Clinical trial NCT02760264
Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne Muscular Dystrophy vamorolone
Sponsor: ReveraGen BioPharma, Inc.
Start date: 2016-06-01; Completion date: 2018-05-01
Enrollment: 48 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to determine whether a new medication called vamorolone is safe and well-tolerated by boys with Duchenne muscular dystrophy (DMD) ages ≥ 4 and \< 7 years old.

Detailed description:
This study will evaluate the safety and tolerability of a new steroid-like medication called vamorolone in boys with DMD ages ≥ 4 years and \< 7 years. Enrolled participants will take the study medication for 14 days followed by a 14 day follow-up period. The potential effectiveness of vamorolone in treating DMD will also be explored.

Arms: arm 1: Participants enrolled in Dose Level Group 1 will receive vamorolone 0.25 mg/kg/day. arm 2: Participants enrolled in Dose Level Group 2 will receive vamorolone 0.75 mg/kg/day. arm 3: Participants enrolled in Dose Level Group 3 will receive vamorolone 2.0 mg/kg/day. arm 4: Participants enrolled in Dose Level Group 4 will receive vamorolone 6.0 mg/kg/day.
Interventions: intervention 1: Vamorolone 0.25 mg/kg/day intervention 2: Vamorolone 0.75 mg/kg/day intervention 3: Vamorolone 2.0 mg/kg/day intervention 4: Vamorolone 6.0 mg/kg/day
Intervention descriptions: intervention 1: Oral administration of 0.25 mg/kg/day daily for 14 days. intervention 2: Oral administration of 0.75 mg/kg/day daily for 14 days. intervention 3: Oral administration of 2.0 mg/kg/day daily for 14 days. intervention 4: Oral administration of 6 mg/kg/day daily for 14 days.

Protocol documents:
Prot_000.pdf: 
 
 
Page 1 of 140 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
REVISED CLINICAL STUDY PROTOCOL 
 
Document Title: 
Revised Clinical Protocol #2 for a Phase IIa Open-Label, 
 
Multiple Ascending Dose Study to Assess the Safety, 
 
Tolerability, Pharmacokinetics, Pharmacodynamics, and 
 
Exploratory Efficacy of Vamorolone in Boys with Duchenne 
 
Muscular Dystrophy (DMD) 
 
Protocol Number: 
VBP15-002 
Document Number: 
VBP15-002-R2 
 
FDA IND No.: 
118,942 
 
Investigational Product: 
Vamorolone 
 
 
Sponsor: 
ReveraGen BioPharma, Inc. 
155 Gibbs Street 
Suite 433 
Rockville, MD  20850 
 
Study Chair: 
Paula R. Clemens, MD 
Phone:  (412) 383-7207 
Email:  clempr@upmc.edu 
 
Medical Monitor: 
Benjamin D. Schwartz, MD, PhD 
Phone:  (314) 220-7067 
Email:  bdschw@camdengroup.com 
 
 
Document Date: 
20 January 2017 
 
 
This document represents proprietary information belonging to ReveraGen BioPharma, Inc.  
Unauthorized reproduction of the whole or part of the document by any means is strictly prohibited.  
This protocol is provided to you as a Principal Investigator, potential Investigator or consultant for 
review by you, your staff and Institutional Review Board or Independent Ethics Committee.  The 
information contained in this document is privileged and confidential and, except to the extent 
necessary to obtain informed consent, must not be disclosed unless such disclosure is required by 
federal or state law or regulations.  Persons to whom the information is disclosed in confidence must be 
informed that the information is confidential and must not be disclosed by them to a third party. 


Vamorolone 
Revised Clinical Protocol #2 
Protocol No. VBPIS-002 
20 January 2017 
Document No. VBPIS-002-R2 
IND 118.942 
SIGNATURES OF AGREEMENT FOR VBP15-002-R2 
Revised Clinical Protocol #2 for a Phase Ila Open-Label, Multiple Ascending Dose 
Study to Assess the Safety, Tolerability, Pbarmacokioetics, Pharmacodyoamics, and 
Exploratory Efficacy of Vamorolone in Boys With Duchenoe Muscular Dystrophy 
(DMD) 
Reviewed and Approved by: 
Eric Hoffman, PhD 
Chief Executive Officer 
ReveraGen BioPharma, Inc. 
Study Chair 
University of Pittsburgh School of Medicine 
Laurel J. Mengle-Gaw, PhD 
Consulting Clinical Monitor 
The Camden Group, LLC 
20 January 2017 
Date 
20 January 2017 
Date 
20 January 2017 
Date 
Date 
ReveraGen BioPhanna, Inc. - CONFIDENTIAL 
Page 2of140 


Vamorolone 
20 January 2017 
Revised Clinical Protocol #2 
Document No. VBP15-002-R2 
Protocol No. VBP15-002 
IND 118,942 
 
Page 3 of 140 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
INVESTIGATOR REVISED PROTOCOL AGREEMENT 
________________________________________________________________________ 
Revised Clinical Protocol #2 for a Phase IIa Open-Label Multiple Ascending Dose 
Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and 
Exploratory Efficacy of Vamorolone in Boys with Duchenne Muscular Dystrophy 
(DMD) 
Protocol Number:   
VBP15-002 
Document Number:   
VBP15-002-R2 
Sponsor: 
ReveraGen BioPharma, Inc. 
Document Date: 
20 January 2017 
____________________________________________________________________________________________________________ 
 
By my signature, I confirm that my staff and I have carefully read and understand this 
protocol, protocol amendment, amended protocol, or revised protocol and agree to 
comply with the conduct and terms of the study specified herein and with any other 
study conduct procedures provided by ReveraGen BioPharma, Inc. 
I agree to conduct the study according to this protocol and the obligations and 
requirements of clinical Investigators and all other requirements listed in 21 CFR part 
312 and all applicable local, state, and federal regulations and ICH guidelines.  I will 
not initiate this study without the approval of an Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC). 
I understand that, should the decision be made by ReveraGen BioPharma, Inc. to 
terminate prematurely or suspend the study at any time for whatever reason, such 
decision will be communicated to me in writing.  Conversely, should I decide to 
withdraw from execution of the study, I will communicate immediately such decision in 
writing to ReveraGen BioPharma, Inc. 
For protocol amendments and amended protocols, I agree not to implement the 
amendment without agreement from ReveraGen BioPharma, Inc. and prior 
submission to and written approval (where required) from the IRB/IEC, except when 
necessary to eliminate an immediate hazard to the subjects, or for administrative 
aspects of the study (where permitted by all applicable regulatory requirements). 
 
 
___________________________________________ 
__________________ 
Investigator’s Signature  
Date 
 
___________________________________________  
Investigator’s Name (Please print) 
Address (Please print): 
 
RETURN THE ORIGINAL SIGNED COPY TO REVERAGEN BIOPHARMA, INC. OR 
DESIGNEE AND KEEP A COPY AT YOUR SITE. 


Vamorolone 
20 January 2017 
Revised Clinical Protocol #2 
Document No. VBP15-002-R2 
Protocol No. VBP15-002 
IND 118,942 
 
Page 4 of 140 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
SERIOUS ADVERSE EVENT CONTACT INFORMATION 
 
In the event of a serious adverse event (SAE) (see Section 7.2.6.1), the Investigator 
will complete the SAE electronic case report form within 24 hours of first awareness 
of the event.  In the unlikely event that the electronic study database is inaccessible 
and the Investigator is unable to complete the SAE electronic case report form 
within 24 hours, the SAE Notification Form (pdf) should be completed and emailed 
or printed/faxed to the PRA safety management team within 24 hours, using the 
contact information below:  
Email CHOSafety@prahs.com 
Drug Safety Fax: 1-888-772-6919 or 1-434-951-3482 
  
SAE Questions: Drug Safety Hotline: 1-800-772-2215 or 1-434-951-3489 


Vamorolone 
20 January 2017 
Revised Clinical Protocol #2 
Document No. VBP15-002-R2 
Protocol No. VBP15-002 
IND 118,942 
 
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ReveraGen BioPharma, Inc. – CONFIDENTIAL 
PROTOCOL AMENDMENT TRACKING 
Document 
Document Number 
Approval Date 
Original Protocol 
VBP15-002 
16 February 2016 
Amended Protocol #1 
VBP15-002- A1 
31 May 2016 
Revised Protocol #1 
VBP15-002-R1 
01 August 2016 
Amended Protocol #2 
VBP15-002-A2 
19 January 2017 
Revised Protocol #2 
VBP15-002-R2 
20 January 2017 
Note: Amended protocols show all changes from last previous document version in 
bold/strike-through format. 
Reason for Revised Protocol #2: 
1. to incorporate all changes from Amended Protocol #2 into a new protocol 
document. 
Reasons for Amended Protocol #2: 
1. to update the nonclinical toxicology information with results of a 26-week 
toxicology study in mice; 
2. to remove reference to a dose escalation plan based on an mTPI design;  
3. to remove the requirement that QTc must be calculated using Fredericia’s 
formula;  
4. to clarify that SAE information is not required to be forwarded to the DSMB 
within 24 hours of first awareness; and 
5. to correct typographical errors. 


Vamorolone 
20 January 2017 
Revised Clinical Protocol #2 
Document No. VBP15-002-R2 
Protocol No. VBP15-002 
IND 118,942 
 
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ReveraGen BioPharma, Inc. – CONFIDENTIAL 
STUDY SYNOPSIS 
Protocol Title 
A Phase IIa, Open-Label, Multiple Ascending Dose Study to Assess the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Exploratory Efficacy 
of Vamorolone in Boys with Duchenne Muscular Dystrophy (DMD) 
Protocol Number 
VBP15-002 
Name of Sponsor 
ReveraGen BioPharma, Inc. 
Drug Substance 
delta-1,4,9(11)-pregnatriene-17-alpha,21-dihydroxy-16-alpha-methyl-3,20-
dione 
Investigational Drug 
Product 
vamorolone, 4% suspension for oral dosing 
Phase of 
Development 
Phase IIa 
Indication 
Treatment of Duchenne muscular dystrophy (DMD) 
Objectives 
Primary: 
1. To evaluate the safety and tolerability of multiple ascending oral doses of 
vamorolone in ambulant boys ages 4-< 7 years with DMD. 
Secondary: 
1. To investigate the single-dose and multiple-dose pharmacokinetics (PK) of 
oral vamorolone at multiple dose levels in ambulant boys ages 4-< 7 years 
with DMD; 
2. To investigate the effects of single and multiple oral doses of vamorolone 
on serum pharmacodynamic (PD) biomarkers in ambulant boys ages 4-< 7 
years with DMD; 
3. To evaluate metabolites of vamorolone in Metabolites in Safety Testing 
(MIST) assessments following administration of multiple ascending oral 
doses.  
Exploratory: 
1. To investigate the effect of multiple oral doses of vamorolone on muscle 
strength, mobility, and functional exercise capacity, as measured by 
Quantitative Muscle Testing (QMT), Time to run/walk 10 meters Test 
(TTRW), Time to Stand Test (TTSTAND), Time to Climb Test 
(TTCLIMB), North Star Ambulatory Assessment (NSAA), and Six-minute 
Walk Test (6MWT) in ambulant boys ages 4-< 7 years with DMD. 
Study Design 
This Phase IIa study is an open-label, multiple ascending dose study to evaluate 
the safety, tolerability, PK, PD, and exploratory clinical efficacy of oral 
vamorolone over the course of a 14-day Treatment Period in ambulant boys 
ages 4-< 7 years with DMD. 
The study is comprised of a 26-day Pretreatment Screening Period, a 1-day 
Pretreatment Baseline Period, a 14-day Treatment Period, and a 14-day Post-
treatment Follow-up Period. 
Note: Subjects who complete the 14-day Follow-up Period will be given the 
option of continuing vamorolone treatment in an extension study under a 
separate protocol (VBP15-003). 
Approximately 12 subjects will be enrolled per dose level at up to four 
ascending dose levels (unless there are dose-limiting toxicities in 2 or more 
subjects at a given dose level) in order to have minimum data for the dose 


Vamorolone 
20 January 2017 
Revised Clinical Protocol #2 
Document No. VBP15-002-R2 
Protocol No. VBP15-002 
IND 118,942 
 
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ReveraGen BioPharma, Inc. – CONFIDENTIAL 
level. If fewer than two of the approximately 12 subjects at any dose level 
experience a dose-limiting toxicity, following review of the available safety 
data for the Treatment and Follow-up Periods for all subjects in the dose cohort 
by the Study Chair and Medical Monitor, the Study Chair and Medical Monitor 
will jointly decide whether to recommend dose escalation to the next dose 
level.  If two or more subjects at any dose level experience a dose-limiting 
toxicity, the Medical Monitor and Study Chair will be notified, and enrollment 
at that dose level will be halted; the MTD will be defined as the previous dose 
level, unless the decision is made to study lower intermediate dose level(s).  
The DSMB will be informed promptly of any dose decisions which are a result 
of dose-limiting toxicities. 
If dose escalation is terminated due to dose-limiting toxicities, the remaining 
dose level groups may be enrolled to evaluate the safety and PK effects of 
vamorolone at lower intermediate dose level(s).  Once safety data from 
additional dose level group(s) are assessed, the MTD will be defined as the 
dose level below the dose at which the DSMB determines there to be an 
unacceptable risk to subjects.  This plan allows the maximum number of safe 
dose level groups to have sufficient numbers for overall estimates of safety, 
PK, PD and baseline assessments of preliminary efficacy outcomes to be 
followed via an extension study (VBP15-003). 
Planned Sample Size 
A total of up to 48 subjects will be enrolled.  Approximately 12 subjects in 
each of 4 dose level groups will be studied, unless 2 or more subjects at a given 
dose level have dose-limiting toxicities and dose escalation is halted.   
Population 
Inclusion Criteria: 
1. Subject’s parent or legal guardian has provided written informed 
consent/Health Insurance Portability and Accountability Act (HIPAA) 
authorization prior to any study-related procedures; 
2. Subject has a confirmed (by Central Genetic Counselor) diagnosis of DMD 
as defined as: 
a) Dystrophin 
immunofluorescence 
and/or 
immunoblot 
showing 
complete dystrophin deficiency, and clinical picture consistent with 
typical DMD, OR 
b) Identifiable mutation within the DMD gene (deletion/duplication of 
one or more exons), where reading frame can be predicted as 'out-of-
frame', and clinical picture consistent with typical DMD, OR 
c) Complete dystrophin gene sequencing showing an alteration (point 
mutation, duplication, other) that is expected to preclude production 
of the dystrophin protein (i.e. nonsense mutation, deletion/duplication 
leading to a downstream stop codon), with a typical clinical picture of 
DMD; 
3. Subject is ≥ 4 years and < 7 years of age at time of enrollment in the study; 
4. Subject is able to complete the Time to Stand Test (TTSTAND) without 
assistance, as assessed at the Screening and Baseline Visits; 
5. Clinical laboratory test results are within the normal range at the Screening 
Visit, or if abnormal, are not clinically significant, in the opinion of the 
Investigator.  (Note: Serum gamma glutamyl transferase [GGT], creatinine, 
and total bilirubin all must be ≤ upper limit of the normal range at the 
Screening Visit); 
6. Subject has evidence of chicken pox immunity as determined by presence 
of IgG antibodies to varicella, as documented by a positive test result from 


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20 January 2017 
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Document No. VBP15-002-R2 
Protocol No. VBP15-002 
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the testing laboratory at the Screening Visit; and 
7. Subject and parent/guardian are willing and able to comply with scheduled 
visits, study drug administration plan, and study procedures. 
Exclusion Criteria: 
1. Subject has current or history of major renal or hepatic impairment, 
diabetes mellitus or immunosuppression; 
2. Subject has current or history of chronic systemic fungal or viral infections; 
3. Subject has had an acute illness within 4 weeks prior to the first dose of 
study medication; 
4. Subject has used mineralocorticoid receptor agents, such as spironolactone, 
eplerenone, canrenone (canrenoate potassium), prorenone (prorenoate 
potassium), mexrenone (mexrenoate potassium) within 4 weeks prior to the 
first dose of study medication; 
5. Subject 
has 
evidence 
of 
symptomatic 
cardiomyopathy 
[Note: 
Asymptomatic cardiac abnormality on investigation would not be 
exclusionary]; 
6. Subject is currently being treated or has received previous treatment with 
oral glucocorticoids or other immunosuppressive agents [Notes: Past 
transient use of oral glucocorticoids or other oral immunosuppressive 
agents for no longer than 3 months cumulative, with last use at least 3 
months prior to first dose of study medication, will be considered for 
eligibility on a case-by-case basis.  Inhaled and/or topical corticosteroids 
prescribed for an indication other than DMD are permitted but must be 
administered at stable dose for at least 3 months prior to study drug 
administration]; 
7. Subject has used idebenone within 4 weeks prior to the first dose of study 
medication; 
8. Subject has an allergy or hypersensitivity to the study medication or to any 
of its constituents; 
9. Subject has severe behavioral or cognitive problems that preclude 
participation in the study, in the opinion of the Investigator; 
10. Subject has previous or ongoing medical condition, medical history, 
physical findings or laboratory abnormalities that could affect safety, make 
it unlikely that treatment and follow-up will be correctly completed or 
impair the assessment of study results, in the opinion of the Investigator; 
11. Subject is taking any other investigational drug currently or has taken any 
other investigational drug within 3 months prior to the start of study 
treatment; or 
12. Subject has previously been enrolled in the study. 
Note:  Any parameter/test may be repeated at the Investigator’s discretion 
during Screening and/or Day -1 to determine sustainability and reproducibility.  
In addition, subjects may be rescreened if ineligible due to a transient condition 
which would prevent the subject from participating, such as an upper 
respiratory tract infection, or if ineligible due to negative anti-varicella IgG 
antibody test result. 
Number of Centers 
The study will be conducted at approximately 10 U.S. and non-U.S. study sites. 
Study Period 
First subject screened: 1Q 2016 
Last subject last visit: 4Q 2016 


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20 January 2017 
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Protocol No. VBP15-002 
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Study Duration 
Up to approximately 12 months total duration, or longer in the event dosing or 
follow-up of a dose level group is extended, dose level group(s) repeated, or 
additional subjects added. 
Individual Subject 
Study Duration 
Up to 8 weeks: 
 
Screening Period: up to 26 days 
 
Baseline Period: 1 day 
 
Treatment Period: 2 weeks 
 
Post-treatment Follow-up Period: 2 weeks 
Subjects who complete the 2-week Follow-up Period will be given the option 
of continuing vamorolone treatment in an extension study under separate 
protocol. 
Study Drug 
Formulation, Dosage 
& Administration 
Vamorolone 4% oral suspension administered once daily over a 14-day 
Treatment Period (total of 14 doses) at the following planned dose levels:  
0.25 mg/kg/day, 0.75 mg/kg/day, 2.0 mg/kg/day, or 6.0 mg/kg/day. 
Four dosing groups of approximately 12 subjects each will receive vamorolone 
once daily for 14 days.  The planned dose levels are 0.25 mg/kg (Dose Level 
Group 1), 0.75 mg/kg (Dose Level Group 2), 2.0 mg/kg (Dose Level Group 3), 
and 6.0 mg/kg (Dose Level Group 4): 
 
Dose Level 
Group 
Number of 
Subjects in 
Dose Level 
Group 
Vamorolone 
Dose Level 
Treatment 
Duration 
1 
12 
0.25 mg/kg 
14 days 
2 
12 
0.75 mg/kg 
14 days 
3 
12 
2.0 mg/kg 
14 days 
4 
12 
6.0 mg/kg 
14 days 
Study drug will be administered at a participating study site on Days 1 and 14; 
all other doses will be administered at home.  Study drug will be administered 
by mouth using a volumetric syringe.  Following administration of the dose of 
study drug, the syringe will be filled once with water and the water will be 
administered by mouth using the volumetric syringe.  The subject will then 
drink approximately 50 mL (approximately 2 ounces) of water to ensure the 
full dose has been ingested. 
Subjects will be asked to take the dose following ingestion of 8 ounces of 
whole milk.  If whole milk is not tolerable to the subject, a serving of another 
high fat food can be substituted.  There are no other food or drink restrictions 
during the study. 
Study Evaluation 
and Sample 
Collection 
This is a Phase IIa, multiple center, open-label, multiple ascending dose study 
of vamorolone administered orally once daily for 14 days to ambulant boys 
ages 4-< 7 years with DMD. 
Each dose level group of approximately 12 subjects will be assessed for safety 
and tolerability, PK, clinical efficacy, and PD biomarker response during the 
14-day Treatment Period and a 14-day Follow-up Period.  Treatment Period 
study visits will occur on Day 1, Week 1 (Day 7) and Week 2 (Days 13 and 
14).  Once-daily study drug dosing on Days 2-13 will occur at home.  During 
the Follow-up Period, a scheduled telephone contact will be made by site study 
staff at Week 3 (Day 21), and a final study visit will occur at Week 4 (Day 28). 
Subjects will receive their first and final doses of study medication on Day 1 


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20 January 2017 
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and Day 14, respectively, at participating study sites. 
Blood will be drawn for PK analysis pre-dose and 1, 2, 4, 6, and 8 hours post-
dose on Study Days 1 and 14.  Blood will be collected for Metabolites in Safety 
Testing (MIST) assessment pre-dose and 1, 2, 4, 6, and 8 hours post-dose on 
Study Day 14.  Once-daily study drug dosing on Days 2-13 will occur at home.  
Additional blood and urine samples for clinical laboratory tests will be 
collected and results will be used for dose escalation decisions.  In addition, 
samples will be collected at scheduled visits throughout the study to assess 
safety and PD biomarker levels (see Section 6.3 for detailed assessment 
schedule). 
A physical examination and 12-lead electrocardiogram (ECG) will be recorded 
at Screening, Week 2 (Day 14), and the final Week 4 (Day 28) Follow-up Visit.  
Exploratory clinical efficacy will be assessed by QMT, TTSTAND, 
TTCLIMB, TTRW, NSAA, and 6MWT conducted at Screening and Baseline, 
Week 2 (Day 13), and the final Week 4 (Day 28) follow-up Visit.  Vital signs 
will be recorded at each study visit.  Adverse events (AEs), including serious 
AEs (SAEs), and concomitant medications will be recorded throughout the 
study. 
Subjects will be discharged from the study following completion of all Follow-
up Week 4 (Day 28) assessments.  In the event that any clinical or laboratory 
parameters remain abnormal at the time of discharge from the study, the subject 
will be followed medically as clinically indicated. 
Dose Escalation 
Plan, Dose-Limiting 
Toxicities, and 
Stopping Criteria 
In this multiple ascending dose study, subjects will be enrolled by dose level 
beginning with Dose Level Group 1, to receive vamorolone at the lowest dose 
level, after completion of all Pretreatment Screening and Baseline assessments.  
Dosing will continue through completion of Dose Level Group 4, or until a 
lower MTD is identified.  If dose-limiting toxicities occur at any time during 
the Treatment or Follow-up Periods, the study design may be modified, in 
consultation with the Study Chair, Medical Monitor, Data and Safety 
Monitoring Board (DSMB), and the Sponsor, depending on the timing and 
nature of the toxicities.   
The Study Chair and the Sponsor’s Medical Monitor will jointly review safety 
and available PK data for all subjects who have completed the 2-week 
Treatment Period at a given dose level, to make dose escalation decisions. 
The DSMB will review at a minimum the PK and safety data from the 
Screening and Treatment Periods for each subject in each dose level group.  
DSMB data review will be cumulative to include all data from previous dose 
level groups and any data from the 14-day Follow-up Periods available at the 
time of review.  The DSMB may make recommendations to the Study Chair, 
Medical Monitor, and Sponsor regarding conduct. 
Subjects may be screened for eligibility for each dose level group up to 26 days 
in advance of the anticipated start of dosing in that dose level group.  Screening 
for the next dose level group may occur when all subjects in the current dose 
level group have completed the 14-day Treatment Period and are being 
monitored in the 14-day Follow-up Period. 
Clinical AEs and clinical laboratory AEs will be graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, 
dated June 14, 2010. 
Dose-limiting toxicities will be defined as follows: 


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1. The presence of a CTCAE Grade ≥ 3 AE, considered to be probably 
or definitely related to study drug, in the opinion of the Investigator; 
2. The presence of a CTCAE Grade ≥ 3 clinical laboratory AE 
considered to be probably or definitely related to study drug, in the 
opinion of the Investigator; or 
3. Deterioration of the muscle condition, unexpected for the natural 
course of DMD and without other clear cause, in the opinion of the 
Investigator.  The possibility to consider the event as a dose-limiting 
toxicity will be discussed by the Study Chair, the Medical Monitor 
and the DSMB.  The SAE data collection tool must be completed if 
the event also meets the criteria for an SAE. 
If a dose-limiting toxicity occurs in two or more subjects in any dose group 
during the Treatment or Follow-up Periods, the Study Chair and Medical 
Monitor will be notified, and enrollment and dosing at that dose level will be 
halted; the MTD will be defined as the previous dose level, unless the decision 
is made to study lower intermediate dose level(s).  The DSMB will be informed 
promptly of any dose decisions which are a result of dose-limiting toxicities. 
If dose escalation is terminated due to dose-limiting toxicities, the remaining 
dose level groups may be enrolled to evaluate the safety and PK effects of 
vamorolone at lower intermediate dose levels.  Once safety data from 
additional dose level group(s) are assessed, the MTD will be defined as the 
dose level below the dose at which the DSMB determines there to be an 
unacceptable risk to subjects. 
Safety Measures 
 Physical examination 
 Weight 
 Vital signs (supine blood pressure, heart rate, respiratory rate, oral 
temperature) 
 Clinical laboratory tests: 
o 
Hematology and biochemistry 
o 
Urinalysis (urine protein and glucose) 
o 
Lipid profile (triglycerides, total cholesterol, low density lipoprotein 
[LDL], high density lipoprotein [HDL]) 
 12-lead ECG 
 Clinical signs and symptoms (AEs and SAEs) 
 Grading of clinical and clinical laboratory AEs will be according to the 
CTCAE, v.4.03 
 MIST assessment 
Pharmacokinetics 
Blood will be collected from subjects for vamorolone PK analysis prior to and 
following dosing on Day 1 and Day 14.  On Day 1, sampling times will be 0.5 
hours pre-dose (prior to administration of the first dose of study medication), 
and at 1, 2, 4, 6, and 8 hours post-dose.  On Day 14, sampling times will be 0.5 
hours pre-dose (prior to administration of the final dose of study medication), 
and at 1, 2, 4, 6, and 8 hours post-dose.   
Subjects will have fasted ≥ 6 hours prior to the pre-dose blood draws on Day 1 
and Day 14. 


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Pharmacodynamic 
Measures 
Blood will be collected for serum PD biomarker testing to explore the effect of 
vamorolone on biomarkers of muscle cellular pathology, and biomarkers 
associated with acute and chronic glucocorticoid treatment.  Samples for 
analysis of acute and chronic PD biomarker response will be collected at 
Screening, Day 1 (pre-dose and 6 hours post-dose), Week 2 (Day 14) (pre-dose 
and 6 hours post-dose), and Week 4 (Day 28).  Blood will also be collected and 
stored for future proteomics profiling and SomaScan studies. 
Subjects will have fasted ≥ 6 hours prior to the pre-dose blood draws on Day 1 
and Day 14 for determination of insulin and glucose levels.  
Exploratory Clinical 
Efficacy Measures 
 Quantitative Muscle Testing (QMT) 
 Time to Stand Test (TTSTAND) 
 Time to Climb 4 steps Test (TTCLIMB) 
 Time to Run/Walk 10 meters Test (TTRW) 
 North Star Ambulatory Assessment (NSAA) 
 Six-minute Walk Test (6MWT) 
Statistical Methods 
Sample Size: 
A sample of 12 in each cohort is large enough to have a confidence interval of 
no wider than 50% for the proportion of adverse events assessed or any other 
event outcome.  For the continuous outcomes such as safety laboratory markers 
or pharmacodynamics markers, a two-sided 95.0% confidence interval for the 
mean will be no wider than 0.8 standard deviation (SD) from the observed 
mean, with 90.0% coverage probability, based on the t statistic; thus, the total 
confidence interval will be approximately 1.6 SDs wide for any continuous 
parameter if its underlying distribution is approximately normal. 
Analysis Sets: 
Safety Population 
All subjects who receive at least one dose of vamorolone study medication will 
be included in the Safety Population. 
PK Population 
All subjects who receive at least one dose of vamorolone study medication and 
have sufficient data for PK analysis will be included in the PK Population. 
Statistical Analysis: 
Owing to the small sample size, no inferential statistical analyses are planned.  
Individual subject listings of endpoints, sorted by escalating dose level group, 
will be reviewed for any evidence of dose-related differences or trends. 
Safety and Tolerability Evaluation: 
Safety analyses will be performed using the Safety Population.  Vital signs, 
12-lead ECG, and clinical laboratory test results will be summarized by dose 
level using descriptive statistics.  Treatment-emergent AEs (TEAEs) will be 
summarized by dose level, system organ class (SOC) and preferred term (using 
the Medical Dictionary for Regulatory Activities [MedDRA] version 18.1), by 
dose level and relationship to study medication, and by dose level and intensity 
(CTCAE grade) as well as AE outcome.  All safety data will be listed by dose 
level. 
Pharmacokinetic Evaluation: 
All PK analyses will be performed using the PK Population.  Plasma 
concentrations and the derived plasma PK parameters will be summarized and 


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listed for vamorolone, as appropriate.  Individual and mean vamorolone 
concentrations versus time will be plotted on linear and semi-logarithmic scales 
by dose for vamorolone, as appropriate. 
Summary statistics (number of subjects, mean, standard deviation [SD], 
minimum, median, maximum, geometric mean, and percentage coefficient of 
variation [%CV]) for the derived PK parameters of vamorolone will be 
presented by dose level for the PK Population.  Plots of plasma concentration-
time profiles will be provided by dose level.  All available concentration-time 
data will be listed.  Derived PK parameters will be listed by treatment. 
A (compartmental) population PK model will be developed based on data 
obtained from VBP15-001 (a study in healthy adults).  As part of this 
procedure, the number of systemic compartments will be determined.  In 
addition, linearity with respect to dose and time and appropriateness of a first-
order absorption model will be evaluated.  The parameters of this model, with 
systemic parameters scaled either by weight or allometrically (clearances 
scaled by weight raised to the 0.75 power), will be applied to the dosing history 
in VBP15-001 to predict the plasma concentration profile for pediatric subjects.  
The observed values will then be compared to the predicted concentration and 
the model adjusted as necessary. 
Pharmacodynamic and Exploratory Efficacy Evaluation: 
The Safety Population will be used for all PD and exploratory efficacy 
evaluations.  Standard descriptive statistics will be used to summarize the PD 
and clinical efficacy endpoints by dose level and overall.  


