 
for other infectious diseases, individual decisions by the Investigator are more appropriate.
2.3.2
Benefit assessment
Treatment duration of 48 weeks is probably insufficient to result in a meaningful individual 
benefit, such as a significant decrease in vision-threatening complications.  However, 
obtaining a 2-step DRSS improvement may be associated with an improvement in disease 
status shown to be beneficial in clinical trials such as the PANORAMA study and Protocol W 
(Maturi et al. 2021, Wykoff 2020).  Whether such change results in an individual functional 
benefit is yet to be demonstrated.  
All patients, including those assigned to the placebo arms, will be under close surveillance 
with regards to their diabetic retinopathy while participating in this study.  The 8-week visit 
intervals in the study are shorter than the standard intervals for ophthalmology monitoring of 
patients with moderately severe to severe diabetic retinopathy (Berufsverband der Augenärzte 
Deutschlands e.V. and Deutsche Ophthalmologische Gesellschaft e.V. 2011, Flaxel et al. 
2020, Nationale VersorgungsLeitlinie 2020, Ophthalmologists TRCo 2012).  Since the 
standard therapeutic approach to NPDR without DME consists of regular monitoring, patients 
assigned to placebo are ensured to have timely surveillance during their participation in the 
study, similar to the highest levels of standard of care.  Progression of DR, including 
development of DME, would be promptly identified in these patients.  This represents a 
relevant benefit, as it expedites the treatment of vision threatening complications.


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3.
Objectives and endpoints
The objectives and endpoints for the study are summarized in Table 3-1.  
Table 3-1
Study objectives and endpoints 
Objectives
Endpoints
Primary objective:  Efficacy
Establish the proof-of-concept for the 
efficacy of the sGC activator runcaciguat
in the treatment of NPDR.
Primary endpoint:
DRSS improvement ≥2 steps at 48 Weeks of treatment in the 
study eye
Secondary endpoints for primary objective:
Vision threatening complications at 48 weeks of treatment in the 
study eye
DRSS improvement ≥2 steps at 24 weeks of treatment in the 
study eye
Other endpoints for primary objective:
Change in visual acuity from baseline
Change in leakage area on Fluorescein Angiography
DRSS changes from baseline in the study and fellow eye
Vision threatening complications in any eye up to 48 weeks of 
treatment
Secondary objective:  Safety 
Investigate the safety and tolerability of 
runcaciguat in patients with NPDR 
Secondary endpoints for secondary objective:
Frequency of treatment emergent adverse events
Other endpoints for secondary objective:
Laboratory parameters 
Vital signs
Electrocardiography
Other objectives
Characterize pharmacodynamic effects of 
runcaciguat in patients with NPDR
Other endpoints
Central retinal thickness
HbA1c
Serum lipoproteins
Characterize pharmacokinetics of 
runcaciguat in patients with NPDR
Population pharmacokinetics
Pre-dose (trough) plasma concentrations of runcaciguat by visit 
Further investigate the study intervention
and similar drugs (e.g. mode-of-action-
related effects, safety) and to further 
investigate pathomechanisms deemed 
relevant to NPDR, (cardio)vascular 
diseases and associated health problems
Various biomarkers (e.g. diagnostic, safety, pharmacodynamic, 
monitoring, or potentially predictive biomarkers)
DRSS = Diabetic Retinopathy Severity Scale; HbA1c = Hemoglobin A1c (glycated hemoglobin); NPDR = Non-proliferative 
diabetic retinopathy


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4.
Study design
4.1
Overall design
The study is subdivided into two components, as shown in Table 4-1. Part 1 is conducted to 
provide data for PK/PD analyses in diabetic patients with NPDR and to explore the value of 
different OCT-A assessments as PD marker in diabetic retinopathy. Part 2 is the main part of 
this proof of concept study and will be conducted in parallel.  Both components follow a 
similar design – except for the randomization ratio and additional examinations in Part 1.  
Both study subparts will be evaluated together, to the extent that common data are available 
and at the same time.
A steering committee consisting of ophthalmologists and diabetologists (masked) is put in 
place to provide scientific and operational recommendations to the study protocol. 
An independent Data Monitoring Committee (DMC) is set up to provide recommendations 
based on unmasked review of data, if needed.
Table 4-1
Overall study plan
Study part
Main purpose
Overall design
Part 1
PK/PD 
PK/PD assessment
Placebo-controlled, double-masked, 2-arm parallel-group design
with 2:1 randomization.  Total n = 18
Intra-individual weekly dose escalation in 30-mg increments up to 
120 mg once daily.  
Each participant will continue treatment at the individual maximum 
dose for a total treatment duration of 48 weeks.
Part 2
Proof of 
concept
Demonstration of proof 
of concept based on 
efficacy outcome after 
48 weeks of treatment
Placebo-controlled, double-masked, 2-arm parallel-group design 
with 1:1 randomization.  n = 40 per treatment arm
Intra-individual weekly dose escalation in 30-mg increments up to 
120 mg once daily.
Each participant will continue treatment at the individual maximum 
dose for a total treatment duration of 48 weeks.
4.1.1
Part 1 – PK/PD
In Part 1, the randomized participants will be titrated at weekly visits in 30-mg increments to 
the target dose of 120 mg QD, or the maximum individually tolerated dose. After the titration 
period, the individually reached highest dose will be maintained until the end of treatment, for 
the total treatment duration of 48 weeks, followed by a 4-week safety follow-up period. A 
total of 18 participants are planned to be randomized into Part 1 (12 active; 6 placebo). A 
schematic study design for Part 1 is provided in Figure 1–1.  
In Part 1, additional safety, PK and PD investigations will be performed during the titration 
phase as described in Table 1-3. On Visits 2 to 6, participants will remain at sites for 4 hours 
post-dose. During this time, the pulse rate and the blood pressure will be checked and OCT-A 
will be used to assess retinal perfusion as PD markers. Blood samples will be drawn for 
population PK and for PK/PD analyses pre-dose and in two post-dose windows. 


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4.1.2
Part 2 – Proof of concept
Recruitment, screening, and randomization of participants for Part 2 of the study is 
independent from Part 1. 
Part 2 of the study is planned to follow the same titration and dosing scheme as Part 1.  
In Part 2, the participants will be randomized to either placebo (n = 40) or runcaciguat 
(n = 40).  The participants are planned to be titrated at 30-mg increments to the maximum 
tolerated dose or sham titrated.  Each participant will continue treatment for a total treatment 
duration of 48 weeks, followed by a 4-week follow-up period.  
The 24-week and 48-week data together are intended to derive proof-of-concept and may
provide information on the durability of the effect.
4.2
Scientific rationale for study design
As of amendment 3, this section was integrated from the Master protocol. 
Results from previous Phase 1 studies in healthy as well as renally impaired study participants 
and from a phase 2 study in patients with chronic kidney disease have demonstrated that 
runcaciguat given as MR tablets was well tolerated, and support the start of further studies in 
patients. 
Due to the mode of action of sGC activators, and based on preclinical data, it is assumed that 
sGC activators administered to patients with NPDR can positively influence retinal perfusion 
and thereby improve fundus morphology and reduce the progression of retinal ischemia and 
prevent vision-threatening later stages like proliferative diabetic retinopathy (DR) and/or 
diabetic macular edema (DME).
Efficacy is to be assessed based on the Diabetic Retinopathy Severity Scale (DRSS), the 
widely accepted standard to assess disease severity and to stage diabetic retinopathy in clinical 
trials.  This scale is based on the presence or absence of disease-specific phenotypes in a 
defined set of highly standardized 7-field color fundus photographs.  The scale was introduced 
by the Early Treatment of Diabetic Retinopathy Study research group (ETDRS report number 
10 1991).  A commonly accepted efficacy endpoint in clinical trials is an improvement in 
DRSS ratings by more than one severity level or step, i.e. so-called DRSS two-step 
improvement.  This has been used as an endpoint in previous diabetic retinopathy 
development programs resulting in regulatory acceptance (FDA 2019).  
Progression rates to vision-threatening events have consistently been shown to be lower in 
patients with lower DRSS severity (ETDRS report number 12 1991, Maturi et al. 2021, 
Wykoff 2020).  Therefore, an improvement in DRSS indicates a regression of diabetic 
retinopathy and is associated with a clinically relevant risk reduction of progression towards 
proliferative retinopathy and other vision threatening complications (Klein et al. 2001).
In previous studies of intra-vitreal anti-VEGF treatments, 2-step DRSS improvements were 
detected as early as 8 weeks after treatment initiation and reached a maximum after 6 to 
12 months of treatment.  However, recent clinical trials of oral agents in NPDR failed after 
treatment periods of up to 24 weeks (e.g. NCT03238963).  Therefore, the primary endpoint 
assessment is planned after 48 weeks of treatment.  Additional assessments are planned for 
DRSS assessment at 12 and 24 weeks of treatment.  


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Assessment of vision threatening complications as secondary endpoint is planned in addition, 
to correlate the DRSS-change with a clinical outcome parameter in support of the efficacy 
assessment in this study. 
Participant input into design
A patient advisory board was conducted to 

Identify potential hurdles in the plans for the clinical trial to recruitment, adherence 
with the study procedures, and patient retention 

Confirm the relevance of the investigated endpoints for patients with diabetic 
retinopathy (DR)

Seek input on medical need and relevant study outcomes in NPDR from the 
perspective of patients with DR 
The feedback from the advisory board was duly integrated in the study protocol.
4.3
Justification for dose
As of amendment 3, this section was integrated from Master Protocol. 
All study medication will be administered as modified-release formulation, as discussed in 
Section 2.3.1.  
A randomized placebo-controlled double-masked study in patients with chronic kidney 
disease is currently ongoing and recruiting patients (CONCORD study 18748, EudraCT: 
2019-003297-53).  This study is exposing participants to the same titration regimen and target 
dose as the present NEON study, and ongoing safety reviews indicate that this regimen and 
target dose are well tolerated, as discussed in Section 2.3.1. 
Starting dose
As this study is conducted in patients, the number of patients assigned to dose levels that are 
expected to have no or only marginal effect should be avoided.  Therefore, the lowest dose to 
be tested is a low dose for which consistent PD effects on the cardiovascular system were 
observed in prior studies(see Section 2.3.1). The 30 mg dose was identified as minimal 
effective dose with regards to vasodilatory effects (study 18747).  At the same time, this dose 
was very well tolerated in healthy subjects and it is anticipated to be safe and well tolerated in 
patients with NPDR participating in this study.  Therefore, the dose of 30 mg was chosen for 
the lowest dose of continuous treatment in this study.
The starting dose of 30 mg was confirmed to be well tolerated in the ongoing study of 
runcaciguat in patients with chronic kidney disease, the CONCORD study 18748.
Dose titration
Daily doses are titrated up to three times by 30-mg increments, to the target dose.  Titration is 
expected to minimize potential cardiovascular adverse effects, based on a pharmacokinetic / 
pharmacodynamic correlation analysis.  In this PK/PD analysis including data from healthy 
participants taking the MR-formulation of runcaciguat, the changes in diastolic blood pressure 


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and heart rate were 2.5 times and 3.5 times higher on the first day of dosing compared with 
repeated dosing, indicating an attenuation to these acute hemodynamic effects.  This indicates 
that titration can be expected to safely achieve higher, presumably more efficacious doses.
The investigator will take an individual decision prior to each titration in each participant after 
approximately 7 days of treatment at the prior dose level.  At this point, steady-state plasma 
levels should have been reached, considering the plasma half-life of approximately 20 hours.  
Depending on the safety and tolerability observed, the decision may be to either titrate as 
planned, to maintain, or to reduce the daily dose.  Clear guidance to support the investigator’s 
decisions is provided in Section 6.5. 
Weekly dose increments of 30 mg were confirmed to be well tolerated in the ongoing study of 
runcaciguat in patients with chronic kidney disease, the CONCORD study 18748.
Highest dose 
The dose of 120 mg/day was selected to increase potential treatment efficacy with a higher 
exposure, while keeping the safety profile similar to the previous dose level.  Pharmacokinetic 
modeling and pre-clinical pharmacology data support this hypothesis.  The following aspects 
related to the PK and PD properties of runcaciguat were carefully considered in the selection 
of the highest dose of 120 mg:
In prior studies in healthy participants, doses up to 90 mg were safe and well tolerated, even 
when administered without dose-titration.  Based on the experience with the sGC stimulators 
riociguat (Merck Sharp and Dohme 2019) and vericiguat tolerability will likely be 
significantly improved with a dose titration design, as implemented in this clinical trial.  Such 
a titration design should allow to safely reach higher doses and to fully exploit the 
pharmacologic activity of runcaciguat.
While the dose-exposure relationship was approximately dose proportional up to a daily dose 
of 75 mg in healthy participants, Cmax,ss values were overlapping at daily doses of 75 mg and 
90 mg (Study 18747).  The observation based on a group comparison with small sample size 
(n=8 participants per dose step) remains to be confirmed, but it suggests that the risk for over-
proportional increases of runcaciguat concentrations at the planned maximum dose of 120 mg 
per day is very low.  With the dose-titration design, appropriate interim evaluations, involving 
an independent Data Monitoring Committee, are in place for timely detection of any potential 
residual risk.  Based on the results from the renal impairment study 18745, no relevantly 
higher exposure is to be expected in participants with moderate impairment of renal function 
(eGFR range 30 to 60 ml/min).  Considering the lower permissible eGFR limit of 30 ml/min 
defined in exclusion criterion 18, the individual dose titration up to a target dose of 120 mg is 
considered to be appropriate. 
The selection of the highest target dose for runcaciguat in this study (120 mg) is further 
supported by PK/PD modeling performed for the runcaciguat POC study in patients with 
chronic kidney disease (Study 18748) utilizing the reduction of the urinary albumin-creatinine 
ratio (uACR) as an efficacy marker.  For that study, a translational PK/PD analysis for 
runcaciguat was performed, linking a population PK/PD model built on the basis of Phase 1 
data, to model derived hemodynamic response and efficacy observations, e.g. uACR reduction 
in the ZSF-1 rat disease model (Petersson and Voelkner 2019).  Dose-dependent uACR 
changes were extrapolated for runcaciguat indicating that with a dose of 120 mg, a slightly 
higher percentage of patients will achieve the efficacy target of >30% reduction in uACR 
compared to the dose of 90 mg (Table 4-2).


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Table 4-2
CONCORD Study 18748 (CKD): Simulated median outcome in % of treated patients [90% CI]
Dose (steady-state)
30 mg
60 mg
90 mg
120 mg
MAP 24 h decrease
Percentage < 3 mmHg decrease
61.5
[54-68]
56.5
[47-64]
53.5
[44-63]
52
[42-61]
uACR decrease
Percentage > 30 % decrease
61
[52-72]
69
[60-78]
73
[64-82]
75
[65-84]
Percentage >30% uACR decrease
AND < 3 mmHg MAP
32.5
[24-40]
33
[24-40]
33
[24-42]
33
[22-42]
CKD = chronic kidney disease; CI = Confidence interval; MAP = mean arterial pressure; uACR = urinary albumin-creatinine ratio
Source: (Petersson and Voelkner 2019)
To substantiate the doses to be used in this clinical study in patients suffering from NPDR, it 
should be noted that similar efficacious exposures were measured in preclinical CKD and DR 
disease models, as shown in Table 4-3.  Lower EC50 in DR models may partially be 
attributed to usage of Ctrough in the STZ DR model vs. Caverage (AUC(0-24)/24h) in the ZSF-1 CKD 
model, owing to animal model-related PK-sampling limitations.  Similar changes in 
triglycerides, an established biomarker for sGC-modulation and which were used in both 
models, support the bridging (Hoffmann et al. 2015).  A dose dependent increase of the ERG 
b wave amplitude values was observed in the STZ DR model.  Similarly, a dose-dependent 
decrease in urinary protein-creatinine ratio was observed in the in the ZSF-1 CKD model.   
Table 4-3
PK/PD relationship in animal models of CKD and DR
Model estimates of EC50 with 90% CI
Model
Observation
Day
EC50 (mg/l)
90%CI
Rat ZSF-1 
UPCR
48, 93
13
5.8-27
CKD model
Triglycerides
48, 93
6.2
3.0-13
Rat STZ
ERG b wave amplitude
60
4.7
2.5-9.0
DR model
Triglycerides
60
2.4
1.4-4.1
CI = confidence interval, CKD = chronic kidney disease, DR = diabetic retinopathy, EC50 = plasma 
concentration of runcaciguat causing half-maximal effect, ERG = electroretinogram, PD = pharmacodynamics, 
PK = pharmacokinetics, UPCR = urinary protein-creatinine ratio 
Based on these nonclinical experiments, the efficacy of runcaciguat is anticipated to be higher 
at the target dose of 120 mg once daily than at 90 mg once daily, but still tolerable in terms of 
cardiovascular effects.
Conclusion
Overall, the selected dose range from 30 mg to 120 mg is expected to deliver significant
efficacy while being safe and well tolerated under individual titration dosing.  Early signs and 
symptoms of e.g. hypotension will be closely monitored during the titration phase and overall 
safety will be assessed during the whole study duration with additional review by the DMC.
A placebo-treated reference group is included in order to allow a more reliable evaluation of 
efficacy and safety.  


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4.4
End-of-study definition
As of amendment 3, this section was integrated from Master Protocol. 
The end of the study as a whole is defined as the date of the last visit of the last participant 
globally.
A participant is considered to have completed the study if he/she has completed the last visit 
of the study . 
5.
Study population
The study will be performed in a representative NPDR study population reflecting the 
composition of study populations in later development stages. Specifically, participants 
should show typical fundus alterations as described in the DRSS criteria for moderately severe 
and severe NPDR without DME in need of treatment and no previous experience of anti-
VEGF treatment. This corresponds to DRSS Levels 47 and 53, which need to be confirmed 
by an independent reading center, in at least one eye.
Treatment of NPDR with runcaciguat targets the retina, which is being investigated for signs 
of efficacy in this clinical trial. In order to be able to examine the retina appropriately at 
screening and during the study, participants whose eyes have anomalies that interfere with 
protocol-required examinations are excluded.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1.
Participant must be ≥18 of age inclusive, at the time of signing the ICF.
Type of participant and disease characteristics
2.
Moderately severe to severe NPDR in the study eye: DRSS levels 47 or 53 
3.
Diabetes type 1 or 2 
4.
BCVA ETDRS letter score in the study eye of ≥69 letters (approximate Snellen 
equivalent of 20/40 or better)
5.
Refraction with a spherical equivalent from -6 dpt to +5 dpt


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Sex and contraceptive/barrier requirements
6.
Male and/or female
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.  Male 
participants must agree to use condoms from signing of ICF signature until the end of 
the study period.  Female participants must be either of non-child bearing potential or 
using a highly effective method of contraception (See Section 10.4). This applies from 
the time of ICF signature until the end of the study period.  
Informed consent
7.
Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form and in this protocol
5.2
Exclusion criteria
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
1.
Uncontrolled diabetes mellitus as defined by HbA1c > 11.0% at screening
2.
Eye disease that significantly interferes with fundus examinations in the study eye
3.
Glaucoma in the study eye 
4.
Dilatation of the pupil < 5 mm in the study eye
5.
Ocular inflammation (including trace or above) or conjunctivitis at screening, or history 
of uveitis in the study eye
6.
Presence or history of macular edema involving the center of the macula (defined as the 
area of the center subfield on OCT) in the study eye with visual impairment or in need 
of treatment with anti-VEGF, immediately or anticipated within the next 3 months, by 
judgement of the investigator or with OCT central subfield thickness above gender
specific thresholds, measured including Bruch’s membrane, ≥305 µm in women, 
≥320 µm in men, as provided by the central reading center
7.
Any kind of neovascular growth in the study eye, including anterior segment 
neovascularization
8.
History of or current retinal vascular or neurodegenerative disease in the study eye, 
including hypertensive retinopathy Grade III or IV
9.
Only one functional eye 
10. Symptomatic arterial occlusive disease, including peripheral artery occlusive disease, 
coronary heart disease (e.g. angina pectoris, myocardial infarction), cerebrovascular 
disease (e.g. transient ischemic attack, stroke), clinically significant aortic stenosis, or 
renal artery stenosis, within 6 months before the screening visit
11. Deep venous thrombosis within 6 months before the screening visit


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12. Thromboembolic events (e.g. acute arterial embolism, pulmonary embolism or stroke) 
within 6 months before the screening visit
13. Heart failure New York Heart Association class III or IV
14. History of clinically relevant cardiac arrhythmia (e.g. atrial fibrillation, atrioventricular
block grade II and III, Wolf-Parkinson-White Syndrome, Sick Sinus Syndrome, 
bradycardia < 45 bpm at rest, tachycardia > 100 bpm at rest) 
15. Arterial hypotension with systolic blood pressure < 100 or diastolic blood pressure 
< 60mmHg; 
16. Uncontrolled arterial hypertension, defined as systolic blood pressure > 160 mmHg or 
diastolic blood pressure > 100 mmHg
17. ALT or AST above 3 x ULN or bilirubin ≥ 1.5 ULN at screening, known ascites
18. Estimated glomerular filtration rate (eGFR CKD-EPI) below 30 ml/min/1.73 m2 at 
screening 
19. Known pulmonary hypertension associated with idiopathic interstitial pneumonia
20. Relevant allergy or hypersensitivity to drugs or excipients administered as part of this 
study, e.g. hereditary galactose intolerance, complete lactase deficiency or glucose-
galactose malabsorption, iodine allergy
21. Any finding in the medical examinations or medical history giving, in the opinion of the 
Investigator, reasonable suspicion of a disease or condition that makes treatment with 
the investigational drug unadvisable, or that might affect interpretation of the results of 
the study or render the patient at high risk for treatment complications
Prior/concomitant therapy
22. Any prior systemic anti-VEGF treatment or IVT anti-VEGF treatment in the study eye
23. Any prior intraocular steroid injection in the study eye
24. Any prior grid or focal laser photocoagulation within 500 microns of the foveal center 
or any prior PRP in the study eye
25. Any intraocular eye surgery within a period of 3 months prior to randomization in the 
study eye
26. Yttrium-Aluminum-Garnet laser treatment performed within 28 days before screening, 
in the study eye
27. Continued use of any prohibited medication during the exclusion period from one to two 
weeks before first study drug administration throughout the treatment period (see 
Table 6-3)
28. Use of nitrates or NO donors (such as amyl nitrate) in any form including topical; PDE5 
inhibitors, non-specific PDE inhibitors within 1 week or less than 5 half-lives
(whichever is longer) before first study drug administration
29. Use of sGC stimulators such as riociguat within 1 week or less than 5 half-lives 
(whichever is longer) before first study drug administration
30. Combination use of angiotensin converting enzyme-inhibitor together with angiotensin 
receptor blocker


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Prior/concurrent clinical study experience
31. Participation in an interventional clinical study within 30 days prior to screening visit 
that involved treatment with any drug (excluding vitamins and minerals) or medical 
device
32. Previous assignment to treatment or randomization during this study
Other exclusion criteria
33. Breastfeeding or positive pregnancy test (ß-hCG in serum or urine)
34. Close affiliation with the investigational site; e.g. a close relative of the investigator, 
dependent person (e.g. employee or student of the investigational site), employee of 
Bayer AG or affiliates
5.3
Lifestyle considerations
No study specific lifestyle restrictions are required. Participation in this study does not 
require modifications of lifestyle. Participants should follow their usual lifestyle, as part of 
their diabetes management plan.
5.4
Screen failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, and eligibility criteria.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened only once. In any case, the investigator must ensure that the repeated screening 
procedures do not expose the participant to an unjustifiable health risk.  For re-screening, the 
participant must re-sign the ICF, even if it was not changed after the participant's previous 
screening.  
Participants who failed screening before protocol Amendment 3 was implemented may be re-
screened in view of the changes in inclusion/exclusion criteria.
Rescreened participants will be assigned a new participant number. 
In case of abnormal or implausible results, which may be caused by intercurrent diseases, 
short-term treatable conditions, other temporary health disorders (e.g. acute infection, 
laboratory changes, blood pressure outside defined range), or inappropriate circumstances 
(e.g. inadequate rest when required, hemolysis) the investigator may decide to repeat the 
respective screening parameter(s) twice.


