An Open-label, Single-arm Study to Evaluate the CYP3A4 Induction Potential of Vamorolone on the Pharmacokinetics of Midazolam (a Sensitive CYP3A4 Probe) in Healthy Subjects.
Phase: PHASE1
Conditions: Drug Interaction
Sponsor: Santhera Pharmaceuticals

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CLINICAL STUDY PROTOCOL 
 
Title Page 
 
Protocol Title:  
An open-label, single-arm study to evaluate the CYP3A4 induction potential of vamorolone on 
the pharmacokinetics of midazolam (a sensitive CYP3A4 probe) in healthy subjects. 
Sponsor Protocol Number: 
SNT-I-VAM-025 
Nuvisan Protocol Number:  
N-A-PH1-23-054  
Investigational Medicinal 
Product: 
Vamorolone 
Study Phase:  
Phase 1 
Brief Title: 
Evaluation of vamorolone CYP3A4 induction on 
midazolam (a sensitive CYP3A4 substrate) 
pharmacokinetics 
Sponsor:  
Santhera Pharmaceuticals (Switzerland) Ltd 
Hohenrainstrasse 24 
4133 Pratteln, Switzerland 
Sponsor’s Legal 
Representative EU: 
 
Nuvisan GmbH 
Wegenerstr. 13 
89231 Neu-Ulm, Germany 
Principal Investigator: 
Michael Lissy 
Nuvisan GmbH 
Wegenerstr. 13 
89231 Neu-Ulm, Germany 
Regulatory Agency Identifier 
Number(s): 
EU CT number: 2024-513845-36-00  
Protocol Version: 
05-JUN-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 ........................................................................................................... 11 
1.1. 
Synopsis .................................................................................................................... 11 
1.2. 
Schema ...................................................................................................................... 13 
1.3. 
Schedule of Activities ............................................................................................... 14 
2. 
Introduction ...................................................................................................................... 17 
2.1. 
Study Rationale ......................................................................................................... 17 
2.2. 
Background ............................................................................................................... 18 
2.2.1. 
Vamorolone........................................................................................................ 18 
2.2.2. 
Midazolam ......................................................................................................... 21 
2.2.3. 
Biomarkers for CYP3A4 Activity ..................................................................... 22 
2.3. 
Benefit/Risk Assessment ........................................................................................... 22 
2.3.1. 
Risk Assessment ................................................................................................ 23 
2.3.2. 
Warnings and Precautions.................................................................................. 25 
2.3.3. 
Benefit Assessment ............................................................................................ 25 
2.3.4. 
Overall Benefit Risk Conclusion ....................................................................... 25 
3. 
Objectives and Endpoints ................................................................................................ 27 
4. 
Study Design .................................................................................................................... 28 
4.1. 
Overall Design........................................................................................................... 28 
4.2. 
Scientific Rationale for Study Design ....................................................................... 28 
4.3. 
Justification for Dose ................................................................................................ 29 
4.4. 
Start / End of Study Definition .................................................................................. 30 
5. 
Study Population .............................................................................................................. 31 
5.1. 
Inclusion Criteria ....................................................................................................... 31 
5.1.1. 
Inclusion Criteria to be Checked at Screening ................................................... 31 

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5.2. 
Exclusion Criteria ...................................................................................................... 33 
5.2.1. 
Exclusion Criteria to be Checked at Screening.................................................. 33 
5.2.2. 
Exclusion Criteria to be re-checked upon Admission........................................ 36 
5.3. 
Lifestyle Considerations ............................................................................................ 37 
5.3.1. 
Meals and Dietary Restrictions .......................................................................... 37 
5.3.2. 
Caffeine, Alcohol, and Tobacco ........................................................................ 37 
5.3.3. 
Activity .............................................................................................................. 38 
5.3.4. 
Other Restrictions .............................................................................................. 38 
5.4. 
Screen Failures .......................................................................................................... 38 
5.5. 
Criteria for Temporarily Delaying Enrollment, Study Treatment............................. 39 
6. 
Study Treatments and Concomitant Therapy .................................................................. 40 
6.1. 
Study Treatments Administered ................................................................................ 40 
6.2. 
Preparation, Handling, Storage, and Accountability ................................................. 41 
6.3. 
Assignment to Study Treatment ................................................................................ 42 
6.4. 
Blinding ..................................................................................................................... 42 
6.5. 
Study Treatment Compliance .................................................................................... 43 
6.6. 
Dose Modification ..................................................................................................... 43 
6.7. 
Continued Access to Study Treatment after the End of the Study ............................ 43 
6.8. 
Treatment of Overdose .............................................................................................. 43 
6.9. 
Prior and Concomitant Therapy ................................................................................ 44 
6.9.1. 
Rescue Medicine ................................................................................................ 45 
7. 
Discontinuation of Study Treatment and Subject Discontinuation/Withdrawal .............. 46 
7.1. 
Discontinuation of Study Treatment ......................................................................... 46 
7.1.1. 
Stopping Rules for Individual Subjects ............................................................. 46 
7.2. 
Subject Discontinuation / Withdrawal from the Study ............................................. 47 
7.2.1. 
Discontinuation / Withdrawal Criteria for Individual Subjects ......................... 47 
7.2.2. 
Replacement of Subjects .................................................................................... 48 
7.3. 
Further Stopping Rules.............................................................................................. 48 
7.3.1. 
Premature Discontinuation of the Complete Study ........................................... 48 

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7.4. 
Lost to Follow-up ...................................................................................................... 49 
8. 
Study Assessments and Procedures ................................................................................. 50 
8.1. 
Administrative and General Procedures .................................................................... 50 
8.1.1. 
Demographic ...................................................................................................... 50 
8.1.2. 
Body Weight and Height, BMI .......................................................................... 51 
8.1.3. 
Medical History ................................................................................................. 51 
8.1.4. 
Other Baseline Characteristics ........................................................................... 51 
8.2. 
Efficacy and Immunogenicity Assessments .............................................................. 51 
8.3. 
Safety Assessments ................................................................................................... 51 
8.3.1. 
Physical Examinations ....................................................................................... 51 
8.3.2. 
Vital Signs .......................................................................................................... 52 
8.3.3. 
Electrocardiograms ............................................................................................ 52 
8.3.4. 
Clinical Safety Laboratory Tests ....................................................................... 52 
8.3.5. 
Pregnancy Testing .............................................................................................. 53 
8.3.6. 
Other Assessments ............................................................................................. 53 
8.4. 
Adverse Events and Serious Adverse Events ............................................................ 53 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .............. 54 
8.4.2. 
Method of Detecting AEs and SAEs ................................................................. 54 
8.4.3. 
Follow-up of AEs and SAEs .............................................................................. 54 
8.4.4. 
Regulatory Reporting Requirements for SAEs .................................................. 54 
8.4.5. 
Pregnancy ........................................................................................................... 55 
8.4.6. 
Adverse Events of Special Interest .................................................................... 56 
8.5. 
Pharmacokinetics ...................................................................................................... 56 
8.5.1. 
Bioanalytical Methods ....................................................................................... 58 
8.5.2. 
Pharmacokinetic Evaluation .............................................................................. 58 
8.6. 
Pharmacodynamics.................................................................................................... 59 
8.7. 
Genetics ..................................................................................................................... 59 
8.8. 
Biomarkers ................................................................................................................ 59 
8.9. 
Immunogenicity Assessments ................................................................................... 60 

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8.10. Medical Resource Utilization and Health Economics............................................... 61 
9. 
Statistical Considerations ................................................................................................. 62 
9.1. 
Statistical Hypotheses ............................................................................................... 62 
9.2. 
Analysis Sets ............................................................................................................. 62 
9.3. 
Statistical Analyses ................................................................................................... 63 
9.3.1. 
Efficacy Analyses .............................................................................................. 63 
9.3.2. 
Safety Analyses .................................................................................................. 63 
9.3.3. 
Pharmacokinetic Analyses ................................................................................. 63 
9.3.4. 
Pharmacodynamic Analyses .............................................................................. 64 
9.3.5. 
Other Analyses ................................................................................................... 64 
9.4. 
Interim Analysis ........................................................................................................ 64 
9.5. 
Sample Size Determination ....................................................................................... 65 
9.6. 
Protocol Deviations ................................................................................................... 65 
9.7. 
Data Management ..................................................................................................... 65 
9.7.1. 
Database Lock .................................................................................................... 65 
9.7.2. 
Soft Lock ............................................................................................................ 66 
9.7.3. 
Data Review Meeting ........................................................................................ 66 
9.7.4. 
Hard Lock .......................................................................................................... 66 
9.7.5. 
Data Standards ................................................................................................... 66 
10. 
Supporting Documentation and Operational Considerations ....................................... 67 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................... 67 
10.1.1. Regulatory and Ethical Considerations .............................................................. 67 
10.1.2. Financial Disclosure........................................................................................... 67 
10.1.3. Clinical Study Insurance and Subject Compensation ........................................ 68 
10.1.4. Informed Consent Process ................................................................................. 68 
10.1.5. Protocol Amendment ......................................................................................... 69 
10.1.6. Recruitment ........................................................................................................ 69 
10.1.7. Data Protection................................................................................................... 69 
10.1.8. Committees Structure......................................................................................... 70 