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT TRACKING....................................................................5 
STUDY SYNOPSIS ...........................................................................................................6 
TABLE OF CONTENTS ................................................................................................14 
LIST OF TABLES ...........................................................................................................20 
LIST OF FIGURES .........................................................................................................21 
LIST OF ABBREVIATIONS .........................................................................................22 
1 
INTRODUCTION ...................................................................................................26 
1.1 
Background and Unmet Need ....................................................................26 
1.2 
Nonclinical Experience ................................................................................28 
1.2.1 
Safety Pharmacology......................................................................29 
1.2.2 
Pharmacokinetics and Metabolism ...............................................30 
1.2.3 
Toxicology.......................................................................................34 
1.3 
Clinical Experience ......................................................................................45 
1.3.1 
Phase I Study in Healthy Adult Volunteers ..................................45 
1.4 
Rationale for Study Design .........................................................................57 
2 
STUDY OBJECTIVES AND ENDPOINTS .........................................................61 
2.1 
Study Objectives ..........................................................................................61 
2.1.1 
Primary Objective ...........................................................................61 
2.1.2 
Secondary Objectives......................................................................61 
2.1.3 
Exploratory Objective .....................................................................61 
2.2 
Study Endpoints ...........................................................................................62 
2.2.1 
Safety Endpoints .............................................................................62 
2.2.2 
Pharmacodynamic Endpoints ........................................................62 
2.2.3 
Exploratory Clinical Efficacy Endpoints ......................................63 
2.2.4 
Endpoints for Subject Reported Outcomes ...................................63 
2.2.5 
Pharmacokinetic Endpoints ...........................................................63 


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3 
STUDY DESIGN .....................................................................................................63 
3.1 
Overall Study Design ...................................................................................63 
3.2 
Dose Escalation Plan ...................................................................................64 
3.3 
Study Summary ...........................................................................................66 
4 
SELECTION AND WITHDRAWAL OF STUDY SUBJECTS .........................66 
4.1 
Subject Screening and Enrollment ............................................................66 
4.2 
Inclusion Criteria .........................................................................................67 
4.3 
Exclusion Criteria ........................................................................................68 
5 
STUDY TREATMENT ...........................................................................................70 
5.1 
Study Medication Administered ................................................................70 
5.2 
Identity of Investigational Product ............................................................70 
5.3 
Dosage Schedule and Administration of Study Medication ....................70 
5.4 
Rationale for Dose Selection .......................................................................71 
5.5 
Treatment Compliance ...............................................................................73 
5.6 
Study Medication Management .................................................................73 
5.6.1 
Packaging and Labeling of Study Medication ..............................73 
5.6.2 
Storage of Study Medication ..........................................................74 
5.6.3 
Study Medication Shipping and Handling ....................................74 
5.6.4 
Study Medication Accountability ...................................................75 
5.7 
Procedures for Assigning Subject Study Numbers ..................................75 
6 
STUDY PROCEDURES .........................................................................................76 
6.1 
Time and Events Schedule ..........................................................................76 
6.2 
Informed Consent/HIPAA Authorization .................................................79 
6.3 
Visit Schedule and Procedures ...................................................................80 
6.3.1 
Screening Period (Day -28 to -3) ...................................................80 
6.3.2 
Baseline Visit (Day -1) ...................................................................82 
6.3.3 
Treatment Period Day 1 Visit ........................................................83 


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6.3.4 
Treatment Period Week 1 (Day 7) Visit (Day 7 ± 1 day) ..............84 
6.3.5 
Treatment Period Week 2 Visits ....................................................85 
6.3.6 
Post-treatment Follow-up Telephone Contact (Day 21 ± 2 
days) ................................................................................................87 
6.3.7 
Post-treatment Follow-up Week 4 (Day 28) Visit (Day 28 ± 3 
days) ................................................................................................88 
6.4 
Prior and Concomitant Medications and Therapies ................................89 
6.4.1 
Prohibited Therapies ......................................................................89 
6.4.2 
Permitted Therapies .......................................................................90 
6.5 
Subject Discontinuation ..............................................................................90 
6.6 
Study Completion ........................................................................................90 
7 
STUDY ASSESSMENTS AND MEASUREMENTS ...........................................91 
7.1 
Demographic Assessments ..........................................................................91 
7.2 
Safety and Tolerability Assessments ..........................................................91 
7.2.1 
Medical History ..............................................................................91 
7.2.2 
Physical Examination with Weight ...............................................91 
7.2.3 
Vital Signs .......................................................................................92 
7.2.4 
Clinical Laboratory Tests ...............................................................92 
7.2.5 
12-Lead ECG ..................................................................................95 
7.2.6 
Adverse Events and Serious Adverse Events .................................96 
7.2.7 
Study Medication Acceptability Assessment ...............................103 
7.2.8 
Metabolites in Safety Testing (MIST) .........................................104 
7.3 
Pharmacodynamic Biomarker Panel .......................................................104 
7.4 
Exploratory Clinical Efficacy Endpoints ................................................105 
7.4.1 
Quantitative Muscle Testing (QMT) ...........................................106 
7.4.2 
Time to Run/Walk Test (TTRW) ..................................................106 
7.4.3 
Time to Stand Test (TTSTAND) ..................................................106 
7.4.4 
Time to Climb Test (TTCLIMB) ..................................................106 


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7.4.5 
North Star Ambulatory Assessment (NSAA) ..............................107 
7.4.6 
Six-Minute Walk Test (6MWT) ...................................................107 
7.5 
Pharmacokinetic (PK) Assessments .........................................................108 
7.6 
Total Blood Volume Required ..................................................................108 
8 
SAFETY PROCEDURES AND PROCESSES ...................................................109 
8.1 
Overall Benefit/Risk ..................................................................................109 
8.2 
Medical Monitor and Data and Safety Monitoring Board ....................110 
8.3 
Study Drug Dose Interruption or Discontinuation (Dose-Limiting 
Toxicities) ...................................................................................................111 
8.4 
Study Stopping Rules ................................................................................112 
8.5 
Withdrawal of Subjects from Study ........................................................112 
8.6 
Replacement of Withdrawn Subjects ......................................................114 
8.7 
Termination of Study ................................................................................114 
9 
DATA COLLECTION ..........................................................................................114 
9.1 
Source Documents .....................................................................................114 
9.2 
Electronic Case Report Form Completion ..............................................115 
9.3 
Data Processing ..........................................................................................116 
10 
STATISTICAL METHODS AND PLANNED ANALYSES ............................116 
10.1 
Statistical and Analytical Plan .................................................................116 
10.2 
Planned Sample Size ..................................................................................116 
10.3 
Analysis Populations .................................................................................116 
10.4 
Interim Analysis .........................................................................................117 
10.5 
Statistical Considerations for Dose Escalation .......................................117 
10.6 
Statistical Analysis .....................................................................................117 
10.6.1 
Analysis of Demographic and Baseline Characteristics .............117 
10.6.2 
Summary of Treatment Data and Subject Disposition ...............117 
10.6.3 
Safety Analyses .............................................................................118 


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10.6.4 
Clinical Efficacy and Pharmacodynamic Analyses ....................119 
10.6.5 
Pharmacokinetic Analyses ...........................................................120 
10.6.6 
Concurrent Medications ..............................................................120 
10.6.7 
Study Deviations and Violations ..................................................121 
11 
STUDY MANAGEMENT AND ETHICAL AND REGULATORY 
REQUIREMENTS ................................................................................................121 
11.1 
Regulatory Approval and Good Clinical Practice ..................................121 
11.2 
Investigator Responsibilities .....................................................................121 
11.2.1 
Subject Information and Informed Consent ...............................121 
11.2.2 
Institutional Review Board/Independent Ethics Committee 
Approval and Other Institutional Requirements ........................122 
11.2.3 
Study Documentation ...................................................................124 
11.2.4 
Delegation of Investigator Responsibilities .................................125 
11.3 
Protocol Deviations and Violations ..........................................................125 
11.3.1 
Protocol Deviation and Violation Definitions .............................125 
11.3.2 
Reporting Deviations/Violations ..................................................126 
11.4 
Study Records Retention and Direct Access to Source Documents ......126 
11.5 
Study Monitoring .......................................................................................127 
11.6 
Quality Assurance .....................................................................................128 
11.7 
Study Termination and Site Closure .......................................................129 
11.8 
Site Termination ........................................................................................130 
11.9 
Discontinuation of Study ...........................................................................130 
12 
DISCLOSURE OF DATA ....................................................................................130 
12.1 
Confidentiality ...........................................................................................130 
12.2 
Publication ..................................................................................................132 
13 
INVESTIGATOR’S PROTOCOL AGREEMENT ...........................................133 
14 
REFERENCES ......................................................................................................134 
15 
APPENDICES ........................................................................................................138 


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Appendix 15.1 Vamorolone Dose Calculation Worksheet ..............................139 
 


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LIST OF TABLES 
Table 1: Summary of pharmacokinetic parameters for vamorolone after oral 
administration of single doses of 0.1, 0.3, 1.0, 3.0, 8.0, and 20.0 mg/kg 
to healthy subjects under fasted conditions .................................................47 
Table 2: Summary of pharmacokinetic parameters for vamorolone after 
single dose oral administration of 8 mg/kg to healthy subjects under 
fed and fasted conditions ...............................................................................49 
Table 3:  Summary of pharmacokinetic parameters for vamorolone during 
oral administration of 1, 3, 9, and 20 mg/kg doses once daily for 14 
days to healthy subjects under fasted conditions ........................................50 
Table 4: Biomarkers previously defined to be responsive to chronic doses of 
glucocorticoids in DMD boys ........................................................................60 
Table 5: Dose level group composition ........................................................................64 
Table 6: Schedule of Study Activities ..........................................................................78 
Table 7: Hematology, Chemistry, and Lipids Clinical Laboratory Tests ...............94 
Table 8: Urinalysis Clinical Laboratory Tests ...........................................................94 
Table 9: Pharmacodynamic Biomarkers ..................................................................105 
Table 10: Blood Sample Volume by Visit ...................................................................109 
 


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LIST OF FIGURES 
Figure 1: Arithmetic mean ± standard error plasma concentrations of 
vamorolone (VBP15) after oral administration of single doses of 0.1, 
0.3, 1, 3, 8, and 20 mg/kg to healthy subjects under fasted conditions - 
linear plot (top); semi-logarithmic plot (bottom) ........................................46 
Figure 2: Relationship between individual subject vamorolone AUC(inf) and 
dose after oral administration of single doses of 0.1, 0.3, 1, 3, 8, and 
20 mg/kg to healthy subjects under fasted conditions ................................47 
Figure 3: Arithmetic mean ± standard error plasma concentrations of 
vamorolone (VBP15) after single dose oral administration of 8 mg/kg 
to healthy subjects under fed and fasted conditions - linear (top 
panel) and semi-logarithmic (bottom panel) axes .......................................48 
Figure 4: Arithmetic mean ± standard error plasma concentrations of 
vamorolone (VBP15) on Days 1 and 14 during oral administration of 
1, 3, 9, and 20 mg/kg doses once daily for 14 days to healthy subjects 
under fasted conditions (linear axes)............................................................51 
Figure 5:  Morning cortisol measures in the vamorolone Phase I MAD 
volunteers.* .....................................................................................................53 
Figure 6:  Fasting serum glucose during the Phase I MAD period (two weeks 
daily treatment) ..............................................................................................55 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition/Term 
 
 
ACTH 
adrenocorticotropic hormone 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24hr 
area under the concentration-time curve from time 0 to 24 hours 
AUC0-t 
area under the concentration-time curve from time 0 to time t 
AUCinf 
area under the concentration-time curve from time 0 to infinity 
AUClast 
area under the concentration-time curve from time 0 to the last 
observed measurable concentration 
BL 
baseline 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
Celsius 
CD23 
cluster designation 23 
CFR 
Code of Federal Regulations 
CINRG 
Cooperative International Neuromuscular Research Group 
CK 
creatine kinase 
CL 
clearance 
ConA 
concanavalin A 
cm 
centimeter 
Cmax 
maximum observed plasma concentration 
CQMS 
CINRG Quantitative Measurement System 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTM 
Clinical Trial Material 
CTX 
carboxy-terminal telopeptide 
CYP 
Cytochrome P450 
dL 
deciliter 
DMD 
Duchenne muscular dystrophy 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 


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Abbreviation 
Definition/Term 
 
 
EDC 
electronic data capture 
F 
Fahrenheit 
F, F% 
bioavailability; percent bioavailability 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
HbA1c 
hemoglobin A1c 
HDL 
high density lipoprotein 
HEENT 
head, eyes, ears, nose and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
hr 
hour 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IGFBP-2 
insulin-like growth factor-binding protein 2 
IGFBP-5 
insulin-like growth factor-binding protein 5 
IL-22BP 
interleukin-22 binding protein 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
K2-EDTA 
dipotassium ethylenediaminetetraacetic acid 
kg 
kilogram 
λz 
elimination rate constant 
L 
liter 
LLC 
Limited Liability Company 
LC-MS 
Liquid Chromatography – Mass Spectrometry 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
m 
meter 
MAD 
multiple ascending dose (study) 
MD 
Medical Doctor (physician) 
MDC 
macrophage-derived chemokine 
mdx 
mouse model lacking dystrophin 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute 


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Abbreviation 
Definition/Term 
 
 
MIST 
Metabolites in Safety Testing 
mITT 
modified Intention to Treat 
mL 
milliliter 
MMP-3 
matrix metalloproteinase-3 
MMP-12 
matrix metalloproteinase-12 
MTD 
maximum tolerated dose 
mTPI 
modified Toxicity Probability Interval 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NF-κB 
nuclear factor kappa-light-chain-enhancer of activated B cells 
ng 
nanogram 
No., n 
number 
nmol 
nanomole 
NOAEL 
no observed adverse effect level 
NSAA 
North Star Ambulatory Assessment 
OTC 
over-the-counter (non-prescription medication) 
%CV 
percentage coefficient of variation 
PBL 
peripheral blood leukocytes 
PD 
pharmacodynamic(s) 
PHI 
Protected Health Information 
P1NP 
serum aminoterminal propeptide of type I collagen 
PK 
pharmacokinetic(s) 
PR [PQ] 
time from onset of P wave to start of the QRS complex 
Q 
quarter 
QMT 
quantitative muscle testing 
QRS 
in electrocardiography, the complex consisting of Q, R, and S 
waves, corresponding to depolarization of ventricles [complex] 
QSAR 
quantitative structure-activity relationship  
QT 
in cardiology, the time between the start of the Q wave and end 
of the T wave 
QTc 
corrected QT interval  
6MWT 
Six-minute Walk Test 
RR 
in electrocardiography, the interval between successive Rs 
(peaks of QRS complexes) 
SAD 
single ascending dose (study) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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Abbreviation 
Definition/Term 
 
 
SCR 
screening 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedures 
SSL 
secure socket layers 
t½  
terminal half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum observed plasma concentration 
TPI 
toxicity probability interval 
TTCLIMB 
Time to Climb (Test) 
TTSTAND 
Time to Stand (Test) 
TTRW 
Time to Run/Walk (Test) 
ULN 
upper limit of normal 
US 
United States 
vs. 
versus 
Vss 
volume of distribution at steady state 
Vz 
terminal phase volume of distribution 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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1 
INTRODUCTION 
1.1 
Background and Unmet Need 
Duchenne muscular dystrophy (DMD) is a rapidly progressive form of muscular 
dystrophy that occurs primarily in males and manifests prior to the age of six years.  
DMD affects approximately 1 in 3,600 to 9,300 male births worldwide.1  Duchenne 
muscular dystrophy is caused by mutations in the dystrophin gene which codes for a 
protein that provides structural stability to the dystroglycan complex on muscle cell 
membranes.2  The lack of dystrophin reduces plasma membrane stability.  Membrane 
destabilization results in altered mechanical properties and aberrant signaling, which 
contribute to membrane fragility, necrosis, inflammation, and progressive muscle 
wasting.3 
In addition to the significant contribution of membrane destabilization and mechanical 
injury in DMD, aberrant intracellular signaling cascades that regulate inflammatory and 
immune processes also contribute to DMD pathophysiology.  Up-regulated inflammatory 
gene expression and activated immune cell infiltrates, at least partially mediated by 
nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, are 
evident during early disease stages and play a significant role in muscle wasting.3  NF-κB 
has been shown to regulate the expression of numerous inflammatory genes in immune 
cells and muscle fibers,4,5,6,7 and the infiltration and activation of these cells can trigger 
muscle fiber death.8,9 
Although significant advances have been made in understanding the etiology of DMD, a 
cure has not been found, and current treatment options are all medications used “off-
label” to alleviate the symptoms of DMD.  Despite scientific advances, only 
glucocorticoids, such as prednisone, have consistently demonstrated efficacy in clinical 
trials.10  Further, many disease modifying technologies that are currently in development 
focus on subsets of dystrophin mutations and therefore do not address the unmet need in 
all persons with DMD.  However, it is likely that glucocorticoids will need to be 
co-administered with many of these compounds for maximum effect and glucocorticoids 
have extensive side effect profiles, often limiting long-term administration.  The current 


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goal of DMD research is to find a mutation-independent treatment that matches or 
exceeds the efficacy of glucocorticoids with a significantly lower side effect profile. 
Vamorolone is a first generation delta-9, 11 chemical compound belonging to the 
structural class of synthetic steroidal drugs, which includes the glucorticoids prednisone, 
methylprednisone, and dexamethasone.11  The chemical structure of vamorolone has 
optimized four subactivities of traditional glucocorticoid drugs, namely transactivation, 
transrepression, physiochemical membrane properties, and mineralocorticoid receptor 
antagonism.11  By reducing transactivation subproperties, retaining transrepression, 
imparting membrane stabilizing properties, and inhibiting the mineralocorticoid receptor 
pathway, vamorolone has favorable efficacy and side effect profiles relative to classic 
glucocorticoids in nonclinical models and is anticipated to be an attractive candidate for 
the treatment of DMD in pediatric patients. 
In vitro and nonclinical data to date suggest that vamorolone may offer a much needed 
alternative to the current glucocorticoids which are standard of care for DMD,12 with 
administration beginning around the age of 5 years in most developed countries, or even 
earlier in some cases. 
The significant effects of glucocorticoids on growth and development, however, prevent 
their routine administration in infancy or ‘toddler’ years, despite evidence that the earlier 
the administration, the better the overall functional outcome.13  The cumulative side 
effects of glucocorticoids, including excess weight, delayed puberty, fragile skin, loss of 
bone mineral density, bruising, and Cushingoid appearance continue to negatively impact 
on the quality of life of the individual, leading to significant variations in clinical 
practice.14  Glucocorticoids also contribute to further muscle damage with long-term 
administration.  Vamorolone has shown few if any of the side effects of traditional 
glucocorticoids in mouse models of DMD.11,15,16 
This study is targeted to explore whether vamorolone will show at least equal efficacy to 
glucocorticoids with a more favorable side effect profile, thereby improving the quality 
of life for DMD patients.  This profile would enable use of vamorolone in DMD boys 


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who are at a younger age than when glucocorticoid treatment is currently initiated.  In 
addition, vamorolone could be prescribed in later stage non-ambulant young men with 
DMD and for a longer period of time, where the risk:benefit balance of glucocorticoids is 
often less favorable. 
Efficacy may also be improved over classic glucocorticoids in the longer term.  In 
addition to the anti-inflammatory properties of vamorolone as a result of NF-B pathway 
inhibition, vamorolone may also improve efficacy over conventional glucocorticoids due 
to the lack of interference in the AKT1/FOXO pathway, a key feature of glucocorticoid 
therapy which leads in the long term to muscle wasting and atrophy.17  Further, 
vamorolone has been recently demonstrated to improve asynchronous remodeling, 
believed to be a component of progressive muscle weakness and wasting in DMD18 and 
may also prevent muscle membrane damage, thereby delaying progression of the disease 
further.  Vamorolone is an antagonist to the mineralocorticoid receptor, whereas 
glucocorticoids are typically agonists.  An antagonist for the mineralocorticoid receptor, 
epleronone, was recently shown to significantly improve DMD heart function.19  Finally, 
vamorolone imparts physical stability to myofiber plasma membranes, whereas 
prednisone destabilizes membranes.  This property addresses the primary defect of 
membrane instability in dystrophin deficient myofibers in DMD.15 
Potentially, the administration of vamorolone to a DMD patient may begin soon after 
birth to slow the dystrophic process of muscle, retaining regenerative capacity and 
substantially improving patient quality of life. 
1.2 
Nonclinical Experience 
The safety pharmacology, pharmacokinetics (PK) and metabolism, and toxicology of 
vamorolone have been evaluated in multiple nonclinical studies in vitro and in mice, rats, 
beagle dogs, and cynomolgus monkeys in vivo. 


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1.2.1 
Safety Pharmacology 
Stunted growth is a significant side effect of chronic glucocorticoid use in children.20,21  
Chronic treatment with glucocorticoids negatively affects bone growth and development 
and can cause osteoporosis.22,23 
The effect of vamorolone as compared to prednisolone on bone growth and development 
was evaluated in the mdx mouse model of DMD that lacks dystrophin due to a premature 
chain-terminating mutation in the mouse homologue of the dystrophin gene.  In the pre-
symptomatic mdx study, tibia length was measured to determine if vamorolone inhibited 
bone growth.  Prednisolone significantly decreased tibia length whereas vamorolone did 
not affect tibia length at any concentration tested.  Micro-computed tomography was 
performed on femurs to examine bone density and structure.  Comparison of vehicle, 
prednisolone, and the highest vamorolone dose showed prednisolone to significantly 
reduce trabecular thickness compared to vehicle, while vamorolone did not.15 
In normal, male CD-1® mice, these effects were reproduced.  Unlike CD-1 mice treated 
with prednisolone, CD-1 mice receiving vamorolone did not experience tibia length 
shortening.16  However, at the highest vamorolone dose tested, mice did have 
significantly reduced body length, though to a lesser extent as compared to prednisolone. 
Duchenne muscular dystrophy is associated with cardiomyopathy that can become life 
threatening, and increased fibrosis with prednisone treatment in heart muscle of the mdx 
mouse has been reported.24  Histologically, clear fibrosis was evident in 50% of young 
(8-week) prednisolone-treated mouse hearts compared to no incidence of fibrosis 
identified in the other groups (wild type; mdx vehicle, and vamorolone -treated). 
Pharmacologically, glucocorticoids show immunosuppressive and immunotoxic 
properties that limit therapeutic windows and long-term use.  Vamorolone (5, 15, 30 
mg/kg/day) was benchmarked against prednisolone (5 mg/kg/day) to determine if similar 
properties were observed.15  Untreated mdx mice showed increased numbers of peripheral 
blood leukocytes (PBL) and enlarged spleens resulting from ongoing muscle damage 
compared to wild type mice.  Vamorolone treatment reduced spleen mass and PBL 


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counts in a dose-dependent manner.  This finding is attributed to a reduction in muscle 
damage by vamorolone that decreases spleen size to levels resembling those in wild type 
mice.  Prednisolone reduced these measures below wild type, suggesting 
immunosuppressive and/or immunotoxic properties.  Further, prednisolone significantly 
decreased viable splenocytes per gram of tissue (p0.005), whereas this decrease was not 
observed for any vamorolone dose tested (ReveraGen Report No. MDX-RBP-VBP15-
02).15 
To further query the potential immune modulation, the effects of vamorolone and 
prednisolone on counts of splenic B and T-lymphocytes isolated from treated mdx mice 
were examined.  CD4+ T-cell activation was assayed by stimulation of splenocytes with 
the T-cell mitogen, concanavalin A (ConA).  Splenocytes obtained from prednisolone-
treated mice displayed a significant reduction of the percentage of splenic activated 
CD4+CD25+ T-cells upon ConA stimulation while splenocytes derived from 
vamorolone-treated mice did not (ReveraGen Report No. MDX-RBP-VBP15-02). 
Taken together, these findings suggest that while prednisolone treatment leads to a 
reduction in T-cell number and activation status, vamorolone modulates inflamed mdx 
immune systems towards a wild type state without compromising T-cell activation status. 
1.2.2 
Pharmacokinetics and Metabolism 
1.2.2.1 
Single Dose 
Vamorolone PK profiles were determined in male CD-1 mice, Sprague Dawley rats and 
beagle dogs after a single intravenous injection of 10 mg/kg and after a single oral dose 
of 50 mg/kg in mice and rats and 30 mg/kg in dogs. 
Pharmacokinetic results for vamorolone following a single intravenous administration of 
10 mg/kg in Crl:CD1(ICR) mice demonstrated a clearance (CL) of 18.8 mL/min/kg.  The 
terminal half-life (t½) was 0.35 hours.  Volume of distribution at steady state (Vss) was 
0.76 L/kg.  Following oral administration of 50 mg/kg in mice, the maximum observed 
plasma concentration (Cmax) of 6787 ng/mL was observed at 2 hours (time to maximum 
observed plasma concentration [Tmax]) after drug administration, and percent 


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bioavailability (F%) was 74.5%.  Following oral administration of 15 mg/kg via cherry 
syrup, the Cmax of 1527 ng/mL was observed at 2 hours after drug administration and 
bioavailability was 47.7% (ReveraGen Report No. PH-DPMK-VBP-10-004). 
Pharmacokinetic results for vamorolone following a single intravenous administration of 
50 mg/kg in Sprague Dawley rats indicated a CL of 20.2 mL/min/kg. The t½ was 
0.58 hours.  Vss was 0.77 L/kg, which was similar to that observed in mice.  After oral 
administration of 50 mg/kg in rats, a Cmax of 2543 ng/mL was observed at 4 hours after 
dose administration, and bioavailability was 47.8% (ReveraGen Report No. PH-DPMK-
VBP-10-007). 
In beagle dogs, vamorolone had a CL of 24.7 mL/min/kg.  The t½ was 5.42 hours and Vss 
was 1.93 L/kg.  After oral administration of 30 mg/kg in dogs, a Cmax of 814 ng/mL was 
observed at 6 hours after dose administration and bioavailability was 53.2% (ReveraGen 
Report No. 48504-10-464). 
Vamorolone clearance was therefore comparable in all 3 species studied 
(19-25 mL/min/kg).  Bioavailability ranged from approximately 50% in mouse (cherry 
syrup), rat, and dog to 75% in the mouse (30% Labrafil) (ReveraGen Report Nos. 
PH-DPMK-VBP-10-004, PH-DPMK-VBP-10-007, 48504-10-464). 
1.2.2.2 
Multiple Dose 
Crl:CD1(ICR) mice were administered vamorolone or vehicle once daily for 
28 consecutive days.  Vamorolone exposure (as assessed by the Cmax and area under the 
concentration-time curve [AUC]) increased with increasing dose on Study Days 1 and 28.  
Repeated dosing of vamorolone over a 28-day duration was associated with decreases in 
mean vamorolone AUClast values in the 30 and 100 mg/kg dose groups compared to 
Day 1, indicating possible enzyme induction.  On Study Day 28, mean AUClast values 
were 1.81-fold and 5.02-fold lower compared to Study Day 1 for the 30 and 100 mg/kg 
dose groups, respectively.  The observed difference in exposure relative to Day 1 
increased with the increase in administered dose of vamorolone (ReveraGen Report No. 
1998-009). 


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Beagle dogs were either administered vamorolone or vehicle once daily for 28 
consecutive days.  Vamorolone exposure in dogs (as assessed by Cmax and AUClast) 
generally increased with increasing dose on Study Days 1 and 28.  For the 2 and 10 
mg/kg dose groups, exposure on Day 28 was generally higher than on Day 1, indicating 
possible inhibition of metabolism of vamorolone at these dose levels.  On Day 28, mean 
AUClast values were 2.35-fold and 2.43-fold (males) and 3.03-fold and 3.23-fold 
(females) higher compared to Study Day 1 for the 2 and 10 mg/kg/day dose groups, 
respectively.  For the 50 mg/kg dose group, exposure on Day 28 was similar to that on 
Day 1.  At the 50 mg/kg dose, AUClast values in males were 1.71-fold lower whereas 
females were 1.22 higher on Day 28 compared to Day 1 (ReveraGen Report No. 
031302). 
Non-naïve cynomolgus monkeys were administered vamorolone (300 and 
600 mg/kg/day) or vehicle once daily for 7 consecutive days.  Vamorolone exposure (as 
assessed by Cmax and AUClast) generally increased with increasing dose on Study Days 1 
and 7 with the exception of male monkeys on Day 7, which showed no clear increase in 
exposure between the 300 and 600 mg/kg/day dose levels.  Repeated dosing over the 
7-day study duration was associated with decreases in mean plasma vamorolone AUClast 
values for female and male monkeys indicating possible metabolic induction.  On Day 7, 
mean AUClast values were 1.60-fold, 2.19-fold, and 2.02-fold lower in females and 
1.20-fold, 2.09-fold, and 2.88-fold lower in males compared to Study Day 1 for the 100, 
300 and 600 mg/kg/day dose groups, respectively (ReveraGen Report Nos. 1998-001, 
SW11-0418). 
1.2.2.3 
Distribution 
In the plasma protein binding studies, percent bound was similar in human and mouse 
cells in culture (88.06% and 86.71%, respectively).  In the blood partition experiment 
done ex vivo, the blood to plasma ratio was similar between human and mouse (0.87 and 
0.68, respectively), but the red blood cell to plasma ratio for the mouse (0.33) was less 
than half that of the human (0.74).  Human in vivo data are presented in Section 1.3 
(VBP15-001).  In the blood/brain concentration mouse experiment in vivo, the plasma 


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concentrations of vamorolone were higher than brain concentrations with the AUC and 
Cmax approximately 2-fold higher in plasma than in brain (ReveraGen Report Nos. 
ADME-NCG-PPB-NC135, ADME-VBP-PPB-V002, ADME-NCG-BP-NC134, NCATS 
2013-38). 
1.2.2.4 
Metabolism 
The in vitro and in vivo data demonstrate that vamorolone can be metabolized via 
multiple metabolic pathways, including glucuronidation, hydroxylation, and reduction.  
Glucuronidation appeared to be the major metabolic pathway in human cells in vitro.  All 
metabolites observed in human in vitro were observed in monkey in vitro.  Most human 
metabolites identified in vitro were also found in mouse and dog.  Thus, there is no 
unique human metabolite identified for vamorolone. 
The metabolic stability of vamorolone was assessed in non-Good Laboratory Practice 
(GLP) studies.  Based on the data generated, vamorolone was highly stable for up to 
60 minutes in human, monkey, dog, and mouse liver microsomes in the presence or 
absence of nicotinamide adenine dinucleotide phosphate (NADPH) and stable for up to 
60 minutes in rat liver in the absence of NADPH.  Moderate metabolism was apparent in 
rat liver microsomes in the presence of NADPH stimulation (35% remaining), suggesting 
that rat was a high metabolizer of vamorolone relative to other species (mouse, dog, 
human) (ReveraGen Report Nos. NIH-R2526, and ADME-VBP-LM-V003). 
Vamorolone did not significantly inhibit any of the cytochrome P450 (CYP) enzyme 
isoforms tested (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4).  Vamorolone 
moderately induced CYP3A4 (24% to 42%), indicating that vamorolone is a potential 
inducer of CYP3A4 (ReveraGen Report Nos. ADME-VBP-Inhibition-V005, ADME-
VBP-Induction-V006, ADME-VBP-Induction-V009). 
1.2.2.5 
Excretion 
Vamorolone showed high plasma clearance in rats but, consistent with the extensive 
metabolism in hepatocytes from this species, the biliary and urinary excretion of the 
parent compound was low with an average of <0.05% of the dose recovered in bile and 


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approximately 0.1% in urine.  Overall, vamorolone showed high plasma clearance and 
extremely low biliary and urinary excretion (ReveraGen Report No. NCATS 2013-44). 
1.2.3 
Toxicology 
1.2.3.1 
Single Dose 
Crl:CD1(ICR) mice were administered vamorolone once via oral gavage at 50, 125, 250, 
and 500 mg/kg and observed for abnormalities.  All animals survived to their scheduled 
termination, and there were no significant abnormalities observed.  There was a slight 
decrease in body weight attributed to vamorolone in both males and females at doses 
above 125 mg/kg.  A dose dependent decrease in food consumption related to 
vamorolone was also observed in males and females.  No other abnormalities were 
observed in experimental mice (ReveraGen Report No. 1998-002). 
Beagle dogs received single 60, 180, 360, and 750 mg/kg doses of vamorolone using an 
escalation study design with a 4-day washout period between doses.  All animals 
survived dose escalation.  Clinical signs attributed to vamorolone (750 mg/kg) included 
red discoloration of the ears and face.  This effect occurred within a few hours of dosing 
and was transient.  The highest dose also resulted in increased white blood cell count 
(increased neutrophils and monocytes [female only] and decreased lymphocytes and 
eosinophils [male and female]).  At the 360 and 750 mg/kg dose levels, slight elevations 
in albumin were observed.  A mild elevation in cholesterol at the 750 mg/kg (and 
possibly 360 mg/kg) dose level was also observed (ReveraGen Report No. 13788.01.01). 
In cynomolgus monkeys, single oral doses of up to 500 mg/kg were well tolerated with 
no significant abnormalities observed (ReveraGen Report No. 1998-001). 
1.2.3.2 
Multiple Dose 
Vamorolone or vehicle was administered to Crl:CD1(ICR) mice once daily for 28 
consecutive days at doses of 10, 30 and 100 mg/kg/day.  All animals survived to their 
scheduled necropsy with the exception of a female mouse (100 mg/kg/day dose group) 


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that was found dead on Day 16.  The cause of death was considered incidental and 
attributed to a dosing injury based on the amount of red fluid in the thoracic cavity. 
No effects attributable to vamorolone were observed in food consumption, ophthalmic 
examination, or urinalysis during the study.  Dose-dependent decrease in body weight 
gain was observed at all doses; however, weight was fully regained during the recovery 
period.  Adrenal gland weights were variable between groups and generally decreased, 
but without a dose response relationship, and correlated microscopically with minimal to 
moderate vacuolar degeneration and cortical atrophy.  After the 2-week recovery period 
there was evidence of vacuolar degeneration of the adrenal gland.  Liver weights were 
significantly increased at the 100 mg/kg/day dose level.  Hepatocellular hypertrophy, 
increased vacuolation, and necrosis (single cell) were seen in a few male mice at 
30 mg/kg/day.  There was evidence of lipid and glycogen accumulation.  Serum alanine 
aminotransferase and aspartate aminotransferase levels were higher with associated 
microscopic hypertrophy/vacuolation/necrosis at 100 mg/kg/day.  Spleen weights 
decreased in a dose-dependent manner and correlated with a decreased number of 
lymphocytes in spleen.  Thymus weights decreased in a dose dependent manner and were 
associated microscopically with lymphoid atrophy.  Mice had dose-dependent reductions 
in serum lymphocytes which were significant in the 100 mg/kg dose group.  After the 
recovery period, all parameters returned to normal (untreated) except for thymus weights, 
which were increased. 
Based on the liver-related findings in this study, the no observed adverse effect level 
(NOAEL) for vamorolone in mice is 30 mg/kg/day (ReveraGen Report No. 1998-009). 
A GLP-compliant study was carried out to evaluate the toxicity of the test article, 
vamorolone, in Crl:CD1®(ICR) mice after administration for 26 weeks, including 
evaluation of the reversibility, progression, or delayed appearance of any observed 
changes following a 4-week post-dose observation period.  Assessment of toxicity was 
based on mortality, clinical observations, body weight, and food consumption; 
ophthalmoscopic examinations; and clinical and anatomic pathology.  Toxicokinetic 
assessment was conducted for the test article. 


