Finerenone Treatment for Diabetic Cardiovascular Autonomic Neuropathy: the FibroCAN Study
Phase: PHASE2
Conditions: Cardiovascular Autonomic Neuropathy, Type 2 Diabetes, Diabetic Neuropathies
Sponsor: Peter Rossing

Protocol v.3 
FibroCAN study 
Date 31/10-24 
 
 
 
 
 
 
 
The FibroCAN study 
Mineralocorticoid receptor antagonist treatment for 
diabetic cardiovascular autonomic neuropathy 
EU trial no.: 2024-516597-30-00 
 
 
 
 
 
 
 
Sponsor:  
Peter Rossing, MD, Professor 
Steno Diabetes Center Copenhagen 
Borgmester Ib Juuls Vej 83 
2730 Herlev 
Denmark 
 
 
 

Protocol v.3 
FibroCAN study 
Date 31/10-24 
Contents 
 
1 
Project summary ........................................................................................................................................ 3 
2 
Study centers and participants ................................................................................................................... 4 
3 
Abbreviations ............................................................................................................................................ 5 
4 
Background ................................................................................................................................................ 6 
5 
Methods ..................................................................................................................................................... 7 
5.1 
Objective & hypothesis ..................................................................................................................... 7 
5.2 
Trial Design ....................................................................................................................................... 8 
5.3 
Study intervention and study medication titration ............................................................................. 8 
5.4 
Trial endpoints ................................................................................................................................... 9 
5.5 
Study visits ...................................................................................................................................... 10 
5.6 
Randomization and blinding ............................................................................................................ 11 
5.7 
Adherence to protocol ..................................................................................................................... 12 
5.8 
Trial termination criteria .................................................................................................................. 12 
5.9 
Study timeline .................................................................................................................................. 13 
6 
Statistical analysis ................................................................................................................................... 13 
6.1 
Sample size estimation .................................................................................................................... 13 
6.2 
Demographics and other baseline characteristics ............................................................................ 13 
6.3 
Treatment efficacy ........................................................................................................................... 14 
6.4 
Safety outcomes ............................................................................................................................... 14 
7 
Participant selection ................................................................................................................................. 14 
7.1 
Inclusion criteria .............................................................................................................................. 14 
7.2 
Exclusion criteria ............................................................................................................................. 15 
7.3 
Withdrawal criteria .......................................................................................................................... 16 
7.4 
Screening of eligible participants .................................................................................................... 16 
7.5 
Initial contact to potential study participants ................................................................................... 17 
7.6 
Participant information visit ............................................................................................................ 17 
7.7 
Screening ......................................................................................................................................... 17 
8 
Study medication: description, handling, and storage ............................................................................. 18 
8.1 
Packaging and labelling ................................................................................................................... 18 
8.2 
Biobank Storage .............................................................................................................................. 18 
9 
Methods and measures............................................................................................................................. 19 
9.1 
Pre-examination restrictions ............................................................................................................ 19 
9.2 
Cardiovascular autonomic reflex testing and heart rate variability ................................................. 19 

Protocol v.3 
FibroCAN study 
Date 31/10-24 
9.3 
Cardiac vagal tone ........................................................................................................................... 20 
9.4 
Blood/urine sampling and molecular (fibrosis and inflammatory proteins) testing ........................ 20 
9.5 
Corneal neuropathy ......................................................................................................................... 21 
9.6 
Retinopathy ...................................................................................................................................... 21 
9.7 
Nerve conduction ............................................................................................................................. 22 
9.8 
Vibration sensation threshold .......................................................................................................... 22 
9.9 
Light touch and pain sensation ........................................................................................................ 22 
9.10 
Cold and warm sensation of foot/lower leg ..................................................................................... 22 
9.11 
Ancle and Patella reflexes (Reflex hammer) ................................................................................... 22 
9.12 
Intraepidermal nerve fiber density (IENFD) ................................................................................... 22 
9.13 
Questionnaires for painful and painless peripheral neuropathy ....................................................... 23 
9.14 
Sudomotor function of the hands/feet ............................................................................................. 23 
9.15 
Questionnaires for autonomic neuropathy ....................................................................................... 23 
9.16 
Orthostatic blood pressure testing ................................................................................................... 23 
10 Biobanks .................................................................................................................................................. 24 
Adverse effects and risks ................................................................................................................................. 25 
10.1 
Adverse effects of finerenone .......................................................................................................... 25 
10.2 
Risk related to procedures ............................................................................................................... 25 
10.3 
Risk/Benefit assessment .................................................................................................................. 26 
10 Assessment of safety and reporting ......................................................................................................... 26 
11.1 
Unblinding ....................................................................................................................................... 26 
11.2 
Safety endpoints .............................................................................................................................. 26 
11.3 
Adverse events and reactions .......................................................................................................... 26 
12 Data management .................................................................................................................................... 28 
13 Quality control and quality assurance...................................................................................................... 29 
13.1 
Monitoring ....................................................................................................................................... 29 
13.2 
Direct access to source data / documents ........................................................................................ 30 
14 Ethical considerations .............................................................................................................................. 30 
15 Budget...................................................................................................................................................... 31 
16 Insurance .................................................................................................................................................. 31 
17 Dissemination of results .......................................................................................................................... 31 
18 References ............................................................................................................................................... 32 
Appendix A ..................................................................................................................................................... 35 
Appendix B ...................................................................................................................................................... 36 
 
 

Protocol v.3 
FibroCAN study 
Date 31/10-24 
1 Project summary 
Background 
Diabetic neuropathy (DN) is a common, severe, and untreatable complication of diabetes. As the prevalence 
of cardiovascular autonomic neuropathy (CAN) is approximately 20%, the condition could affect as many as 
100 million of the people living with diabetes in the world leading to increased morbidity and mortality, 
primarily due to the lack of disease-modifying treatment. CAN and other manifestations of neuropathy is 
associated with increased formation of fibrosis. This fibrosis formation may be a possible pathway to 
neuropathy and may present a new possible treatment target. Recently, treatment with mineralocorticoid 
receptor antagonists (MRAs) such as finerenone has shown to improve autonomic neuropathy in non-diabetic 
conditions, such as heart and kidney failure, reduce fibrosis and inflammation in addition to possessing cardio- 
and reno-protective effects. Thus, finerenone may be a potentially effective therapy for the treatment of CAN. 
 
Objective  
To assess if finerenone may have an effective disease modifying effect on CAN in a 78-week trial of people 
with type 2 diabetes and early-stage CAN. In addition, treatment effects on other forms of neuropathy and 
related pathological (and molecular) mechanisms causing the complication will be explored. 
 
Methods 
The study is a two-centre, two-armed, double-blinded parallel randomised placebo-controlled trial assessing 
78 weeks treatment with finerenone/placebo on cardiovascular autonomic reflex testing (primary endpoint) in 
people with type 2 diabetes and early-stage CAN defined as on pathological cardiovascular autonomic reflex 
test; the E/I ratio. 
 
Implications 
This study will test if the previously shown cardio- and reno-protective effects of finerenone extents to a 
disease modifying effect for CAN. Ultimately, the findings may reveal a new treatment target for CAN. 
 
 
 

Protocol v.3 
FibroCAN study 
Date 31/10-24 
2  Study centers and participants 
 
 
 
 
Study centers
Steno Diabetes Center Copenhagen (SDCC) 
 
Borgmester Ib Juuls Vej 83  
 
2730 Herlev, Denmark  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Steno Diabetes Center Northern Denmark (SDCN) 
Mech-Sense 
Aalborg University Hospital 
9000 Aalborg, Denmark 
 
 
 
 
 
 
 
 
 
Information regarding investigators and third parties involved in the study can be found in the Clinical Trials 
Information System (CTIS). 
 