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10.1.9. Dissemination of Clinical Study Data................................................................ 71 
10.1.10. Data Quality Assurance ..................................................................................... 71 
10.1.11. Source Documents ............................................................................................. 72 
10.1.12. Study and Site Closure ....................................................................................... 72 
10.1.13. Publication Policy .............................................................................................. 73 
10.1.14. Clinical Study Report ......................................................................................... 73 
10.2. Appendix 2: Clinical Laboratory Tests ..................................................................... 74 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .................................................................................................... 77 
10.3.1. Definitions.......................................................................................................... 77 
10.3.2. Definition of SAE .............................................................................................. 78 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................... 80 
10.3.4. Reporting of SAEs ............................................................................................. 83 
10.4. Appendix 4: Contraceptive Guidance ....................................................................... 85 
10.4.1. Definitions.......................................................................................................... 85 
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ............ 87 
10.6. Appendix 6: Pharmacokinetic Parameters Definition ............................................... 90 
10.7. Appendix 7: Sponsor Signature Page ........................................................................ 91 
10.8. Appendix 8: Principal Investigator Signature Page .................................................. 92 
11. 
References ..................................................................................................................... 93 
 

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List of Tables 
Table 1: 
Schedule of Activities ................................................................................................. 15 
Table 2: 
Objectives and Endpoints ........................................................................................... 27 
Table 3: 
Study Treatments ........................................................................................................ 40 
Table 4: 
Pharmacokinetic Blood Collection Schedule for Midazolam and 
1’-Hydroxymidazolam .................................................................................................................. 57 
Table 5: 
Pharmacokinetic Blood Collection Schedule for Vamorolone................................... 57 
Table 6: 
Non-compartmental Pharmacokinetic Parameters for Midazolam and 
1’-Hydroxymidazolam .................................................................................................................. 59 
Table 7: 
Blood Collection Schedule for 4β-Hydroxycholesterol ............................................. 60 
Table 8: 
Urine Collection Schedule for 6β-Hydroxycortisol to Cortisol Ratio ........................ 60 
Table 9: 
Protocol-Required Safety Laboratory Assessments ................................................... 75 
 
List of Figures  
Figure 1: 
Overall Study Design .............................................................................................. 13 
Figure 2: 
Chemical Structure of Vamorolone ........................................................................ 18 
 

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List of Abbreviations 
Abbreviations of PK parameters are provided in Section 10.6. 
ADaM 
Analysis data model 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
anti-HIV 
Anti-human immunodeficiency virus antibody 
anti-HCV 
Anti-hepatitis C virus antibody 
AST 
Aspartate aminotransferase 
AxMP 
Auxiliary medicinal product 
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 phosphokinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRF 
Case report form 
CTIS 
Clinical Trials Information System 
CTS 
Clinical trial supplies  
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
CYP3A4 
Cytochrome P450 3A4 
DDI 
Drug-drug interaction 
DMD 
Duchenne Muscular Dystrophy 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 

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eCRF 
Electronic case report form  
ED 
Early discontinuation 
eGFR 
Estimated glomerular filtration rate 
ENT 
Ear, nose, throat 
EU 
European Union 
FSH 
Follicle stimulating hormone 
FU 
Follow-up 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate dehydrogenase 
GR 
Glucocorticoid receptor 
HBsAg  
Hepatitis B virus surface antigen  
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HRT 
Hormonal replacement therapy 
IB 
Investigator's Brochure 
ICF 
Informed consent form 
ICH 
International conference for harmonization 
IEC 
Independent ethics committee 
IgM 
Immunoglobulin M 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IUD 
Intrauterine device 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Mineralocorticoid receptor 
NIMP 
Non-investigational medicinal product 
PK 
Pharmacokinetic(s) 

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PR(Q) 
ECG parameter: PR(Q) interval 
QRS 
ECG parameter: QRS duration; part of electrocardiographic wave 
representing ventricular depolarization  
QT 
ECG parameter: QT interval uncorrected 
QTc 
ECG parameter: QT interval corrected 
QTcF 
ECG parameter: QT interval corrected for ventricular rate calculated 
according to the formula of Fridericia 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SDTM 
Study data tabulation model 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of activities 
SOP  
Standard operating procedure  
SUSAR  
Suspected unexpected serious adverse reaction  
TEAE 
Treatment emergent adverse event 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
USA 
United States of America 
USPI 
United States prescribing information 
WHO 
World Health Organization 
WOCBP 
Woman of child-bearing potential 
WONCBP 
Woman of non-childbearing potential 
 

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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  
An open-label, single-arm study to evaluate the CYP3A4 induction potential of vamorolone on 
the pharmacokinetics of midazolam (a sensitive CYP3A4 probe) in healthy subjects. 
Brief Title:  
Evaluation of vamorolone CYP3A4 induction on midazolam (a sensitive CYP 3A4 substrate) 
pharmacokinetics  
Regulatory Agency Identifier Number(s):  
EU CT number: 2024-513845-36-00 
Rationale:  
The purpose of this study is to investigate the CYP3A4 induction properties of vamorolone in 
humans. In vitro experiments showed a concentration-dependent CYP3A4 induction, with less 
than a 2-fold increase in enzyme activity and mRNA levels at concentrations of 5 µM and below. 
The therapeutic dose of vamorolone (6.0 mg/kg) in patients with DMD results in unbound Cmax 
values at least 5-fold lower than concentrations that cause in vitro CYP3A4 induction. However, 
the potential for reduced plasma concentrations due to co-administration of vamorolone with 
other CYP3A4 substrates cannot be excluded. Using midazolam as a CYP3A probe drug, the 
study will measure pharmacokinetics on Days 1 and 14 to assess potential DDIs. Conducted in 
healthy subjects, the study is designed to predict outcomes in the intended patient population for 
vamorolone. The results will guide labeling for CYP3A4-related DDIs with vamorolone. 
 

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The treatment duration will be up to 2 weeks and each subject will receive the following 
treatments: 
• Day 1: Single oral dose of 2.5 mg midazolam. 
• Day 2: Wash-out day. 
• Days 3 to 13: Daily oral doses of 6 mg/kg vamorolone. 
• Day 14: Single oral doses of 2.5 mg midazolam and 6 mg/kg vamorolone. 
The follow-up visit is planned 24 hours after last midazolam dose, on Day 15. A safety follow-up 
call is planned 14 days after the last vamorolone dose, on Day 28. Early discontinuation 
assessments will be conducted at an early discontinuation visit for subjects who withdraw 
prematurely.  
Data Monitoring/Other Committee: No 
 
1.2. 
Schema 
Figure 1: 
Overall Study Design 
 
Screening procedures will be performed within 28 to 2 days prior to the first administration of 
study treatment. 
 
 
 

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1.3. 
Schedule of Activities 
The 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 -1 evaluations): 
1. 12-lead ECG, vital signs; 
2. Blood sampling (PK, CYP3A4 activity biomarkers, and safety) as close as possible to 
the nominal time; 
3. All other assessments and procedures. 
Any meals or water intake will be served after 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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Table 1: 
Schedule of Activities 
Procedure 
SCR 
Study Day 
FU/ED 
Notes 
-28 
to -2 –1 1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15* 28 
*Not earlier than 24 hours after the last midazolam 
dose / after early discontinuation. 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 To be obtained prior to any screening activity. Refer 
to Section 10.1. 
Ambulatory visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Hospitalization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 In the morning in fasted state. 
In-house stay 
 
X X X X X X X X X X X X X X X X 
  
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 After completion of FU/ED assessments. 
Safety Phone Call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Refer to Sections 5.1.1 and 5.2.1. 
Confirmation of eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Recheck of clinical status on Day -1, and subject 
eligibility. 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Refer to Section 8.1.1. 
Relevant medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Including history of illegal drugs, alcohol, tobacco, 
and caffeine use. Refer to Section 8.1.3.  
Prior medication 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any medication (including prescription, 
non-prescription drugs, dietary and herbal 
supplements) taken which had been stopped prior to 
the first administration of study treatment. 
Physical examination  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 Refer to Section 8.3.1. 
Height, weight  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 Height will be measured at screening only.  
BMI will be calculated. Refer to Section 8.1.2. 
Serum pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 In all female subjects. Refer to Section 8.3.5. 
TSH, FSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Refer to Section 10.2. 
FSH only for suspected postmenopausal females. 
Serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 HIV, Hepatitis B and C screening. Refer to 
Section 10.2. 
Urine drug and cotinine screen and 
alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Refer to Section 8.3.6 and Section 10.2. 
Safety laboratory assessments 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Hematology, coagulation, clinical chemistry, 
urinalysis. Refer to Section 10.2. 
Day 3 and 9: predose; no urinalysis. 