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There were no vamorolone-related effects on mortality, detailed clinical observations, 
food consumption, ophthalmology, sperm evaluations, or bone lengths (femur or tibia). 
Five test article-treated mice were unscheduled deaths (euthanized in extremis or found 
dead) during the dosing phase.  Three of these were considered to be potentially due to 
dosing injury based on microscopic findings in mediastinum, epicardium, or lung.  One 
of these unscheduled deaths was attributed to moderate progressive nephropathy; a 
spontaneous background finding. The death of one male at the 5 mg/kg/day dose was 
undetermined since there were no major pathologic findings to explain the unscheduled 
death of this animal; there was no target organ toxicity in the mouse.  Target organ 
toxicity was not considered a contributor to the death of these animals and there was no 
dose-relationship in incidence. 
A vamorolone-related increase in body weight gain was observed relative to controls in 
males (+14%) and females (+23%) at the 45 mg/kg/day dose.  Increases in body weights 
at 45 mg/kg/day were not considered to be adverse due to the general health of the 
animals overall.  During the recovery phase, bodyweights in males returned to 
comparable levels as controls, however female body weights remained increased 
compared to female controls. 
Evidence of a minimal to mild vamorolone-related hepatic effects were observed in males 
at doses ≥5 mg/kg/day and females at 45 mg/kg/day, indicated by mild to moderate 
increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase 
activities, and/or total bilirubin, as related to microscopic hepatocellular vacuolation, 
inflammation, and/or necrosis in males at ≥ 15 mg/kg/day and females at 45 mg/kg/day; 
these changes had generally resolved at recovery collections with the exception of 
minimal increases in alanine aminotransferase activity in females at 45 mg/kg/day, which 
may have correlated to microscopic liver pathology. 
A mild vamorolone-related increase in neutrophil counts was observed in both sexes at 
45 mg/kg/day with concurrent decreases in lymphocyte counts in females at 
45 mg/kg/day consistent with a glucocorticoid-like effect, as related to microscopic 


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lymphoid depletion.  However, an inflammatory stimulus may have contributed to 
increases in neutrophil counts, as related to microscopic liver inflammation; these 
changes had generally resolved at recovery collections. 
A mild vamorolone -related decrease in chloride was observed in males at doses ≥ 5 
mg/kg/day and females at doses ≥ 15 mg/kg/day that lacked correlative findings among 
other study endpoints; resolution for this observation could not be determined. 
A mild vamorolone -related increase in albumin was observed in males at doses 
≥ 5 mg/kg/day and females at 45 mg/kg/day with concurrent mild increases in globulin in 
females at 45 mg/kg/day; these changes had resolved at recovery collections. 
A minor vamorolone -related alteration in lipid metabolism was observed in both sexes at 
the 45 mg/kg/day dose and females at the 15 mg/kg/day dose indicated by increases in 
triglyceride and/or cholesterol; these changes had resolved at recovery collections. 
Vamorolone-related macroscopic findings occurred in the liver of mice at the 
45 mg/kg/day dose.  Tan discoloration occurred in one female and four males at this dose 
in the dosing phase. This correlated with microvesicular/macrovesicular hepatocyte 
vacuolation.  There were no test article-related macroscopic findings in recovery animals. 
Test article-related microscopic findings occurred in adrenal gland (cortical atrophy with 
correlating decreases in adrenal weights in females), liver (increased severity of 
centrilobular hypertrophy; hepatocyte vacuolation; and inflammation/necrosis), lymphoid 
tissues (thymus, spleen, mandibular lymph node, mesenteric lymph node, and gut 
associated lymphoid tissue [GALT]) skin, and pancreatic islets (minimal to mild 
hypertrophy).  Observed changes in these tissues are considered pharmacologically-
mediated and not adverse. 
An increased incidence of decreased anagen hair follicles occurred in mice at the 
45 mg/kg/day dose.  Decreased anagen hair follicles were documented for individual 
animals when there were no anagen hair follicles in the section of skin.  Incidence in 
controls and mice at the 5 and 15 mg/kg/day doses were similar.  A severity score was 


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not given to the decrease as this may have been somewhat dependent on size of skin 
sample.  This change is not considered adverse. 
There was full reversibility of lymphoid changes in thymus, spleen, mesenteric lymph 
node, mandibular lymph node, and GALT.  There no meaningful differences between 
treated animals and controls at the end of the recovery tissues for these lymphoid tissues.  
There was recovery of adrenal gland findings in females and partial recovery of adrenal 
gland findings in males.  In addition, there was partial reversibility of liver findings for 
males and females.  Minor changes persisted in the pancreas and skin. 
Systemic exposure to vamorolone appeared to be sex-dependent on Day 1 (males > 
females) and appeared to be independent of sex on Day 179.  Following daily 
administration of vamorolone in females and males, systemic exposure (AUC0-24hr) and 
Cmax values of vamorolone increased with increasing dose in a greater than 
dose-proportional manner on Day 1 and in an approximately dose-proportional manner 
on Day 179.  Systemic exposure to vamorolone in females appeared to increase following 
repeated administration of vamorolone at 5 mg/kg/day, did not appear to change 
following repeated administration of vamorolone at 15 mg/kg/day, and appeared to 
decrease following repeated administration of vamorolone at 45 mg/kg/day.  Systemic 
exposure to vamorolone in males appeared to decrease following repeated administration 
of vamorolone. 
The once daily administration of vamorolone via oral gavage to mice for 26 weeks at 5, 
15, and 45 mg/kg/day did not produce any adverse effects.  Therefore, the NOAEL is 
considered to be 45 mg/kg/day under the conditions of this study. 
Vamorolone or vehicle was administered to beagle dogs once daily for 28 consecutive 
days at doses of 2, 10 and 50 mg/kg/day.  All animals survived to their scheduled 
termination and no effect of vamorolone was noted on gross visual inspection, body 
weight, body temperature, food consumption, ophthalmology, electrocardiography or 
urinalysis parameters at necropsy.  A dose-dependent decrease in the expected normal 


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body weight gain was observed at all doses but weights generally increased to a normal 
level during the recovery period. 
Adrenal gland weights decreased with vamorolone treatment, which correlated with mild 
or moderate diffuse bilateral atrophy of the adrenal cortex, mild multifocal bilateral 
vacuolation of the adrenal cortex, increased white blood cell and neutrophil counts, and 
decreased eosinophil counts.  Liver weights increased in the 50 mg/kg/day dose group, 
which correlated with diffuse hypertrophy and vacuolation and increased levels of 
alkaline phosphatase and gamma glutamyltransferase.  Spleen weights decreased, which 
correlated with lymphoid depletion.  Thymus weights decreased, which corresponded to 
diffuse lymphoid depletion.  With the exception of diffuse depletion of lymphocytes in 
thymus in the 50 mg/kg group, all abnormal parameters returned to normal during the 
recovery period. 
The NOAEL was considered by the study director to be 10 mg/kg/day.  Although 
reversible, the liver changes were considered adverse at 50 mg/kg/day because the 
severity score was moderate and the changes were diffuse in nature in all animals treated 
at the high dose.  This determination is in contrast to the conclusion drawn by the study 
pathologist, who considered the NOAEL to be 50 mg/kg/day due to reversibility 
following cessation of dosing (ReveraGen Report No. 31302). 
Vamorolone or vehicle was administered to beagle dogs once daily for 39 weeks at doses 
of 2, 10 and 50 mg/kg/day.  Six dogs of each sex received each dose or placebo, and two 
of the six dogs of each sex at each dose or placebo were followed for an additional 
4 weeks to evaluate reversibility, progression, or delayed appearance of any observed 
changes.  One male dog who received 50 mg/kg/day was euthanized in extremis on Day 
273 due to paraphimosis (an extended penis).  All other animals survived to their 
scheduled termination.   
Detailed clinical observations considered test article-related at 50 mg/kg/day, and 
reversible included decreased activity (considered adverse), struggling during dosing, 
feces soft, limb function impaired, interdigital cysts, and unkempt appearance 


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(considered adverse).  Test article-related, dose-dependent increases in body weight gains 
correlating with increases in food consumption were observed relative to controls in 
males at all dose levels and in females at 10 and 50 mg/kg/day.  Test article-related, 
reversible increases in average mean food consumption, relative to controls, over the 
course of the 39-week dose phase were observed in both sexes at 10 and 50 mg/kg/day.   
No test article-related ophthalmological effects were noted.  No test-article-related 
changes were noted in respiratory rates or rectal temperatures.  There may have been a 
mild dose related reversible increase in the heart rate at the terminal post-dose interval 
that was significantly different from vehicle in both sexes following the 50 mg/kg/day 
dose.  Semen analysis/evaluation for test article affects could not be conducted as there 
were not enough viable samples collected. 
Test article-related effects on clinical pathology endpoints with microscopic correlates 
included the following: 
 A hepatocellular and hepatobiliary effect in males at 10 mg/kg/day and both sexes 
at 50 mg/kg/day, which included increased alkaline phosphatase, gamma 
glutamyltransferase, alanine aminotransferase and aspartate aminotransferase 
activity.  These changes correlated with microscopic changes in the liver, bile 
duct and gall bladder.  This spectrum of changes was considered adverse in both 
sexes at 50 mg/kg/day.   
 There was also evidence of an inflammatory response in both sexes at 
50 mg/kg/day, which included increased total leukocyte, neutrophil and monocyte 
counts, and increased fibrinogen and/or globulin concentrations.  The 
inflammatory response was likely secondary to inflammation in the liver 
associated with hepatocellular necrosis.  Platelet counts were also increased in 
both sexes at 50 mg/kg/day and may have been secondary to the inflammatory 
response. 
Following a 4-week recovery period, all noted clinical pathological changes resolved, 
with the exceptions of increased alanine aminotransferase activity in both sexes at 
50 mg/kg/day, and increased globulin in males at 50 mg/kg/day. 


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Reversible, test article-related macroscopic findings included mildly to moderately 
enlarged livers in males and females at 50 mg/kg/day, which correlated microscopically 
with panlobular hepatocellular hypertrophy and/or hepatocellular vacuolation; 
hemorrhage in the gall bladder of one 50 mg/kg/day female, that was associated with 
moderate acute inflammation and mild vascular necrosis, and considered to be adverse; 
red focus/foci within the pylorus of the stomach of one 50 mg/kg/day female and one 
male at 10 mg/kg/day, which correlated microscopically with mild acute inflammation in 
the female.   
Test article-related organ weight changes at the terminal necropsy included decreases in 
adrenal gland weights in both sexes at ≥ 2 mg/kg/day (microscopic correlate of bilateral 
cortical atrophy); increases in liver weights in both sexes at ≥ 10 mg/kg/day (microscopic 
correlates of panlobular hepatocellular hypertrophy and/or hepatocellular vacuolation); 
increases in kidney weights in females at ≥ 10 mg/kg/day and males at 50 mg/kg/day 
(microscopic correlate of bilateral tubular vacuolation); decreases in prostate gland 
weights in males at 50 mg/kg/day (microscopic correlate of decreased secretory product).  
These organ weight changes were all reversible, except for the decreases in the prostate 
gland.  Microscopic evaluation revealed the following test article-related changes: 
adrenal glands (atrophy of the zona fasciculata and zona reticularis and 
hypertrophy/hyperplasia of the zona glomerulosa in both sexes at ≥ 10 mg/kg/day and 
atrophy was considered adverse); esophagus and pylorus of the stomach 
(erosion/ulceration in a few animals of both sexes at 50 mg/kg/day); gallbladder 
(hypertrophy/hyperplasia of the mucosal epithelium in both sexes at ≥ 10 mg/kg/day and 
cytoplasmic vacuolation of the mucosal epithelium in males at ≥ 10 mg/kg/day and 
females at ≥ 2 mg/kg/day); liver (hepatocellular vacuolation in males at ≥ 10 mg/kg/day 
and females at ≥ 2 mg/kg/day, panlobular hypertrophy in males at 50 mg/kg/day and 
females at ≥ 10 mg/kg/day, and inflammation/necrosis in both sexes at 50 mg/kg/day and 
considered adverse, bile duct hyperplasia in both sexes at 50 mg/kg/day, bile duct 
hypertrophy in males at 50 mg/kg/day and females at ≥ 10 mg/kg/day, and cytoplasmic 
vacuolation of the bile duct epithelium in both sexes at ≥ 10 mg/kg/day); kidneys 
(bilateral tubular vacuolation in males at 50 mg/kg/day and females at ≥ 10 mg/kg/day 


Vamorolone 
20 January 2017 
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and an increased incidence of bilateral basophilic tubules in males and females at 
50 mg/kg/day); lymphoid depletion in both sexes at 50 mg/kg/day in mandibular and 
mesenteric lymph nodes, thymus and spleen (with extramedullary hematopoiesis in 
50 mg/kg/day females); bone marrow in the sternum (increased adipocytes in males at 
≥ 2 mg/kg/day and females at 50 mg/kg/day); testes (spermatocyte/spermatid 
degeneration in males at 50 mg/kg/day); epididymides (oligospermia/germ cell debris in 
males at 50 mg/kg/day); ovaries (absent corpora lutea in females at ≥ 2 mg/kg/day and 
considered adverse); the mammary gland and other tissues in the female reproductive 
tract (uterus, cervix, and vagina) of these animals were consistent with animals that have 
not ovulated; vacuolation in the epithelium of the mammary gland duct in females at 
50 mg/kg/day; parotid salivary gland (cytoplasmic alteration in both sexes at 
≥ 10 mg/kg/day); biceps femoris (atrophy of the skeletal muscle in both sexes at 
50 mg/kg/day); skin (atrophy and alopecia/hypotrichosis in males at 50 mg/kg/day and 
females at ≥ 10 mg/kg/day); prostate gland (decreased secretory product in males at 
50 mg/kg/day); thyroid glands (bilateral increased colloid in males at ≥ 10 mg/kg/day). 
Many of the findings were felt by the Study Director to be consistent with the 
pharmacology of the test article including cortical atrophy of the adrenal glands (affecting 
the zona fasciculata and reticularis), generalized lymphoid depletion in lymphoid tissues 
(thymus, spleen, and lymph nodes), increased adipocytes in the bone marrow, atrophy of 
the skeletal muscle, alopecia/hypotrichosis and atrophy of the skin (thinning of the 
dermal collagen and atrophy of hair follicles and adnexa), an absence of corpora lutea in 
the ovary (likely indicative of delayed puberty), decreased secretory product in the 
prostate gland, and multiple changes in the liver.  The liver had panlobular hypertrophy 
and vacuolation of hepatocytes consistent with glycogen accumulation.  Due to the 
magnitude of hypertrophy and vacuolation, there were (likely secondary) foci of 
hepatocellular necrosis and inflammation. 
Test article-related microscopic findings at the recovery necropsy were present in the 
adrenal glands, liver, gallbladder, kidneys, stomach (pylorus), female reproductive tract 
(ovaries), male reproductive tract (testes, epididymides, prostate gland), mesenteric  
lymph node, skeletal muscle (biceps femoris), and parotid salivary gland. 


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20 January 2017 
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The No Observed Adverse Effect Level was 2 mg/kg/day for males; a No Observed 
Adverse Effect Level was not observed for females (ReveraGen Report No. 1998-014).  
Non-naive cynomolgus monkeys were administered vamorolone or vehicle once daily for 
7 consecutive days at doses of 100, 300, and 600 mg/kg.  All animals survived until the 
end of the study period.  There were effects on clinical observations, food consumption, 
and urinalysis attributable to vamorolone that are described below. 
There was a dose proportional decrease in body weight gain observed in males and 
females at each dose (up to 11% and 9% respectively) related to vamorolone.  A 
cessation of the body weight loss in treatment was observed during the recovery phase 
but no recovery of body weight lost during the 7 days of dosing was observed. 
At termination there were nonsignificant increases in red cell mass and decreases in 
lymphocytes (up to 56%) in the 600 mg/kg/day dose group.  However, most individual 
animals, including controls, had decreases in lymphocytes (up to 81%) at termination 
relative to their respective pretest.  They had resolved by the recovery interval in both 
sexes. 
In both sexes receiving ≥ 300 mg/kg/day, there was increased urea nitrogen (up to 141%), 
creatinine (up to 58%), total protein (up to 15%), albumin (up to 11%), globulin (up to 
25%), and/or potassium (up to 39%) with concurrent decreases in sodium (up to 10%) 
and chloride (up to 10%) relative to controls.  At the recovery interval, the majority of 
these effects had resolved (ReveraGen Report No. 1998-001). 
1.2.3.3 
Genotoxicity 
The mutagenic and genotoxic potential of vamorolone was assessed in several assays.  A 
non-GLP Ames screen was negative for bacterial mutations (ReveraGen Report No. 
BIO-VBP-001-AMES).  In a GLP Ames test, no background lawn toxicity was observed; 
however, a reduction in revertant counts was observed (ReveraGen Report No. 
AD79DT.502ICH.BTL).  Vamorolone was negative for inducing chromosomal 
aberrations in cultured mouse lymphocytes without and with metabolic activation 
(ReveraGen Report No. AD79DT.704.BTL). 


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Femoral bone marrow was microscopically evaluated for the presence of polychromatic 
erythrocytes (PCEs) containing micronuclei.  No significant reductions in the PCEs/EC 
(total erythrocytes) ratio were observed in the vamorolone groups compared to the 
vehicle control group.  Although statistically significant increases in the incidence of 
micronucleated PCEs in the vamorolone treated groups were observed, no dose response 
was observed with respect to other groups and the values of micronuclei for the 
individual animals were within the historical range.  Therefore, the statistically 
significant increase was considered as biologically insignificant (ReveraGen Report No. 
AD76BK.123012ICH.BTL). 
A study was performed to evaluate the potential mutagenicity of two theoretical epoxide 
impurities related to the drug substance vamorolone (formerly VBP15), which is a 
steroid-like structure containing a delta 9,11 double bond.  The delta 9,11 epoxide 
structures evaluated were VBP15-B-3, which is structurally similar to vamorolone except 
for the epoxide moiety, and VBP15-B-2, which has a 21-acetate substitution (vamorolone 
and VBP15-B-3 contain a 21-hydroxy moiety).  Two validated and complementary 
in silico prediction methodologies were used for assessing mutagenic potential.  The 
statistics-based quantitative structure-activity relationship (QSAR) program MultiCASE 
CASE Ultra was used, employing four different modules (GT1_A7B, GT1_AT_ECOLI, 
PHARM_ECOLI, and PHARM_SAL) designed to cover a wide range of molecular 
substructures collected from both proprietary and public compounds.  In addition, the 
expert rule-based SAR program Derek Nexus was used to determine if the theoretical 
impurities contained structural alerts associated with known genotoxicants.  CASE Ultra 
predicted both VBP15-B-2 and VBP15-B-3 as negative for mutagenicity [ReveraGen 
Report “In Silico Mutagenicity Evaluation of Delta 9,11 Epoxide Structures of VBP15: 
VBP15-B-2 (21-Acetate) and VBP15-B-3 (21-Hydroxy)”]. 
Taken together, these data indicate vamorolone has not generated a mutagenic signal 
based on these simulations. 


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20 January 2017 
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1.3 
Clinical Experience 
1.3.1 
Phase I Study in Healthy Adult Volunteers 
Clinical experience is limited to a single Phase I clinical trial of vamorolone in healthy 
adult volunteers (VBP15-001).  This study evaluated the safety, tolerability, and PK of 
vamorolone in a Phase I randomized, placebo-controlled, double-blind, single ascending 
dose (SAD) and multiple ascending dose (MAD) study.  In the SAD portion of the study, 
Cohorts 1 through 5 and Cohort 7 were comprised of eight subjects each; six subjects in 
each cohort received a single oral dose of vamorolone (0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 
3.0 mg/kg, 8.0 mg/kg, and 20 mg/kg, respectively) and two subjects in each cohort 
received placebo under fasted conditions.  In Cohort 6, six subjects received a single oral 
dose of 8.0 mg/kg vamorolone within 30 minutes of beginning a high fat/high calorie 
meal.  The MAD portion of the study had four cohorts (6 drug, 2 placebo in each) 
receiving 14 daily doses of vamorolone (1.0, 3.0, 9.0 and 20.0 mg/kg/day).  The clinical 
conduct for all seven SAD cohorts, and all four MAD cohorts has been completed; data 
analysis is ongoing. 
The primary objectives of the Phase I study were to evaluate the safety and tolerability of 
single and multiple oral doses of vamorolone, and to evaluate the PK of single doses and 
multiple doses of vamorolone.  A secondary objective was to evaluate the effect of food 
on the absorption and PK of vamorolone.  Other objectives were to obtain samples from 
subjects on Day 1 (pre-dose) and Day 14 of the MAD cohorts for use in Metabolites in 
Safety Testing (MIST) assessments, and to test back-up PK samples from a subset of 
MAD subjects for pharmacodynamic (PD) biomarkers. 
1.3.1.1 
SAD Cohorts 
1.3.1.1.1 
SAD Cohorts – Pharmacokinetics Fasted 
Vamorolone PK data shows strong adherence to dose linearity and dose proportionality, 
with relatively little subject-subject variation (Figure 1, Table 1, Figure 2).  The half-life 
was about 2 hours for doses 0.1-1.0 mg/kg.  Doses at 3.0, 8.0 and 20.0 mg/kg showed an 
extended tail, increasing half-life to 2.5, 3.8 and 3.8 hours, respectively (Figure 1). 


Vamorolone 
20 January 2017 
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Figure 1: 
Arithmetic mean ± standard error plasma concentrations of 
vamorolone (VBP15) after oral administration of single doses of 0.1, 0.3, 
1, 3, 8, and 20 mg/kg to healthy subjects under fasted conditions - linear 
plot (top); semi-logarithmic plot (bottom) 
 
 


Vamorolone 
20 January 2017 
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Table 1: 
Summary of pharmacokinetic parameters for vamorolone after oral 
administration of single doses of 0.1, 0.3, 1.0, 3.0, 8.0, and 20.0 mg/kg to 
healthy subjects under fasted conditions 
 
Cmax = maximum observed plasma concentration; Tmax = time to maximum observed plasma concentration; AUC(0-t) = 
area under concentration-time curve from time 0 to time t; AUC(inf) = area under concentration-time curve from time 0 
to infinity; z = elimination rate constant; t½ = terminal half-life; CL/F = apparent total clearance from plasma; Vz/F = 
apparent volume of distribution during terminal phase. 
Figure 2: 
Relationship between individual subject vamorolone AUC(inf) and dose 
after oral administration of single doses of 0.1, 0.3, 1, 3, 8, and 20 mg/kg 
to healthy subjects under fasted conditions 
 
1.3.1.1.2 
SAD Cohorts – Pharmacokinetics Fed 
For the food effect group, a high fat meal (45 grams fat) was given to a cohort of Phase I 
SAD volunteers with the 8.0 mg/kg dose of vamorolone.  These data were then compared 
to the fasted 8.0 mg/kg cohort data.  This showed that absorption was increased by 2.5-
fold by the high fat meal, consistent with the lipophilic character of vamorolone (steroidal 
compound) (Figure 3, Table 2). 


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20 January 2017 
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Figure 3: 
Arithmetic mean ± standard error plasma concentrations of 
vamorolone (VBP15) after single dose oral administration of 8 mg/kg to 
healthy subjects under fed and fasted conditions - linear (top panel) and 
semi-logarithmic (bottom panel) axes 
 
 


Vamorolone 
20 January 2017 
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Table 2: 
Summary of pharmacokinetic parameters for vamorolone after single 
dose oral administration of 8 mg/kg to healthy subjects under fed and 
fasted conditions 
 
*Geometric mean (%CV) (N) except Tmax for which the median (N) is reported. 
†Ratio of the geometric means. 
Cmax = maximum observed plasma concentration; Tmax = time to maximum observed plasma concentration; AUC(0-t) = 
area under concentration-time curve from time 0 to time t; AUC(inf) = area under concentration-time curve from time 0 
to infinity; z = elimination rate constant; t½ = terminal half-life; CL/F = apparent total clearance from plasma; Vz/F = 
apparent volume of distribution during terminal phase. 
1.3.1.1.3 
SAD Cohorts – Adverse Events 
One subject in the SAD 8.0 mg/kg showed a delayed mild elevation of liver enzymes.  
This was not felt to be drug-related due to timing of the elevations, and it is not known if 
this was a drug-treated or placebo subject (study remains blinded).  There were no other 
adverse events (AEs) seen in any dose group. 
1.3.1.2 
MAD Cohorts  
The Phase I MAD treatment plan was discussed in light of the initial PK data.  The 
relatively short half-life of vamorolone (2-4 hours), coupled with the planned daily dose 
schedule, would be expected to give PK data on each single dose, not cumulative dose, as 
the dosing interval was > 5 × t½.  Thus, the MAD component would be a study of 
individual daily doses, rather than dose-related accumulation and pharmacodistribution 
related to cumulative drug exposure.  In other words, a typical goal of a MAD study is to 
determine steady state drug levels after multiple doses; yet with the short half-life of 
vamorolone, useful information would not be expected to be gained with the current daily 


Vamorolone 
20 January 2017 
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dosing schedule.  Safety and tolerability are additional goals of the MAD study, and these 
remain important endpoints independent of the PK studies. 
1.3.1.2.1 
MAD Cohorts – Pharmacokinetics Fasted 
The original design for the Phase I MAD was modified to remove the two lowest doses 
(0.1, 0.3 mg/kg/day), and to begin dosing at 1.0 mg/kg/day.  The clinical conduct of all 
four cohorts has been completed (1.0 mg/kg/day, 3.0 mg/kg/day, 9.0 mg/kg/day, 
20.0 mg/kg/day) for the MAD study (Table 3).    
Table 3:  
Summary of pharmacokinetic parameters for vamorolone during oral 
administration of 1, 3, 9, and 20 mg/kg doses once daily for 14 days to 
healthy subjects under fasted conditions 
 
Vamorolone Dose 
1 mg/kg 
3 mg/kg 
9 mg/kg 
20 mg/kg 
Day 1 
Cmax (ng/mL) 
153 (15.9) 
281 (36.9) 
1,082 (23.3) 
2,416 (51.1) 
Tmax (hr) 
3.04 
2.01 
1.75 
1.00 
[1.50 – 4.00] 
[1.00 – 3.00] 
[1.00 – 6.00] 
[0.50 – 3.00] 
AUC(0-t) 
(hrxng/mL) 
686 (22.4) 
1,471 (23.6) 
5,709 (29.9) 
10,182 (28.1) 
AUC(0-24) 
(hr×ng/mL) 
686 (22.4) 
1,471 (23.6) 
5,709 (29.9) 
10,182 (28.1) 
AUC(inf) 
(hr×ng/mL) 
695 (22.1) 
1,487 (23.7) 
5,745 (29.5) 
10,190 (27.0) 
z (1/hr) 
0.3848 (10.9) 
0.2918 (18.1) 
0.2317 (22.6) 
0.1747 (44.3) 
t½ (hr) 
1.80 (10.9) 
2.38 (18.1) 
2.99 (22.6) 
3.97 (44.3) 
CL/F (L/hr/kg) 
1.44 (22.1) 
2.02 (23.7) 
1.57 (29.5) 
1.96 (27.0) 
Vz/F (L/kg) 
3.74 (16.9) 
6.91 (34.8) 
6.76 (46.9) 
11.2 (77.6) 
Day 14 
Cmax (ng/mL) 
203 (30.1) 
276 (35.6) 
935 (48.3) 
2,491 (27.9) 
Tmax (hr) 
2.96 
2.50 
1.25 
2.00 
[1.50 – 3.00] 
[1.00 – 4.00] 
[0.55 – 3.00] 
[1.00 – 2.00] 
AUC(0-24) 
(hr×ng/mL) 
794 (22.3) 
1,494 (18.6) 
4,366 (20.2) 
9,309 (38.8) 
z (1/hr) 
0.3993 (20.4) 
0.3273 (25.2) 
0.1629 (63.5) 
0.1879 (31.6) 
t½ (hr) 
1.74 (20.4) 
2.12 (25.2) 
4.25 (63.5) 
3.69 (31.6) 
CL/F (L/hr/kg) 
1.26 (22.3) 
2.01 (18.6) 
2.06 (20.2) 
2.15 (38.8) 
Vz/F (L/kg) 
3.15 (20.6) 
6.14 (39.7) 
12.7 (79.9) 
11.4 (49.1) 
Cmax = maximum observed plasma concentration; Tmax = time to maximum observed plasma concentration; AUC(0-t) = 
area under concentration-time curve from time 0 to time t; AUC(0-24) = area under concentration-time curve from time 0 
to 24 hours; AUC(inf) = area under concentration-time curve from time 0 to infinity; z = elimination rate constant; t½ = 
terminal half-life; CL/F = apparent total clearance from plasma; Vz/F = apparent volume of distribution during terminal 
phase. 


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Taking into account the small numbers and different subjects, the geometric mean values 
for Cmax, AUC(0-t), and AUC(inf) are not different for the SAD and MAD cohorts.  Within 
the MAD, there is good agreement between Days 1 and 14 at all dose groups.  There is no 
accumulation — the geometric mean Cmax and AUC(0-24) on Days 1 and 14 are not 
different, consistent with the t½ (~2 hour) and dosing interval (24 hours) (Figure 4; 
Table 3).  
Figure 4: 
Arithmetic mean ± standard error plasma concentrations of 
vamorolone (VBP15) on Days 1 and 14 during oral administration of 
1, 3, 9, and 20 mg/kg doses once daily for 14 days to healthy subjects 
under fasted conditions (linear axes) 
 
 
1.3.1.2.2 
MAD Cohorts – Adverse Events 
Three subjects have discontinued dosing; one subject (1.0 mg/kg/day group) withdrew 
consent on Day 10 so that he could receive care for an exacerbation of a previously 
existing dental condition.  Dosing was discontinued in a second subject on Day 9 (on 
placebo in the 1.0 mg/kg/day cohort after completing 8 days of dosing) due to an increase 
in alanine aminotransferase (ALT).  The subject’s baseline value was 40 (normal ≤ 50); 
on Days 7, 8, and 9, it was 70, 86, and 106, respectively.  Following cessation of dosing, 
the ALT has slowly declined and is continuing to be followed.  Aspartate 


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aminotransferase (AST) was within normal limits with the exception of a value of 47 on 
Day 9 (normal ≤ 45), which was again normal the following day.  Alkaline phosphatase, 
bilirubin, and coagulation parameters have remained within normal limits and the subject 
has remained asymptomatic.  A third subject who was on active drug in the 20 mg/kg 
dose group was discontinued after 9 days of dosing due to an increase in ALT.  The 
subject’s baseline value was 43 (normal ≤ 50) at screening; on Days 7, 8, and 9, it was 
56, 60, and 73, respectively.  Following cessation of dosing, the ALT increased to 96 and 
104 on Days 10 and 12; on Day 17, it had declined to 85.  The subject continues to be 
followed and has remained asymptomatic.  Aspartate aminotransferase was within 
normal limits with the exception of a value of 47 on Day 12 (normal ≤ 45); total bilirubin 
was 0.7 at screening (normal 0.2-1.2); it was increased at 1.4, 1.9, and 1.4 on Days 1, 2, 
and 3, respectively, and within normal limits for the remainder of dosing and follow-up.  
No subject in the 3.0 or 9.0 mg/kg/day cohorts had to discontinue dosing for an AE. 
1.3.1.2.3 
Pharmacodynamic Safety Biomarkers 
Vamorolone has shown improved safety profiles relative to prednisone in pre-clinical 
testing, both in vitro and in vivo.15,17  Safety concerns with glucocorticoids include 
suppression of the adrenal axis and insulin resistance.  Pharmacodynamic biomarker 
assays of suppression of the adrenal axis (serum cortisol) and insulin resistance (serum 
glucose) were measured in the Phase I MAD studies of vamorolone. 
Suppression of the adrenal axis.  Prednisone directly impinges on cortisol regulatory 
pathways (adrenal axis) both acutely and chronically.  Acute suppression of adrenal 
function is seen within hours of doses of a single 0.1 mg/kg/day (approximate) dose of 
prednisone, as evidenced by reductions in adrenocorticotropic hormone (ACTH) levels in 
normal volunteers.25  More chronic suppression of the adrenal axis, characterized as 
severe, is typically diagnosed when morning cortisol is < 100 nmol/L (< 3.6 
microgram/dL) when drawn > 24 hrs after the last dose of pharmacological steroids. 
Morning serum cortisol levels were measured in the vamorolone Phase I MAD cohorts, at 
baseline (prior to drug administration), 24 hours after the first dose (Day 1), and 24 hours 
after the 14-day dose (Day 15) (Figure 5).  Active substance volunteers at four MAD 


Vamorolone 
20 January 2017 
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dose levels are shown (1.0 mg/kg/day; 3.0 mg/kg/day; 9.0 mg/kg/day; 20.0 mg/kg/day); 
all subjects were treated for 14 days with daily dosing.  The red hatched line on each 
graph shows a typical threshold for adrenal axis suppression (< 100 nmol/L, or 
< 3.6 µg/dL).  P values shown are for paired T test, indicating significance of the 
consistency of longitudinal changes of subjects relative to their own individual baseline 
values.  Acute adrenal axis suppression is measured at 24 hours (after first dose), whereas 
chronic adrenal axis suppression is measured after 14 days of daily dosing (24 hours after 
last dose).  
Figure 5:  
Morning cortisol measures in the vamorolone Phase I MAD 
volunteers.* 
* Placebo subjects from each of the four MAD cohorts are graphed together.   
Vamorolone showed little evidence of either acute (24 hour data), or chronic (Day 15 
data) suppression of the adrenal axis at doses of either 1.0 mg/kg/day or 3.0 mg/kg/day.  
The data suggest that vamorolone induces variable, mild, acute and chronic suppression 
of the adrenal axis at 9.0 mg/kg/day, and stronger evidence of both acute and chronic 
adrenal axis suppression at 20.0 mg/kg/day.  Prednisone typically shows both acute and 
chronic adrenal axis suppression approximately at 0.1 mg/kg/day,25 suggesting that 
vamorolone has an improved safety window regarding adrenal axis suppression. 


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Vamorolone thus shows approximately a 100-fold improvement in safety window 
compared to prednisone on a mg/kg comparative basis.  These data are consistent with in 
vitro and ex vivo pre-clinical mouse data comparing VBP15/vamorolone to prednisone 
for adrenal suppression.15 
Insulin resistance.  Prednisone induces the safety signal of insulin resistance, where 
glucose is not efficiently taken up from the blood by target tissues, such as muscle and 
liver, leading to hyperglycemia.25  Insulin resistance may be an important safety signal 
for dystrophic muscle, where the dysfunctional myofibers have been shown to have 
inadequate energy stores,18,26 and insulin resistance likely limits availability of glycogen 
substrates for glycolysis.  The hyperglycemia, in turn, leads to chronic increases in 
insulin levels (hyperinsulinemia).   
Levels of fasting glucose and insulin are reasonably sensitive and reliable measures of 
insulin resistance in non-diabetic individuals.  Glucose is acutely (single dose) and 
chronically (multiple doses) elevated after treatment with pharmacological 
glucocorticoids.  Glucose is elevated 24 hours after a single administration of 
glucocorticoids (2.0 mg/kg).27,28 
In the Phase I MAD of vamorolone, fasting serum glucose was measured at 10 time 
points during the 2-week study; each sample was taken 24 hours after the previous dose 
of vamorolone (Figure 6). 