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5.5
Criteria for temporarily delaying randomization / study intervention 
administration
If a participant is otherwise eligible, acute intercurrent conditions may allow to postpone start 
of study intervention in a participant to a time when the condition has resolved.  Under these 
circumstances, the screening period may be extended to 6 weeks. 
5.6
Selection of the study eye
Only one eye will be designated as the study eye in every participant. For participants who 
meet eligibility criteria in both eyes during the screening phase, the eye without DME and 
with the higher DRSS should be selected. If both eyes have the same score, the eye with the 
clearest lens and ocular media will be selected. If there is no objective basis for selecting the 
study eye, factors such as ocular dominance (better focus ability), other ocular pathology and 
participant preference should be considered in making the selection. The final selection will 
be done by the investigator at baseline and must not be changed during the course of the 
study.
6.
Study intervention(s) and concomitant therapy
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study interventions administered
6.1.1
Study interventions
In this study, several doses of runcaciguat or placebo, will be given to the NPDR participants, 
as shown in Table 6-1. Participants will be treated following an intra-individual dose-titration 
design with three titration steps.
Tablets containing runcaciguat and corresponding placebo are identical in appearance (size, 
color, shape). In order to remain masked, study interventions will be packaged in bottles 
labeled with a unique number which will be pre-printed on each bottle.
The following doses are envisaged for the intra-individual dose titration steps with four dose 
levels.


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Table 6-1
Study interventions
Arm name
Runcaciguat (BAY 1101042)
Placebo
Intervention name
Runcaciguat (BAY 1101042)
Placebo
Type 
Active drug
Placebo
Dose formulation
Modified-release tablets
Tablet
Unit dose strength(s)
15 mg
not applicable
Dose levels (once daily)
30 mg
60 mg
90 mg
120 mg
not applicable
Route of administration
Oral
Oral
Use
Experimental
Placebo
Packaging and labeling
Study intervention will be provided in high-density polyethylene bottles closed 
with child-resistant screw cap. 
Each bottle will be labeled as required per country requirement.
Titrated oral doses of runcaciguat or matching placebo will be given once a day on top of 
respective standard of care treatment before, during or closely after the first meal in the 
morning. The study intervention (tablets) are not to be broken, halved or crushed, they should 
be swallowed whole with a glass of water. If a participant has missed a dose or forgotten to 
take the medication and > 16 hours have passed from the regular scheduled time, the dose 
should be skipped and the next dose should be taken promptly the next day in the morning. 

On Visit days (except Visit 7) study intervention is to be administered at site after 
blood draws.

On non-visit days and on the day of Visit 7 study intervention is to be taken in the 
morning at home.
6.1.2
Medical devices
No sponsor manufactured devices or devices manufactured for the sponsor are used in this 
study. Other medical devices (not manufactured by or for sponsor) provided for use in this 
study are:

ECG machine for central ECG reading
Instructions for medical device use are provided in the corresponding manual. All device 
deficiencies (including malfunction, use error and inadequate labelling) that caused or could 
have caused a SAE to a study participant shall be documented and reported by the investigator 
throughout the clinical investigation and appropriately managed by the sponsor.
A device deficiency is an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance. Device deficiencies include malfunctions, use 
errors, and inadequate labeling. 
For any device deficiencies related to a study participant AE or SAE:  the investigator should 
complete the AE CRF and safety reports (complementary pages) in addition to the Medical 
Device Incident (MDI) CRF.


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6.2
Preparation / handling / storage / accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants randomized in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator or the head of the institution (where applicable) is responsible for study 
intervention accountability, reconciliation, and record maintenance (i.e. receipt, reconciliation, 
and final disposition records). Drug receipt, reconciliation and destruction information on the 
study sites will be captured in the IWRS.
Further guidance and information for the final disposition of unused study interventions are 
provided in the Investigator Site File. 
6.3
Measures to minimize bias: Randomization and masking
All participants will be centrally assigned to randomized study intervention using IWRS. 
Before the study is initiated, the log in information and directions for the IWRS will be 
provided to each site. 
Participants will be randomized to either Placebo or Runcaciguat.  Randomization will be 
stratified by baseline DRSS score (47 or 53). In Part 1, the randomization ratio will be 2:1
runcaciguat : placebo and in Part 2 it will be 1:1.
Potential bias will be reduced by the use of central randomization via the IWRS. The level of 
masking is presented in Table 6-2.
Table 6-2
Level of masking – Part 1 and 2
Masked
Unmasked
Participant 
●
Care provider 
●
Investigator 
●
Outcomes assessor 
●
Sponsor study team 
(except Bioanalytical / PK group)
●
Sponsor Bioanalytical / PK group
●
PK = pharmacokinetics
The IWRS will be programmed with instructions on how to break / unmask a participant’s 
randomized treatment. In case of an emergency, the investigator has the responsibility for 
determining if unmasking of a participant’s intervention assignment is warranted. If the 
investigator is unavailable, and a treating physician not associated with the study requests 
emergency unmasking, the emergency unmasking requests are forwarded to the emergency 
medical advice 24 hours / 7 day service. Participant safety must always be the first 


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consideration in making such a determination. If the investigator decides that unmasking is 
warranted, the investigator should make every effort to contact the sponsor prior to unmasking 
a participant’s intervention assignment unless this could delay emergency treatment of the 
participant. If a participant’s intervention assignment is unmasked, the sponsor must be 
notified within 24 hours after the unmasking. Date and reason for the unmasking must be 
recorded in the source documentation and case report form, as applicable.
Bioanalytics and pharmacometrics staff will be unmasked according to Sponsor’s standard 
operating procedures. Pharmacometrics analysis and report will be done under a separate 
cover. Bioanalysis and pharmacometrics evaluation might be started prior to database lock: 
if this is applicable, appropriate measures will be taken to maintain masking of the study team, 
e.g. data will be stored separately, and members of the study team will not have access to the 
unmasked data.
The primary outcome measure, DRSS, will be assessed centrally by a masked reading center, 
in order to have a standardized assessment throughout study sites and in order to minimize 
potential bias.
6.4
Study intervention compliance
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning
and counting returned tablets during the site visits and documented in the source documents 
and eCRF. Deviation(s) from the prescribed dosage regimen should be recorded. Unopened 
and undamaged bottles of returned study intervention may be re-dispensed to the same 
participant.
A record of the quantity of tablets dispensed to and administered by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded.
A system to remind the participants of study intervention self-administration and to document 
the intake may be used.  Such a system may consist of a mobile application and web portal 
components.  Study drug intake may be documented by the participants by scanning a barcode 
with a mobile phone using a dedicated smartphone application.  These scans are recorded via 
a web-portal. An alternative methodology, e.g. a paper based diary, may be used for 
documenting study intervention intake. If study intervention intake has not yet been 
documented, the participants may be reminded to take the study intervention, e.g. by 
telephone, email, push-notification, text message, at defined time points prior and after the 
scheduled time of study intervention intake.  
IWRS will be used for drug accountability on a patient basis. Drug returns, reconciliation and 
destruction information will be captured in the IWRS.
On all visit days during the treatment period, plasma samples will be taken to determine the 
concentrations of the study intervention.
Taken together, these measures are deemed appropriate to support participants adherence and 
to detect participants that are systematically non-adherent.


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6.5
Dose modification
The doses to be administered are provided in Table 6-1. 
In exceptional cases, participants may request to reschedule visits.  Visits 3, 4, and 5 may be 
shifted by no more than one day to an earlier or later timepoint. Actual dates of dose titrations 
may be shifted as a result. The treatment duration at the subsequent dose level may be 
shortened or extended by one day to compensate the effect on the total treatment duration. 
6.5.1
Intra-individual dose-titration decisions 
Doses will be titrated on a weekly basis from 30 mg to 60 mg to 90 mg and to 120 mg once 
daily. The decision to titrate to the next higher dose will be taken by the investigator upon 
availability of all relevant safety data on study days 8, 15, and 22. The decision to increase 
the dose should not be taken in presence of any condition where dose titration is deemed 
unadvisable by the investigator. 
The investigator should not confirm the dose titration but, instead, maintain the dose if 
systolic blood pressure (SBP) 

SBP ≥90 and <105 mmHg, or 

>30 mmHg decrease from previous visit (even if SBP ≥105)
The investigator should not confirm the dose titration but rather reduce the dose if the 
participant previously experienced:

A serious adverse event considered to be related to treatment with runcaciguat. 

A severe adverse event considered to be related to treatment with runcaciguat.

Relevant hypotension (e.g. symptoms of hypotension or SBP < 90 mmHg or both). 
Restart with last well-tolerated dose after ≥48 hours if SBP recovers above 90 mm Hg and 
symptoms resolve within 24 hours.
If there is evidence for clinically relevant side effects (e.g. dizziness, diarrhea), the 
investigator can decide to maintain the dose at its current level or, if side-effects are
considered as sustained intolerability or safety risk, even lower the dose back to the previous 
dose level (the dose modification and the reason for it have to be captured accordingly in the 
eCRF). 
For each participant, up to two dose reductions are permissible with continued study 
participation at any point of the clinical study. The final reduced dose level should be 
maintained until the end of the study.
Please refer to Section 7.1.2 for temporary treatment discontinuations.
6.5.2
Stopping rules (study level)
In addition to the general criteria as listed in Section 10.1.9, the following criteria result in an 
immediate stop of dosing and will result in a temporary halt of the study:


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
Any relevant information, from this trial or from outside of this trial, indicating a 
relevant deterioration of the benefit-risk ratio. In particular, consistently observed 
SAEs or severe drug-related AEs will be thoroughly assessed.

Safety findings observed by DMC which indicate unacceptable pharmacological 
effects, reasonably attributable to runcaciguat 
Resuming the trial after a temporary halt requires an approved substantial amendment. 
For discontinuation of study intervention for individual study participants see Section 7.1.
6.6
Continued access to study intervention after the end of the study
No treatment with study medication will be provided after the end of the planned treatment 
period or after early withdrawal of treatment.
6.7
Treatment of overdose
An overdose is defined as any occasion when participants have been exposed to more tablets 
than the maximum number foreseen per intake and/or per day in the protocol (accidentally or 
intentionally).  
There is no known specific treatment or antidote for an overdose with runcaciguat. 
Accordingly, overdose of the study intervention should be treated as clinically indicated based 
on symptoms and signs. Due to the pharmacological profile of runcaciguat, cardiovascular
effects are to be expected in case of overdose. If symptoms develop after the overdose, any 
therapy that becomes necessary has to be guided by the predominant symptoms. Participants 
have to remain under medical supervision until all relevant adverse effects have subsided.
Overdose per se will not be reported as an AE/SAE unless it is an intentional overdose taken 
with possible suicidal/self-harming intent, or if this resulted in clinical signs or symptoms 
diagnosed as AE/SAE by the investigator.
In the event of an overdose, the investigator should:
Contact the sponsor immediately.
Evaluate the participant to determine, in consultation with the Medical Monitor, whether 
study intervention should be interrupted or whether the dose should be reduced.
Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
runcaciguat can no longer be detected systemically (at least 3 days).
Obtain a plasma sample for PK analysis as soon as possible from the date of the last 
dose of study intervention if requested by the Medical Monitor (determined on a case-
by-case basis).
Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
based on the clinical evaluation of the participant. The investigator may consult the Medical 
Monitor as needed.


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6.8
Concomitant therapy
Only drugs prescribed by a health care professional are permitted while the study is ongoing. 
Exceptionally, short-term intake of paracetamol/acetaminophen ≤2000 mg/day is acceptable. 
Such intake is to be recorded (see below).
Concomitant medications are to be recorded in the eCRF, in particular international non-
proprietary names, dosing frequency, individual dose, route, indication are to be documented.  
This includes anti-diabetic treatments.  
Participants are requested to record the dose of antidiabetic treatments that are dosed variably, 
e.g. insulin, in a diary along with glycemia test results.  Other concomitant medications taken 
intermittently should be documented in the same diary.
Participants with HbA1c concentrations outside of the recommended corridor should be 
instructed to contact their diabetologist to seek support in achieving better diabetic control.
The medications provided in Table 6-3 are not allowed for use during treatment with the study 
intervention and one or two weeks prior to start of treatment.
Table 6-3
List of prohibited medications
Drug class
Drug 
Last permissible intake before
start of study medication
Inducers of 
Artemisinin
>2 weeks
metabolizing enzymes
Avasimibe
>2 weeks
Bosentan 
>2 weeks
Carbamazepine
>2 weeks
Enzalutamide
>2 weeks
Efavirenz
>2 weeks
Etravirine
>2 weeks
Mitotane
>2 weeks
Modafinil
>2 weeks
Nafcillin
>2 weeks
Phenobarbital
>2 weeks
Phenytoin
>2 weeks
Primidone
>2 weeks
Rifabutin
>2 weeks
Rifampicin
>2 weeks
St. John’s Wort Hypericum perforatum
>2 weeks
Inhibitors of 
Fluconazole
>2 weeks
metabolizing enzymes
Fluvoxamine
>2 weeks
Fluoxetine
>2 weeks
Probenecid 
>1 week
Ticlopidine 
>2 weeks
Valproic acid
>1 week
PDE inhibitors 
Theophylline
>1 week
(non-specific, PDE5)
Dipyridamole
>1 week
Sildenafil
>1 week
Vardenafil
>1 week
Tadalafil
>1 week
sGC stimulators
Riociguat
>1 week
Vericiguat
>1 week
Nitrates or NO donors
Amyl nitrate
>1 week
NO = nitric oxide; PDE = phosphodiesterase; PDE5 = phosphodiesterase 5; sGC = soluble guanylyl cyclase


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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
7.
Discontinuation of study intervention and participant 
discontinuation/withdrawal 
7.1
Discontinuation of study intervention
7.1.1
Permanent discontinuation
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is permanently discontinued, an 
End-of-Treatment visit should be performed in line with Visit 15. The participant remains in 
the study for continued assessment of study outcomes following the visit schedule in 
section 1.3.
Unscheduled visits may be performed as deemed appropriate by the investigator, in particular 
in case of withdrawal because of an adverse event.
Participants must be withdrawn from the study intervention for any of the following reasons: 

Increases in transaminases as described in Table 10-3 (confirmed by analysis of 
two blood samples; additional laboratory examinations may be performed if 
necessary):

Safety concerns for a participant by the investigator or the sponsor, e.g. due to 
obvious non-compliance.

Pregnancy (see Section 8.3.5 for details)

Temporary discontinuation exceeding 14 consecutive days or 21 days overall
Participants may be withdrawn from the study intervention for any of the following reasons: 

Repeated incidents of relevant hypotension or tachycardia 

Repeated temporary discontinuation of study intervention

Vision threatening complication or progression to PDR
Necessity to withdraw the participant from the study will be assessed case by case by the 
investigator.


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7.1.2
Temporary discontinuation
Treatment should be withheld temporarily if any of the following conditions apply:

Relevant hypotension or tachycardia considered to be related to treatment with 
runcaciguat, e.g. SBP < 90 mmHg with symptoms of hypotension persisting 
> 24 hours, or AE indicating non tolerability with regard to mode of action (e.g. severe 
dizziness, orthostatic dysregulation, syncope). In case of additional, subsequent  
temporary discontinuation(s), the investigator should consider whether a permanent
discontinuation of the study intervention is appropriate.

Temporary discontinuation for drop in eGFR from baseline: 
If the participant presents a decrease of eGFR ≥40% compared with baseline, the 
investigator should temporarily discontinue study intervention and perform 
confirmatory laboratory examinations. If eGFR decrease by ≥40% is confirmed, 
study intervention should be discontinued permanently (see Section 7.1.1). If the 
re-assessed laboratory result indicates a decrease in eGFR <40% from baseline, study 
intervention may be re-started at the same dose as before this temporary 
discontinuation, in line with section 7.1.3. The investigator should consider a close 
observation of the case (e.g. repeated laboratory investigation of renal function).

The investigator may decide to temporarily discontinue treatment for other reasons if 
deemed appropriate for the safety and well-being of the participant.
A temporary discontinuation exceeding 14 consecutive days or 21 days overall results in a 
permanent discontinuation (see section 7.1.1)
7.1.3
Re-challenge / re-start of study intervention
Participants who permanently discontinue the study intervention must not be re-challenged.
After a temporary discontinuation, study intervention intake may be resumed as follows:

≤48 hours since last intake: 
resume intake at same dose as prior discontinuation

> 48 hours to < 7 days (168 hours) since last intake: 
resume intake at one titration step below dose prior to discontinuation.  Titration to 
target dose at the discretion of the investigator, as described in Section 6.5. 

> 7 days (168 hours) since last intake: 
resume intake with complete re-titration of study intervention, as described in 
Section 6.5.  
The dose-titrations after temporary discontinuation should follow the same procedures as 
described for the initial dose titrations. This may result in conducting one or more 
unscheduled visit/s, analogously to Visit 4. Additional assessments and examinations may be 
performed, depending on the reason for the temporary discontinuation. Titration steps may be 
extended, e.g. for operational reasons, to the next scheduled visit.
The final dose at the end of re-titration should not exceed the dose at which the decision for 
temporary discontinuation was taken, but the dose may be lower than prior to the temporary 
discontinuation. This also includes cases of prior dose reduction.


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7.2
Participant discontinuation / withdrawal from the study
Participants must be withdrawn from the study for any of the following reasons: 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This includes cases where, in the investigator's opinion, continued 
participation in the study would be harmful to the participant's well-being. This is expected to 
be uncommon.

At the time of discontinuing from the study, if possible, Visit 15 should be 
conducted as early discontinuation visit, followed by safety follow-up (Visit 16) as 
shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be 
completed.

The participant will be permanently discontinued both from the study intervention 
and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a withdrawal 
of consent.
Participants may be withdrawn from the study for the following reasons:
Non-compliance with the study conditions or instructions from the study team. 
7.3
Lost to follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1,
Appendix 1.


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8.
Study assessments and procedures
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (e.g. blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
Individual pharmacokinetic results could unmask the study and will not be reported to 
investigative sites or other masked personnel until the study has been unmasked.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
After signing an informed consent, participants will be invited to a screening visit, Visit 1, to 
evaluate their eligibility for this study.  Eligible patients with NPDR who meet all of the 
inclusion criteria and none of the exclusion criteria, will be randomized to treatment with 
either runcaciguat or placebo. During the treatment period, participants will be monitored for 
adverse events and concomitant medication, and undergo the assessments outlined in the SoA, 
Section 1.3. 
The treatment period comprises Visits 2 to 15 (Week 1 to Week 49), the End-of-Treatment 
visit.
An End-of-Study visit, Visit 16, is planned approximately 28 days after last administration of 
study drug.

The maximum amount of blood collected from each participant over the duration 
of the study, including any extra assessments that may be required, will not exceed 
300 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 


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8.1
Efficacy assessments
Planned time points for all efficacy assessments are provided in the SoA.
8.1.1
Ophthalmology assessments
Unless specified otherwise, ophthalmology examinations will be done for both eyes.
Source data of all ophthalmology examinations will be archived at the site.  This includes data
and images sent to the central reading center for evaluation.
8.1.1.1
Color fundus photography (CFP)  
The anatomical state of the retinal vasculature will be evaluated by an ophthalmologist from
posterior segment (Section 8.1.1.6) examination and CFP. All digital CFP images need to be 
taken by a certified technician following an acquisition protocol for ETDRS 7-Fields of the 
central reading center at the visits indicated in the SoA.
All CFPs will be transmitted to the central reading center for ETDRS diabetic retinopathy 
severity scale (DRSS, Table 8-1) grading and storage. The images of the screening visit of 
both eyes will be used as part of the eligibility assessment regarding the severity of diabetic 
retinopathy.
CFPs may, in addition, be evaluated for additional, exploratory, endpoints. This may include 
assessment of microaneurysm turnover (Nunes et al. 2009) or measurement of diameters of 
retinal vessels as described previously (Lundberg et al. 2013).  This may involve transmission 
of CFP to additional central reading centers.
Table 8-1
ETDRS final retinopathy severity scale (for individual eyes)
Level
Severity
10
DR absent
20
Microaneurysms only
35
Mild NPDR
43
Moderate NPDR
47
Moderately severe NPDR
53
Severe NPDR
61
Mild PDR
65
Moderate PDR
71
High-risk PDR
75
High-risk PDR
81
Advanced PDR: fundus partially obscured, center of macula attached
85
Advanced PDR: posterior fundus obscured, or center of macula detached
90
Cannot grade, even sufficiently for level 81 or 85
ETDRS = Early Treatment Diabetic Retinopathy Study; DR = diabetic retinopathy; 
NPDR = non-proliferative DR; PDR = proliferative DR; 
Modified from (Staurenghi et al. 2018)


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8.1.1.2
Best corrected visual acuity (BCVA)
Visual function will be assessed using a modified ETDRS protocol starting at 4 meters
(AREDS 1999).  Visual Acuity examiners must be certified to ensure consistent measurement 
of BCVA. 
8.1.1.3
Fluorescein angiography (FA)
The anatomical state of the retinal vasculature of the study eye (transit eye) and the fellow eye 
(non-transit eye) will be evaluated by FA. All FAs will be conducted by a certified technician
following an acquisition protocol of the reading center. The angiographic images will be 
evaluated by a study ophthalmologist for individual safety decisions, and by the central 
reading center to support the DRSS assessment. All FA images will be sent to the central 
reading center for evaluation.  
At screening a standardized set of FA images with the study eye as transit eye will be sent to 
the reading center for evaluation and eligibility assessment.  
8.1.1.4
Optical coherence tomography (OCT)
Structural OCT will be performed preferably by using spectral domain devices. The specific 
device models accepted for the study will be defined by the reading center. OCTs will be 
performed by certified technicians following an acquisition protocol of the reading center as 
scheduled in the SoA for local safety assessment. Newly found clinically relevant pathologies 
should be reported as adverse event. All obtained images will be sent to the reading center for 
evaluation at the visits stated in the SoA.
At screening a standardized set of OCT images will be sent to the reading center for 
evaluation and eligibility assessment.  
OCT Central Subfield Thickness (CST) will be analyzed by the reading center to guide the 
investigator relating to Exclusion criterion 6, which excludes participants with macular edema
requiring treatment. The thresholds depend on gender (+15 µm in men) and on the inclusion 
or exclusion of Bruch’s membrane by the OCT-devices segmentation algorithm.  
The reference threshold for the CST will be determined by the central reading center using the 
Heidelberg-Engineering segmentation algorithm as a standard, which includes Bruch’s 
membrane.  For other OCT-devices, equivalent CST values will be provided by the central 
reading center.
The CST thresholds used are:

≥305 µm in women, ≥320 µm in men
8.1.1.5
Optical coherence tomography angiography (OCT-A) 
For Part 1, OCT-A is mandatory, for Part 2, OCT-A is optional. In any case, the OCT-A 
needs to be performed by a certified technician following an acquisition protocol of the 
reading center as scheduled in the SoA. The specifications of this OCT-A can be found in the 
acquisition protocol of the Reading center. Images obtained via OCT-A will be sent to the 
Central Reading Center for evaluation.