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Procedure 
SCR 
Study Day 
FU/ED 
Notes 
-28 
to -2 –1 1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15* 28 
*Not earlier than 24 hours after the last midazolam 
dose / after early discontinuation. 
12-lead ECG 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 Days 3 and 14: approximately 2 hours postdose. For 
details refer to Section 8.3.3. 
Vital signs including body 
temperature  
X 
X X X X X X X X X X X X X X X X 
 Day 1 and Days 3 to 14: Predose. Days 2 and 15: 
24 hours postdose. For details refer to Section 8.3.2. 
Study treatment administration 
midazolam 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 Refer to Section 6.1. 
PK blood sampling for midazolam 
and 1’-hydroxymidazolam 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
At predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 
10 hours after each midazolam dose. Refer to 
Section 8.5. 
Study treatment administration 
vamorolone 
 
 
 
 
X X X X X X X X X X X X 
 
 
Refer to Section 6.1. 
For dose calculation, weight of Day –1 will be 
taken. 
PK blood sampling vamorolone 
 
 
 
 
X X 
 
 
X 
 
 
 
X 
 
X X 
 
 Predose. Refer to Section 8.5. 
Blood sampling for 
4β-hydroxycholesterol  
 
 
X 
 
X X 
 
 
X 
 
 
 
X 
 
 
X X 
 On Day 15: 24 hours postdose. On other days: 
predose. Refer to Section 8.8. 
Urine collection for 
6β-hydroxycortisol and cortisol 
 
 
X 
 
X X 
 
 
X 
 
 
 
X 
 
 
X X 
 From approximately 8:00 to 12:00 a.m.. Refer to 
Section 8.8. 
(S)AE review 
X 
X X X X X X X X X X X X X X X X X Any event with start after ICF signature. Refer to 
Sections 8.4 and 10.5. 
Concomitant medication review 
 
 
X X X X X X X X X X X X X X X X 
Any medication taken at/after time of first study 
treatment, regardless of whether it had started prior 
to the study or not. Refer to Section 6.9. 
AE=adverse event; BMI=body mass index; ECG=electrocardiogram; ED=early discontinuation visit; FSH=follicle-stimulating hormone; FU=follow-up visit; 
HIV=human immunodeficiency virus; ICF=informed consent form; PK=pharmacokinetics; SAE=serious adverse event; SCR: Screening; TSH=thyroid-
stimulating hormone. 

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2. 
Introduction 
Vamorolone belongs to the structural class of synthetic steroidal drugs but shows unique 
pharmacodynamic properties combining selective glucocorticoid receptor agonism with 
mineralocorticoid receptor antagonism (Reeves et al, 2013).  
Vamorolone 40 mg/mL oral suspension (commercial name AGAMREE®) received Marketing 
Authorisation in the EU and in the USA 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 the present study is to address the CYP3A4 induction properties of vamorolone 
in humans. 
Based on in vitro experiments, CYP3A4 induction by vamorolone was found to be 
concentration-dependent, resulting in less than a 2-fold increase in enzyme activity in 
hepatocytes at concentrations of 5 µM and below. Similarly, less than a 2-fold induction based 
on mRNA was observed in hepatocytes at concentrations of 1.5 µM and below. The unbound 
Cmax values associated with the therapeutic dose of 6.0 mg/kg administered daily to patients with 
DMD (0.327 µM) are at least 5-fold lower than the concentrations causing CYP3A4 induction 
in vitro. However, it is not ruled out that co-administration of vamorolone with other compounds 
acting as substrates of CYP3A4 may potentially lead to reduced plasma concentrations. 
Midazolam is primarily metabolized in the liver and gut by human CYP3A4 to its pharmacologic 
active metabolite, 1’-hydroxymidazolam and has been used widely as a sensitive CYP3A probe 
drug for evaluating the effect of an inducer on CYP3A activity in vivo. 
Pharmacokinetics of midazolam will be measured on Day 1, and then on Day 14 to investigate 
the potential DDI between the two compounds resulting from potential induction by vamorolone 
for the CYP3A4 enzyme. 
The study will be conducted in healthy subjects as the findings in this population should predict 
findings in the patient population for which vamorolone is intended. The planned administrated 
doses have been shown to be safe and no genotoxicity was observed in vitro and in vivo 
assessments. 
The study results will provide guidance for labelling with respect to CYP3A4-related DDIs with 
vamorolone.  

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2.2. 
Background 
2.2.1. 
Vamorolone 
Vamorolone is a structural analogue of prednisolone in which the sub-activities have been 
dissociated, i.e., transrepression retained, transactivation reduced, membrane stabilization 
increased, and cross-reactivity with the mineralocorticoid receptor changed from agonist to 
antagonist.  
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 
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 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. 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 USA in October 2023 and in the EU in 
December 2023 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. 
More detailed information on DMD and BMD can be found in the current IB (IB). 
 
2.2.1.1. 
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. 

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• 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. 
• 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 gastrointestinal 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 overall low, however the 
pharmacologically mediated adverse effects were generally reversible and are monitorable in 
the clinic. 
• As DMD is a predominantly male disease, a focused microscopic analysis of the male 
reproductive organs and sperm analysis were included in chronic toxicology studies both the 
mouse and dog. 
• There were no signals for either mutagenicity or genotoxicity in any of the studies 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). 
2.2.1.2. 
Summary of Clinical Studies 
6 clinical studies have been completed with healthy subjects as part of the clinical pharmacology 
program for vamorolone. 4 clinical studies have been completed in subjects first enrolled at ages 

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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. 
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 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 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%), diarrhoea (7.1%), vomiting (14.3%), rhinitis (7.1%), arthropod 

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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%). 
• 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%), diarrhoea (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.  
Additional detailed information about the clinical studies of vamorolone can be found in the 
current IB (IB).  
2.2.2. 
Midazolam 
Midazolam is a benzodiazepine available as midazolam solution for oral administration. Oral 
midazolam provides safe and effective sedation and anxiolysis prior to surgical procedures 
requiring anesthesia and prior to other procedures requiring sedation without anesthesia. 
Midazolam is also used for short-term treatment of sleep disorders. Time to onset of effect is 
most frequently reported as 10 to 20 minutes (Nordt et al, 1997). 
Pharmacokinetics and metabolism of midazolam: 
Following a single oral dose, peak midazolam concentration is usually achieved at 0.5 to 1 hour. 
The Cmax values of midazolam are reported to average 10 ng/mL and 24 ng/mL, following a 
single oral dose of 2 mg and 5 mg, respectively. The elimination half-life of midazolam is 
approximately 3.6 hours. The extent of plasma protein binding of midazolam is moderately high 
and concentration independent. In adults and pediatric patients older than 1 year, midazolam is 
approximately 97% bound to plasma protein, principally albumin. Midazolam is metabolized via 
CYP3A4 to 1’-hydroxymidazolam and is a sensitive substrate of CYP3A4. In healthy subjects, 
1’-hydroxymidazolam is bound to the extent of 89%. 
Safety profile of midazolam: 

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Midazolam has been associated with reports of respiratory depression, airway obstruction, 
oxygen desaturation, hypoxia, and apnea, most often when used concomitantly with other central 
nervous system depressants (e.g. opioids). 
Midazolam must only be administered to subjects if they will be monitored by direct visual 
observation by a health care professional. 
More detailed information on midazolam can be found in the SmPC (SmPC midazolam). 
2.2.3. 
Biomarkers for CYP3A4 Activity 
Endogenous 4β-hydroxycholesterol is mediated by CYP3A4 and CYP3A5 and had been 
proposed as a reliable marker of CYP3A4/5 activity. Patients treated with drugs known to be 
strong inducers of CYP3A4/5 (e.g. rifampicin) have shown dose-related increases in circulating 
4β-hydroxycholesterol levels (Diczfalusy et al, 2011). 4β-Hydroxycholesterol is a metabolite of 
cholesterol formed by CYP3A4-catalyzed metabolism, for which plasma concentrations show no 
diurnal variation and low intra-individual variability (Kanebratt et al, 2008). In addition, the 
6β-hydroxycortisol-to-cortisol ratio will be also measured in urine samples as a conservative 
approach (Tran et al, 1999). 
2.3. 
Benefit/Risk Assessment 
As of November 2023, subjects in 10 completed and 2 ongoing studies have been exposed to 
vamorolone including healthy subjects, patients with DMD and patients with BMD.  
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. 
The vamorolone treatment duration in this study will be 12 days in total. The maximum daily 
dose of 6 mg/kg corresponds to the maximum clinical dose in DMD pediatric patients. This 
regimen does not exceed the maximum exposure of 20 mg/kg given daily for up to 14 days 
which was shown to be well tolerated in previous studies with healthy subjects.  
Considering the nonclinical and clinical data available to date, the study is considered reasonable 
and adequate according to the specifications outlined in this protocol. 

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Identified and Potential 
Risks of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Hypersensitivity including 
angioedema, and anaphylactic 
shock, rash, urticaria, pruritus 
(frequency unknown) 
Contraindication and a known 
side effect of midazolam 
according to the SmPC. 
Subjects with known 
hypersensitivity to 
midazolam will not be 
included in the study (see 
Section 5.2). 
Subjects will stay in-house 
during the midazolam dosing 
periods and will be closely 
monitored for signs and 
symptoms of 
hypersensitivity. 
Respiratory depression, 
apnea, respiratory/cardiac 
arrest, dyspnea, bradycardia, 
laryngospasm 
Contraindication and known 
side effects. 
Midazolam dose used in this 
study is markedly lower than 
recommended therapeutic 
dose (see Section 4.3). 
Subjects will be in-house on 
midazolam administration 
days. 
Subjects with known 
respiratory/cardiac 
impairment and sleep apnea 
will not be included in the 
study (see Section 5.2). 
Use in subjects with hepatic 
and renal impairment. 
In patients with renal 
impairment (creatinine 
clearance < 30 mL/min) 
midazolam may be 
accompanied by more 
pronounced and prolonged 
sedation possibly including 
clinically relevant respiratory 
and cardiovascular 
depression. 
Hepatic impairment reduces 
the clearance of intravenous 
midazolam with a subsequent 
increase in terminal half-life. 
Subjects with known hepatic 
and renal impairment will not 
be included in the study (see 
Section 5.2). 