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Figure 6:  
Fasting serum glucose during the Phase I MAD period (two weeks daily 
treatment) 
 
Glucose levels for all vamorolone dose groups were similar to those of the placebo group.  
There was no evidence of elevations of glucose levels at any time point or any dose of 
vamorolone, suggesting that the side effect of insulin resistance was not seen with 
vamorolone.  These data are consistent with a pre-clinical study in a dystrophin-deficient 
mouse model, where chronic treatment of prednisolone (5 mg/kg/day) versus vamorolone 
(15 mg/kg/day; 30 mg/kg/day) showed development of insulin resistance with 
prednisolone, but not vamorolone.29 
1.3.1.3 
Summary of Phase I data 
In summary: 
 Vamorolone PK data show strong adherence to dose linearity and dose 
proportionality, with relatively little subject-subject variation (both SAD and 
MAD). 
 The half-life was about 2 hours for doses 0.1-1.0 mg/kg.  Doses at 3.0, 8.0, and 
20.0 mg/kg showed an extended tail, increasing half-life to 2.5, 3.8, and 3.8 hours, 
respectively.  The PK for the MAD cohorts was very similar to the SAD cohorts, 


Vamorolone 
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showing little if any drug accumulation, consistent with the short half-life and daily 
dosing schedule. 
 For the food effect group, a high fat meal was given to a cohort of Phase I SAD 
volunteers with the 8.0 mg/kg dose of vamorolone.  These data were then compared 
to the fasted 8.0 mg/kg cohort data.  The comparison showed that absorption was 
increased by 2.5-fold by the high fat meal, consistent with the lipophilic character 
of vamorolone (steroidal compound). 
 For the MAD cohorts, there were no AEs precluding further escalations in dosing.   
 Regarding the primary target organ, liver, one subject on placebo in the 1.0 
mg/kg/day cohort and one subject on vamorolone in the 20 mg/kg/day cohort 
showed mild elevations of liver enzymes, and drug dosing was halted.  No subjects 
in the 3.0 or 9.0 mg/kg/day MAD cohorts showed elevations of liver enzymes. 
 Safety PD biomarker studies showed that vamorolone had an improved safety 
window for adrenal axis suppression (100-fold increase in therapeutic window), and 
no evidence of insulin resistance, compared to prednisone studies reported in the 
literature. 
The results show that the half-life of vamorolone is very similar to glucocorticoids, such 
as prednisone.  Despite the short half-life, prednisone is typically given once per day for 
most indications (including DMD), and once daily dosing is also proposed for 
vamorolone.  Previous studies of increasing the frequency of drug administration of 
glucocorticoids have shown that this has increased side effect profiles without a 
significant gain in efficacy.  Thus, the mechanism of action of glucocorticoids may be 
related to the short-term (pulsed) daily drug exposure.  As vamorolone is thought to share 
a similar anti-inflammatory mechanism of action as glucocorticoids (NF-κB inhibition), it 
is felt that the daily pulsed exposure in the Phase I MAD is most relevant to the planned 
clinical trials in DMD including the Phase II MAD and Phase II efficacy/safety studies, 
where daily dosing schedules will be followed.  The option of increasing the dosing 
regimen in the Phase I MAD to better study drug accumulation and steady state PD was 
considered, but this was felt to be unrelated to planned Phase II trials, and drug 
mechanism of action. 


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1.4 
Rationale for Study Design 
Vamorolone is under development for the treatment of DMD.  The first-in-human clinical 
assessment of vamorolone is in the SAD/MAD study (VBP15-001) and is providing an 
initial clinical assessment and assessment of the PK characteristics of vamorolone 
following administration of an oral suspension of vamorolone in healthy adult subjects.  
While there are likely to be some differences between adults and children, and between 
healthy and DMD subjects, the data from VBP15-001 have established the 2-4 hour half-
life of vamorolone, food effect, dose proportionality and variability between subjects. 
The current study is designed to determine the safe and tolerable dose(s) to enable future 
studies with chronic administration in DMD subjects, ages 4-< 7 years.  The narrow age 
window for this study is driven by several factors: 1) the average age of diagnosis is still 
approximately 4.8 years due to lack of screening programs; 2) the current standards of 
clinical care in Western countries, where glucocorticoid therapy is typically initiated 
between 5 and 7 years of age for DMD patients; and 3) the observation that peak function 
for DMD patients occurs at around 7 years (after which time most affected males with 
DMD will begin to decline), all of which result in a narrow age window to identify 
steroid-naïve males with DMD. 
The starting dose level of 0.25 mg in this study is one quarter of the dose of 1 mg, which 
was administered to healthy adult males in the MAD, resulting in an AUC0-24hr of 
794 ng x hr/mL on Day 14. The maximum proposed dose in this study of 6 mg/kg is 
lower than the 9 mg/kg dose administered to healthy adult males in the MAD which  
resulted in an AUC0-24hr of 4366 ng x hr/mL, which is the lowest dose at which possible 
adrenal suppression was seen..  Thus, this range of doses seems appropriate to test in the 
first-in-patient study of vamorolone.29 
Key safety parameters in conjunction with PK data will be evaluated during the course of 
the study to assess vamorolone safety and tolerability. 
Placebo has not been included in this initial study in DMD for the following reasons:  
1) AE incidence versus placebo will have already been assessed for both single and 


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multiple doses in the prior SAD/MAD study VBP15-001; 2) the rarity of this disease 
makes it difficult to recruit large numbers of patients across the entire program; 3) as 
specified above, the patient pool is reduced further due to the narrow window of 
opportunity to enroll DMD boys not yet receiving glucocorticoids between the ages of 4 
and 7 years; and 4) there are increasing numbers of DMD clinical studies using drugs of 
different modalities, all competing for the same population, i.e., those boys most likely to 
benefit and show a response.  
The trial design includes the study of acute and chronic responses of PD biomarkers 
bench-marked against historical prednisone PD biomarker data.  Acute responses in the 
Phase I study (hours after a single dose) will be studied in back-up PK samples on Day 1, 
to generate data on 17-hydroxyprogesterone and ACTH (adrenal axis suppression), 
insulin and glucose (insulin resistance), and osteocalcin (bone turn over), and data 
compared to prednisone-treated subjects in Kauh et al. (2012).25  Chronic responses of 
PD biomarkers will be studied after 2 weeks of vamorolone treatment, and 2 weeks of 
wash out.  Samples will be studied for glucocorticoid-responsive biomarkers in DMD 
patients previously defined in the Cooperative International Neuromuscular Research 
Group (CINRG) Duchenne Natural History Study.30  Exploratory PD biomarkers 
examining tissue breakdown and repair will also be evaluated. 
The rationale for assessing acutely-responsive glucocorticoid PD biomarkers (back-up 
PK samples) is as follows.  Kauh et al. (2012)25 reported acutely-responsive serum 
glucocorticoid biomarkers after a single morning fasted dose of prednisone (dose groups: 
0, 0.13 mg/kg, 0.33 mg/kg, 0.8 mg/kg) in adult volunteers. 
They found that established biomarkers for known safety signals for glucocorticoids 
showed marked changes in blood levels within a few hours of a single dose of 
prednisone.  These included: 
 Reductions in ACTH with all doses, reflecting adrenal axis suppression 
 Increased insulin and glucose with all doses, reflecting impaired insulin 
suppression of hepatic glucose production, and insulin resistance 


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 Decreased osteocalcin (bone turnover marker) at all doses, reflecting 
perturbations of bone remodeling 
Nonclinical studies of vamorolone treatment of mice have shown that vamorolone does 
not show the glucocorticoid PD signals of adrenal axis suppression, insulin resistance, 
and increased bone turnover.  Thus, we anticipate that DMD patients will similarly not 
show these same PD signals.  To monitor the glucocorticoid PD biomarkers reflective of 
adrenal axis suppression, insulin resistance, and bone turnover, serum samples from this 
Phase II study of vamorolone in young DMD boys will be assayed for these same 
biomarkers as in the studies by Kauh et al. (2012).25 
In addition to these acutely-responsive glucocorticoid biomarkers, a panel of biomarkers 
in DMD patient sera that show response to chronic (~4 month) treatment with 
glucocorticoids has been identified.  These chronic prednisone PD biomarkers were 
discovered through study of serum samples of DMD patients enrolled in the CINRG 
Duchenne Natural History Study.  SomaScan aptamer panels testing 1,200 serum proteins 
were used to discover a candidate set of prednisone-responsive biomarkers; a subset of 
these were validated in a longitudinal sample set (individual DMD patients pre/post 
steroid treatment).  These PD biomarkers were assigned to a safety panel or efficacy 
panel based on comparison to normal controls and information concerning the function of 
each protein (Table 4).  All safety biomarkers were validated in a separate cohort of 
pediatric inflammatory disease patients (longitudinal pre/post steroids).  The same 
SomaScan assay will be used on the chronic samples from the vamorolone Phase IIa trial 
(entry, 2 weeks treatment, 2 weeks washout), with initial data analyses limited to those 
validated biomarkers shown (Table 4). 


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Table 4: 
Biomarkers previously defined to be responsive to chronic doses of 
glucocorticoids in DMD boys 
Chronic safety 
Assay method 
Chronic efficacy 
Assay method 
MMP-3  
SomaScan 
CD23 
SomaScan 
Leptin  
SomaScan 
MDC 
SomaScan 
Insulin  
SomaScan 
IL-22BP 
SomaScan 
IGFBP-5  
SomaScan 
Lymphotoxin a1/b2 
SomaScan 
Angiotensinogen  
SomaScan 
IGFBP-2 
SomaScan 
Afamin 
SomaScan 
Integrin a1b1; CD49a 
SomaScan 
17-hydroxyprogesterone 
LC-MS 
MMP-12 
SomaScan 
Corticosterone 
LC-MS 
 
 
Testosterone 
LC-MS 
 
 
11-deoxycortisol 
LC-MS 
 
 
 
Adrenal axis suppression is a well-documented safety signal with chronic use of 
glucocorticoids.  As noted above, pre-clinical data suggest that vamorolone may not 
cause adrenal axis suppression.  To test if two weeks of vamorolone treatment causes 
chronic adrenal axis suppression, four steroid hormones will be tested by liquid 
chromatography-mass spectrometry (LC-MS) in the vamorolone-treated DMD boys 
(17-hydroxyprogesterone, corticosterone, testosterone, 11-deoxycortisol) (Table 4).  All 
four steroid hormones showed significant reductions after glucocorticoid treatment in 
DMD boys in the cross-sectional and longitudinal CINRG Duchenne Natural History 
Study. 
It is obligatory that the Investigator become familiar with all sections of the Vamorolone 
Investigator’s Brochure.29 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
The primary objective of this study is: 
To evaluate the safety and tolerability of multiple ascending oral doses of 
vamorolone in ambulant boys ages 4-< 7 years with DMD. 
2.1.2 
Secondary Objectives 
The secondary objectives of this study are: 
1. To investigate the single-dose and multiple-dose PK of oral vamorolone at 
multiple dose levels in ambulant boys ages 4-< 7 years with DMD; 
2. To investigate the effects of single and multiple oral doses of vamorolone on 
serum PD biomarkers in ambulant boys ages 4-< 7 years with DMD; 
3. To evaluate metabolites of vamorolone in Metabolites in Safety Testing (MIST) 
assessments following administration of multiple ascending oral doses. 
2.1.3 
Exploratory Objective 
The exploratory objective of this study is: 
1. To investigate the effect of multiple oral doses of vamorolone on muscle strength, 
mobility, and functional exercise capacity, as measured by Quantitative Muscle 
Testing (QMT), Time to run/walk 10 meters Test (TTRW), Time to Stand Test 
(TTSTAND), Time to Climb Test (TTCLIMB), North Star Ambulatory 
Assessment (NSAA), and Six-minute Walk Test (6MWT) in ambulant boys ages 
4-< 7 years with DMD. 


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20 January 2017 
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2.2 
Study Endpoints 
2.2.1 
Safety Endpoints 
1. Treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs), by system organ class (SOC): overall by treatment, by treatment 
and relationship, by treatment and outcome, and by treatment and intensity 
(Common Terminology Criteria for Adverse Events [CTCAE] grade) (see 
Section 7.2.6); 
2. Vital sign [supine blood pressure (BP), heart rate, respiratory rate, oral 
temperature] values: change from Pretreatment to each of the scheduled on-
treatment and post-treatment assessment time points; 
3. Body weight: change from Pretreatment to each of the scheduled on-
treatment and post-treatment assessment time points; 
4. Clinical laboratory values: change from Pretreatment to each of the 
scheduled on-treatment and post-treatment assessment time points in: 
 Hematology and biochemistry 
 Lipid profile (triglycerides, total cholesterol, low density lipoprotein 
[LDL], high density lipoprotein [HDL]) 
 Urinalysis (urine protein and glucose); 
5. Concentrations of serum metabolites of vamorolone; 
6. 12-lead electrocardiogram (ECG) results: change from Pretreatment to Day 
14 and Day 28; and 
7. Physical examination findings of abnormality. 
2.2.2 
Pharmacodynamic Endpoints 
1. Concentration of acute and chronic serum PD biomarkers (change from 
Pretreatment to on-treatment and post-treatment time points): osteocalcin, 
serum aminoterminal propeptide of type I collagen (P1NP), carboxy-
terminal telopeptide (CTX), cortisol, ACTH, 17-hydroxyprogesterone, 
testosterone, corticosterone, and 11-deoxycortisol, insulin, and glucose. 


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 Samples will also be collected for additional SomaScan and proteomics 
profiling. 
2.2.3 
Exploratory Clinical Efficacy Endpoints 
All exploratory clinical efficacy measures are assessed as change from Pretreatment to 
each of the scheduled on-treatment and post-treatment assessment time points: 
1. Quantitative Muscle Testing (QMT): unilateral elbow and knee muscle 
flexion and extension; 
2. Time to Stand Test (TTSTAND) from a supine position; 
3. Time to Climb 4 Steps Test (TTCLIMB); 
4. Time to Run/Walk 10 meters Test (TTRW); 
5. North Star Ambulatory Assessment (NSAA); and 
6. Six-minute Walk Test (6MWT). 
2.2.4 
Endpoints for Subject Reported Outcomes  
Safety endpoints based on subject reports of adverse experiences are listed in 
Section 2.2.1.  Additionally, subjects will be asked to assess acceptability of vamorolone 
by a 5-point hedonic scale.  No other subject reported outcomes are planned. 
2.2.5 
Pharmacokinetic Endpoints 
Plasma PK parameters derived from serial blood samples collected 0.5 hour pre-dose and 
1, 2, 4, 6, and 8 hours after the first and final doses of study drug on Day 1 and Day 14 
(see Section 7.5). 
3 
STUDY DESIGN 
3.1 
Overall Study Design 
This is a Phase IIa, multiple site, open-label, multiple ascending dose study to evaluate 
the safety, tolerability, PK, PD biomarker responsiveness, and exploratory clinical 
efficacy of vamorolone administered once daily by liquid oral suspension over a 
Treatment Period of 14 days to ambulant boys ages 4-< 7 years with DMD. 


Vamorolone 
20 January 2017 
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The study is comprised of a Pretreatment Screening Period of up to 26 days duration, a 
1-day Pretreatment Baseline Period, a 14-day Treatment Period, and a 14-day Follow-up 
Period.  Four dose level groups of approximately 12 subjects each will receive 
vamorolone once daily for 14 days (Table 5).  The planned dose levels are 0.25 mg/kg 
(Dose Level Group 1), 0.75 mg/kg (Dose Level Group 2), 2.0 mg/kg (Dose Level Group 
3), and 6.0 mg/kg (Dose Level Group 4). 
Table 5: Dose level group composition 
Planned Dose Level 
Group 
No. Subjects in Dose 
Level Group 
Vamorolone Dose 
Treatment Duration 
1 
12 
0.25 mg/kg 
14 days 
2 
12 
0.75 mg/kg 
14 days 
3 
12 
2.0 mg/kg 
14 days 
4 
12 
6.0 mg/kg 
14 days 
 
Subjects will be enrolled into this study only after completion of all Pretreatment 
Screening and Baseline assessments. 
3.2 
Dose Escalation Plan 
Treatment of the approximately 12 subjects in each dose level group will be completed 
and safety results evaluated prior to enrollment of subjects in each subsequent dose level 
group.  The process of dose escalation will be based on the appearance of dose-limiting 
toxicities.  See Section 8.3 for definitions of dose-limiting toxicities.  
Subjects may be screened for eligibility up to 26 days in advance of the anticipated start 
of dosing.  The first two subjects in Dose Level Group 1 may be entered immediately 
upon completion of screening.  The first two subjects in subsequent dose level groups 
may be entered immediately upon completion of screening and the decision of escalation 
to the next dose.  Screening for next subjects may occur when at least 11 of the 
approximately 12 enrolled and treated subjects have completed the 2-week Treatment 
Period and are being monitored in the 14-day Follow-up Period.  If fewer than two of the 
approximately 12 subjects at any dose level experience a dose-limiting toxicity, following 
review of the available safety data for the Treatment and Follow-up Periods for all 


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subjects at a given dose level by the Study Chair and Medical Monitor, the Study Chair 
and Medical Monitor will jointly decide whether to recommend dose escalation to the 
next dose level.  If two or more subjects at any dose level experience a dose-limiting 
toxicity, the Medical Monitor and Study Chair will be notified, and enrollment and 
dosing at that dose level will be halted; the MTD will be defined as the previous dose 
level, unless the decision is made to study lower intermediate dose level(s).  The DSMB 
will be informed promptly of any dose decisions which are a result of dose-limiting 
toxicities.   
If dose escalation is terminated due to dose-limiting toxicities, the remaining dose level 
groups may be enrolled to evaluate the safety and PK effects of vamorolone at lower 
intermediate dose level(s).  Once safety data from additional dose level group(s) are 
assessed, the MTD will be defined as the dose level below the dose at which the DSMB 
determines there to be an unacceptable risk to subjects.  This plan allows the maximum 
number of safe dose level groups to have sufficient numbers for overall estimates of 
safety, PK, PD and baseline assessments of preliminary efficacy outcomes to be followed 
via an extension study (VBP15-003). 
Each dose level group of approximately 12 subjects will be assessed for safety and 
tolerability, PK, clinical efficacy, and PD during the 14-day Treatment Period and a 14-
day Follow-up Period.  Treatment Period study visits will occur on Day 1, Week 1(Day 
7), and Week 2 (Days 13 and 14).  During the Follow-up Period, a scheduled telephone 
contact will be made by site study staff on Week 3 (Day 21), and a final study site visit 
will occur on Week 4 (Day 28).  Subjects will receive their first and final doses of study 
medication on Day 1 and Week 2 (Day 14), respectively, at the study site; blood will be 
drawn for PK analysis 0.5 hours pre-dose, and 1, 2, 4, 6, and 8 hours post-dose on Day 1 
and Week 2 (Day 14).  Blood will be collected for MIST assessment 0.5 hours pre-dose 
and 1, 2, 4, 6, and 8 hours post-dose at Week 2 (Day 14).  Once-daily study drug dosing 
on Days 2-13 will occur at home.  Additional blood and urine samples for clinical 
laboratory tests and serum PD biomarkers will be collected at scheduled visits throughout 
the study (see Section 6.3 for detailed assessment schedule).  A physical examination and 


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12-lead ECG will be recorded at Screening, Week 2 (Day 14), and the final Week 4 (Day 
28) Follow-up Visit.  Exploratory clinical efficacy will be assessed by QMT, TTRW, 
TTSTAND, TTCLIMB, NSAA, and 6MWT at Screening and Baseline, Week 2 
(Day 13), and the final Week 4 (Day 28) Follow-up Visit.  Vital signs will be recorded at 
each study visit.  Adverse events, including SAEs, and concomitant medications will be 
recorded throughout the study.  Subjects will be discharged from the study following 
completion of all Week 4 (Day 28) Follow-up assessments.  In the event that any clinical 
or laboratory parameters remain abnormal at the time of discharge from the study, the 
subject will be followed medically as clinically indicated. 
Subjects who have completed the 2-week Follow-up Period may choose to receive 
vamorolone in an open-label extension study under a separate clinical protocol 
(VBP15-003) or receive standard of care treatment (including glucocorticoids) for DMD.  
Subjects choosing to enroll in the vamorolone extension study will receive the same dose 
of vamorolone in the extension study as they received in the current study VBP15-002. 
3.3 
Study Summary 
This Phase IIa study is an open-label, multiple ascending dose study to evaluate the 
safety, tolerability, PK, PD, and exploratory clinical efficacy of vamorolone 0.25 mg/kg, 
0.75 mg/kg, 2.0 mg/kg, or 6.0 mg/kg administered daily by liquid oral suspension over a 
Treatment Period of 14 days to ambulant boys ages 4-< 7 years with DMD. 
The study is comprised of a Pretreatment Screening Period of up to 26 days duration, a 
1-day Pretreatment Baseline Period, a 14-day Treatment Period, and a 14-day Follow-up 
Period. 
4 
SELECTION AND WITHDRAWAL OF STUDY SUBJECTS 
4.1 
Subject Screening and Enrollment 
Subjects will be recruited through the clinics of participating site investigators and other 
mechanisms including, but not limited to: posting on www.clinicaltrials.gov, posting on 
the Sponsor and/or designee website, and patient foundations.  After identification of a 


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possible subject, the site investigator will discuss the study with the subject’s parent or 
legal guardian.  The subject’s parent or guardian will be provided with a copy of the 
informed consent document and allowed time to consider participation prior to signing.  
Individuals interested in participating will be asked to come to one of the participating 
study sites to complete the informed consent process with a site investigator or designee 
prior to initiation of screening procedures.  Subjects will not be excluded on the basis of 
race, ethnicity, or age, except that the target population for the trial is 4-< 7 years of age. 
A subject screening log will be maintained at each investigational site for all subjects 
who are considered for the study, including those not enrolled.  Limited data will be 
collected for these subjects, including initials, date of birth, and reason for exclusion from 
the study.  Subject screening and enrollment logs will be maintained for all subjects 
enrolled in the study.  These logs will be reviewed during routine monitoring calls and/or 
visits. 
4.2 
Inclusion Criteria 
To qualify for enrollment in this study, the subject must satisfy the following inclusion 
criteria: 
1. Subject’s parent or legal guardian has provided written informed consent/Health 
Insurance Portability and Accountability Act (HIPAA) authorization prior to any 
study-related procedures; 
2. Subject has a confirmed (by Central Genetic Counselor) diagnosis of DMD as 
defined as: 
a. Dystrophin immunofluorescence and/or immunoblot showing complete 
dystrophin deficiency, and clinical picture consistent with typical DMD, OR 
b. Identifiable mutation within the DMD gene (deletion/duplication of one or 
more exons) where reading frame can be predicted as ‘out-of-frame’, and 
clinical picture consistent with typical DMD, OR 
c. Complete dystrophin gene sequencing showing an alteration (point mutation, 
duplication, other) that is expected to preclude production of the dystrophin 


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protein (i.e. nonsense mutation, deletion/duplication leading to a downstream 
stop codon), with a typical clinical picture of DMD; 
3. Subject is ≥ 4 years and < 7 years of age at time of enrollment in the study; 
4. Subject is able to complete the Time to Stand Test (TTSTAND) without assistance, 
as assessed at the Screening and Baseline Visits; 
5. Clinical laboratory test results are within the normal range at the Screening Visit, or 
if abnormal, are not clinically significant, in the opinion of the Investigator.  (Note: 
Serum gamma glutamyl transferase [GGT], creatinine, and total bilirubin all must 
be ≤ upper limit of the normal range at the Screening Visit);  
6. Subject has evidence of chicken pox immunity as determined by presence of IgG 
antibodies to varicella, as documented by a positive test result from the testing 
laboratory at the Screening Visit; and 
7. Subject and parent/guardian are willing and able to comply with scheduled visits, 
study drug administration plan, and study procedures. 
4.3 
Exclusion Criteria 
A subject will be excluded from enrollment in this study if the subject meets any of the 
following exclusion criteria: 
1. 
Subject has current or history of major renal or hepatic impairment, diabetes 
mellitus or immunosuppression; 
2. 
Subject has current or history of chronic systemic fungal or viral infections; 
3. 
Subject has had an acute illness within 4 weeks prior to the first dose of study 
medication; 
4. 
Subject has used mineralocorticoid receptor agents, such as spironolactone, 
eplerenone, canrenone (canrenoate potassium), prorenone (prorenoate 
potassium), mexrenone (mexrenoate potassium) within 4 weeks prior to the first 
dose of study medication; 
5. 
Subject has evidence of symptomatic cardiomyopathy.  [Note: Asymptomatic 
cardiac abnormality on investigation would not be exclusionary]; 


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6. 
Subject is currently being treated or has received previous treatment with oral 
glucocorticoids or other immunosuppressive agents.  [Notes: Past transient use of 
oral glucocorticoids or other oral immunosuppressive agents for no longer than 3 
months cumulative, with last use at least 3 months prior to first dose of study 
medication, will be considered for eligibility on a case-by-case basis.  Inhaled 
and/or topical corticosteroids prescribed for an indication other than DMD are 
permitted but must be administered at stable dose for at least 3 months prior to 
study drug administration]; 
7. 
Subject has used idebenone within 4 weeks prior to the first dose of study 
medication; 
8. 
Subject has an allergy or hypersensitivity to the study medication or to any of its 
constituents; 
9. 
Subject has severe behavioral or cognitive problems that preclude participation 
in the study, in the opinion of the Investigator; 
10. Subject has previous or ongoing medical condition, medical history, physical 
findings or laboratory abnormalities that could affect safety, make it unlikely that 
treatment and follow-up will be correctly completed or impair the assessment of 
study results, in the opinion of the Investigator; 
11. Subject is taking any other investigational drug currently or has taken any other 
investigational drug within 3 months prior to the start of study treatment; or 
12. Subject has previously been enrolled in the study. 
Note:  Any parameter/test may be repeated at the Investigator’s discretion during 
Screening and/or Day -1 to determine sustainability and reproducibility.  In addition, 
subjects may be rescreened if ineligible due to a transient condition which would prevent 
the subject from participating, such as an upper respiratory tract infection, or if ineligible 
due to negative anti-varicella IgG antibody test result (see Section 7.2.4 for vaccination 
and retest parameters). 


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5 
STUDY TREATMENT 
5.1 
Study Medication Administered 
Vamorolone will be administered to all subjects as an oral liquid suspension.  The 
suspension formulation utilized for this study is the same as that utilized in the Phase I 
clinical trial in adult volunteers. 
Planned vamorolone dose levels: 0.25 mg/kg, 0.75 mg/kg, 2.0 mg/kg, and 6.0 mg/kg. 
For each Dose Level Group 1-4, vamorolone will be administered once daily for 14 days, 
from Study Day 1 through Study Day 14. 
5.2 
Identity of Investigational Product 
The Study Sponsor will supply the following investigational study medication: 
Name: 
Vamorolone 
Active Substance: 
VBP15 
Strength: 
4% by weight 
Dosage Form: 
Oral suspension 
Manufacturer: 
Velesco Pharma 
5.3 
Dosage Schedule and Administration of Study Medication 
Subjects who meet all eligibility criteria (see Sections 4.2 and 4.3) and complete all 
Baseline assessments will be enrolled into the study.  The unique subject study number 
assigned to the subject during the Screening Period will carry forward with the subject 
after enrollment.  Subjects must meet all eligibility criteria to qualify for initial dosing in 
the study.  Subjects will be enrolled just prior to receiving the initial dose of study 
medication. 
The site pharmacist or designated site study staff will dispense study medication in 
100 mL bottles sufficient for 16 days of oral dosing to each subject enrolled in the study 
after completion of all Baseline assessments and enrollment into the study.  Bottles will 
be fitted with adaptors by the site pharmacist or designated site study staff prior to 


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dispensing.  The number of 100 mL bottles to be dispensed to each subject depends on 
subject weight and the dose level group; see Appendix 15.1 for complete instructions on 
calculating dose volume.  Clinical supplies dispensed by the study site staff and ready for 
administration to subjects will be labeled with subject study number, dispense date, 
protocol number, dose level, volume to dispense per dose, and cautionary statement. 
Enrolled subjects will receive all doses of vamorolone under the supervision of trained 
study staff or parent or legal guardian.  Day 1 and Day 14 doses will be administered at 
the participating study site; all other doses will be administered at home.  Study drug will 
be administered by mouth using a volumetric syringe.  Following administration of the 
dose of study drug, the syringe will be filled once with water and the water will be 
administered by mouth using the volumetric syringe.  The subject will then drink 
approximately 50 mL (approximately 2 ounces) of water to ensure the full dose has been 
ingested.  Subjects should receive each dose of study medication at approximately the 
same time of day. 
On Days 1 and 14 only, the subject will be asked to consume an 8 ounce glass of whole 
milk (or equivalent high fat food portion) and 1 cup of cereal at the study site 30 minutes 
prior to administration of the dose of study medication.  Subjects will be asked to 
consume an 8 ounce glass of whole milk (or equivalent high fat food portion) each day 
prior to dosing during Study Days 2-13.  There are no other food or drink restrictions 
during the study. 
The dose per subject (in mg) throughout the Treatment Period will be calculated based on 
the recorded Screening weight of the subject (in kg) (see Appendix 15.1 for dose 
calculation worksheet).  All missed or incomplete doses will be documented.  The 
dispensed study medication bottle(s) will be returned to the study site at the Week 2 Visit. 
5.4 
Rationale for Dose Selection 
Escalating doses of 0.25 mg/kg, 0.75 mg/kg, 2.0 mg/kg, and 6.0 mg/kg of vamorolone 
were chosen for this study to ensure the safety of subjects enrolled in the study, to allow 
demonstration of PD effects, and to ensure adequate safety in future clinical studies.  All 


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dosing will be done in the morning with a glass of whole milk (8 ounces or 230 mL) or 
similar fat equivalent meal (approximately 8 grams fat).  Dose escalations are 2- to 3-fold 
increases for each subsequent dose level group. 
The rationale for the starting dose of 0.25 mg/kg/day with a glass of whole milk is as 
follows.  As Phase II dosing in 4-< 7 year old DMD children will be done at home in the 
morning, challenges were considered with participant and parent compliance with either 
fasting in the morning (prior to school or other activities), or a rigid prescribed diet of 
known fat content.  To balance compliance with appropriate assessments of 
bioavailability and monitoring of safety, it was decided to administer morning doses at 
home with a glass of whole milk (approximately 8 grams of fat) or similar fat content 
meal. 
From the Phase I study in adult volunteers (VBP15-001), a high fat diet (40 grams) 
increased bioavailability of vamorolone (8.0 mg/kg/day) by 250% compared to the fasted 
cohort at this dose.  Because a formal food effect study has not been done, it must be 
assumed that any fat intake with drug delivery has the potential to have a 250% increase 
in bioavailability vs. the fasted state.  Thus, a conservative approximation of vamorolone 
drug exposure in DMD children when taken with a whole glass of milk is 250% of the 
fasted bioavailability.  A starting dose of 0.25 mg/kg/day with a glass of milk would be 
equivalent to 0.625 mg/kg/day fasted, and this starting dose is 3.1% of the highest safe 
dose tested in adults (20.0 mg/kg/day fasted). 
A starting dose of 0.25 mg/kg/day, with four dose groups increasing by 2 to 3-fold 
increments, leads to dose groups of 0.25, 0.75, 2.0, and 6.0 mg/kg/day.  The highest dose 
tested, 6.0 mg/kg/day, will similarly be given with a glass of milk, with an expected 
increased bioavailability of 250%, or equivalent to 15.0 mg/kg/day fasted.  As 20.0 
mg/kg/day fasted in adult volunteers was shown to be safe in the Phase I adult volunteer 
study, the proposed highest dose in 4-< 7 year old children is approximately 75% of the 
highest safe adult dose.  Based on the Phase I PD biomarker safety data presented in 
Section 1.3, safety signals reflective of insulin resistance are not anticipated at any of the 
planned Phase IIa doses.  Also based on the Phase I data, regarding the safety signal of 


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suppression of the adrenal axis, no evidence of adrenal axis suppression is anticipated at 
the 0.25 mg/kg/day, 0.75 mg/kg/day and 2.0 mg/kg/day doses planned in the Phase IIa 
study, but suppression of the adrenal axis may be observed in the 6.0 mg/kg/day Phase 
IIa dose level group.   
5.5 
Treatment Compliance 
Subject compliance with the dosing schedule will be assessed by site maintenance of 
accurate study drug dispensing and return records, and accurate recording of administered 
doses on all at-home administration days (Study Days 2-13) by completion of a diary by 
the subject’s parent or guardian.  Food and drink consumed prior to dosing on Study 
Days 2-13 will also be recorded in subject diaries.  The Investigator is responsible for 
ensuring that dosing is administered in compliance with the protocol.  The Investigator or 
designee will instruct the subject’s parent or guardian with regard to proper dosing of 
study medication and completion of subject diaries, and will reinforce the importance of 
taking all study medication per protocol instructions.  Doses of study drug on Day 1 and 
Day 14 will be administered at the participating study site by a trained investigational 
staff member.  All complete, incomplete, or missed doses are to be documented in the 
source document and in the appropriate electronic case report form (eCRF). 
5.6 
Study Medication Management 
5.6.1 
Packaging and Labeling of Study Medication 
The site pharmacist or designated study staff will receive clinical trial material (CTM) 
when all regulatory requirements have been completed by the site.  Additional CTM will 
be available upon request.  The Study Sponsor through the designated central pharmacy 
will provide CTM in bulk quantities sufficient to satisfy the protocol requirement.  
Vamorolone will be shipped in bulk to the study site’s registered pharmacist or 
designated study staff in suitably labeled study cartons.  Cartons will contain study 
medication packaged in sterile 100 mL glass bottles; each bottle will contain 4 grams of 
vamorolone as a 4% suspension in sterile water.  Bulk drug supplies will be labeled with 
the name of Sponsor, protocol number, lot number, expiration or retest date, and other 