 

Protocol v.3 
FibroCAN study 
Date 31/10-24 
 
3 Abbreviations  
AE 
 
 
 
Adverse event 
AR 
 
 
 
Adverse reaction 
CARTs  
 
 
Cardiovascular autonomic reflex tests 
DNS 
 
 
 
Diabetic Neuropathy Symptom  
DN4 
 
 
 
Douleur Neuropathique en 4 questionnaire 
DPN 
 
 
 
Diabetic peripheral neuropathy  
HRV 
 
 
 
Heart rate variability  
IENFD  
 
 
Intraepidermal nerve fiber density 
MRA   
 
 
Mineralocorticoid receptor antagonist 
NDS 
 
 
 
Neuropathy disability score 
SAR 
 
 
 
Serious adverse event 
SUSAR 
 
 
Suspected unexpected serious adverse reaction  
SDCC   
 
 
Steno Diabetes Center Copenhagen  
SDCN   
 
 
Steno Diabetes Center North Denmark 
UAR 
 
 
 
Unexpected adverse reaction 
PT 
 
 
 
Post treatment follow-up 
 
 

Protocol v.3 
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4 
Background 
Cardiovascular autonomic neuropathy (CAN) (1)is caused by damage to the nerves regulating the heart and 
vessel function and affects people with diabetes by being an independent predictor of cardiovascular mortality 
and morbidity including arrhythmia, silent ischemia (1-4), and diabetic kidney disease shown by us (5) and 
others. People with diabetes and CAN have higher mortality rate compared with people without CAN (1, 6-
8). Also, poorer measures of CAN have been associated with preclinical coronary atherosclerosis (9) and heart 
failure(10). Prevalence of CAN in newly diagnosed T2D is up to 20% (11)(12, 13). Presently, it is estimated 
that 537 million people suffer from diabetes worldwide with an estimated increase of more than 750 million 
people in 2040(14). These estimates extrapolate to at least 100 million people suffering from CAN presently 
with an estimated rise to 150 million people in 2040. Thus, preventing CAN may reduce excess morbidity and 
mortality in diabetes. 
Early stages of CAN and other forms of neuropathy have a component of reversibility (12, 15). However, later 
stages may be irreversible. Prevention of progression to late stages of CAN and reversal of disease are therefore 
paramount. Several drug trials have failed to show disease-modifying effects on neuropathy. Possible reasons 
are that most studies have been performed in people with late irreversible stages of CAN. Secondly, CAN is a 
slow-progressing disease where long-term intervention studies are needed to assess the efficacy of treatment.  
 
Fibrosis assessed by collagen turnover markers such as serum PRO-C6 and C3M have been associated with 
impaired nerve function in animal models (16, 17) and in people with diabetes (18-20). Neuropathy associated 
with collagen turnover may be a result of increased fibrosis of the extracellular matrix of nerves but also by 
pro-fibrotic and pro-inflammatory effects induced by the markers themselves (21). We have recently 
demonstrated that high serum levels of fibrosis markers are significantly associated with the risk of CAN and 
peripheral neuropathy (22). Taken together, fibrosis is a part of the pathophysiological mechanisms leading to 
diabetic neuropathy and could therefore be a future treatment target for the complication.  
 
Mineralocorticoid receptor antagonists (MRAs) may constitute a novel treatment option for CAN. In addition 
to disease-modifying effects on congestive heart failure, diabetic kidney disease, and cardiovascular disease, 
MRAs have beneficial effects on autonomic dysfunction. Most human studies on CAN have been performed 
with the first-generation MRA spironolactone. Here, randomised placebo-controlled trials in people with 
congestive heart failure demonstrate improvements in autonomic function measured by Holter monitor-derived 
heart rate variability (HRV) indices after treatment periods varying from 8 to 52 weeks (23-25). Similar results 
have come from trials in people in hemodialysis after 12 to 24 weeks of treatment (26, 27), indicating that 
MRAs' effects on autonomic function are not disease-specific. Whether these improvements are mediated 
through a reduction in systemic inflammation or by direct effects on the central nervous system as shown in 
animal studies (28) is, not known. Finerenone is a third-generation well-tolerated MRA that has had remarkable 

Protocol v.3 
FibroCAN study 
Date 31/10-24 
 
effects on cardiovascular and renal complications in diabetes patients (29) and concomitantly reduces fibrosis 
and inflammation (30). Finerenone is now approved and used for the treatment of diabetic kidney disease. 
Thus, finerenone is a readily available drug that could be used to treat or prevent CAN in diabetes.  
 
5 
Methods 
5.1 
Objective & hypothesis 
The objective of this study is to investigate the disease modifying effect of finerenone on early CAN in a 78-
week doubled blinded, randomized placebo-controlled multi-centre trial of people with type 2 diabetes and 
early-stage CAN. Treatment effects on neuropathy measures, levels of fibrosis and inflammation and heart 
function will be explored. 
 
We hypothesize that treatment with the MRA finerenone is efficacious in reversing early CAN and that these 
effects are associated with a reduction of levels of fibrosis and inflammation. Furthermore, we hypothesize 
that improved autonomic function can be demonstrated in a 78-week trial by improvements in cardiovascular 
autonomic reflex tests (CARTs) and resting heart rate variability (HRV), in addition to measures of other forms 
of neuropathy and cardiac function. As the CART the E/I ratio is often the first to be affected in the progression 
to definite CAN we hypothesize that people who only have this CART affect have a reversible state of CAN. 

Protocol v.3 
FibroCAN study 
Date 31/10-24 
 
5.2 
Trial Design 
This study is a two-armed double blind randomized control multi-centre trial performed with participant 
treatment at SDCC and SDCN (Figure 1).
 
 
Figure 1 FibroCAN detailed study design and study visits 
 
5.3 
Study intervention and study medication titration 
Participants will be randomized 1:1 to either finerenone or a matching placebo. The participants will take one 
tablet daily orally for 78-weeks. 
We expect a dose-dependent reduction in neuropathy and hypothesize that 40 mg of finerenone is equipotent 
to 50 mg of spironolactone, which has shown efficacy in decreasing a CAN measure. Participants will be 
titrated to 40 mg oral dose following a stepwise titration based on eGFR and with close monitoring of 
potassium and eGFR. Previous studies have found 40 mg to be safe and well-tolerated, including the 
FINEART-HF study (31) with 3003 patients on finerenone, utilizing doses up to 40 mg, and a phase 1 program 
where 80 mg was the highest investigated single dose and 40 mg oral dose was the highest studied multiple-
dose regimen (Investigator Brochure). Titration of finerenone will be based on baseline eGFR.  

Protocol v.3 
FibroCAN study 
Date 31/10-24 
 
Participants with eGFR > 60 
Participants with eGFR > 60 mL/min/1.73m² will start on a 20mg dosage. Medication dosage will be increased 
to 40 mg after an additional one month if serum potassium < 4.8 mmol/l. If side effects occur at any dosage, 
the dosage will be reduced to the previous level.  
Participants with eGFR < 60 and >25 
Participants with eGFR < 60 mL/min/1.73m² (and eGFR < 25 mL/min/1.73m²) will start on a 10mg dosage. 
Medication dosage will be increased to 20 mg after an additional one month if serum potassium < 4.8 mmol/l. 
Subsequently, Medication dosage will be increased to 40 mg after an additional one month if serum potassium 
< 4.8 mmol/l.  If side effects occur at any dosage, the dosage will be reduced to the previous level. Additional 
serum potassium monitoring during the trial will be considered by the study-affiliated medical doctor based 
on an individual assessment based on patient characteristics and serum potassium levels. 
 
5.4 
Trial endpoints 
Endpoints are between-group (finerenone vs. placebo) differences in changes of endpoint measures from 
baseline to 78-week follow-up. 
 
Primary endpoint:  
 
The CART E/I ratio (by the Vagustm device)  
 
Secondary endpoint:   
Cardiovascular reflex tests: R/S ratio, Valsalva manoeuvre (CARTs) 
HRV indices (SDNN, RMSSD, Low and high-frequency power) (by the Vagustm device) 
Fibrosis markers (serum PRO-C6 and C3M assessed by ELISA) 
Fibrosis markers in skin biopsies (Pro-C6 and C3M by immunostaining (Only week 0, 36, 78) 
 
 
Exploratory Endpoint:  
 
Inflammation markers (plasma proteomic analyses, O-link platform) 
Markers of corneal neuropathy (to quantify the severity of small nerve fibre damage by confocal corneal 
microscopy) 
Cardiac vagal tone (by the eMotion Faros). 
 
