An Open-label, Randomized, 3-arm, Parallel-group, Positive- and Negative-arm Controlled Study to Evaluate the Mineralocorticoid Receptor Antagonism Effect of Vamorolone in Healthy Subjects
Phase: PHASE1
Conditions: Pharmacodynamic
Sponsor: Santhera Pharmaceuticals

SNT-I-VAM-026  
Title Page 
 
Protocol Title:  
An open-label, randomized, 3-arm, parallel-group, positive- and negative-arm controlled 
study to evaluate the mineralocorticoid receptor antagonism effect of vamorolone in healthy 
subjects 
Sponsor Protocol Number: 
SNT-I-VAM-026 
Nuvisan Protocol Number:  
N-A-PH1-23-067 
Investigational Medicinal 
Product:  
Vamorolone 
Study Phase:  
Phase 1 
Brief Title: 
Evaluation of vamorolone mineralocorticoid receptor 
antagonism in healthy subjects 
Sponsor:  
Santhera Pharmaceuticals (Switzerland) AG 
Hohenrainstrasse 24 
4133 Pratteln 
Switzerland 
Sponsor’s Legal 
Representative EU: 
 
Nuvisan GmbH 
Wegenerstr. 13 
89231 Neu-Ulm 
Germany 
Principal Investigator(s): 
Steffen Haffner, MD 
Nuvisan GmbH 
Wegenerstrasse 13 
89231 Neu-Ulm 
Germany 
Regulatory Agency Identifier 
Number(s): 
EU CT Number: 2024-512101-60-00  
Protocol Version: 
26-FEB-2024/Version Final 1.0  
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. 
Copyright © Nuvisan GmbH, Germany. All rights reserved. 
PPD

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Table of Contents 
 
Title Page  ................................................................................................................................. 1 
Table of Contents ....................................................................................................................... 2 
List of Abbreviations ................................................................................................................. 8 
1. 
Protocol Summary ................................................................................................. 12 
1.1. 
Synopsis .................................................................................................................... 12 
1.2. 
Flow Chart ................................................................................................................. 16 
1.3. 
Schedule of Activities ............................................................................................... 17 
2. 
Introduction ........................................................................................................... 22 
2.1. 
Study Rationale ......................................................................................................... 22 
2.2. 
Background ............................................................................................................... 22 
2.2.1. 
Vamorolone........................................................................................................ 22 
2.2.2. 
Eplerenone ......................................................................................................... 23 
2.2.3. 
Fludrocortisone .................................................................................................. 24 
2.2.4. 
Summary of Non-Clinical Studies ..................................................................... 24 
2.2.5. 
Summary of Clinical Studies ............................................................................. 25 
2.3. 
Benefit/Risk Assessment ........................................................................................... 27 
2.3.1. 
Risk Assessment ................................................................................................ 28 
2.3.2. 
Warnings and Precautions.................................................................................. 30 
2.3.3. 
Benefit Assessment ............................................................................................ 30 
2.3.4. 
Overall Benefit Risk Conclusion ....................................................................... 30 
3. 
Objectives and Endpoints ...................................................................................... 31 
4. 
Study Design.......................................................................................................... 32 
4.1. 
Overall Design........................................................................................................... 32 
4.2. 
Scientific Rationale for Study Design ....................................................................... 34 
4.3. 
Justification for Dose ................................................................................................ 35 
4.4. 
Start / End of Study Definition .................................................................................. 35 
5. 
Study Population.................................................................................................... 36 
5.1. 
Inclusion Criteria ....................................................................................................... 36 
5.1.1. 
Inclusion Criteria to be Checked at Screening ................................................... 36 

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5.2. 
Exclusion Criteria ...................................................................................................... 37 
5.2.1. 
Exclusion Criteria to be Checked at Screening.................................................. 37 
5.2.2. 
Exclusion Criteria to be Re-Checked upon Admission ..................................... 40 
5.3. 
Lifestyle Considerations ............................................................................................ 41 
5.3.1. 
Meals and Dietary Restrictions .......................................................................... 41 
5.3.2. 
Caffeine, Alcohol, and Tobacco ........................................................................ 43 
5.3.3. 
Activity .............................................................................................................. 43 
5.3.4. 
Other Restrictions .............................................................................................. 43 
5.4. 
Screen Failures .......................................................................................................... 44 
5.5. 
Criteria for Temporarily Delaying Enrollment, Randomization, Study Treatment .. 44 
6. 
Study Treatments(s) and Concomitant Therapy .................................................... 45 
6.1. 
Study Treatments Administered ................................................................................ 45 
6.2. 
Preparation, Handling, Storage, and Accountability ................................................. 47 
6.3. 
Assignment to Study Treatment ................................................................................ 48 
6.4. 
Blinding ..................................................................................................................... 49 
6.5. 
Study Treatment Compliance .................................................................................... 49 
6.6. 
Dose Modification ..................................................................................................... 49 
6.7. 
Continued Access to Study Treatment after the End of the Study ............................ 49 
6.8. 
Treatment of Overdose .............................................................................................. 50 
6.9. 
Prior and Concomitant Therapy ................................................................................ 51 
6.9.1. 
Rescue Medicine ................................................................................................ 51 
7. 
Discontinuation of Study Treatment and Subject Discontinuation/Withdrawal ... 52 
7.1. 
Discontinuation of Study Treatment ......................................................................... 52 
7.1.1. 
Stopping Rules for Individual Subjects ............................................................. 52 
7.2. 
Subject Discontinuation / Withdrawal from the Study ............................................. 53 
7.2.1. 
Discontinuation / Withdrawal Criteria for Individual Subjects ......................... 53 
7.2.2. 
Replacement of Subjects .................................................................................... 54 
7.3. 
Further Stopping Rules.............................................................................................. 55 
7.3.1. 
Premature Discontinuation of the Complete Study ........................................... 55 
7.4. 
Lost to Follow-up ...................................................................................................... 55 
8. 
Study Assessments and Procedures ....................................................................... 56 

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8.1. 
Administrative and General Procedures .................................................................... 57 
8.1.1. 
Demographic ...................................................................................................... 57 
8.1.2. 
Body Weight and Height, BMI .......................................................................... 57 
8.1.3. 
Medical History ................................................................................................. 57 
8.1.4. 
Other Baseline Characteristics ........................................................................... 57 
8.2. 
Efficacy and/or Immunogenicity Assessments ......................................................... 57 
8.3. 
Safety Assessments ................................................................................................... 57 
8.3.1. 
Physical Examinations ....................................................................................... 58 
8.3.2. 
Vital Signs .......................................................................................................... 58 
8.3.3. 
Electrocardiograms ............................................................................................ 58 
8.3.4. 
Clinical Safety Laboratory Tests ....................................................................... 59 
8.3.5. 
Other Assessments ............................................................................................. 60 
8.4. 
Adverse Events and Serious Adverse Events ............................................................ 60 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .............. 60 
8.4.2. 
Method of Detecting AEs and SAEs ................................................................. 61 
8.4.3. 
Follow-up of AEs and SAEs .............................................................................. 61 
8.4.4. 
Regulatory Reporting Requirements for SAEs .................................................. 61 
8.4.5. 
Adverse Events of Special Interest .................................................................... 62 
8.5. 
Pharmacokinetics ...................................................................................................... 62 
8.5.1. 
Bioanalytical Methods ....................................................................................... 63 
8.5.2. 
Pharmacokinetic Evaluation .............................................................................. 63 
8.6. 
Pharmacodynamics.................................................................................................... 64 
8.7. 
Genetics ..................................................................................................................... 66 
8.8. 
Biomarkers ................................................................................................................ 66 
8.9. 
Immunogenicity Assessments ................................................................................... 66 
8.10. Medical Resource Utilization and Health Economics............................................... 66 
9. 
Statistical Considerations ...................................................................................... 67 
9.1. 
Statistical Hypotheses ............................................................................................... 67 
9.2. 
Analysis Sets ............................................................................................................. 67 
9.3. 
Statistical Analyses ................................................................................................... 67 
9.3.1. 
Efficacy Analyses .............................................................................................. 68 

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9.3.2. 
Safety Analyses .................................................................................................. 68 
9.3.3. 
Pharmacokinetic Analyses ................................................................................. 68 
9.3.4. 
Pharmacodynamic Analyses .............................................................................. 68 
9.3.5. 
Other Analyses ................................................................................................... 69 
9.4. 
Interim Analysis ........................................................................................................ 69 
9.5. 
Sample Size Determination ....................................................................................... 69 
9.6. 
Protocol Deviations ................................................................................................... 69 
9.7. 
Data Management ..................................................................................................... 70 
9.7.1. 
Database Lock .................................................................................................... 70 
9.7.2. 
Soft Lock ............................................................................................................ 70 
9.7.3. 
Data Review Meeting ........................................................................................ 70 
9.7.4. 
Hard Lock .......................................................................................................... 70 
9.7.5. 
Data Standards ................................................................................................... 70 
10. 
Supporting Documentation and Operational Considerations ................................ 71 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................... 71 
10.1.1. Regulatory and Ethical Considerations .............................................................. 71 
10.1.2. Financial Disclosure........................................................................................... 72 
10.1.3. Clinical Study Insurance and Subject Compensation ........................................ 72 
10.1.4. Informed Consent Process ................................................................................. 72 
10.1.5. Protocol Amendment ......................................................................................... 73 
10.1.6. Recruitment ........................................................................................................ 73 
10.1.7. Data Protection................................................................................................... 73 
10.1.8. Committees Structure......................................................................................... 74 
10.1.9. Dissemination of Clinical Study Data................................................................ 75 
10.1.10. Data Quality Assurance ..................................................................................... 75 
10.1.11. Source Documents ............................................................................................. 76 
10.1.12. Study and Site Closure ....................................................................................... 76 
10.1.13. Publication Policy .............................................................................................. 77 
10.1.14. Clinical Study Report ......................................................................................... 77 
10.2. Appendix 2: Clinical Laboratory Tests ..................................................................... 78 

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .................................................................................................... 81 
10.3.1. Definitions.......................................................................................................... 81 
10.3.2. Definition of SAE .............................................................................................. 82 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................... 84 
10.3.4. Reporting of SAEs ............................................................................................. 87 
10.4. Appendix 4: Pharmacokinetic Parameters ................................................................ 88 
10.5. Appendix 5: Sponsor Signature Page ........................................................................ 89 
10.6. Appendix 6: Principal Investigator Signature Page .................................................. 90 
11. 
References ............................................................................................................. 91 
 

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List of Tables 
Table 1: 
Schedule of Activities ............................................................................................ 18 
Table 2: 
Objectives and Endpoints ...................................................................................... 31 
Table 3: 
Food and drink before and after dosing of study treatments ................................. 42 
Table 4: 
Study Treatments ................................................................................................... 45 
Table 5: 
Pharmacokinetic Blood Collection Schedule for Vamorolone.............................. 62 
Table 6: 
Pharmacokinetic Blood Collection Schedule for Eplerenone ............................... 63 
Table 7: 
Non-compartmental Pharmacokinetic Parameters for Vamorolone and Eplerenone 
in Plasma................................................................................................................ 64 
Table 8: 
Urine Collection Schedule for Sodium and Potassium Measurements ................. 65 
Table 9: 
Analysis Sets.......................................................................................................... 67 
Table 10: 
Protocol-Required Safety Laboratory Assessments ........................................... 79 
 
List of Figures  
Figure 1: 
Overall Study Design – Schematic Overview ................................................... 16 
Figure 2: 
Chemical Structure of Vamorolone ................................................................... 23 
 

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List of Abbreviations 
Abbreviations of PK parameters are provided in Section 10.4. 
ADaM 
Analysis data model 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
anti-HIV 
Anti-human immunodeficiency virus antibodies 
anti-HCV 
Hepatitis C antibody 
AST 
Aspartate aminotransferase 
AxMP 
Auxiliary medicinal product 
BA 
Bioavailability 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte (German Federal 
Institute for Drugs and Medical Devices) 
BMD 
Becker muscular dystrophy 
BMI 
Body mass index 
CA 
Competent authority 
CDISC 
Clinical data interchange standards consortium 
COVID-19 
Coronavirus disease 2019 
CK 
Creatine kinase 
CKD-EPI 
Chronic kidney disease epidemiology collaboration 
CRF 
Case report form  
CRO 
Contract research organization 
CTS 
Clinical trial supplies department  
CV 
Coefficient of variation 
CYP 
Cytochrome P450 

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DMD 
Duchenne muscular dystrophy 
DRM 
Data review meeting 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form  
ED 
Early discontinuation 
eGFR 
Estimated glomerular filtration rate 
ENT 
Ear, nose, throat 
EOS 
End of study 
EU 
European Union 
FU 
Follow-up 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GLDH 
Glutamate dehydrogenase 
GLP  
Good laboratory practice  
GR 
Glucocorticoid receptor 
HBsAG  
Hepatitis B virus surface antigen  
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator's brochure 
ICF 
Informed consent form 
ICH 
International conference for harmonization 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 

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INR 
International normalized ratio 
IUD 
Intrauterine device 
K 
Potassium 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantification 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Mineralocorticoid receptor 
MRA 
Mineralocorticoid receptor antagonist 
Na 
Sodium 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PR 
Pulse rate 
QP 
Qualified person 
QRS 
Part of electrocardiographic wave representing ventricular depolarization 
RSI 
Reference safety information 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SDTM 
Study data tabulation model 
SmPC 
Summary of product characteristics 

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SoA 
Schedule of activities 
SOC 
System organ class 
SOP  
Standard operating procedure  
SUSAR  
Suspected unexpected serious adverse reaction  
TEAE 
Treatment emergent adverse event 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
 

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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: 
An open-label, randomized, 3-arm, parallel-group, positive- and negative-arm controlled 
study to evaluate the mineralocorticoid receptor antagonism effect of vamorolone in healthy 
subjects 
Brief Title: 
Effect of vamorolone on mineralocorticoid receptor in healthy subjects 
Regulatory Agency Identifier Number(s):  
EU CT number: 2024-512101-60-00 
Rationale:  
The purpose of this study is to evaluate the PD antagonistic effect of a single dose of 
vamorolone at the MR. This will be assessed by determining the anti-aldosterone activity 
after repeated administration of fludrocortisone in healthy subjects.  
The potential anti-mineralocorticoid properties of vamorolone suggested by preclinical 
studies are promising given the known involvement of the renin-angiotensin-aldosterone axis 
in the pathogenesis of skeletal muscle fibrosis and cardiomyopathy in DMD (Rodriguez-
Gonzalez et al., 2020; Howard et al., 2022). 
Urinary Na and K levels after fludrocortisone challenge are used to determine the 
anti-aldosterone activity of vamorolone, as it should reverse the urinary electrolyte effect 
induced by fludrocortisone, which is known to have a strong sodium retention capacity.  
To increase the reliability and validity of the study results by minimizing bias and controlling 
for confounding variables, the study design will have 3 different arms: vamorolone 
experimental arm, eplerenone active control arm, and no treatment negative control arm. All 
study arms will receive a fludrocortisone challenge. The urine levels of Na and K will be 
compared before and after fludrocortisone administration. 
This information is critical to translating the findings to the intended DMD patient population 
with a better understanding of the potential risks and benefits. 
The proposed doses, which have been previously shown to be safe, have undergone extensive 
in vitro and in vivo evaluation with no genotoxicity observed. 
Only male subjects will be enrolled to eliminate potential effects of circulating hormones on 
endpoints. 