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The following parameters will be quantified and assessed prior to start of treatment with the 
study intervention, after the first study intervention administration and at steady state 
treatment with each of the dose levels as shown in the SoA (Section 1.3). For the following 
vascular regions in the central 3 mm x 3 mm will be assessed separately to the extent feasible:

Superficial retinal layer

Intermediate retinal layer

Deep retinal layer

Retina (cumulative, all layers combined)
The following parameters will be assessed for these vascular regions, as applicable:

Perfusion density

Vessel density

Foveal avascular zone
Cross-sectional macular full depth line scans acquired with an experimental software used for 
positioning the scan lines and to average the information obtained for each scan will be 
analyzed for 

Total perfusion

Vessel density
8.1.1.6
Slit lamp biomicroscopy (anterior and posterior segment)
The slit lamp examination (anterior and posterior segment) will be performed according to 
local medical practice and applicable medical standards at the site as stated in the SoA. 
Abnormal findings are to be recorded in the eCRF as either medical history or adverse event 
as applicable.
8.1.1.7
Tonometry (intraocular pressure (IOP) measurement)
Intraocular pressure is to be measured with any locally approved non-contact tonometer. 
In case that there is no non-contact tonometer available at the site, applanation tonometry 
(Goldmann, Tonopen or other locally approved alternatives) may be used. In any case, where 
both methods are available the non-contact method is to be used. 
The same method of IOP measurement must be used throughout the study for each individual 
participant. Values and measuring type are to be recorded in the eCRF.
8.1.2
Vision-threatening complications
Vision-threatening complications are defined as occurrence of any of the following adverse 
events:

PDR

Any ocular neo-vascularization


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
Center-involved (ci) (central ETDRS subfield) DME

Drop of BCVA of 10 letters or more from baseline
The assessment will be continued after treatment discontinuation if possible.
Treatment of the vision threatening complication should follow local standards and 
guidelines, i.e. treatment of ci DME with anti-VEGF or other appropriate measures, at the 
discretion of the investigator. 
8.1.3
Albuminuria
Albuminuria evaluations were removed from the protocol via Amendment 3. 
8.1.4
Visual function questionnaire (VFQ-25)
VFQ-25 evaluations were removed from the protocol via Amendment 3. 
8.2
Safety assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Physical examination
A physical examination (by means of inspection, palpation, auscultation) will be performed 
by a physician at the study site and will cover at least the organs of the cardiovascular, 
respiratory and abdominal systems.  Measuring the body temperature will be included.
Abnormal physical examination findings are recorded either as medical history or as AEs in 
the eCRF.
Body weight will be measured by a member of the investigator’s team under the following 
conditions:

Participant in light clothing without shoes after having emptied the bladder

Analogue or digital scale physician scale, measurement precision 0.1 kg
Height will be taken at screening only.
The BMI will be calculated by Data Management on the eCRF based on weight and height.
8.2.2
Vital signs
Pulse rate and systolic / diastolic blood pressure will be measured repeatedly pre-dose, and on 
the time points provided in the SoA (Section 1.3) after the initial dose and at steady state of 
each dose-level. 


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Vital signs will be measured in a supine or semi-supine position after ≥5 minutes rest. Vital 
signs should always be measured before blood draws when scheduled at the same time point.  
Blood pressure and pulse rate measurements will be performed with a completely automated 
device. 
8.2.3
Electrocardiograms
ECGs are recorded with a computerized 12-lead ECG device after the participants rested for 
at least 5 minutes in supine position (small pillow under head allowed).  These ECGs are 
evaluated by the investigator for safety signals. ECGs will be transferred to central reading 
center for evaluation. 
During Part 1 up to study Visit 6 (inclusive), triplicate ECG tracings are to be recorded. 
These triplicate tracings may be transferred to a central ECG reading center for later QT 
evaluation. The results of the QT evaluations may be reported separately.
For part 2 single ECGs will be recorded and transferred to a central ECG reading center for
evaluation.
The following ECG parameters will be determined and transferred to the database:

Ventricular rate, PR interval, QRS-duration, QT interval.  
The QT interval will also be corrected for the heart rate using QTcB and Fridericia's method, 
i.e. by dividing the observed QT interval by the cube-root of RR:
QTcF = QT
√RR

8.2.4
Clinical safety laboratory assessments
See Section 10.2 for the list of clinical laboratory tests to be performed and to the SoA for the 
timing and frequency. 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. 
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant unless judged by the investigator to be more severe than expected for the 
participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within one month after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or the medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified, and the sponsor notified.
All protocol-required laboratory tests, as defined in Section 10.2, must be conducted in 
accordance with the laboratory manual and the SoA. 


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If laboratory values from non-protocol specified laboratory tests performed at the institution’s 
local laboratory require a change in participant management or are considered clinically 
significant by the investigator (e.g. SAE or AE or dose modification), then the results must be 
recorded.
Clinically relevant changes, especially when resulting in a decision against dose titration, are 
to be documented as AE, with details on the respective lab results provided in the comment 
field of the AE page in the eCRF.
In case of clinically relevant abnormal laboratory results, the investigator has the discretion to 
perform unscheduled repeat laboratory examinations earlier than at the intervals provided in 
the SoA in Section 1.3.  These unscheduled examinations should be processed by the central 
lab to ascertain that the data will be included in the database.  At the investigator’s discretion, 
additional laboratory parameters may be investigated and samples may be processed by the 
local lab. In case of relevant liver enzyme elevation (see also Section 10.5), the investigator 
should perform a repeat serum chemistry panel 2 times per week (including serum 
transaminases [AST and ALT] and serum bilirubin), frequency of retesting can decrease to 
once a week if laboratory abnormalities decrease and participant is asymptomatic.
Estimation of glomerular filtration rate (eGFR)
eGFR will be calculated using CKD-EPI formula, using the serum creatinine concentration 
measured at screening (Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work 
Group 2013).  The calculation will be done by the central laboratory. In case of a decrease by 
≥40%, a critical alert will be provided to the investigator, as it may represent a reason for 
treatment discontinuation, as described in Section 7.1.2.
8.2.5
Pregnancy testing
During the initial treatment phase, both urine and serum ß-hCG pregnancy tests are planned to 
be conducted in women enrolled in this clinical study.  Dip stick urine pregnancy tests allow 
the investigator to take action while the participant is at site in case of a positive test. Serum 
pregnancy tests are intended to confirm negative test results with higher reliability than urine 
tests. Later during the study, urine pregnancy tests do not need to be performed at visits 
where blood is drawn for a serum pregnancy test.
Pregnancy tests are to be performed in all female study participants, unless anatomically 
sterile, at all study visits, regardless of age and fertility status. When visit intervals are 
extended to 8 weeks after completion of 24 weeks of treatment (Visit 12), additional urine 
pregnancy tests are to be performed four weeks after each visit up to Visit 15, in line with the 
CTFG contraception guidance (CTFG 2014).  


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8.3
Adverse events (AEs), serious adverse events (SAEs) and other safety 
reporting
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 10.3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up all AEs, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7).
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.
8.3.1
Time period and frequency for collecting AE and SAE information
All AEs/SAEs will be collected from the signing of the ICF until 28 days after end-of 
treatment or until the follow-up visit (whichever comes later) at the time points specified in 
the SoA (Section 1.3).
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of learning of the event, as indicated in 
Section 10.3.4. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
TEAEs will be defined as those AEs that occurred after first dosing and those existing pre-
dose AEs that worsened severity post-dose during the main treatment period until 28 days 
after the last dose of the study drug.
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation / the End-of-Study visit. However, if the investigator learns of any 
AE/SAE, including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study intervention or study 
participation, the investigator must promptly notify the sponsor. 
8.3.2
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.


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8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in 
Section 8.3.6), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Section 10.3. 
8.3.4
Regulatory reporting requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.

For all studies except those using medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
8.3.5
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until the end-of 
study visit.

If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours after obtaining the 
necessary signed informed consents from the parents.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE.

Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs, and will be reported as 
such.

The participant /pregnant female partner will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the participant /
pregnant female partner and the neonate and the information will be forwarded to the 
sponsor.


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
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants /pregnant female partner, he or she may learn of an SAE 
through spontaneous reporting.

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention.
8.3.6
Adverse events of special interest (AESI)
Adverse events of special interest have to be reported to the sponsor along the timelines set 
for serious adverse events (even though they may not be classified as serious), i.e. within 
24 hours of the investigator´s awareness, as described in Section 10.3.4.
Adverse events of special interest are:

Adverse events suggestive of hepatic injury (please refer to Section 10.5)

Syncope/loss of consciousness 

Acute kidney injury suggested by 2.0 fold increase in serum creatinine or > 50% 
decrease in eGFR
8.4
Pharmacokinetics

Plasma samples will be collected for measurement of plasma concentrations of 
runcaciguat and its metabolites M1, M6 and M7 as specified in SoA. Instructions for the 
collection and handling of biological samples will be provided by the sponsor. At visits 
with pre-dose (trough, before intake of study intervention) sampling, study intervention 
will be administered at the study center by study personnel and the exact time of study 
intervention intake on the day before the visit and on the day of the visit and the exact 
sampling time will be recorded in the eCRF. Ideally the study personnel should contact 
the participant prior to these visits to remind them not to take the study intervention as 
usual in the morning at home and to document the exact time of study intervention intake 
on the days before the visit.  For Visit 7, the participants should be advised to take their 
drug as usual in the morning at home and document the time of drug intake.

The actual date and time (24-hour clock time) of each sample will be recorded. In 
addition, the actual date and time of study intervention intake on the day prior to the visit 
day and the actual date and time of study intervention intake on the visit day will be 
documented.in the eCRF.

Concentration data will be summarized descriptively. These data are trough (pre-dose) 
plasma concentrations of runcaciguat by visit at Visits 3-6, and 815. Further details will 
be specified in the statistical analysis plan.  


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
Pharmacokinetic data for runcaciguat collected during the study will be analyzed at the 
end of study using nonlinear mixed effects models. Mixed effects models, or population 
type models, describe the relationship between e.g. dose, time and pharmacological 
observations such as plasma drug concentrations. Both structural and random effects are 
involved in this relationship. A population PK model may be developed to characterize 
the PK of runcaciguat over the entire treatment period using individual runcaciguat 
concentration data. Individual PK parameters of runcaciguat may be calculated. PK/PD 
models may be developed to relate parameters of clinical safety and efficacy response 
with runcaciguat plasma concentrations. The details of the analyses will be described in a 
separate M&S Analysis Plan, and the results will be reported in a separate M&S 
Report separately from the main clinical study report.

Drug concentration information that would unmask the study will not be reported to 
investigative sites or blinded personnel until the study has been unmasked.

Details about the collection, processing, storage and shipment of samples will be 
provided separately (e.g. sample handling sheets or laboratory manual).
8.5
Genetics
Genetic analyses may be part of the biomarker investigations in this study. Genetic analyses 
are primarily done to address altered drug metabolism, in particular genetic variants that may 
influence runcaciguat exposure and factors predisposing to cardiovascular and/or eye diseases. 
The exact genetic variant may arise during the clinical program. 
Genetic analyses relate to gene variants such as single nucleotide polymorphisms of drug 
transporters and/or drug metabolizing enzymes including enzymes of the cytochrome P450
system, the Solute Carrier Family or uridine 5′-diphosphate-glucuronosyltransferase. 
Different variants predispose to altered metabolization of drugs and may result in differences 
in runcaciguat exposure. Genetic analyses may be pivotal to understanding the pharmacology 
of runcaciguat and support its safe and efficacious use resulting in an improved benefit/risk 
ratio.
Genetic factors predisposing to cardiovascular and/or eye disease may be variants which 
effect oxidative stress and/or the NO pathway. Oxidative stress and a dysfunctional NO 
pathway are hallmarks of diabetic retinopathy and other (cardio-)vascular diseases. The study 
drug acts on soluble guanylate cyclase to produce cGMP in the absence of sufficient NO. 
Therefore, it is conceivable that certain genetic variants encoding components of the NO-
cGMP pathway or genetic variants associated with oxidative stress may influence a 
participants response to treatment with runcaciguat. In addition, genetic variants may 
influence the course of disease. For example, asymmetric dimethyl arginine inhibits 
endogenous NO production. Its breakdown is mainly governed by two enzyme isoforms for 
which several genetic variants exist. Studies have demonstrated that different variants are 
associated with different asymmetric dimethyl arginine levels and therefore NO and cGMP 
bioavailability. 
The genetic sample may be used to test for individual single nucleotide polymorphisms
deemed relevant to better understand observations related to pharmacokinetics, mode-of-
action-related and / or safety of runcaciguat and to further investigate pathomechanisms 


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deemed relevant to diabetic retinopathy, cardiovascular disease, and associated health 
problems. Whole genome sequencing is excluded.
8.6
Biomarkers
In this study, genetic as well as non-genetic biomarkers will be investigated. 
8.6.1
Laboratory biomarkers
Biomarkers will be evaluated in samples collected before, during and after treatment in order 
to determine the impact of runcaciguat. These markers fall into the following categories:
A. Biomarkers which may be related to the mode-of-action of the study drug:
e.g. vasoactive agents such as cGMP, Kynurenines or other tryptophan metabolites
B. Functional markers of the cardiovascular system and cardiometabolic markers:
e.g. B-type natriuretic peptide, Kidney Injury Molecule-1, neutrophil gelatinase-
associated lipocalin, clusterin, osteopontin, cystatin-C, uromodulin, heart-fatty acid 
binding protein, markers of inflammation and/or fibrosis, metabolic markers 
(e.g. adiponectin, apolipoproteins, HbA1c, glucose, (gluco)corticoids), or markers 
reflecting the oxidative stress status.
C. OMICS / Untargeted Multiplex Analysis: A sample may be collected for 
(untargeted) analysis (e.g. untargeted metabolomics) in order to identify ‘de novo’ 
pharmacodynamic biomarkers, biomarkers which support the understanding of the 
mode-of-action and/or biomarkers which may indicate disease progression. 
D. Further biomarkers related to the mode of action or the safety of runcaciguat and
similar drugs may be examined. The same applies to further biomarkers deemed 
relevant to NPDR, (cardio)vascular diseases and associated health problems. These 
investigations may include e.g. diagnostic, safety, PD, monitoring, or potentially 
predictive biomarkers.
The following sample types will be collected for biomarker analysis:

Plasma
PK or safety lab samples (leftovers) may be used for biomarker investigations. 
Generally, plasma is collected for biomarker analysis. Refer to sample handling 
sheets for further details as some laboratories may request serum for particular 
tests.

Serum (optional)

Whole blood
Timing – The planned time points of sample collection are provided in the SoA in 
Section 1.3. If deemed necessary, the sampling time points or frequency according to the SoA 
may be adjusted.
Sample handling and storage – details on the collection, processing, shipment and storage of 
samples will be provided in separate documents (e.g. sample handling sheets or lab manual). 


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Samples may be stored for a maximum of 15 years (or according to local regulations) 
following the end of the study at a facility selected by the Sponsor to enable further analyses.
Reporting – Biomarker investigations may be reported separately (e.g. in a biomarker
evaluation report) except for biomarkers of Category A above, and serum lipoprotein(s). 
8.6.2
Ambulatory blood pressure monitoring (ABPM) – only in Part 1
ABPM evaluations were removed from the protocol via Amendment 3.
8.7
Immunogenicity assessments
Not applicable.
8.8
Health economics
Health Economics/Medical Resource Utilization parameters are not evaluated in this study.
9.
Statistical considerations
As of amendment 3, this Section and its sub-sections were integrated from Master Protocol. 
In this section, the following terminology will be used:
‘Clinical activity’ will be used as a synonym for ‘superiority of runcaciguat vs placebo’. 
‘Clinical relevance’ will be used with its usual meaning (i.e. an effect that is sufficiently 
high to be of clinical interest).
9.1
Statistical hypotheses
The primary endpoint is the proportion of patients with “≥2-step improvement in DRSS at 
48 weeks of treatment in the study eye”.  This proportion will be denoted as  within the 
runcaciguat treatment arm and as  within the Placebo treatment arm.
The study will be evaluated using a Bayesian approach with non-informative prior 
distribution.  Using this approach for inference it is possible to base decisions directly on the 
posterior probabilities of the hypotheses of interest.  Therefore, in a Bayesian setting it is not 
necessary to specify an alternative hypothesis.
The hypotheses of interest are the following: 

Hypothesis of clinical activity:  > 

Hypothesis of clinical relevance:  > 0.25


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9.2
Sample size determination 
The overall planned sample size is displayed in Table 9-1.
Table 9-1
Planned sample size
Target
dose
Part 1
Part 2
Total
Randomized
Placebo
6
40
46
30 mg
-
-
-
60 mg
-
-
-
90 mg
-
-
-
120 mg
12
40
52
Overall
18
80
98
Evaluable*
80
*minimum evaluable for primary endpoint
The relative contribution of Part 1 and Part 2 to the combined total of N = 98 randomized 
participants may vary.  The assessment of the primary endpoint will include the combined 
total of all evaluable participants.  
If unexpectedly high dropout rates occur (e.g. due to COVID-19), the number of randomized 
participants may be increased by up to 20%.
The study will use a Bayesian concept for inference, which is based on the posterior 
probabilities that the research hypotheses are true.  Proof of concept shall be defined as 
fulfillment of the following criteria:  

≥90% posterior probability for the hypothesis of clinical activity
(i.e. ( > |) ≥0.9) 

≥50% posterior probability for the hypothesis of clinical relevance
(i.e. ( > 0.25|) ≥0.5).
The sample size has been chosen to provide at least 90% probability to obtain proof of 
concept.
The following assumptions have been used

True response probability for placebo: 10%

True response probability for runcaciguat 120 mg: 35%
The response criterion is assumed to be binomially distributed.  For the Bayesian evaluation, a 
Jeffries’ prior (i.e. a Beta (0.5;0.5)-prior) has been used.  Sample size was determined with a 
simulation approach using the R environment. 
To be able to declare both clinical activity and clinical relevance ≥40 evaluable patients are 
needed in both groups.
98 participants will be randomly assigned to the study intervention such that approximately 
80 evaluable participants complete the study.  Of 98 participants, 18 participants will be 
randomized with a ratio of 2:1 to highest runcaciguat dose and placebo for Part 1 (PK/PD).  
80 participants will be randomized with a ratio of 1:1 to placebo and runcaciguat for Part 2
(Table 9-1).


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9.3
Analysis sets
For the purposes of analysis, the following analysis sets are defined in Table 9-2.  
Participants will be analyzed by their actual treatment (i.e. placebo or runcaciguat, irrespective 
of the actual dose they were titrated to).  It is planned to pool the data of participants from 
Part 1 and Part 2 for analysis.  
Table 9-2
Analysis sets
Participant 
Assignment rule
analysis set
Full analysis set
(FAS)
All participants of the respective study part randomized to 
treatment who fulfilled the relevant selection criteria.  
Per protocol set
(PPS)
All FAS participants of the respective study part without validity 
finding.  
Pharmacokinetic 
analysis set (PKS)
All participants of the respective study part without validity 
findings affecting the PK analysis and with ≥1 valid PK samples
who received at least one dose of study intervention. 
Safety analysis set
(SAF)
All participants of the respective study part who took ≥1 dose of 
study intervention.  
9.4
Statistical analyses
The statistical analysis plan will be finalized prior to unmasking and it will include a more 
technical and detailed description of the statistical analyses described in this section.  This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints.
9.4.1
General considerations
All data will be listed and study summary tables as well as graphical illustrations will be 
provided where appropriate.  Summary statistics will be presented per dose step for the 
participants treated with runcaciguat and for all participants treated with placebo for the 
original data as well as for the difference to baseline.  Frequency tables will be provided for 
qualitative data.
For handling of missing data for the primary endpoint, see Section 9.4.2.  Statistical analysis 
will be based on the available data.  Analysis will be performed considering all valid data 
observed for the respective analysis sets.  All missing or partial data will be presented in the 
subject data listing as they are recorded on the case report form.  
Baseline is defined as the last pre-dose assessment before first study intervention. 
Statistical analysis will be performed using Statistical Analysis System (SAS).  The version 
used will be specified in the statistical analysis plan.


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9.4.2
Primary endpoint
The primary endpoint is “≥2-step improvement in DRSS at 48 weeks of treatment in the
study eye”.  
Missing data for this endpoint will be imputed using the last measured DRSS score prior to 
this.
If the last measured DRSS score already showed an improvement by ≥2 steps at the last 
measurement prior to the missing assessment, the participant will be considered a responder 
for the primary endpoint.  Otherwise, the participant will be considered a non-responder.
Participants that had a vision-threatening complication as defined in Section 8.1.2 prior to the 
missing assessment will be considered non-responders.
The primary analysis will be conducted using a Bayesian framework.  This decision depends 
upon the following criteria: 
(a) there is ≥90% posterior probability for superiority vs placebo and 
(b) if there is ≥50% posterior probability that the proportion of patients with DRSS 
≥2-step improvement exceeds 25%.  
The response criterion is assumed to be binomially distributed within each treatment arm.  For 
the Bayesian evaluation, a Jeffries’ prior (i.e. a Beta (0.5;0.5)-prior) will be used.  Under these 
assumptions, the posterior distribution for the parameter will be a Beta (k+0.5,n-k+0.5)-
distribution, where 

k is the number of patients with DRSS ≥2step improvement within the respective 
study arm and 

n is the number of participants within the respective study arms.
In order to demonstrate criterion (a), the posterior distribution of  − will be used to 
establish the posterior probability that  − > 0 (e.g. by using a Monte-Carlo-
approach). 
The posterior distribution for criterion (b) can be directly evaluated from the Beta (k+0.5,n-
k+0.5)- distribution in the runcaciguat arm. 
This primary analysis will be conducted on the PPS.  A sensitivity analysis will be performed 
on the FAS.  Further sensitivity analyses will include a separate analysis for each runcaciguat 
dose level that was reached during titration (on the PPS), as well as an analysis in the 
subpopulation of participants without major changes in vital signs (i.e. systolic blood pressure 
and pulse rate). Another sensitivity analysis will be conducted using multiple imputations for 
missing data. This analysis will be described in the SAP in a more detailed way.
9.4.3
Secondary endpoint(s)
9.4.3.1
Efficacy
The secondary endpoints for primary objective (efficacy) of study are 


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
“≥2step improvement in DRSS in the study eye” at 24 weeks of treatment:
These endpoints will be analyzed descriptively with a similar methodology 
described for the primary endpoints.

Vision-threatening complications in study eye up to 48 weeks of treatment.
These endpoints will be analyzed by the Kaplan-Meier-method.  Participants 
dropping out from the study without a vision-threatening complication will be 
censored at the last visit with evidence of no event.
9.4.3.2
Safety
The secondary objective of the study is to investigate the safety and tolerability of runcaciguat 
in patients with NPDR.  The secondary endpoints in the safety of runcaciguat are treatment-
emergent adverse events (TEAEs) from first dosing up to 28 days after last dose of study 
intervention.
The incidence of TEAEs and drug-related TEAEs, respectively, will be summarized by 
treatment and total using MedDRA terms. AEs are considered to be treatment-emergent if 
they have started or worsened after first application of study intervention up to 28 days after 
end of treatment with study intervention.
9.4.4
Other efficacy analyses
For further addressing the primary objective (efficacy) of the study, the following additional 
endpoints will be analyzed descriptively:

DRSS change in study and fellow eye by ≥1, ≥2, or ≥3 steps over time 

Change in visual acuity from baseline (study and fellow eye) 

Vision-threatening complications in any eye up to 48 weeks of treatment 

Change in leakage area on fluorescein angiography
9.4.5
Other safety analysis
All safety analyses will be made on the Safety Population.  A detailed description will be 
given in the statistical analysis plan.
For the secondary objective (safety) of the study, the following additional endpoints will be 
considered and analyzed:
Laboratory parameters
Vital signs
Electrocardiography
Quantitative data will be described by the following summary statistics: arithmetic mean, 
standard deviation, median, minimum and maximum.  These summary statistics will be 
presented by treatment for the original data as well as for the difference to baseline.  
Frequency tables will be provided for qualitative data.  Laboratory data outside the reference 


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range will be listed and flagged with ‘L’ for low and ‘H’ for high.  Additional tables with all 
abnormal values will be presented.
Graphical displays of individual data as well as mean values with standard deviation will be 
included.
9.4.6
Other analysis
Other objectives of the study are to assess pharmacodynamics and pharmacokinetics of 
runcaciguat.  Pharmacodynamics analyses include following endpoints:
Change in central retinal thickness
Change in HbA1c 
Change in serum lipoproteins 
Pharmacokinetic analyses will be performed on the population valid for pharmacokinetics and 
pharmacodynamic analyses will be performed on the population valid for pharmacodynamics.  
Summary statistics (arithmetic mean, standard deviation, median, minimum and maximum for 
quantitative variables) will be presented and frequency tables for qualitative data will be 
provided.
For demographic and baseline characteristics summary statistics (arithmetic mean, standard 
deviation, median, minimum and maximum for quantitative variables) will be presented for 
total and each treatment group in the FAS.  Frequency tables for qualitative data will be 
provided.  Medical history findings will be summarized using MedDRA terms.  Prior and 
concomitant medication will be summarized by World Health Organization Drug Dictionary 
using the latest effective version of the dictionaries.
9.5
Interim analysis
No interim analysis is planned.