Markers of retinopathy (nonproliferativ/proliferative retinopathy and retinal nerve fibre layer thickness by 
optical coherence tomography) 
 
Markers of peripheral neuropathy:  
 

Protocol v.3 
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Date 31/10-24 
 
Sural nerve conduction and amplitude (DPNCheck) 
Vibration sensation threshold (Biothesiometry)  
Light touch and pain sensation (10 and 75 g monofilament and 40g needle)  
Cold and warm sensation of foot and lower leg by (Rolltemp) 
Ancle and Patella reflexes (Reflex hammer) 
Intraepidermal nerve fiber density (IENFD) (Skin biopsies week 0,36,78)  
Questionnaires for painful and painless neuropathy DN4, MNSI. 
Markers of autonomic neuropathy:  
 
Sudomotor function of the skin in hands and feet (Sudoscan) 
Questionnaires for autonomic neuropathy (Compass-31 and GCSI) 
Orthostatic blood pressure testing  
 
 
 
 
 
5.5 
Study visits  
During the study the participants will attend six physical study visits at SDCC or SDCN at week 0, 12, 24, 36, 
52, and 78 where all study outcomes will be assessed except for skin biopsies and eye examinations (CCM 
and retinopathy) which will only be performed at week 0, 36 and 78. In addition, safety serum potassium tests 
will be performed at week 4, 8, 24, 36, 52, 64, 78 and additionally after 4 and 20 weeks if study drug dosage 
is changed (see overview figure 1). All participants will undergo a post-treatment follow-up via telephone after 
4 weeks (+/-5 days) of their last study visit, during which adverse events will be recorded. 
At the screening visit demographic and anthropometric measures (Height, weight, BMI, hip- and waist 
circumference) as well as lifestyle habits will be inquired (alcohol, smoking, exercise levels). At the screening 
visit 7 ml of blood will be drawn after informed consent is given. The blood will be analyzed immediately to 
assess exclusion biomarkers: potassium, HbA1c and eGFR (see table in section “9.4 
Blood/urine 
sampling and molecular (fibrosis and inflammatory proteins) testing.”). Results from blood analyses will be 
assessed by study personnel prior to randomization. 
 
 

Protocol v.3 
FibroCAN study 
Date 31/10-24 
 
In the trial overview below measures obtained at each visit are listed below.  
 
Information 
Screening 
W0 
W4 
W8 
W12 
W24 
W36 
W52 
W64 
W78 
ENROLMENT 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
In/exclusion criteria 
 
x 
 
 
 
 
 
 
 
 
 
Demography 
 
x 
 
 
 
 
 
 
 
 
 
Medical history 
 
x 
 
 
 
 
 
 
 
 
 
Biochemistry*  
 
Screening 
 
x 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
x 
 
 
 
 
 
 
 
 
Follow-up 
 
 
 
 
 
x 
x 
x 
x 
 
x 
SAFETY OUTCOMES 
Serum potassium + eGFR 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
PRIMARY OUTCOME 
E:I ratio (CART) 
 
x 
x 
 
 
x 
x 
x 
x 
 
x 
SECONDARY OUTCOMES 
CARTs (other than E:I) 
 
x 
x 
 
 
x 
x 
x 
x 
 
x 
HRV indices 
 
 
x 
 
 
x 
x 
x 
x 
 
x 
Cardiac vagal tone 
 
 
x 
 
 
x 
x 
x 
x 
 
x 
Fibrosis markers 
 
 
x 
 
 
x 
x 
x 
x 
 
x 
EXPLORATORY OUTCOMES 
Sudomotor function 
 
 
x 
 
 
x 
x 
x 
x 
 
x 
Orthostatic blood pressure 
 
 
x 
 
 
x 
x 
x 
x 
 
x 
Peripheral neuropathy 
 
 
x 
 
 
x 
x 
x 
x 
 
x 
Questionnaires  
 
 
x 
 
 
x 
x 
x 
x 
 
x 
Inflammatory markers 
 
 
x 
 
 
x 
x 
x 
x 
 
x 
Skin biopsy 
 
 
x 
 
 
 
 
x 
 
 
x 
Corneal neuropathy 
 
 
x 
 
 
 
 
x 
 
 
x 
Retinopathy 
 
 
x 
 
 
 
 
x 
 
 
x 
Table 1. 
* List of analytes can be found in section 9.4. 
 
5.6 
Randomization and blinding 
Participants will be randomized between the screening visit and study visit week 0. Participants will be 
randomized 1:1 by block randomization with four participants per block. Randomization lists will be made 
using the online tool at sealedenvelope.com.  
The Hospital Pharmacy of The Capital Region of Denmark (Marielundvej 25, 2730 Herlev) will coordinate 
the randomization process and allocation concealment. The randomization will be based on a computer 
generated random-number allocation sequence stored at the pharmacy. The randomization sequence will not 
be available to staff involved in data management, analysis, report writing or patient care until breaking 

Protocol v.3 
FibroCAN study 
Date 31/10-24 
 
of randomization code. Envelopes will be sequentially numbered, opaque and closed with tamper-proof seals 
and will be prepared by adequately trained staff at the pharmacy certified in handling of medicine and un-
blinded to the allocation sequence, but not involved in participant contact, data management or data analysis 
during the trial. Each center will have their participants randomize individually. Sealed codes are marked 
according to randomization code and distributed according to a pre-described order. 
 
Group allocation will be concealed to patients as well as investigators, and only revealed at the end of trial or 
if unblinding is needed.  
 
Should the unblinding of a study participant be necessary because of an emergency, a dedicated person at 
SDCC or SDCN not involved in the study will perform the procedure. Alternatively, the Principal investigator 
will be able to perform unblinding (as stated in the section “11.1 Unblinding”).  
Finerenone tablets and matching placebo tablets will be provided by Bayer and shipped to The Hospital 
Pharmacy of The Capital Region of Denmark (Marielundvej 25, 2730 Herlev) , Denmark where containers 
will be labeled and distributed to the study sites. 
 
5.7 
Adherence to protocol   
Drug accountability (pill count) will be performed at physical visits to document adherence to the study 
protocol. Adverse effects will be recorded at all study visits (as described below). 
 
5.8 
Trial termination criteria 
The trial will be terminated when: 
a) Participant number 100 has completed his/her last visit OR  
b) 74 participants have completed a full trial with data on a least the primary endpoint at last follow-up 
AND the remaining participants in the trial at this time point have completed their trial. 
 
 

Protocol v.3 
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Date 31/10-24 
 
5.9 
Study timeline  
The trial protocol will be approved by the Medical Research Ethics Committee (MREC) and the Danish 
Medicines Agency in 2024 with expected first patient first visit (FPFV) in January 2025 and last patient first 
visit in the end of 2025. Last patient last visit is expected to be in March 2027.  
The first papers on unblinded baseline measures of fibrosis, inflammation and neuropathy are expected to be 
published in mid-2026, whereas the first paper on trial outcomes will be published in around august 2027. 
Secondary papers in last quarter of 2027 to first quarter 2028 (see figure 2 below).  
 
Figure 2 FibroCAN Study timeline 
6 Statistical analysis  
6.1 
Sample size estimation 
Previously, 50 mg spironolactone has been shown to increase the resting heart rate variability measures (CAN 
measure) in the range of 2% (50) to 45% (51) in patients with congestive heart failure. We hypothesize that 40 
mg finerenone is equipotent to 50 mg spironolactone. However, to address i) that the present study consists of 
people with diabetes without heart failure and ii) a high variance of effect sizes in previous studies, and iii) 
that we will calculate power for an autonomic reflex test (CART), we estimate a modest efficacy of finerenone 
on the primary outcome (E/I ratio). We conservatively hypothesize that 40 mg finerenone will increase the E/I 
ratio by 15% compared to the placebo. A 15% increase in CAN measures is clinically relevant as the natural 
history of CAN is a reduction in all CAN measures over time (5).  
From a larger CAN screening study performed at SDCC, we have calculated that people with type 2 diabetes 
and early CAN have an E/I ratio of 1.13 ± 0.2. Thus, a 15% increase in E/I ratio equals to 0.17. With 90% 
power and a two-sided significance level of 0.05, the sample size needed to detect this change (with no 
expected placebo effect) is 37 participants in each group or 74 participants in total. Expecting a dropout rate 
of 20 % and to accommodate for the inaccuracies of assumptions above we aim for a sample size of 50 
participants in each group. Thus, a total of 100 participants will be recruited for the study. 