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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 8.3.4), and observation of vital signs and ECGs 
(Sections 8.3.2 and 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 non-randomized, single-center, open-label, single-sequence, single-arm Phase I 
study in 18 healthy male and female subjects.  
• The total duration in the study for a subject is approximately 8 weeks, including the 
screening period (maximum 4 weeks), 2 weeks of treatment period, and a safety follow-up 
period of 2 weeks. 
• A screening period will occur from Day -28 to Day -2. Subjects will be admitted to the study 
site on Day -1 and will remain resident throughout the study conduct period until follow-up 
visit on Day 15. A follow-up safety phone call is planned on Day 28. 
• Day 1: Subjects will receive a single dose of 2.5 mg midazolam in fasted state in the 
morning. 
• Day 2: Wash-out period. 
• Days 3 to 13: Subjects will receive daily doses of 6 mg/kg vamorolone in the morning within 
30 minutes after start of a standard breakfast. 
• Day 14: Subjects will receive single doses of 2.5 mg midazolam and 6 mg/kg vamorolone in 
fasted state in the morning. 
• Safety and tolerability parameters will be collected during the entire study phase from 
screening to follow-up. 
• Blood samples for PK assessment of midazolam and 1’-hydroxymidazolam will be collected 
from predose through 10 hours following the midazolam doses on Days 1 and 14.  
• Blood samples for PK assessment of vamorolone will be collected throughout the 
vamorolone dosing period. 
• Blood and urine biomarkers samples for CYP3A4 induction assessment will be collected 
throughout the treatment period.  
A study scheme and a detailed SoA with more information on the specific time points indicated 
for the scheduled study visits and required procedures are provided in Sections 1.2 and 1.3.  
4.2. 
Scientific Rationale for Study Design 
The trial design and endpoints are typical for a drug interaction trial of this type.  
The CYP3A4 induction effect of vamorolone would be examined on Day 14, i.e. 12 days after 
vamorolone first dosing, which is considered adequate to achieve the induction potential of 
vamorolone. 

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Midazolam will be administered as a single dose once alone (Day 1) and once after 12 days of 
daily vamorolone administration (Day 14) to investigate the combined interaction potential. 
Based on the apparent elimination half-life of up to 2.5 hours for midazolam and up to 1 hour for 
1’-hydroxymidazolam in healthy adult subjects (SmPC midazolam), a one-day washout period 
on Day 2 should be sufficient between Day 1 midazolam and Day 3 vamorolone administration 
to avoid carryover of midazolam concentrations.  
PK blood samples for the determination of plasma midazolam and 1’-hydroxymidazolam will be 
collected on Day 1 (PK midazolam alone) and Day 14 (PK midazolam when co-administrated 
with vamorolone) from predose to 10 hours postdose. 
PK blood samples for the determination of plasma vamorolone will be collected on Days 3, 4, 7, 
11, 13 and 14 at predose to determine the vamorolone levels during the induction phase. 
The follow-up visit is planned 24 hours after the last midazolam and vamorolone dose. That 
exceeds 5 times the elimination half-lives of both vamorolone and midazolam.  
The follow-up phone call on Day 28 is foreseen to monitor potential AEs after vamorolone 
withdrawal that are mainly but not exclusively related to adrenal suppression. Vamorolone was 
shown to cause adrenal suppression as seen in low morning cortisol levels (see IB). Cortisol 
levels were shown to be back to baseline 2 weeks after vamorolone withdrawal. 
The single arm, sequential design allows for intra-individual comparison of the effects of 
CYP3A4 induction by vamorolone and reduces the impact of inter-individual variability. 
4.3. 
Justification for Dose 
Vamorolone 
The recommended clinical dose for the paediatric population, as defined in DMD, is 6 mg/kg, to 
be administered orally once daily, with a maximum daily dosage of 300 mg for patients weighing 
more than 50 kg (USPI vamorolone). The objective of this study is to assess the potential for 
vamorolone to induce the CYP3A4 enzyme in healthy adults. It is plausible that the maximum 
daily flat dose of 300 mg, when administered to paediatric patients with a body weight of over 
50 kg, may result in reduced exposure in adults, particularly those weighing over 70 kg. 
Therefore, the selected daily single dose of vamorolone for this study is 6 mg/kg. For dose 
calculation, weight of Day –1 will be taken. 
The selected dosing regimen for this study is considered safe as in previous studies single and 
multiple doses of vamorolone up to 20 mg/kg given daily for 14 days were well tolerated in 
healthy adult subjects (see IB).  

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Midazolam 
The clinically recommended dose for midazolam is from 0.25 mg/kg to 1.0 mg/kg in adults. An 
oral dose of 2.5 mg midazolam is considered appropriate to achieve the study objectives for drug 
interaction studies and is considered safe (Wiebe et al, 2020).  
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 (refer to 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 
The study will be conducted in a total of 18 healthy adult male and female subjects.  
No subject may be assigned to study treatment unless adherence to all eligibility criteria as given 
in Sections 5.1 and 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 the 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.  Male and female. 
Contraceptive use by men and women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 

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Male subjects:  
• If the subject is a sexually active man and not surgically sterilized, he must be willing to: 
− Abstain from sexual intercourse or 
− Use a condom plus another form of contraception, (e.g., spermicide, IUD, birth control 
pills taken by female partner) if engaging in sexual intercourse with a woman who could 
become pregnant.  
− Use a condom during sexual intercourse with pregnant or lactating women. 
− 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. 
Female subjects:  
All women (regardless of their status, i.e. WOCBP and WONCBP; for definitions see 
Section 10.4.1) must have a negative serum β-hCG pregnancy test prior to the initiation of the 
study treatments. FSH levels of suspected postmenopausal females must be > 30 mIU/mL.  
Vamorolone has the potential to induce CYP3A4, which may result in a reduction in the 
effectiveness of contraceptives that are metabolized by CYP3A4 such as hormonal 
contraceptives when co-administered with vamorolone. Therefore, hormonal contraceptives by 
any route of administration are contraindicated. 
Women participating in the study must be either: 
• WONCBP or 
• WOCBP using, during the length of the study and for at least 3 months after the stop of the 
study treatments, 1 of the following contraceptive methods plus a condom: 
− IUD during the study and up to 3 months after the last administration of the study 
treatments 
− Any IUD with published data showing that the lowest expected failure rate is less than 
1% per year (not all IUDs meet this criteria) 
− Any other methods with published data showing that the lowest expected failure rate for 
birth control is less than 1% per year, or 
− Abstinent from intercourse for 2 weeks before exposure to the study treatments, 
throughout the clinical trial until 3 months following discontinuation of the study 
treatments, or 
− Have a male partner who is sterile prior to the woman’s entry into the study and is the 
sole sexual partner for that woman during the study period. 
The Investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 

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Drugs and Stimulants 
5. Subject is a non-smoker for at least 3 months prior exposure to the study treatments. Subject 
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 treatments. 
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 ≥ 90 mmHg and ≤ 140 mmHg; diastolic blood pressure 
≥ 50 mmHg and ≤ 90 mmHg and pulse rate ≥ 45 bpm and ≤ 90 bpm, and tympanic body 
temperature ≥ 35.0 °C 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 
10. A past medical history of clinically significant abnormalities or a history/family history of 
long QT interval syndrome, structural cardiac abnormalities (including but not limited to 
hypertrophic cardiomyopathy, valvulopathy, and congenital defects), or cardiogenic syncope. 
11. An abnormal ECG, defined as: 
• PR > 215 msec and < 100 msec, QRS complex > 120 msec; QTcF > 450 msec by 
automated reading 
• Any clinically significant ST/T wave abnormalities 
• Any atrial or ventricular arrhythmias 

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12. 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). 
13. A past medical history of peptic ulcers, diverticulitis, and non-specific ulcerative colitis. 
14. History of complaints of frequent dizziness and /or vomiting spells or lightheadedness 
(“frequent” defined as incidence occurs more than once every week) or history of/or present 
sleep apnea. 
15. 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. 
16. Known Gilbert’s syndrome. 
17. 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). 
18. Known or suspected hypersensitivity or contraindications to vamorolone and/or midazolam 
or any components of the formulation used. 
19. 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 
20. 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 or ibuprofen up to 1.2 g/day (medicinal products 
in their original packaging, approved and marketed in Germany) is permitted.  
Oral, injectable, and implantable contraceptives as outlined in Section 5.1 are permitted. 
21. Previous exposure to vamorolone. 
22. Any use of corticoids within 6 months prior to the first administration of the study 
treatments. 