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10.
Supporting documentation and operational considerations
10.1
Appendix 1: Regulatory, ethical, and study oversight considerations
10.1.1
Regulatory and ethical considerations

This study will be conducted in accordance with the protocol and with the 
following:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants. Any substantial 
modification of the protocol will be submitted to the competent authorities as 
substantial amendments for approval, in accordance with ICH Good Clinical 
Practice and national and international regulations.

Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations
10.1.2
Financial disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.


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10.1.3
Informed consent process

The investigator or his/her representative will explain the nature of the study to the 
participants and answer all questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act requirements, where applicable, and the 
IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participants. 

Participants who are rescreened are required to sign a new ICF.
10.1.4
Data protection

Participants will be assigned a unique identifier by the sponsor. Any participant
records, datasets or biological samples that are transferred to the sponsor will 
contain the identifier only; participant names or any information which would 
make the participant identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.


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10.1.5
Committees structure
10.1.5.1
Central reading centers 
The digital retinal images, OCT scans, fluorescence angiographies, and ECG print-outs will 
be assessed by independent central reading centers.
10.1.5.2
Steering committee
A steering committee consisting of experts in the field is created to provide scientific and 
operational recommendations to the study protocol and to potential day to day decisions in 
study conduct. The composition of the committee, the functional roles, and responsibilities 
can be found in the Steering Committee charter.
10.1.5.3
Data monitoring committee (DMC)
An independent DMC is set up to provide recommendations based on unmasked review of 
data if needed. The DMC consists of a combination of experts in the clinical field and 
statistical analysis.
10.1.5.4
Safety assessment group
An internal safety assessment group will perform masked reviews of the safety and 
tolerability data from the study at the request by any of its members.  The safety assessment 
group may call for an unmasked review of study data by the DMC, if deemed appropriate.

The internal safety assessment group consists of Study medical expert (chair), Early 
clinical lead, Global clinical lead, Global safety lead and PK expert.  

The safety assessment group will review severe adverse reactions, SAEs, and AESIs, 
AEs resulting in treatment interruption or discontinuation, as well as other AEs 
deemed relevant by any of its members.

In particular, it will support the safety review by the DMC in case stopping criteria are 
met (see Sections 6.5.2, 7.1)
10.1.6
Dissemination of clinical study data
Result Summaries of Sponsor's sponsored clinical trials in drug development Phases 2, 3 and 
4 and Phase 1 studies in patients are provided in the Sponsor’s Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases". In addition, results of clinical drug 
trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU 
Clinical Trials Register in line with the applicable regulations.
The Sponsor commits to sharing upon request from qualified scientific and medical 
researchers patient-level clinical trial data, study-level clinical trial data, and protocols from 
clinical trials in patients for medicines and indications approved in the United States (US) and 


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European Union (EU) on or after 01 JAN 2014 as necessary for conducting legitimate 
research. 
All of the Sponsor sponsored clinical trials are considered for publication in the scientific 
literature irrespective of whether the results of the clinical trials are positive or negative.
10.1.7
Data quality assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g. laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

Guidance on completion of CRFs will be provided in eCRF completion guidelines.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

Quality tolerance limits (QTLs) will be pre-defined in the Integrated Data Review Plan
to identify systematic issues that can impact participant safety and/or reliability of 
study results. These pre-defined parameters will be monitored during the study and 
important deviations from the QTLs and remedial actions taken will be summarized in 
the clinical study report.

Monitoring details describing strategy (e.g. risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g. Contract Research Organizations).

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor. 
10.1.8
Source documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.


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
Definition of what constitutes source data can be found in the Source Data Location 
List.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
10.1.9
Study and site start and closure
First act of recruitment
The first act of recruitment is the first patient first visit and will be the study start date.
Study/site termination
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
For study termination:

Discontinuation of further study intervention development
For site termination:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator

Total number of participants included earlier than expected.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.


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10.1.10
Publication policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
10.2
Appendix 2:  Clinical laboratory tests
The tests detailed in Table 10-1 will be performed by a central laboratory apart from urine 
pregnancy test, that will be performed locally. 
Investigators must document their review of each laboratory safety report.
The laboratory parameters to be analyzed are defined in Table 10-1. The time points of 
analysis are defined in the schedule of activities.
Additional laboratory tests (see Table 10-4 for examples) may be performed as deemed 
appropriate by the Investigator, e.g. in case of signs of liver toxicity.


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Table 10-1
Protocol-required laboratory tests
Parameters (by category)
Sample destination
Blood / 
plasma / 
serum  
Hematology
Leukocytes, 
Erythrocytes, 
Hemoglobin, 
Hematocrit, 
HbA1c, 
Mean corpuscular volume (MCV), 
Mean corpuscular hemoglobin (MCH), 
Platelets, 
Neutrophils, 
Eosinophils, 
Basophils, 
Lymphocytes, 
Monocytes
Central laboratory
Biochemistry
Alanine aminotransferase (ALT), 
Aspartate aminotransferase (AST), 
Gamma-glutamyl transferase (GGT), 
Alkaline phosphatase (AP), 
Total bilirubin (if elevated: differentiation of direct bilirubin), 
Lactate dehydrogenase (LDH), 
Creatinine, 
Urea, 
Creatine kinase, 
Chloride, 
Potassium, 
Sodium, 
Calcium, 
Phosphate, 
Glucose, 
Total protein, 
Albumin, 
Triglycerides, 
Cholesterol (total, LDL, HDL), 
ß-hCG (women)
Central laboratory
Plasma PK
BAY 1101042 and its metabolites M1, M6 and M7
Central laboratory
Biomarkers in 
plasma/serum
See Section 8.6.1 for details
Central laboratory 
Hormones
Thyroid stimulating hormone (TSH)
Central laboratory
Urine
ß-hCG pregnancy test (women)
Local evaluation
HDL = high-density lipoprotein, LDL = low-density lipoprotein; PK = pharmacokinetics; HbA1c= hemoglobin A1c (glycated 
hemoglobin); ß-hCG = β-subunit of human chorionic gonadotropin


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10.3
Appendix 3: AEs and SAEs: Definitions and procedures for recording, 
evaluating, follow-up, and reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, associated 
with the use of study intervention, whether or not considered related to the study 
intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g. ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e. not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention
interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT meeting the AE definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g. endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.


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10.3.2
Definition of SAE
An SAE is defined as any AE that, at any dose:
a.
Results in death
b.
Is life-threatening

The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the participant was at risk of death at the time of the event. It does not 
refer to an event, which hypothetically might have caused death, if it were more 
severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
d.
Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.

This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse.


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10.3.3
Recording and follow-up of AE and/or SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review 
all documentation (e.g. hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE information.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to sponsor in lieu of completion of the AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by sponsor. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to sponsor.

The investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the 
diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE.
Assessment of intensity

The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe.


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Assessment of causality

The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and 
other risk factors, as well as the temporal relationship of the event to study 
intervention administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to sponsor. However, it is 
very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to 
sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by sponsor to elucidate the nature and/or causality of the AE or SAE 
as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 
24 hours of receipt of the information.
10.3.4
Reporting of SAEs
SAE reporting to sponsor via an electronic data collection tool

The primary mechanism for reporting an SAE to sponsor will be the electronic 
data collection tool.


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
If the electronic system is unavailable, then the site will use the paper SAE data 
transmission (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection 
tool has been taken off-line, then the site can report this information on a paper 
SAE form (see next section) or to the Sponsor’s Medical Monitor by telephone.

Contacts for SAE reporting can be found in the Investigator Site File.
SAE reporting to sponsor via paper data collection tool

Email transmission of the SAE paper data collection tool is the preferred method 
to transmit this information to the Sponsor.

In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
time frames.

Contacts for SAE reporting can be found in the Investigator Site File.
10.4
Appendix 4: Contraceptive guidance and collection of pregnancy 
information
Definitions:
Woman of childbearing potential
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered women of childbearing potential
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy


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For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g. mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.

A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more 
than one FSH measurement is required. 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.
Contraception guidance:
Female participants of child bearing potential must use a highly effective method of 
contraception, as shown in Table 10-2. Male participants must agree to use condoms. This
applies from the time of ICF signature until the end of the study period.  
Table 10-2
Highly effective contraception methods
Implantable hormonal contraception associated 
with inhibition of ovulation
Intrauterine device
Intrauterine hormone-releasing system
Bilateral tubal occlusion
Hormonal contraception with inhibition of ovulation, 
either estrogen and progestogen containing or 
progesterone-only
Vasectomized partner if sole sexual partner
Sexual abstinence
Modified from: Clinical Trial Facilitation Group 2014: Recommendations related to contraception and pregnancy testing in clinical 
trials (CTFG 2014).
Collection of pregnancy information:
Male participants with partners who become pregnant 

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in this 
study. This applies only to male participants who receive study intervention.


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
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.
Female participants who become pregnant 

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and will 
be reported as such. 

Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention.
10.5
Appendix 5: Liver safety: Suggested actions and follow-up assessments 
Discontinuation of study intervention for abnormal liver function should be considered by the 
investigator when a participant meets one of the conditions outlined in Table 10-3 or if the 
investigator believes that it is in best interest of the participant. 


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Table 10-3
Liver-safety-related monitoring and discontinuation criteria
Laboratory result
Measures
ALT or AST > 3 x ULN 
after start of study intervention
‘Close observation’ as defined below
ALT or AST > 3 x ULN and TBL > 2 x ULN 
Withdraw study intervention and 
close observation as outlined below
ALT or AST > 3 x ULN and INR > 1.5 x ULN
in the absence of anti-coagulants
Withdraw study intervention and 
close observation as outlined below
ALT or AST > 3 ULN with appearance of fatigue, 
nausea, vomiting, right upper abdominal quadrant pain 
or tenderness, fever, rash and/or eosinophilia (> 5%)
Withdraw study intervention and 
close observation as outlined below
ALT or AST > 5 x ULN for more than 2 weeks
Withdraw study intervention 
and close observation as outlined below
ALT or AST > 8 x ULN
Withdraw study intervention 
and close observation as outlined below
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR= international normalized ratio, 
TBL = total bilirubin, ULN = upper limit of normal (all referring to serum/plasma)
In participants fulfilling one of the criteria listed in Table 10-3, investigators and participants 
should be alerted regarding non-specific symptoms which may be associated with liver 
dysfunction, including anorexia, nausea, fatigue, right upper abdominal discomfort, vomiting, 
malaise, jaundice, fever, and rash. Information on these symptoms should be asked for. The 
study participants should be reminded to contact the study site immediately, if they are 
concerned about such symptoms and unscheduled liver parameters should be considered. 
A close observation has to be initiated if any of the criteria listed in Table 10-3 occurs.
Close observation includes:

Repeat serum chemistry panel (including serum transaminases and serum bilirubin) up
to two times per week. Frequency of retesting can decrease to once a week or less if 
laboratory abnormalities decrease and participant is asymptomatic.

Obtaining a more detailed history of the symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets.

Investigation of potential alternative causes of liver disease.  This may include ruling 
out liver injury by acute viral infection, autoimmune or alcoholic hepatitis; 
nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy and biliary tract disease. 
This may require performing additional procedures, e.g. ultrasound examinations or 
laboratory examinations, including but not limited to those listed in Table 10-4. If 
requested, tests will be done retrospectively using residual blood/serum samples 
collected at visits before laboratory abnormalities occurred.

Obtaining a history of exposure to environmental chemical agents.

Obtaining additional tests to evaluate liver function as required, as outlined in a 
separate liver injury follow-up questionnaire.


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Table 10-4
Laboratory examinations for workup of liver safety findings
Parameters
Albumin
Alkaline phosphatase (AP)
Alanine-aminotransferase (ALT)
Aspartate-aminotransferase (AST)
Bilirubin : total, direct
Complete blood count including differentials
Cholesterol (total, LDL, HDL)
Cholinesterase
Conjugated (direct) bilirubin
Creatine kinase (CK)
Gamma-glutamyltransferase (γ-GT = GGT)
Glutamate dehydrogenase (GLDH)
Hemoglobin
International normalized ratio (INR)
Lactate dehydrogenase (LDH)
Prothrombin time (Quick) (PT)
Triglycerides
Anti-Hepatitis A virus Antibodies
Hepatitis B virus (HB): surface antigen (HBs), anti-HBs, anti-HB core antibodies (IgM, IgG), HB PCR 
Anti-Hepatitis C virus (HCV) antibodies, HCV PCR
Anti-Hepatitis D virus (HDV) antibodies (if positive, automatically test HDV RNA)
Anti-Hepatitis E virus (HEV) IgM (if positive, automatically test HEV RNA)
Anti-Cytomegalovirus (CMV) IgM Antibodies
Anti-Epstein-Barr Virus (EBV) IgM Antibodies
Herpes simplex IgM (anti HSV IgM)
SARS-COV-2 antibodies
Immunoglobulins: (Ig) G level (gamma globulins), IgA, IgM
Antineutrophil cytoplasmic antibodies (c-ANCA, p-ANCA)
Anti-mitochondrial antibodies
Anti-native double-stranded DNA Antibodies
Anti-Smith Antibodies
Alpha-1 antitrypsin (A1AT) level
Ceruloplasmin
Ferritin
Iron
Total iron binding capacity (TIBC)
HDL = High density lipoprotein; IgA = Immunoglobulin A; LDL = Low density lipoprotein; IgM = Immunoglobulin M; PCR = 
Polymerase chain reaction; RNA = Ribonucleic acid
10.6
Appendix 6:  Standardized meal 
Standardized meals were removed from the protocol via Amendment 3.


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10.7
Appendix 7: Abbreviations
ABPM
Ambulatory blood pressure 
measurement
AE(s)
Adverse event(s)
AESI(s)
Adverse event(s) of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BCVA
Best corrected visual aquity
ß-hCG
β-subunit of human chorionic 
gonadotropin
BMI
Body mass index
BP
Blood pressure
CFP
Color fundus photography
CKD
Chronic kidney disease
CKD-EPI
Chronic Kidney Disease-Epidemiology 
Collaboration
cGMP
Cyclic guanosine monophosphate
CRF(s)
Case report form(s)
CST
Central subfield thickness
CTFG
Clinical trial facilitation group
DMC
Data Monitoring Committee 
DME
Diabetic macular edema
DR
Diabetic retinopathy
DRSS
Diabetic Retinopathy Severity Scale
ECG(s)
Electrocardiogram(s)
eCRF(s)
Electronic case report form(s)
eGFR
Estimated glomerular filtration rate
ETDRS
Early Treatment Diabetic Retinopathy 
Study
EU
European Union
EudraCT
European Union Drug Regulating 
Authorities Clinical Trials Database
FA
Fluorescein angiography
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GLDH
Glutamate dehydrogenase
HbA1c
Hemoglobin A1c (glycated hemoglobin)
HRT
Hormonal replacement therapy
IB
Investigator’s brochure
ICF(s)
Informed consent form(s)
ICH
International conference on 
harmonisation
IEC
Independent ethics committee
INR
International normalized ratio
IOP
Intraocular pressure
IRB
Institutional review board
IVT
Intra-vitreal drug treatment
IWRS
Interactive Web Response System
NO
Nitric oxide
NPDR
Non-proliferative diabetic retinopathy
OCT
Optical coherence tomography
OCT-A
Optical coherence tomography 
angiography
PD
Pharmacodynamics
PDE
Phosphodiesterase
PDE 5
Phosphodiesterase 5
PDR
Proliferative diabetic retinopathy
PK
Pharmacokinetics
PoC
Proof of Concept
PRP
Pan-retinal photocoagulation
QD
Quaque die, daily
QTLs
Quality tolerance limits
SAE(s)
Serious adverse event(s)
SBP
Systolic blood pressure
sGC
Soluble guanylyl cyclase
SoA
Schedule of activities
TEAE(s)
Treatment emergent adverse event(s)
TMF
Trial master file
uACR
Ratio of urinary albumin and creatinine 
concentrations
ULN
Upper limit of normal
VEGF
Vascular endothelial growth factor


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10.8
Appendix 8: Protocol amendment history
10.8.1
Amendment 4
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
10.8.2
Amendment 3
As of Amendment 3 and in line with the change in overall development strategy, Part B of the 
study is obsolete and has been removed from the protocol previously consisting of 3 modules 
(Master, Part A, Part B). At the same instance, for ease of documentation and to enhance 
readability a single protocol document was created integrating the relevant information from 
the Master- and Part A documents.
Amendment 3 (04 NOV 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall rationale for Amendment 3: 
A description of changes and a brief rationale is outlined in the table at the end of this section.  
An overview is given below.
Parallel start of Part 1 and 2 of former Part A 
The sponsor’s clinical development program for runcaciguat comprises two currently ongoing 
Phase 2a studies in different indications: Study 20739 (NEON) in patients with NPDR and 
Study 18748 (CONCORD; EudraCT: 2019-003297-53) in patients with chronic kidney 
disease (CKD).  Initially, both studies were planned to start at the same time which is why the 
NEON-NPDR study had been designed to start with the safety-data-generating Part 1 before 
initiation of the subsequent study parts. Runcaciguat, in the two proposed indications, is 
planned to be studied in the same doses, 30, 60, 90 and 120 mg OD orally administered, with 
the same up-titration schedule. However, the CONCORD study started earlier and generated 
safety data from 147 randomized participants before randomization of the first NEON-NPDR 
participant.  DMC reviews of these data confirm the tolerability of the planned dosing 
schedule of runcaciguat in a similar patient population.  Details are provided in the master 
protocol Section 2.3.1.
In view of the above considerations, Part 1 is no longer considered to be a prerequisite to 
initiate the main study Part 2.  Therefore, both study parts are initiated independently from 
each other and will be conducted in parallel.  Also, the focus of the 18 patients to be enrolled 


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in study Part 1 was shifted from generating safety data to obtaining pharmacodynamic data, 
mainly OCT-A, for PK/PD analyses.  
Study population 
After initiation of the NEON study, 12 out of 16 screened patients were found to be ineligible. 
Since the initial conception of the NEON-NPDR protocol, two landmark studies in treatment 
of NPDR with intravitreal aflibercept have been published. The first is Protocol W (Maturi et 
al. 2021) sponsored by the DRCR Retina Network providing important new insights. The 
second is the PANORAMA study (Brown et al. 2021), investigating intravitreal injection of 
aflibercept as compared to sham, in a similar population with moderately-severe to severe 
NPDR as in Protocol W.  In addition, the CONCORD study investigating runcaciguat in renal 
disease provided preliminary safety data indicating that runcaciguat is well tolerated by 
participants with HbA1c up to 11% and renal impairment with eGFR as low as 
25 mL/min/1.73 m2.
The eligibility criteria were, therefore, more closely aligned with other recent studies in 
similar diabetic patient populations with NPDR or renal disease. This included the 
CONCORD study investigating runcaciguat in renal disease, the PANORAMA study and 
DRCR Protocol W both investigating aflibercept in NPDR.  Based on these studies it was 
deemed safe to include patients with HbA1c up to 11% and renal impairment with eGFR of at 
least 30 mL/min/1.73 m2 and the definition of diabetic macula edema was specified.
The in- and exclusion criteria of the study were adjusted to better reflect the envisaged study 
population. 
Streamlining of study conduct
Furthermore, some eligible patients refused participation in Part A1 of the clinical trial due to 
the high number and intensity of study visits.  Therefore, the overall treatment duration was 
shortened to 48 weeks.  In Part 1, the baseline profile Visit 1b was removed, the length of 
Visits 2 to 6 was shortened to up to 4 hours post dose and the number of assessments was 
reduced.  These changes can safely be implemented based on the experience and data obtained 
from the CONCORD study and are expected to significantly reduce the burden on study 
participants.
Change in overall development Strategy
The clinical development of runcaciguat so far showed that the compound is well tolerated. 
However, pharmaceutical challenges may lead to inconvenient dosing regimens and a difficult 
to manage product supply chain. 
 
The Sponsor still plans to run the NEON-NPDR study with runcaciguat as a Proof of Concept 
(PoC) trial for sGC activators in NPDR, although runcaciguat will not be further developed. 
The Sponsor believes that this PoC trial will enable the optimal development of other sGC 
activators in NPDR and envisages to switch to such a compound in its portfolio.
CCI


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Removal of Part B from the study
As of Amendment 3 and in line with the change in overall development strategy, Part B of the 
study is obsolete and has been removed from the protocol dossier. At the same instance, for 
ease of documentation and to enhance readability, a single protocol document was created 
integrating the relevant information from the Master- and Part A documents. This was done 
by moving all Sections applicable to the Study Part A document (Section 2 and all of its 
subsections, Sections 4.2 to 4.4, and Section 9 and all of its subsections) from the Master 
protocol into the Protocol Part A document without general highlighting as change. Only 
changes compared with the prior version of the Master protocol are listed in this Protocol 
document.
The Terms Part A and Part B were retired. Part 1 now refers to the PK/PD substudy and Part 2 
refers to the main part of the PoC study.
Key changes in study design
Section # 
and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis / 
Rationale
Reference added to CONCORD 
study
Preliminary safety information can be 
derived from the CONCORD study that 
investigates runcaciguat in patients with 
chronic kidney disease.
Section 1.1 Synopsis / 
Rationale
Rationale expanded, by explaining 
the role of the clinical trial in the 
development of a subsequent sGC 
activator for treatment of NPDR
Late stage clinical development is not 
planned to be pursued with runcaciguat 
but with other sGC-activator(s).
Section 1.1 Synopsis 
Section 1.3 Schedule of 
Activities (SoA) 
Deletion of baseline-visit 1b.
The screening visit is called Visit 1 in 
both Parts 1 and 2.
Owing to the safety information that 
became available in the meantime from 
the CONCORD study, a baseline profile is 
no longer considered required for the 
assessment of cardiovascular and 
metabolic effects.
Therefore, Visit 1b in Part 1 was 
eliminated; eliminating the need to 
differentiate the two pre-treatment visits.
Section 1.1 Synopsis 
Section 4.1 Overall design 
Parts 1 and 2 will run in parallel.  
Therefore, Part 1 was relabeled as 
“PK/PD” sub-part, and description of 
study Parts 1 and 2 adapted 
accordingly. 
With CONCORD safety data available, 
collection of safety data in a run-in is no 
longer needed prior to conducting Part 2 
at ophthalmology sites. Part 1 is kept to 
investigate the PK/PD of runcaciguat in a 
subset of participants.