Protocol v.3 
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6.2 
Demographics and other baseline characteristics  
Baseline characteristics and demographics will be presented by treatment group and overall. The 
characteristics will include, but are not limited to, age, body mass index, hip and waist measures, smoking 
history, alcohol consumption, medical history including diabetes duration and baseline blood samples. 
6.3 
Treatment efficacy 
Treatment efficacy will be analysed by linear mixed-effect models with visit and treatment as fixed factors and 
a patient-specific random intercept to account for the correlation of repeated measurements within patients. 
Analyses will be done as intention-to-treat analyses as the primary analyses and subsequently as per-protocol 
analyses. The endpoints are analysed as between-group (finerenone vs. placebo) differences from baseline to 
78-week follow-up. The endpoints are listed in section 5,4 and with a focus on between-group changes in 
neuropathy (cardiovascular autonomic neuropathy, peripheral neuropathy and corneal/retinopathy) fibrosis, 
inflammation markers and other endpoints. We also plan a baseline analysis of baseline measures of endpoints 
to investigate possible association between fibrosis markers and inflammatory markers to the level of both 
autonomic and peripheral neuropathy. 
Statistical analysis will be performed using appropriate statistical software such as R or SAS. Descriptive 
statistics will be reported as mean (standard deviation) or median (quartile range) or frequencies and 
percentages for categorical variables. In between group differences will be analyzed using Fisher’s exact test 
or T-test. A two-sided P-value of 0.05 will be considered statistically significant.  
 
6.4 
Safety outcomes 
Serious adverse events, changes in serum potassium, and cases of hyperkalemia (moderate >5.5 mmol/L and 
severe >6.0 mmol/L) will be assessed. This includes the number of subjects hospitalized for hyperkalemia or 
discontinuing the study drug due to it. Renal function changes (eGFR) will be monitored, along with 
hospitalizations and drug discontinuations due to worsening renal function. Changes in other lab values will 
also be recorded. 
 
7 Participant selection  
7.1 
Inclusion criteria 
To be included in this study the participants must fulfill the following inclusion criteria. 
- 
Given informed consent 
- 
Type 2 diabetes defined by WHO criteria 
- 
Aged 40 ≥ at inclusion 

Protocol v.3 
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- 
Pathological E/I ratio (Mean value of three measures) 
7.2 
Exclusion criteria 
Participants will be excluded in one or more of the following criteria are met. 
- 
No CAN (no abnormal CARTs) 
- 
Definite CAN (more than one abnormal CART) 
- 
HbA1C >100 mmol/mol 
- 
Treatment with potassium-sparing diuretics (amiloride) or MRAs e.g., spironolactone or eplerenone 
which cannot be discontinued 4 weeks prior to screening visit. The patient’s primary physician, who 
is not involved in this study, will determine if discontinuation is possible. 
- 
Atrial fibrillation/flutter 
- 
Congestive heart failure (NYHA class 3-4)  
- 
History of cardiac arrhythmia  
- 
Severe forms of respiratory disease including asthma and COPD 
- 
Any nondiabetic cause of neuropathy 
- 
All female subjects of childbearing potential (WOCBP) must have a negative result of a highly 
sensitive urine HCG (pregnancy test) performed at screening. Subjects of childbearing potential must 
agree to use a highly effective form of contraception throughout the duration of the study (list of 
definition on WOCBP and accepted contraception in appendix A).  
- 
Severe hepatic impairment 
- 
Lactose intolerance 
- 
Breastfeeding 
- 
Nephropathy requiring dialysis 
- 
Beta-blocker-use 
- 
Hyperkalemia at screening visit (serum potassium >4.8 mmol/l) 
- 
eGFR < 25 ml/min/1.73m2 
- 
serum potassium > 4.8 mmol/l (at randomization)  
- 
Treatment with strong CYP3A4-inhibitors (e.g. Itraconazol, ketoconazol, ritonavir, cobicistat, 
clarithromycin) which cannot be discontinued 4 weeks prior to screening visit 
- 
Treament with moderate to strong CYP3A4-induceres (e.g. rifampicin, carbamazepine, phenytoin, 
phenobarbital, St John’s Wort or efavirenz) which cannot be discontinued 4 weeks prior to screening 
visit 
- 
have received chemotherapeutic treatment within last 12 months 
- 
Grapefruit consumption that cannot be discontinued during the study period 
- 
inability to complete study protocol, assessed to investigator 

Protocol v.3 
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Date 31/10-24 
 
- 
not able to read, write and/or understand Danish  
 
7.3 
Withdrawal criteria 
Participants will be withdrawn from the study if: 
- 
The following diagnoses are given during the study  
o Pregnancy 
o Cancer 
o Addison’s disease 
- 
The investigator judges it necessary e.g., due to medical reasons or severe non-compliance to the 
protocol.  
Withdrawal on participants request will be accepted at any time without further justification or consequence 
to regular treatment at SDCC and SDCN. Withdrawn patients will not be replaced. 
7.4 
Screening of eligible participants 
Screening cohorts 
Participants will be recruited by the treatment responsible doctor or study personnel affiliated with SDCC or 
SDCN. Participants will be identified from 1) business intelligence-generated reports identifying specific 
patients based on relevant ICD-10 codes, 2) cohorts of previous studies (if they have agreed to be contacted 
regarding other studies in diabetes research) e.g., a recently finalized neuropathy screening study (the DANES 
study) at SDCC, where participants have agreed to be contacted regarding other studies. Here 899 people with 
type 2 diabetes were screened for CAN. From the DANES study and a previous CAN screening study, we 
know that the prevalence of early CAN at SDCC is approximately 26% (32) amounting to 234 type 2 patients 
from the DANES study eligible for recruitment. Moreover, a backup cohort of 700 people with type 2 diabetes 
screened for CAN at SDCC in 2013 is available as a secondary source of participants. At SDCN participants 
will be recruited among former participants from previous studies investigating CAN, where 170 participants 
have agreed to be contacted regarding clinical studies. Moreover, patients may be recruited from reading 
recruitment posters placed in the primary sector, out-patient clinics, patient associations, and health community 
centers (Sundhedshuse). Both centres will recruit 50 participants.  
 
Use of electronic patient records 
Potential study participants will be prescreened for inclusion and exclusion criteria by access to their electronic 
medical record. This assess will be granted by the treatment-responsible doctor at the treatment center. This 
will be conducted in accordance with Sundhedsloven § 46, stk 1, under the responsibility of the primary 

Protocol v.3 
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investigator at the respective centers. This pre-screening approach will allow the researchers to avoid, 
contacting un-eligible persons and thus save time and costs. 
 
7.5 
Initial contact to potential study participants 
Eligible participants will be contacted by digital post (e-boks) or regular letter by study personnel to enquire 
if the person is interested in participating. If this is the case, written information about the study will be send. 
People will be given a 7-day period to respond to the contact. If no response has been recorded, the person will 
be contacted in writing a second time. After an additional 7 days of no response, study personnel will contact 
the given person by telephone to ask for interest in participation. 
 
The written material will be sent (‘Deltagerinformation’) along with the leaflet about the rights of participants 
in a clinical trial (‘Dine rettigheder som forsøgsperson i forsøg med medicin’). The patients will have the 
possibility to contact the investigators responsible for the study by telephone or e-mail in the time of reflection 
to inquire about the study.  
 
7.6 
Participant information visit 
Prior to enrolment participants will be invited to an information visit where they will receive verbal information 
about the study by a health care professional at the study site in a quiet room. During this information visit, 
study personnel will inform the potential participant about the purpose of the study and the explain the 
experimental procedures, the potential benefits/risks and answer all study-related questions. It is underlined 
that participation is voluntary and the participant can withdraw his/her consent anytime without consequences. 
All individuals are informed that they can bring an assessor to both the information session and study visits. 
 