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Number of Subjects: 
30 healthy male subjects (18 to 55 years, inclusive) will be randomized to one of the 3 study 
arms: 
 Study arm 1 (experimental arm): vamorolone  
 Study arm 2 (positive control arm): eplerenone  
 Study arm 3 (negative control arm): no treatment 
Dropouts may be replaced if the number of evaluable subjects completing the study becomes 
or is expected to become less than 24 subjects in total, i.e., less than 8 subjects in each study 
arm. 
Study Treatment Groups and Duration: 
The maximum total duration for a subject in the study will be approximately 32 days, from 
screening until the follow-up safety phone call. 
Subjects will be screened for eligibility within 19 days of admission. Subjects will be 
admitted to the study site on Day -2 and will remain inpatient at the study site under medical 
supervision until discharge on Day 4. 
The treatment duration will be 3 days and subjects will receive the study treatments as 
follows: 
 Fludrocortisone challenge on Days 1 to 3 (for all subjects): 
o Day 1:  
 Fludrocortisone 1 mg at 9 h predose vamorolone /eplerenone 
administration/corresponding timepoint for negative control arm 
o Day 2: 
 Fludrocortisone 0.5 mg at the same time of vamorolone/eplerenone 
administration in the morning (0 h) /corresponding timepoint for negative 
control arm. 
 Fludrocortisone 0.1 mg at 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 14 h 
vamorolone/eplerenone postdose administration/corresponding timepoint for 
negative control arm. 
 Fludrocortisone 0.5 mg at 16 h vamorolone/eplerenone postdose 
administration/corresponding timepoint for negative control arm.  
o Day 3: 
 Fludrocortisone 0.1 mg at 24 h vamorolone/eplerenone postdose 
administration on Day 2/corresponding timepoint for negative control arm. 

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 Day 2: drug administration period (vamorolone or eplerenone or no treatment) 
o 10 subjects randomized to study arm 1 will receive a single oral dose of 20 mg/kg 
vamorolone 
o 10 subjects randomized to study arm 2 will receive a single oral dose of 200 mg 
eplerenone 
o 10 subjects randomized to study arm 3 will receive no treatment 
Subjects will be served diet-controlled meals from Day -2 to Day 3, i.e., containing similar 
quantities of sodium and potassium. 
In-house follow-up assessments are planned on Day 4, 1 day after the last dose of study 
treatment. A follow-up safety phone call is planned on Day 11. 
Early discontinuation assessments will be conducted at an early discontinuation visit for 
subjects who have withdrawn prematurely. 
Data Monitoring/Other Committee: No 

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1.3. 
Schedule of Activities 
A SoA presenting the timepoints for the study-related measures / actions is provided in Table 1. 
 Whenever different assessments and procedures are to be performed at the same nominal 
time, the following sequence will be followed (except for screening and Day -2 evaluations): 
1. 12-lead ECG / vital signs 
2. Urine sampling as most important for the primary objective in this study will end 
immediately before blood sampling each. 
3. Blood sampling (PK and safety) as close as possible to the nominal time  
4. All other assessments and procedures 
 Any assessments / actions at the timepoint of dosing will be performed predose and 
administration of the study treatments is the last action for the respective timepoint, unless 
indicated otherwise.  
 Any meals or fluid intake will be provided once the assessments / actions for a given 
timepoint are completed.  
 Assessment time windows will be defined according to Nuvisan SOP in a separate document. 
Any time deviations falling into the allowed time windows will not be considered a protocol 
deviation. 
 
 

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2. 
Introduction 
Vamorolone 40 mg/mL oral suspension has received Marketing Authorization in the European 
Union, UK, and the US for use in patients with DMD. Vamorolone is also being developed for 
use in BMD; this indication is under clinical investigation. 
2.1. 
Study Rationale 
The purpose of this study is to evaluate the PD antagonistic effect of a single dose of vamorolone 
at the MR. This will be assessed by determining the anti-aldosterone activity after repeated 
administration of fludrocortisone in healthy subjects.  
The potential anti-mineralocorticoid properties of vamorolone suggested by preclinical studies 
are promising given the known involvement of the renin-angiotensin-aldosterone axis in the 
pathogenesis of skeletal muscle fibrosis and cardiomyopathy in DMD (Rodriguez-Gonzalez et 
al., 2020; Howard et al., 2022). 
Urinary Na and K levels after fludrocortisone challenge will be used to determine the 
anti-aldosterone activity of vamorolone, as it should reverse the urinary electrolyte effect 
induced by fludrocortisone, which is known to have a strong sodium retention capacity. To 
increase the reliability and validity of the study results by minimizing bias and controlling for 
confounding variables, the study design will have 3 different arms: vamorolone experimental 
arm, eplerenone active control arm, and no treatment negative control arm. All study arms will 
receive a fludrocortisone challenge. The urine levels of Na and K will be compared before and 
after fludrocortisone administration. 
This information is critical to translating the findings to the intended DMD patient population 
with a better understanding of the potential risks and benefits. 
The proposed doses, which have been previously shown to be safe, have undergone extensive in 
vitro and in vivo evaluation with no genotoxicity observed. 
Only male subjects will be enrolled to eliminate potential effects of circulating hormones on 
endpoints. 
2.2. 
Background 
2.2.1. 
Vamorolone 
Vamorolone as a dissociative corticosteroid selectively binds to the GR, triggering 
anti-inflammatory effects, and binds to the MR, inhibiting MR activation by aldosterone. 
Vamorolone changes the subsequent activity of the receptors, which may possibly dissociate its 
effectiveness from the known side effects of corticosteroids.  
Vamorolone (17α,21-dihydroxy-16α-methyl-pregna-1,4,9(11)-triene-3,20-dione), is a synthetic 
steroidal drug and differs from traditional glucocorticoids by having a double bond between 

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carbons 9 and 11 of the steroid C ring instead of the 11β-hydroxy or carbonyl moiety on C11 
found in most members of the corticosteroid class. The chemical structure of vamorolone is 
shown in Figure 2. 
Figure 2: 
Chemical Structure of Vamorolone 
 
Molecular formula: C22H28O4  
Molecular weight: 356.46  
Vamorolone belongs to the structural class of synthetic steroidal drugs, which includes the 
glucocorticoids prednisone, methylprednisolone, and dexamethasone (Reeves, 2013). It is a 
structural analogue of prednisolone in which sub-activities have been dissociated, i.e., 
transrepression retained, transactivation reduced, membrane stabilization increased, 
cross-reactivity with mineralocorticoid receptor changed from agonist to antagonist.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of vamorolone is 
provided in the current IB (IB).  
Vamorolone oral suspension has been approved in the United States in October 2023, in the 
European Union in December 2023, and in the UK in January 2024 for use in patients with DMD 
and is being developed for BMD. Both are allelic disorders, where DMD is marked by the 
absence of dystrophin in skeletal muscle, while BMD exhibits the presence of abnormal 
dystrophin in skeletal muscle. 
Detailed information on DMD and BMD can be found in the current IB (IB). 
2.2.2. 
Eplerenone 
Eplerenone is classified as an aldosterone antagonist and is used in the management and 
treatment of heart failure with reduced ejection fraction and hypertension.  
Eplerenone binds with high selectivity to MRs. It prevents the binding of aldosterone, a key 
hormone in the renin-angiotensin-aldosterone-system, which is involved in the regulation of 
blood pressure and the pathophysiology of cardiovascular disease. This results in increased 
excretion of water and sodium with simultaneous retention of potassium. Due to the narrow 
therapeutic limits of serum potassium, it must be monitored regularly during therapy with 
eplerenone to prevent hyperkalemia.  

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Cmax is reached after approximately 1.5 to 2 hours and steady state is reached within 2 days, 
absorption is independent from food intake. The metabolism of eplerenone is mainly mediated 
via CYP3A4. Approximately 32% is excreted in the feces and approximately 67% in the urine. 
The elimination plasma half-life t1/2 of eplerenone is approximately 3 to 6 hours, the apparent 
plasma clearance is approximately 10 L/h. Preclinical studies of safety pharmacology, 
genotoxicity, carcinogenic potential and reproductive toxicity revealed no special hazard for 
humans. 
Eplerenone is administered orally with a daily dose between 25 mg and 50 mg. 
More details on eplerenone can be found in the SmPC (eplerenone SmPC). 
2.2.3. 
Fludrocortisone 
Fludrocortisone is a synthetic aldosterone analogue that belongs to the group of 
mineralocorticoids and is used for the partial replacement therapy for primary adrenal 
insufficiency in Addison's disease and for the treatment of salt-losing adrenogenital syndrome. 
Fludrocortisone binds to MR and thus increases the reabsorption of sodium and chloride ions in 
the kidneys. In addition, the renal excretion of potassium, hydrogen and ammonium ions is also 
increased. The resulting increase in blood volume raises blood pressure. Fludrocortisone has an 
approximately 400-fold higher potency and 1,000-fold higher MR affinity than hydrocortisone, 
as it is not inactivated by 11β-hydroxysteroid dehydrogenase. 
Fludrocortisone is rapidly and completely absorbed after oral administration. Cmax is reached 
after 4 to 8 hours. It is hydrolyzed in the liver and 80% are excreted via the kidneys and 20% in 
the feces. The plasma half-life t1/2 is about 3.5 hours. The effect lasts for 12 to 36 hours. 
Clinically, fludrocortisone is administered orally with a daily dosage range of 0.05 to 0.3 mg 
fludrocortisone acetate tablets orally. The dosing regimen chosen for this study is based on the 
design used to evaluate the activity of the MRA (Nakamura and Kawaguchi, 2021). 
More details on fludrocortisone can be found in the SmPC (fludrocortisone SmPC). 
2.2.4. 
Summary of Non-Clinical Studies 
A comprehensive package of non-clinical pharmacology, PK, and toxicology studies was 
completed for vamorolone. A summary of the non-clinical experience is presented below. 
 In-vitro and in-vivo mechanistic studies show that the pharmacological mode of action of 
vamorolone is through agonist activity towards the GR and antagonist activity towards the 
MR. Unlike all members of the corticosteroid class, vamorolone is likely not a substrate for 
11β hydroxysteroid dehydrogenase enzymes (HSD11B1, HSD11B2), either systemically or 
locally in cells and tissues, as it lacks the 11β moiety on the steroidal C ring. Thus, it is not 
subject to systemic or local pro-drug/drug conversion. 

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 A tissue distribution study using radioactively labelled vamorolone showed widespread 
distribution among body organs with a peak concentration between 2 to 6 hours for most 
tissues/organs. The highest exposure was noted in the GI organs (cecum, large intestine, 
small intestine) and the liver. Vamorolone is not excreted unchanged into bile or urine. In the 
rat mass balance study 87% of drug related material was recovered in feces and 10% in urine. 
The PK of vamorolone is generally dose proportional and shows no systematic sex 
differences. The elimination half-life (t1/2) after oral single administration is 0.68 hours in 
mice, 2.29 hours in rats, and 2.25 hours in dogs. Plasma protein binding is 77% to 88% 
across species. 
 Vamorolone can be metabolized via multiple Phase 1 and Phase 2 pathways, such as 
glucuronidation, hydroxylation, and reduction. Based on in-vitro studies, it is unlikely that 
vamorolone inhibits CYP isoenzymes, uridine 5′diphosphoglucuronosyltransferase 
isoenzymes, solute-linked carrier transporters or efflux transporters at clinically relevant 
concentrations. Induction of CYP3A4 was observed in-vitro at high doses ≥ 1.5 μM. 
 The nonclinical toxicology program showed a consistent safety profile across both the mouse 
and dog studies. There was a dose-dependent decrease in body weight gain and the adrenal 
glands, liver, spleen, and thymus were identified as target organs. Animal safety margins 
relative to the human exposure at the highest therapeutic dose are low, but the 
pharmacologically mediated adverse effects were generally reversible and monitorable in the 
clinic. 
 As DMD is a predominantly male disease, a focused microscopic analysis of the male 
reproductive organs as well as sperm analysis were included in chronic toxicology studies of 
both, the mouse and dog. 
 There were no signals for either mutagenicity or genotoxicity and there were no 
preneoplastic lesions in the chronic toxicology studies; carcinogenicity studies will be 
conducted as a post approval commitment. 
Please refer to the current IB for additional information (IB). 
2.2.5. 
Summary of Clinical Studies 
6 clinical studies have been completed with healthy volunteers as part of the clinical 
pharmacology program for vamorolone. 4 clinical studies have been completed in subjects first 
enrolled at ages 4 to < 7 years with DMD. An additional study to expand the age range (ages 2 to 
< 4 years, 7 to < 18 years) was initiated in April 2022 and is currently ongoing. 