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Section # 
and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis (Table 1-
1)
Section 1.2 Schema 
Section 1.3 Schedule of 
activities (SoA) 
Section 3 Objectives and 
endpoints
Section 7.2 Participant 
discontinuation
Section 8 Study assessments
By shortening the treatment period to 
48 weeks, the end-of-study visit was 
moved to Visit 16, and the 
descriptions of the visits were 
changed accordingly. 
Also, the timeframe for secondary 
and “other“ efficacy endpoints has 
been adapted to the new treatment 
duration.
The maximum amount of blood 
collected from each participant over 
the duration of the study was adapted 
to the shortened study duration.
48 weeks provide a sufficiently long 
treatment period to investigate the 
endpoint of 2-step improvement and may 
provide some preliminary information on 
the occurrence of vision-threatening 
complications. 
Section 2 Introduction
The role of the NEON-NPDR in the 
context of sGC activator development 
was reworded.
Information was added as to the 
exposure of patients with CKD to 
runcaciguat.
Clarification on the role of the NEON-
NPDR study in the context of Sponsor’s 
sGC program. 
New information available from clinical 
trial with runcaciguat in other indication 
became available.
Section 2.1 Study rationale
The role of the study in the context of 
the development of an sGC activator 
for treatment of NPDR was amended
Change in development strategy.
Section 4.1. Overall study 
design
Section 9.4.3.1 Efficacy
Section 9.4.4 Other Efficacy 
analyses
The treatment period was shortened 
to 48 weeks. Accordingly, the 
timeframe for secondary and “other“ 
efficacy endpoints has been adapted 
to new treatment duration.
48 weeks provide a sufficiently long 
treatment period to investigate the 
endpoint of 2 step improvement and may 
provide some preliminary information on 
the occurrence of vision-threatening 
complications.
The primary endpoint analysis at 24 
weeks and the secondary evaluations at 
48 week will allow sufficient data for the 
sponsor’s decisions on the future 
development program of runcaciguat.
Section 4.1. Overall study 
design
Section 4.1.1 Part 1 – PK/PD
Section 9.5 Interim analysis
Parts 1 and 2 will be run parallel.  
Reference to „run-in“ for Part 1 
deleted, and description of study 
Parts 1 (PK/PD) and 2 (Proof of 
Concept) aligned to current situation.
With masked CONCORD safety data 
available on a large number of
participants, Part 1, with planned 18 
patients, is no longer needed as a run-in 
preceding Part 2.  The titration scheme 
has been confirmed in the CONCORD 
study.
Section 4.1.2 
Part 2 – Proof of concept 
Interdependence of Part 2 with Part 1 
deleted, interim snap-shot review 
deleted, treatment duration changed 
to 48 weeks.
With CONCORD safety data available, 
Part 1 is no longer needed as a run-in 
preceding Part 2.
Section 9.5 Interim analysis
Masked safety review at end of 
titration phase of Part 1 deleted.
Review no longer required, since safety of 
the titration regimen was confirmed in 
CKD patients in the CONCORD study.
Section 10.1.5.4 Safety 
assessment group
Masked safety review at end of 
titration phase of Part 1 deleted.
Review no longer required, since safety of 
the titration regimen was demonstrated in 
CKD patients in the CONCORD study. 


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Other substantial changes
Section # 
and Name
Description of Change
Brief Rationale
Section 1.3 Schedule of 
activities (SoA) (Table 1-3)
Section 10.2 
Appendix 2: Clinical laboratory 
tests 
Section 10.6 
Appendix 6:Standardized meal 
(Part 1)
Glucose stix and standard meals 
were deleted.
With CONCORD safety data available, 
glucose measurements were limited to 
venous glucose from the central safety 
lab analysis.  As a result, standardized 
meals are dispensable as well.
Section 1.3 Schedule of 
activities (SoA) (Tables 1-3, 1-
4)
Deletion of “Anterior and posterior 
segment examination” as well as 
“DRSS 7-field fundus photography“ 
on Visit 6. 
Reduction of burden for patients by 
reducing examinations with pupil dilation 
which are not expected to generate 
essential efficacy data.  
Section 1.3 Schedule of 
activities (SoA) 
Deletion of the 4-6 hour post-dose 
time point in Part 1. 
Activities scheduled for the 4-6 hour 
timepoint were moved to 2-4 hours 
post dose.
This change is intended to reduce patient 
burden.
In healthy participant Phase 1 studies, the 
steep increase in plasma concentrations 
took place within 4 hours post-dose.  
Therefore, plasma concentrations at 4 
hours post dose are considered a 
reasonable approximation of the effective 
concentration.
Section 1.3 Schedule of 
activities (SoA) 
Section 3 Objectives and 
endpoints
Section 8.1.4 Visual function 
questionnaire (VFQ-25)
Deletion of visual function 
questionnaire (VFQ-25).
This change is intended to reduce patient 
burden.
The study recruits patients without 
significant visual impairment.  Also, no 
change in visual function could be seen in 
studies such as the Panorama Study or 
Protocol W over treatment periods of up 
to 2 years.  
Therefore, the VFQ-25 is not expected to 
be sensitive to assess efficacy in this 
clinical trial over a period of only 48 
weeks.
Section 1.3 Schedule of 
activities (SoA) (Tables 1-3, 1-
4)
Deletion of “Anterior and posterior 
segment examination” as well as 
“DRSS 7-field fundus photography“ 
on Visit 6. 
Reduction of burden for patients by 
reducing examinations with pupil dilation 
which are not expected to generate 
essential efficacy data.  
Section 1.3 Schedule of 
activities (SoA) (Table 1-3)
Section 6.1.2 Medical devices
Section 8.6.2 Ambulatory blood 
pressure monitoring (ABPM)
Ambulatory blood pressure 
monitoring was deleted.
This change is intended to reduce patient 
burden.
Based on the experience from the 
CONCORD study, ambulatory blood 
pressure monitoring is no longer 
considered essential for the compound 
safety assessment in diabetic patients 
treated with runcaciguat. 


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Section # 
and Name
Description of Change
Brief Rationale
Section 1.3 Schedule of 
activities (SoA) 
Section 8.1.3 Albuminuria
Section 8.6.1 Laboratory 
biomarkers
Section 10.2 
Appendix 2: Clinical laboratory 
tests 
uACR assessment and consecutively 
also urine biomarker sample were 
deleted.
Similar data are expected to be generated 
in the CONCORD study. Therefore, the 
uACR assessments were deleted to 
reduce patient burden.
Section 1.3 Schedule of 
activities (SoA) (Table 1-3)
Phone contact 1 and 2 days post visit 
was deleted.
Active phone check-up no longer 
considered necessary, considering the 
experience from CKD patients treated 
with runcaciguat indicating good 
tolerability.
Section 1.3 Schedule of 
activities (SoA) 
Section 8.2.5 Pregnancy 
testing
Urine pregnancy test deleted from 
Visit 7 onwards. 
Redundant with serum pregnancy test. 
Removed to reduce participant burden. 
Section 2.3.1 Risk assessment
Section 4.3 Justification for 
dose
Sections updated with exposure and 
safety information derived from 
unmasked assessment of safety data 
from the CONCORD study, along with 
DMC recommendations from the 
CONCORD study.
Updates required to justify reduction of 
safety assessments in Part 1 and the 
parallel conduct of Parts 1 and 2.
Tolerability of the dosing regimen and 
titration scheme were confirmed in 
CONCORD study.
Section 2.3.1 Risk assessment
Section 4.3 Justification for 
dose
The permissible eGFR limit has been 
lowered from 45 ml/min to 30 ml/min.
In the Phase 2 study of runcaciguat in 
chronic kidney disease (CONCORD), 
runcaciguat was well tolerated when 
participants with eGFR ≥ 25 mL/min were 
included.
Since a similar tolerability is expected in 
patients with NPDR, it is considered 
appropriate to lower the eGFR exclusion 
threshold. This change is expected to 
facilitate recruitment and to improve the 
generalizability of the study data (safety 
and efficacy) across the general NPDR 
patient population.
Section 2.3.2 Benefit 
assessment
An individual clinical benefit from 
participation in the study over 48 
weeks of treatment is unlikely.
Discussion of potential benefits modified 
according to shortened treatment period 
Section 5.2 Exclusion criteria 
Exclusion criteria 1 and 18 changed 
to allow enrolment of patients with 
HbA1c up to 11% and eGFR as low 
as 30 mL/min.
Alignment with selection criteria of the 
Phase 2 CONCORD study.  In the 
CONCORD study, inclusion of 
participants with HbA1c up to 11% and 
eGFR ≥25 mL/min was well tolerated.
The change is expected to facilitate 
recruitment and to improve the 
generalizability of the study data (safety 
and efficacy) across the general NPDR 
patient population.


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Section # 
and Name
Description of Change
Brief Rationale
Section 5.2 Exclusion criteria 
Definition of diabetic macular edema 
in exclusion criterion 6 changed to 
allow recruitment of patients with 
increased retinal thickness not 
needing treatment intervention, as per 
Investigator judgement, and below 
OCT-determined thickness 
thresholds.
Exclusion criterion changed not to 
exclude patients with minor, not clinically 
significant DME unlikely to interfere with 
the planned study interventions and 
assessments. The exclusion criterion is 
similar to the equivalent exclusion 
criterion in Protocol W.
Section 5.4 Screen failures
Rescreening allowed for participants 
screen-failed under prior protocol 
versions.
Considering the changes in I/E criteria 
and the time passed since prior 
screening, re-screening of participants 
screen-failed under protocol versions up 
to 3.0 is deemed appropriate.
7.1.1 Permanent 
discontinuation
7.1.2.Temporary 
discontinuation
Permanent discontinuation after 
repeated relevant hypotension and 
any other repeated discontinuation is 
no longer mandatory but at the 
discretion of the investigator.
An upper duration limit was defined 
for temporary discontinuations.
Based on the experience from the 
CONCORD study, a strict rule for 
permanent discontinuation does not seem 
to be warranted in case of repeat 
discontinuations. 
Instead an upper limit of days 14 
continuous or 21 days overall off 
treatment was defined as resulting in 
permanent discontinuation
Section 7.1.2 Temporary 
discontinuation 
eGFR criterion for temporary 
discontinuation aligned with 
CONCORD study protocol.
Change necessary due to change in 
exclusion criterion 18 relative to eGFR.
Section 8.2.1 Physical 
examination 
Assessment of Neuropathy Disability 
score deleted from physical 
examination.
Non-core assessment deleted to reduce 
patient burden.  Furthermore, 
ophthalmologists often lack equipment 
and expertise to perform the assessment.
Section 8.2.3 
Electrocardiograms
Transfer of ECGs to Central reading 
center for QT-assessment to be 
decided later
Considering the change in overall 
development strategy, standardized QT 
assessment may not be performed. No 
risk for QT prolongation was identified for 
runcaciguat.
Section 9.2 Sample size 
determination
A clarification was added that the 
primary-endpoint assessment will 
include all patients from Part 1 and 
Part 2.  A combined total of 
approximately 98 patients are 
planned to be randomized in both 
parts.  The relative contribution of 
Part 1 and Part 2 to the combined 
total may vary.
The number of participants in Part 1 could 
deviate from the planned target of 18.  As 
the statistical analysis will be done on the 
combined total of participants in Part 1 
and 2, sample size calculations were not 
done separately for either subpart.
Section 9.4.6 Other Analysis
Change in urinary albumin/creatinine 
ratio (UACR) was deleted from the 
protocol.
UACR assessment, from the group of 
“other” endpoints, was deleted to reduce 
patient burden as it was considered as 
non-essential for the objective of this 
study in NPDR patients.


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Section # 
and Name
Description of Change
Brief Rationale
Section 9.5 Interim analysis
Interim analysis will be after 24 weeks 
of treatment with top-line efficacy and 
safety results over both parts.
Since the duration of the study has been 
shortened to 48 weeks, the Week 48 
analysis will be the final analysis, rather 
than the previously planned interim 
analysis.
Organizational changes, corrections, and clarifications
Section # 
and Name
Description of Change
Brief Rationale
Throughout
Description of the protocol package 
has been deleted, together with 
mentions to referring to Study Part 
B, Part B Study protocol, and Master 
protocol.
As of this amendment, Part B of the study 
has been removed. Late stage clinical 
development is not planned to be pursued 
with runcaciguat but with other sGC-
activator(s).
Former Part A now corresponds to the 
study as a whole. Therefore, for ease of 
readability, all applicable sections of 
Master protocol have been transferred to 
the current protocol. All mentions of Part 
B and Master protocol have been 
removed throughout the document. 
Terminology throughout the 
document
Part A.1 renamed Part 1, 
Part A.2 renamed Part 2.
With the deletion of Part B from the 
protocol, the term “Part A” was 
eliminated.
Section 1.3 Schedule of 
activities (SoA)
Dispensation of urine pregnancy test 
at Visits 13 and 14 was added.
Added as separate activity after deletion 
of on-site pregnancy test.
Section 4.1.1 
Part 1 – PK/PD 
Text changed to reflect the changes 
to the Schedule of Activities.
Alignment with changes to schedule of 
activities.  For details see changes to 
Section 1.3, above.
Section 4.2 Scientific rationale 
for study design
Mention of CONCORD data in 
addition to previously performed 
Phase 1 studies
Available masked CONCORD data 
support the planned use of runcaciguat in 
the NEON-NPDR study
Section 4.3 Justification for dose Reference to masked CONCORD 
data added and discussed in the 
context of dose-justification and 
titration regimen
The titration scheme in the NEON-NPDR 
is the same as in the CONCORD study. 
This titration scheme was well tolerated.  
Section 5 Study population
A clarification was added that 
participants should show typical 
fundus alterations as described in 
the DRSS criteria for moderately 
severe and severe NPDR without 
DME in need of treatment and no 
previous experience of anti-VEGF 
treatment.
To depict better the study population.
Section 5.6 Selection of the 
study eye 
Preference for choosing the eye 
without any sign of DME as study 
eye added.
To minimize risk of intermittent 
requirement of DME treatment.


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Section # 
and Name
Description of Change
Brief Rationale
Section 6.3 Measures to reduce 
bias
Re-dispensing of unopened and 
undamaged bottles to the same 
participant allowed. Sentence 
moved to section 6.4.
To avoid wasting of clinical trial supplies.
Section 6.4 more appropriate.
Section 6.8 Concomitant 
Therapy
sGC stimulator vericiguat added to 
list of prohibited medications.
Vericiguat obtained marketing approval. 
Section 8.1.1 Ophthalmology 
assessments 
Further clarification on archiving 
ophthalmology data on the site was 
provided.
Clarification 
Section 8.1.1.3 Fluorescein 
angiography 
All FA images will be archived. The 
method of archiving was deleted.   
Method of archiving left to the discretion 
of the investigational site.
Section 8.1.1.4 OCT
A reference was added to specify 
the use of CRT measured by central 
reading Centre in the context of the 
amended EC6.
Change necessary in the context of the 
amendment of EC 6.
Section 8.2.1 Physical 
examination
Clarification that height is measured 
only at screening was added.
Clarification
Section 8.2.3 
Electrocardiograms
The resting time before ECG 
recordings was reduced from 10 to 
5 minutes.
The resting time was aligned throughout 
the protocol and with vital sign 
assessments.  The 5-minute resting 
period is deemed sufficient for the 
purpose of ECG-assessments in this 
study.
Section 8.2.4 Clinical safety 
laboratory assessments
Section 10.2. Appendix 2: 
Clinical laboratory tests
eGFR calculation to be done by the 
central laboratory.
Paragraph on eGFR calculation 
deleted from Section 10.2 as 
unnecessary.
eGFR to be determined by central 
laboratory to allow real-time reporting of 
results which are used as a stopping 
criterion.
Section 8.4 Pharmacokinetics
Duration of PK sampling only until 
Visit 12.
Snap-shot interim analysis deleted. 
PK data will first be assessed at the 
24-week interim analysis.
Aligned with reduced treatment duration.
Aligned with new plans for interim 
analyses.
Section 8.4 Pharmacokinetics
Sentence “Non-compartmental PK 
parameters will not be evaluated in 
this study“ was deleted.
The sentence was deleted to allow 
greater flexibility and the possibility of 
exploratory analyses.
Section 9.5 Interim analysis
Interim analysis will be after 24 
weeks of treatment with top-line 
efficacy and safety results over both 
parts. Interim analysis for Part 1 
restricted to week 24 only.
Since the duration of the study has been 
shortened to 48 weeks, the Week 48 
analysis will be the final analysis, rather 
than the previously planned interim 
analysis.
Section 10.2 
Appendix 2: Clinical laboratory 
tests 
Two paragraphs explaining the 
possibility to perform additional 
laboratory tests were deleted as 
they were redundant with a third 
paragraph that remains. 
Deletion to avoid redundant text.
Redundant with paragraph in protocol 
Section 8.2.4


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In addition, minor editorial and formatting revisions, including clarifications of existing text, 
have been made throughout the document.
10.8.3
Amendment 2
Amendment 2 (13 JAN 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall rationale for the amendment: 
This amendment was implemented to accommodate requests by Competent Authorities and 
Independent Ethics Committees on the use of the smartphone app to support drug adherence. 
In addition, endpoint assessments were specified and additional endpoints included. 
A description of changes applicable to protocol part A and a brief rationale is outlined in the 
table below.
Section # 
and Name
Description of Change
Brief Rationale
Table 1-5
Section 8.2.3 
Electrocardiograms
Triplicate ECGs only recorded up to study 
Visit 6 (inclusive) of Part A.1
Triplicate ECG recordings to be done 
throughout the titration period only to 
support analyses of QT-time relative 
to exposure on visit days with 
extended duration.
Section 6.4 Study 
intervention compliance
Use of the smartphone app for supporting and 
tracking participant adherence to study drug 
intake was changed to be optional.
Competent Authority and Ethics 
Committee request
Section 8.1.1.1 Color 
fundus photography 
(CFP)
Additional exploratory efficacy endpoints based 
on color fundus photographs were added.
Potential additional explorative 
assessments to be disclosed. 
Section 8.1.1.5 Optical 
coherence tomography 
angiography (OCT-A)
The experimental nature of the software used to 
assess cross -sectional macular full depth line 
scans was indicated.
It was deemed appropriate to highlight 
the experimental nature of this OCT-A 
based image acquisition.
In addition, minor editorial and formatting revisions have been made throughout the 
document.
10.8.4
Amendment 1
Amendment 1 (23 NOV 2020)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 


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Overall rationale for the amendment:
This amendment was implemented to follow requests from the Bundesinstitut für Arzneimittel 
und Medizinprodukte (BfArM) and central Independent Ethics Committee (IEC). 
A description of changes applicable to protocol Part A and a brief rationale is outlined in the 
table below.
Section # and Name
Description of Change
Brief Rationale
Section 4.1.1
Part A1 – Run in
Section 10.1.5.4 Safety 
assessment group
Decisions made by safety assessment group will be 
reviewed by DMC.
Health authority request
Section 5.2 Exclusion 
criteria
Exclusion criterion 27 has been modified to include 
time period for prohibited medication
Health authority request
Section 5.2 Exclusion 
criteria
Exclusion criteria 28 and 29 have been modified to 
prohibit the use of nitrates, NO donors, PDE5 
inhibitors, non-specific PDE inhibitors and sGC 
stimulators within 1 week or less than 5 half-lives 
(whichever is longer) before first study drug 
administration 
Health authority request
Section 6.5.1  Intra-
individual dose-titration 
decisions
Investigator should reduce the dose instead of 
maintaining it in cases of serious or severe AEs 
related to runcaciguat, or in cases of relevant 
hypotension (e.g. symptoms of hypotension in 
combination with either SBP < 90 mmHg or SBP 
decrease by >30 mmHg or both)
Health authority request
Section 6.5.2 
Stopping rules (study 
level)
Safety findings observed by DMC which preclude
indicate unacceptable pharmacological effects, 
reasonably attributable to runcaciguat [result in an 
immediate stop of dosing and will result in a temporary 
halt of the study]
Correction of obvious mistake
Section 7.1.1 
Permanent 
discontinuation
Modification of discontinuation criteria:
participants must be withdrawn from study intervention 
on all cases of repeated incidents of relevant 
hypotension or tachycardia, and in cases of safety 
concerns for a participant by the investigator or the 
sponsor
Health authority request
Section 8.1.2 
Vision threatening 
complications
Treatment of the vision threatening complication 
should follow local standards and guidelines.
Health authority scientific 
advice recommendation
Section 8.2.5 Pregnancy 
testing
Urine pregnancy testing was corrected to be done 
locally, serum pregnancy test is done centrally.
Non-substantial correction


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Section # and Name
Description of Change
Brief Rationale
Section 8.5 Genetics
Section 8.6 Biomarkers
More detailed description of the genetic testing was 
included
Ethics Committee request 
Section 10.1.5.4 Safety 
assessment group
Addition that the decision by the safety assessment 
group will be reviewed by the DMC based on an 
unmasked safety review.
Health authority request
Section 10.1.5.1 
Central reading centers
The digital retinal images OCT scans, fluorescence 
angiographies, and ECG print-outs will be assessed by 
independent central reading centers
Correction of obvious mistake 
in protocol as to examinations 
to be provided to central 
reading centers, in accordance 
with existing language in 
protocol Sections 8.1.1.1, 
8.1.1.3, 8.1.1.4, 8.1.1.5.
Section 10.2 
Appendix 2: Clinical 
laboratory tests
Missing serum pregnancy test was added
Non-substantial correction
In addition, minor editorial and formatting revisions have been made throughout the 
document.
11.
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SAP_003.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A Phase 2 randomized, placebo-controlled, double-masked proof-
of-concept study to investigate the efficacy and safety of 
runcaciguat (BAY 1101042) in patients with moderately severe to 
severe non-proliferative diabetic retinopathy 
NCT Number: 
NCT04722991 
Document Date: 
03-May-2024 
 


CONFIDENTIAL 
Statistical Analysis Plan 
BAY 1101042 / 20739 
 
Version 3.0 
Page:  1 of 35 
 
 
Title Page 
Protocol Title: A Phase 2 randomized, placebo-controlled, double-masked proof-of-concept 
study to investigate the efficacy and safety of runcaciguat (BAY 1101042) in patients with 
moderately severe to severe non-proliferative diabetic retinopathy 
Protocol Number: 20739 
Compound Number: BAY 1101042 / Runcaciguat 
Short Title: Non-proliferative diabetic retinopathy treated with runcaciguat 
Acronym: NEON-NPDR 
Sponsor Name: Non-US: Bayer AG 
US territory: Bayer HealthCare Pharmaceuticals Inc. 
Legal Registered Address: Non-US: 51368 Leverkusen, Germany 
US territory: 100 Bayer Boulevard, P.O. Box 915, Whippany NJ 07981-0915, USA 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
(p)IND 
149136 
EudraCT 
2020-002333-15 
 
 
 
Date: 03 MAY 2024 
Version: 3.0 
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate signature document. 
 


CONFIDENTIAL 
Statistical Analysis Plan 
BAY 1101042 / 20739 
 
Version 3.0 
Page:  2 of 35 
 
 
Table of Contents 
Title Page ............................................................................................................................... 1 
Table of Contents ................................................................................................................. 2 
Table of text tables ............................................................................................................... 3 
Table of text figures .............................................................................................................. 3 
Version History ..................................................................................................................... 4 
List of Abbreviations and Definitions of Terms ................................................................ 5 
1. 
Introduction ................................................................................................................... 7 
1.1 
Objectives and Endpoints ............................................................................................ 8 
1.2 
Study Design .............................................................................................................. 11 
2. 
Statistical Hypotheses ................................................................................................. 13 
2.1 
Multiplicity Adjustment ............................................................................................. 13 
3. 
Analysis Sets ................................................................................................................ 13 
4. 
Statistical Analyses ...................................................................................................... 14 
4.1 
General Considerations .............................................................................................. 14 
4.1.1 
General Principles................................................................................................... 14 
4.1.2 
End of Treatment .................................................................................................... 14 
4.1.3 
Missing Data ........................................................................................................... 14 
4.1.4 
Discontinuations ..................................................................................................... 15 
4.1.5 
Adverse events ........................................................................................................ 16 
4.1.6 
Medical history ....................................................................................................... 16 
4.1.7 
Prior and concomitant medication .......................................................................... 17 
4.1.8 
Laboratory and Biomarker values .......................................................................... 17 
4.1.9 
Data Rules .............................................................................................................. 18 
4.2 
Primary Endpoint Analysis ........................................................................................ 18 
4.2.1 
Definition of Endpoint ............................................................................................ 18 
4.2.2 
Main Analytical Approach ..................................................................................... 18 
4.2.3 
Sensitivity Analysis ................................................................................................ 20 
4.2.4 
Subgroup Analyses ................................................................................................. 20 
4.2.5 
Descriptive Analysis ............................................................................................... 21 
4.3 
Secondary Endpoint Analysis .................................................................................... 21 
4.3.1 
Secondary Endpoints .............................................................................................. 21 
4.3.2 
Subgroup Analyses ................................................................................................. 23 
4.3.3 
Supportive Secondary Endpoints ........................................................................... 23 
4.4 
Other Endpoint Analysis ............................................................................................ 23 
4.4.1 
Best corrected visual acuity .................................................................................... 23 
4.4.2 
Fluorescein angiography......................................................................................... 23 
4.4.3 
Optical coherence tomography and OCT-angiography .......................................... 23 
4.4.4 
Slit lamp biomicroscopy (anterior and posterior segment) .................................... 24 
4.4.5 
Tonometry (intraocular pressure measurement) ..................................................... 24 
4.5 
Other Safety Analyses ............................................................................................... 24 
4.5.1 
Treatment Compliance, Duration and Exposure .................................................... 25 
4.5.2 
Adverse Events ....................................................................................................... 25 
4.5.3 
Laboratory assessments .......................................................................................... 26 


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4.5.4 
eGFR ....................................................................................................................... 27 
4.5.5 
Vital signs ............................................................................................................... 27 
4.5.6 
Additional Safety Assessments .............................................................................. 28 
4.6 
Other Analyses ........................................................................................................... 28 
4.6.1 
Pharmacokinetics .................................................................................................... 28 
4.6.2 
PK/PD by groups and by dose level maintained at least for 50% of the study ...... 29 
4.6.3 
Biomarkers ............................................................................................................. 29 
4.7 
Interim Analyses ........................................................................................................ 31 
4.7.1 
Data Monitoring Committee ................................................................................... 31 
4.8 
Changes to Protocol-planned Analyses ..................................................................... 31 
5. 
Sample Size Determination ........................................................................................ 31 
6. 
Supporting Documentation ........................................................................................ 32 
6.1 
Appendix 1: Participant disposition ........................................................................... 32 
6.2 
Appendix 2: Baseline characteristics and demographics ........................................... 33 
6.3 
Appendix 3: Protocol deviations ................................................................................ 33 
6.4 
Appendix 4: Medical history ..................................................................................... 34 
6.5 
Appendix 5: Prior and concomitant medication ........................................................ 34 
6.6 
Appendix 6: ETDRS final retinopathy severity scales .............................................. 34 
7. 
References .................................................................................................................... 35 
 
Table of text tables 
Table 1-1: Study objectives and endpoints ................................................................................ 8 
Table 1-2: Overall study plan ................................................................................................... 11 
Table 3-1: Analysis sets ........................................................................................................... 13 
Table 4-1: Formula for eGFR calculation ................................................................................ 27 
Table 5-1: Planned sample size ................................................................................................ 32 
Table 6-1: ETDRS final retinopathy severity scale for individual eyes .................................. 34 
Table 6-2: Abbreviated Summary of ETDRS final retinopathy severity scale for persons ..... 35 
 
Table of text figures 
Figure 1-1: Schematic study design ......................................................................................... 12 
 


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Version History 
This Statistical Analysis Plan (SAP) for study 20739 is based on the clinical study protocol 
(CSP) (Version 5.0, Amendment number 4, dated 09 FEB 2023). 
 