All study individuals who participate in the information visit sessions will be allowed time to reflect about 
their participation, however no longer than 14 days. The information visit and screening visit can be scheduled 
to the same day if the patient wishes and gives informed consent.  
7.7 
Screening 
Following informed consent, participants will be invited for a screening visit at one of the study sites. This 
screening visit may be performed at the same day as the participant information visit if the participant whishes 
this. The screening will be performed by a study-affiliated medical doctor, who will go through medical 
history, medication and if necessary, examine the participant. If the study-affiliated medical doctor can confirm 
eligibility the participant will be enrolled in this study. At the screening visit 7 ml of blood will be drawn after 
informed consent is given. The blood will be analyzed immediately to assess exclusion biomarkers: potassium, 

Protocol v.3 
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HbA1c and eGFR (see table in section “9.4 
Blood/urine 
sampling 
and 
molecular 
(fibrosis 
and 
inflammatory proteins) testing.”). Results from blood analyses will be assessed by study personnel prior to 
randomization. 
 
When the participant has been enrolled, he/she will be randomized to a study arm. Participants will be 
randomized between the screening visit and study visit week 0 by authorized study personnel as described 
under “5.6 Randomization and blinding”. 
 
8 Study medication: description, handling, and storage 
Excessive overactivation of the mineralocorticoid receptors promotes reactive oxygen species (ROS) 
production, and mediates inflammatory and fibrogenic processes, which can lead to myocardial hypertrophy, 
ventricular remodeling, glomerular hypertrophy, glomerulosclerosis, and vascular endothelial dysfunction (27, 
28). Finerenone is a selective mineralocorticoid receptor antagonist and by blocking the mineralocorticoid 
receptor the binding of receptor coactivator and the following pro-inflammatory and pro-fibrotic gene 
transcription is inhibited. 
 
8.1 
Packaging and labelling 
The study medication will be manufactured, packaged, and distributed in accordance with the principles of 
Good Manufacturing Practice, under the responsibility of Bayer. Finerenone and matching placebo tablets will 
be delivered by Bayer to The Hospital Pharmacy of The Capital Region of Denmark (Marielundvej 25, 2730 
Herlev). Tablets will be provided in a container labelled with study name, batch number, “study medication”, 
a unique Id number, daily dosing paradigm and contact information. Labeling and secondary packaging will 
be performed by trained and qualified personnel in The Hospital Pharmacy of The Capital Region of Denmark 
(Marielundvej 25, 2730 Herlev) according to Annex 13 of the Good Manufacturing Practice guidelines of the 
European Commission, ICH, GCP guidelines, and local law. No manipulation, repackaging, or relabeling of 
study medication is permitted after qualified person release by The Hospital Pharmacy of The Capital Region 
of Denmark (Marielundvej 25, 2730 Herlev). Control of receipt will be done according to the Good Clinical 
Practice Guideline by qualified personnel at the investigational site. Trained and qualified study site staff will 
provide each participant with sufficient finerenone or placebo tablets until their next physical visit. 
 
8.2 
Biobank Storage 
All study medication will be stored in a secure place in a dedicated room under appropriate storage conditions 
(locked, dark room at room temperature) at each study site. Only authorized study personnel will have access. 

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All medication will be labeled with information that it is only intended for use in a clinical trial. Left-over and 
unused study medication will be disposed of according to local and GCP guidelines. A detailed count of the 
study medication dispersion and storage will be kept. 
9 Methods and measures 
 
9.1 
Pre-examination restrictions 
All testing of CARTs will be performed between 8 and 12 o´clock. Participants will be asked to fast from 
midnight prior to testing.  The participants will be asked to refrain from nicotine, caffeine, and alcohol 8 hours 
before an examination visit. Participants will be asked to refrain from strenuous exercise 24 hours prior to an 
examination day.  
 
9.2 
Cardiovascular autonomic reflex testing and heart rate variability 
Cardiac autonomic reflex tests (CARTs) are the gold standard to assess CAN (33) CARTs are measured using 
the Vagus™ device (Medicus Engineering, Aarhus, Denmark) that use a 1-lead ECG to obtain R-R intervals. 
The Vagus™ device is CE-marked and recognized internationally for its role in screening for diabetic 
autonomic neuropathy (CAN)(34, 35). Prior to testing the participants will see video instruction of how to 
perform the tests. The participants will be guided though the test by the examinator and information on the 
screen of the VagusTM-device. Prior to testing the participants will rest in the supine position in a quiet room 
for 10 minutes. The test will consist of the following tests.   
- 
A 5-minute resting heart rate variability measurement in the supine position. 
- 
The 30/15 ratio: the ratio between the 30th RR-interval (the longest) and the 15th (the shortest) after 
shifting from lying to standing position. 
- 
The E/I ratio: the ratio of the RR-intervals during expiration and inspiration in a one-minute cycle of 
deep breathing. (Primary endpoint), (Performed three times). 
- 
The Valsalva ratio: the ratio of the longest RR-interval after a 15 second strained expiration (40 
mmHg) and the shortest RR interval during the strained expiration. 
All tests will be separated by one minute of rest. The CAN diagnosis is defined as two or more abnormal tests, 
early CAN by one abnormal test, and no CAN when the obtained tests were within the normal range of the 
specific age-dependent cut-off values (36). 
 
The following heart rate variability (HRV) indices will be derived from test 5-minute resting HRV: 
- 
SDNN: standard deviation of NN-intervals 

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- 
SDANN: standard deviation of the average NN-intervals 
- 
SDNNi: mean of the standard deviations of all the NN-intervals 
- 
RMSSD: Root mean square of successive NN-interval differences 
- 
VLF: very low frequency power (<0.04 Hz) 
- 
LF: low-frequency power (0.04–0.15 Hz) 
- 
HF: high-frequency power (0.15–0.4 Hz) 
- 
Total power (≤ 0.4 Hz) 
 
9.3 
Cardiac vagal tone 
During the 5-minute resting HRV measurement with the VagusTM device, the participant will be equipped with 
a three lead ECG recorder with a sampling rate 8 kHz for 5 minutes using the commercially available system 
(eMotion Faros, Mega Electronics Ltd, Kuopio, Finland). Cardiac vagal tone is quantified by phase 
demodulation of high-resolution time domain of RR-intervals. 
 
9.4 
Blood/urine sampling and molecular (fibrosis and inflammatory proteins) 
testing 
At each study visit blood and urine will be sampled for basic biochemical measures, inflammation, and fibrosis 
markers. Blood and urine samples will be collected according to the table below.  
 
Analyses of the following markers will be performed at the StenoLab at Steno Diabetes Center Copenhagen 
or the department of biochemistry at Aalborg University Hospital, Aalborg: HbA1c, lipids, eGFR, creatinine, 
potassium, sodium, ALAT, CRP, vitamin B12, hemoglobin, and blood glucose, urine albumin/creatine ratio.  
 
Serum samples will be analyzed for fibrosis markers including but not limited to PRO-C6 and C3M with 
enzyme-linked immunosorbent assay (ELISA) (Nordic Bioscience A/S Herlev, Denmark).  
 
Inflammation markers will be analyzed with the Olink Proteomic Target 96 Inflammation panel (Olink, 
Uppsala, Sweden). Samples will be analyzed by BioXpedia A/S 
 
Urine HCG, pregnancy test will be performed at screening visit, W36 and W78 for all women with childbearing 
potential (WOCBP). All WOCBP will be offered a urine HCG, pregnancy test at every visit. More information 
in Appendix A.  
 