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A summary of the human experience is presented below. 
 The completed clinical trials included 153 adult subjects treated with 0.1 to 20 mg/kg 
vamorolone (including 8 subjects with hepatic impairment) in clinical pharmacology trials 
and 164 subjects from 4 years of age and older with DMD who received vamorolone at daily 
doses ranging from 0.25 to 6 mg/kg. The exposure duration in completed clinical trials 
ranged from 1.4 to 32 months. 
 The PK of vamorolone is dose proportional following single and multiple ascending doses. 
After oral administration with food, vamorolone is rapidly absorbed with median tmax about 
2 hours. Consistent with a short half-life t1/2 of 2 hours, no accumulation is observed after 
repeated daily administration. Vamorolone undergoes direct glucuronidation and 
hydrogenation with subsequent glucuronidation. 2 plasma metabolites are observed at greater 
than 10% of the parent drug in human plasma, but both are pharmacologically inactive 
O-glucuronides. Approximately, 30% of the dose is excreted in feces (15.4% unchanged) and 
57% of the dose is excreted in urine.  
In vitro, vamorolone is metabolized by CYP3A4/5, CYP2C8, and CYP2C9. A rise of 33.7%. 
for AUC0-inf and a tmax delay by 2 hours are observed when combined with itraconazole, a 
potent CYP3A4 inhibitor. The recommended dose of vamorolone when administered with 
strong CYP3A4 inhibitors (e.g., telithromycin, clarithromycin, voriconazole, grapefruit juice) 
is 4 mg/kg/day. Acid reducing agents are not expected to impact the absorption of 
vamorolone. 
 Moderate hepatic impairment elevates vamorolone exposure by a 1.7- and 2.6-fold increase 
in Cmax and AUC0-inf respectively, compared to matched healthy adults. Exposure parameters 
of subjects with mild hepatic impairment are expected to be less affected and should 
represent an increase in vamorolone concentration of between 10 to 15% (1.1- to 1.5-fold 
increase in AUC0-inf) compared to those individuals with normal liver function, which is not 
considered clinically relevant. 
 In the pivotal double-blind controlled (placebo and prednisone) study, significant and 
clinically meaningful improvements were seen with vamorolone 2 mg/kg and 6 mg/kg 
compared with placebo for multiple measures of lower limb function. When evaluated 
globally, the improvements seen with vamorolone 6 mg/kg were similar to those seen with 
prednisone while the improvements seen with vamorolone 2 mg/kg were slightly smaller. 
o TEAEs reported ≥ 5% of subjects in the vamorolone 6 mg/kg group and at a higher 
frequency (at least 1 subject difference) than placebo: cushingoid (28.6%), abdominal 
pain upper (7.1%), diarrhea (7.1%), vomiting (14.3%), rhinitis (7.1%), arthropod bite 
(7.1%), fall (10.7%), weight increased (10.7%), Vitamin D deficiency (10.7%), headache 
(7.1%), irritability (10.7%), and cough (7.1%). 

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 In the vamorolone 2-6 mg/kg integrated safety group (i.e., 163 subjects with DMD treated 
with vamorolone 2 mg/kg or 6 mg/kg in any study), 86.5% of subjects experienced a TEAE, 
regardless of drug relatedness, and 48.5% experienced a TEAE assessed by the Investigator 
as drug related. The TEAEs, regardless of drug relatedness, reported for ≥ 10% of subjects in 
the vamorolone 2-6 mg/kg group across all DMD studies were: pyrexia (20.2%), 
nasopharyngitis (18.4%), cough (18.4%), upper respiratory tract infection (17.2%), vomiting 
(16.6%), pain in extremity (13.5%), headache (12.9%), constipation (11.7%), cushingoid 
(11.7%), diarrhea (11.0%), and weight increased (10.4%). 9 SAEs have been reported in 
subjects receiving 2-6 mg/kg vamorolone in the clinical studies for the DMD program. 
Additionally, SAEs of pneumonia were reported for 2 subjects receiving 0.75 mg/kg 
vamorolone. All these SAEs were considered unrelated to study treatment. 
 As of 30 Sep 2023, there have been a total of 24 SAEs in the expanded access/compassionate 
use setting. Except for 1 case (adrenal insufficiency), each of these SAEs was considered 
unrelated to study treatment by both the Investigator and the Sponsor, and none of them 
resulted in discontinuation from the study or program. There was no fatal event.  
More detailed information about the clinical studies of vamorolone can be found in the current 
IB (IB).  
2.3. 
Benefit/Risk Assessment 
In the clinical pharmacology program, 125 healthy volunteers and 8 subjects with moderate 
hepatic impairment, males and females, were exposed to vamorolone. 164 subjects have received 
vamorolone across all of the completed DMD clinical studies. As of 30 September 2023, 
44 DMD subjects had been treated with vamorolone in the VBP15-006 study and 8 subjects 
enrolled in the BMD clinical study VBP15-BMD-001 had been treated with vamorolone 500 mg 
(250 mg for body weight < 50 kg) daily or placebo. 
Vamorolone was generally safe and well tolerated in all subjects. The TEAEs have been 
primarily mild to moderate in severity. 
More detailed information about the known and expected benefits and risks and reasonably AEs 
of vamorolone may be found in the current IB (IB).  
Based on the available nonclinical and clinical data to date, the conduct of the study, as specified 
in this protocol, is considered justifiable. 

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Identified and Potential 
Risks of Clinical 
Significance 
Summary of 
Data/Rationale for Risk 
Mitigation Strategy 
ECG 
Contact allergies can 
develop during ECG 
procedures. 
Subjects with known contact 
allergies will not be included 
in the study.  
AE=adverse event, ECG=electrocardiogram. 
2.3.2. 
Warnings and Precautions 
Detailed information about the warnings and precautions for administration of vamorolone can 
be found in the current IB (IB).  
2.3.3. 
Benefit Assessment 
Healthy subjects may expect no direct benefits from participating in this clinical study.  
2.3.4. 
Overall Benefit Risk Conclusion 
Considering the currently available nonclinical and clinical safety data, the measures taken to 
minimize risk to subjects participating in this study, in conjunction with the predicted exposures 
of 20 mg/kg of vamorolone single dose and implementing close medical monitoring of safety 
and tolerability, the potential risks identified in association with vamorolone are justified by the 
anticipated benefits that may be afforded to patients with DMD and BMD. Similarly, a single 
dose of eplerenone is unlikely to be associated with risk to healthy volunteers. The short-term 
fludrocortisone challenge used in this study has been shown to be safe and well tolerated in 
healthy subjects (Nakamura and Kawaguchi, 2021). 
Risk minimization measures routinely implemented in early phase clinical studies are considered 
adequate, including exclusion criteria for laboratory parameters (Section 5.2), close biochemical 
and hematology laboratory monitoring (Section 10.2), and observation of vital signs 
(Section 8.3.2) and ECGs (Section 8.3.3). Administration will be discontinued in case of events 
that unacceptably endanger the safety of the subjects (Section 7).  
This clinical study will start after the favorable opinion of the IEC and once permission of the 
CA has been obtained. All investigations will be conducted in compliance with the clinical study 
protocol, ICH GCP, and any additional applicable regulatory requirements. 

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4. 
Study Design 
4.1. 
Overall Design 
This will be a single-center, randomized, open-label, 3-arm, parallel-group, positive- and 
negative-controlled, Phase 1 study in 30 healthy male subjects (Sections 1.2 and 1.3). Only male 
subjects will be enrolled to eliminate potential effects of circulating hormones on the endpoints. 
Subjects aged 18 to 55 years will be randomized to 3 study arms (see below). 
The purpose of this study is to investigate the antagonistic effect of vamorolone on the MR by 
measuring the anti-aldosterone activity using mineralocorticoid challenge with fludrocortisone, 
compared to eplerenone as a positive control and to a negative control without treatment. 
Furthermore, the safety and tolerability of concomitant administration of fludrocortisone and 
vamorolone will be assessed and the PK of single dose vamorolone and single dose eplerenone 
will be evaluated. 
 The total time in the study for a subject is approximately 32 days, including the screening 
period (maximum 19 days), a baseline/diet calibration visit (2 days), a treatment period 
(3 days), and a safety follow-up period of 8 days (in-house follow-up assessments on Day 4 
and a safety follow-up phone call on Day 11). 
 The screening period will occur from Day -21 to Day -3. Eligible subjects will be admitted to 
the study site on Day -2 and will remain resident throughout the treatment period until the 
safety follow-up on Day 4. Subjects will be discharged from the study center after the last 
urine collection interval (40-48 h postdose vamorolone/eplerenone/corresponding timepoint 
for negative control arm) and Day 4 assessments are completed. A follow-up safety phone 
call is planned on Day 11. 
 10 subjects each will receive vamorolone, eplerenone, or no treatment, randomly allocated to 
1 of 3 study arms: 
o Study arm 1 (experimental arm): vamorolone oral suspension 
o Study arm 2 (positive control arm): eplerenone tablets 
o Study arm 3 (negative control arm): no treatment 
 Fludrocortisone challenge on Days 1 to 3 (for all subjects): 
o Day 1:  
 Fludrocortisone 1 mg at 9 h predose vamorolone/eplerenone 
administration/corresponding timepoint for negative control arm. 

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o Day 2: 
 Fludrocortisone 0.5 mg at the same time of vamorolone/eplerenone 
administration in the morning (0 h) /corresponding timepoint for negative 
control arm. 
 Fludrocortisone 0.1 mg at 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 14 h 
vamorolone/eplerenone postdose administration/corresponding timepoint for 
negative control arm. 
 Fludrocortisone 0.5 mg at 16 h vamorolone/eplerenone postdose 
administration/corresponding timepoint for negative control arm.  
o Day 3: 
 Fludrocortisone 0.1 mg at 24 h vamorolone/eplerenone postdose administration 
on Day 2/corresponding timepoint for negative control arm.  
 Day 2: Drug administration period (vamorolone or eplerenone or no treatment; in fasted state 
in the morning):  
o Subjects randomized to study arm 1 will receive a single dose of 
20 mg/kg vamorolone. 
o Subjects randomized to study arm 2 will receive a single dose of 200 mg eplerenone. 
o Subjects randomized to study arm 3 will receive no treatment. 
 Subjects will be served diet-controlled meals from Day -2 to Day 3, i.e., containing similar 
quantities of sodium and potassium (Section 5.3.1). 
 Blood samples for safety laboratory assessments (hematology, coagulation, and clinical 
chemistry) will be collected at screening (Day -21 to Day -3), at baseline (Day -2), on Days 2 
and 3, and at EOS. 
 Urine samples for routine urinalysis will be collected at screening (Day -21 to Day -3), at 
baseline (Day -2), on Days 2 and 3, and at EOS. 
 Blood samples for PK assessments of plasma vamorolone (study arm 1) or plasma 
eplerenone (study arm 2) will be collected from predose through 24 hours following 
vamorolone / eplerenone dosing on Day 2. 
 Urine samples for sodium and potassium measurement will be collected during 14 collection 
intervals (see Table 8):  
 Day 1: 24-9 h predose and 9-0 h predose vamorolone/eplerenonea 
 Day 2: 0-2 h, 2-4 h, 4-6 h, 6-8 h, 8-10 h, 10-12 h, 12-14 h, 14-16 h, 16-24 h postdosea 
vamorolone/eplerenone 
 Day 3: 24-32 h, 32-40 h, 40-48 h postdosea vamorolone/eplerenonea 

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a or at corresponding timepoint for negative control arm 
A flow chart and a detailed SoA with more information on the specific timepoints for the 
scheduled study visits and required procedures are provided in Sections 1.2 and 1.3.  
4.2. 
Scientific Rationale for Study Design 
In this study, the MRA effect of vamorolone will be evaluated by determining the 
anti-aldosterone activity after repeated administration of fludrocortisone in healthy subjects.  
The primary endpoint for evaluating the MRA effect of vamorolone is to assess urinary sodium 
(Na) and potassium (K) levels following a fludrocortisone challenge. The goal is to demonstrate 
the anti-aldosterone activity of vamorolone, specifically its ability to reverse the urinary 
electrolyte effects induced by fludrocortisone, a substance known for its strong sodium retention 
capacity.  
The pharmacological effect of the MRA is measured against a background of mineralocorticoid 
excess induced by the administration of an exogenous mineralocorticoid, such as fludrocortisone. 
Fludrocortisone is a renal mineralocorticoid agonist that binds to aldosterone receptors, resulting 
in increased sodium reabsorption and potassium excretion.  
The methodology is based on the observation that oral doses of mineralocorticoid fludrocortisone 
affect the sodium/potassium (Na/K) ratio in overnight urine. This effect follows a logarithmic 
dose-response pattern similar to aldosterone. The ratio tends to return to normal levels in the 
presence of aldosterone antagonists, providing a reliable quantitative assay for these substances 
in humans. Antagonist activity is identified by increased sodium excretion, decreased potassium 
excretion, and an increased Na/K ratio observed in overnight urine 2-10 hours after treatment. 
Eplerenone is selected as positive control because of its enhanced MR selectivity and superior 
safety profile compared to spironolactone, particularly in terms of a reduced incidence of sex 
hormone-related AEs (Nakamura and Kawaguchi, 2021).  
This trial will be conducted in 30 healthy subjects to standardize the trial population and to 
minimize exposure variability.  
The trial will be conducted in 30 healthy subjects in 3 arms of 10 each, and this sample size is 
determined by the need for adequate representation rather than statistical power. The rationale 
for the determination of the sample size is described in Section 9.5. 
Safety and tolerability of vamorolone co-administrated with fludrocortisone will be reported and 
the blood samples will be collected to follow the plasma levels of vamorolone and eplerenone. 
The open-label design is considered acceptable and justified because the main assessment 
criterion is a PD parameter that is unlikely to be subject to Investigator or subject induced bias. 