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appropriate study information.  Carton and bottle labels will include the following 
statement: “Caution: New Drug – Limited by Federal Law to Investigational Use.” 
5.6.2 
Storage of Study Medication 
All CTM for use in the trial must be stored in a locked container/cabinet free from 
environmental extremes, under the responsibility of the study site Investigator or site 
pharmacist.  Bulk CTM should be stored at refrigerated temperature (2°C-8°C; 
36°F-46°F).  Excursions to ambient temperature are allowed.  Access to CTM stored at 
participating study sites must be limited to authorized research personnel. 
5.6.3 
Study Medication Shipping and Handling 
Clinical trial material will be shipped to the study sites only after receipt of required 
documents in accordance with applicable regulatory requirements and Sponsor 
procedures.  Study sites will receive CTM in bulk in sufficient quantity for one subject.  
After a subject is enrolled, the site will be sent CTM in bulk in sufficient quantity for one 
additional subject until the study has completed enrollment. 
Clinical trial material will only be dispensed to the subject once the subject’s 
parent/guardian has (1) a signed informed consent form (ICF) and HIPAA (as applicable) 
authorization on file, (2) met all eligibility criteria for entry into the study, (3) completed 
all screening requirements, and (4) been enrolled. 
It is essential to this study that all CTM be accounted for during the study period.  All 
unused study medication will be retained at the study center for reconciliation and 
collection by the Sponsor's study monitors (or designee) during routine monitoring visits.  
Study site personnel should not dispose of any CTM.  Final disposition of all unused 
CTM will be coordinated by the Sponsor's study monitor (or designee) at the end of the 
study (see Section 5.6.4). 
Clinical trial material must be dispensed and administered according to the procedures 
described in this protocol.  Only subjects enrolled in the study may receive study 
medication, in accordance with all applicable regulatory requirements.  Only authorized 


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study personnel may supply or administer CTM.  Authorized study personnel refers to the 
Investigator (or designee), in accordance with all applicable regulatory requirements and 
the Site Signature Log/Delegation of Authority. 
5.6.4 
Study Medication Accountability 
The site Investigator is responsible for the control of drugs under investigation.  Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained.  The Drug Dispensing Log must be kept 
current and should contain the following information: 
 The identification of the subject to whom the study drug was dispensed. 
 The date(s) and quantity of the study drug dispensed to the subject. 
 The date(s) and quantity of the study drug returned by the subject. 
All records and drug supplies must be available for inspection by the Monitor at every 
monitoring visit.  Unused medication will be returned to the Study Sponsor or its 
designee at the end of the study.  The completed Drug Dispensing Log and Drug Return 
Record(s) will be returned to the Study Sponsor or its designee.  The Investigator’s copy 
of the Drug Return Record(s) must accurately document the return of all study drug 
supplies to the Study Sponsor or its designee. 
5.7 
Procedures for Assigning Subject Study Numbers 
Following the signing of the written ICF, subjects will be assigned a unique site-specific 
6-digit subject study number in sequential order of screening into the study.  The subject 
study number will be assigned by the site at the time of submission of the de-identified 
genetic test and/or muscle biopsy report to the Central Genetic Counselor to confirm that 
the subject meets the diagnostic eligibility criteria.  If the de-identified genetic test and/or 
muscle biopsy report are submitted to the Central Genetic Counselor prior to signing of 
the ICF (only if acceptable per local Institutional Review Board [IRB]/Independent 
Ethics Committee [IEC]), then a screening number will be assigned to the potential 
subject by the Coordinating Center.  Upon signing of the ICF, the site will assign the 


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subject a 6-digit subject study number and notify the Coordinating Center of the newly 
assigned subject number.  
All data will be identified using the unique 6-digit subject study number.  These subject 
study numbers assigned upon signing of the written ICF will be retained through 
enrollment and throughout participation in the study.  Subject study numbers assigned to 
subjects who fail screening may not be used again.   
The Investigator will keep a record relating the names of the subjects to their subject 
study numbers (Subject Identification Log) to permit efficient verification of data subject 
files, when required.  This record will also include the dates of subject enrollment and 
completion/termination.   
6 
STUDY PROCEDURES 
6.1 
Time and Events Schedule 
The study procedures to be conducted for each subject are divided into the following 
study periods: 
 Pretreatment Screening Period:  From subject’s parent or guardian signing of 
the Informed Consent/HIPAA authorization until completion of all designated 
Screening procedures, 48 hours prior to the first dose of study medication. 
 Pretreatment Baseline Period:  The 24-hour period immediately prior to 
administration of the first dose of study medication, which includes completion of 
all Baseline assessments and enrollment into the study.  
 Treatment Period:  The 14-day interval starting with administration of the first 
dose of study medication on Day 1 and continuing through the time of 
administration of the final dose of study medication on Week 2 (Day 14) and 
completion of Week 2 safety, PK, PD, and clinical efficacy assessments. 
 Post-treatment Follow-up Period:  The 14-day interval beginning following 
completion of all Week 2 (Day 14) study assessments and continuing through the 
final Week 4 (Day 28) Follow-up Visit.  Telephone contact to assess safety will 


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be made on Week 3 (Day 21), and final safety, PD, and clinical efficacy 
assessments will be performed at the final Week 4 (Day 28) Visit.  Subjects will 
be discharged from the study following completion of all Week 4 (Day 28) safety, 
PD, and clinical efficacy assessments. 
The procedures to be completed during each study period are presented as the Schedule 
of Study Activities in Table 6 and in the sections that follow.  Detailed descriptions of 
the assessments and the definition of study endpoints are provided in Sections 7 and 2.2.  
Any deviation from study procedures should be noted in the source documents and in the 
eCRF, and significant deviations should be reported immediately to the Sponsor or their 
designee. 
Overall, approximately 8 weeks are allocated for each subject to complete the study, 
including a 26-day Pretreatment Screening Period, a 1-day Pretreatment Baseline Period, 
a 2-week Treatment Period, and a 2-week Post-treatment Follow-up Period. 


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Table 6: 
Schedule of Study Activities 
Pretreatment 
Period 
Treatment Period 
Post-treatment 
Follow-up 
SCR 
BL 
 
Day 
Day 
Week 
Week 
Visit/Contact 
-28 to -3 
-1 
1 
1 
(71d) 
2a 
(141d) 
3 
(212d) 
4b 
(283d) 
Informed Consentc 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
Blood for Chicken Pox Immunity 
Xd 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
X 
Vital Signse 
X 
Xf 
Xf 
X 
Xf 
 
X 
Blood for Clinical Labsg 
X 
 
 
 
X 
 
X 
Urinalysisg 
X 
 
 
 
X 
 
X 
12-lead ECG 
Xh 
 
 
 
Xh 
 
Xh 
Enrollment 
 
X 
 
 
 
 
 
Dispense Study Medication 
 
 
X 
 
 
 
 
Return Study Medication 
 
 
 
 
X 
 
 
Study Medication Dosingi 
 
 
X 
 
X 
 
 
Blood for Plasma PK 
 
Xj 
Xj 
 
Xj 
 
 
Blood for Metabolites in Safety Testing 
(MIST)q 
 
 
 
 
Xq 
 
 
Blood for Serum PD Biomarker Panel 
Xk 
Xl 
Xm 
 
Xl,n 
 
Xn 
Quantitative Muscle Testing (QMT) 
X 
X 
 
 
Xo 
 
X 
Time to Run/Walk 10 Meters Test 
(TTRW) 
X 
X 
 
 
Xo 
 
X 
Time to Stand Test (TTSTAND) 
X 
X 
 
 
Xo 
 
X 
Time to Climb Test (TTCLIMB) 
X 
X 
 
 
Xo 
 
X 
North Star Ambulatory Assessment 
(NSAA) 
X 
X 
 
 
Xo 
 
X 
Six-minute Walk Test (6MWT) 
X 
X 
 
 
Xo 
 
X 
Study Medication Acceptability 
Assessment 
 
 
Xp 
 
Xp 
 
 
Study Medication Accountability 
 
 
 
 
X 
 
 
Safety Monitoring 
 
 
X 
X 
X 
X 
X 
AE/SAE Recording 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
 
X 
X 
X 
X 
X 
Telephone Contact 
 
 
 
 
 
X 
 
Discharge from Study 
 
 
 
 
 
 
X 
SCR=Screening Period; BL=Baseline Period, within 24 hours prior to administration of the first dose of study drug. 
a. 
Subjects who prematurely discontinue from the study prior to Week 2 (Day 14) should complete the Week 2 (Days 
13 and 14) procedures at the time of early discontinuation and enter the 14-day Follow-up Period. 
b. 
Subjects who prematurely discontinue from the study after Week 2 (Day 14) but prior to the scheduled Week 4 
(Day 28) Follow-up Visit should return to the study site for Week 4 (Day 28) procedures. 
c. 
Informed Consent must be obtained prior to any study-related procedures. 
d. 
All subjects will have blood collected at the Screening Visit for testing for IgG antibodies to varicella.  Eligibility 
for study enrollment is dependent upon availability of positive result prior to enrollment. 


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e. 
Supine blood pressure, oral temperature, respiratory rate, and heart rate.  At visits where blood is also drawn, vital 
signs must be recorded prior to blood draws.  
f. 
On Days 1 and 14, vital signs will be recorded at 0.5 hour pre-dose and 0.5, 1, 2, 4, 6, and 8 hours post-dose, prior 
to PK blood draws where time points coincide. 
g. 
Blood for chemistry, hematology, lipids; urinalysis by dipstick and microscopic analysis. 
h. 
ECG must be conducted prior to vital signs.  
i. 
The first dose of study medication on Day 1 and the final dose of study medication on Day 14 will be 
administered in the study clinic; all other doses will be taken at home. 
j. 
Blood collected for plasma PK analysis on Day -1 (0.5 hour pre-dose) and 1, 2, 4, 6, and 8 hours post-dose on Day 
1; and 0.5 hour pre-dose and 1, 2, 4, 6, and 8 hours post-dose on Day 14.  Subjects must be fasting at the time of 
collection of Day 1 and Day 14 pre-dose samples. 
k. 
cortisol, ACTH, P1NP, osteocalcin, CTX, 17- hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol, 
hemoglobin A1c (HbA1c), SomaScan, and proteomics testing. 
l. 
Blood collected for insulin and glucose on Day -1 (0.5 hour pre-dose) and on Day 14 (0.5 hour pre-dose).  Subjects 
must be fasting at the time of blood collection. 
m. Day 1, 6 hours post dose: cortisol, ACTH, P1NP, osteocalcin, CTX, 17- hydroxyprogesterone, testosterone, 
corticosterone, 11-deoxycortisol.  
n. 
Day 14, 6 hours post-dose and Week 4 (Day 28): cortisol, ACTH, P1NP, osteocalcin, CTX, 
17- hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol, SomaScan, and proteomics testing. 
o. 
Week 2 clinical efficacy assessments to be completed on Day 13. 
p. 
Study medication acceptability assessment performed immediately pre-dose (smell) and post-dose (taste). 
q. 
MIST assessment will be performed on portions of the blood samples collected for PK analysis; no additional blood 
will be collected. 
6.2 
Informed Consent/HIPAA Authorization 
Each subject’s parent or guardian will receive an explanation of the nature and purposes 
of the study from the Investigator or designee.  The Investigator or designee will ensure 
the study is appropriate for the subject.  Consent must be obtained in accordance with the 
principles outlined in the current version of the Declaration of Helsinki.  The subject’s 
parent or guardian will confirm that s/he understands that the study is for research 
purposes only and that it may not provide any therapeutic benefit to the individual.  Each 
subject’s parent or guardian will confirm that s/he understands that the subject is free to 
withdraw from the study at any time without prejudice.  The Investigator or designee will 
review the elements of the HIPAA and Protected Health Information (PHI) with each 
subject’s parent or guardian and each subject’s parent or guardian will confirm that s/he 
understands HIPAA authorization and PHI.  The Investigator (or designated staff) will 
obtain the written informed consent and HIPAA authorization on the approved ICF by 
the appropriate IRB/IEC at each site, from the subject’s parent or guardian prior to any 
study-related procedures, including agreement to discontinuation of any prohibited 
medications, prior to the start of the study.  The written assent of children will be 
obtained per individual site guidelines. 


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The ICF must be dated and signed by the Investigator or designee and the subject’s legal 
representative and the original signed consent form must be kept by the Investigator in 
the study subject’s file.  “Legal representative” means an individual or judicial or other 
body authorized under applicable law to consent on behalf of a prospective study subject 
to the subject’s participation in the procedure(s) involved in the research.  The study 
subject’s legal representative will receive a copy of the signed consent form. 
6.3 
Visit Schedule and Procedures 
During the study, there will be a total of 7 study visits: 1) Pretreatment Screening Visit 
(Day -28 to Day -3); 2) Pretreatment Baseline Visit (Day -1); 3) Treatment Period Day 1 
Visit; 4) Treatment Period Week 1 (Day 7) Visit (7 ± 1 day after the first dose of study 
medication); 5) Treatment Period Week 2 (Day 13) Visit (13 ± 1 day after the first dose 
of study medication); 6) Treatment Period Week 2 (Day 14) Visit (14 ± 1 day after the 
first dose of study medication); and 7) a Post-treatment Follow-up Visit at Week 4 (Day 
28) (28 ± 3 days after the first dose of study medication, and approximately 14 days after 
the final dose of study medication).  Additionally, a telephone contact will be made at 
Week 3 (Day 21) (21 ± 2 days after the first dose of study medication).  Each subject will 
receive the investigational product for a period of 14 days.  The Baseline Day -1 and 
Treatment Day 1 procedures may be performed at a single study visit, at the discretion of 
the Investigator and according to study site resources. The Week 2 assessments will be 
divided over a 2-day period (Days 13 and 14), with all exploratory clinical efficacy 
assessments performed on Day 13 and the remainder of the scheduled Week 2 
assessments performed on Day 14.  See Section 7 for a detailed description of the safety, 
clinical efficacy, PD, and PK assessments to be performed in this study. 
6.3.1 
Screening Period (Day -28 to -3) 
The Investigator or study staff will discuss with each subject and the subject’s parent or 
legal guardian, the nature and purpose of the study and the required study procedures.  
The subject’s medical history and medication history will be reviewed to determine initial 
eligibility for participation in the study and the subject’s de-identified dystrophin genetic 
test report and/or muscle biopsy report will be sent to the Central Genetic Counselor(s) 


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for confirmation that the subject meets the DMD diagnostic inclusion criteria.  Following 
the signing of the written ICF, subjects will be assigned a unique site-specific 6-digit 
subject study number that will be comprised of protocol, site, and subject numbers in 
sequential order of screening into the study.  All data will be identified using the unique 
subject study number.  The site Investigator will keep a record relating the names of the 
subjects to their subject study numbers (Subject Screening Log) to permit efficient 
verification of data subject files, when required.  This record will also include the dates of 
subject enrollment and completion/termination.  The Coordinating Center will not collect 
names or other identifiers except dates (of birth, diagnosis, study visits) and the subject 
study number. 
Subjects will undergo the following procedures (the procedures may be completed over 
the course of several visits, if necessary, but all scheduled Screening procedures must be 
completed within the 26-day timeframe designated for the Pretreatment Screening Period 
and the actual date each procedure is performed must be recorded in the source document 
and eCRF).  Any parameter/test may be repeated at the Investigator’s discretion during 
Pretreatment Screening and/or Baseline Day -1 to determine sustainability and 
reproducibility.  In addition, subjects may be rescreened if ineligible due to a transient 
condition which would prevent the subject from participating, such as an upper 
respiratory tract infection.  Any subject who is ineligible due to a negative test result at 
Screening for IgG antibodies to varicella may be vaccinated or revaccinated and return 
for rescreening approximately 30 days after vaccination. 
 Review of the Inclusion and Exclusion Criteria (see Section 4.2 and 4.3) 
 Recording of the medical history, including any toxicities or allergy-related 
events to prior treatments (see Section 7.2.1) 
 Recording of Medication History (see Section 6.4) 
 Complete physical examination, including weight (in kilograms) and height (see 
Section 7.2.2) 
 Recording of vital signs (supine blood pressure, heart rate, oral temperature, 
respiratory rate) (see Section 7.2.3) 


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 Testing for chicken pox immunity (see Section 7.2.4) 
 Clinical labs including hematology, clinical chemistry, lipids, and urinalysis 
tests (see Section 7.2.4) 
 Blood drawn for PD biomarkers including cortisol, ACTH, P1NP, osteocalcin, 
CTX, 17- hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol, 
and hemoglobin A1c (HbA1c).  Blood will also be collected and stored for 
future proteomics profiling and SomaScan studies (see Section 7.3) 
 12-lead ECG (see Section 7.2.5) 
 Quantitative Muscle Testing (QMT) (see Section 7.4.1) 
 Time to Run/Walk Test (TTRW) (see Section 7.4.2) 
 Time to Stand Test (TTSTAND) (see Section 7.4.3) 
 Time to Climb Test (TTCLIMB) (see Section 7.4.4) 
 North Star Ambulatory Assessment (NSAA) (see Section 7.4.5) 
 Six-minute Walk Test (6MWT) (see Section 7.4.6) 
 Recording of AEs and SAEs beginning at the time written informed consent is 
obtained (see Section 7.2.6). 
6.3.2 
Baseline Visit (Day -1) 
Following availability of the results of all Screening eligibility tests, subjects meeting all 
Screening eligibility criteria will return to the study site during the Pretreatment Baseline 
Period (Day -1, the 24-hour interval immediately preceding administration of the first 
dose of study medication) for baseline assessments and study enrollment.  Subjects will 
retain their 6-digit study identification number which was assigned during the Screening 
Period. 
The following procedures will be completed at the Pretreatment Baseline Visit: 
 Recording of Medication History (see Section 6.4) 
 Recording of weight (in kilograms) (see Section 7.2.2) 
 Quantitative Muscle Testing (QMT) (see Section 7.4.1) 
 Time to Run/Walk Test (TTRW) (see Section 7.4.2) 


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 Time to Stand Test (TTSTAND) (see Section 7.4.3) 
 Time to Climb Test (TTCLIMB) (see Section 7.4.4) 
 North Star Ambulatory Assessment (NSAA) (see Section 7.4.5) 
 Six-minute Walk Test (6MWT) (see Section 7.4.6) 
 Enrollment  
 Recording of AEs and SAEs; review of all AEs for resolution status and date (see 
Section 7.2.6) 
6.3.3 
Treatment Period Day 1 Visit 
Treatment Period Day 1 begins with administration of the first dose of study medication.  
The Day 1 Visit occurs on the day following the Baseline Visit.  However, the 0.5 hour 
pre-dose vital signs and PK and PD blood draws must occur at the same visit as the Day 1 
procedures, and therefore are listed below as part of the Day 1 Visit procedures. 
Subjects must have fasted ≥ 6 hours prior to arrival at the study site for Day 1 procedures 
and assessments.  The pre-dose blood draws for PK and PD (insulin and glucose) 
determination must be collected after subjects have fasted for ≥ 6 hours.  Breakfast will 
be served at the study site, prior to administration of the first dose of study medication. 
The following procedures will be completed at the Day 1 Visit: 
Pre-dose Assessments: 
 Recording of vital signs (supine blood pressure, heart rate, oral temperature, 
respiratory rate) at 0.5 hour prior to first dose of study medication (see 
Section 7.2.3) 
 Blood collected for plasma PK analysis at 0.5 hour prior to first dose of study 
medication; subjects must have fasted for ≥ 6 hours prior to blood draw (see 
Section 7.5) 
 Blood samples for PD biomarkers (i.e., insulin and glucose only) at 0.5 hour prior 
to first dose of study medication; subjects must have fasted for ≥ 6 hours prior to 
blood draw (see Section 7.3) 


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 Consumption of an 8 ounce glass of whole milk (or equivalent high fat food 
portion) and 1 cup of cereal 30 minutes prior to administration of the dose of 
study medication. 
 Dispense study medication and subject diaries (see Sections 5.3, 5.6.1, and 5.5) 
 Study Medication Acceptability Assessment (smell) (see Section 7.2.7) 
 Administration of the first dose of study medication (see Section 5.3) 
Post-dose Assessments: 
 Study Medication Acceptability Assessment (taste) (see Section 7.2.7) 
 Recording of vital signs (supine blood pressure, heart rate, oral temperature, 
respiratory rate) at 0.5, 1, 2, 4, 6, and 8 hours post-dose (see Section 7.2.3) 
 Blood samples for PK at 1, 2, 4, 6, and 8 hours post-dose (see Section 7.5) 
 Blood samples for PD biomarkers including cortisol, ACTH, P1NP, osteocalcin, 
CTX, 17- hydroxyprogesterone, testosterone, corticosterone, and 11-deoxycortisol 
at 6 hours post-dose.  (see Section 7.3) 
 Safety monitoring at the participating study site for at least 8 hours after dosing  
 Recording of AEs and SAEs; review of all AEs for resolution status and date (see 
Section 7.2.6) 
 Recording of concomitant medications administered after study medication 
dosing (see Section 6.4) 
The subject will remain at the participating study site for at least 8 hours after 
administration of the first dose of study medication to accommodate PK and PD blood 
sampling and to allow safety monitoring.  Following the 8-hour post-dose assessments, 
the subject, when stable, may leave the center. 
6.3.4 
Treatment Period Week 1 (Day 7) Visit (Day 7 ± 1 day) 
Subjects will return to the study site for the Week 1 (Day 7) safety assessments 
7 days ± 1 day after receiving the first dose of study medication. 
The following procedures will be completed at the Week 1 Visit: 


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 Recording of vital signs (supine blood pressure, heart rate, oral temperature, 
respiratory rate) (see Section 7.2.3) 
 Recording of AEs and SAEs; review of all AEs for resolution status and date (see 
Section 7.2.6) 
 Recording of concomitant medications (see Section 6.4) 
 Return of subject diaries and distribution of new subject diaries (see Section 5.5) 
The subject may leave the center following completion of all scheduled Week 1 
assessments. 
6.3.5 
Treatment Period Week 2 Visits 
6.3.5.1 
Treatment Period Week 2 (Day 13) Visit (Day 13 ± 1 day) 
Subjects will return to the study site on Day 13 (± 1 day after receiving the first dose of 
study medication) for the scheduled Week 2 exploratory clinical efficacy assessments.  
The following assessments will be performed on Day 13: 
 Quantitative Muscle Testing (QMT) (see Section 7.4.1) 
 Time to Run/Walk Test (TTRW) (see Section 7.4.2) 
 Time to Stand Test (TTSTAND) (see Section 7.4.3) 
 Time to Climb Test (TTCLIMB) (see Section 7.4.4) 
 North Star Ambulatory Assessment (NSAA) (see Section 7.4.5) 
 Six-minute Walk Test (6MWT) (see Section 7.4.6) 
The subject may leave the center following completion of all scheduled Day 13 
assessments. 
6.3.5.2 
Treatment Period Week 2 (Day 14) Visit (Day 14 ± 1 day) 
Subjects will return to the study site for the Week 2 (Day 14) safety, PK, and PD 
assessments 14 days ± 1 day after receiving the first dose of study medication.  The final 
dose of study medication will be administered at the Week 2 (Day 14) Visit following 
pre-dose PK and PD blood draws. 


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Subjects must have fasted ≥ 6 hours prior to arrival at the study site for Week 2 (Day 14) 
procedures and assessments.  The pre-dose blood draws for PK and PD (insulin and 
glucose) determination must be collected after subjects have fasted for ≥ 6 hours.  
Breakfast will be served at the study site, prior to administration of the final dose of study 
medication. 
The following procedures will be completed during the Week 2 Visit: 
Pre-dose Assessments: 
 Recording of vital signs (supine blood pressure, heart rate, oral temperature, 
respiratory rate) at 0.5 hour prior to final dose of study medication (see 
Section 7.2.3) 
 Blood samples for PK at 0.5 hour prior to final dose of study medication; subjects 
must have fasted for ≥ 6 hours prior to blood draw (see Section 7.5).  Sample will 
also be used for MIST assessment (see Section 7.2.8). 
 Blood samples for PD biomarkers (i.e., insulin and glucose only) at 0.5 hour prior 
to final dose of study medication; subjects must have fasted for ≥ 6 hours prior to 
blood draw (see Section 7.3) 
 Consumption of an 8 ounce glass of whole milk (or equivalent high fat food 
portion) and 1 cup of cereal 30 minutes prior to administration of the dose of 
study medication. 
 Study Medication Acceptability Assessment (smell) (see Section 7.2.7) 
 Administration of the final dose of study medication (see Section 5.3) 
Post-dose Assessments: 
 Study Medication Acceptability Assessment (taste) (see Section 7.2.7) 
 Complete physical examination, including weight (in kilograms) (see Section 
7.2.2) 
 Recording of vital signs (supine blood pressure, heart rate, oral temperature, 
respiratory rate) at 0.5, 1, 2, 4, 6, and 8 hours post-dose (see Section 7.2.3) 


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 Blood samples for PK at 1, 2, 4, 6, and 8 hours post-dose (see Section 7.5).  
Samples will also be used for MIST assessment (see Section 7.2.8). 
 Clinical labs including hematology, clinical chemistry, lipids, and urinalysis at 8 
hours post-dose (see Section 7.2.4) 
 Blood samples for PD biomarkers including cortisol, ACTH, P1NP, osteocalcin, 
CTX, 17-hydroxyprogesterone, testosterone, corticosterone, and 11-deoxycortisol 
(6 hours post-dose).  Blood will also be collected and stored for future proteomics 
profiling and SomaScan studies (see Section 7.3). 
 12-lead ECG (see Section 7.2.5) 
 Recording of AEs and SAEs; review of all AEs for resolution status and date (see 
Section 7.2.6) 
 Recording of any concomitant medications administered to the subject (see 
Section 6.4) 
 Return of study medication and subject diaries (see Sections 5.3 and 5.5) 
The subject will remain at the study site for at least 8 hours after administration of the 
final dose of study medication to accommodate post-dose PK/MIST blood sampling and 
safety assessments.  The subject, if stable, may leave the center following completion of 
all scheduled Week 2 assessments. 
6.3.6 
Post-treatment Follow-up Telephone Contact (Day 21 ± 2 days) 
Study staff will contact the subject’s parent or guardian by telephone at Week 3 (Day 21) 
(Day 21 ± 2 days after administration of the first dose of study medication, and 
approximately 7 days after receiving the final dose of study medication) to query the 
parent or guardian regarding any AEs or SAEs experienced by the subject and any 
concomitant medications taken.  Any AEs or SAEs that meet the criteria for dose-limiting 
toxicities (see Section 8.3) must be reported immediately to the Study Chair and Medical 
Monitor and/or PRA safety management team (SAEs only).  Adverse events and SAEs 
will be recorded in the source document and in the eCRF. 


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6.3.7 
Post-treatment Follow-up Week 4 (Day 28) Visit (Day 28 ± 3 days) 
Subjects will return to the study site for the Post-treatment Follow-up safety, PD, and 
exploratory clinical efficacy assessments at Week 4 (Day 28) (Day 28 ± 3 days after 
administration of the first dose of study medication, and approximately 14 days after 
receiving the final dose of study medication). 
The following procedures will be completed during the Post-treatment Follow-up Visit: 
 Complete physical examination, including weight (in kilograms) (see Section 
7.2.2) 
 Recording of vital signs (supine blood pressure, heart rate, oral temperature, 
respiratory rate) (see Section 7.2.3) 
 Clinical laboratory evaluation including hematology, clinical chemistry, lipids, 
and urinalysis tests (see Section 7.2.4)  
 Blood samples for PD biomarkers including cortisol, ACTH, P1NP, osteocalcin, 
CTX, 17- hydroxyprogesterone, testosterone, corticosterone, and 
11-deoxycortisol.  Blood will also be collected and stored for future proteomics 
profiling and SomaScan studies (see Section 7.3). 
 12-lead ECG (see Section 7.2.5) 
 Quantitative Muscle Testing (QMT) (see Section 7.4.1) 
 Time to Run/Walk Test (TTRW) (see Section 7.4.2) 
 Time to Stand Test (TTSTAND) (see Section 7.4.3) 
 Time to Climb Test (TTCLIMB) (see Section 7.4.4) 
 North Star Ambulatory Assessment (NSAA) (see Section 7.4.5) 
 Six-minute Walk Test (6MWT) (see Section 7.4.6) 
 Recording of AEs and SAEs; review of all AEs for resolution status and date (see 
Section 7.2.6) 
 Recording of any concomitant medications administered to the subject (see 
Section 6.4) 


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Following completion of the Post-treatment Week 4 Follow-up assessments, the subject 
may be discharged from the study and offered enrollment in the extension study. 
6.4 
Prior and Concomitant Medications and Therapies 
All medications (prescription and over-the-counter [OTC]) taken within 30 days prior to 
the Screening Visit and during the study must be recorded in the source document and in 
the eCRF, including the name of the medication (or device or procedure), the dosage and 
regimen, the indication, and the treatment start and stop dates.  All past (lifetime) steroid 
use will be recorded.  Furthermore, each change in concomitant medications (e.g., new 
treatment, discontinuation of treatment, or change in dosage/regimen) during the study 
must be documented in the same manner.  Details of any non-pharmacological therapies 
(e.g., devices, procedures), including name and dates of therapy, will also be recorded.  
Site personnel will review the information with the subject or his parent or guardian, if 
applicable, for completeness and accuracy at each study visit. 
6.4.1 
Prohibited Therapies 
Subjects must discontinue use of the following medications prior to participation in the 
study, as indicated, and refrain from using these medications throughout the duration of 
the study: 
 Mineralocorticoid receptor agents, such as spironolactone, eplerenone, canrenone 
(canrenoate potassium), prorenone (prorenoate potassium), mexrenone 
(mexrenoate potassium); use must be discontinued at least 4 weeks prior to the 
first dose of study medication; 
 Oral glucocorticosteroids or other oral immunosuppressive agents.  Subjects who 
have received more than 3 months cumulative treatment with oral 
immunosuppressive agents or last treatment within 3 months prior to first dose of 
study medication are ineligible for study entry.  [Note: Inhaled and/or topical 
corticosteroids prescribed for an indication other than DMD are permitted but 
must be administered at stable dose for at least 3 months prior to study drug 
administration]; 


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 Idebenone (use must be discontinued at least 4 weeks prior to first dose of study 
medication); 
 Live attenuated vaccines (use must be avoided for the duration of participation in 
the study); 
 Any investigational medications other than vamorolone (use must be discontinued 
at least 3 months prior to the first dose of study medication). 
The Investigator should contact the Study Chair and Medical Monitor concerning 
individual medications or therapies not listed that may be of concern. 
6.4.2 
Permitted Therapies 
Every effort should be made NOT to take any new prescription or OTC medications 
during the study, but particularly on Day 1 and Week 2 (Day14) Visit days.  Concomitant 
medications should be maintained at the same dose and regimen throughout the study 
whenever possible.  However, all other medications other than those specifically 
prohibited above may be taken during the study, if clinically indicated, provided they are 
recorded in the source document and in the eCRF. 
6.5 
Subject Discontinuation 
In the event that a subject withdraws early from the study at any time, the reason for 
discontinuation must be fully documented in the source documents and the eCRF.  The 
site personnel will document any AEs and other assessments in the source documents and 
will make every effort to complete all applicable Week 2 (Days 13 and 14) assessments 
(for subjects who withdraw prior to the scheduled Week 2 [Day 14] Visit - see Section 
6.3.5) and Post-treatment Follow-up Week 4 (Day 28) assessments (for all subjects who 
withdraw early - see Section 6.3.7). 
6.6 
Study Completion 
A completed subject is defined as a subject who has completed the 14-day Treatment 
Period and the 14-day Post-treatment Follow-up Period, and has not prematurely 
withdrawn from the study for any reason. 


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7 
STUDY ASSESSMENTS AND MEASUREMENTS 
7.1 
Demographic Assessments 
Demographic information (birth date, race, and ethnicity) will be collected during the 
Pretreatment Screening Period and will be recorded on the appropriate eCRF. 
7.2 
Safety and Tolerability Assessments 
7.2.1 
Medical History 
The medical history will be recorded at the Screening Visit and will include significant 
past medical or surgical procedures as well as previous and current co-existent diseases.  
It should include the date (month/year) the subject was diagnosed with DMD, initial 
symptoms of DMD and the age at which they were first identified, and any toxicities 
or allergies to prior treatments.  It should include relevant medical history for the 
following body systems: head, eyes, ears, nose and throat (HEENT), respiratory, 
cardiovascular, gastrointestinal, endocrine, hematological, dermatological, genital-
urinary, neurological, musculoskeletal, psychological/psychiatric, and any other history 
of medical significance.  The medical history will be recorded on the appropriate eCRF. 
7.2.2 
Physical Examination with Weight 
A complete physical examination including height (in cm) and weight (in kg) will be 
performed at the Screening, Week 2 (Day 14), and Week 4 (Day 28) Visits, and will 
include examination of the following: head, eyes, ears, nose, and throat, neck (including 
an examination of the thyroid), heart, lungs, abdomen (including an examination of the 
liver and spleen), lymph nodes, extremities, nervous system, and skin.  Height will be 
recorded at the Screening Visit only.  Weight recorded at the Screening Visit will be used 
to calculate the vamorolone dose volume to be administered daily throughout the 14-day 
Treatment Period (see Appendix 15.1).  Weight will also be recorded at the Baseline 
Day -1 Visit.  Additional unscheduled symptom-directed physical examinations may be 
conducted at any time per the Investigator’s discretion.  Results will be recorded on the 
appropriate eCRF. 