SAP 
Version 
Date 
Section 
Change 
Rationale 
1.0 
31 AUG 2023 Not applicable Not applicable 
Original version 
2.0 
17 NOV 2023 1.1 Objectives 
and Endpoints 
4.2.2 Main 
Analytical 
Approach 
The estimands 
framework was added for 
objectives and endpoints 
related to the DRSS. 
To make the best use of all available 
data, including data from 
participants who discontinue the 
study early, the estimands 
framework was applied to the DRSS 
endpoints. 
4.3.1 
Secondary 
Endpoints 
The scale for DRSS 
across both eyes was 
changed to the for 
persons scale and the 
analysis was adapted 
accordingly. 
Based on feedback from HAs the 
primary endpoint for Phase III 
studies in NPDR will be the DRSS 
for persons scale (see Section 6.6). 
Accordingly, the DRSS endpoints 
across both eyes was adapted to 
gain insights and allow 
comparability. 
1.1 Objectives 
and Endpoints 
4.6.3 
Biomarkers 
The list of biomarker 
endpoints was adapted, 
and more comprehensive 
analyses of biomarkers 
were added. 
The study team decided to include 
the analysis of biomarkers within the 
CSR, and not write a separate BER. 
Furthermore, see Section 4.8. 
Further 
sections 
Other minor corrections 
(e.g., typos) not affecting 
the final analysis. 
3.0 
03 MAY 2024 4.3.2 Subgroup 
Analyses 
Definition of an additional 
subgroup 
An improvement from PDR to NPDR 
is extremely unlikely. The subgroup 
was defined to only include 
participants without PDR at 
baseline. 
Further 
sections 
Minor corrections and 
additions 
 


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List of Abbreviations and Definitions of Terms 
ACIR 
Assessment criteria and identification requirements 
AE(s) 
Adverse event(s) 
AESI(s) 
Adverse event(s) of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BCVA 
Best corrected visual acuity 
BM 
Biomarker 
BMI 
Body mass index 
CEC 
Clinical endpoint committee 
CFP 
Color fundus photography 
CI 
Confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COVID-19 
Coronavirus disease of 2019 
CRF 
Case report form 
CRT 
Central retinal thickness 
CSP 
Clinical study protocol 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
DMC 
Data Monitoring Committee  
DME 
Diabetic macular edema 
dpt 
Diopter 
DR 
Diabetic retinopathy 
DRSS 
Diabetic Retinopathy Severity Scale 
EC 
Ethics committee 
ECG(s) 
Electrocardiogram(s) 
eCRF 
Electronic case report form 
(e)GFR 
(Estimated) glomerular filtration rate 
EoS 
End of study 
EoT 
End of treatment 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein angiography 
FAS 
Full analysis set 
HbA1c 
Hemoglobin A1c (glycated hemoglobin) 
HDL 
High density lipoprotein 
HLGT 
High-level group term 
ICF 
Informed consent form 
INR 
International normalized ratio 


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IQR 
Interquartile range 
IRB 
Institutional review board 
LDL 
Low density lipoprotein 
LLOQ 
Lower limit of quantification 
LOCF 
Last observation carried forward 
MedDRA 
Medical dictionary for regulatory activities 
MH 
Medical history 
NPDR 
Non-proliferative diabetic retinopathy 
OCT 
Optical coherence tomography 
OCT-A 
Optical coherence tomography angiography 
PD 
Pharmacodynamics 
PDR 
Proliferative diabetic retinopathy 
PK 
Pharmacokinetics 
PKS 
Pharmacokinetic analysis set 
PoC 
Proof-of concept 
Pop-PK 
Population pharmacokinetics 
PPS 
Per protocol set 
PT 
Preferred term 
QD 
Quaque die, daily 
SAC 
Statistical analysis center 
SAE(s) 
Serious adverse event(s) 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical analysis system 
SBP 
Systolic blood pressure 
SCr 
Serum creatinine 
SD 
Standard deviation 
sGC 
Soluble guanylyl cyclase 
SoA 
Schedule of activities 
SOC 
System organ class 
TEAE(s) 
Treatment emergent adverse event(s) 
TLF specification Table, listing and figure specification 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
VTC 
Vision threatening complications 
WHO-DD 
World Health Organization Drug Dictionary 
 


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1. 
Introduction 
Runcaciguat (BAY 1101042) is a sGC activator that improved function and retinal structure 
in pre-clinical DR models. 
This PoC study includes a subpart with PK/PD assessments (Part 1). Part 1 enrolls a subset of 
patients at a more intense investigation in specific study sites. Part 2 is the main PoC part, to 
be conducted in ophthalmology sites, that enrolls the majority of participants. PoC will be 
based on the evaluation of outcomes in participants from both parts, which will be running in 
parallel. 
The present study is to be conducted to obtain information on sGC activators by investigating  
1. whether runcaciguat improves the diabetic retinopathy score in patients with 
moderately severe to severe NPDR 
and to 
2. explore the PK/PD relationship of runcaciguat on retinal perfusion 
This SAP describes the final analysis of the study. No statistical interim analysis will be 
performed. TLF specifications are contained in a separate document. The analysis of Pop-PK 
data will not be described here but will be done in a separate analysis plan. 
 


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1.1 
Objectives and Endpoints 
The objectives and endpoints are summarized in Table 1-1. 
Table 1-1: Study objectives and endpoints 
Objectives 
Endpoints 
Primary objective:  Efficacy 
Establish the PoC for the efficacy of the 
sGC activator runcaciguat in the treatment 
of NPDR. 
Primary endpoint: 
• DRSS improvement ≥ 2 steps at 48 weeks of treatment in the 
study eye 
Secondary endpoints for primary objective: 
• VTC at 48 weeks of treatment in the study eye 
• DRSS improvement ≥ 2 steps at 24 weeks of treatment in the 
study eye 
• DRSS improvement ≥ 3 steps at 48 weeks of treatment on the 
scale for persons 
Other endpoints (for primary objective): 
• DRSS worsening of ≥ 3 steps at 48 weeks of treatment in the 
study eye 
• Change in visual acuity from baseline 
• Change in leakage area on FA 
• DRSS changes from baseline in the study and fellow eye 
• VTC in any eye up to 48 weeks of treatment 
Secondary objective:  Safety 
Investigate the safety and tolerability of 
runcaciguat in patients with NPDR 
Secondary endpoints for secondary objective: 
• 
Frequency of TEAEs 
Other endpoints (for secondary objective): 
• Laboratory parameters 
• Vital signs 
• Electrocardiography 
Other objectives 
Characterize PD effects of runcaciguat in 
patients with NPDR 
Other endpoints 
• Central retinal thickness 
• HbA1c 
• Other biomarkers 
Characterize PK of runcaciguat in patients 
with NPDR 
• Pop-PK 
• Pre-dose (trough) plasma concentrations of runcaciguat by visit 
Further investigate the study intervention 
and similar drugs (e.g., mode-of-action 
related effects, safety) and to further 
investigate pathomechanisms deemed 
relevant to NPDR, (cardio)vascular 
diseases and associated health problems 
• 
Various biomarkers (e.g., diagnostic, safety, PD, monitoring, or 
potentially predictive biomarkers) 
 


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The primary estimand (analysis on PPS) is defined below: 
Primary Objective: See above. 
Estimand label: primary 
Endpoint: 
All DRSS derived efficacy endpoints 
Population: 
Adult patients with 
• 
moderately severe to severe NPDR in the study eye (DRSS levels 47 or 53) 
• 
Diabetes type 1 or 2 
• 
BCVA ETDRS letter score in the study eye of ≥ 69 letters (approximate Snellen equivalent of 20/40 or 
better) 
• 
Refraction with a spherical equivalent from -6 dpt to +5 dpt 
Additionally, subpopulations as defined in Section 4.2.3 will be used for the analysis. 
Treatment condition: 
Runcaciguat vs. placebo 
Population level summary: 
The estimated difference in the proportion of responders between interventions. 
Intercurrent events: 
• 
Dropout due to a VTC in the study eye: 
composite variable strategy (analyze study participant as non-responder) 
• 
Dropout … 
… before Visit 9 (week 12) 
composite variable strategy (analyze study participant as non-responder) 
… after Visit 9 (week 12) with EoT DRSS assessment performed within 4 weeks of treatment 
discontinuation 
while on treatment strategy (use the last available DRSS assessment (LOCF) 
… after Visit 9 (week 12) with EoT DRSS assessment performed more than 4 weeks after treatment 
discontinuation 
while on treatment strategy (use the last available DRSS assessment prior to treatment 
discontinuation (LOCF)) 
• 
Non-compliance with study intervention, defined as actual drug intake lower than 80% or higher 
than 120% of the planned drug intake per protocol: 
principal stratum strategy (exclusion from analysis, as an adequate imputation of response 
information is considered not possible) 
The secondary estimand (analysis on FAS) is identical to the primary estimand (analysis on 
PPS) with the exception that the condition relating to compliance is not included. 


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The other estimand (analysis on PPS) is defined below: 
Primary Objective: See above. 
Estimand label: other 
Endpoint: 
DRSS improvement ≥ 2 steps at 48 weeks of treatment in the study eye 
Population: 
Adult patients with 
• 
moderately severe to severe NPDR in the study eye (DRSS levels 47 or 53) 
• 
Diabetes type 1 or 2 
• 
BCVA ETDRS letter score in the study eye of ≥ 69 letters (approximate Snellen equivalent of 20/40 or 
better) 
• 
Refraction with a spherical equivalent from -6 dpt to +5 dpt 
Treatment condition: 
Runcaciguat vs. placebo 
Population level summary: 
The estimated difference in the proportion of responders between interventions. 
Intercurrent events: 
• 
Dropout due to a VTC in the study eye: 
composite variable strategy (analyze study participant as non-responder) 
• 
Missing DRSS assessment on Visit 15 (week 48) due to early discontinuation: 
hypothetical strategy (multiple imputations will be performed for the responder criterium) 
• 
Non-compliance with study intervention, defined as actual drug intake lower than 80% or higher 
than 120% of the planned drug intake per protocol: 
principal stratum strategy (exclusion from analysis, as an adequate imputation of response 
information is considered not possible) 
 


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1.2 
Study Design 
This is a randomized, double-masked parallel study with two study arms enrolling N=98 
patients with NPDR. The study is conducted as a placebo-controlled study. Total treatment 
duration is 48 weeks. The primary endpoint will be the number of participants with a ≥ 2-step 
improvement (reduction) in the DRSS after 48 weeks of treatment in the study eye. 
A steering committee consisting of ophthalmologists and diabetologists (masked) is put in 
place to provide scientific and operational recommendations to the study protocol and may be 
consulted to support decisions in study conduct. An independent DMC is set up to provide 
recommendations based on unmasked review of data, if needed (see section 4.7.1). 
This Phase 2 study is conducted to determine whether runcaciguat, administered at once daily 
oral doses of a modified-release formulation, is more effective in treating NPDR than placebo.  
The study is subdivided into two components, as shown in Table 1-2. Part 1 is conducted to 
provide data for PK/PD analyses in diabetic patients with NPDR and to explore the value of 
different OCT-A assessments as PD marker in DR. Part 2 is the main part of this PoC study 
and will be conducted in parallel. Both components follow a similar design – except for the 
randomization ratio and additional examinations in Part 1. Both study subparts will be 
evaluated together, to the extent that common data are available and at the same time. 
Table 1-2: Overall study plan 
Study part 
Main purpose 
Overall design 
Part 1 
PK/PD 
PK/PD assessment 
Placebo-controlled, double-masked, 2-arm parallel-group design 
with 2:1 randomization.  Total n = 18 
Intra-individual weekly dose escalation in 30-mg increments up to 
120 mg once daily.   
Each participant will continue treatment at the individual maximum 
dose for a total treatment duration of 48 weeks. 
Part 2 
PoC 
Demonstration of PoC 
based on efficacy 
outcome after 48 weeks 
of treatment 
Placebo-controlled, double-masked, 2-arm parallel-group design 
with 1:1 randomization.  n = 40 per treatment arm 
Intra-individual weekly dose escalation in 30-mg increments up to 
120 mg once daily. 
Each participant will continue treatment at the individual maximum 
dose for a total treatment duration of 48 weeks. 
In Part 1, the randomized participants will be titrated at weekly visits in 30-mg increments to 
the target dose of 120 mg QD, or the maximum individually tolerated dose. After the titration 
period, the individually reached highest dose will be maintained until the EoT, for the total 
treatment duration of 48 weeks, followed by a 4-week safety follow-up period. A total of 18 
participants are planned to be randomized into Part 1 (12 active; 6 placebo). A schematic 
study design for Part 1 is provided in Figure 1-1. 
In Part 1, additional safety, PK and PD investigations will be performed during the titration 
phase. On Visits 2 to 6, participants will remain at sites for 4 hours post-dose.  During this 
time, the pulse rate and the blood pressure will be checked, and OCT-A will be used to assess 
retinal perfusion as PD markers. Blood samples will be drawn for Pop-PK and for PK/PD 
analyses pre-dose and in two post-dose windows. 
Recruitment, screening, and randomization of participants for Part 2 of the study is 
independent from Part 1. Part 2 of the study is planned to follow the same titration and dosing 
scheme as Part 1. In Part 2, the participants will be randomized to either placebo (n = 40) or 
runcaciguat (n = 40).  The participants are planned to be titrated at 30-mg increments to the 


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maximum tolerated dose or sham titrated. Each participant will continue treatment for a total 
treatment duration of 48 weeks, followed by a 4-week follow-up period. 
Figure 1-1: Schematic study design 
Placebo (Part 1 n = 6;  Part 2 n = 40)
Runcaciguat (Part 1 n = 12;  Part 2 n = 40)
Screening
Study treatment
total of 48 weeks
Follow up
4 weeks
         
Randomization
Last 
protocol-
stipulated 
procedure
Titration
4 weeks
30 mg
60 mg
90 mg
120 mg
End of 
titration
48 weeks
Primary 
endpoint
 
To assess the efficacy, the retinal morphology will be investigated by 7-field CFP supported 
by 7-field FA images for the assessment of the DRSS by a central reading center. Two-step 
DRSS improvement at 48 weeks of treatment will be the primary efficacy endpoint. 
Additional DRSS assessments are done after 12 and 24 weeks of treatment. In addition, VTC 
will be recorded throughout the study and assessed as secondary efficacy endpoint. 
During the study, 16 visits are planned, including the screening visit (Visit 1) and the end-of-
study visit (Visit 16). For the SoA refer to Section 1.3 of the clinical study protocol. 
Participants are randomly assigned to one of two study arms. Randomization will be done 
stratified by baseline DRSS (47 or 53). A combined total of approximately 98 participants for 
Part 1 and 2 will be randomly assigned for an estimated total of ≥ 40 participants per 
intervention group evaluable for primary endpoint assessment. 
During the initial 4 weeks, treatment will be titrated to the target dose of 120 mg runcaciguat 
or matching placebo. Treatment will continue at the highest tolerated dose until completion of 
48 weeks of treatment if tolerated, or until development of a VTC or development of PDR. 
An EoS visit will be performed 4 weeks after EoT. This includes both participants who 
complete the planned treatment period, and participants who discontinue treatment early 
including treatment discontinuation due to VTC. 
The study population is characterized by the following main inclusion criteria: 
• Age ≥ 18 years 
• Moderately severe to severe NPDR in the study eye: DRSS levels 47 or 53 
• Diabetes type 1 or 2 


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• BCVA ETDRS letter score in the study eye of ≥ 69 letters (approximate Snellen 
equivalent of 20/40 or better) 
• Refraction with a spherical equivalent from -6 dpt to +5 dpt 
2. 
Statistical Hypotheses 
The primary endpoint is the proportion of patients with “≥ 2-step improvement in DRSS at 48 
weeks of treatment in the study eye”. This proportion will be denoted as 𝜋𝐴𝐶𝑇 within the 
runcaciguat treatment arm and as 𝜋𝑃𝐿𝐶within the placebo treatment arm. 
The study will be evaluated using a Bayesian approach with non-informative prior 
distribution. Using this approach for inference it is possible to base decisions directly on the 
posterior probabilities of the hypotheses of interest. Therefore, in a Bayesian setting it is not 
necessary to specify an alternative hypothesis. 
The hypotheses of interest are the following: 
• Hypothesis of clinical activity: 𝜋𝐴𝐶𝑇 > 𝜋𝑃𝐿𝐶 
• Hypothesis of clinical relevance: 𝜋𝐴𝐶𝑇 > 0.25 
2.1 
Multiplicity Adjustment 
Not applicable. 
3. 
Analysis Sets 
Final decisions regarding the assignment of participants to analysis sets will be made during 
the review of study data and documented in the final list of important deviations, validity 
findings and assignment to analysis sets. 
For the purposes of analysis, the following analysis sets are defined in Table 3-1. The same 
definitions apply for Part 1 and Part 2. 
Table 3-1: Analysis sets 
Participant analysis set 
Assignment rule 
Full analysis set (FAS) 
All participants of the respective study part randomized to treatment who fulfilled 
in/exclusion criteria. 
Per protocol set (PPS) 
All FAS participants of the respective study part without validity findings. 
Pharmacokinetic analysis 
set (PKS) 
All participants of the respective study part with PK information not affected by 
relevant validity findings and with at least one valid post-dose plasma concentration. 
Safety analysis set (SAF) All participants of the respective study part who took at least one dose of study 
intervention. 
It is planned to pool the data of participants from Part 1 and Part 2 for analysis, without 
further stratification by analysis parts, considering that selection criteria and recruitment time 
periods were identical and all study procedures in Part 2 were performed also in participants 
enrolled in Part 1. Participants will be analyzed by their actual treatment to which they were 
treated for most of the time (i.e., placebo or runcaciguat, irrespective of the planned dose they 
were planned to be titrated to). 
The detailed definitions of validity findings and the assignment of participants to the analysis 
sets will be based on the ACIR document. 


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4. 
Statistical Analyses 
4.1 
General Considerations 
4.1.1 
General Principles 
The SAP will be finalized prior to unmasking. 
The statistical evaluation will be performed by using the software SAS (release 9.4 or higher; 
SAS Institute Inc., Cary, NC, USA) and R (version 3.5.2 or higher; R Foundation for 
Statistical Computing, Vienna, Austria). 
All data will be listed and summarized in tables. Graphical illustrations will be provided by 
treatment group (runcaciguat, placebo) where appropriate. Summary statistics will be 
presented for the participants treated with runcaciguat and for the participants treated with 
placebo. Descriptive statistics by visit will be provided for the original data as well as for 
change from baseline, where applicable. Additional summary statistics per dose of 
runcaciguat administered will be presented, where meaningful. Doses may be grouped to 
reach more meaningful sample sizes. Frequency tables will be provided for qualitative data. 
Continuous variables assumed to be normally distributed will be summarized using the 
number of participants, mean, standard deviation, minimum, lower quartile, median, upper 
quartile and maximum. The geometric mean and SD will be provided additionally for the 
variables where log-normal distributions are assumed. 
Generally, data will be analyzed comparing the two intervention groups against each other. 
Furthermore, for the runcaciguat treatment group, summary statistics by visit for continuous 
variables will be further broken down by the actual maintenance dose level, i.e., the dose level 
reached after the end of the titration phase (at Visit 6) (in case a sufficient number of patients 
pertains to this dose level). 
Data from unscheduled measurements will be listed, but not included in summary statistics or 
frequency tables. 
Listings will be provided sorted by treatment group (runcaciguat, placebo), DRSS at baseline 
(47, 53) and participant identifier. 
Baseline is defined as the last pre-dose assessment before first study intervention. 
4.1.2 
End of Treatment 
Beside the Visit 15 EoT, the EoT values will also be derived to account for eCRF entry errors. 
The EoT value is the value of the visit at the last treatment day. In case no visit occurred at the 
last treatment day, the EoT value is the value of the first visit after last treatment. 
4.1.3 
Missing Data 
For handling of missing data for the primary efficacy endpoint, see Section 5.3.2. 
Statistical analysis will be based on the available data. Analysis will be performed considering 
all valid data observed for the respective analysis sets. All missing or partial data will be 
presented in the subject data listing as they are recorded on the CRF. 
Date of first dose of study intervention is defined as the date of first dose from the appropriate 
CRF page capturing the study intervention (runcaciguat or placebo) if this date is complete. 
Date of last dose of study intervention is defined as the date of last dose from the appropriate 


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CRF page capturing the study intervention if this date is complete. If the first and the last dose 
dates are missing or incomplete, we will consider the following scenarios for imputation of 
missing dates: 
First dose date is missing or incomplete 
Imputation rule 
Only day of first dose date is missing 
Impute the first dose date as maximum of the 
date of randomization and first day of month. 
Month and day of first dose date are missing 
Impute the first dose date as randomization 
date. 
First dose date is completely missing but last 
dose date is available 
Impute the first dose date as randomization date 
but no later than the date of last dose. 
First dose date and last dose date are missing 
Impute the first dose date as randomization date 
if tablet boxes were dispensed and if these 
tablet boxes were not returned unused. 
Last dose date is missing or incomplete 
Imputation rule 
Only day of last dose date is missing 
1. Impute the last dose date using last day of 
the month. 
2. Derive last dose date as minimum of 
(imputed last dose date, the date of death, 
the last visit date before follow-up) but no 
earlier than the date of first dose. 
Month and day of last dose date is missing 
1. Impute the last dose date using last day of 
the year. 
2. Derive last dose date as minimum of 
(imputed last dose date, the date of death, 
the last visit date before follow-up) but no 
earlier than the date of first dose. 
Last dose date is completely missing but first 
dose date is available or can be imputed 
Impute last dose date as minimum of (the date 
of death, or the last visit date) but no earlier than 
the date of first dose. 
4.1.4 
Discontinuations 
Participants who discontinue the study prematurely (i.e., dropout) will not be replaced. A 
temporary discontinuation exceeding 14 consecutive days or 21 days overall results in a 
permanent discontinuation. If unexpectedly high dropout rates occur (e.g., due to COVID-19), 
the number of randomized participants may be increased by up to 20%. For further details 
with respect to the analysis of dropouts refer to the Section 4.1.3 on handling of Missing Data. 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This includes cases where, in the investigator's opinion, continued 
participation in the study would be harmful to the participant's well-being. This is expected to 
be uncommon. At the time of discontinuing from the study, if possible (if the participant is 
not lost to follow-up and if the health status of the participant allows), Visit 15 should be 
conducted as early discontinuation visit, followed by safety follow-up (Visit 16). Data 
collected at early discontinuation visits will be handled as follows: If a valid DRSS 
assessment is available from the early discontinuation visit, this value will be considered for 
analyses for the respective visit. Other variables assessed at early discontinuation visits will 
be listed for individual follow-up but not be considered for summary statistics. 
Participants who permanently discontinue study treatment are invited to continue to attend all 
protocol-specified study visits. Values assessed at visits after discontinuation from study 
treatment will be listed for individual follow-up but not be considered for summary statistics. 
All values assessed after study treatment discontinuation will be flagged in the listings. 