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The treatment allocation is conducted in a randomized manner to support the scientific integrity 
of the trial by creating comparable treatment groups, reducing the risk of bias, and maintaining 
the statistical and ethical fundamentals. Details about randomization are provided in Section 6.3.  
4.3. 
Justification for Dose 
Vamorolone 
The selected dose was determined by considering the maximum dose administered in both SAD 
and MAD studies in healthy adult subjects, which was 20 mg/kg. This has been shown to be well 
tolerated and safe in this population (see the current IB).  
Eplerenone 
A single dose of 200 mg eplerenone was selected since this dose has been shown to be safe and 
well tolerated in healthy adults while also confirming the mineralocorticoid antagonist effect 
(Nakamura and Kawaguchi, 2021).  
Fludrocortisone 
All subjects in the 3 arms will receive fludrocortisone at the doses specified in Section 4.1. This 
choice of dose is based on its established efficacy in influencing the overnight Na/K ratio. In 
addition, fludrocortisone has proven to be safe and well tolerated when administered over a 
2-day period, even in subjects not treated with a MRA (Nakamura and Kawaguchi, 2021).  
4.4. 
Start / End of Study Definition 
The study start is defined as the date of the first informed consent signature of the first subject. 
Subjects are considered to have completed the study, if they have completed all phases of the 
study including the last scheduled procedure shown in the SoA (Section 1.3). 
The end of the study is defined as the date of the last scheduled procedure shown in the SoA for 
the last subject.  
Information on study termination or discontinuation criteria is provided in Section 7. 

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5. 
Study Population 
A total of 30 healthy adult males will be randomized to the 3 study arms with 10 subjects 
assigned to each arm. 
No subject may be randomly assigned to study treatments unless adherence to all eligibility 
criteria as given in Sections 5.1and 5.2 is established.  
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Individuals who do not meet the eligibility criteria due to medical findings will be advised to 
consult a doctor as applicable. 
5.1. 
Inclusion Criteria 
A subject is eligible to be included in the clinical study only if all following criteria apply: 
5.1.1. 
Inclusion Criteria to be Checked at Screening  
Age 
1. Age of 18 to 55 years inclusive, at the time of signing the informed consent. 
Type of Subject and Disease Characteristics 
2. Subject is overtly healthy as determined by medical evaluation including medical history, 
physical examination, vital signs, laboratory tests and ECG.  
Weight 
3. Body weight ≥ 50 kg and a BMI ≥ 18 kg/m2 and ≤ 29.9 kg/m2 at screening. 
Sex and Contraceptive/Barrier Requirements 
4. Contraceptive use by men and women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
Male subjects:  
 If the subject is a sexually active man and not surgically sterilized, he must be willing to: 
o Abstain from sexual intercourse or 
o Use a condom plus another form of contraception (e.g., spermicide, IUD, birth control 
pills taken by female partner, diaphragm with spermicide) if engaging in sexual 
intercourse with a woman who could become pregnant.  
o Use a condom during sexual intercourse with pregnant or lactating women. 
o Must not father a child and must refrain from donating sperm from administration of the 
first dose and up to 3 months after the last dose of study treatment. 

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Drugs and Stimulants 
5. Subject is a non-smoker for at least 3 months prior to exposure to the study treatments. 
Subjects must also have abstained from use of other nicotine containing products (e.g., 
nicotine patch, chewing gum or e-cigarettes) for at least 3 months before exposure to the 
study treatment. 
Informed Consent 
6. Capable of giving signed informed consent as described in Section 10.1, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol prior 
to any clinical study specific procedure. 
Vital Signs 
7. Supine systolic blood pressure of ≥ 90 mmHg and ≤ 140 mmHg, diastolic blood pressure of 
≥ 50 mmHg and ≤ 90 mmHg, pulse rate of ≥ 45 bpm and ≤ 90 bpm, and tympanic body 
temperature of ≥ 35.0 and ≤ 37.5°C at screening. 
Other Inclusion Criteria 
8. Subjects must be able to communicate well with the Investigator and comply with the 
protocol requirements, instructions, and protocol related restrictions (e.g., dietary, fluid and 
lifestyle restrictions from screening to study completion; Section 5.3). 
9. Subjects must be able to swallow the study treatments as per protocol. 
5.2. 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
5.2.1. 
Exclusion Criteria to be Checked at Screening  
Medical Conditions 
1. A past medical history of clinically significant abnormalities or a history/family history of 
long QT interval syndrome. 
2. An abnormal ECG, defined as: 
o PR > 215 msec and < 120 msec, QRS complex > 120 msec; QTcF > 440 msec by 
automated reading 
o Any clinically significant cardiac conduction abnormalities 
o Any atrial or ventricular arrhythmias 
3. A past medical history of myocardial infarction, angina pectoris, atherosclerosis, or other 
clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, 
history of labile hypertension). 

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4. A past medical history of peptic ulcers, diverticulitis, and non-specific ulcerative colitis. 
5. History of complaints of frequent dizziness and /or vomiting spells or lightheadedness 
(“frequent” defined as incidence occurs more than once every week). 
6. Any history or evidence of any clinically relevant, gastrointestinal, respiratory, hepatic, renal, 
endocrinologic, hematologic, immunologic, metabolic, genitourinary, pulmonary, neurologic, 
dermatologic, musculoskeletal, and/or other major disease or malignancy as determined by 
medical evaluation (including physical examination) capable of significantly altering the 
absorption, metabolism, or elimination of drugs; constituting a risk when taking the study 
treatments; or interfering with the interpretation of data. 
7. Known Gilbert’s syndrome. 
8. Any clinically relevant history of allergic conditions requiring hospitalization or prolonged 
systemic treatment (including drug allergies, allergic asthma, eczema, allergies requiring 
therapy with corticosteroids or anaphylactic reactions); but excluding untreated, 
asymptomatic, seasonal allergies at time of dosing or allergic contact sensitizations (e.g., 
nickel allergy). 
9. Known or suspected hypersensitivity or contraindications to the study treatments or any 
components of the formulation used, e.g., vamorolone, eplerenone and fludrocortisone (see 
vamorolone IB, eplerenone SmPC, fludrocortisone SmPC).  
10. Relevant current acute or chronic/recurrent viral, bacterial, fungal or parasitic infections (e.g., 
pulmonary/upper respiratory, gastrointestinal, urinary, skin, or ENT infections) at screening 
or within 28 days prior to administration of the study treatments.  
Prior/Concomitant Therapy 
11. Use of any concomitant medication or any drugs / medicines (including dietary supplements, 
natural and herbal remedies, and hormone replacement therapy) within 2 weeks or 5 times 
the half-life of the respective drug, whichever is longer, prior to the first administration of the 
study treatments.  
Occasional use of paracetamol up to 2 g/day (medicinal product in its original packaging, 
approved and marketed in Germany) is permitted.  
Oral, injectable, and implantable contraceptives as outlined in Section 5.1 are permitted.  
12. Previous exposure to vamorolone. 
13. Any use of corticoids within 6 months prior to the first administration of the study 
treatments. 

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14. Administration of live, attenuated, replication-competent vaccines within 6 weeks prior to the 
first administration of study treatment until 2 weeks after the follow-up visit. Administration 
of inactivated vaccines or vector-based or mRNA COVID-19 vaccines within 2 weeks prior 
to the first administration of the study treatments until 2 weeks after the follow-up visit.  
15. Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) 
within 3 months or 5 half-lives (whichever is longer) prior to the first administration of the 
study treatments. 
Prior/Concurrent Clinical Study Experience 
16. Use of any investigational drug or participation in any clinical study within 30 days or 
5 half-lives (whichever is longer) prior to the expected date of first administration of study 
treatments or planning to take other investigational drugs during the study.  
Diagnostic Assessments 
17. Positive results for HBsAg, anti-HCV, anti-HIV 1 and 2, and HIV 1-p24 antigen at 
screening. 
18. Positive screen for alcohol, drugs of abuse and cotinine at screening.  
19. Elevations in ALT ≥ 1.1 x ULN, AST ≥ 1.1 x ULN, serum bilirubin ≥ 1.0 x ULN, creatinine 
≥1.0 x ULN and HbA1c > ULN at screening. A case-by-case decision for any abnormality 
must be discussed with the Sponsor before inclusion.  
20. Sodium, potassium, magnesium, chloride blood concentration below the lower limit of 
normal at screening. 
21. TSH and coagulation outside of normal ranges. 
22. eGFR based on the CKD-EPI (details for calculation see Section 10.2) of < 90 mL/min at 
screening.  
Other Exclusions 
23. Subjects who are unwilling to adhere to contraceptive requirements.  
24. Higher than low-risk alcohol consumption i.e., consumption of an average weekly alcohol 
intake of > 21 units/week for men. 1 unit (12 g) corresponds to 0.3 L of beer/day or 0.12 L of 
wine/day or 1 glass (at 2 cL) of spirits/day. 
25. Excessive consumption of caffeine- or xanthine-containing food or beverages (> 5 cups of 
coffee a day or equivalent) or inability to stop consuming from 48 hours prior to first planned 
administration of study treatments. 
26. Consumption of alcohol from 48 hours prior to admission. 

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27. Consumption of high-dose resveratrol-containing products or products with enzyme-inducing 
or enzyme-inhibiting properties (for details refer to Section 5.3.1) 14 days prior to first 
administration of study treatments. 
28. Regular consumption of poppy seed containing food prior to first administration of study 
treatments.  
29. No sweets/teas containing liquorice are allowed within 2 weeks prior to first administration 
of study treatments up to the follow-up examination. 
30. Any use of drugs-of-abuse or alcohol abuse within 1 month prior to dosing. 
31. Subject with vegetarian, vegan, or restricted diet (e.g., gluten-free) or not willing or able to 
eat the complete standard meals. 
32. Donation or loss of more than 400 mL of blood or received a transfusion of any blood or 
blood products within 30 days, or donated plasma within 30 days prior to first administration 
of study treatments. 
33. Strenuous physical activity within 72 h to admission. 
34. Employee of the Sponsor, the Nuvisan Group, or other Contract Research Organization 
involved in the clinical study. 
35. Legal incapacity or limited legal capacity, or incarceration and vulnerable subjects. 
36. Inability to understand or communicate reliably with the Investigator or considered by the 
Investigator to be unable to or unlikely to co-operate with the protocol requirements, 
instructions, and study-related restrictions. 
37. History of non-compliance to medical regimens and subjects who are considered potentially 
unreliable (e.g., refuse to comply with study regulations). 
38. Any other conditions or factors which in the opinion of the Investigator may interfere with 
study conduct. 
5.2.2. 
Exclusion Criteria to be Re-Checked upon Admission 
Medical Conditions 
39. Changes in medical conditions compared to screening, as judged by the Investigator. 
40. Body weight < 50 kg. 
Prior/Concomitant Therapy 
41. Changes in prior/concomitant therapy compared to screening, as judged by the Investigator. 

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Diagnostic Assessments 
42. Positive for an acute common cold/respiratory or other infection upon admission. 
43. Positive screen for alcohol, drugs of abuse and cotinine test upon admission. 
Other Exclusions 
44. Changes in other exclusion criteria compared to screening, as judged by the Investigator. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
 Subjects will be required to refrain from consumption of red wine, Seville oranges, 
grapefruit, or grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or all fruit 
juices from 14 days before the start of study treatments until after collection of the final 
blood PK sample. Abstinence from liquorice containing sweets and teas 14 days before 
admission until follow-up examination.  
 Subjects will be required to refrain from consumption of poppy seeds from 72 hours before 
the start of study treatments until the end of confinement.  
 During the in-house stay (Day -2 to Day 4), the subjects may only consume food and 
beverages provided by the study site.  
 From Day -2 to Day 3, subjects will be served diet-controlled meals, i.e., containing similar 
quantities of sodium and potassium. The diet provided (maximum of 4 meals per day) will 
consider the imposed restrictions. To standardize the meals as much as possible, for 
breakfast, lunch and dinner, the same meals will be served on each of the 5 days, based on a 
diet plan. For lunch and dinner, the meals will be prepared once for this period (1 for lunch, 
1 for dinner), split in 5 portions for each day, vacuum-packed, refrigerated and reprepared 
when needed. A diet-controlled breakfast with similar quantities of sodium and potassium 
will be provided based on a diet plan. 
 On Day 2, subjects will fast for at least 10 hours before first administration of 
vamorolone/eplerenone/corresponding timepoint for negative control arm and will continue 
fasting for 2 hours.  
 Fluid consumption will be controlled as outlined in Table 3.  
 From Day -2 to Day 3, subjects must drink at least 2.5 L/day, on Days 1 to 3 exactly as 
defined in Table 3 (non-carbonated water of defined electrolyte composition). This is to 
ensure urine flow during the urinary Na/K assessment period.  
 All study treatments will be administered in an upright position with 240 mL of 
non-carbonated water of defined electrolyte composition. 