 

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Assessment 
Analytes 
Amount  
Screening visit 
Potassium, HbA1c, eGFR 
7 ml for immediate 
analyses 
Baseline biochemistry 
(week 0) 
Markers of fibrosis and inflammation  
HbA1c, lipids, eGFR, creatinine, potassium, sodium, 
ALAT, CRP, vitamin B12, hemoglobin, and blood 
glucose, urine albumin/creatine ratio 
Research biobank: 30 
ml blood, 6 ml urine ml 
Future research biobank: 
20 ml blood, 5 ml urine. 
Follow-up 
biochemistry 
(Visit week 12, 24, 36, 
52, and 78) 
Markers of fibrosis and inflammation  
HbA1c, eGFR, creatinine, potassium, blood glucose, 
urine albumin/creatine ratio.  
Research biobank: 30 
ml blood, 6 ml urine ml 
Future research biobank: 
20 ml blood, 5 ml urine. 
Safety visits  
(Visit week 4, 8, 12, 
24, 36, 52, 64 and 78 
And after 4 and 20 
weeks at study 
medication dosage 
change) 
 
Potassium + eGFR 
4 ml blood for research 
biobank 
 
 
9.5 
Corneal neuropathy 
Confocal corneal microscopy will be used to assess the following outcomes: corneal nerve fiber density 
(CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and inferior whorl length 
(IWL). During CCM images from both central sub-basal nerve plexus and the inferior whorl region will be 
obtained, and images will be manually quantified. Measures will be obtained by use of the Rostock Cornea 
Module on the HRT3 platform (Heidelberg Engineering, Heidelberg, Germany).  
9.6 
Retinopathy 
The state of retinopathy will be assessed by fundus photo grading and optical coherence tomography (OCT) 
using the Topcon DRI OCT Triton or the Topcon 3D OCT2000 (Topcon Corporation, Tokyo, Japan). OCT 
enables imaging of the layers of the retina measuring their thickness. The average thickness of the retina as 
well as of thickness of the superior, inferior, nasal, and temporal quadrants will be assessed. Sural nerve 
conduction and amplitude 

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9.7 
Nerve conduction  
Nerve conduction velocity and amplitude of the Sural nerve will be assessed the average of three measures on 
both the left and right leg by use of the NC-StatR DPNCheck (NeuroMetrix, Inc., Waltham, USA). Age- and 
height-stratified perception thresholds will be applied for both tests (37). 
9.8 
Vibration sensation threshold 
Vibration perception threshold (VPT) will be measured by using biothesiometry (Bio-medical instruments, 
Ohio, USA) applied to the distal tip of the first toe on both feet. Cut-off above 25 V and age-sex-height specific 
cut-offs was applied (38, 39). Biothesiometry measurements will be repeated three times and averaged of the 
measures will be used.  
9.9 
Light touch and pain sensation 
Ten-gram and 75-gram monofilament (Neuropen, Owen Mumford Ltd, Oxford, UK) will be applied three 
times at four points on the plantar aspect of the foot (first toe, proximal to the first toe, third toe and fifth toe) 
in addition to the proximal to the nail on the first dorsal, third and fifth toes on each foot (33). All measures 
will be obtained on both feet. DPN will be defined as absence of sensation at all locations. 
 
Pain sensation will be assessed by pinprick (Neuropen, Owen Mumford Ltd, Oxford, UK). Pinpricks will be 
applied proximal to the nail on the first dorsal, third and fifth toes on each foot. DPN will be defined as no 
pain at any tested location. 
9.10 Cold and warm sensation of foot/lower leg  
Thermal sensation (25°C and 40°C) will be assessed by applying metal rolls bilaterally on the dorsal side of 
the first toe, dorsum of the foot and the anterior part of the low leg from 10 centimeter above the lateral 
malleolus and 10 centimeter proximately by Rolltemp-II (Somedic SenseLab AB)(40). All measures will be 
obtained on both legs. Abnormal sensation will be defined as bilateral abnormalities at the toes, either with or 
without an abnormal sensation of the foot and leg.  
9.11 Ancle and Patella reflexes (Reflex hammer) 
Ancle and Patella reflexes will be perform using a reflex hammer on both sides.  
9.12 Intraepidermal nerve fiber density (IENFD) 
Two skin punch biopsy will be obtained at week 0, 36 and 78 in accordance with published guidelines. Skin 
biopsies will be taken on the left leg on all participants and a less than ½ centimeter apart. Skin biopsies can 
be taken on the right side if there is a contra indication of performing a biopsy on the right side e.g. a skin 
condition.  
After intradermal injection of 1% lidocaine 10 cm proximal to the lateral malleolus, two skin biopsy will be 
obtained using sterile technique with a disposable 3-mm punch. Samples will be fixed with Zamboni fixative 

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overnight and then cryoprotected in 20% sucrose 0.1 M phosphate buffer. The biopsies will be stored at -80°C 
until further processing. Sections will be stained using the free-floating protocol, and intraepidermal nerve 
fiber density (IENFD quantified following international guidelines (41). The biopsies will be immunostained 
for fibrosis markers including but not limited to PRO-C6 and C3M (Nordic Bioscience A/S Herlev, Denmark). 
Analyses will be performed at Danish Pain Research Center, Aarhus University, Aarhus, Denmark 
 
9.13 Questionnaires for painful and painless peripheral neuropathy  
The following neuropathy questionnaires will be used to assess peripheral neuropathy: 
- 
The Douleur Neuropathique 4 (DN4) to assess painful peripheral neuropathy with a cut-off ≥ 4 (42).  
- 
Michigan Neuropathy Screening Instrument (MNSI) with ≥ 4 a cut-off  (43) 
The Toronto Consensus Criteria will be applied to categorize DPN into four groups: possible, probable, definite 
and subclinical (46). 
9.14 Sudomotor function of the hands/feet 
Peripheral small-fibre autonomic function will be assessed by electrochemical skin conduction (ESC) test on 
the hands and feet by the Sudoscan™ device (Impeto Medical, Paris, France. Age and gender stratified ESC 
thresholds for hands and feet were used (47). 
 
9.15 Questionnaires for autonomic neuropathy  
Autonomic dysfunction will be evaluated using the Composite Autonomic Symptom Scale 31 (Compass 31), 
where a cut-off ≥ 16(48) will be applied. Gastrointestinal symptoms were evaluated using the gastrointestinal 
symptom rating scale (GSRS) (cut-off  ≥ 1.53(49)) and the presence of symptoms of gastroparesis with the 
gastroparesis cardinal symptom index (GCSI) (cut-off  ≥ 2.6(50). 
 
9.16 Orthostatic blood pressure testing 
Supine blood pressure will be measured three times after 10 minutes of rest and the average of the last two was 
calculated. Standing blood pressure will be measured one, two, three, four and five minutes after rising from 
supine position. Orthostatic hypotension will be defined as decline in systolic blood pressure from lying 
position ≥ 20 mmHg or diastolic blood pressure ≥ 10 mmHg or a decrease in systolic blood pressure to < 90 
mmHg within five minutes of standing in accordance with guidelines of the European society of Cardiology 
(51). Blood pressure will be measured by automated oscillometric blood pressure (AND UA-787plus, A&D 
medical, California, USA). 
 
 

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10 Biobanks 
Research biobank 
A study related research biobank will be established to store samples for analyzing blood, and urine markers 
at all physical study visits obtained during the study. Theses samples are only to be used to assess predefined 
study biomarkers that are not analyzed immediately after drawing of blood. Participants will fill out the 
informed consent form regarding this biobank. The biobank will be established at the to study sites at SDCC 
and at SDCN for storage at -80 degrees Celsius until analysis. 30 ml blood and 6 ml urine will be collected 
from each visit. One 3-mm punch skin biopsy will be collected the research biobank at study visits week 0, 36, 
78.  
 
This material will be stored for analysis as described above in connection to the study. Safety potassium 
samples will be analysed immediately and will not be stored in any biobank. The final biochemical analysis 
will be carried out at SDCC. The samples will be destroyed when the last biochemical analysis has been 
performed no later than one year after last patient last visit.  
 
Biobank for future research 
All participants will be asked if they are willing to donate extra biological material to a biobank for future 
research. Guidelines from Danish data protection guidelines will be followed throughout the process. 
Participants will sign a separate informed consent form if they agree to have their biological material stored in 
the biobank for future use. If the participant wishes the material can be destroyed at any time.  
 