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7.2.3 
Vital Signs 
Vital signs (supine blood pressure, heart rate, respiration rate, and oral temperature) will 
be recorded at each study visit.  On Days 1 and 14, vital signs will be recorded at 0.5 hour 
pre-dose and 0.5, 1, 2, 4, 6, and 8 hours post-dose.  At time points which coincide with 
PK blood draws, vital signs will be recorded prior to the PK blood draw. 
Vital signs will be recorded after the subject has been resting for at least 5 minutes.  
Results will be recorded on the appropriate eCRF. 
If vital signs assessment is performed at the same study visit as blood sampling and ECG 
recording, the following sequence should be followed: 1) ECG recording; 2) vital signs 
assessment; and 3) blood sampling. 
7.2.4 
Clinical Laboratory Tests 
Each subject will have blood drawn and urine collected for the hematology, chemistry, 
lipids, and urinalysis clinical laboratory tests listed in Table 7 and Table 8.  Clinical 
laboratory testing will be performed at the Screening, Week 2 (Day 14), and Week 4 
(Day 28) Visits.  In addition, all subjects will have blood drawn at the Screening Visit for 
determination of anti-varicella IgG antibodies; a positive test result, as assessed by the 
testing laboratory, must be recorded prior to enrollment in the study.  All blood and urine 
samples will be sent to the designated central laboratory for testing. 
Any subject deemed ineligible for enrollment due to a negative test result at Screening for 
anti-varicella IgG antibodies may be vaccinated and return for rescreening and retest 
approximately 30 days following vaccination. 
For the hematology, chemistry, and lipids laboratory tests, blood will be collected by 
direct venipuncture of peripheral veins.  Approximately 4.5 mL of blood will be obtained 
for clinical laboratory tests (hematology, chemistry, and lipids) at each scheduled visit.  
An additional 2.5 mL of blood will be collected by direct venipuncture of peripheral 
veins for anti-varicella IgG antibody testing.  A total of approximately 16.0 mL of blood 


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will be collected over the course of this study for clinical laboratory evaluation (see 
Section 7.6 for details of blood volumes to be collected during the study). 
If blood sampling is performed at the same study visit as vital signs assessment and ECG 
recording, the following sequence should be followed: 1) ECG recording; 2) vital signs 
assessment; and 3) blood sampling.  If PK and PD or clinical laboratory blood samples 
are to be collected at the same time point, the PK blood sample should be collected prior 
to the PD blood sample(s), which in turn should be collected prior to the clinical 
laboratory blood samples. 
Any abnormal hematology, chemistry, lipid, or urinalysis test result deemed clinically 
significant by the Investigator or medically qualified sub-investigator may be repeated, 
including test results obtained on the final study day.  Clinically significant results 
obtained at Screening should elicit a referral to the subject’s personal healthcare provider. 
Any treatment-emergent abnormal laboratory test result that is clinically significant, i.e., 
meeting one or more of the following conditions, should be recorded as a single diagnosis 
on the AE section of the eCRF: 
 Accompanied by clinical symptoms 
 Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy, 
or treatment) 
 Is otherwise considered clinically significant by the Investigator 
Any clinically significant test abnormality as defined above should be recorded as an AE 
(unless it was considered spurious), and repeat analysis performed until resolution or 
until the Investigator or medically qualified sub-investigator determines that resolution of 
the abnormality is not expected. 


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Table 7: 
Hematology, Chemistry, and Lipids Clinical Laboratory Tests 
Hematology 
Red Blood Cell Count 
Numerical platelet count (estimate not acceptable) 
Hemoglobin 
White Blood Cells (WBC) with differential 
(percent) 
Hematocrit 
 
Chemistry 
Sodium 
Total Bilirubina 
Potassium 
Uric Acid 
Chloride 
Glucose 
Calcium 
Alkaline phosphatase (ALP) 
Inorganic Phosphorus 
Gamma Glutamyl Transferase (GGT) 
Blood Urea Nitrogen (BUN) 
Aspartate aminotransferase (AST) 
Creatinine 
Alanine aminotransferase (ALT) 
Total Protein 
Creatine kinase (CK) 
Albumin 
Lipase  
Bicarbonate 
Amylase  
Lactate Dehydrogenase (LDH) 
 
Lipids 
Triglycerides 
Low Density Lipoprotein (LDL) 
Total cholesterol 
High density Lipoprotein (HDL) 
aIf outside normal range, direct bilirubin will be measured and reported. 
 
Urine will be collected for routine analysis, by dipstick and microscopic analysis, for the 
tests described in Table 8.  Urine will be analyzed by dipstick and microscopic analysis 
by the central laboratory at all assessment time points. 
Table 8: Urinalysis Clinical Laboratory Tests 
Urinalysis (including microscopic examination) 
Dipsticka 
Microscopic Analysis 
Protein 
WBC/hpf 
Glucose 
RBC/hpf  
Ketones 
Casts 
pH 
Bacteria 
Leukocyte esterase 
 
Blood 
 
aA midstream clean-catch urine specimen will be collected for dipstick analysis.   
 


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Clinical laboratory tests will be performed by a central laboratory; results will be reported 
to the study site and transferred electronically into the clinical study database. 
The procedures for the collection, handling, and shipping of laboratory samples will be 
specified in the Laboratory Manual(s) provided to the study site. 
7.2.4.1 
Follow-up of Abnormal Laboratory Test Results 
In the event of a medically significant, unexplained, or abnormal clinical laboratory test 
value, the test(s) may be repeated, evaluated by the Investigator for sustainability and 
reproducibility to determine if the abnormality represents an AE, and followed-up until 
the results have returned to the normal range, stabilized, and/or an adequate explanation 
for the abnormality is found.  If a clear explanation is established, it should be recorded in 
the source document and eCRF.  The clinical laboratory will clearly mark all laboratory 
test values that are outside the normal range and the site Investigator will indicate which 
of these deviations are clinically significant.  These clinically significant deviating 
laboratory results will then be further described as AEs, and the relationship to the 
treatment will be indicated (see Section 7.2.6). 
7.2.5 
12-Lead ECG 
A 12-lead ECG will be recorded at the Screening, Week 2 (Day 14), and Week 4 (Day 
28) Visits.  12-lead ECGs must be performed using a standard high-quality, high-fidelity 
machine equipped with computer-based interval measurements.  Digital ECG recording 
is recommended.  Automated ECG intervals (QRS duration, PR [PQ] interval, RR 
interval [interbeat interval], QT interval, QTc, and heart rate) will be captured or 
calculated. 
12-lead ECGs will be obtained over a 3 to 5-minute period after the subject has been 
resting quietly in a supine position for at least 5 minutes.  12-lead ECGs should be 
recorded prior to vital signs at each assessment time point. 
12-lead ECG results will be read locally.  Results must be interpreted and recorded on the 
appropriate eCRF. 


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7.2.6 
Adverse Events and Serious Adverse Events 
An AE is any untoward medical occurrence in a subject which does not necessarily have 
to have a causal relationship with the intervention.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of an investigational 
product, whether or not considered related to the product.  Pre-existing conditions that 
worsen during a study are to be reported as AEs. 
Adverse events will be recorded from the date of informed consent and through the time 
of the subject’s last study visit (study completion or early discontinuation).  Serious 
adverse events will be recorded from the date of informed consent, throughout the 
clinical trial, and for up to 30 days after the final administration of study drug.  Subjects 
who enroll in the VBP15-003 extension study will have any AEs which initiated during 
VBP15-002 participation and which are ongoing at the time of enrollment into VBP15-
003 recorded in the VBP15-003 eCRF and followed during VBP15-003 participation.  In 
addition, subjects (and their parent or legal guardian) will be questioned by study staff at 
each study visit for any new signs or symptoms or changes in existing signs or symptoms. 
All AEs and SAEs that are spontaneously reported, identified during questioning, or are 
apparent from a participant’s physical appearance will be recorded in the source 
document and in the subject’s eCRF.  The date and time of onset will be recorded.  Any 
laboratory abnormality that is outside the normal range and is considered an AE (see 
Section 7.2.4) should be recorded as an AE on the appropriate eCRF.  The details 
recorded shall include the nature, date of onset, final outcome and its date, intensity 
assessment (CTCAE grade), and a determination of the relationship of the event to 
administration of the study drug (i.e., causality).  All AEs will be graded by CTCAE, 
Version 4.03.  Details of any medications given to the subject to abate the AE should be 
recorded in the appropriate eCRF. 


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Intensity 
All clinical AEs encountered during the clinical study will be recorded in the eCRF.  
Intensity of AEs will be graded using the most current version of the Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03, 5-point scale, and 
reported in detail as indicated on the eCRF.  A description of the intensity scales can be 
found below: 
Mild (Grade 1):  Asymptomatic or mild symptoms: clinical or diagnostic observations 
only; intervention not indicated. 
Moderate (Grade 2):  Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL). 
Severe (Grade 3):  Severe or medically significant but not immediately life-
threatening: hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL; incapacitating with inability to work or perform normal daily 
activity. 
Life-Threatening (Grade 4):  Urgent intervention indicated. 
Death (Grade 5):  Death related to AE. 
Relationship 
Relationship to study drug will be graded on a 5-point scale (definite, probable, possible, 
remote, or unrelated).  A description of the relationship scale can be found below: 
Definite:  This category applies to an AE that meets at least criteria 1, 2, and 4 of the 
“Probable‟ category. 
Probable:  This category applies to those AEs that are considered, with a high degree 
of certainty, to be related to the study drug.  An AE may be considered probable, if 
(must include first 3): 
1. It follows a reasonable temporal sequence from administration of the study 
drug. 


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2. It cannot be reasonably explained by the known characteristics of the 
subject’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the subject. 
3. It disappears or decreases after dosing is complete.  (There are important 
exceptions when an AE does not disappear upon discontinuation of study 
drug, yet drug relatedness clearly exists, e.g., [1] bone marrow depression 
and [2] tardive dyskinesia.)  
4. It follows a known pattern of response to the suspected study drug. 
Possible:  This category applies to those AEs for which the connection with study 
drug administration appears unlikely but cannot be ruled out with certainty.  An AE 
may be considered possibly related to study drug if or when (must include first 2): 
1. It follows a reasonable temporal sequence from administration of the study 
drug. 
2. It may have been produced by the subject’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the subject. 
3. It follows a known pattern of response to the suspected study drug. 
Remote: In general, this category is applicable to an AE that meets the following 
criteria (must include the first 2): 
1. It does not follow a reasonable temporal sequence from administration of 
the study drug. 
2. It may readily have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to 
the subject. 
3. It does not follow a known pattern of response to the suspected study drug. 
Unrelated: This category is applicable to those AEs which are judged to be clearly 
and incontrovertibly due only to extraneous causes (disease, environment, etc.) and 
do not meet the criteria for study drug relationship listed under remote, possible, or 
probable. 


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Clinical Laboratory Test Abnormalities 
Clinical laboratory test results will be recorded in the designated eCRF.  The intensity of 
abnormal clinical laboratory test results that are AEs will also be graded using the most 
current version of the CTCAE, version 4.03, 5-point scale and reported in detail as 
indicated in the eCRF.  A description of the intensity scale can be found above. 
Any treatment-emergent abnormal clinical laboratory test result that is clinically 
significant, i.e., meeting one or more of the following conditions, should be recorded as a 
single diagnosis on the AE section of the eCRF: 
 Accompanied by clinical symptoms 
 Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy, or 
treatment) 
 Is otherwise considered clinically significant by the Investigator 
This applies to any protocol and non-protocol-specified safety laboratory result from 
tests performed after the first dose of study drug, which falls outside the laboratory 
reference range and meets the clinical significance criteria per Investigator standard 
operating procedures (SOPs). 
This does not apply to any abnormal laboratory result that falls outside the laboratory 
reference range, but does not meet the clinical significance criteria (which will be 
analyzed and reported as laboratory abnormalities); those that are considered AEs of the 
type explicitly exempted by the protocol; or those that are the result of an AE which has 
already been reported. 
Please Note: any clinical laboratory abnormality fulfilling the criteria for an SAE should 
be reported as such, in addition to being recorded as an AE in the eCRF. 


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Follow-Up of Adverse Events 
Adverse events will be followed until they have returned to baseline status, stabilized, or 
the Investigator, Study Chair, Medical Monitor and Sponsor agree that follow-up is no 
longer needed.  If a clear explanation of cause is established, it should be recorded in the 
source document and eCRF.  In the event of unexplained abnormal laboratory test values, 
the tests may be repeated as soon as possible and followed up until they have returned to 
the normal range or baseline value and/or an adequate explanation of the abnormality is 
found.  In case of ongoing AEs at the time of database closure, the data obtained at the 
time of database closure will be used in the statistical analysis.  The follow-up of AEs 
will be documented in the source documents and will be described in the final report only 
if considered relevant by the Investigator, the Study Chair, the Medical Monitor and/or 
the Sponsor. 
In addition, the Medical Monitor may request additional blood tests, diagnostic imaging 
studies, or specialist physician consultations in order to further evaluate any AE or test 
abnormality considered to be clinically significant by the Study Sponsor. 
Dosing Error 
For the purposes of this study, a dosing error is defined as a dose exceeding or less than 
the scheduled dose of 0.25 mg/kg, 0.75 mg/kg, 2.0 mg/kg, or 6.0 mg/kg specified for 
each dose level group.  Such occurrences should be reported and recorded in the dosing 
page of the eCRF and as follows: 
 Use of study medication in doses in excess of that specified in the protocol should 
not be recorded as an AE unless there are associated signs or symptoms. 
 A dosing error with associated non-serious AEs should be recorded as AEs on the 
relevant AE forms in the eCRF. 
 A dosing error with an associated SAE should be recorded as an SAE. 


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 Details of all dosing errors, including actual dose administered, should be 
documented in the source document and recorded on the Protocol Deviations 
eCRF. 
7.2.6.1 
Serious Adverse Events 
For treatment-eligible subjects, SAEs will be collected and reported during the study 
from the time informed consent is obtained through 30 days after the final dose of study 
medication, according to the protocol and applicable regulations. 
All SAEs, including those that continue beyond the normal AE collection period (i.e., are 
ongoing at the subject’s last study visit), will be followed until resolution or until 
stabilized without sequelae.  Serious adverse events that begin after the subject’s 
participation in the study is complete but that the Investigator considers to be related to 
study drug will be reported to the Sponsor within 24 hours or discovery by the 
Investigator. 
During the SAE collection period, the Investigator or clinical site personnel should notify 
the PRA safety management team of all SAEs, regardless of relationship to the 
investigational drug, within 24 hours of clinical staff becoming aware of the event; 
notification to the PRA safety management team will trigger alerts to the Coordinating 
Center, Study Chair, the Sponsor, and the Medical Monitor.  The Investigator will 
provide the initial notification by completing the SAE eCRF in the electronic data capture 
(EDC), which must include the Investigator’s assessment of the relationship of the event 
to investigational drug.  In the unlikely event that the electronic study database is 
inaccessible and the Investigator is unable to complete the SAE eCRF within 24 hours, 
the SAE Notification Form (pdf) should be completed and emailed or printed/faxed to the 
PRA safety management team. 
In addition, notification is sent by the Investigator to the IRB and the subject’s Primary 
Care Physician. 


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Follow-up information, or new information regarding an ongoing SAE, must be provided 
promptly to the PRA safety management team within 24 hours of knowledge of the new 
or follow-up information, which will forward the information to the Coordinating Center, 
Study Chair, the Sponsor, and the Medical Monitor. 
All SAE reports should be completed within the EDC. 
An AE or suspected adverse reaction is considered serious if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
 Is fatal (results in the outcome of death) 
 Is life-threatening  
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions 
 Is a congenital anomaly or birth defect 
 Is an important medical event that may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
The term “sudden death” should only be used when the cause is of a cardiac origin as per 
standard definition. 
The terms death and sudden death are clearly distinct and must not be used 
interchangeably. 
Any AE or clinically significant abnormal laboratory test value, as determined by the 
Investigator, that is serious and which occurs during the course of the study (as defined 
above) must be reported to the PRA safety management team, who will notify the 
Coordinating Center, Study Chair, the Sponsor, and the Medical Monitor within 24 hours 
of the Investigator becoming aware of the event.  Additional information that becomes 
available for an SAE after the initial report is submitted will be reported to the PRA 
safety management team, who will notify the Coordinating Center, Study Chair, the 


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Sponsor, and the Medical Monitor within 24 hours of the Investigator becoming aware of 
the new information. 
Related SAEs MUST be collected and reported regardless of the time elapsed from the 
last administration of study drug, even if the study has been closed.  Unrelated SAEs 
must be collected and reported during the study from the time of informed consent 
through 30 days after the final dose of study medication. 
If, at any time during the study, a subject experiences an SAE, appropriate care should be 
instituted. 
In the event of an SAE, the Investigator will complete the SAE eCRF within 24 
hours of first awareness of the event.  In the unlikely event that the electronic study 
database is inaccessible and the Investigator is unable to complete the SAE eCRF 
within 24 hours, the SAE Notification Form (pdf) should be completed and emailed 
or printed/faxed to the PRA safety management team within 24 hours, using the 
contact information below: 
Email CHOSafety@prahs.com 
Drug Safety Fax: 1-888-772-6919 or 1-434-951-3482 
 
SAE Questions: Drug Safety Hotline: 1-800-772-2215 or 1-434-951-3489 
Serious Adverse Events will be recorded from the time the subject’s written informed 
consent is obtained.  Serious adverse events that occur within 30 days of study drug 
dosing must continue to be recorded and reported to the Study Sponsor or its designee.  
Should there be an SAE that occurs that suggests an increased risk to the participants, the 
following steps will be considered, depending on the number and severity of the SAE(s): 
modification of the protocol, investigation of the relationship of the SAE(s) to study drug, 
suspension of the study, and/or discontinuation of the study. 
7.2.7 
Study Medication Acceptability Assessment 
Acceptability of the study medication will be assessed using a 5-point hedonic scale 
immediately before (to assess smell) and after (to assess taste) dosing on Study Days 1 


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and 14.  The assessments will be administered by trained study staff.  Results will be 
recorded in the source documents and eCRF. 
7.2.8 
Metabolites in Safety Testing (MIST) 
A portion of each blood sample collected for PK testing (see Section 7.5) at each of the 
Week 2 (Day 14) assessment time points will be used for analysis of vamorolone 
metabolites.  No additional blood volume will be collected for MIST assessment (see 
Table 10).  
7.3 
Pharmacodynamic Biomarker Panel 
The effect of vamorolone on biomarkers of muscle cellular pathology and biomarkers 
associated with acute and chronic glucocorticoid treatment, as listed in Table 9, will be 
explored through periodic blood sampling.  Samples for analysis of PD biomarkers 
response will be collected at Screening, Baseline Day -1 (0.5 hours pre-dose), Day 1 (6 
hours post-dose), Week 2 (Day 14) (0.5 hours pre-dose and 6 hours post-dose), and 
Week 4 (Day 28). The biomarker analysis will include cortisol, ACTH, P1NP, 
osteocalcin, CTX, 17-hydroxyprogesterone, testosterone, corticosterone, 
11-deoxycortisol, glucose, and insulin.  In addition, HbA1c will be drawn at screening as 
a baseline.  An additional assay by Immulite technology will be done to assess levels of 
these PD biomarkers from leftover blood samples collected for the PK sampling done on 
Day 1 and Day 14.  Blood will also be collected at Screening, Week 2 (Day 14), and 
Week 4 (Day 28) and stored at these time points for future proteomics profiling and 
SomaScan studies.   
Subjects must have fasted ≥ 6 hours prior to the pre-dose blood draws for insulin and 
glucose PD determination on Day 1 and Day 14. 
A total of 68 mL of blood will be collected for PD biomarkers over the course of the 
8-week study. 


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Table 9: 
Pharmacodynamic Biomarkers 
Adrenal Axis Suppression 
Cortisol 
17- hydroxyprogesterone 
ACTH 
Testosterone 
Corticosterone 
11- deoxycortisol 
Insulin Resistance 
Glucose 
Insulin 
HbA1c 
Bone Turnover 
Osteocalcin 
P1NP 
CTX 
Exploratory Biomarkers 
SomaScan and Proteomics Profiling 
If blood sampling is performed at the same study visit as vital signs assessment and ECG 
recording, the following sequence should be followed: 1) ECG recording; 2) vital signs 
assessment; and 3) blood sampling.  If PK and PD or clinical laboratory blood samples 
are to be collected at the same time point, the PK blood sample should be collected prior 
to the PD blood sample(s), which in turn should be collected prior to the clinical 
laboratory blood samples.  The exact times of blood sampling will be recorded in the 
source document and eCRF.  Tests for PD biomarkers will be performed by a central 
laboratory; results will be reported to the study site and transferred electronically into the 
clinical study database.  The procedures for the collection, handling, and shipping of 
laboratory samples will be specified in the Laboratory Manual(s) provided to the clinical 
study sites. 
7.4 
Exploratory Clinical Efficacy Endpoints 
Exploratory clinical efficacy parameters will be assessed at the Screening and Baseline 
Visits, and at the Week 2 (Day 13) and Week 4 (Day 28) Visits. 


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7.4.1 
Quantitative Muscle Testing (QMT) 
Quantitative Muscle Testing (QMT) will be administered to all subjects using the CINRG 
Quantitative Measurement System (CQMS).31  The QMT will measure unilateral strength 
of four muscle groups: elbow flexion/extension, and knee flexion/extension.31  Complete 
instructions for administering the QMT are given in the study manual to be supplied to 
the sites prior to study start. 
Results will be collected using the CQMS3 software and transferred into the eCRF. 
7.4.2 
Time to Run/Walk Test (TTRW) 
The Time to Run/Walk Test (TTRW) measures the time (in seconds) that it takes the 
subject to run or walk 10 meters and is administered as part of the NSAA (see 
Section 7.4.5). Complete instructions for administering and scoring the TTRW are given 
in the study manual to be supplied to sites prior to study start. 
Results will be recorded in the source document and in the eCRF. 
7.4.3 
Time to Stand Test (TTSTAND) 
The Time to Stand Test (TTSTAND) measures the time (in seconds) required for the 
subject to stand to an erect position from supine (floor), and is administered as part of the 
NSAA (see Section 7.4.5).  The TTSTAND test must be performed without assistance at 
the Screening and Baseline Visits to qualify for enrollment into the study.  Complete 
instructions for administering and scoring the TTSTAND are given in the study manual 
to be supplied to the sites prior to study start. 
Results will be recorded in the source document and in the eCRF. 
7.4.4 
Time to Climb Test (TTCLIMB) 
The Time to Climb Test (TTCLIMB) measures the time (in seconds) required for the 
subject to climb 4 standard stairs, beginning and ending in a standing position with arms 
at the sides.32  Complete instructions for administering the TTCLIMB are given in the 
study manual to be supplied to the sites prior to study start. 


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Results will be recorded in the source document and in the eCRF. 
7.4.5 
North Star Ambulatory Assessment (NSAA) 
The North Star Ambulatory Assessment (NSAA) is a clinical assessment scale 
specifically designed to measure functional ability in ambulant boys with DMD.33  The 
NSAA consists of 17 scored items and 2 timed tests, including the TTRW and the 
TTSTAND (see Section 7.4.3). 
Subjects should be barefoot and wear comfortable clothing.  Complete instructions for 
administering and scoring the NSAA are given in the study manual to be supplied to the 
sites prior to study start. 
The NSAA should be administered BEFORE the 6MWT at study visits where both tests 
are administered. 
Results will be recorded in the source document and in the eCRF. 
7.4.6 
Six-Minute Walk Test (6MWT) 
Functional exercise capacity and mobility will be assessed in all subjects by means of the 
modified version of the Six-Minute Walk Test (6MWT), adapted for use in DMD 
subjects.34 
The total distance traveled, in meters, should be recorded along with the validity of the 
test as assessed by the test administrator.  If a subject cannot complete 6 minutes of 
walking, the total meters and the time until discontinuation of the test should be recorded.  
Complete instructions for administering the 6MWT are given in the study manual to be 
supplied to the sites prior to study start. 
The 6MWT should be administered AFTER the NSAA at study visits where both tests 
are administered. 
Results will be recorded in the source document and in the eCRF. 


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7.5 
Pharmacokinetic (PK) Assessments 
On Treatment Period Day 1 and Day 14, all subjects will have blood collected for PK 
assessments at 0.5 hour pre-dose and at 1, 2, 4, 6, and 8 hours post-dose.  Approximately 
2 mL of blood will be collected into K2-EDTA tubes at each assessment time point.  A 
total of approximately 24 mL of blood will be collected for PK analysis over the course 
of the 8-week study.  
Subjects should have fasted ≥ 6 hours prior to collection of PK blood samples at the 
0.5 hour pre-dose time points on Days 1 and 14. 
Plasma concentrations of vamorolone will be measured using a specific and validated 
liquid chromatography tandem mass spectrometry assay.  PK assessments will be 
performed by a central laboratory.  The procedures for the collection, handling, and 
shipping of laboratory samples will be specified in the Laboratory Manual(s) provided to 
the study sites. 
The exact times of blood sampling will be recorded in the source document and eCRF. 
If PK and PD or clinical laboratory blood samples are to be collected at the same time 
point, the PK blood sample should be collected prior to the PD blood sample(s), which in 
turn should be collected prior to the clinical laboratory blood samples. 
7.6 
Total Blood Volume Required 
The number and volume of blood samples and total volume of blood to be collected from 
each subject throughout the duration of the 8-week study are summarized in Table 10. 


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Table 10: 
Blood Sample Volume by Visit 
 
Total mL of Blood 
Test 
SCR 
Day -1 
Day 1 
Week 2 
(Day 14) 
Week 4 
(Day 28) 
Total Volume 
Clinical Safety Labsa 
7.0 
 
 
4.5 
4.5 
16.0 
PD Biomarker Panel 
17b 
 
11c 
15d 
15d 
58 
PD Insulin/Glucose 
 
5e 
 
5e 
 
10 
PK 
 
2f 
10g 
12f,g 
 
24 
Total Volume by Visit 
24 
7 
21 
36.5 
19.5 
 
Total Volume: 108.0 mL 
SCR = Screening Period. 
a Hematology, Chemistry, Lipids.  Volume collected at Screening includes 2.5 mL blood for determination of anti-
varicella IgG antibodies. 
b cortisol, ACTH, P1NP, osteocalcin, CTX, 17-hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol, 
HbA1c, SomaScan, and proteomics testing. 
c Day 1, 6 hours post dose: cortisol, ACTH, P1NP, osteocalcin, CTX, 17-hydroxyprogesterone, testosterone, 
corticosterone, 11-deoxycortisol. 
d Day 14, 6 hours post-dose, and Week 4 (Day 28): cortisol, ACTH, P1NP, osteocalcin, CTX, 
17-hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol, SomaScan, and proteomics testing. 
e Insulin and glucose measured at 0.5 hour pre-dose on Day 1 and Day 14.  Subjects must have fasted ≥ 6 hours prior 
to blood draws. 
f Blood drawn for PK at 0.5 hour pre-dose on Day 1 and Day 14.  Subjects must have fasted ≥ 6 hours prior to blood 
draws.  Volume collected on Day 14 includes blood for MIST assessment. 
g 1, 2, 4, 6, and 8 hours post-dose.  Volume collected on Day 14 includes blood for MIST assessment.  Back-up 
samples used for immunoassay panel. 
8 
SAFETY PROCEDURES AND PROCESSES  
8.1 
Overall Benefit/Risk 
The current study is a Phase IIa study in young boys with DMD.  It is anticipated that the 
side effect profile of the investigational product will be more favorable than standard of 
care glucocorticoids in the long term.  The short-term side effects over the 14-day 
treatment period are not currently known but are predicted to be benign based on Phase I 
14-day treatment in adult volunteers.  In the Phase I study, no SAEs were observed in any 
cohort.  Cohorts tested in the MAD portion of the Phase I study were 1.0, 3.0, 9.0 and 
20.0 mg/kg/day for 14 days.  In the Phase I clinical trial in adult volunteers, vamorolone 
has shown suppression of the adrenal axis at higher doses (9.0 mg/kg/day and 20.0 
mg/kg/day in the fasted state).29 
Subjects will not receive any known health benefit from participating in the study.  It is 
not anticipated that two weeks of treatment will fundamentally alter the course of their 


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disease, but minor, temporary cellular benefits within the muscle may result from 
vamorolone treatment.  In view of the initial clinical evidence of safety and the ability to 
monitor key nonclinical toxicological findings, the available data support an acceptable 
risk profile for vamorolone. 
8.2 
Medical Monitor and Data and Safety Monitoring Board 
The Sponsor will appoint a Medical Monitor for the study.  The Medical Monitor will 
review all SAE reports and is responsible for identifying any safety concerns with the 
study.  The Medical Monitor will also review all AEs that are dose-limiting in an 
individual subject.  The Medical Monitor will review all summaries of safety data and 
monitor the conduct of the study on behalf of the Sponsor.  The Medical Monitor will be 
available to the Coordinating Center for any reported SAEs.  The Medical Monitor will 
work closely with the Study Chair on the evaluation of any dose-limiting toxicities and 
dose escalation decisions.  
The independent Data and Safety Monitoring Board (DSMB) will be consulted to review 
the safety data from each dose level group.  The DSMB will receive reports when it is 
assessed that a dose level group is completed and no more de-escalations to that dose are 
expected, but no less frequently than every 6 months.  The DSMB will meet at regular 
intervals to review all pertinent safety data.  The DSMB will also be notified at any point 
where a dose de-escalation occurs and the dose is deemed to have unacceptable toxicity.  
The DSMB may request summaries at other points in time.  In addition, the Medical 
Monitor may request at any time that the DSMB review safety data if the Medical 
Monitor has specific concerns. 
In all cases, data will be compiled by the Coordinating Center and presented to the 
DSMB in a format that allows for complete review of all compiled safety data.  The 
DSMB can recommend to the Sponsor altering or terminating the trial for safety or other 
study integrity-related issues. 


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8.3 
Study Drug Dose Interruption or Discontinuation (Dose-Limiting Toxicities) 
Subjects will be monitored for clinical signs and symptoms throughout the duration of the 
study.  Subjects will remain at the participating study site for at least 8 hours following 
administration of the first dose of study medication on Day 1 for safety monitoring of 
AEs and SAEs, and at least 8 hours after administration of the last dose on Day 14.  
Clinical AEs and clinical laboratory AEs will be graded according to the CTCAE, version 
4.03. 
Administration of study drug to individual subjects either at the study site or at home 
should be discontinued and the case reported to the Coordinating Center and discussed 
with the Medical Monitor within 24 hours under any of the following circumstances 
which constitute a dose-limiting toxicity: 
1. Any CTCAE Grade ≥ 3 AE considered to be probably or definitely related to 
study medication, in the opinion of the site Investigator; 
2. The presence of a CTCAE Grade ≥ 3 clinical laboratory AE considered to be 
probably or definitely related to study drug, in the opinion of the Investigator; or 
3. Deterioration of the muscle condition, unexpected for the natural course of DMD 
and without other clear cause, in the opinion of the site Investigator.  The 
possibility to consider the event as a dose-limiting toxicity will be discussed by 
the Medical Monitor and the DSMB.  The SAE data collection tool must be 
completed if the event also meets the criteria for an SAE. 
The Coordinating Center information is below: 
Coordinating Center 
Study Management Team 
Phone:  (412) 383-7207 or (412) 224-2030 
Email:  info@cinrgresearch.org 
The Coordinating Center will notify the Medical Monitor, the Study Chair, and the 
Sponsor of any dose-limiting toxicity reported, whether it is an SAE or not. 


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All results will be retained in the source document, and results will be recorded in the 
eCRF. 
8.4 
Study Stopping Rules 
If a dose-limiting toxicity occurs in two or more subjects at any dose level during the 
two-week Treatment Period or during the Follow up Period, the Study Chair and Medical 
Monitor will be immediately notified, and enrollment and dosing at that dosing level will 
be halted; the MTD will be defined as the previous dose level, unless the decision is 
made to study lower intermediate dose level(s).  The DSMB will be informed promptly 
of any dose decisions which are a result of dose-limiting toxicities.   
If dose escalation is terminated due to dose-limiting toxicities, the remaining dose level 
groups may be enrolled to evaluate the safety and PK effects of vamorolone at lower 
intermediate dose level(s).  Once safety data from additional dose level group(s) are 
assessed, the MTD will be defined as the dose level below the dose at which the DSMB 
determines there to be an unacceptable risk to subjects.   
If any death occurs, the study will be immediately suspended to new enrollment, the 
Sponsor will be notified (as well as the relevant IRB/IECs), in addition to the Study 
Chair, the Medical Monitor and the DSMB.  Subjects currently receiving treatment will 
not be asked to stop their treatment unless the Medical Monitor or the DSMB requires 
that, but no new subjects will be enrolled until the DSMB finds it safe to do so. 
The study will be considered to have completed accrual when approximately 12 subjects 
are enrolled at each of the safe dose levels. 
8.5 
Withdrawal of Subjects from Study 
A subject may withdraw from the study, or may be withdrawn by his parent or guardian 
at any time without the need to justify the decision. 
The Investigator has the right to terminate participation of a subject in the study for any 
of the following reasons: 


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 The subject’s parent/legal guardian is uncooperative/noncompliant and does not 
adhere to study responsibilities, including failure to appear at study visits 
 Difficulty in obtaining blood samples from the subject for safety monitoring 
 The subject experiences an unmanageable or non-tolerable AE/SAE which is 
considered to be possibly, probably, or definitely related to study drug, in the 
opinion of the Investigator 
 The Sponsor terminates the study 
 Any other reason relating to subject safety or integrity of the study data. 
In the event a subject is withdrawn from the study, the Coordinating Center will be 
informed within one business day.  If there is a medical reason for withdrawal, the 
subject will remain under the supervision of the Investigator until resolution of the event. 
The Coordinating Center will inform the Medical Monitor and the Study Chair. 
All subjects who withdraw early from the study should enter the Post-Treatment 
Follow-up Period where possible and continue to be monitored for at least 14 days 
after the last dose of study drug or for as long as clinically indicated, assuming the 
subject has not withdrawn informed consent.  Subjects who have received at least one 
dose of study medication and are withdrawn prior to Day 14, should undergo the 
Day 14 assessments at the time of early discontinuation prior to entering the 14-day 
Follow-up Period.  Subjects who prematurely discontinue from the study after Day 14 
but prior to the scheduled Day 28 Follow-up Visit should continue to be followed for 
at least 14 days after the last dose of study drug.  In all cases, subjects should return to 
the study site for completion of the scheduled Day 28 assessment 14 days after the 
final dose of study drug, where possible.  In the event a subject withdraws informed 
consent, no further study procedures should be performed and no additional data 
should be collected.  Any data collected up to the point of withdrawal may be used by 
the Sponsor. 