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5.4. 
Screen Failures 
Screen failures are defined as subjects who consented to participate in the clinical study but are 
not subsequently randomly assigned to study treatment. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE. 
Subjects who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, however, only under the following conditions: 
 The subject had successfully passed the screening procedures but could not start subsequent 
treatment on schedule. 
 The in-/exclusion criteria preventing the subject’s initial attempt to take part in the study 
have been changed (via protocol amendment). 
 The violation of the respective in-/exclusion criteria is considered minor and temporary by 
the Investigator. 
Up to 2 rescreenings will be allowed. Rescreened subjects will be assigned a new screening 
number for every rescreening event. The previous screening number of the subject will be 
documented in the eCRF to effectively track the screening processes. Subjects who are 
rescreened are required to sign a new ICF, even if it was not changed after the subject’s previous 
screening (see Section 10.1). 
In case of abnormal results caused by intercurrent diseases, short-term treatable conditions, or 
other temporary health disorders (e.g., acute infection, iron deficiency, blood pressure outside 
defined range), the Investigator may decide to repeat the respective screening parameter(s) 
within the predetermined screening period. As a rule, up to 2 repetitions are acceptable. Outside 
of the predetermined screening period, the subject shall be rescreened as described above. 
In any case, the Investigator has to ensure that the repeated procedures, whether the recheck 
during initial screening or a rescreening, do not expose the subject to an unjustifiable health risk. 
5.5. 
Criteria for Temporarily Delaying Enrollment, Randomization, 
Study Treatment 
Not applicable.  

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4. Nuvisan CTS Department will document the receipt of vamorolone and must confirm 
appropriate conditions (e.g., temperature) have been maintained during transit for all study 
treatment received and any discrepancies are reported and resolved before use of the study 
treatment. 
5. Vamorolone will be labelled study specifically by the Nuvisan CTS department before the 
clinical part of the study starts including final QP release as per the German clinical study 
labelling requirements. 
6. Nuvisan CTS Department will be responsible for transfer of vamorolone and dosing 
devices to the site. Details will be described in an IMP manual. 
7. Only subjects enrolled in the study may receive study treatment and only authorized site 
staff may supply, prepare, or administer study treatment. All study treatment must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the Investigator and 
authorized site staff. 
8. All study treatment administrations will be performed in accordance with the specifications 
in the IMP manual, by site staff authorized by the Principal Investigator. 
9. The Investigator is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).  
10. The number of unused study treatment will be documented by Nuvisan CTS Department. 
According to the provisions of the Sponsor the unused study treatment will be destroyed or 
sent back to the Sponsor. 
11. Further guidance and information for the final disposition of unused study treatments are 
provided in the IMP manual.  
6.3. 
Assignment to Study Treatment 
Subjects will be randomized to 1 of the following 3 study arms, with 10 subjects assigned to each 
treatment: 
 Study arm 1 (experimental arm): vamorolone  
 Study arm 2 (positive control arm): eplerenone  
 Study arm 3 (negative control arm): no treatment 
After informed consent procedure, every subject is given a screening number. Only subjects who 
comply with all eligibility criteria (Sections 5.1 and 5.2) can be included into the study.  

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On Day 1, prior to administration of fludrocortisone the subjects enrolled will be assigned a 
unique 3-digits assignment number (randomization number, e.g., 101, 102, 103…/ 201, 202, 
203…/ 301, 302, 303…etc.) in ascending numerical order at the study site. The randomization 
number encodes the subject’s assignment to 1 of the 3 study arms, per the randomization 
schedule generated prior to the study by Nuvisan CTS Department.  
In case of replacement of already randomized subjects, the replaced subject will be assigned to 
the study treatment as the original subject. Randomization number will be the number of the 
original subject plus 500. For example, the replacement for randomization number 110 will 
receive the randomization number 610. For details on replacement of subjects, see Section 7.2.2.  
The Investigator will keep a record relating the subject identifiers (screening and randomization 
number) and the names of all subjects who have given their informed consent, to allow easy 
checking of data in subject files, when required. This record will also include the date of 
subject’s enrolment and completion, as well as subjects who could not be randomly assigned to 
study treatment for whatever reason. 
6.4. 
Blinding 
Not applicable, as the study will be performed using an open-label design.  
6.5. 
Study Treatment Compliance 
The administration of the study treatments will be performed in the clinical unit by qualified 
clinical professionals of the Investigator’s team. The date and time of each dose administered in 
the clinic will be recorded in the source documents and recorded in the eCRF.  
If the individual dose for a subject is distributed from a bulk supply (i.e., eplerenone and 
fludrocortisone), the preparation of the dose will be confirmed and documented by a second 
member of the study site staff. 
A member of the study site staff other than the person administering the study treatment will 
confirm the study treatment dose and study subject identification at the time of dosing.  
Study site personnel will examine each subject’s mouth to ensure that the study treatment was 
ingested. 
6.6. 
Dose Modification 
No dose modifications are envisaged during this study. 
6.7. 
Continued Access to Study Treatment after the End of the Study 
After the end of this study, further treatment is not necessary since only healthy subjects will be 
included in the study. If there are findings that are unclear in the final examination, a detailed 
assessment, a follow-up and, if necessary, specific medical treatment may be required. 

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6.8. 
Treatment of Overdose 
For this study, any dose of vamorolone higher than the protocol defined dose will be considered 
an overdose. Treatment of acute overdosage is by immediate supportive and symptomatic 
therapy. Gastric lavage or emesis can be considered (IB). 
For this study, any dose of eplerenone and fludrocortisone higher than the protocol-defined dose 
will be considered an overdose. 
Overdose following administration of eplerenone should be treated as clinically indicated. No 
cases of AEs associated with overdose of eplerenone in humans have been reported. The most 
likely manifestation of human overdose would be anticipated to be hypotension or hyperkalemia. 
If symptomatic hypotension should occur, supportive treatment should be initiated. If 
hyperkalemia develops, standard treatment should be initiated. Eplerenone cannot be removed by 
hemodialysis. It has been shown to bind extensively to charcoal (eplerenone SmPC). 
Overdose following administration of fludrocortisone should be treated as clinically indicated. 
Acute intoxications with fludrocortisone are not known. In the event of an overdose, there may 
be an increase in side effects, especially on the electrolyte balance. In case of significant 
overdose, glucocorticoid effects affecting the endocrine system and metabolism may also occur 
(fludrocortisone SmPC).  
In the unlikely event of an overdose, the Investigator should: 
1. Evaluate the subject to decide, in consultation with the medical expert of the Sponsor, if 
possible, whether study treatment should be interrupted or whether the dose should be 
reduced. 
2. Closely monitor the subject for any AE/SAE and laboratory abnormalities as medically 
appropriate and at least until scheduled follow-up. 
3. If requested by the medical expert of the Sponsor (determined on a case-by-case basis), 
obtain a plasma sample for PK analysis as soon as possible after the overdose intake and on 
further timepoints thereafter. 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
5. In case of symptomatic and clinically significant, it will be reported as an AE.  
The Investigator will use clinical judgment when treating an overdose of an investigational drug.  
Decisions on dose interruptions or modifications will be made by the Investigator in consultation 
with the Sponsor based on the clinical evaluation of the subject. 

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6.9. 
Prior and Concomitant Therapy 
Any medication taken at or after the time of first study treatment, regardless of whether it had 
started prior to the study or not, is to be recorded as concomitant medication. Prior medications 
are defined as any medication taken which had been stopped prior to the first study treatment.  
Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and 
dietary or herbal supplements as well as liquorice containing sweets and teas) within 2 weeks or 
5 half-lives (whichever is longer) before the start of study treatment until completion of the 
follow-up visit, unless, in the opinion of the Investigator and Sponsor, the medication will not 
interfere with the study. Information on non-permitted prior or concomitant therapy including 
drugs and herbal remedies is provided in the list of exclusion criteria (Section 5.2).  
Except when necessary to treat an AE, subjects are not allowed to use those medications, starting 
from the specified timepoints until completion of the study. 
Paracetamol up to 2 g per day may be allowed for the symptomatic treatment of AEs (e.g., 
headache) after consulting the Investigator when medically indicated. Other concomitant 
medication may be considered on a case-by-case basis to avoid immediate hazard to the subjects 
by the Investigator or in consultation with the Sponsor if required.  
Additional restrictions that subjects should adhere to during the study are detailed in 
Section 5.3.1. 
For any concomitant therapy used, the name of the drug, the reason for use, dates of 
administration including start and end dates and dosage information including dose and 
frequency will be recorded in the eCRF. In consultation with the Sponsor, a decision may be 
taken by the Investigator to withdraw a subject from the study when other concomitant 
medication is required or has been taken without consulting the Investigator. 
6.9.1. 
Rescue Medicine 
No specific antidote is available for vamorolone, eplerenone and fludrocortisone. 

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7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal  
7.1. 
Discontinuation of Study Treatment 
In rare instances, it may be necessary for a subject to permanently discontinue study treatment. If 
study treatment is permanently discontinued, the subject will remain in the study. Safety, and 
tolerability data as well as PK and PD data will be collected to the furthest possible extent and 
the subject will be asked to participate in the early discontinuation visit.  
See the SoA (Section 1.3) for data to be collected at the time of discontinuation of study 
treatment and safety follow-up / early discontinuation visit and for any further evaluations that 
need to be completed. 
7.1.1. 
Stopping Rules for Individual Subjects 
In the case of stopping rules apply, evaluable parameters can still be used for statistical analysis. 
The Investigator will withdraw a subject from receiving further study treatment in the following 
cases: 
 Occurrence of an AE of severe intensity in case of causal relationship to study treatment or 
an SAE. 
 Relevant signs or symptoms affecting subject safety. Any events (SAE or severe AE) that 
unacceptably endanger the safety of the subject. 
 If, in the Investigator's opinion, continuation of the study would be harmful to the subject’s 
well-being.  
 Hypersensitivity reactions classified as severe. 
 Vomiting within 4 hours after vamorolone, within 4 hours after eplerenone, and within 
4 hours after fludrocortisone administration (corresponding to approximately 2 times 
expected median tmax) for each study treatment). 
 Impossibility to obtain blood samples in general.  
 Abnormal blood pressure including hypotension defined as systolic < 70 mmHg and/or 
diastolic < 40 mmHg, or hypertension defined as systolic > 160 mmHg and/or diastolic 
> 110 mmHg (evaluated with the subject in supine position for a minimum of 5 minutes and 
confirmed by 2 repeat measurements). If there is no other situational explanation for such 
abnormal findings, see above, this should lead to direct study withdrawal. 
 Marked ECG changes, e.g., induced by electrolyte balance disturbances like significant AV 
blocks, T wave changes, or QT prolongation, significant arrhythmias or extrasystoles.  
 Creatinine > 1.5 x ULN, hypokalemia < 3.2 mmol/L, hyperkalemia > 6 mmol/L  

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 Use of non-permitted concomitant medications. However, any medications considered 
necessary for the subject’s well-being may be given at the discretion of the Investigator. 
7.1.1.1. 
Liver Chemistry Stopping Criteria 
Discontinuation of study treatment for abnormal liver tests is required by the Investigator when a 
subject meets one of the following conditions or if the Investigator believes that it is in best 
interest of the subject: 
 Increase in ALT or AST ≥ 3 x ULN and/or total bilirubin > 2 x ULN considered by the 
Investigator to be at least possibly related to the study treatment.  
 ALT ≥ 3 x ULN and bilirubin ≥ 2 x ULN (> 35% direct bilirubin) has to be reported as SAE 
(confirmed by analysis of 2 blood samples taken on different days; additional laboratory 
examinations may be necessary) (refer to Section 10.3).  
7.1.1.2. 
QTc Stopping Criteria 
The Investigator will withdraw a subject from receiving further study treatment in the following 
cases: 
 QTcF ≥ 500 ms and/or an increase of QTcF from baseline of ≥ 60 ms, confirmed by repeated 
ECGs.  
7.2. 
Subject Discontinuation / Withdrawal from the Study 
7.2.1. 
Discontinuation / Withdrawal Criteria for Individual Subjects 
 A subject may withdraw from the study at any time at their own request without giving 
reasons. The subject will not suffer any disadvantage as a result. A subject may be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon.  
 At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA in Section 1.3 for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.  
 If the subject withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
 If a subject withdraws from the study, they may request destruction of any samples taken and 
not tested, and the Investigator must document the destruction in the site study records. 
 Subjects who discontinue may not re-enter the study.  

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 Depending on the timepoint of discontinuation, a withdrawn subject is referred to as either 
“screening failure” (prior to randomization) or “dropout” as specified in Sections 5.4 and 
Section 7.2.2. 
The Investigator will withdraw a subject from the study in the following cases: 
 Request by the subject to discontinue (withdrawal of consent).  
 At the specific request of the Sponsor and in liaison with the Investigator (e.g., obvious 
non-compliance). 
 Any clinically relevant symptom or sign which in the opinion of the Investigator and/or 
Sponsor warrants subject withdrawal. 
 Impossibility to obtain samples. 
 Protocol deviation judged as significant by the Investigator, including non-compliance to the 
required study considerations (e.g., food/diet requirements). 
 Evidence of significantly impacting viral/bacterial infections. 
 Depending on the timepoint of withdrawal, a withdrawn subject will be referred to as either 
“screening failure” or “dropout” as specified in Sections 5.4 and Section 7.2.2.  
7.2.2. 
Replacement of Subjects  
A subject who discontinues the study prematurely for any reason is defined as a “dropout” if the 
subject has already been randomly assigned to study treatments.  
The decision to replace a subject will be taken on a case-by-case basis, in agreement between the 
Sponsor and the Principal Investigator. 
Drop-outs might be replaced if the number of evaluable subjects completing the study becomes 
or is expected to become less than 24 subjects in total, i.e., less than 8 subjects in each study arm. 
For details regarding treatment assignment of replacement subjects, please refer to Section 6.3.  
The data obtained from dropouts will be used in the evaluation to the largest possible extent.  