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23. Administration of live, attenuated, replication-competent vaccines within 6 weeks prior to the 
first administration of the study treatments until 2 weeks after the follow-up visit. 
Administration of 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.  
24. 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 
25. 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 
26. Positive results for HBsAg, anti-HCV, anti-HIV 1 and 2, and HIV 1-p24 antigen at 
screening. 
27. Positive screen for alcohol, drugs of abuse and cotinine at screening. 
28. Elevations in ALT > 1.1 x ULN, AST > 1.2 x ULN, serum bilirubin > 1.2 x ULN, 
creatinine > 1.1 x ULN and and HbA1c > ULN at screening. A case-by-case decision for any 
abnormality must be discussed with the Sponsor before inclusion.  
29. TSH outside of normal ranges. 
30. eGFR based on the CKD-EPI (details for calculation see Section 10.2) of < 90 mL/min at 
screening. 
31. Potassium or magnesium blood concentration below the lower limit of normal at screening.  
Other Exclusions 
32. Subjects who are unwilling to adhere to contraceptive requirements.  
33. Higher than low-risk alcohol consumption i.e., consumption of an average weekly alcohol 
intake of > 21 units/week for men and > 14 units/week for women. 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. 
34. 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. 
35. Consumption of alcohol from 48 hours prior to admission. 

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36. 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 treatment. 
37. Regular consumption of poppy seed containing food prior to first administration of study 
treatment.  
38. Any use of drugs-of-abuse or alcohol abuse within 1 month prior to dosing. 
39. Subject with vegetarian, vegan, or restricted diet (e.g., gluten-free) or not willing or able to 
eat the complete standard meals. 
40. Female subject who has been pregnant within 6 months prior to screening or breastfeeding or 
lactating within 3 months prior to screening or plans to become pregnant during the clinical 
study period and for 3 months after final study treatment administration. 
41. 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 treatment. 
42. Strenuous physical activity within 72 h to admission. 
43. Employee of the Sponsor, the Nuvisan Group, or other Contract Research Organization 
involved in the clinical study. 
44. Legal incapacity or limited legal capacity, or incarceration and vulnerable subjects. 
45. 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. 
46. History of non-compliance to medical regimens and subjects who are considered potentially 
unreliable (e.g., refuse to comply with study regulations). 
47. 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 
48. Changes in medical conditions compared to screening, as judged by the Investigator. 
49. Body weight < 50 kg. 
Prior/Concomitant Therapy 
50. Changes in prior/concomitant therapy compared to screening, as judged by the Investigator. 

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Diagnostic assessments 
51. Positive screen for alcohol, drugs of abuse and cotinine test upon admission. 
Other Exclusions 
52. 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 treatment until after collection of the final blood 
PK sample.  
• Subjects will be required to refrain from consumption of poppy seeds from 72 hours before 
the start of study treatment until the end of confinement.  
• During the in-house stay, the subjects may only consume food and beverages provided by the 
study site. The diet provided (maximum of 4 meals per day) will consider the imposed 
restrictions. Meals will be served at customary times. For further restrictions on dosing days 
refer to Section 6.1.  
• On Days 1 and 14, subjects will fast for at least 10 hours before and 4 hours after 
administration of study treatments. On Days 3 to 13 administration of vamorolone will be 
done within 30 minutes after start of a standard breakfast. 
• On Days 1 and 14, water consumption will be allowed ad libitum (as desired) except for 
1 hour before until 1 hour after study treatment intake (apart from the water taken with the 
dose). Subjects should drink at least 1.5 L/day. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
• Subjects will abstain from ingesting caffeine- or xanthine-containing food and beverages 
(e.g., coffee, tea, cola, and chocolate) from 48 hours before admission to the study until after 
the end of confinement. 
• Subjects will abstain from alcohol for 48 hours before admission to the study site until the 
end of confinement. 
• The use of tobacco / nicotine containing products is not permitted during the study. 

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5.3.3. 
Activity 
• Subjects will abstain from strenuous exercise and sauna from 72 hours prior to admission 
until the end of confinement.  
• Subjects may participate in light recreational activities during hospitalization phase (e.g., 
watching television, reading). 
• Subjects will remain in semi-supine position until 4 hours after dosing of midazolam but may 
get up to go to the toilet. 
• Subjects will remain in semi-supine position until 1 hour after dosing on Days 3 to 13 but 
may get up to go to the toilet. 
5.3.4. 
Other Restrictions 
Not applicable. 
5.4. 
Screen Failures 
Screen failures are defined as subjects who consented to participate in the clinical study but are 
not subsequently 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. 
• Initial screening occurred too early to complete the required wash-out period after prior 
therapy. 
• 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 in order 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 (Section 10.1). 

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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, Study Treatment 
Not applicable. 

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6. 
Study Treatments and Concomitant Therapy 
Study treatments are all prespecified investigational and non-investigational medicinal products, 
medicinal devices, and other treatments (e.g., surgical, and behavioral) including marketed 
product(s), or placebo, or a combination of the same as per study plan, intended to be 
administered / applied to a study subject during the study conduct. 
6.1. 
Study Treatments Administered 
The treatments to be administered in this study are displayed in Table 3. 
Table 3: 
Study Treatments 
Treatment Label 
Test Drug 
Reference Drug 
Treatment Name 
Vamorolone 
Midazolam 
Treatment Description 
Oral suspension 
Oral solution 
Type  
Drug  
Drug 
Dose Formulation 
Suspension  
Solution 
Unit Dose Strength(s) 
4.0% w/v (40 mg/mL) 
To be described in the IMP manual. 
Dosage Level(s) 
6 mg/kg once daily dosing over 12 days.  
For dose calculation, weight of Day –1 
will be taken. 
2.5 mg once daily dosing on 2 days 
Route of Administration 
Oral 
Oral 
State for Administration 
Days 3 to 13: after a standard breakfast 
Day 14: fasted  
Fasted 
Use 
Experimental 
Experimental 
Dosing Instructions 
7.5 mL to be taken in the morning. 
To be taken in the morning. 
Manufacturer/Marketing 
Authorization Holder 
To be described in the IMP manual. 
To be described in the IMP manual. 
IMP and NIMP/AxMP 
IMP 
IMP 
Sourcing 
The Sponsor will provide Nuvisan 
GmbH with the medication released by 
the Sponsor Qualified Person (QP) 
according to Good Manufacturing 
Practice Annex 13. 
Nuvisan GmbH will source medication 
available on the local market. 
Packaging and Labelling 
Study medication will be primary 
packaged in amber glass bottles. Each 
bottle will be labelled according to 
country requirement. 
Study medication will be used as 
unchanged product with market 
authorization. 

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Subjects will receive single oral dose of midazolam on Days 1 and 14 and multiple oral doses of 
vamorolone on Days 3 to 14. On Day 14, when both study treatments are administered together, 
the subjects will first take vamorolone and directly afterwards midazolam. 
The cumulative doses per subject will be 5 mg midazolam and 3.6 g vamorolone. 
Both study treatments will be administered in an upright position with a total of 240 mL of 
non-carbonated water. Prior to each midazolam administration on Days 1 and 14 subjects will be 
fasting for at least 10 hours and abstain from consumption of additional fluid from 1 hour before 
until 1 hour after dosing (apart from the water taken with the dose). After each midazolam 
administration subjects will continue fasting for 4 hours postdose. On Days 3 to 13 vamorolone 
will be administered after a standard breakfast. 
Standardized meals will be served 4 hours (lunch), 7 hours (snack), and 10 hours (dinner) after 
midazolam dosing on Days 1 and 14.  
Other meals will be served at customary times during inpatient period. 
6.2. 
Preparation, Handling, Storage, and Accountability 
The Sponsor will supply sufficient amounts of vamorolone to Nuvisan CTS Department. The 
Sponsor will provide administration devices (8 mL oral syringes) in an appropriate quantity. 
IMPs will be stored and handled by Nuvisan according to product specific storage conditions (for 
storage conditions of Vamorolone 4% suspension, refer to the current Quality Agreement 
between Nuvisan and the Sponsor). IMPs will be stored in a secure, environmentally controlled 
and monitored area with access limited to authorized staff. 
Nuvisan will source commercially available midazolam. Details will be described in the IMP 
manual. 
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. 
Vamorolone will be packed and labelled study specifically by the Sponsor before the clinical part 
of the study starts including final QP release as per the German clinical study labelling 
requirements. 
Nuvisan CTS Department will be responsible for transfer of vamorolone and dosing devices to 
site. Details will be described in an IMP manual. 

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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. 
All study treatment administrations will be performed in accordance with the specifications in 
the IMP manual, by site staff authorized by the Principal Investigator. 
The Investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).  
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. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the IMP manual. 
6.3. 
Assignment to Study Treatment 
Randomization is not applicable in this study. All subjects receive the same study treatments in 
the same sequence on the same study days. 
Each subject is identified by the study site’s unique subject identification number. After 
informed consent procedure, every subject is given a screening number. Only subjects who 
comply with all eligibility criteria can be included into the study. On Day 1 subjects will be 
assigned a unique 3-digit assignment number (e.g. 101, 102, 103, etc.) in ascending numerical 
order (in accordance with Nuvisan SOP).  
If subjects who already have been assigned to study treatment need to be replaced, the 
assignment number will be the number of the original subject plus 100. For example, the 
replacement for assignment number 102 will receive the assignment number 202. For details on 
replacement of subjects see Section 7.2.2.  
The Investigator will keep a record relating the subject identifiers (screening and assignment 
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 assigned to study 
treatment for whatever reason. 
6.4. 
Blinding  
Not applicable. This is an open-label study. 