A total blood volume of approximately 20 ml blood will be draw for the biobank for future research at each 
physical visit and divided into samples of 3 x 1.8 ml plasma, 5 x 1.8 ml serum, 2 x 1 ml buffy-coat. In addition,  
1 x 5 ml urine. At visits 0+36+78 one 3-mm punch skin biopsy will be collected and stored. The material in 
the biobank for future use will be stored at SDCC or SDCN during the study in a freezer at -80 degrees Celsius. 
Study material will be shipped frozen (on dry ice) from SDCN to SDCC when appropriate and no later than 2 
months after last patient last visit.  
 
The material in the biobank for future use will be stored at SDCC, Borgmester Ib Juuls Vej 83, 2730 Herlev, 
in a freezer at -80 degrees Celsius. The material will be stored for 50 years.  
 

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Adverse effects and risks  
10.1 Adverse effects of finerenone 
Finerenone is currently under ‘supplerende monitorering” meaning all potential adverse reactions will be 
reported to the Danish Medicines Agency. The table below gives an overview of the known adverse reactions.  
Adverse reactions to finereone by System Organ Class (SOC) and frequency 
System Organ Class 
Potentially 
serious 
adeverse 
reactions 
Usually, non-serious adverse 
reactions 
Very common (>10%) 
Metabolism 
Hyperkalemia 
 
Common (1-10%) 
Test 
Elevated serum urate 
 
Metabolism 
Hyponatremia 
 
Renal system 
Reduced renal function 
 
Skin 
 
Pruritus  
Vascular  
Hypotension 
 
Non common (0.1-1%) 
Test 
 
Reduced hemoglobin 
 
10.2 Risk related to procedures 
The table below provides an overview of the risk related to the study procedures. 
Assessment  
Potential risks 
CARTs 
Dizziness 
HRV indices 
No risks 
Cardiac vagal tone 
Allergy (gel) 
Blood sampling 
Risk of bruises and/or infection 
Urine sampling 
No risks 
Corneal neuropathy 
Moderate discomfort on eye during examination 
Retinopathy 
Moderate discomfort on eye during examination 
Sural nerve assessment 
Transient discreet electrical pain 
Vibration sensation threshold 
No risk  
Light touch and pain sensation 
Transient discreet pain  
Cold/warm sensation 
Transient pain and/or unpleasantness  
Skin biopsy 
Bleeding, bruising and/or infection 
Questionnaires: peripheral neuropathy 
No risks 
Sudomotor function 
No risks 
Questionnaires: autonomic neuropathy 
No risks 
Orthostatic blood pressure 
Dizziness 
 
 

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10.3 Risk/Benefit assessment  
Finerenone may present a valuable therapeutic option for cardiovascular autonomic neuropathy (CAN), a 
severe complication affecting over 100 million people with diabetes globally and linked to increased 
morbidity and mortality. CAN independently predicts adverse cardiovascular outcomes such as arrhythmia, 
silent ischemia, and diabetic kidney disease. Hyperkalemia is a recognized risk of finerenone, reported in 
14% of treated patients versus 6.9% with placebo; however, most cases are mild and manageable, with 
serious events being rare (1.1%) (Investigator Brochure). In the FINEART-HF study, involving 3,000 
patients receiving finerenone (up to 40 mg), hyperkalemia-related hospitalizations were low (0.5% in the 
active group vs. 0.2% placebo) with no fatalities, supporting finerenone's potential favorable risk-benefit 
profile in CAN management for people with diabetes (31). 
11.  Assessment of safety and reporting  
11.1 
Unblinding 
The code for randomization numbers will be stored at The Hospital Pharmacy of The Capital Region of 
Denmark (Marielundvej 25, 2730 Herlev) until the study is completed, so that the investigators are not familiar 
with the contents behind the treatment. In addition, all sites receive for each randomization number a sealed 
envelope with information on the treatment given. The sealed envelopes will be kept in a secured place but 
authorized personnel (including investigator) will have access to the sealed envelopes at all times during the 
study period in case of emergency unblinding.If necessary, the investigator shall unblind the treatment code of 
the study medication immediately and as a result may occur without prior contact with the monitor/sponsor. 
However, the sponsor shall be contacted shortly (within 24 hours) after unblinding of the treatment code. If 
the envelope with the treatment code is broken, the date, time, the reason for unblinding and name of the person 
who broke the treatment code is recorded. 
11.2 
Safety endpoints 
All adverse events will be reported from week 0 to the end of safety follow-up visit four weeks after the 
participant has received the last dose of the investigational medication. An adverse event related to finerenone 
treatment is hyperkalemia therefore safety serum potassium tests will be performed at week 4, 8, 24, 36, 52, 
64, 78 and additionally after 4 and 20 weeks if study drug dosage is changed.  
 
11.3 
Adverse events and reactions 
Definitions of serious adverse events (SAE), serious adverse reactions (SAR) and suspected unexpected 
serious adverse rations (SUSAR) 

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- 
Serious adverse event (SAE) or serious adverse reaction (SAR) an untoward medical occurrence or 
affect that at any dose results in death, is life-threatening, requires hospitalization or prolongation of 
existing hospitalization, results in persistent or significant disability, or is a congenital anomaly or 
birth defect. 
- 
Suspected unexpected serious adverse reaction (SUSAR) an untoward and unintended response to a 
study drug, which is not listed is the applicable product information, and meets one of the following 
serious criteria: results in death, is life-threatening, requires hospitalization or prolongation of an 
existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital 
anomaly or birth defect. 
Definition of adverse event (AE), adverse reactions (AR), unexpected adverse reactions (UAR)   
 
- 
Adverse event (AE) any untoward medical occurrence in the patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with this 
treatment, as assessed by the investigator, as this is a medical decision. 
- 
Adverse reaction (AR) any untoward and unintended response to an investigational medicinal 
product related to any dose administered.  
- 
adverse reaction (AR) any untoward and unintended response to an investigational medicinal 
product related to any dose administered.  
Guideline for assessing the relationship between adverse events and treatment 
- 
Unrelated - no temporal relationship or other etiologies are very likely the cause. 
- 
Unlikely related – unlikely temporal relationship or other etiologies are more likely the cause. 
- 
Possibly related - less clear temporal relationship, other etiologies are also possible. 
- 
Probably related - clear temporal relationship with improvement after discontinuation of medicament 
and not reasonably explained by the patient's clinical condition known. 
- 
Related - clear temporal relationship with laboratory confirmation or a positive new additional 
treatment trial. 
Severity grading 
- 
Mild: Usual transient and generally not interfering with normal activities 
- 
Moderate: discomforting enough to interfere with normal activities 
- 
Severe: Prevents normal activities 
Reporting of adverse events 
The investigator will assess causality of AEs/SAEs and the investigator shall report all SAEs to the sponsor 
within 24 hours. This is for the sponsor in time to enter the event(s) to the Eudravigilance database if it is 

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considered a SUSAR. The information to the sponsor should include patient number, name of investigator, 
detailed description of the SAE, investigator’s assessment of the relationship between the adverse events and 
the study drug, a statement that the event is serious and that it is unexpected, and the consequence for the study 
and the serious adverse event form. 
 
The sponsors shall ensure that information about all unexpected and serious adverse reactions, which are fatal 
or life-threatening, are registered and reported through the Eudravigilance database as soon as possible and not 
later than 7 days after the sponsor has been made aware of such a suspected adverse reaction. Not later than 8 
days after the reporting, the sponsor shall notify the relevant authorities (e.g., the Danish Medicines Agency 
and the Ethics Committee) with all relevant information on sponsor's and investigator's follow-up on the report. 
All other unexpected and serious suspected adverse reactions shall be reported to DMA and EC not later than 
15 days after the sponsor has been made aware of these. SUSAR reporting will be done electronically using 
the Eudravigilance database. 
 
Once a year during the entire trial period, the sponsor will prepare a list of all suspected serious adverse 
reactions, which have occurred during the trial period, and a report on the trial subjects' safety. List and report 
will be submitted to the Clinical Trials Information System (CTIS). 
 
Follow-up after reporting of an adverse reaction 
Following the adverse effect reported by the patient, this will be followed up at the next visit. If the patient 
drops out of the trial, the adverse event will be followed up with a telephone call after one month. 
 
Reference Document 
The SmPC from the Danish Health and Medicine Authority is used as a reference document for assessing 
SUSARs. 
 