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7.3. 
Further Stopping Rules 
7.3.1. 
Premature Discontinuation of the Complete Study 
The Sponsor may discontinue the complete study at any time, for ethical or scientific reasons. 
The Principal Investigator is entitled to stop the study at any time due to medical reasons. In such 
a case, the Principal Investigator should consult the Sponsor at the earliest opportunity. 
The study may be terminated prematurely or temporarily halted if any unacceptable findings are 
identified. The occurrence of 1 of the following stopping criteria shall result in an immediate 
stop of dosing and a temporary halt of the study:  
 A serious adverse reaction (i.e., a SAE considered at least possibly related to the study 
treatment administration) in 1 subject.  
 AEs of at least moderate severity in ≥ 50% of the subjects in one cohort with a reasonable 
relationship to the study treatment or study-related procedures. 
 Severe non-serious adverse reaction (i.e., severe non-serious AEs considered as, at least, 
possibly related to the study treatment administration) in 2 subjects, independent of within or 
not within the same SOC. 
 Unacceptable risks, any relevant toxicity, or a negative change in the risk/benefit assessment 
is identified. This might include the occurrence of AEs which character, severity or 
frequency is new in comparison to the existing risk profile.  
 Any data derived from other clinical studies or toxicological studies become available which 
negatively influence the risk/benefit assessment. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs, 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 subject and should ensure appropriate 
subject therapy and/or follow-up. 
Further information on study and site closure is provided in Section 10.1.12. 
7.4. 
Lost to Follow-up 
Not applicable. 

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8. 
Study Assessments and Procedures 
 Prior to performing any study assessments, the Investigator will obtain written informed 
consent as specified in Section 10.1.4.  
 Study procedures and their timing are summarized in the SoA (Section 1.3). Adherence to the 
study design requirements, including those specified in the SoA, is essential and required for 
study conduct.  
 Protocol waivers or exemptions are not allowed. 
 Immediate safety concerns should be discussed with the Sponsor immediately (within 
24 hours) upon occurrence or awareness to determine if the subject should continue or 
discontinue study treatment. 
 All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
 In the event of a significant study-continuity issue (e.g., caused by a pandemic), alternate 
strategies for subject visits, assessments, medication distribution and monitoring may be 
implemented by the Sponsor or the Investigator, as per local health authority / ethics 
requirements. All procedures adapted to the situation must be submitted, if required as per 
local regulations, through a protocol amendment to the Regulatory Authority and IEC for 
approval prior to implementation of mitigation procedures. 
 The maximum amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will be up to approximately 115 mL 
(approximately 65 mL for safety laboratory samples and up to 50 mL for PK samples; exact 
volumes will be defined in the laboratory manual). Repeat or unscheduled samples may be 
taken for safety reasons or for technical issues with the samples.  
 If subjects agree, samples collected during this clinical study may be used for future research 
outside the clinical protocol when additional consent for this purpose is given 
(Appendix 10.1.4). Any such testing will not be reported in the CSR.  

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8.1. 
Administrative and General Procedures 
8.1.1. 
Demographic 
For demographic assessment the following parameters will be recorded: age (incl. year of birth), 
sex, race/ethnicity. 
8.1.2. 
Body Weight and Height, BMI 
Body weight will be measured by a member of the Investigator’s team under the following 
conditions: 
 Subject in underwear and without shoes after having emptied their bladder 
 Electronic physician (column) scale with digital display, measurement units 0.1 kg 
The subject’s height (without shoes) will be measured to calculate the BMI. The BMI will be 
calculated by data management directly in the eCRF. The study site might calculate in addition 
for eligibility check.  
8.1.3. 
Medical History 
Medical history findings (i.e., previous diagnoses, diseases, or surgeries) considered relevant to 
the study will be collected: 
Any relevant findings from the past that occurred prior to signing the ICF or started prior to 
signing the ICF and are still ongoing but resolve before start of first study treatment 
administration will be recorded in the medical history section of the eCRF. 
Any relevant findings after obtaining informed consent or presently occurring and worsening 
after signing the ICF will be recorded in the AE section of the eCRF. 
8.1.4. 
Other Baseline Characteristics 
Information on smoking and alcohol consumption will be collected.  
8.2. 
Efficacy and/or Immunogenicity Assessments 
This section is not applicable as efficacy and/or immunogenicity is not assessed in this study. 
8.3. 
Safety Assessments 
The safety profile of the study treatment will be assessed through the recording, reporting and 
analysis of baseline medical conditions, AEs, physical examination findings, vital signs, ECGs, 
and clinical laboratory tests. 

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Collection of safety assessments will start when the subjects give informed consent and 
throughout the study. The Investigator will report any AEs, whether observed by the Investigator 
or reported by the subject; the reporting period is specified in Section 8.3. 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). Additional 
assessments during the study will be conducted, if required, at the discretion of the Investigator. 
8.3.1. 
Physical Examinations 
 A comprehensive physical examination will be performed by a physician and will include at 
a minimum, assessment of the eyes, ears, nose, and throat as well as assessment of the 
cardiac, peripheral vascular, pulmonary, musculoskeletal, neurologic, abdominal, lymphatic, 
and dermatologic system. 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 All preexisting and relevant medical events must be recorded and described in the source 
documents. All efforts to attach support documentation (i.e., reports, results, etc.) must be 
done. 
8.3.2. 
Vital Signs 
 Vital signs will be measured by a member of the Investigator’s team after at least 5 minutes 
rest in a supine position and will include body temperature, pulse rate, and systolic and 
diastolic blood pressure at the timepoints specified in the SoA (Section 1.3). 
 Blood pressure and pulse should not be measured on the same arm where blood samples are 
taken from. 
 Body temperature will be measured auricularly with a calibrated device. 
 Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only in case of doubt or if an automated device is not 
available. 
 Further vital signs measurements during the clinical study are at the discretion of the 
Investigator.  
8.3.3. 
Electrocardiograms 
 Single 12-lead ECGs will be obtained by a member of the Investigator’s team at timepoints 
provided in the SoA (Section 1.3) using an ECG machine that automatically calculates the 
heart rate and measures PR(Q) interval, QRS duration, QT interval uncorrected (QT) and 
corrected for ventricular rate calculated according to the formula of Fridericia (QTcF). Refer 
to Section 7.1.1.2 for QTc withdrawal criteria. 

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 Subjects should rest for at least 5 minutes in supine position before ECG recording is 
performed and should be obtained prior to blood sampling. 
 Per timepoint, the ECG results will be stored electronically, timely reviewed, and approved 
electronically by the Investigator.  
 Each ECG should be interpreted (normal/abnormal) by the Investigator. For abnormal ECGs, 
the clinical significance (yes/no) should be judged by the Investigator and the abnormality is 
to be specified. ECG recording will be repeated as appropriate. 
 For all study arms, the ECG will be obtained on Day 2 predose, and approximately 8 and 
12 hours after administration of vamorolone/eplerenone/corresponding timepoint for negative 
control arm, as well as on Day 3, 24 hours postdose vamorolone/eplerenone/corresponding 
timepoint for negative control arm, to monitor ECG alterations, e.g., induced by electrolyte 
imbalance. 
 For study arm 1 only, the ECG will additionally be obtained in the morning of Day 2, 
approximately 2 hours after vamorolone administration at its expected Cmax. 
8.3.4. 
Clinical Safety Laboratory Tests 
 Clinical laboratory assessments will be performed and analyzed at Nuvisan GmbH. 
 All protocol-required laboratory assessments, as defined in Section 10.2 (list of clinical 
laboratory tests), must be conducted in accordance with the laboratory manual and the SoA 
(Section 1.3, timing and frequency of clinical laboratory tests). 
 Any abnormalities in any of the laboratory parameters will be judged by an Investigator 
individually in relation to the reference ranges. 
 The Investigator must review the laboratory results, document this review, and record any 
clinically significant changes occurring during the study after first dosing as an AE. The 
laboratory results must be retained with source documents.  
 All laboratory tests with values considered clinically significantly abnormal, with major 
deviation and/or possible pathological relevance during participation in the study should be 
repeated until the values return to normal or baseline or the absence of clinical relevance can 
be confirmed. If clinically significant values do not return to normal/baseline within a period 
judged reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 
 Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 

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8.3.5. 
Other Assessments 
Alcohol breath tests, cotinine, and urine drug screens will be performed as outlined in the SoA 
(Section 1.3).  
8.4. 
Adverse Events and Serious Adverse Events 
 The definitions of AEs and SAEs can be found in Section 10.3. 
 SAEs will have to be reported to the Sponsor within 24 hours of awareness, filling in the 
adequate safety form provided. Contact details are provided in Section 10.3.4.  
 An AE will be reported by the subject or observed by members of the study team elicited by 
general questioning or by the Investigator/designee. The Investigator will review this data 
and determine the seriousness, the severity/intensity, the causality, and the action taken with 
the IMP. 
 AEs will be documented in the eCRF, and the following information will be given for each 
AE: description of the AE, onset date and time, end date and time, maximum severity, action 
taken, outcome, seriousness, and relationship to an IMP. 
 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 unresolved AEs. 
 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. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
 All AEs and SAEs will be collected from the signing of the informed consent until the safety 
follow-up call /early discontinuation visit at the timepoints specified in the SoA 
(Section 1.3). 
 All SAEs will be recorded and reported to the Sponsor or designee within the time frames 
indicated in Section 10.3.  
 Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SADR (SAE considered related to 
the IMP), at any time it has to be reported to the Sponsor.  

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8.4.2. 
Method of Detecting AEs and SAEs 
During the reporting period unfavorable changes in the subject’s condition will be recorded as 
AEs, regardless, if reported by the subjects or observed by the investigative team. Care will be 
taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading 
verbal questioning of the subject is the preferred method to inquire about AE occurrences (e.g., 
"How do you feel?” or “How have you been feeling since the last questioning?"). 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All AEs and SAEs will be followed until resolution, stabilization, or 
the event is otherwise explained. Further information on follow-up procedures is given in 
Section 10.3.  
8.4.4. 
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 subjects and the safety of a study 
treatment under clinical investigation are met. 
 The Sponsor has a legal responsibility to notify both the CA and other regulatory agencies 
about the safety of a study treatment under clinical investigation. The Sponsor will comply 
with country-specific regulatory requirements relating to safety reporting to the regulatory 
authorities, IEC, and Investigators. 
 The Sponsor is responsible for assessing whether an SAE is expected or not (see also 
Section 10.3). The IB of vamorolone (IB) and the SmPCs of selected eplerenone (eplerenone 
SmPC) and fludrocortisone products (fludrocortisone SmPC) to be administered will be used 
as RSI for this clinical study. 
 SUSARs must be reported by the Sponsor as detailed in Article 42 of European Regulation 
536/2014. 
 The Sponsor must report all unexpected events which affect the benefit-risk balance of the 
clinical study but are not SUSARs as detailed in Article 53 of European 
Regulation 536/2014. 
 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 IB and will notify the IEC, if appropriate according to local 
requirements. 
 Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 

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8.4.5. 
Adverse Events of Special Interest 
No AEs of special interest are defined for this study. 
8.5. 
Pharmacokinetics 
 All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein in accordance with the SoA (Section 1.3). Detailed information on 
sample collection, handling, storage, and shipment will be provided in a laboratory manual. 
 All sample handling procedures, including the date/time of each sample collection, the 
date/time of placement into frozen storage (at the end of the sample processing), and the 
date/time of transfer or shipment of the samples to the responsible analyst will be 
documented in detail. 
 Blood samples will be collected for measurement of plasma concentrations of vamorolone 
(study arm 1; 7 blood samples) or eplerenone (study arm 2; 7 blood samples) up to 24 hours 
after dosing, as specified in Table 5, Table 6, and in the SoA (Section 1.3). 
 The actual date and time (24-hour clock time) of each sample will be recorded. In case the 
actual sampling time deviates from the scheduled sampling time, a comment must be given 
in the e-source. Samples collected within the time windows defined (see Section 1.3), will 
not be considered a protocol deviation. Actual time will be considered when calculating the 
final PK parameters.  
 Samples collected for analyses of vamorolone plasma concentrations may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study.  
Table 5: 
Pharmacokinetic Blood Collection Schedule for Vamorolone 
Study Day 
Time (hours postdosea) 
Volume (mL) 
Day 2 
0 (predosea) 
2 
1 
2 
2 
2 
4 
2 
8 
2 
12 
2 
Day 3 
24 
2 
Total blood collected 
 
14 
a: Vamorolone administration. 
 

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Table 6: 
Pharmacokinetic Blood Collection Schedule for Eplerenone 
Study Day 
Time (hours postdosea) 
Volume (mL) 
Day 2 
0 (predosea) 
up to 5 
1 
up to 5 
2 
up to 5 
4 
up to 5 
8 
up to 5 
12 
up to 5 
Day 3 
24 
up to 5 
Total blood collected 
 
up to 35 
a: Eplerenone administration. 
8.5.1. 
Bioanalytical Methods 
 Bioanalytical analyses will be performed at Nuvisan GmbH Bioanalytical Department.  
 Bioanalytical analyses will be performed in accordance to the principles of GLP and GCP. 
The procedure for determination of concentrations of vamorolone and eplerenone in plasma 
samples will be described in bioanalytical protocols.  
 Information relating to the responsible persons, specification of communication rules, 
handling of the informed consent and confidentiality of personal data, specification of the 
analytical method (matrix, calibration range, samples volume, etc.), sample storage, 
“Incurred Samples”, specification of the applicable regulatory guidelines and archiving 
process will be described in the bioanalytical protocols. 
 Plasma samples will be analyzed for concentrations of vamorolone and eplerenone using 
validated liquid chromatography-tandem mass spectrometry methods.  
8.5.2. 
Pharmacokinetic Evaluation 
 The following PK parameters will be calculated from the individual plasma concentration 
time data of vamorolone and eplerenone for each treatment by noncompartmental analysis 
using Phoenix® WinNonlin® Version 8.0 or higher. 
 