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6.5. 
Study Treatment Compliance 
The administration of the study treatment will be performed in the clinical unit by qualified 
clinical professionals of the Investigator’s team. Deviation(s) from the planned dosage regimen 
should be recorded in the eCRF.  
If the individual dose for a subject is distributed from a bulk supply, the preparation of the dose 
will be confirmed and documented by a second member of the study site staff. 
The dose of study treatment and subject identification will be confirmed at the time of dosing by 
a member of the study site staff other than the person administering the study treatment. 
Study site staff 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 
In patients, dose tapering is foreseen if vamorolone has been administered for more than one 
week. Due to the short treatment duration, i.e. less than 2 weeks, and the previous experience 
with vamorolone in two studies treating patients and healthy subjects for up to 2 weeks and then 
stopping without tapering, a tapering for this study is not foreseen (IB).  
Furthermore, as this is a study in healthy subjects who are not under concomitant therapy, no 
treatment is planned after the end of 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. 
6.8. 
Treatment of Overdose 
For this study, any dose of vamorolone greater 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 midazolam greater than the highest recommended clinical dose in the 
SmPC will be considered an overdose (SmPC midazolam). In the event of an overdose with 
midazolam, subjects should be closely monitored e.g. for signs and symptoms of sedation, 
confusion, lethargy, muscle relaxation and paradoxical excitation. Further absorption of 
midazolam may be prevented using an appropriate method e.g. treatment within 1-2 hours with 
activated charcoal. If activated charcoal is used, airway protection is imperative for drowsy 
patients. Midazolam can be antagonized by flumazenil, a benzodiazepine antagonist. However, it 
should only be used under closely monitored conditions and in case of severe central nervous 
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In the event of an overdose, the Investigator should: 
1. Evaluate the subject to determine, 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 one or more plasma samples for PK analysis as soon as possible and on further 
timepoints thereafter. 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
The Investigator will use appropriate clinical judgment when treating an overdose of an 
investigational drug.  
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor based on the clinical evaluation of the subject. 
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) within 2 weeks or 5 half-lives (whichever is longer) before the 
start of study treatment until completion of the safety follow-up phone call, 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 and ibuprofen up to 1.2 g per day may be allowed for the 
symptomatic treatment of AEs (e.g., headache) after consulting the Investigator when medically 
indicated. Contraceptive methods as outlined in Section 5.1.1 are also permitted. 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.  

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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. 
Flumazenil, a specific benzodiazepine-receptor antagonist, is an antidote for midazolam (see 
Section 6.8).  
 

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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 biomarker 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 
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 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 and within 4 hours after midazolam 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). In case of repeat abnormal findings, see above, this 
should lead to direct study withdrawal.  
• Creatinine > 1.3 x ULN. 
• Use of nonpermitted concomitant medications. However, any medications considered 
necessary for the subject’s wellbeing may be given at the discretion of the Investigator. 
• Occurrence of pregnancy. See Section 8.4.5. 

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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 10.5). 
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 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.  
• The subject will be permanently discontinued from both the study treatment and the study at 
that time. 
• 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 this in the site study records. 
• Subjects who discontinue may not re-enter the study.  
• Depending on the timepoint of discontinuation, a withdrawn subject is referred to as either 
“screening failure” or “dropout” as specified in Sections 5.4 and 7.2.2. 

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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. 
• Positive results from alcohol, cotinine, pregnancy and drug testing.  
• Protocol deviation judged as significant by the Investigator, including non-compliance to the 
required study considerations (e.g., food/diet requirements). 
• 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 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 assigned to study treatment. Dropouts might be replaced if the number 
of evaluable subjects completing the study becomes or is expected to become less than 16 
subjects in total. The decision to replace a subject will be taken on a case-by-case basis, in 
agreement between the Sponsor and the Principal Investigator. 
The data obtained from dropouts will be used in the evaluation to the largest possible extent.  
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., an 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 for which a causal relationship to 
the study treatment or study related procedures cannot be excluded. 

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• 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 system organ class. 
• 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 
Subjects will be considered lost to follow-up if they are unable to be contacted by the study site 
for the follow-up safety call on Day 28 or an ad-hoc safety follow-up visit. 
Before a subject is deemed lost to follow-up, the Investigator or designee must make every effort 
to regain contact with the subject (where possible, contact via email along with 3 telephone calls 
and, if necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record. 
Should the subject continue to be unreachable, they will be considered to have withdrawn from 
the study.  
 

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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 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 approximately 150 mL 
(approximately 66 mL for safety laboratory samples and 84 mL for PK and biomarkers 
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 (see 
Section 10.1.4). Any such testing will not be reported in the CSR.  
8.1. 
Administrative and General Procedures 
8.1.1. 
Demographic 
For demographic assessment the following parameters will be recorded: age (incl. year of birth), 
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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, 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 informed consent form 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 Immunogenicity Assessments 
This section is not applicable as efficacy and immunogenicity are not assessed in this study. 
8.3. 
Safety Assessments 
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 
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• 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 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.  
• 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.  
• Body temperature will be measured auricularly with a calibrated device. 
• Vital sign measurements will be repeated as appropriate. 
8.3.3. 
Electrocardiograms 
• Single 12-lead ECGs will be obtained as outlined in the SoA (Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR(Q), QRS, QT, and 
QTcF. Refer to Section 7.1.1.2 for QTc withdrawal criteria. 
• Subjects should rest for at least 5 minutes in supine position before ECG collection 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. 
8.3.4. 
Clinical Safety Laboratory Tests 
• Clinical laboratory assessments will be performed by Nuvisan GmbH. 
• All protocol-required laboratory assessments, as defined in Section 10.2, must be conducted 
in accordance with the laboratory manual and the SoA (Section 1.3). 
• Any abnormalities in any of the laboratory parameters will be judged by an Investigator 
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• 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. 
8.3.5. 
Pregnancy Testing 
• Female subjects should only be included after a negative highly sensitive serum pregnancy 
test at screening and admission day. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected during the time from ICF signature until follow-up 
visit/early discontinuation visit. 
8.3.6. 
Other Assessments 
Alcohol breath tests 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 and pregnancy cases 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, 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. 

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• 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 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. 
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, the 
event is otherwise explained, or the subject is lost to follow-up (as defined in Section 7.4). 
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 competent authority 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. 

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• The Sponsor is responsible for assessing whether an SAE is expected or not (see also 
Section 10.3). The IB of vamorolone and the SmPC of the selected midazolam product to be 
administered will be used as reference safety information 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. 
8.4.5. 
Pregnancy 
Adequate birth control measures are defined for the study subjects to prevent pregnancies 
(Section 5.1). However, in case, a pregnancy occurs in the period from start of study treatment 
until 3 months after last administration of study treatment, the following applies: 
• The Investigator will attempt to collect pregnancy information on the pregnant female 
(whether it is a female subject or a male subject’s female partner). 
• After obtaining the necessary signed informed consent from the pregnant female, she will be 
followed to determine the outcome of the pregnancy.  
• The Investigator will record pregnancy information on the appropriate form and submit it to 
the Sponsor within 24 hours of learning of the pregnancy (after obtaining the necessary 
signed informed consent from the female partner).  
• Whenever possible, a pregnancy should be followed to term, any premature terminations 
should be reported, and the status of the mother and child should be reported to the Sponsor 
after delivery. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• Any poststudy pregnancy-related SAE considered reasonably related to the study treatment 
by the Investigator will be reported to the Sponsor as described in Section 8.4.4. While the 

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Investigator is not obligated to actively seek this information in former pregnant females, he 
or she may learn of an SAE through spontaneous reporting. 
• The Investigator will collect follow-up information on the pregnant female and the neonate, 
and the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date for a healthy 
newborn. In case of a congenital anomaly or other illness of the newborn, follow-up will 
continue until the illness has resolved or there is a definite outcome of the event. 
• Any female subject who becomes pregnant while participating in the study will discontinue 
study treatment or be withdrawn from the study. 
8.4.6. 
Adverse Events of Special Interest 
No AEs of special interest are defined for this study. 
8.5. 
Pharmacokinetics 
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 workup), and the date/time of transfer 
or shipment of the samples to the responsible analyst will be documented in detail. 
22 blood samples for determination of midazolam and 1’-hydroxymidazolam concentrations will 
be collected up to 10 hours after midazolam dosing on Days 1 and 14 as specified in Table 4 and 
in the SoA (Section 1.3). 