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8.6 
Replacement of Withdrawn Subjects 
Subjects prematurely discontinued from the study for reasons other than safety may be 
replaced to ensure adequate numbers of evaluable subjects.  The decision to replace a 
withdrawn subject will be made at the discretion of the Sponsor.  The decision regarding 
the replacement of subjects will be documented. 
8.7 
Termination of Study 
This study may be prematurely terminated if, in the opinion of the Sponsor, there is 
sufficient reasonable cause.  An example of a circumstance that may warrant termination 
is determination of unexpected, significant, or unacceptable risks to subjects. 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Study Chair, the Coordinating Center and the regulatory authority(ies) of the termination 
or suspension and the reason(s) for the termination or suspension.  The Coordinating 
Center will inform the study sites who will inform their IRB(s)/IEC(s) and provide the 
reason(s) for the termination or suspension. 
Subject enrollment at a given site may be terminated by the Sponsor or the Study Chair.  
Possible reasons for termination of the study at a given site include, but are not limited to: 
1. Unsatisfactory enrollment with respect to quantity or quality 
2. Inaccurate or incomplete data collection 
3. Falsification of records 
4. Failure to adhere to the protocol. 
9 
DATA COLLECTION 
9.1 
Source Documents 
Source documents are defined as original documents, data, and records.  These 
documents may include hospital records, clinical and office charts, laboratory 
data/information, subjects’ diaries or evaluation checklists, pharmacy dispensing and 
other records, recorded data from automated instruments, microfilm or magnetic media, 


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and/or x-rays.  Data collected during this study must be recorded on the appropriate 
source documents. 
A subject screening/enrollment log is to be completed at each study site.  Data recorded 
on the screening/enrollment log are to include a subject identifier, the date of screening, 
and the reason the subject was not entered (if applicable).  All subjects initially screened 
are to be recorded in this log. 
The investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC 
review, and regulatory inspection(s), providing direct access to source data documents. 
9.2 
Electronic Case Report Form Completion 
Subject data will be collected in this study using an EDC system.  The EDC and database 
system will be OpenClinica by Akaza Research, LLC.  OpenClinica is a web-based 
(https://www.openclinica.com) data entry system utilizing a high security environment.  
The underlying storage facility will be PostgreSQL, whose structure permits the linking 
of subject information across all tables in relational databases.  OpenClinica uses secure 
socket layers (SSL) and in its Enterprise version used in this study is 21 Code of Federal 
Regulations (CFR) Part 11 compliant.  Once an eCRF is created in the database, a data 
dictionary exists and the data team creates compatible paper source documentation. 
The Coordinating Center will design an electronic data base in OpenClinica for this 
study.  Access rights to the EDC system for the study site team members will need to be 
requested.  Every user of the system will be made aware of the fact that user name and 
password should never be shared and their electronic signature constitutes the legally 
binding equivalent of a handwritten signature.  Only trained personnel certified by the 
Coordinating Center will receive a user name and password. 
All data will be directly entered or collected on a source document and then entered into 
OpenClinica or transferred electronically to the study database (e.g., clinical laboratory 
results, quantitative muscle testing).  The Coordinating Center data management team 
will monitor the eCRFs for completeness and acceptability throughout the course of the 


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study.  The study Sponsor or their designee will be allowed access to all source 
documents in order to verify eCRF entries. 
9.3 
Data Processing 
A clinical study database will be constructed from the eCRFs and any data merged 
electronically, and the data will be validated both manually and electronically.  
Clarification of data will be requested from the study site as required.  The database will 
be quality assured in accordance to the data management plan and will be available for 
statistical analysis according to the methods outlined in Section 10.6 and the Statistical 
Analysis Plan (SAP). 
 
10 
STATISTICAL METHODS AND PLANNED ANALYSES 
10.1 
Statistical and Analytical Plan 
Given the small sample size of this Phase IIa open-label study, no inferential statistical 
analyses are planned.  However, all analyses will be based on modified Intention to Treat 
(mITT) in which all subjects who received at least one dose of vamorolone will be 
included in analyses.  Detailed methods will be presented in the SAP, finalized prior to 
database lock. 
10.2 
Planned Sample Size 
A sample of 12 in each cohort is large enough to have a confidence interval of no wider 
than 50% for the proportion of adverse events assessed or any other event outcome.  For 
the continuous outcomes such as safety laboratory markers or pharmacodynamics 
markers, a two-sided 95.0% confidence interval for the mean will be no wider than 0.8 
standard deviation (SD) from the observed mean, with 90.0% coverage probability, based 
on the t statistic; thus, the total confidence interval will be approximately 1.6 SDs wide 
for any continuous parameter if its underlying distribution is approximately normal. 
10.3 
Analysis Populations 
Two populations will be defined for data analysis. 


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Safety Population: 
All subjects who receive at least one dose of vamorolone study medication will be 
included in the Safety Population. 
Pharmacokinetic Population: 
All subjects who receive at least one dose of vamorolone study medication and have 
sufficient data for PK analysis will be included in the PK population. 
10.4 
Interim Analysis 
No interim statistical evaluations of data will be conducted. 
10.5 
Statistical Considerations for Dose Escalation 
There are no statistical considerations for dose escalation.  The process of dose escalation 
will be based on the appearance of dose-limiting toxicities.  See Section 8.3 for 
definitions of dose-limiting toxicities.   
10.6 
Statistical Analysis 
10.6.1 
Analysis of Demographic and Baseline Characteristics 
Subject demographics (age, race, and ethnicity) and baseline characteristics (height, 
weight, body mass index [BMI] and BMI percentile, and months/years since DMD 
diagnosis) will be summarized descriptively and the anthropometric measures plotted as 
box and whisker plots for all subjects combined and by dose level group.  The summaries 
will be compared visually by dose level group and reviewed for any differences among 
the dose level groups. 
10.6.2 
Summary of Treatment Data and Subject Disposition 
The number of subjects at each dose level, the determinations within the dose level of the 
mTPI algorithm and the compliance and completion rates of dosing at each dose level 
will be summarized.  The number of discontinuations (if any) and whether they occurred 
before Day 14 or after Day 14 but before Day 28 and whether the Day 28 assessments 
were completed will be summarized by dose level group. 


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10.6.3 
Safety Analyses 
All subjects who received at least one dose of vamorolone (Safety Population) will be 
included in the safety analyses.  In general, descriptive statistics for each safety endpoint 
will be presented by dose level, while individual subject listings of safety endpoints, 
sorted by dose level group, will be reviewed for any evidence of dose-related differences 
or trends in the safety profile of vamorolone. 
All safety data will be listed. 
10.6.3.1 
Adverse Events Summaries 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 18.1.  The incidence of TEAEs will be summarized by dose level, 
SOC and preferred term; dose level, SOC, and intensity (CTCAE grade; CTCAE version 
4.03); dose level, SOC, and outcome; and dose level, SOC and relationship to study drug. 
Clinical laboratory test results will be categorized relative to the laboratory’s normal 
range as low, within range, or high, and shift tables comparing the distributions from 
Screening to Week 2 (Day 14) and Week 4 (Day 28) will be provided for each parameter. 
Physical examination results will be listed only. 
10.6.3.2 
Vital Signs and Laboratory Outcomes 
Vital signs, 12-lead ECG intervals, clinical laboratory test results, and other laboratory 
test results will be summarized by dose level using descriptive statistics and box and 
whisker plots.  Descriptive statistics include median, interquartile range, and minimum 
and maximum.  For those parameters that are either approximately normal, or can be 
transformed to achieve normality, a mean and 95% confidence interval (potentially back 
transformed) will be provided by dose level and overall. 


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10.6.4 
Clinical Efficacy and Pharmacodynamic Analyses 
The evaluations of exploratory clinical efficacy and PD will be performed using the 
Safety Population.  The last non-missing value prior to the first dose of study medication 
will be used as the baseline value for analyses. 
The QMT measurements will be done unilaterally using the dominant site, if known. 
There may also be a training session in which the subject has a practice QMT 
measurement prior to the corresponding study measurement.  Once calculated, each 
muscle group (knee extension/flexion, elbow extension/flexion) will be summarized at 
each time point and dose assessed.  Summaries will include as above descriptive statistics 
and box and whisker plots.  Since change in strength is not expected from a two-week 
treatment period, all measurements will be used to obtain coefficients of variation and 
assess reliability in this age group.  The coefficients of variation vs. age will be plotted to 
see whether within this developing age group, the reliability increases with growth and 
better comprehension of the test, or if within this narrow age group, there is no change in 
reliability. 
The same approach will be taken for all timed function tests (TTRW, TTSTAND, 
TTCLIMB, 6MWT) and the NSAA. 
Percentage change from Baseline in serum PD biomarker concentrations will be 
summarized.  Descriptive statistics, including mean, standard deviation, median and 
range, will be provided. 
Individual clinical efficacy and PD data will be listed.  Individual subject changes in 
clinical efficacy and PD variables over time, together with their mean changes by dose 
group, will be presented and reviewed for any evidence of dose-related trends or any 
relations between the PD data and the individual clinical efficacy outcomes. 
Acutely-responsive glucocorticoid PD biomarker (cortisol, ACTH, 
17-hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol, osteocalcin, 
CTX, P1NP) data will be listed, accompanied by indication of whether the parameter is 


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out of range.  A summary listing of values outside the reference range will be presented 
and compared to published data on these same markers in glucocorticoid-treated subjects. 
10.6.5 
Pharmacokinetic Analyses 
All PK analyses will be performed using the PK Population.  Plasma concentrations and 
the derived plasma PK parameters will be summarized and listed for vamorolone, as 
appropriate.  Individual and mean vamorolone concentrations versus time will be plotted 
on linear and semi-logarithmic scales by dose for vamorolone, as appropriate. 
Summary statistics (number of subjects, mean, SD, minimum, median, maximum, 
geometric mean, and percentage coefficient of variation [%CV]) for the derived PK 
parameters of vamorolone will be presented by dose level for the PK Population.  
Derived PK parameters for vamorolone will be listed by dose level.  Plots of plasma 
concentration-time profiles will be provided by dose level.  All available concentration-
time data will be listed. 
A (compartmental) population PK model will be developed based on data obtained from 
VBP15-001 (a study in healthy adults).  As part of this procedure, the number of systemic 
compartments will be determined.  In addition, linearity with respect to dose and time and 
appropriateness of a first-order absorption model will be evaluated.  The parameters of 
this model, with systemic parameters scaled either by weight or allometrically (clearances 
scaled by weight raised to the 0.75 power), will be applied to the dosing history for 
pediatric subjects in VBP15-002 to predict the plasma concentration profile.  The 
observed values will then be compared to the predicted concentration and the model 
adjusted as necessary. 
10.6.6 
Concurrent Medications 
A summary of all concomitant medications taken during the course of the study will be 
presented in tabular form by therapeutic drug class and generic drug name using the 
World Health Organization (WHO) Drug classification (Version 4.3).  All concomitant 
medications will be detailed in the subject data listings. 


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10.6.7 
Study Deviations and Violations 
A summary of study deviations and violations will be provided by dose level group and 
by study site. 
11 
STUDY MANAGEMENT AND ETHICAL AND REGULATORY 
REQUIREMENTS 
11.1 
Regulatory Approval and Good Clinical Practice 
This study will be conducted in accordance with the principles of the 18th World Medical 
Assembly (Helsinki, June 1964), and amendments of the 29th (Tokyo, 1975), 35th 
(Venice, 1983), 41st (Hong Kong, 1989), 48th (Somerset West, 1996), 52nd (Edinburgh, 
2000), 53rd (Washington, 2002), 55th (Tokyo, 2004), 59th (Seoul, 2008), and 64th 
(Fortaleza, 2013) World Medical Assemblies. 
Further, the trial will be conducted in accordance with: 
 International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical 
Practice (GCP) 
 The United States (US) Food and Drug Administration (FDA) Code of Federal 
Regulations, Title 21 CFR Part 312 – IND Application, Part 50 – Protection of 
Human Patients with particular focus in SubPart D, and/or Part 56 – Institutional 
Review Boards 
 US Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
11.2 
Investigator Responsibilities 
11.2.1 
Subject Information and Informed Consent 
Before being admitted to the clinical study, a parent/guardian for each subject must 
consent in writing for the subject to participate.  Written or verbal assent will also be 
obtained from each subject as required per regulations.  An approved ICF will be given to 
each parent/guardian, which will contain all United States federally required elements, all 
ICH-required elements, and HIPAA authorization information, if applicable, in language 


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that is understandable to the parent/guardian.  The consent should note that the 
Investigator is receiving compensation for the expenses of conducting the study. 
The process of obtaining the informed consent will be in compliance with all federal 
regulations, ICH requirements, and local laws. 
The Investigator or designee will review the study with the parent/guardian of each 
subject.  The review will include the nature, scope, procedures, and possible 
consequences of the subject’s participation in the study.  The consent, assent, and review 
must be in a form understandable to the parent/guardian of the subject.  The Investigator 
or designee and the parent/guardian of the subject must both sign and date the ICF after 
review and before the subject can participate in the study.  The parent/guardian of the 
subject will receive a copy of the signed and dated form, and the original will be retained 
in the site study files.  The Investigator or designee must emphasize to the 
parent/guardian of the subject that study participation is entirely voluntary and that 
consent regarding study participation may be withdrawn at any time without penalty or 
loss of benefits to which the subject is otherwise entitled. 
If the ICF is amended during the study, the Investigator must follow all applicable 
regulatory requirements pertaining to all new subjects and repeat the consent process with 
the amended ICF for any ongoing subjects. 
11.2.2 
Institutional Review Board/Independent Ethics Committee Approval and 
Other Institutional Requirements 
Before the start of the study, the study protocol, ICF, and any other appropriate 
documents will be submitted to the IRB/IEC for review and approval.  Per institutional 
requirements, the study protocol and any other appropriate documents will be submitted 
to scientific committees for approval. 
The Investigator will forward to the Sponsor, or designee (Coordinating Center), a copy 
of the IRB/IEC’s approval of this protocol, amendments, ICF and any changes to the ICF, 
based on the FDA regulations set forth in Part 56 of Title 21 of the CFR.  The 


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Investigator will also keep documentation of study approval by internal scientific 
committees per institutional requirements. 
Study medication can only be supplied to the Investigator after documentation of all 
ethical and legal requirements for starting the study has been received by the Sponsor or 
designee (Coordinating Center).  This documentation must also include an IRB/IEC 
membership list that contains members’ occupations and qualifications.  If the IRB/IEC 
will not disclose the names of the committee members, it should be asked to issue a 
statement confirming that the composition of the committee is in accordance with GCP.  
The IRB Assurance Number may be accepted as a substitute for the IRB membership list. 
The Investigator will keep the IRB/IEC informed regarding the progress of the study, per 
institutional requirements.  No changes will be made in the study without IRB/IEC 
approval, except when required to eliminate apparent immediate hazards to the subjects. 
While the study is ongoing and at study completion/discontinuation, the Investigator must 
submit to the IRB/IEC the following information in accordance with US Federal 
regulatory requirements: 
1. Information on serious or unexpected AEs, showing due diligence in providing 
this information as soon as possible 
2. Periodic reports on the progress of the study 
3. Final Study Summary upon study completion or closure. 
Notification of the end of the trial will be sent to the IRB/IEC within 30 days after 
completion of the study close-out visit.  In case the study is ended prematurely, the 
IRB/IEC will be notified within 15 days, including the reasons for the premature 
termination.  The end of the trial is defined as the date of final analysis of the study data 
according to the SAP. 


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11.2.3 
Study Documentation 
11.2.3.1 
Before the Start of the Study 
The following study documentation will be in place at the study site prior to the first 
administration of study drug: 
 Fully signed protocol and protocol-supporting manuals 
 Investigator’s Brochure29 
 Protocol Acceptance form signed by the Investigator 
 IRB/IEC-approved copy of the ICF 
 Curriculum vitae of the Investigator and all sub-investigators listed on the FDA 
Form 1572 
 A letter of IRB/IEC approval for protocol 
 A list of members of the IRB/IEC and their affiliations 
 A copy of the Investigator-signed FDA 1572 form 
 An Investigator-signed financial disclosure form 
11.2.3.2 
During the Study 
The following documentation should be added to the site study file during study conduct: 
 Any paper source forms completed and subsequently entered into the study 
database.  An explanation should be given for all missing data and any protocol 
deviations documented in the site study file. 
 Any changes to the documentation identified above in Section 11.2.3.1 
 Shipping documents relating to shipment of medication (drug accountability) 
and bioanalytical samples 
 Copies of relevant correspondence such as letters, emails, meeting notes, and 
telephone calls 


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11.2.3.3 
After the Study 
After completion or premature termination of the trial, all of the documents identified 
should be in the file, together with the following: 
 Study drug accountability documents 
 Audit certificates (if applicable) 
 Investigator delegation of responsibilities log 
 Site signature log 
 Subject screening and enrollment logs 
 Substantive correspondence with the Sponsor and IRB/IEC 
 Notification of the end of the trial to the IRB/IEC 
11.2.4 
Delegation of Investigator Responsibilities 
The Investigator must (a) ensure that any individual to whom a task is delegated is 
qualified by education, training, and experience (and licensure, if relevant) to perform the 
task; and (b) provide adequate supervision.  The Investigator should maintain a list of 
sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties. 
11.3 
Protocol Deviations and Violations 
11.3.1 
Protocol Deviation and Violation Definitions 
11.3.1.1 
Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that is under the Investigator’s control and that has not 
been approved by the IRB/IEC. 
Changes or alterations in the conduct of the trial which do not have a major impact on the 
subject's rights, safety or well-being, or the completeness, accuracy and reliability of the 
study data are considered minor protocol deviations. 


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11.3.1.2 
Protocol Violation 
A protocol violation is a deviation from the IRB/IEC-approved protocol that may affect 
the subject’s rights, safety, or well-being and/or the completeness, accuracy and 
reliability of the study data.  This includes examples such as inappropriate consent, errors 
in drug dosing, or lack of reporting of safety data. 
11.3.2 
Reporting Deviations/Violations 
Upon discovery of a major protocol deviation or violation, the Investigator is responsible 
for reporting protocol deviations or violations to the IRB/IEC and Sponsor or designee 
(Coordinating Center) within 24 hours of discovery. 
All other deviations must be reported in writing within 7 days of the event or its 
discovery. 
11.4 
Study Records Retention and Direct Access to Source Documents 
Federal regulations require that, following completion of a clinical study, a copy of all 
records of that study be maintained by the Investigator for at least the shorter of the 
following two time periods: 
 Two years after FDA approval of the drug for the indication for which it was 
investigated, or 
 In situations where no application is to be submitted or an application is not 
approved for such indication, 2 years after the Investigational New Drug (IND) 
Application is discontinued and the FDA is notified. 
The Investigator must maintain a copy of all data collected for each subject treated 
(including eCRFs and source data).  In order to assure the accuracy of data collected in 
the eCRF, it is mandatory that representatives of the Sponsor, or designee, as well as 
representatives of the FDA or other health authorities have direct access to original 
source documents (e.g., subject records, subject charts, and laboratory reports).  During 
the review of these documents, the anonymity of the subject will be respected with strict 
adherence to professional standards of confidentiality. 


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The Sponsor reserves the right to terminate the study for refusal of the Investigator to 
supply source documentation of work performed in this clinical study. 
The following includes, but is not limited to, the records that must be retained by the 
Investigator: 
1. 
Signed informed consent documents for all subjects 
2. 
Subject screening log and enrollment log 
3. 
Record of all relevant communications between the Investigator and the IRB/IEC. 
4. 
Composition of the IRB/IEC 
5. 
Record of all relevant communications between the Investigator and the Sponsor 
(or designee) 
6. 
List of sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their 
roles in the study and their signatures 
7. 
Drug accountability records (see Section 5.6.4) 
8. 
Record of any body fluids or tissue samples retained 
9. 
All other source documents (subject records, hospital records, laboratory records, 
etc.) 
10. All other documents as listed in Section 8 of the ICH consolidated guideline on 
GCP (Essential Documents for the Conduct of a Clinical Trial). 
11.5 
Study Monitoring 
In accordance with applicable regulations, GCP, and the procedures of the Sponsor or its 
designees, the Study Monitor will periodically contact the site and conduct on-site visits.  
The extent, nature, and frequency of on-site visits will be based on enrollment rate and 
data quality at the site.  Through frequent communications (e.g., letter, e-mail, and 
telephone), the Study Monitor will ensure that the investigation is conducted according to 
protocol and regulatory requirements. 
During these contacts, the monitoring activities will include: 


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1. Checking and assessing the progress of the study 
2. Reviewing study data collected to date for completeness and accuracy 
3. Reviewing compliance with protocol assessments 
4. Conducting source document verification by reviewing eCRF database data 
against source documents when available (e.g., medical records, subject diaries, 
ICF [and assent, if applicable], laboratory result reports, raw data collection 
forms) 
5. Identifying any issues and addressing resolutions. 
These activities will be done in order to verify that the: 
1. Data are authentic, accurate, and complete 
2. Safety and rights of the subjects are being protected 
3. Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
The Investigator will allow the Study Monitor direct access to all relevant documents, 
and allocate his/her time and the time of his/her staff to the Study Monitor to discuss 
findings and any relevant issues. 
In addition to contacts during the study, the Study Monitor will contact the site prior to 
the start of the study to discuss the protocol and data collection procedures with site 
personnel. 
At study closure, Study Monitors will conduct all activities as indicated in Section 11.7. 
11.6 
Quality Assurance 
At its discretion, the Sponsor or its designee may conduct a quality assurance audit of this 
study.  Auditing procedures of the Sponsor and/or its designee will be followed in order 
to comply with GCP guidelines and ensure acceptability of the study data for registration 
purposes.  If such an audit occurs, 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 any relevant issues. 


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In addition, regulatory authorities and/or the IRB/IEC may conduct an inspection of this 
study.  If such an inspection occurs, the Investigator will allow the inspector direct access 
to all source documents, eCRFs, and other study documentation for source data check 
and/or on-site audit inspection.  The Investigator must allocate his/her time and the time 
of his/her staff to the inspector to discuss findings of any relevant issues. 
An explanation will be given for all missing, unused, and spurious data in the relevant 
section of the study report. 
11.7 
Study Termination and Site Closure 
Upon completion of the study, the following activities, when applicable, must be 
conducted by the Study Monitor in conjunction with the Investigator, as appropriate: 
1. Provision of all study data to the Sponsor 
2. Data clarifications and/or resolutions 
3. Accounting, reconciliation, and final disposition of used and unused study 
medication 
4. Review of site study records for completeness. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely 
terminate this study for any reason. 
If the study is suspended or terminated for safety reason(s), the Sponsor will promptly 
inform the Investigator, and will also inform the regulatory authorities of the suspension 
or termination of the study and the reason(s) for the action.  The Investigator is 
responsible for promptly informing the IRB/IEC, and providing the reason(s) for the 
suspension or termination of the study. 
If the study is prematurely terminated, all study data must be returned to the Sponsor.  In 
addition, the site must conduct final disposition of all unused study medications in 
accordance with the Sponsor procedures for the study. 


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11.8 
Site Termination 
The Sponsor may at any time, at its sole discretion, terminate the study site for various 
reasons, including, without limitation, the following: 
1. Failure of the Investigator to enroll subjects into the study at a reasonable rate 
2. Failure of the Investigator to comply with applicable laws and/or pertinent FDA 
regulations 
3. Submission of knowingly false information from the research facility to the 
Sponsor, Study Monitor, FDA, or other regulatory authorities 
4. Insufficient adherence to protocol requirements. 
If participation of a study center is terminated, the Sponsor and Study Chair will issue a 
written notice to the Investigator.  The written notice will contain the reasons for taking 
such action.  If the study site is terminated for noncompliance, appropriate regulatory 
authorities will also be notified by the Sponsor. 
Study termination and follow-up will be performed in compliance with the conditions set 
forth in 21 CFR 312.50 and 21 CFR 312.56. 
11.9 
Discontinuation of Study 
The Sponsor reserves the right to discontinue the study for any reason at any time.  In 
addition, the study may be stopped at any time if, in the opinion of the Sponsor and 
Medical Monitor, safety data suggest that the medical safety of subjects is being or may 
become compromised.  Dose escalation may be halted upon review of data by the 
Sponsor and DSMB, according to the criteria and process described in Section 3.2. 
12 
DISCLOSURE OF DATA 
12.1 
Confidentiality 
The rights and privacy of participants in this study will be protected at all times.  All 
personal details of subjects will be treated as confidential by the Investigator and 


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handling of personal data will be in compliance with HIPAA.  All applicable data 
protection laws in the relevant countries will be adhered to at all times. 
Subject names will remain confidential and will not be included in the database.  Only 
enrollment number and birth date will be recorded on the eCRF.  If the subject’s name 
appears on any other document collected (e.g., hospital discharge summary), the name 
must be obliterated before the document is transmitted to the Sponsor or its designee.  All 
study findings will be stored in electronic databases.  The subjects’ parents or guardians 
will give explicit permission for representatives of the Sponsor, regulatory authorities, 
and the IRB/IEC to inspect the subjects’ medical records to verify the information 
collected.  The subjects’ parents or guardians will be informed that all personal 
information made available for inspection will be handled in the strictest confidence and 
in accordance with all state, local, and federal data protection/privacy laws, including, 
without limitation, the HIPAA, as applicable. 
The parents or guardians of all participants in the United States will provide written 
authorization to disclose private health information either as a part of the written ICF or 
as a separate authorization form.  The authorization will contain all required elements 
specified by 21 CFR 50, and will contain a waiver of subject access to study-related 
private health information until the conclusion of the clinical study.  The authorization 
will remain valid and in full force and effect until the first to occur of (1) the expiration of 
2 years after the study medication is approved for the indication being studied, or (2) the 
expiration of 2 years after the research program is discontinued.  Individual subject 
medical information obtained during this study is confidential, and its disclosure to third 
parties (other than those mentioned in this section) is strictly prohibited.  In addition, 
medical information obtained during this study may be provided to the subject’s personal 
physician or to other appropriate medical personnel when required in connection with the 
subject’s continued health and welfare. 
The study Investigator will maintain a subject identification log (enrollment numbers and 
corresponding subject names) to enable records to be identified. 


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12.2 
Publication 
The study Sponsor retains the ownership of all data and results collected during this 
study.  Therefore, the Sponsor reserves the right to use the data from this present study, 
either in the form of eCRFs (or copies of these), or in the form of a report, with or 
without comments and analysis in order to submit them to the US FDA or the Health 
Authorities of any country. 
Furthermore, in the event that the clinical research leads to patentable results, the 
Investigator (or entity acting on his/her behalf according to local requirements) shall 
refrain from filing patent application(s).  Patent applications will be filed by the study 
Sponsor or another entity delegated by the Sponsor. 
All information concerning the product as well as any information such as clinical 
indications for the drug, its formula, methods of manufacture and other scientific data 
relating to it, that have been provided by the Sponsor or designee, and are unpublished, 
are confidential and must remain the sole property of the Sponsor.  The Investigator will 
agree to use the information only for the purposes of carrying out this study and for no 
other purpose unless prior written permission from the Sponsor is obtained.  The Sponsor 
has full ownership of the eCRFs completed as part of the study. 
By signing the study protocol, the Investigator agrees that the results of the study may be 
used for the purposes of national and international registration, publication, and 
information for medical and pharmaceutical professionals by the Sponsor.  If necessary, 
the authorities will be notified of the Investigator's name, address, qualifications, and 
extent of involvement. 
The Sponsor or designee will prepare a final report on the study.  The Investigator may 
not publish or present any information on this study without the express written approval 
of the Sponsor.  Additionally, the Sponsor, may, for any reason, withhold approval for 
publication or presentation. 


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13 
INVESTIGATOR’S PROTOCOL AGREEMENT 
The Investigator's Revised Protocol Agreement at the front of this document must be 
signed by the study site Investigator.  The original or a copy must be kept on file by the 
Sponsor and the Investigator must retain the original or a copy.  The completed Revised 
Protocol Agreement signifies review and acceptance of the revised protocol by the 
Investigator prior to initiation of the study. 


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14 
REFERENCES 
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review and meta-analysis on the epidemiology of Duchenne and Becker 
muscular dystrophy. Neuromuscul Disord. 2014; 24(6): 482-91. 
2. Hoffman EP, Brown RH and Kunkel LM. Dystrophin: the protein product of 
the Duchenne muscular dystrophy locus. Cell. 1987; 51: 919-28. 
3. Evans NP, Misyak SA, Robertson JL, Bassaganya-Riera J, Grange RW. 
Immune mediated mechanisms potentially regulate the disease time course of 
Duchenne muscular dystrophy and provide targets for therapeutic 
intervention. PM R. 2009; 1(8): 755-68. 
4. Kumar A and Boriek AM. Mechanical stress activates the nuclear factor-
kappa B pathway in skeletal muscle fibers: a possible role in Duchenne 
muscular dystrophy. FASEB J. 2003; 17(3): 386-96. 
5. Acharyya S, Villalta SA, Bakkar N, et al. Interplay of IKK/NF-kappa B 
signaling in macrophages and myofibers promotes muscle cell degeneration in 
Duchenne muscular dystrophy. J Clin Invest. 2007; 117(4): 889-901. 
6. Dogra C, Changotra H, Wergedal JE, Kumar A. Regulation of 
phosphatidylinositol-3-kinase (PI3K)/Akt and nuclear factor-kappa B 
signaling pathways in dystrophin-deficient skeletal muscle in response to 
mechanical stretch. J Cell Physiol. 2006; 208(3): 575-85. 
7. Pahl HL. Activators and target genes of Rel/NF-kappa B transcription factors. 
Oncogene. 1999; 18(49): 6853-66. 
8. Spencer MJ, Montecino-Rodriguez E, Dorshkind K, Tidball JG. Helper 
(CD4(+)) and cytotoxic (CD8(+)) T cells promote the pathology of 
dystrophin-deficient muscle. Clin Immunol. 2001; 98(2): 235-43. 
9. Spencer MJ and Tidball JG. Do immune cells promote the pathology of 
dystrophin-deficient myopathies? Neuromuscul Disord. 2001; 11(6-7): 
556-64. 
10. Malik V, Rodino-Klapac L and Mendell JR. Emerging drug for Duchenne 
muscular dystrophy. Expert Opin Emerg Drugs. 2012; 17(2): 261-77. 
11. Reeves EK, Hoffman EP, Nagaraju K, Damsker JM, McCall JM. VBP15: 
preclinical characterization of a novel anti-inflammatory delta 9,11 steroid. 
Bioorg Med Chem. 2013; 21(8): 2241-9. 


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12. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of 
Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and 
psychosocial management. Lancet Neurol. 2010; 9(1): 77-93. 
13. Pane M, Mazzone ES, Sivo S, et al. Long term natural history data in 
ambulant Boys with Duchenne muscular dystrophy: 36-month changes. 
PlosOne. 2014; 10: 1371/journal.pone.0108205. 
14. Manzur AY, Kuntzer T, Pike M, Swan AV. Glucocorticoid corticosteroids for 
Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2008; (1): 
CD003725. 
15. Heier CR, Damsker JM, Yu Q, et al. VBP15, a novel anti-inflammatory and 
membrane-stabilizer improves muscular dystrophy without side effects. 
EMBO Mol Med. 2013; 5(10): 1569-85. 
16. Damsker JM, Dillingham BC, Rose MC, et al. VBP15, a glucocorticoid 
analogue, is effective at reducing allergic lung inflammation in mice. Plos 
One. 2013; 8(5): e63871. 
17. Dillingham BC, Knoblach SM, Many GM, et al. VBP15, a novel anti-
inflammatory, is effective at reducing the severity of murine experimental 
autoimmune encephalomyelitis. Cell Mol Neurobiol. 2015; 35(3): 377-87. 
18. Dadgar S, Wang Z, Johnston H, et al. Asynchronous remodeling is a driver of 
failed regeneration in Duchenne muscular dystrophy. J Cell Biol. 2014; 
207(1): 139-58.  
19. Raman SV, Hor KN, Mazur W, Halnon NJ, Kissel JT, He X, Tran T, Smart S, 
McCarthy B, Taylor MD, Jefferies JL, Rafael-Fortney JA, Lowe J, Roble SL, 
Cripe LH. Eplerenone for early cardiomyopathy in Duchenne muscular 
dystrophy: a randomised, double-blind, placebo-controlled trial. Lancet 
Neurol. 2015; 14(2): 153-61. 
20. Avioli LV. Glucocorticoid effects on statural growth. Br J Rheumatol. 1993;  
32 Suppl 2: 27-30. 
21. Wolthers OD and Pedersen S. Short term linear growth in asthmatic children 
during treatment with prednisolone. BMJ. 1990; 301(6744): 145-8. 
22. Bircan Z, Soran M, Yildirim I, et al. The effect of alternate-day low dose 
prednisolone on bone age in children with steroid dependent nephrotic 
syndrome. Int Urol Nephrol. 1997; 29(3): 357-61. 