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Table 7: 
Non-compartmental Pharmacokinetic Parameters for Vamorolone and 
Eplerenone in Plasma 
Main Parameters 
AUC0-tlast 
 
AUC0-inf 
 
Cmax 
Additional Parameters 
t1/2 
 
tmax 
 
z 
For definition of PK parameters, refer to Section 10.4. 
 Individual PK parameters will be calculated using actual sampling times.  
 For calculation of PK parameters, concentrations below the LLOQ will be treated as zero.  
 Unreliable parameters will be listed and flagged accordingly and set to missing for 
calculation of descriptive statistics and statistical analysis.  
 More details on the PK evaluation will be provided in the SAP.  
8.6. 
Pharmacodynamics 
 Urine samples will be collected for measurement of sodium and potassium in the 3 study 
arms, i.e., vamorolone, eplerenone and the study arm with no study treatment administered, 
as specified in Table 8 and in the SoA (Section 1.3). 

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Table 8: 
Urine Collection Schedule for Sodium and Potassium Measurements 
Study Day 
Urine Collection Period 
(hours postdosea) 
Aliquot Volume (mL) 
Day 1 
24-9 (predosea) 
up to 5 
9-0 (predosea) 
up to 5 
Day 2 
0-2 
up to 5 
2-4 
up to 5 
4-6 
up to 5 
6-8 
up to 5 
8-10 
up to 5 
10-12 
up to 5 
12-14 
up to 5 
14-16 
up to 5 
16-24 
up to 5 
Day 3 
24-32 
up to 5 
32-40 
up to 5 
40-48 
up to 5 
Total urine volume 
 
up to 70 
a: Vamorolone/eplerenone administration/corresponding timepoint for negative control arm 
 Urine will be collected from Day 1 to Day 3 as specified in Table 8. At the end of each 
collection interval, all subjects will be instructed to void their bladder. During each collection 
interval, the urine portions will be pooled, and the total volume of urine will be determined 
and recorded together with the exact time for start and end in the eCRF. 
 Detailed information on urine sample collection, handling, storage, and shipment will be 
provided in a laboratory manual. 

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 The following data will be provided by Nuvisan Biostatistics for statistical analysis: 
o The ratio of the amount of sodium to potassium (Na/K) as well as the corresponding 
logarithm of the Na/K ratio in urine will be calculated for each urine collection interval of 
vamorolone, eplerenone, and for the study arm with no treatment administered 
(Section 9.3.4). To avoid negative values, ratio will be multiplied by 10 before 
transformation (log10 10*Na/K).  
o In cases where the subject is not able to urinate and/or concentration of sodium and/or 
potassium is missing, the ratio will set to be missing. 
8.7. 
Genetics 
Pharmacogenetics are not evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this study. 
8.10. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 

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9. 
Statistical Considerations 
The statistical analyses will be performed by Nuvisan GmbH. 
9.1. 
Statistical Hypotheses 
No formal statistical hypotheses have been defined for this exploratory study. 
9.2. 
Analysis Sets 
For purposes of analysis, the following populations are defined. 
Table 9: 
Analysis Sets 
Analysis Set 
Description 
Full set 
All subjects enrolled in the study. 
Safety  
All subjects assigned to study treatment and who receive at least 
1 dose of study treatment. Subjects will be analyzed according to 
the treatment they received. This population will be used for 
safety analyses, if not stated otherwise 
Pharmacokinetics 
This set is a subset of the safety set and includes all subjects who 
complete the study without any or findings/events likely affecting 
PK. This population will be used for PK analyses, if not stated 
otherwise. 
Pharmacodynamics  
This set is a subset of the safety set and includes all subjects who 
complete the study without any findings/events likely affecting 
PD. This population will be used for PD analyses, if not stated 
otherwise. 
PD=pharmacodynamics, PK=pharmacokinetics. 
Finding/events leading to the exclusion from analysis sets will be prespecified in a deviation 
manual. 
The final decision to exclude subjects from any analysis set will be made during a DRM prior to 
database lock. The respective meeting minutes will be signed together with the Sponsor. 
9.3. 
Statistical Analyses 
Statistical analysis will be performed using SAS® and the version used will be specified in the 
SAP, which will be finalized before database lock. The SAP will contain a more comprehensive 
explanation than described below of the methodology used in the statistical analyses. The SAP 
will also contain the rules and data handling conventions to be used to perform the analyses. 
Objectives and endpoints are described in Section 3 (Table 2).  

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9.3.1. 
Efficacy Analyses 
This section is not applicable as efficacy is not assessed in this study. 
9.3.2. 
Safety Analyses 
All safety analyses will be performed on the safety analysis set. 
 Safety data will be listed by subject. 
 Summary tables by treatment will be generated for TEAEs (as defined in Section 10.3.1), 
sorted by SOC and PT, in which the number and percentages of subjects with TEAEs and 
frequency of the events are reported. 
 Laboratory values outside the normal ranges will be flagged. A listing of abnormal laboratory 
values and clinically relevant abnormal laboratory values will also be provided. 
 Descriptive statistics of vital signs and ECG data will be presented for each timepoint by 
treatment.  
 The ECG interpretation of the Investigator will be tabulated as the number and percentage of 
subjects with “normal”, “abnormal, not clinically significant”, or “abnormal, clinically 
significant” results by treatment and timepoint. 
9.3.3. 
Pharmacokinetic Analyses  
 All PK analyses will be performed on the PK analysis set, if not stated otherwise. 
 Plasma concentrations and PK parameters will be listed and tabulated by treatment. 
 The following statistics will be calculated for each of the sampling points: number of cases, 
geometric “n”, geometric mean, geometric standard deviation (re-transformed standard 
deviation of the logarithms) and CV, arithmetic mean, standard deviation and CV, minimum, 
median, maximum value, and the number of measurements.  
 Individual and arithmetic mean plasma concentration versus time curves (using the actual 
sampling times for individual plots and the planned sampling times for mean plots) will be 
plotted by treatment using both linear and log-linear scale. 
 Missing data will not be replaced or imputed in any way.  
9.3.4. 
Pharmacodynamic Analyses 
 All PD analyses will be performed on the PD analysis set, if not stated otherwise. 
 Concentration and amount of sodium and potassium as well as the ratio of the amount of 
sodium to potassium (Na/K) and the corresponding logarithm of Na/K ratio will be listed and 
tabulated by treatment for each collection interval. The amounts of sodium and potassium 
will be calculated by multiplying the concentrations by the amount of urine. 

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 In cases where the subject is not able to urinate and/or concentration of sodium and/or 
potassium is missing, the sodium and potassium concentrations as well as the ratios will be 
set to be missing. 
 The following statistics will be calculated for the concentrations: number of cases, geometric 
“n”, geometric mean, geometric standard deviation (re-transformed standard deviation of the 
logarithms) and CV, arithmetic mean, standard deviation and CV, minimum, median, 
maximum value, and the number of measurements. For the amounts as well as the ratios, 
only arithmetic statistics will be provided. 
 Time curves of individual and arithmetic mean log10 10*Na/K ratio versus time (urinary 
collection interval) will be plotted by treatment. 
 More details on PD analyses will be provided in the SAP. 
9.3.5. 
Other Analyses  
Not applicable.  
9.4. 
Interim Analysis  
Not applicable. 
9.5. 
Sample Size Determination 
30 subjects will be randomly assigned to study treatment such that 24 evaluable subjects 
complete the study, i.e., 8 subjects in each study arm. For information on subject replacement, 
refer to Section 7.2.2). The estimated sample size was based on sample sizes from previous 
studies (Nakamura and Kawaguchi, 2021). 
9.6. 
Protocol Deviations 
 A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. Protocol deviations will be identified prior to database 
lock. 
 Important protocol deviations are a subset of protocol deviations that may significantly affect 
the completeness, accuracy and/or reliability of the study data or that may significantly affect 
a subject’s rights, safety, or well-being.  
 Protocol deviations will be prespecified in a deviation manual, discussed on an ongoing basis 
and finally categorized as important/non-important during the DRM. A protocol deviation 
may also be declared as finding / event that leads to an exclusion of data or complete subjects 
from an analysis set (see Section 9.2). 
 Important protocol deviations will also be described in the clinical study report.  

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9.7. 
Data Management 
Nuvisan GmbH will be responsible for clinical data management activities for this study. The 
full details of procedures for data handling will be documented in the data management plan.  
Medical coding will be done using the latest version of the coding dictionaries for MedDRA for 
AEs and medical history to the primary SOC and WHO Drug Global Dictionary for concomitant 
medications. Coding will be performed by data management and needs to be approved by the 
Investigator and Sponsor. 
9.7.1. 
Database Lock 
Study database must be soft and hard locked to ensure their integrity for the generation of results, 
analysis, and submissions. 
9.7.2. 
Soft Lock 
When validation (including external data reconciliation), SAE reconciliation and all coding 
activities, as well as medical review activities and quality control activities have been completed 
and there are no further open issues or open queries the database will be soft locked. 
9.7.3. 
Data Review Meeting 
A DRM will be held for the study by the biostatistician to check the data status, discuss any open 
issues and provide proposals for resolution, as well as finally agree on the categorization of the 
protocol deviations and assignment of subjects to analysis sets.  
9.7.4. 
Hard Lock 
After finalization and approval of the DRM minutes and after all actions resulting from the DRM 
are completed, e.g., additional solving of queries, the database will be hard locked. Hard lock 
needs to be authorized by the study team. 
9.7.5. 
Data Standards 
The database and the electronic external data will be converted to CDISC / SDTM and ADaM. 
The procedure will be described in the study specific data management plan and in the SAP. 

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
Before the start of the study, Nuvisan on behalf of the Sponsor will apply for approval for the 
performance of the study at the CA (German Federal Institute for Drugs and Medical Devices 
[BfArM]) and the IEC.  
10.1.1. 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
o Applicable ICH GCP Guidelines 
o Applicable laws and regulations 
 The protocol, modifications to the protocol (modifications), ICF, IB, and other relevant 
documents (e.g., advertisements) must be submitted to an IEC and reviewed and approved by 
the IEC before the study is initiated. 
 Any substantial modification to the protocol (substantial modification) will require CA and 
IEC approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects. 
 The Investigator will be responsible for the following: 
o Notifying the IEC of SAEs or other significant safety findings as required by IEC 
procedures 
o Providing oversight of the conduct of the study at the site and adherence to ICH 
guidelines, the IEC, European Regulation 536/2014, and all other applicable local 
regulations 
o Performing a benefit-risk assessment on an ongoing basis and informing the IEC about 
any changes. Moreover, making sure that any substantial modifications to the protocol 
(substantial modifications) will be submitted and approved prior to implementation 

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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 study 
and for 1 year after completion of the study. 
10.1.3. 
Clinical Study Insurance and Subject Compensation 
 In accordance with local law, insurance coverage will be provided for all subjects 
participating in this study. 
 Subjects will be paid compensation for participation and will be reimbursed for travel-related 
costs. 
10.1.4. 
Informed Consent Process 
 The Investigators or their representative will explain the nature of the study to the subject and 
answer all questions regarding the study. 
 Subjects must be informed that their participation is voluntary. Subjects will be required to 
sign a statement of informed consent that meets the requirements of local regulations, ICH 
guidelines, and the IEC. 
 The written ICF must be signed and personally dated by the subject and by the Investigator 
who conducted the informed consent discussion.  
 Subjects should be informed of the possibility to withdraw consent without giving any reason 
and to require that all previously retained identifiable samples will be destroyed to prevent 
future analyses, according to national provisions. The information should include a statement 
that the consequence of the subject’s withdrawal of consent will be that no new information 
will be collected from the subject and added to existing data or database. 
 All subjects who sign the ICF will be assigned a screening number. 
 Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. Any revised ICF must receive the IEC approval / favorable opinion 
in advance of use. 
 One original of the signed and dated ICF will be provided to the subject. A second original 
will be retained in the Investigator site file. 
 The Investigator should maintain a log of all subjects who signed the ICF. 
 Subjects who are rescreened are required to sign a new ICF and receive a new screening 
number. 

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 A separate ICF will be prepared that addresses the use of remaining mandatory samples for 
optional exploratory research. The Investigator or authorized designee will explain to each 
subject the objectives of the exploratory research. Subjects will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during 
the storage period. A signature on this ICF for future use will be required to document a 
subject's agreement to allow any remaining specimens to be used for exploratory research. 
Subjects who decline to participate in this optional research will not provide this separate 
signature. 
10.1.5. 
Protocol Amendment 
Modifications of the signed protocol, where substantial, are only possible by approved protocol 
amendments and with the agreement of all responsible persons. The procedure for approval of a 
protocol amendment is identical to that for approval of the protocol. The IEC must be informed 
of all substantial amendments and should be asked for its opinion as to whether a full 
reevaluation of the ethical aspects of the study is necessary by the committee. This should be 
fully documented.  
The Investigator must not implement any deviation from, or change to the protocol, without 
discussion with, and agreement by Santhera Pharmaceuticals (Switzerland) Ltd. and prior review 
and documented approval/favorable opinion of the amendment from the relevant EC, except 
where it is necessary to eliminate an immediate hazard to study subjects, or where the change(s) 
involves only logistical or administrative aspects of the study, i.e., non-substantial (e.g., change 
in monitor(s), change of telephone number(s)).  
Protocol amendments will be submitted to the appropriate authority(ies) as required by the 
applicable regulatory requirement(s). 
10.1.6. 
Recruitment 
 The study will be performed in adult subjects fully capable of giving informed consent. 
 Healthy volunteers for the study will be recruited from suitable candidates in the database of 
the investigational site. Interested volunteers can actively contact the site directly via a public 
website offering information about studies currently recruiting. 
 Detailed description of the recruitment strategy will be provided in country-specific 
documentation as required.  
10.1.7. 
Data Protection 
Personal and sensitive personal data will be treated as confidential. The results of the study will 
be made available for review by authorized representatives of the Sponsor and/or submitted to 
one or more Sponsor offices worldwide, the EC and regulatory authorities. Data may be 
transferred to other countries.  