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4.1.5 
Adverse events 
For the purpose of date imputation, the treatment follow-up period date is defined as the last 
available visit date including unscheduled visits after the EoS visit. 
If the start or stop time of the AE is missing completely, the duration of the AE will be 
calculated based on the start and stop date. If only the start or stop minutes are missing, the 
duration will be calculated based on the dates and hours. If the start date is partially missing, 
the first day of that month will be used when only the day is missing. If the stop date is 
partially missing, the last day of the month will be used when only the day is missing. If both 
the day and the month are missing, the date will be missing. 
Imputed dates will only be used for summary tables. Listings will contain the original entries. 
TEAEs are AEs that occurred after first dosing and existing pre-dose AEs that worsened in 
severity post-dose during the main treatment period until 28 days after the last dose of the 
study drug. 
To determine if an AE is treatment-emergent the following rules will be applied considering a 
worst-case scenario: 
• If the date and time of AE start are completely missing, the AE will be considered as 
treatment-emergent unless the stop date and time suggest otherwise 
• If the time of AE start is missing, but the start date (day, month, and year) of the AE is 
known, the AE will be considered as treatment-emergent if the AE start date is 
between the date of treatment start and the date of treatment end plus 28 days (both 
included), unless the stop date and time of the AE (or other information) suggest 
otherwise 
• If the time and day of AE start are missing, but the month and year is known, the AE 
will be considered as treatment-emergent if the month of AE start is between the 
month of treatment start and the month of treatment end date plus 28 days (both 
included), unless the stop date and time of the AE (or other information) suggest 
otherwise 
• If the time, day, and month of AE start are missing, but the year is known, the AE will 
be considered as treatment-emergent if the year of AE start is between the year of 
treatment start and the year of treatment end date plus 28 days (both included), unless 
the stop date and time (or other information) suggest otherwise. 
4.1.6 
Medical history 
Completely or partially missing end dates will not be imputed. For imputation of missing 
diagnosis date, the following rules will be applied: 
 


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MH start date 
Imputation rule 
Only the day is missing 
Impute the date as minimum of first day of the 
month and treatment start date - 1 
Month and day are missing  
Impute the date as minimum of July 1st of the 
year and treatment start date - 1 
Start date is completely missing but parts of the 
stop date are available, or medication is ticked 
as ongoing 
Impute the start date as minimum of (July 1st of 
the year of the initial visit and the treatment start 
date - 1) 
4.1.7 
Prior and concomitant medication 
Generally, partially missing prior and concomitant medication start dates will be set to the 
earliest logically possible date. Partially missing stop dates will be set to the latest logically 
possible date. For prior and concomitant medication, the following imputation rules will be 
applied: 
Start of medication is missing 
Imputation rule 
Only the day is missing 
Impute the date as first day of the month. 
Month and day are missing  
Impute the date as January 1st of the year. 
Start date is complete missing but parts of the 
stop date are available, or medication is ticked 
as ongoing 
Impute the start date as minimum of (January 1st 
of the year of the initial visit and the previous or 
concomitant medication stop date), since 
information is available that the patient took 
previous or concomitant medication, and it can 
be assumed the patient was on medication 
already at study start. 
Stop of medication is missing 
Imputation rule 
Only the day is missing 
Impute the date as minimum of date of death, 
date of last contact and day of incomplete date 
replaced by last day of the month. 
Month and day are missing 
Impute the date as the minimum of date of 
death, date of last contact and day and month of 
incomplete date replaced by December 31st. 
Stop date is complete missing but medication is 
ticked as ongoing 
Impute the date as the minimum of date of death 
and date of last visit. 
4.1.8 
Laboratory and Biomarker values 
Regarding the imputation of PK concentrations below the LLOQ see Section 4.6.1. 
Descriptive statistics at any time will only be calculated if at least 2/3 of the individual data 
were measured and were above the LLOQ and below the ULOQ. For the calculation of 
descriptive statistics, a data point below LLOQ will be substituted by one half of this limit, a 
data point above ULOQ will be substituted by ULOQ. 
In tables showing descriptive statistics, where values below LLOQ or above ULOQ are 
included, these statistics will be marked. Differences (i.e., changes from baseline) will not be 
calculated if both measurements are substituted. 
Values incorporated as ‘< x’ into the database will be substituted by x/2, values incorporated 
as ‘> y’ will be substituted by y itself for calculation of summary statistics. 
In case that more than one normal range is available for a laboratory parameter, all normal 
ranges will be provided in the tables and the widest normal range will be displayed in the 
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If not stated otherwise, summary statistics (minimum and maximum excluded) (and figures) 
focused on mean values will be provided if evaluable data of ≥ 3 participants are available. 
Minimum and maximum will be provided if at least one evaluable data point exists. 
4.1.9 
Data Rules 
Summary statistics of continuous variables assumed as normally distributed will be provided 
including absolute changes from baseline as described in Section 4.1.1. Absolute changes 
from baseline will be calculated as post-dose value minus baseline value unless noted 
otherwise. In case of continuous variables assumed to be log-normally distributed summary 
statistics will comprise relative changes from baseline. Relative changes from baseline will be 
calculated as post-dose divided by baseline value unless noted otherwise. Baseline is defined 
as the last pre-dose assessment before first study intervention. 
In case of replicate measurements for one visit mean values of the unrounded original values 
will be calculated by participant and visit. Summary statistics of these mean values will be 
provided. 
Box plots will be displayed with whiskers of 1.5 times the interquartile range (i.e., third 
quartile minus first quartile) above the third quartile, and a distance of 1.5 times the 
interquartile range below the first quartile. All data points above or below the whiskers will be 
printed separately. 
4.2 
Primary Endpoint Analysis 
4.2.1 
Definition of Endpoint 
The primary endpoint is ‘≥ 2-step improvement in DRSS at 48 weeks of treatment in the 
study eye’.  
The proportion of patients with ‘≥ 2-step improvement’ will be denoted as πACT within the 
runcaciguat treatment arm and as πPLC within the placebo treatment arm. 
To assess the efficacy, the retinal morphology will be investigated by 7-field CFP used for 
assessment of the DRSS by a central reading center. The images of the screening visit of both 
eyes will be used as part of the eligibility assessment regarding the severity of DR. 
4.2.2 
Main Analytical Approach 
For the primary analysis, the last observation before missing DRSS values will be carried 
forward (LOCF) to impute missing values if the participant dropped out after visit 9 (week 
12) and the EoT DRSS assessment was performed within 4 weeks of treatment 
discontinuation (while on treatment strategy). If the last measured DRSS score already 
showed an improvement by ≥ 2 steps at the last measurement prior to the missing assessment, 
the participant will be considered a responder for the primary endpoint. Otherwise, the 
participant will be considered a non-responder. If the participant dropped out after visit 9 
(week 12) and the EoT DRSS assessment was performed more than 4 weeks after treatment 
discontinuation the last available DRSS assessment prior to treatment discontinuation will be 
used (LOCF) (while on treatment strategy). Participants who dropped out before visit 9 (week 
12), or who had a VTC in the study eye prior to the missing assessment will be considered 
non-responders regardless of the DRSS level (composite variable strategy). 
Treatment groups will be runcaciguat and placebo, actually administered dose levels will not 
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Primary efficacy analyses will be performed on the PPS and will include only study 
intervention compliant participants (principal stratum strategy). In addition, sensitivity 
analyses will be performed on the FAS. Further analyses may include a separate analysis for 
each runcaciguat maintenance dose level that was reached during titration (on the PPS). 
Participants will be analyzed according to the treatment (i.e., runcaciguat or placebo) they 
actually received. 
The study will be analyzed using Bayesian inference with non-informative priors. PoC shall 
be defined as fulfillment of the following criteria: 
• P(𝜋𝐴𝐶𝑇- 𝜋𝑃𝐿𝐶 > 0 | data) ≥ 0.9  
i.e., the posterior probability that the difference between 𝜋𝐴𝐶𝑇 and 𝜋𝑃𝐿𝐶 is greater than 
0 (clinical activity) given the data observed in the study needs to be 90% or more, 
and 
• P(𝜋𝐴𝐶𝑇> 0.25 | data) ≥ 0.5  
i.e., the posterior probability that 𝜋𝐴𝐶𝑇 is greater than 0.25 (clinical relevance) given 
the data observed in the study needs to be 50% or more. 
95% credible intervals will also be presented for πACT and for πPLC 
The response criterion is assumed to be binomially distributed within each treatment arm. For 
the Bayesian evaluation, a Jeffrey’s prior (i.e., a Beta (0.5,0.5)-prior) will be used. Under 
these assumptions, the posterior distribution for the parameter  will be a Beta (k+0.5, n-
k+0.5)-distribution, where 
• k is the number of patients with DRSS ≥ 2-step improvement within the respective 
study arm and 
• n is the number of patients within the respective study arms. 
In order to demonstrate the clinical activity, the posterior distribution of 𝜋𝐴𝐶𝑇−𝜋𝑃𝐿𝐶 will be 
used to establish the posterior probability that 𝜋𝐴𝐶𝑇−𝜋𝑃𝐿𝐶> 0 by using a Monte-Carlo-
approach. 
The posterior distribution for clinical relevance can be directly evaluated from the Beta 
(k+0.5, n-k+0.5)-distribution in the runcaciguat arm. 
The Bayesian posterior probabilities P(𝜋𝐴𝐶𝑇- 𝜋𝑃𝐿𝐶 > 0 | data) and P(𝜋𝐴𝐶𝑇> 0.25 | data) will 
be calculated using a Monte Carlo Approach: Within each arm, 100000 samples will be 
obtained from the posterior distribution (i.e., a Beta (k+0.5, n-k+0.5)-distribution). As a seed 
for random number generation, a fixed seed will be used. This seed has to be included into the 
program output, in order to ensure that the analysis can be repeated. 
From these random samples, the following quantities will be obtained: 
• Estimation of P(𝜋𝐴𝐶𝑇- 𝜋𝑃𝐿𝐶 > 0 | data): 
• Difference 𝛿(𝑖) between the ith sampled proportion in the active arm 
(=𝜋𝐴𝐶𝑇
(𝑖) ) and the ith sampled proportion in the placebo arm (=𝜋𝑃𝐿𝐶
(𝑖) ): 
𝛿(𝑖) = 𝜋𝐴𝐶𝑇
(𝑖) −𝜋𝑃𝐿𝐶
(𝑖)  
• Relative frequency of the event ‘𝛿(𝑖) > 0’ within the samples of 𝛿(𝑖) 
• Estimation of P(𝜋𝐴𝐶𝑇> 0.25 | data): 
• Relative frequency of the event ‘𝜋𝐴𝐶𝑇
(𝑖) > 0.25’ within the samples of 𝜋𝐴𝐶𝑇
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4.2.3 
Sensitivity Analysis 
For the sensitivity analysis, a multiple imputation with 100 repetitions will be performed to 
receive the responder criterium for participants with missing DRSS assessment on Visit 15 
(week 48) due to early discontinuation (hypothetical strategy). The imputation model used to 
generate complete data sets will be a logistic regression for the responder criterium with 
stratum (baseline DRSS) and treatment group as effects. To use the regression method, the 
pattern of missingness need to be monotone. 
Participants who had a VTC in the study eye prior to the missing assessment will be 
considered non-responders regardless of the DRSS level (composite variable strategy). 
Treatment groups will be runcaciguat and placebo, actually administered dose levels will not 
be considered for this analysis. 
The analyses will be performed on the PPS and will include only study intervention compliant 
participants (principal stratum strategy). 
The analysis using Bayesian inference with non-informative priors, as described in the section 
above, will be repeated on the complete data sets obtained from the multiple imputation. 
4.2.4 
Subgroup Analyses 
To build hypothesis on subpopulations with better treatment response and on parameters that 
may be useful as biomarkers for activity, the following subgroups may be assessed if of 
relevant size (at least 10 participants per arm), as the underlying characteristics may influence 
the primary efficacy endpoint: 
DRSS at baseline 
• 47 
• 53 
Sex 
• Male 
• Female 
Diabetes 
• Type 1 
• Type 2 
Age 
• ≥ median age 
• < median age 
Hypertension at baseline 
• Yes (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg) 
• No (SBP < 140 mmHg and DBP < 90 mmHg) 
 


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Decrease in DBP (Visit 6 vs. Baseline) 
• Yes: decrease ≥ 5 mmHg 
• Yes: decrease ≥ 10 mmHg 
• No 
HbA1c at baseline 
• ≤ 8.5% 
• > 8.5% 
Renal function at baseline by eGFR 
• eGFR ≤ 60 mL/min 
• eGFR ≤ 45 mL/min (only if ≥ 10 participants) 
The primary analysis will be repeated by subgroups as defined above. This way it is possible 
to assess the treatment effect on DRSS improvement within subgroups. The analyses of 
subgroups will be performed on the PPS. 
4.2.5 
Descriptive Analysis 
Descriptive statistics for DRSS including change from baseline will be provided. Graphs 
displaying DRSS versus time will be generated. In addition, individual plots by stratum 
(DRSS at baseline) and treatment group will be presented. Furthermore, graphs for changes of 
DRSS at 12, 24, 48 weeks of treatment versus baseline will be provided. 
• Descriptive statistics of DRSS including change to baseline will also be broken down 
by the subgroups defined above and by country (US vs. Non-US). 
4.3 
Secondary Endpoint Analysis 
4.3.1 
Secondary Endpoints 
4.3.1.1 
Definition of Endpoints 
‘≥/< x steps improvement/deterioration in DRSS (for persons)’ at 48 (resp. 12, 24) 
Weeks of treatment (in the study eye) 
These endpoints will be assessed using the same methodology described for the primary 
efficacy endpoint (see Section 4.2.2). 
• ‘≥ 2 steps improvement in DRSS’ at 12, 24 Weeks of treatment in the study eye 
• ‘< 2 steps deterioration in DRSS’ at 12, 24, 48 Weeks of treatment in the study eye 
• ‘≥ 1 step improvement in DRSS’ at 12, 24, 48 Weeks of treatment in the study eye 
• ‘≥ 3 step improvement in DRSS’ at 12, 24, 48 Weeks of treatment in the study eye 
• ‘≥ 3 step improvement in DRSS for persons’ at 12, 24, 48 Weeks of treatment 
• ‘< 3 step deterioration in DRSS’ at 12, 24, 48 Weeks of treatment in the study eye 
• ‘< 3 step deterioration in DRSS for persons’ at 12, 24, 48 Weeks of treatment 
DRSS for persons will be derived according to Table 6-2. 
 


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Responder and non-responder definition for the endpoints above: 
• For ‘≥ x steps improvement in DRSS’ endpoints 
• Participants with ‘≥ x steps improvement in DRSS’ will be counted as 
responder 
• Participants with ‘< x steps improvement in DRSS’ will be counted as 
non-responder 
• For ‘< x steps deterioration in DRSS’ endpoints 
• Participants with ‘< x steps deterioration in DRSS’ will be counted as 
responder 
• Participants with ‘≥ x steps deterioration in DRSS’ will be counted as 
non-responder 
Vision-threatening complications at 12, 24, 48 Weeks of treatment in the study eye 
Assessment of VTC as secondary endpoint is planned in addition, to correlate the DRSS-
change with a clinical outcome parameter in support of the efficacy assessment in this study. 
VTC are defined as occurrence of any of the following AEs: 
• PDR (DRSS ≥61) 
• Any ocular neo-vascularization (retinal or anterior-segment neovascularization) 
• Center-involved (central ETDRS subfield) DME 
• Drop of BCVA of 10 letters or more from baseline 
Study investigations may be continued after treatment discontinuation, after investigator 
assessment. Treatment of the VTC should follow local standards and guidelines, at the 
discretion of the investigator. 
Number of participants with TEAEs 
For the definition of TEAEs refer to section 4.1.5. 
4.3.1.2 
Main Analytical Approach 
‘≥ x steps improvement/deterioration in DRSS (for persons)’ at 48 (resp. 12, 24) Weeks 
of treatment (in the study eye) 
This endpoint will be assessed using the same methodology described for the primary efficacy 
endpoint (see Section 4.2.2) on the PPS and in addition, as a sensitivity analyses on the FAS. 
95% credible intervals and point estimates for the difference between the active and placebo 
response rates will be provided. 
Vision-threatening complications at 12, 24, 48 Weeks of treatment in the study eye 
VTC will be recorded continuously during the study. Predefined timepoints for assessment 
are 12, 24, and 48 weeks of treatment. VTC are recorded separately for the study eye and the 
fellow eye. Separate assessments will be done for the study eye and across both eyes 
(timepoint when a VTC appears in any eye). These endpoints will be analyzed by the Kaplan-
Meier-method on the PPS and in addition, as a sensitivity analyses on the FAS. Confidence 
intervals will be provided for probability of having a vision threatening event up to these time 
points. Participants dropping out from the study without a VTC will be censored at the last 
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Furthermore, if deemed necessary, the endpoint VTC in any eye (yes/no) will be analyzed 
using the same Bayesian analysis described for the primary efficacy endpoint (see Section 
4.2.2) on the PPS. 
Number of participants with TEAEs 
For analysis of AEs refer to Section 4.5.2. 
4.3.2 
Subgroup Analyses 
The secondary analysis of DRSS for persons will be repeated for the following subgroup: 
DRSS for persons at baseline 
• ≤ 53 / 53 (scale step ≤ 11) 
4.3.3 
Supportive Secondary Endpoints 
Supportive secondary endpoints will be analyzed descriptively for the PPS and the FAS and 
will include the following: 
• Changes in DRSS from baseline in the study and fellow eye 
• Changes in DRSS for persons from baseline 
DRSS for persons will be derived according to Table 6-2. 
Changes in DRSS from baseline in the study and fellow eye 
Frequencies for changes of DRSS versus baseline in the study and fellow eye will be 
provided. Furthermore, frequencies for changes of DRSS for persons versus baseline will be 
provided. In addition, graphs for changes of DRSS for persons at 12, 24, 48 weeks of 
treatment versus baseline will be provided. 
4.4 
Other Endpoint Analysis 
If not mentioned otherwise, these endpoints will be analyzed by descriptive statistics for 
continuous variables and frequency tables for categorical variables. Furthermore, these 
endpoints will be analyzed separately for study eye and fellow eye, if not mentioned 
otherwise. 
4.4.1 
Best corrected visual acuity 
Change in BCVA from baseline: BCVA will be assessed using a modified ETDRS protocol 
starting 4 meters (AREDS, 1999). Descriptive statistics for visual acuity including change 
from baseline will be provided using geometric and arithmetic means as defined in Section 
4.1. 
4.4.2 
Fluorescein angiography 
Change in leakage area on FA: The anatomical state of the retinal vasculature of the study eye 
(transit eye) and the fellow eye (non-transit eye) will be evaluated by FA. The angiographic 
images will be evaluated by a study ophthalmologist for individual safety decisions. 
Fluorescein leakage area will be evaluated using FA. Descriptive statistics including box plots 
will be provided for the change in quantitative FA assessments from baseline to Week 24 and 
48 by treatment group using geometric and arithmetic means as defined in Section 4.1. 
4.4.3 
Optical coherence tomography and OCT-angiography 
The following parameters will be assessed, as applicable: 


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• CRT 
• OCT-A perfusion density, vessel density 
• OCT-A size of foveal avascular zone in study eyes and across both eyes 
• OCT-A-DART scans: assessment of vessel thickness 
These will be analyzed separately by study part. Furthermore, only relative changes will be 
provided for the above-mentioned endpoints. 
Change in central retinal thickness 
CRT will be evaluated using OCT and will be collected at each visit. Data will be provided by 
the central reading center for central subfield thickness, center point thickness, and total 
macular volume. The absolute values and relative changes from baseline with 95% CI in these 
parameters at each visit will be summarized descriptively by treatment group. 
Change in vessel density, perfusion density, size of foveal avascular zone 
Vessel density (skeleton), perfusion density, size of foveal avascular zone will be measured 
by the central reading center for study eye and the fellow eye. Vessel density and perfusion 
density are evaluated for the different retinal layers assessed: Superficial Retinal Layer, 
Intermediate Retinal Layer and Deep Retinal Layer and Retina (cumulative, all layers 
combined). 
Relative changes from baseline will be assessed for study eyes and across both eyes. 
Furthermore, sub-analyses of relative changes will be done for all (individual) eyes by DRSS 
at baseline. Parameters will be summarized using number of eyes/participants, arithmetic 
mean, arithmetic SD, arithmetic CV, minimum, median, maximum. In addition, relative 
change from baseline with 95% CI will be provided. 
Change in retinal vessel flow 
Retinal vessel flow will be measured by the central reading center from OCT-A DART scans 
for study eye and the fellow eye. 
Relative changes from baseline will be assessed for study eyes and across both eyes. 
Furthermore, sub-analyses of relative changes will be done for all (individual) eyes by DRSS 
at baseline. Parameters will be summarized using number of eyes/participants, arithmetic 
mean, arithmetic SD, arithmetic CV, minimum, median, maximum. In addition, relative 
change from baseline with 95% CI will be provided. 
4.4.4 
Slit lamp biomicroscopy (anterior and posterior segment) 
Abnormal findings will be recorded in the eCRF as either MH or AE, as applicable, and will 
be analyzed analogously. 
4.4.5 
Tonometry (intraocular pressure measurement) 
Descriptive statistics for intraocular pressure including change from baseline will be provided 
using arithmetic means. The used methods will be listed only. 
4.5 
Other Safety Analyses 
The secondary objective of the study is to investigate the safety and tolerability of runcaciguat 
in patients with NPDR. All safety analyses will be performed on the SAF, if not stated 
otherwise. Participants will be analyzed according to the treatment they actually received. 