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Table 4: 
Pharmacokinetic Blood Collection Schedule for Midazolam and 
1’-Hydroxymidazolam 
Study Day 
Time (hours postdose) 
Volume (mL) 
Day 1 
0 (predose) 
2 
0.25 
2 
0.5 
2 
1 
2 
1.5 
2 
2 
2 
3 
2 
4 
2 
6 
2 
8 
2 
10 
2 
Day 14 
0 (predose) 
2 
0.25 
2 
0.5 
2 
1 
2 
1.5 
2 
2 
2 
3 
2 
4 
2 
6 
2 
8 
2 
10 
2 
Total Blood Collected 
44 
 
6 blood samples for determining trough plasma concentration of vamorolone will be collected as 
specified in Table 5 and in the SoA (Section 1.3).  
Table 5: 
Pharmacokinetic Blood Collection Schedule for Vamorolone 
Study Day 
Time (hours) 
Volume (mL) 
Day 3 
0 (predose) 
2 
Day 4 
0 (predose) 
2 
Day 7 
0 (predose) 
2 
Day 11 
0 (predose) 
2 
Day 13 
0 (predose) 
2 
Day 14 
0 (predose) 
2 
Total Blood Collected 
12 

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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 (Section 1.3), will not be 
considered a protocol deviation. Actual time will be considered when calculating the final PK 
parameters.  
Samples collected for PK analyses may also be used to evaluate safety or efficacy aspects related 
to concerns arising during or after the study.  
8.5.1. 
Bioanalytical Methods 
• All bioanalytical analyses will be performed at Nuvisan GmbH Bioanalytical Department.  
• Bioanalytical analyses will be performed in accordance with the applicable principles of 
Good Laboratory Practice and GCP.  
• The procedure for determination of concentrations of vamorolone, midazolam, and 
1’-hydroxymidazolam 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” (ISR), specification of the applicable regulatory guidelines and archiving 
process will be described in the bioanalytical protocol. 
• Samples for midazolam, 1’-hydroxymidazolam, and vamorolone will be analyzed using 
validated LC-MS/MS methods. 
8.5.2. 
Pharmacokinetic Evaluation 
• The following PK parameters will be calculated from the individual plasma 
concentration-time data of midazolam and 1’-hydroxymidazolam for each treatment by 
non-compartmental analysis using Phoenix® WinNonlin® Version 8.0 or higher (applying 
linear trapezoidal linear/log interpolation method for calculation of AUC):  

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Table 6: 
Non-compartmental Pharmacokinetic Parameters for Midazolam and 
1’-Hydroxymidazolam 
Main Parameters 
AUC0-tlast 
AUC0-inf  
Cmax 
Additional Parameters 
t1/2 
tmax 
λz 
Vz/f (for midazolam only) 
CL/f (for midazolam only) 
For definitions of PK parameters refer to Section 10.6. 
• Trough values (Ctrough) will be calculated from the individual plasma concentration time data 
of vamorolone only. 
• Individual PK parameters will be calculated using actual sampling times.  
• For calculation of PK parameters, concentrations below the lower limit of quantification 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 will be provided in the SAP. 
8.6. 
Pharmacodynamics 
Not applicable. 
8.7. 
Genetics 
Pharmacogenetics are not evaluated in this study. 
8.8. 
Biomarkers 
4β-Hydroxycholesterol 
The 4β-hydroxycholesterol plasma concentration will be measured by a validated LC-MS/MS 
assay and used as an in vivo marker for the assessment of CYP3A4 induction as specified in 
Table 7 and in the SoA (Section 1.3).  

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Table 7: 
Blood Collection Schedule for 4β-Hydroxycholesterol 
Study Day 
Time (hours) 
Volume (mL) 
1 
0 (predose) 
4 
3 
0 (predose) 
4 
4 
0 (predose) 
4 
7 
0 (predose) 
4 
10 
0 (predose) 
4 
14 
0 (predose) 
4 
15 
24 (postdose) 
4 
Total Blood Collected 
28 
 
6β-Hydroxycortisol to Cortisol Ratio 
The ratio of 6β-hydroxycortisol to cortisol will be measured by a validated LC-MS/MS assay 
and used as an in vivo marker for the assessment of CYP3A4 induction. 7 urine samples will be 
collected as specified in Table 8 and in the SoA (Section 1.3). 
Table 8: 
Urine Collection Schedule for 6β-Hydroxycortisol to Cortisol Ratio 
Study Day 
Period 
Aliquot Volume (mL) 
1 
Morning 
up to 5 
3 
Morning 
up to 5 
4 
Morning 
up to 5 
7 
Morning 
up to 5 
10 
Morning 
up to 5 
14 
Morning 
up to 5 
15 
Morning 
up to 5 
Total Urine Aliquot Volume 
up to 35 
Urine will be collected in the morning from approximately 8:00 to 12:00 a.m.. Each subject should 
void his/her bladder at the beginning and at the end of each urine sampling period. During each 
sampling 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 sample collection, handling, storage, and shipment will be provided in a 
laboratory manual. 
The procedures for determination of 4β-hydroxycholesterol in plasma samples and 
6β-hydroxycortisol and cortisol in urine samples will be described in the respective bioanalytical 
protocols.  
8.9. 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this study.  

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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. 
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: 
Set 
Description 
Full set 
All subjects enrolled in the study. 
Safety set 
All subjects assigned to study treatment and who receive at least 
1 dose of study treatment. Subjects will be analysed according to 
the treatment they actually received. 
This population will be used for safety analyses, if not stated 
otherwise. 
PK set - midazolam 
This analysis set is a subset of the safety set and includes all 
subjects who complete the scheduled vamorolone and midazolam 
dose and provide evaluable midazolam PK profile on at least one 
of the following days: Day 1 and Day 14, without any 
findings/events or with findings/events unlikely affecting PK. No 
vomiting should occur within 4 hours following midazolam 
and/or vamorolone administration. 
This PK set will be used for PK concentration summary and PK 
parameter summary for midazolam and 1’-hydroxymidazolam.  
PK set - vamorolone 
This analysis set is a subset of the safety set and includes all 
subjects who completed at least one scheduled vamorolone dose 
without vomiting within 4 hours immediately following that 
vamorolone administration and provided at least one valid PK 
concentration data for vamorolone.  
This PK set will be used for PK concentration summary and PK 
parameter summary for vamorolone. 
 
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.  

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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).  
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 system organ class and preferred term, in which the number and percentages of 
subjects with treatment-emergent AEs and frequency of the events are reported. 
• AE occurring after administration of any study treatment will be counted towards the last 
treatment received before the onset, even if the event is not resolved at the beginning of the 
following treatment. An AE that worsens after a later treatment period will be counted 
towards both study treatments. 
• 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 Set, if not stated otherwise. 
• For midazolam and 1’-hydroxymidazolam, concentration-time courses and PK parameters 
will be tabulated by treatment. 

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• 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 coefficient of variation (CV), arithmetic mean, standard 
deviation and CV, minimum, median, maximum value, and the number of measurements.  
• For midazolam and 1’-hydroxymidazolam, 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. 
• A linear mixed model with a fixed effect for TREATMENT and a random effect for 
SUBJECT will be applied to log-transformed PK parameters AUC0-tlast, AUC0-inf, and Cmax of 
midazolam and 1’-hydroxymidazolam based on the PK Set to assess treatment differences on 
the log scale of midazolam with vamorolone vs midazolam alone (Day 14 vs Day 1). Least-
squares (LS) means, LS treatment difference, and 90% confidence intervals (CI) for the 
treatment differences on the log-scale will be obtained. The results will be back-transformed 
to the original scale by exponentiation to provide geometric least-square means, point 
estimate of the geometric mean ratio (Day 14 vs Day 1) and its corresponding 90% CI. 
• Missing data will not be replaced or imputed in any way. 
• The trough values of vamorolone will also be listed and tabulated by treatment as well as 
displayed graphically as described above. 
9.3.4. 
Pharmacodynamic Analyses 
Not applicable.  
9.3.5. 
Other Analyses  
 Analyses for CYP3A4 biomarkers will be performed on the safety set. 
Data of plasma 4β-hydroxycholesterol as well as urine 6β-hydroxycortisol, cortisol, and 
6β-hydroxycortisol to cortisol ratio by visit will be listed and appropriate summary tables will be 
provided. 
Concentration of plasma 4β-hydroxycholesterol and both urine 6β-hydroxycortisol and cortisol 
versus time curves will be plotted using the actual sampling times. Ratio of 6β-hydroxycortisol 
to cortisol will also be plotted using the actual sampling times. In addition, for 
4β-hydroxycholesterol summary statistics will be also provided for change from baseline and the 
baseline is defined as the assessment taken predose on Day 1. 
9.4. 
Interim Analysis  
Not applicable. 

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9.5. 
Sample Size Determination 
Sample size is based on feasibility and to ensure adequate precision in estimation of treatment 
differences. Assuming the intra-subject CV of 22% for midazolam (Prueksaritanont et al, 2000) 
with a total of 18 subjects the precision or half-width of 90% CI for treatment difference on the 
log-scale will extend approximately 0.179 from the observed difference in means. The above 
half-width translates into the following 90% confidence intervals when the observed mean ratio 
for comparison is 1; 90% CI = (0.84 ,1.20). 
Approximately 18 subjects will be assigned to study intervention such that 16 evaluable subjects 
complete the study. For information on subject replacement refer to Section 7.2.2. 
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. 
9.7. 
Data Management 
Nuvisan will be responsible for clinical data management activities for this study. The full details 
of procedures for data handling will be described in the study specific 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 system organ class 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. 