Patient dropout because of events 
Any patient can because of an event, regardless of the time, be excluded from the trial according to the 
investigator's discretion. 
12 Data management 
All personal information will be protected under the General Data Protection Regulation (GDPR), and in 
accordance with GDPR article 30. The project will be registered in both Capital Region of Denmark (SDCC) 
and North Denmark Region (SDCN). 
 

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Essential study documents will be stored in REDCap, secure computer drives or at the study site in the trial 
master file. The investigator is responsible for archiving all relevant source documents so that the trial data can 
be compared against source data after completion of the study. Data will be stored for 25 years. The principal 
investigator must maintain complete and accurate records to ensure that the execution of the study is fully 
documented, and the study data subsequently can be verified. These documents should be classified into two 
separate categories: (1) the researcher's Trial Master File and (2) the participant's clinical source documents 
(eCRF). The trial master file must contain the protocol/amendments, correspondence with the Medical 
Research Ethics Committee and Danish Data Protection Agency, informed consent, staff curriculum vitae, 
forms, and other appropriate documents/correspondence. Investigator allows direct access to all source data 
and documents, auditing, and inspection. 
 
Electronic Case Report Forms (eCRFs) will be completed for each subject enrolled in this study, to the extent 
possible directly in Research Electronic Data Capture (REDCap) without the use of a paper CRF. The site 
investigator will document subject data in his/her own subject files or in REDCap. These subject files will 
serve as source data for the study. Errors and corrections are logged as provided by the REDCap interface, and 
information from the original version will still be available. When data have been entered, reviewed, and 
verified, the data will be locked to prevent editing. 
 
13 Quality control and quality assurance 
The study will be conducted in accordance with Good Clinical Practice (GCP). 
13.1 
Monitoring 
This trial will be monitored by the GCP Unit at Aalborg University Hospital and Copenhagen University. The 
monitor (the person who is responsible for monitoring) will advise the investigator on the experimental 
implementation and assist him/her in working in accordance with the protocol, GCP and the regulatory 
requirements. 
 
The investigator will allow the sponsor or its representatives to conduct periodic monitoring during the trial 
and after the trial has been completed, control/monitoring of all CRFs and the corresponding source documents. 
The monitor must therefore have direct access to these records. Monitoring visits will give the sponsor or his 
representatives the opportunity to evaluate the progress of the trial to verify the accuracy and completeness of 
CRFs, to ensure that all protocol requirements, applicable local authority regulations and investigator 
obligations are met and to resolve any inconsistencies in the trial records. 

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13.2 
Direct access to source data / documents 
Investigators will permit trial-related monitoring by or on behalf of the sponsor, Medical Research Ethics 
Committee, the GCP unit and regulatory controller(s) by providing direct access to source data / documents. 
Source documents are original registrations in which raw data is first recorded. These include CRFs, eCRFs, 
diaries and patient records; definitive clarification of source data will be detailed in the trial master file. All 
source documents must be accurate, clear, unambiguous, lasting, and able to undergo audits. They are made 
using a permanent form of registration (ink, typing or optical disk). 
14 Ethical considerations 
This clinical study will be conducted in compliance with Good Clinical Practice (CPMP/ICH/135/95) 
Regulation 536/2014)), the protocol, designated Standard Operating Procedures, the Danish Medicines 
Agency, the Medical Research Ethics Committee, and within the principles of the Declaration of Helsinki 
(amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013).  
 
The trial will only be initiated once the approval from the Danish Medicines Agency and the Medical Research 
Ethics Committee is granted. Any significant modifications to the protocol will be submitted as protocol 
amendments and subsequently approved by the regulatory authorities. Information about the participants is 
protected by The General Data Protection Regulation and The Danish Health Care Act. 
 
 

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15 Budget  
The project is initiated by principal investigator Peter Rossing. This study has received funding from several 
entities, Svend Andersen Fonden has granted 700,000 DKK, Vissing Fonden has granted 442,400 DKK and 
Novo Nordisk fonden has granted 10,8 mio. DKK. Expenses covered by the various funding bodies are 
described in the table below.  
Study medication and matching placebo has been provided from Bayer A/S.  
The budget is sufficient to cover all material and study related human resources. The amount is administered 
from SDCC.  
None of the researchers have financial interest in the study. 
Foundation  
 
DKK 
Svend Andersen Fonden  Operational expenses 
700.000 
Vissing Fonden 
Equipment and operational expenses 
442.400 
Novo Nordisk Fonden 
Salary for Ph.d. students, post docs, senior researchers, 
operational expenses, dissemnination activities, travel costs, 
participation in international congresses and symposiums, 
administration costs and publication fees 
10.800.000 
 
Participants will receive travel reimbursement according to current legislation. The amount is not liable to tax. 
 
16 Insurance 
Participants are covered by the Danish Patient Compensation Association (Patienterstatningen). 
 
17  Dissemination of results  
The results of the study will be published regardless of the outcome. A summary of the results will be 
submitted to the CTIS portal as soon as possible and no later than one year after the study has ended. 
 
 

Protocol v.3 
FibroCAN study 
Date 31/10-24 
 
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19. 
Bradley JL, King RH, Muddle JR, Thomas PK. The extracellular matrix of peripheral nerve in diabetic 
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32. 
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Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G, et al. Intraepidermal nerve fiber 
density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst. 2010;15(3):202-7. 

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42. 
Spallone V, Morganti R, D'Amato C, Greco C, Cacciotti L, Marfia GA. Validation of DN4 as a 
screening tool for neuropathic pain in painful diabetic polyneuropathy. Diabet Med. 2012;29(5):578-85. 
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Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the 
prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia. 
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Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: 
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Greco C, Di Gennaro F, D'Amato C, Morganti R, Corradini D, Sun A, et al. Validation of the 
Composite Autonomic Symptom Score 31 (COMPASS 31) for the assessment of symptoms of autonomic 
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Moya A, Sutton R, Ammirati F, Blanc JJ, Brignole M, Dahm JB, et al. Guidelines for the diagnosis 
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Evangelista A, Flachskampf F, Lancellotti P, Badano L, Aguilar R, Monaghan M, et al. European 
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reporting of echocardiographic studies. Eur J Echocardiogr. 2008;9(4):438-48.  
 
 
 

Protocol v.3 
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Appendix A 
 
The following list comes from the Clinical Trials Coordination Group. This study will follow their 
recommendation (link: https://www.hma.eu/fileadmin/dateien/HMA_joint/00-_About_HMA/03-
Working_Groups/CTCG/2024_HMA_CTCG_Contraception_guidance_Version_1.2__March_2024.pdf).  
Short summary:  
Definition of women of childbearing potential: 
A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient.  
List of highly effective contraceptions that can be used in the trial:  
1. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition 
of ovulation1: 
a. Oral 
b. Intravaginal 
c. Transdermal 
 
2. progestogen-only hormonal contraception associated with inhibition of ovulation1:  
a. oral 
b. injectable 
c. implantable2 
3. intrauterine device (IUD)2 
4. intrauterine hormone-releasing system ( IUS)2 
5. bilateral tubal occlusion2 
6. vasectomised partner2,3 
7. sexual abstinence4 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of 
the contraception method (see section 4.3) 
2 Contraception methods that in the context of this guidance are considered to have low user dependency. 
3 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of 
the surgical success. 
4 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and 
the preferred and usual lifestyle of the subject.  

Protocol v.3 
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Appendix B 
 
List of medication that is prohibited during the trial: 
1. CYP3A4 inducers  
a. Rifampicin 
b. Carbamazepine 
c. Phenytoin 
d. Phenobarbital 
e. St John’s Wort / Perikon 
f. Efavirenz 
2. CYP3A inhibitors:  
a. Itraconazol 
b. Ketoconazol 
c. Ritonavir 
d. Cobicistat 
e. Clarithromycin 
f. Grapefruit 
3. MRA or potassium-sparing diuretics  
a. Amilorid 
b. Eplerenone  
c. Spironolactone  
4. Other 
a. Beta-blocker use 
b. Chemotherapeutic treatment within last 12 months