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4.5.1 
Treatment Compliance, Duration and Exposure 
Tables will be presented for the FAS and PPS. 
Frequency tables and summary statistics will be presented for total dose, treatment dose per 
week, and treatment duration (absolute duration and frequencies with weekly intervals). In 
addition, treatment compliance will be summarized presenting the percent of tablets that were 
actually taken out of the planned number of tablets. Frequencies of participants showing 
compliance <80%, 80-120%, and >120% of the planned tablets will be presented. 
The frequencies of dose modifications will be presented by treatment group and visit, 
especially to assess the escalation, maintenance, reduction, and withdrawal of doses, including 
the reasons for maintenance, reduction, or withdrawal. Furthermore, the frequency of 
participants being treated on a certain dose level will be presented by treatment group, visit 
and dose level to assess the titration level being reached during up-titration and in the 
maintenance phase. 
A listing with the actual dose levels or sham-titration levels for each visit will be presented to 
get an overview of the individual titration schemes. 
4.5.2 
Adverse Events 
Individual listings of all AEs will be provided indicating whether the AE is treatment-
emergent or treatment-emergent related to study intervention and including AE onset relative 
to start of treatment, the actual dose (or sham titration) level at the start of the AE, and the 
duration of the AE.  
AEs will be summarized using the MedDRA terms by SOC, HLGT (if feasible) and PT. 
The following AEs have been defined as AESIs and are recorded as such: 
• AEs suggestive of hepatic injury, 
• Syncope/loss of consciousness,  
• Acute kidney injury suggested by 2.0-fold increase in serum creatinine or >50% 
decrease in eGFR. 
The number of participants with at least one such event in the following TEAE categories will 
be given by treatment and total: 
• Any AE 
• any TEAE, 
• any mild, moderate, severe TEAE (maximum intensity), 
• any TEAE related to study intervention, 
• any mild, moderate, severe TEAE related to study intervention, 
• any TEAE related to study procedures, 
• any treatment emergent SAE, 
• any TEAE leading to death, 
• any treatment emergent SAE related to study intervention, 
• any TEAE leading to not up-titrating study intervention, 
• any TEAE leading to dose reduction of study intervention, 
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• any TEAE leading to permanent discontinuation of study intervention, and 
• any treatment emergent AESI (also broken down by category of special interest as 
stated above). 
These frequency tables will also be presented broken down by maximum intensity of the 
TEAEs, where appropriate. 
Individual listings will be provided for serious TEAE, deaths, treatment emergent AESI, 
TEAE leading to study intervention interruption, TEAE leading to not up-titrating study 
intervention, TEAEs leading to study intervention reduction, and TEAEs leading to study 
intervention discontinuation. 
Participants on active treatment are expected to be up titrated to different dose levels of 
runcaciguat. Thus, the frequencies of participants with TEAEs will also be presented for each 
dose level. This summary will be presented for 30, 60, 90, 120 mg of runcaciguat, and a 
combined placebo group (corresponding to a dose level of zero, i.e., sham titrations will not 
be handled as different placebo dose levels). Since the exposure times for each dose level will 
not be comparable, incidences will be calculated with respect to the exposure time in the 
respective dose level. An AE will be allocated to the dose level on which it started. The 
number of participants with AEs allocated to a certain dose level will be presented and 
divided by the exposure time of that dose level considering all participants on that dose level. 
The result will be multiplied by 100 to present incidences of participants with TEAEs per 
100 participant-years. In addition, the analysis will be broken down by titration phase and 
maintenance phase to check whether TEAEs on a new higher dose level differ from TEAEs 
on maintenance treatment. The following time windows will be assigned to titration phase and 
maintenance phase for the respective runcaciguat dose levels: 
• 30 mg:   Titration phase: week 1 
Maintenance phase: week 2-97 
• 60 mg:   Titration phase: week 2 
Maintenance phase: week 3-97 
• 90 mg:   Titration phase: week 3 
Maintenance phase: week 4-97 
• 120 mg: Titration phase: week 4 
Maintenance phase: week 5-97 
The table will be repeated summarizing incidences of participants with treatment emergent 
AESIs. 
AEs will be displayed graphically (if feasible) by HLGT, grouped by SOC. 
4.5.3 
Laboratory assessments 
• HbA1c 
• Triglycerides 
• HDL- / LDL-/ total serum cholesterol 
• Further parameters are detailed in Section 10.2 of the CSP 
Continuous laboratory values will be summarized descriptively by parameter including 
absolute changes from baseline. Frequency tables will be provided for qualitative data. 
In addition, the frequencies for liver abnormality criteria as defined in CSP Section 10.5 will 
be presented: 
• ALT or AST >3 x ULN, 
• ALT or AST >3 x ULN and Total bilirubin >2 x ULN, 


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• ALT or AST >3 x ULN and INR >1.5 x ULN, 
• ALT or AST >5 x ULN for more than 2 weeks, 
• ALT or AST >8 x ULN. 
4.5.4 
eGFR 
eGFR will be calculated using CKD-EPI formula, using the serum creatinine (SCr) 
concentration measured at screening. The calculation will be done by the central laboratory 
using the formulas specified in Table 4-1. 
Table 4-1: Formula for eGFR calculation 
 
SCr level at 
screening 
Formula 
Women ≤ 0.7 mg/dL 
GFR = 144 × (SCr
0.7 )
−0.329
× 0.993𝐴𝑔𝑒 [× 1.159 if black] 
 
≤ 62 µmol/L 
GFR = 144 × (SCr
62  )
−0.329
× 0.993𝐴𝑔𝑒 [× 1.159 if black] 
 
> 0.7 mg/dL 
GFR = 144 × (SCr
0.7 )
−1.209
× 0.993𝐴𝑔𝑒  [× 1.159 if black] 
 
> 62 µmol/L 
GFR = 144 × (SCr
62  )
−1.209
× 0.993𝐴𝑔𝑒  [× 1.159 if black] 
Men 
≤ 0.9 mg/dL 
GFR = 144 × (SCr
0.9 )
−0.411
× 0.993𝐴𝑔𝑒 [× 1.159 if black] 
 
≤ 80 µmol/L 
GFR = 144 × (SCr
80  )
−0.411
× 0.993𝐴𝑔𝑒 [× 1.159 if black] 
 
> 0.9 mg/dL 
GFR = 144 × (SCr
0.9 )
−1.209
× 0.993𝐴𝑔𝑒  [× 1.159 if black] 
 
> 80 µmol/L 
GFR = 144 × (SCr
80  )
−1.209
× 0.993𝐴𝑔𝑒  [× 1.159 if black] 
GFR = glomerular filtration rate in mL/min/1.73 m2, eGFR = Estimated glomerular filtration rate, SCr = Serum creatinine 
The eGFR values based on serum creatinine are assumed to be log-normally distributed and 
will be summarized descriptively including relative changes from baseline with 95% CI. The 
eGFR values will be summarized using summary statistics as defined for log-normally 
distributed variables. 
Geometric mean eGFR including one SD range over time will be plotted. Individual plots of 
eGFR values will also be presented by stratum (DRSS at baseline) and treatment group. 
A frequency table will be presented summarizing decreases in eGFR values from baseline by 
>50%, >40%, >30%, etc. including cumulative frequencies. Decrease in eGFR [%] will be 
calculated as 1- (eGFR post-dose / eGFR at baseline) *100. 
4.5.5 
Vital signs 
• SBP, DBP 
• Heart rate 
The measurements at each visit during the titration phase will be summarized for each time 
point descriptively by parameter including absolute changes from baseline. Arithmetic mean 
plots including standard deviation over time will be presented. 


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Frequencies of participants with a decrease in SBP from the previous visit by >30 mmHg will 
be presented. In addition, frequencies for the following combinations of the above criteria will 
be summarized reflecting the up-titration criteria: 
• ≥105 mmHg SBP and ≤30 mmHg decrease from previous visit (dose increase), 
• ≥105 mmHg SBP and >30 mmHg decrease from previous visit  
or  
<105 mmHg and ≥90 mmHg SBP (dose maintenance), 
• <90 mmHg SBP (dose decrease to previous level). 
4.5.6 
Additional Safety Assessments 
ECG 
During Part 1 up to study Visit 6 (inclusive), triplicate ECG tracings will be recorded. These 
triplicate tracings may be transferred to a central ECG reading center for later QT evaluation. 
The results of the QT evaluations may be reported separately. For part 2, single ECGs will be 
recorded and transferred to a central ECG reading center for evaluation. 
ECG parameters (ventricular rate, PR interval, QRS-duration, and QT interval) will be 
determined and transferred to the database. The QT interval will also be corrected for the 
heart rate using Fridericia's method (QTcF), i.e., by dividing the observed QT interval by the 
cube-root of RR: 
QTcF = QT
√RR
3
 
Corrected QT intervals and the heart rate will be provided by the central ECG lab and 
summarized descriptively by parameter including absolute changes from baseline. 
A frequency table will be provided for the ECG findings, presence of sinus rhythm and atrial 
fibrillation and overall interpretation of ECGs (normal; abnormal, clinically insignificant; 
abnormal, clinically significant), by visit including any visit. 
4.6 
Other Analyses 
4.6.1 
Pharmacokinetics 
All analyses of PK will be made on the PK analysis set. 
The concentration data will be included in a Pop-PK model, and this will be described in a 
separate M&S Analysis Plan. The results will be reported in a separate M&S Report 
separately from the main clinical study report. 
The concentration-time courses of runcaciguat will be tabulated separated by dose group and 
sampling time window. The following statistics will be calculated for each of the sampling 
windows: geometric mean, geometric SD (re-transformed SD of the logarithms) and CV, 
arithmetic mean, SD and CV, minimum, median, maximum values, and the number of 
measurements. These statistics (except for minimum and maximum) at any time will only be 
calculated if at least 2/3 of the individual data were measured and were above the LLOQ. For 
their calculation, a data point below LLOQ will be substituted by one half of this limit. 
Statistics will be marked in the tables if values below the LLOQ are included in their 
calculation. 
Furthermore, the following parameters will be analyzed by the statistics mentioned above: 


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• Ctrough 
• C1-2 hours 
• C2-4 hours 
4.6.2 
PK/PD by groups and by dose level maintained at least for 50% of the 
study 
• CRT by Ctrough 
• Retina perfusion by Ctrough 
Scatter plots for change from baseline of CRT vs. Ctrough and changes from baseline of retina 
perfusion vs. Ctrough will be provided by dose level maintained at least for 50% of the study. 
4.6.3 
Biomarkers 
All Biomarker analyses will be performed on the PPS. Biomarker analyses include the 
following endpoints: 
• HbA1c 
• Plasma cyclic guanosine monophosphate (cGMP) 
• plasma kynurenine 
• serum cystatin C (CysC) 
• plasma norepinephrine (NE) (optional if measured) 
Descriptive Statistics 
Summary statistics including ratio to baseline and change to baseline will be presented (using 
arithmetic and geometric means) and frequency tables for qualitative data will be provided. 
All biomarkers are assumed to be log-normally distributed and will be summarized using 
number of participants, geometric mean, geometric SD, arithmetic mean, arithmetic SD, 
minimum, median, IQR, maximum. In addition, ratios to baseline with 95% CI will be 
provided. These summary statistics will be presented at each planned time point by study 
intervention for the observed data. 
In addition, geometric mean plots of biomarker absolute concentrations, geometric mean plots 
(including one standard deviation range) of biomarker ratio to baseline and arithmetic mean 
plots (including one arithmetic standard deviation range) of biomarker change to baseline 
over time will be presented for all biomarkers. Individual plots of biomarker concentrations 
will be presented for the absolute concentrations, the ratio to baseline, and change to baseline. 
Inferential Statistics 
Biomarkers will be assumed log-normally distributed. Therefore, biomarker values will be 
log-transformed for inferential analyses (unless specified otherwise). The change to baseline 
of log-transformed measurements is equivalent to the log-transformed ratio-to-baseline: 
𝒍𝒐𝒈(𝑩𝑴) −𝒍𝒐𝒈(𝑩𝑴𝒃𝒍) = 𝒍𝒐𝒈( 𝑩𝑴
𝑩𝑴𝒃𝒍
) 
In order to analyze the impact of treatment on the log-transformed biomarker ratio-to-baseline 
levels over time (ΔBM.𝑡𝑖𝑚𝑒), a linear mixed model will be utilized with ΔBM.𝑡𝑖𝑚𝑒 levels post-
dose as the dependent variable and corresponding (log-transformed) biomarker baseline level, 


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intervention group, visit and the interaction of intervention group and visit as the independent 
variables: 
∆𝐵𝑀.𝑡𝑖𝑚𝑒~𝐵𝑀.𝐵𝐿+ 𝑖𝑛𝑡𝑒𝑟𝑣𝑒𝑛𝑡𝑖𝑜𝑛 𝑔𝑟𝑜𝑢𝑝+ 𝑣𝑖𝑠𝑖𝑡+ 𝑖𝑛𝑡𝑒𝑟𝑣𝑒𝑛𝑡𝑖𝑜𝑛 𝑔𝑟𝑜𝑢𝑝∗𝑣𝑖𝑠𝑖𝑡
+  error(within subject) +  error(residual) 
A similar linear mixed model will be applied as sensitivity analysis for the absolute difference 
to baselines of biomarkers without log-transformation. 
The subject information will enter the model as a random effect, which will be modelled as an 
individual random intercept, to account for repeated measures per patient. Time related 
dependencies per participant will be modelled using an autoregressive correlation structure of 
order one [AR(1)]. The structure of the covariance matrix might be adapted, e.g., in case of 
convergence problems. 
In addition, least-square means will be calculated and back-transformed (only if biomarkers 
are log-transformed) per intervention group as well as for treatment effect (difference between 
intervention group and placebo) and reported with 95% CI and p-value for each time points 
and across all time points. 
Plots of least-square means (back-transformed, if required) for ratios and changes to baseline 
per intervention group, as well as the treatment effect, at each time point and 95% CI will be 
provided. 
Further analyses may include a separate analysis for each runcaciguat maintenance dose level 
that was reached during titration. 
Responder Analysis 
Participants from the runcaciguat group will be classified as responders and non-responders 
based on the primary outcome definition: responders ‘≥ 2-step improvement in DRSS at 48 
weeks of treatment in the study eye’. 
To assess if biomarkers could predict responders vs non-responders at baseline, a univariate 
logistic regression will be applied for each of the biomarker at baseline (log-transformed, unless 
specified otherwise). The odds ratio (back-transformed, only if biomarkers were log-
transformed) with 95% CI will be reported, as well as the p-value. 
Furthermore, in order to analyze the impact of responder group (responders vs non-
responders) on the log-transformed biomarker ratio-to-baseline levels over time, a linear 
mixed model including all available visits (after the first dose) will be applied. The 
corresponding (log-transformed) biomarker at baseline, responder group, visit, and the 
interaction of responder group and visit will be used as independent variables. Time related 
dependencies per participant will be modelled using an autoregressive correlation structure of 
order one [AR(1)]. The structure of the covariance matrix might be adapted, e.g., in case of 
convergence problems using a compound symmetry structure. 
In addition, least-square means will be calculated and back-transformed (only if biomarkers 
are log-transformed) per responder group as well as for the responder effect (difference 
between responders and non-responders) and reported with 95% CI and p-value for each time 
points and across all time points. 
Plots of least-square means (back-transformed, if required) for ratios to baseline per responder 
group, as well as the responder effect, at each time point and 95% CI will be provided. 


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A similar linear mixed model will be applied as sensitivity analysis for the absolute difference 
to baselines of biomarkers without log-transformation. 
4.7 
Interim Analyses 
Not applicable. 
4.7.1 
Data Monitoring Committee 
An independent DMC will be in place to monitor the safety of the participants and PK 
throughout the trial based on unmasked data (refer to the DMC Charter for further details). 
There is no plan to perform interim efficacy analyses to terminate the study for early evidence 
of efficacy. The DMC will monitor outcomes only to determine the relative benefit/risk. In 
addition, the DMC will provide a recommendation to the Steering Committee to continue or 
stop recruitment in any treatment arm. The DMC will consist of a chair, and members who 
have appropriate qualifications for their respective professions (ophthalmologist, expert for 
hypertension and cardiovascular risks, and medical statistician); and who are independent 
from and external to the Sponsor, SAC, EC/IRB, Coordinating or Principal Investigator(s), 
site Investigator(s) or site Sub-Investigator(s) and Steering Committee membership, Advisory 
Board membership, CEC membership, if applicable or any other capacity related to study 
operations. DMC meetings will comprise an open and a closed session. Open sessions will 
describe the data in a manner which will not destroy the masking of the study. Closed 
sessions will present unmasked data. To keep the masked status for sponsor employees, an 
independent SAC will be in place to prepare unmasked tables and provide them to the DMC 
prior to each DMC meeting. 
4.8 
Changes to Protocol-planned Analyses 
The exploratory biomarker serum lipoprotein was not considered necessary to be analyzed for 
NEON based on available data from the CONCORD study (BAY 1101042 / 18748) and was 
therefore removed from the SAP. 
5. 
Sample Size Determination 
For the evaluation, a Bayesian concept for inference will be used, which is based on the 
posterior probabilities that the research hypotheses are true. Clinically relevant benefit of 
runcaciguat in treatment of advanced NPDR will be considered established and will result in 
“PoC” if the following criteria are met: 
• ≥ 90% posterior probability for the hypothesis of clinical activity 
(i.e., 𝑃(𝜋𝐴𝐶𝑇> 𝜋𝑃𝐿𝐶|𝑑𝑎𝑡𝑎) ≥0.9) 
• ≥ 50% posterior probability for the hypothesis of clinical relevance 
(i.e., 𝑃(𝜋𝐴𝐶𝑇> 0.25|𝑑𝑎𝑡𝑎) ≥ 0.5). 
The sample size has been chosen to provide at least 90% probability to obtain PoC under the 
following assumptions: 
• True response probability for placebo: 10% 
• True response probability for runcaciguat 120 mg: 35% 
The response criterion is assumed to be binomially distributed. For the Bayesian evaluation, a 
Jeffries’ prior (i.e., a Beta (0.5;0.5)-prior) has been used. Sample size was determined with a 
simulation approach using the R environment. 


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To be able to declare both clinical activity and clinical relevance ≥ 40 evaluable participants 
are needed in both groups. 
98 participants will be randomly assigned to the study intervention such that approximately 
80 evaluable participants complete the study. Of 98 participants, 18 participants will be 
randomized with a ratio of 2:1 to highest runcaciguat dose and placebo for Part 1. 80 
participants will be randomized with a ratio of 1:1 to placebo and runcaciguat for Part 2 
(Table 5-1). 
Table 5-1: Planned sample size 
 
Target 
 
 
 
 
dose 
Part 1 
Part 2 
Total 
Randomized 
Placebo 
6 
40 
46 
 
30 mg 
- 
- 
- 
 
60 mg 
- 
- 
- 
 
90 mg 
- 
- 
- 
 
120 mg 
12 
40 
52 
 
Overall 
18 
80 
98 
Evaluable* 
 
 
 
80 
*Minimum evaluable for primary endpoint. 
6. 
Supporting Documentation 
6.1 
Appendix 1: Participant disposition 
Based on all participants enrolled, i.e., signed the ICF, an overview will be given of all 
participants who reached the following milestones: 
• Screening 
• Randomization 
• Start of treatment 
• Completion of 12 weeks of treatment (Visit 9) 
• Completion of 24 weeks of treatment (Visit 12) 
• Completion of 48 weeks of treatment (Visit 15, unless early discontinuation) 
• Completion of the study (Visit 16, unless early discontinuation). 
Participants will be considered as study completers if they completed the EoT Visit (week 
48), irrespective of treatment discontinuations or interruptions. Participants will be considered 
as treatment completers if they were on treatment until the EoT Visit (week 48). Completion 
status of the study will be presented for all epochs: screening (all participants enrolled), 
treatment (i.e., titration and maintenance phase), follow-up (both based on all participants 
randomized), including reasons for not completing the respective epoch. 
In addition, an overview of all participants in the different analysis sets will be provided 
together with reasons for restrictions of validity (based on all participants randomized). 
 


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6.2 
Appendix 2: Baseline characteristics and demographics 
Demographic data and baseline characteristics will be presented for total and each treatment 
group in the FAS, PPS, SAF, and PKS (if different). Summary statistics will be provided for 
quantitative demographic data and baseline characteristics, including 
• Age 
• Weight 
• Height 
• BMI 
• HbA1c 
• eGFR 
• BCVA score 
• OCT CRT 
Frequency statistics will be provided for qualitative data, including 
• DRSS of study eye (stratification criterion) 
• Study eye 
• Sex 
• Race 
• Ethnicity 
• Smoking status, 
• Alcohol consumption 
• Caffeine consumption 
• Country 
Diabetic retinopathy history will be summarized separately: 
• Duration of diabetic retinopathy (difference between the reported onset date and the 
patient’s date of randomization). 
• N (%) of patients reporting a history of type 1 and type 2 diabetes mellitus. 
• Duration of diabetes mellitus type 1 and type 2 (difference between the reported onset 
date and the patient’s date of randomization). 
• N (%) of patients reporting a history of arterial hypertension, myocardial infarction, 
transient ischemic attacks, stroke, and diabetic nephropathy. 
6.3 
Appendix 3: Protocol deviations 
The important protocol deviations will be listed and summarized in a frequency table (based 
on all participants randomized). COVID-19 pandemic associated reasons for discontinuation 
might be included in the table, i.e., the information whether decision for discontinuation was 
made by the participant, the physician or was due to logistical reasons. 
Impact of COVID-19 may be presented. Descriptive tables displaying number of participants 
affected and number and type of COVID-19 related protocol deviations are added if needed. 
A separate listing displays all participants affected by the COVID-19 related study disruption 
by unique participant identifier and by investigational site. 


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The number of participants who prematurely discontinue study participation and those who 
discontinue study treatment permanently for any reason, as well as the respective reasons, will 
be reported. Plots for “Time to end of study” and “Time to permanent discontinuation of 
study treatment” will be provided for runcaciguat and placebo group in one plot. 
6.4 
Appendix 4: Medical history 
MH findings will be summarized overall and differentiating between past and ongoing 
disorders using MedDRA terms using the most recent effective MedDRA version (based on 
the SAF population). 
6.5 
Appendix 5: Prior and concomitant medication 
Prior and concomitant medication will be summarized, separately by WHO-DD using the 
latest effective version of the dictionary (based on the SAF population). Prior medication is 
medication that was terminated before first study intervention intake. Concomitant medication 
is medication that was not terminated before first study intervention intake or started after first 
study intervention intake. 
6.6 
Appendix 6: ETDRS final retinopathy severity scales 
Table 6-1: ETDRS final retinopathy severity scale for individual eyes 
Level 
Severity 
Scale step 
10 
DR absent 
1 
20 
Microaneurysms only 
2 
35 
Mild NPDR 
3 
43 
Moderate NPDR 
4 
47 
Moderately severe NPDR 
5 
53 
Severe NPDR 
6 
61 
Mild PDR 
7 
65 
Moderate PDR 
8 
71 
High-risk PDR 
9 
75 
High-risk PDR 
10 
81 
Advanced PDR: fundus partially obscured, center of macula attached 
11 
85 
Advanced PDR: posterior fundus obscured, or center of macula detached 
12 
90 
Cannot grade, even sufficiently for level 81 or 85 
13 
ETDRS = Early Treatment Diabetic Retinopathy Study; DR = diabetic retinopathy; NPDR = non-
proliferative DR; PDR = proliferative DR 
 


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Table 6-2: Abbreviated Summary of ETDRS final retinopathy severity scale for 
persons 
Level 
Description 
Scale step 
10 / 10 
No DR 
1 
20 / <20 
Microaneurysms only, one eye 
2 
20 / 20 
Microaneurysms only, both eyes 
3 
35 / <35 
Mild NPDR, one eye 
4 
35 / 35 
Mild NPDR, both eyes 
5 
43 / <43 
Moderate NPDR, one eye 
6 
43 / 43 
Moderate NPDR, both eyes 
7 
47 / <47 
Moderately severe NPDR, one eye 
8 
47 / 47 
Moderately severe NPDR, both eyes 
9 
53 / <53 
Severe or very severe NPDR, one eye 
10 
53 / 53 
Severe or very severe NPDR, both eyes 
11 
61 / <61 
Mild PDR, one eye 
12 
61 / 61 
Mild PDR, both eyes 
13 
65 / <65 
Moderate PDR, one eye 
14 
65 / 65 
Moderate PDR, both eyes 
15 
71+ / <71 
High risk PDR, one eye 
16 
71+ / 71+ 
High risk PDR, both eyes 
17+ 
Modified from N Engl J Med 2010; 363:233-244, supplementary appendix, Table 2. 
7. 
References 
Fisch R, Jones I, Jones J, Kerman J, Rosenkranz GK and Schmidli H. Bayesian Design of 
Proof-of-Concept Trials, Therapeutic Innovation & Regulatory Science. 2015; 49(1):155-162 
The Age-Related Eye Disease Study (AREDS): design implications. AREDS report no. 1. 
Control Clin Trials. 1999; 20(6): 573-600.