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9.7.2. 
Soft Lock 
When validation (including external data reconciliation), SAE reconciliation and all coding 
activities, as well as medical review activities, 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 
minutes 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 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 
competent authority 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. 
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.  

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• 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/favourable 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 subjects for the study will be recruited from suitable candidates in the database of 
the investigational site. Interested subjects 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- and site-specific 
documentation, as applicable. 
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 ethics committee and regulatory authorities. Data 
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Prior to the subject’s enrolment in the study, the subject’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. 
These measures are defined in the CRO’s SOPs regarding IT Security and Serious Breaches. 
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. 
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 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 
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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, source documentation on adverse events 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. 
 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 9 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 9: 
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 
aminotransferasea 
Calcium 
Lactate dehydrogenase 
Albumin 
Chloride 
Lipase 
Alkaline phosphatase 
Cholesterol 
Magnesium 
Amylase 
Creatinine 
Potassium 
Aspartate 
aminotransferase 
Creatine phosphokinasec 
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.  
Other Tests 
• Urine drug screen:  
Amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, 
methamphetamines, methylenedioxymethamphetamine, methadone, 
opiates, tricyclic antidepressants, phencyclidine 
• Urine cotinine test 
• Serum hCG pregnancy test (female subjects only) 

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Laboratory 
Assessments 
Parameters 
• At screening only: 
o TSHd 
o FSH (to confirm postmenopausal status) 
o HbA1c 
o Fibrinogen 
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 and Section 10.5. All events of ALT ≥ 3 × upper limit of normal 
(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 subjects. 
For male subjects: 
If serum creatinine ≤ 80 µmol/L: eGFR [mL/min] = ((141 x (serum creatinine [µmol/L] / 79.6)-0.411 x 
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) 
For female subjects: 
If serum creatinine ≤ 62 µmol/L: eGFR [mL/min] = ((144 x (serum creatinine [µmol/L] / 61.9)-0.329 x 
0.993Age[years])) x (0.20247 x ((height/100)0.725) x (weight0.425) / 1.73) 
If serum creatinine > 62 µmol/L: eGFR [mL/min] = ((144 x (serum creatinine [µmol/L] / 61.9)-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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b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the 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. 

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• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE form within the designated reporting time frames. 
 

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10.4. 
Appendix 4: Contraceptive Guidance  
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal unless permanently sterile (see 
below) 
• A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
o A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. However, 
in the absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement (> 30 mIU/mL) is required.  
o Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrolment. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study treatment, additional evaluation should be considered. 
 

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Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenopausal female with permanent infertility due to one of the following (for the purpose 
of this study): 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, medical examination, or medical history interview. 
2. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
o A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. However, 
in the absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement (> 30 mIU/mL) is required. 
o Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrolment. 

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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Phase 1 liver chemistry stopping criteria are designed to assure subject safety and to evaluate 
liver event etiology. 
Phase 1 Liver Chemistry Stopping Criteria and Follow-Up Assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
 
ALT/AST-absolute 
 
ALT or AST ≥ 3 x ULN 
ALT or AST ≥ 3 x ULN AND total bilirubin ≥ 2 x ULN OR 
international normalized ratio (INR) > 1.5, report to the Sponsor in 
expedited manner and as an SAE if SAE criteria are met a,b. 
Suggested Actions, Monitoring, and Follow up Assessments 
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment. 
• Report the event to the Sponsor within 
24 hours. 
• Complete the liver event eSource and 
complete an SAE data collection tool if the 
event also met the criteria for an SAEb 
• Perform liver follow-up assessments as 
described in the Follow Up Assessment 
column.  
• Do not restart/rechallenge subject with 
study treatment.  
• Monitor the subject until liver chemistry test 
abnormalities resolve, stabilize, or return to 
baseline (see MONITORING). 
 
MONITORING: 
If ALT or AST ≥ 3 x ULN AND total bilirubin 
≥ 2 x ULN or INR > 1.5: 
• Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, total bilirubin, 
and INR) and perform liver event follow-up 
assessments within 24 hours. 
• Monitor subject twice weekly until liver 
chemistry test abnormalities resolve, 
stabilize, or return to baseline. 
• Viral hepatitis serologyc 
• Obtain blood sample for PK analysis -
as soon as possible after the most recent 
dosed.  
• Obtain CK, LDH, GGT, GLDH and 
serum albumin. 
• Fractionate bilirubin if total bilirubin 
≥ 2 x ULN. 
• Obtain complete blood count with 
differential to assess eosinophilia. 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE CRF.  
• Record use of concomitant medications 
(including acetaminophen, recreational 
drugs, herbal remedies, and other over-
the-counter medications) on the 
concomitant medications CRF. 
• Record alcohol use on the liver event 
alcohol intake CRF. 
 

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• A specialist or hepatology consultation is 
recommended. 
 
If ALT or AST ≥ 3 x ULN AND total bilirubin 
< 2 x ULN and INR ≤ 1.5: 
• Perform liver chemistry tests (include ALT, 
AST, alkaline phosphatase, total bilirubin, 
and INR) and liver chemistry follow-up 
assessments within 24 to 72 hours. 
• Monitor subjects weekly until liver chemistry 
abnormalities resolve, stabilize, or return to 
baseline. 
 
If ALT or AST ≥ 3 x ULN AND total 
bilirubin ≥ 2 x ULN or INR > 1.5 obtain 
the following in addition to the assessments 
listed above: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins. 
• Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) to 
evaluate liver disease; complete liver 
imaging CRF. 
• Liver biopsy may be considered and 
discussed with local specialist if 
available, for instance: 
o In subjects when serology raises the 
possibility of autoimmune hepatitis 
(AIH) 
o In subjects when suspected DILI 
progresses or fails to resolve on 
withdrawal of study treatment 
o In subjects with acute or chronic 
atypical presentation  
• If liver biopsy is conducted, then 
complete liver biopsy CRF. 

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Notes: 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment if ALT or AST ≥ 3 x ULN and total bilirubin ≥ 2 x ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable 
urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury.  
b All events of ALT or AST ≥ 3 x ULN and total bilirubin ≥ 2 x ULN (for subjects with known Gilbert’s 
syndrome these criteria only apply if total bilirubin ≥ 2 x ULN, and direct bilirubin > 2 x ULN and at least 
doubled from baseline value) or ALT or AST ≥ 3 x ULN and INR > 1.5 may indicate severe liver injury (possible 
‘Hy’s Law’) and must be reported to Sponsor in an expedited manner and as an SAE if SAE criteria met 
(excluding studies of hepatic impairment or cirrhosis). The INR stated threshold value will not apply to 
subjects receiving anticoagulants.  
c Includes: Hepatitis A IgM antibody; HBsAg and Hepatitis B core antibody; hepatitis C RNA; cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or 
monospot testing); and hepatitis E IgM antibody. 
d Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
the PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. Instructions for sample handling and shipping are in the laboratory manual. 
 
 
 

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10.6. 
Appendix 6: Pharmacokinetic Parameters Definition 
 
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  
CL/f 
The apparent total body clearance of study treatment following extravascular 
administration. CL/f= Dose /AUC0-inf. This parameter will be estimated for 
midazolam only. 
Cmax 
Maximum observed concentration.  
Ctrough 
The concentration observed at the end of a dosing interval immediately before 
next dosing. This parameter will be estimated for vamorolone only. 
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). 
λz 
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. 
Vz/f 
The apparent volume of distribution during the terminal phase following 
extravascular administration. Vz/F = Dose/(AUC0-inf*λz) following single dose. 
This parameter will be estimated for midazolam only: 

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10.7. 
Appendix 7: 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) Ltd 
Address: 
Hohenrainstrasse 24 
4133 Pratteln, Switzerland 
Telephone number: 
 
E-mail address: 
 
 
PPD
PPD
PPD
PPD

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10.8. 
Appendix 8: 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), International Conference for Harmonization (ICH) guidelines for 
current Good Clinical Practice (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: 
Michael Lissy, MD 
Function/Title: 
Principal Investigator 
Institution: 
Nuvisan GmbH 
Address: 
Wegenerstrasse 13 
89231 Neu-Ulm, Germany  
Telephone number: 
 
Fax number: 
 
E-mail address: 
 
 
PPD
PPD
PPD

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11. 
References 
Diczfalusy U, Nylén H, Elander P, Bertilsson L. 4β-Hydroxycholesterol, an endogenous marker 
of CYP3A4/5 activity in humans. Br J Clin Pharmacol. 2011 Feb;71(2):183-9. 
Investigator’s Brochure Vamorolone, Edition 13, 30-NOV-2023. 
Kanebratt KP, Diczfalusy U, Bäckström T, Sparve E, Bredberg E, Böttiger Y, Andersson TB, 
Bertilsson L. Cytochrome P450 induction by rifampicin in healthy subjects: determination using 
the Karolinska cocktail and the endogenous CYP3A4 marker 4β-hydroxycholesterol. Clin 
Pharmacol Ther. 2008 Nov;84(5):589-94.  
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers 
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