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Prior to the subject’s enrolment in the study, the patient’s consent is required for the data to be 
used for these purposes and to gain direct access to their medical records for data verification 
purposes. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing subject data.  
Authorized access only is assured by strict rules on Nuvisan firewall. Nuvisan uses strict rules to 
separate the networks within the company. User groups with various permission sets are 
maintained within Nuvisan network to ensure confidentiality of records. Connections to the 
Nuvisan network from the off-site access point have to use a virtual private network. The 
Nuvisan network is constantly being monitored for potential threats, viruses, and other security 
related issues by a separate security operation center. To prevent a security breach, all Nuvisan 
employees are trained on how to proceed in case of receiving suspicious email. 
 Subjects will be assigned a unique identifier. Any subject records or datasets that are 
transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. Only the Investigator and 
the clinical team will be able to link the subjects’ trial data to the subjects via an 
identification list kept at the site. The subjects’ original medical data that are reviewed at the 
site during source data verification by the monitor, audits and during health authority 
inspections will be kept strictly confidential. 
 The subject must be informed that their personal study-related data will be used by the 
Sponsor in accordance with the EU General Data Protection Regulation. The level of 
disclosure must also be explained to the subject. 
 The subject must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor and by 
inspectors from regulatory authorities without violating the confidentiality of the subject to 
the extent permitted by law and regulations. 
 All personal data collected and processed for the purpose of this study will be managed by 
the Investigator and their staff with adequate precautions to ensure confidentiality of those 
data, as per national and/or local laws and regulations on personal data. 
 Measures are in place to mitigate the possible adverse effects of a data security breach and 
are in line with the EU General Data Protection Regulation and relevant national legislations. 
10.1.8. 
Committees Structure 
Not applicable. 

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10.1.9. 
Dissemination of Clinical Study Data 
This clinical study will be registered in a clinical study database before enrolment of the first 
subject. All data and results and all intellectual property rights in the data and results derived 
from the study will be the property of the Sponsor who may utilize them in various ways, such as 
for submission to government regulatory authorities or disclosure to other Investigators. 
Regarding public disclosure of study results, the sponsor will fulfil its obligations according to 
all applicable laws and regulations. The sponsor is interested in the publication of the results of 
every study it performs. 
10.1.10. 
Data Quality Assurance 
 The clinical trial protocol, each step of the data capture procedures, and the handling of the 
data, including the final clinical trial/study report, will be subject to independent Quality 
Assurance activities. Audits may be conducted at any time during or after the trial to confirm 
the validity and integrity of the trial data. The Investigator will give the auditor direct access 
to all relevant documents and will allocate his/her time and the time of his/her staff to the 
auditor as may be required to discuss findings and relevant issues. In addition, Regulatory 
bodies (e.g., Regulatory Authorities, IECs, at their discretion may conduct inspections and 
the Investigator agrees to cooperate fully during conduct and discuss any relevant issues.  
The Investigator has the obligation to immediately inform the Sponsor of an inspection 
notification or request by a Regulatory Authority and will ensure direct access to source data 
and all study related documentation during Regulatory Authority inspections. 
 All subject data relating to the study will be recorded and transmitted to the Sponsor or 
designee electronically. The Investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the eCRF. 
 The Investigator must permit study-related monitoring, audits, IEC review, and regulatory 
agency inspections and provide direct access to source data documents including electronic 
medical records.  
 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. 
 Nuvisan GmbH 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). 

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 Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects 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. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 25 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. 
10.1.11. 
Source Documents 
 All source documents must follow the ALCOA principle of data integrity (Attributable, 
Legible, Contemporaneous, Original and Accurate). Changes to source data should be 
traceable, should not obscure the original entry, and should be explained, if necessary (e.g., 
audit trail). The Sponsor ensures that the Investigator has control of and continuous access to 
the (e)CRF data reported to the Sponsor.  
All subject data relating to the study will be recorded on the (e)CRF. In addition, some study 
related data (e.g., laboratory data, Quality of Life, source documentation on AEs etc.) could 
be required to be provided to Sponsor or representative and AEs need to be reported to the 
Sponsor, as further detailed in this protocol. At all times, subject confidentiality is and will be 
protected. 
 Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. 
 eCRF data must be consistent with the source documents, or the discrepancies must be 
explained.  
 Definition of what constitutes source data can be found in the source data location form. 
10.1.12. 
Study and Site Closure 
 The Sponsor 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. 

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 Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to: 
o Failure of the Investigator to comply with the protocol, the requirements of the IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines. 
o Inadequate recruitment of subjects by the Investigator. 
o Discontinuation of further study treatment development. 
10.1.13. 
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.  
 Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.14. 
Clinical Study Report 
 After completion of the study, a clinical study report covering clinical and statistical aspects 
of the study will be prepared by Nuvisan GmbH in consultation with the Sponsor. 
 All information supplied by the Sponsor in connection with this study will remain the sole 
property of the Sponsor and is to be considered confidential information. No confidential 
information will be disclosed to others without obtaining prior written consent from the 
Sponsor and will not be used except in the performance of this study. 
 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
 The tests detailed in Table 10 will be performed by the local laboratory at the timepoints 
specified in the SoA (Section 1.3). 
 Details of all methodology and reference ranges will be provided in the Trial Master File. 
 Investigators must document their review and assess clinical relevance, of each laboratory 
safety report. 
 The results of each test will be transferred electronically to the clinical database. 
 Protocol-specific requirements for inclusion or exclusion of subjects are detailed in Section 5 
of the protocol. 
 Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations.  

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Table 10: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology Platelet count 
Mean corpuscular 
volume (MCV) 
Mean corpuscular 
hemoglobin (MCH) 
Mean corpuscular 
hemoglobin 
concentration (MCHC) 
White Blood Cell Count 
with Differential 
(absolute and %): 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Reticulocytes 
Hemoglobin 
Hematocrit 
Red blood cell count 
White blood cell count 
Clinical 
Chemistry 
Alanine 
aminotransferase (ALT)a 
Calcium 
Lactate dehydrogenase 
Albumin 
Chloride 
Lipase 
Alkaline phosphatase 
(ALP) 
Cholesterol 
Magnesium 
Amylase 
Creatinine 
Potassium 
Aspartate 
aminotransferase (AST) 
Creatine phosphokinase 
(CK)c 
Sodium 
Bilirubin (total)a,b 
γ-Glutamyl-transferase 
Total protein 
Blood urea nitrogen 
Glucose 
Triglycerides 
C-reactive protein 
Inorganic phosphate 
Uric acid 
Coagulation  Activated Partial Thromboplastin Time (aPTT) 
 Prothrombin time (INR, %) 
Urinalysis 
 Specific gravity 
 pH, hemoglobin, urobilinogen, bilirubin, protein, ketones, nitrite, leukocyte 
esterase by dipstick 
 In case of positive results for protein, leukocyte esterase, hemoglobin or 
nitrite on the dip stick, flow cytometry count and classification will be 
performed.  

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Laboratory 
Assessments 
Parameters 
Other Tests 
 Urine drug screen:  
Amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, 
methamphetamines, methylenedioxymethamphetamine, methadone, 
opiates, tricyclic antidepressants, phencyclidine 
 Urine cotinine test 
 At screening only: 
o 
TSHd 
o Fibrinogen 
o HbA1c 
o Glomerular filtration ratee 
 Serology: 
HBsAg, anti-HCV, anti-HIV 1 + 2, and HIV p24 antigen combined 
Notes: 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7. All events of ALT ≥ 3 × ULN and bilirubin ≥ 2 × ULN (> 35% direct 
bilirubin) which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE. 
b In case of increased bilirubin (total), the direct bilirubin will be determined. 
c If increased, creatine kinase (muscle-brain type) and Troponin I (if CK-MB/CK-total x 100 > 6.0% or CK-MB 
> 25 U/L) will be determined. 
d If TSH is out of range, additionally free triiodothyronine and free thyroxine will be determined. 
e eGFR will be calculated as follows based on the CKD-EPI serum creatinine equation (Levey et al., 2009 and 
2011) adjusted to the body surface area (BSA = 0.20247 x ((height/100)^0.725) x (weight^0.425)) of the subject. 
For male subjects: 
If serum creatinine ≤ 80 µmol/L: eGFR [mL/min] = ((141 x (serum creatinine [µmol/L] / 79.6) -0.411x 
0.993Age[years])) x (0.20247 x ((height/100)0.725) x (weight0.425) / 1.73) 
If serum creatinine > 80 µmol/L: eGFR [mL/min] = ((141 x (serum creatinine [µmol/L] / 79.6)-1.209 x 
0.993Age[years])) x (0.20247 x ((height/100)0.725) x (weight0.425) / 1.73) 
If a subject is Black, the initial result calculated as shown above will have to be multiplied by 1.159 to arrive at 
the eGFR.  
 
 
 

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c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject 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. Procedures done 
in or visits to a clinic or outpatient facility are not considered SAEs. Admission to a 
rehabilitation facility, transitional care unit, or nursing home is not considered a hospitalization. 
A hospitalization for an elective treatment of a preexisting condition that did not worsen from 
baseline, or a routinely scheduled treatment is not considered an SAE because a “procedure” or 
“treatment” is not an untoward medical occurrence. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfils 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. 
d. Results in persistent 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 
Intrauterine development of an organ or structure that is abnormal in form, structure, or 
position. 
f. Other situations 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject 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 in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 

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10.4. 
Appendix 4: Pharmacokinetic Parameters 
 
Symbol 
Definition 
AUC0-tlast 
The area under the concentration-time curve (AUC) from time zero 
(= dosing time) to the time of the last quantifiable concentration (tlast), 
calculated using linear trapezoidal rule. 
AUC0-inf
The AUC from time zero (dosing time) extrapolated to infinity estimated 
using the log-linear regression for λz determination (see below).  
AUC0-inf AUC0-tlast +Clast / λz  
Cmax 
Maximum observed concentration.  
t1/2 
Terminal half-life. t1/2 = ln (2)/λz. 
tmax 
The time to reach the maximum observed concentration collected during a 
dosing interval (unless otherwise defined, take the 1st occurrence in case of 
multiple/identical Cmax values). 
z 
Terminal first order (elimination) rate constant. Determined from the 
terminal slope of the concentration curve using log-linear regression on 
terminal data points of the curve. 
 

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10.5. 
Appendix 5: Sponsor Signature Page 
 
The people signing hereby declare that they have read this protocol and agree to its contents.  
 
 
 
 
 
 
 
 
____________________________________ 
____________________________ 
Signature 
 
 
 
 
 
Date of Signature 
 
Name, academic degree: 
 
Function/Title: 
 
Institution: 
Santhera Pharmaceuticals (Switzerland) AG 
Address: 
Santhera Pharmaceuticals (Switzerland) AG 
Hohenrainstrasse 24 
4133 Pratteln 
Switzerland 
Telephone number: 
 
E-mail address: 
 
 
PPD
PPD
PPD
PPD

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10.6. 
Appendix 6: Principal Investigator Signature Page 
The people signing hereby declare that they have read this protocol and agree to its contents. 
They confirm that the study will be conducted and documented in full accordance with the 
protocol (and modifications), ICH guidelines for current GCP specified herein, the national drug 
law, and applicable regulatory requirements. They will also ensure that sub-Investigator(s) and 
other relevant members of their staff have access to copies of this clinical study protocol and the 
ICH GCP guidelines to enable them to work in accordance with the provisions of these 
documents. 
 
 
 
 
 
 
 
 
____________________________________ 
____________________________ 
Signature 
 
 
 
 
 
Date of Signature 
 
Name, academic degree: 
Steffen Haffner, MD 
Function/Title: 
Principal Investigator 
Institution: 
Nuvisan GmbH, Wegenerstrasse 13, 89231 Neu-Ulm 
Address: 
Nuvisan GmbH 
Wegenerstrasse 13 
89231 Neu-Ulm 
Germany 
Telephone number: 
 
E-mail address: 
 
 
PPD
PPD

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11. 
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Fludrocortisone Summary of Product Characteristics (Fachinformation). Fludrocortisone Acetate 
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(SmPC) - (emc) (medicines.org.uk). Last updated on emc: 22 February 2023. Last accessed on 
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dystrophy. JCI Insight. 2022; 7(19):e159875. 
Investigator’s Brochure Vamorolone, Edition 13, 30 November 2023. 
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Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern 
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characterization of a novel anti-inflammatory delta 9,11 steroid. Bioorg Med Chem. 2013; 21(8): 
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Rodriguez-Gonzalez M, Lubian-Gutierrez M, Cascales-Poyatos HM, et al. Role of the Renin-
Angiotensin-Aldosterone System in Dystrophin-Deficient Cardiomyopathy. Int J Mol Sci. 2020; 
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