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20 January 2017 
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23. Manolagas SC, Weinstein RS. New developments in the pathogenesis and 
treatment of steroid-induced osteoporosis. J Bone Miner Res. 1999; 14(7): 
1061-6. 
24. Sali A, Guerron AD, Gordish-Dressman H, et al. Glucocorticoid-treated mice 
are an inappropriate positive control for long-term preclinical studies in the 
mdx mouse. Plos One. 2012; 7(4): e34204.8 
25. Kauh E, Mixson L, Malice M-P, Mesens S, Ramael S, Burke J, Reynders T, 
Van Dyck K, Beals C, Rosenberg E, and Ruddy M. Prednisone affects 
inflammation, glucose tolerance, and bone turnover within hours of treatment 
in healthy individuals. European J Endocrinol. 2012; 166: 459–67. 
26. Wehling-Henricks M, Oltmann M, Rinaldi C, Myung KH, and Tidball JG. 
Loss of positive allosteric interactions between neuronal nitric oxide synthase 
and phosphofructokinase contributes to defects in glycolysis and increased 
fatigability in muscular dystrophy. Hum Mol Genet. 2009; 18(18): 3439-51. 
27. Younes M, Neffati F, Touzi M, Hassen-Zrour S, Fendri Y, Bejia I, Ben Amor 
A, Bergaoui N, and Najjar MF. Systemic effects of epidural and intraarticular 
glucocorticoid injections in diabetic and non-diabetic patients. Joint Bone 
Spine. 2007; 74(5): 472-6. 
28. Moon HJ, Choi KH, Lee SI, Lee OJ, Shin JW, and Kim TW. Changes in 
blood glucose and cortisol levels after epidural or shoulder intra-articular 
glucocorticoid injections in diabetic or nondiabetic patients. Am J Phys Med 
Rehabil. 2014; 93(5): 372-8. 
29. Investigator’s Brochure, Version 3, Vamorolone (17α,21-dihydroxy-16α-
methyl-pregna-1,4,9(11)-triene-3,20-dione) 4% Oral Suspension,  ReveraGen 
BioPharma, Inc., January 23, 2016. 
30. Hathout Y, Brody E, Clemens PR, et al. Large-scale serum protein biomarker 
discovery in Duchenne muscular dystrophy. Proc Natl Acad Sci USA. 2015; 
112(23): 7153-8. 
31. Mayhew JE, Florence JM, Mayhew TP, et al. Reliable surrogate outcome 
measures in multicenter clinical trials of Duchenne muscular dystrophy. 
Muscle Nerve. 2007; 35(1): 36-42. 
32. Brooke MH, Griggs RC, Mendell JR, et al. Clinical trial in Duchenne 
dystrophy. I. The design of the protocol. Muscle & Nerve. 1981; 4(3): 186-97. 


Vamorolone 
20 January 2017 
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Document No. VBP15-002-R2 
Protocol No. VBP15-002 
IND 118,942 
 
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33. Mazzone ES, Messina S, Vasco G, et al. Reliability of the North Star 
Ambulatory Assessment in a multicentric setting. Neuromuscul Disord. 2009; 
19(7): 458-61. 
34. McDonald CM, Henricson EK, Han JJ, et al. The 6-minute Walk Test as a 
new outcome measure in Duchenne muscular dystrophy. Muscle Nerve. 2010; 
41(4): 500-10. 


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15 
APPENDICES 


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Appendix 15.1 
Vamorolone Dose Calculation Worksheet 
The volume per dose is determined by the subject’s dosing level (dose level group) and 
screening body weight (in kg): 
Subject Weight (kg) x  Dose Level (mg/kg) 
= Subject Dose (in mL) 
40 mg/mL 
Subject weight (in kg) should be rounded to the nearest whole integer for the calculation 
of volume per dose.  
Calculated dose volume will be rounded to the nearest 0.01 mL (1 mL syringe), 0.1 mL 
(3 mL syringe), or 0.2 mL (5 mL syringe), depending upon the total dose volume and 
calibration of the volumetric syringe to be used for administration of dose, as shown in 
the examples below: 
Example 1: Dose volume calculation for a subject enrolled in Dose Level Group 1 
(0.25 mg/kg) with a body weight of 19 kg:  
Subject Weight (19 kg) x  Dose Level (0.25 mg/kg) 
= 0.119 mL 
40 mg/mL 
The subject will receive a dose volume of 0.119 mL per dose throughout the 14-day 
Treatment Period.  Dose will be administered using a 1 mL volumetric syringe rounded 
to the nearest 0.01 mL, or for this subject, 0.12 mL daily. 
Example 2: Dose volume calculation for a subject enrolled in Dose Level Group 2 
(0.75 mg/kg) with a body weight of 15 kg:  
Subject Weight (15 kg) x Dose Level (0.75 mg/kg) 
= 0.281 mL 
40 mg/mL 
The subject will receive a dose volume of 0.281 mL per dose throughout the 14-day 
Treatment Period.  Dose will be administered using a 1 mL volumetric syringe rounded 
to the nearest 0.01 mL, or for this subject, 0.28 mL daily. 
Example 3: Dose volume calculation for a subject enrolled in Dose Level Group 3 
(2.0 mg/kg) with a body weight of 27 kg:  
Subject Weight (27 kg) x Dose Level (2.0 mg/kg) 
=1.35 mL 
40 mg/mL 


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The subject will receive a dose volume of 1.35 mL per dose throughout the 14-day 
Treatment Period.  Dose will be administered using a 3 mL volumetric syringe rounded 
to the nearest 0.1 mL, or 1.4 mL daily. 
Example 4: Dose volume calculation for a subject enrolled in Dose Level Group 4 
(6.0 mg/kg) with a body weight of 23 kg:  
Subject Weight (23 kg) x  Dose Level (6.0 mg/kg) 
=3.45 mL 
40 mg/mL 
The subject will receive a dose volume of 3.45 mL per dose throughout the 14-day 
Treatment Period.  Dose will be administered using a 5 mL volumetric syringe rounded 
to the nearest 0.2 mL, or 3.4 mL daily. 
 
Each subject enrolled in the study will be dispensed 100 mL bottle(s) of vamorolone 4% 
suspension at the Day 1 Visit, for use throughout the Treatment Period, Days 1-14.  Each 
bulk dispensed bottle should be used for one subject only.  Each bottle dispensed to the 
subject and ready for administration to subjects will be labeled with subject study 
number, dispense date, protocol number, dose level and volume to dispense per dose.  
Any unused or partially used drug product should be returned at the Week 2 Visit and 
retained at the study site for investigational drug accountability monitoring. 
 

SAP_001.pdf: 
 
 
 
ReveraGen BioPharma, Inc. 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol Title: 
A Phase IIa, Open-Label, Multiple Ascending Dose Study to 
Assess the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, and Exploratory Efficacy of Vamorolone 
in Boys with Duchenne Muscular Dystrophy (DMD) 
Protocol Number 
VBP15-002 
Phase: 
Phase IIa 
Sponsor: 
ReveraGen BioPharma, Inc. 
155 Gibbs Street  
 
Suite 433 
Rockville, MD  20850 
 
Author: 
Philip Shale, PhD 
Summit Analytical, LLC 
8354 Northfield Blvd., Bldg. G Suite 3700 
Denver, CO 80238 
SAP Date: 
2018-01-31 
Status: 
FINAL V1.0 
 
 
 




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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS .......................................................................................................................... 3 
2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................ 6 
3. 
INTRODUCTION..................................................................................................................................... 9 
3.1. 
Preface .......................................................................................................................................... 9 
3.2. 
Purpose of Analyses...................................................................................................................... 9 
3.3. 
Summary of Statistical Analysis Changes to the Protocol ............................................................ 10 
4. 
STUDY OBJECTIVES AND ENDPOINTS............................................................................................ 11 
4.1. 
Study Objectives ......................................................................................................................... 11 
4.1.1. 
Primary Objective...................................................................................................... 11 
4.1.2. 
Secondary Objectives ................................................................................................ 11 
4.1.3. 
Exploratory Objectives .............................................................................................. 11 
4.2. 
Study Endpoints .......................................................................................................................... 12 
4.2.1. 
Primary Endpoints ..................................................................................................... 12 
4.2.2. 
Secondary Endpoints ................................................................................................. 13 
4.2.3. 
Exploratory Endpoints ............................................................................................... 14 
5. 
STUDY METHODS ............................................................................................................................... 16 
5.1. 
General Study Design and Plan ................................................................................................... 16 
5.2. 
Inclusion – Exclusion Criteria and General Study Population ...................................................... 19 
5.3. 
Randomization and Blinding ....................................................................................................... 19 
5.4. 
Analysis Variables ...................................................................................................................... 19 
6. 
SAMPLE SIZE ....................................................................................................................................... 19 
7. 
GENERAL CONSIDERATIONS ........................................................................................................... 19 
7.1. 
Analysis Populations................................................................................................................... 19 
7.1.1. 
Safety Population ...................................................................................................... 19 
7.1.2. 
Pharmacokinetic Population (PK) .............................................................................. 20 
7.2. 
Covariates and Subgroups ........................................................................................................... 20 
7.2.1. 
Planned Covariates .................................................................................................... 20 
7.2.2. 
Planned Subgroups .................................................................................................... 20 
7.2.3. 
Post hoc Subgroups ................................................................................................... 20 
7.3. 
Management of Analysis Data .................................................................................................... 20 
7.3.1. 
Data Handling ........................................................................................................... 20 
7.3.2. 
Missing Data ............................................................................................................. 20 
7.3.3. 
Handling of Early Termination Visit Information ...................................................... 22 
7.3.4. 
Pooling of Investigational Sites ................................................................................. 22 
7.3.5. 
Coding Conventions for Events and Medications ....................................................... 22 
7.3.6. 
Baseline Visits ........................................................................................................... 22 
7.3.7. 
Analysis Software...................................................................................................... 23 
7.3.8. 
Study Data ................................................................................................................. 23 
7.4. 
Planned Study Analyses .............................................................................................................. 24 
7.4.1. 
Statistical Summaries: Descriptive and Inferential ..................................................... 24 
7.4.2. 
Interim Analyses and Data Monitoring ...................................................................... 25 
7.4.3. 
Final Analysis............................................................................................................ 25 
7.5. 
Multiple Testing Procedures ....................................................................................................... 25 


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8. 
SUMMARY OF STUDY DATA ............................................................................................................ 26 
8.1. 
Subject Summary Grouping ........................................................................................................ 26 
8.2. 
Patient Disposition ...................................................................................................................... 26 
8.3. 
Protocol Deviations/Violations ................................................................................................... 26 
8.4. 
Demographics and Baseline Characteristics ................................................................................ 26 
8.5. 
Medical History .......................................................................................................................... 26 
8.6. 
Prior and Concomitant Medications ............................................................................................ 27 
8.7. 
Treatment Compliance ................................................................................................................ 27 
9. 
EFFICACY ANALYSES ........................................................................................................................ 27 
9.1. 
Clinical Efficacy ......................................................................................................................... 27 
10. SAFETY ANALYSES ............................................................................................................................ 28 
10.1. 
Adverse Events ........................................................................................................................... 28 
10.2. 
Vital Signs, 12-Lead ECG, and Laboratory Outcomes ................................................................ 29 
10.3. 
Physical Exam ............................................................................................................................ 30 
10.4. 
Other Safety Measures ................................................................................................................ 30 
11. PHARMACOKINETIC (PK) ANALYSES ............................................................................................. 30 
12. PHARMACODYNAMIC (PD) SERUM AND OTHER BIOMARKERS................................................ 30 
13. REPORTING CONVENTIONS .............................................................................................................. 31 
13.1. 
General Reporting Conventions .................................................................................................. 31 
11.1 
Population Summary Conventions .............................................................................................. 32 
12 
REFERENCES ....................................................................................................................................... 33 
13 
APPENDICES ........................................................................................................................................ 34 
13.1 
List of Planned Tables ................................................................................................................ 34 
13.2 
List of Planned Listings .............................................................................................................. 37 
13.3 
List of Planned Figures ............................................................................................................... 39 
13.4 
Calculating BMI Z-Scores .......................................................................................................... 41 
13.5 
SAP Amendment Summary of Changes ...................................................................................... 42 
 
 


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LIST OF TABLES 
 
Table 1: 
Dose level group composition .................................................................................... 16 
Table 2 
Schedule of Time and Events..................................................................................... 17 
 
 
LIST OF FIGURES 
 
Figure 1 
SDTM, ADaM, and TFL Development and Validation .............................................. 24 
 
 
 


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2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Only abbreviations and terms relevant to the SAP are repeated herein. The reader is referred 
to the protocol for the complete and comprehensive list of abbreviations and definitions of 
terms for the study. 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BL 
baseline 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
Celsius 
CD23 
cluster designation 23 
CDC 
Centers for Disease Control and Prevention 
CINRG 
Cooperative International Neuromuscular Research Group 
CK 
creatine kinase 
cm 
centimeter 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
carboxy-terminal telopeptide 
DHEA 
Dehydroepiandrosterone 
dL 
deciliter 
DMD 
Duchenne muscular dystrophy 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GLDH 
Glutamate dehydrogenase 
GLP 
Good Laboratory Practice 


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HbA1c 
hemoglobin A1c 
HDL 
high density lipoprotein 
HEENT 
head, eyes, ears, nose and throat 
HIPAA 
Health Insurance Portability and Accountability Act 
hr 
hour 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IGFBP-2 
insulin-like growth factor-binding protein 2 
IGFBP-5 
insulin-like growth factor-binding protein 5 
IL-22BP 
interleukin-22 binding protein 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
L 
liter 
LLC 
Limited Liability Company 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
m 
meter 
MAD 
multiple ascending dose (study) 
MD 
Medical Doctor (physician) 
MDC 
macrophage-derived chemokine 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute 
MIST 
Metabolites in Safety Testing 
mL 
milliliter 
MMP-3 
matrix metalloproteinase-3 
MMP-12 
matrix metalloproteinase-12 
MTD 
maximum tolerated dose 
ng 
nanogram 
No., n 
number 
nmol 
nanomole 
NSAA 
North Star Ambulatory Assessment 
%CV 
percentage coefficient of variation 
PD 
pharmacodynamic(s) 
P1NP 
serum aminoterminal propeptide of type I collagen 
PK 
pharmacokinetic(s) 


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PR [PQ] 
time from onset of P wave to start of the QRS complex 
QMT 
quantitative muscle testing 
QRS 
in electrocardiography, the complex consisting of Q, R, and S 
waves, corresponding to depolarization of ventricles [complex] 
QT 
in cardiology, the time between the start of the Q wave and end 
of the T wave 
QTc 
corrected QT interval  
QTcF 
QT corrected for HR using Fridericia's method 
6MWT 
Six-minute Walk Test 
RR 
in electrocardiography, the interval between successive Rs 
(peaks of QRS complexes) 
SAD 
single ascending dose (study) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCR 
screening 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TTCLIMB 
Time to Climb (Test) 
TTSTAND 
Time to Stand (Test) 
TTRW 
Time to Run/Walk (Test) 
ULN 
upper limit of normal 
US 
United States 
vs. 
versus 
WBC 
white blood cell 
WHO 
World Health Organization 
 


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3. 
INTRODUCTION 
3.1. 
Preface 
This document presents a statistical analysis plan (SAP) for ReveraGen BioPharma, Inc. 
Protocol VBP15-002, (A Phase IIa Open-Label, Multiple Ascending Dose Study to Assess the 
Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Exploratory Efficacy of 
Vamorolone in Boys with Duchenne Muscular Dystrophy (DMD)). This SAP will provide the 
details and methods for analysis and reporting of the subject characteristics, safety, and 
exploratory efficacy information. A separate PK Analysis plan, and report, will be developed 
for this study that provides the details and methods for the analysis and reporting of 
pharmacokinetic (PK) and Metabolite in Safety Testing (MIST) analyses.  
Reference materials for this statistical plan include the protocol VBP15-002 (Revision #2 
Dated: 20 January 2017) and Case Report Forms (Version 1.0, 1.1, and 1.2). 
The SAP described hereafter is an a priori plan.  The SAP will be finalized and approved 
prior to database lock.  Statistical programming may occur as study data accumulate in order 
to have analysis programs ready at the time the study finishes.     
The conduct of the study in the field is to be considered independent of any study outcome 
that might materialize upon enactment of the currently proposed statistical plan.  
3.2. 
Purpose of Analyses 
The purposes of the planned analyses described in this SAP are to assess the safety, 
tolerability, pharmacodynamics, and exploratory efficacy of multiple ascending oral doses of 
vamorolone in ambulant boys ages 4-< 7 years with DMD, and to investigate exploratory 
muscle strength and flexibility endpoints.  Results from the analyses completed will be 
included in the final clinical study report for VBP15-002, and may also be utilized for 
regulatory submissions, manuscripts, additional endpoint specific reports, or other clinical 
development activities. 
Post-hoc exploratory analyses not identified in this SAP may be performed to further 
examine the study data and provide context for study results. These analyses will be clearly 
identified, where appropriate, in the final clinical study report.  
Additional analyses not prospectively identified in this SAP may also be completed for 
publications, additional endpoint specific reports, regulatory, or funding inquiries. These 
analyses, if performed, may not be reported in the clinical study report, but will be fully 
documented in the document containing the additional analyses. 


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3.3. 
Summary of Statistical Analysis Changes to the Protocol 
The analyses described in this analysis plan are consistent with the analyses described in the 
study protocol with the exceptions noted below. 
Safety lab and PD biomarker results will be tested inferentially using paired t-tests.  The 
protocol states that no inferential statistics will be presented. 
Laboratory endpoints that will be included in this SAP that are not included in the protocol 
include GLDH, serum creatine kinase, and safety pharmacodynamic biomarkers (, cortisone, 
androstenedione, progesterone, DHEA, Leptin, MMP-3, Angiotensinogen, Afamin, IGFBP-
5, GHBP), and efficacy pharmacodynamic biomarkers (CD23, MDC/CCL22, IL-22RA2/IL-
22BP, Lymphototoxin a1/b2, IGFBP-2, CD49a/ITGa1/b1, MMP-12, Protein C, ANGPT2, 
FGG, LY9. 
  


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4. 
STUDY OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints defined in the protocol include safety, tolerability, 
pharmacokinetics, pharmacodynamics, and exploratory efficacy endpoints. Objectives and 
pre-specified endpoints are as follows: 
4.1. 
Study Objectives 
4.1.1. 
Primary Objective 
• To evaluate the safety and tolerability of multiple ascending oral doses of vamorolone 
in ambulant boys ages 4-< 7 years with DMD. 
4.1.2. 
Secondary Objectives 
• To investigate the single-dose and multiple-dose pharmacokinetics (PK) of oral 
vamorolone at multiple dose levels in ambulant boys ages 4-< 7 years with DMD; 
• To investigate the effects of single and multiple oral doses of vamorolone on serum 
pharmacodynamic (PD) biomarkers bridged to later clinical safety concerns (adrenal 
suppression [first in morning cortisol], bone turnover [osteocalcin, CTX, P1NP], 
insulin resistance [fasting insulin, glucose; HbA1c]) in ambulant boys ages 4-< 7 
years with DMD; 
• To evaluate metabolites of vamorolone in Metabolites in Safety Testing (MIST) 
assessments following administration of multiple ascending oral doses. 
Note: Secondary objectives associated with the characterization of  PK parameter 
estimates, and MIST will be specified in a separate PK analysis plan and report. 
 
4.1.3. 
Exploratory Objectives 
• To investigate the effect of multiple oral doses of vamorolone on muscle strength, 
mobility, and functional exercise capacity, as measured by Quantitative Muscle 
Testing (QMT), Time to Run/Walk 10 meters Test (TTRW), Time to Stand Test 
(TTSTAND), Time to Climb Test (TTCLIMB), North Star Ambulatory Assessment 
(NSAA), and Six-minute Walk Test (6MWT) in ambulant boys ages 4-< 7 years with 
DMD. 
• To investigate the effect of multiple oral doses of vamorolone on pharmacodynamic 
biomarkers for safety and efficacy, not bridged to later clinical safety or efficacy 
endpoints. 


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These exploratory endpoints are to assess the potential efficacy and provide signal 
information that may be used for planning future efficacy studies with vamorolone 
4.2. 
Study Endpoints  
4.2.1. 
Primary Endpoints 
Primary endpoints from the protocol include the following: 
• Adverse events  
• Vital Signs 
o Supine blood pressure 
o Heart rate 
o Respiratory rate 
o Oral temperature 
• Body weight 
• Laboratory tests 
o Hematology 
 Red blood cell (RBC) count 
 Hemoglobin 
 Hematocrit 
 Numerical platelet count 
 WBC count and differential 
• White blood cell counts 
• Neutrophils cell counts 
• Lymphocytes cell counts 
• Eosinophils cell counts 
o Chemistry 
 Sodium 
 Potassium 
 Chloride 
 Calcium 
 Inorganic phosphorus 
 Blood urea nitrogen (BUN) 
 Creatinine 
 Total protein 
 Albumin 
 Bicarbonate 
 Lactate dehydrogenase (LDH) 
 Total Bilirubin (if out of normal range, direct bilirubin will be 
reported) 
 Uric acid 
 Glucose 


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 Alkaline phosphatase (ALP) 
 Gamma glutamyl transferase (GGT) 
 Aspartate aminotransferase (AST) 
 Alanine aminotransferase (ALT) 
 Glutamte dehydrogenase (GLDH) 
 Lipase 
 Amylase 
o Urinalysis 
 Urine glucose 
 Urine protein 
 Ketones 
 pH 
 Leukocyte esterase 
 Blood 
 WBC/hpf 
 RBC/hpf 
 Casts 
 Bacteria 
o Lipid profile 
 Triglycerides 
 Total cholesterol 
 Low density lipoprotein (LDL) 
 High density lipoprotein (HDL) 
o Liver Safety 
 GLDH 
• 12-lead electrocardiogram (ECG) 
o QRS duration 
o PR [PQ] interval 
o RR interval [interbeat interval] 
o QT interval  
o QTc 
o QTcF 
o Heart rate 
• Physical exam findings of abnormality 
• Subject assessment of vamorolone acceptability by a 5-point hedonic scale 
 
4.2.2. 
Secondary Endpoints 
Secondary endpoints from the protocol include the following: 
• PK 
o plasma concentration levels of vamorolone and metabolites (Metabolites in 
Safety Testing – MIST) (Addendum – Separate report). 


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o pharmacokinetic parameter estimates for vamorolone (Addendum – Separate 
report). 
• PD 
o Bone turnover marker immunoassay 
 Osteocalcin 
 Serum aminoterminal propeptide of type I collagen (P1NP) 
 Carboxy-terminal telopeptide (CTX) 
o Adrenal axis suppression immunoassay 
 Cortisol (first in morning) 
 11-deoxycortisol (daytime) 
 17-hydroxyprogesterone (daytime) 
 Adrenocorticotropic hormone (daytime) 
 Corticosterone (daytime) 
 Testosterone (daytime) 
 Cortisol (daytime) 
o Insulin resistance 
 Fasting insulin 
 Fasting glucose 
 HbA1C 
 
4.2.3. 
Exploratory Endpoints 
• Efficacy 
o QMT 
o TTSTAND 
o TTCLIMB 
o TTRW 
o NSAA 
o 6MWT 
• Biomarker (Addendum – separate report) 
o SOMAscan aptamers for safety 
 Insulin 
 Leptin 
 MMP-3 
 Angiotensinogen 
 Afamin 
 IGFBP-5 
 GHBP 
o  SOMAscan aptamers for efficacy 
 CD23 
 MDC or CCL22 
 IL-22RA2 or IL-22BP 
 Lymphototoxin a1/b2 
 IGFBP-2 


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 CD49a or ITGa1/b1 
 MMP-12 
 Protein C 
 ANGPT2 
 FGG 
 LY9 
o Serum chemistry markers for efficacy 
 Serum Creatine Kinase 
 


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5. 
STUDY METHODS 
5.1. 
General Study Design and Plan 
As background for the statistical methods presented below, this section provides an overview 
of the study design and plan of study execution.  The protocol is the definitive reference for 
all matters discussed in what follows. 
This is a Phase IIa, multiple site, open-label, multiple ascending dose study to evaluate the 
safety, tolerability, PK, PD biomarker responsiveness, and exploratory clinical efficacy of 
vamorolone administered once daily by liquid oral suspension over a Treatment Period of 14 
days to ambulant boys ages 4-< 7 years with DMD. 
The study is comprised of a Pretreatment Screening Period of up to 26 days duration, a 1-day 
Pretreatment Baseline Period, a 14-day Treatment Period, and a 14-day Follow-up Period.  
Four dose level groups of approximately 12 subjects each will receive vamorolone once daily 
for 14 days (Table 1).  The planned dose levels are 0.25 mg/kg (Dose Level Group 1), 0.75 
mg/kg (Dose Level Group 2), 2.0 mg/kg (Dose Level Group 3), and 6.0 mg/kg (Dose Level 
Group 4).  Treatment of the approximately 12 subjects in each dose level group will be 
completed and safety results evaluated prior to enrollment of subjects in each subsequent 
dose level group.  The process of dose escalation will be based on the appearance of dose-
limiting toxicities. 
Table 1: 
Dose level group composition 
Planned Dose 
Level Group 
No. Subjects in 
Dose Level Group 
Vamorolone Dose 
Treatment 
Duration 
1 
12 
0.25 mg/kg 
14 days 
2 
12 
0.75 mg/kg 
14 days 
3 
12 
2.0 mg/kg 
14 days 
4 
12 
6.0 mg/kg 
14 days 
 
Table 2 presents the schedule of study procedures. 
 
 


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Table 2 
Schedule of Time and Events 
 
Pretreatment 
Period 
Treatment Period 
Post-treatment 
Follow-up 
SCR 
BL 
 
Day 
Day 
Week 
Week 
Visit/Contact 
-28 to -3 
-1 
1 
1 
(7±1d) 
2a 
(14±1d) 
3 
(21±2d) 
4b 
(28±3d) 
Informed Consentc 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
Blood for Chicken Pox Immunity 
Xd 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
X 
Vital Signse 
X 
Xf 
Xf 
X 
Xf 
 
X 
Blood for Clinical Labsg 
X 
 
 
 
X 
 
X 
Urinalysisg 
X 
 
 
 
X 
 
X 
12-lead ECG 
Xh 
 
 
 
Xh 
 
Xh 
Enrollment 
 
X 
 
 
 
 
 
Dispense Study Medication 
 
 
X 
 
 
 
 
Return Study Medication 
 
 
 
 
X 
 
 
Study Medication Dosingi 
 
 
X 
 
X 
 
 
Blood for Plasma PK 
 
Xj 
Xj 
 
Xj 
 
 
Blood for Metabolites in Safety Testing (MIST)q 
 
 
 
 
Xq 
 
 
Blood for Serum PD Biomarker Panel 
Xk 
Xl 
Xm 
 
Xl,n 
 
Xn 
Quantitative Muscle Testing (QMT) 
X 
X 
 
 
Xo 
 
X 
Time to Run/Walk 10 Meters Test (TTRW) 
X 
X 
 
 
Xo 
 
X 
Time to Stand Test (TTSTAND) 
X 
X 
 
 
Xo 
 
X 
Time to Climb Test (TTCLIMB) 
X 
X 
 
 
Xo 
 
X 
North Star Ambulatory Assessment (NSAA) 
X 
X 
 
 
Xo 
 
X 
Six-minute Walk Test (6MWT) 
X 
X 
 
 
Xo 
 
X 
Study Medication Acceptability Assessment 
 
 
Xp 
 
Xp 
 
 


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Pretreatment 
Period 
Treatment Period 
Post-treatment 
Follow-up 
SCR 
BL 
 
Day 
Day 
Week 
Week 
Visit/Contact 
-28 to -3 
-1 
1 
1 
(7±1d) 
2a 
(14±1d) 
3 
(21±2d) 
4b 
(28±3d) 
Study Medication Accountability 
 
 
 
 
X 
 
 
Safety Monitoring 
 
 
X 
X 
X 
X 
X 
AE/SAE Recording 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
 
X 
X 
X 
X 
X 
Telephone Contact 
 
 
 
 
 
X 
 
Discharge from Study 
 
 
 
 
 
 
X 
SCR=Screening Period; BL=Baseline Period, within 24 hours prior to administration of the first dose of study drug. 
a. 
Subjects who prematurely discontinue from the study prior to Week 2 (Day 14) should complete the Week 2 (Days 13 and 14) procedures at the time of early 
discontinuation and enter the 14-day Follow-up Period. 
b. 
Subjects who prematurely discontinue from the study after Week 2 (Day 14) but prior to the scheduled Week 4 (Day 28) Follow-up Visit should return to the study site for 
Week 4 (Day 28) procedures. 
c. 
Informed Consent must be obtained prior to any study-related procedures. 
d. 
All subjects will have blood collected at the Screening Visit for testing for IgG antibodies to varicella.  Eligibility for study enrollment is dependent upon availability of 
positive result prior to enrollment. 
e. 
Supine blood pressure, oral temperature, respiratory rate, and heart rate.  At visits where blood is also drawn, vital signs must be recorded prior to blood draws.  
f. 
On Days 1 and 14, vital signs will be recorded at 0.5 hour pre-dose and 0.5, 1, 2, 4, 6, and 8 hours post-dose, prior to PK blood draws where time points coincide. 
g. 
Blood for chemistry, hematology, lipids; urinalysis by dipstick and microscopic analysis. 
h. 
ECG must be conducted prior to vital signs.  
i. 
The first dose of study medication on Day 1 and the final dose of study medication on Day 14 will be administered in the study clinic; all other doses will be taken 
at home. 
j. 
Blood collected for plasma PK analysis on Day -1 (0.5 hour pre-dose) and 1, 2, 4, 6, and 8 hours post-dose on Day 1; and 0.5 hour pre-dose and 1, 2, 4, 6, and 8 hours 
post-dose on Day 14.  Subjects must be fasting at the time of collection of Day 1 and Day 14 pre-dose samples. 
k. 
cortisol, ACTH, P1NP, osteocalcin, CTX, 17- hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol, hemoglobin A1c (HbA1c), SomaScan, and proteomics 
testing. 
l. 
Blood collected for insulin and glucose during Screening (0.5 hour pre-dose) and on Day 14 (0.5 hour pre-dose).  Subjects must be fasting at the time of blood collection. 
m. Day 1, 6 hours post dose: cortisol, ACTH, P1NP, osteocalcin, CTX, 17- hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol.  
n. 
Day 14, 6 hours post-dose: ): cortisol, ACTH, P1NP, osteocalcin, CTX, 17- hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol, SomaScan, and 
proteomics testing. Week 4 (Day 28): cortisol, ACTH, P1NP, osteocalcin, CTX, 17- hydroxyprogesterone, testosterone, corticosterone, 11-deoxycortisol,  and proteomics 
testing. 
o. 
Week 2 clinical efficacy assessments to be completed on Day 13. 
p. 
Study medication acceptability assessment performed immediately pre-dose (smell) and post-dose (taste). 
q. 
MIST assessment will be performed on portions of the blood samples collected for PK analysis; no additional blood will be collected. 


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5.2. 
Inclusion – Exclusion Criteria and General Study Population 
Approximately 12 subjects with confirmed diagnosis of DMD (4-<7 years of age) will be 
enrolled into each of the four cohorts (48 subjects total).  The inclusion and exclusion criteria 
defined in the protocol apply to all subjects and are not repeated herein the SAP. 
5.3. 
Randomization and Blinding 
This is an open-label study, and no randomization schedule or blinding of study medication 
is applicable. Subjects were assigned to dosing cohort sequentially on enrollment and 
screening. 
5.4. 
Analysis Variables 
Variables to be analyzed include demographics and baseline characteristics, safety variables, 
efficacy variables, PK variables (observed and predicted concentration levels and estimated 
pharmacokinetic parameters), etc. as described throughout this SAP.  Derived variables from 
study endpoints are described with the sections describing the analyses for these endpoints. 
Unless otherwise noted, baseline is defined as the last measurement taken prior to first 
exposure to study drug, including Day 1 measurements taken pre-dosing. 
6. 
SAMPLE SIZE 
A sample of 12 in each cohort is large enough to have a confidence interval of no wider than 
50% for the proportion of adverse events assessed or any other event outcome.  For the 
continuous outcomes such as safety laboratory markers or pharmacodynamics markers, a 
two-sided 95.0% confidence interval for the mean will be no wider than 0.8 standard 
deviation (SD) from the observed mean, with 90.0% coverage probability, based on the 
t statistic; thus, the total confidence interval will be approximately 1.6 SDs wide for any 
continuous parameter if its underlying distribution is approximately normal. 
7. 
GENERAL CONSIDERATIONS 
7.1. 
Analysis Populations 
There will be two (2) analysis populations defined for this study.  
7.1.1. 
Safety Population 
All subjects who receive at least one dose of vamorolone study medication will be included 
in the Safety Population. 


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7.1.2. 
Pharmacokinetic Population (PK) 
All subjects who receive at least one dose of vamorolone study medication and have 
sufficient quantifiable plasma concentration data for PK analysis will be included in the PK 
population. [Note that the PK population will be determined by the study pharmacokineticist 
upon review of the concentration information for each subject in each cohort. Inclusion or 
exclusion into the PK population will be fully documented.] 
7.2. 
Covariates and Subgroups 
7.2.1. 
Planned Covariates 
No covariates will be included in statistical analyses. 
7.2.2. 
Planned Subgroups 
Descriptive summaries for BMI and efficacy endpoints will be presented by age of study 
subjects (4 to 5 years and 6 to <7 years).   
7.2.3. 
Post hoc Subgroups 
No post-hoc subgroups are initially planned for this study. However, after all planned 
analyses are completed additional post-hoc subgroups may be defined to further explore 
study results. Any additional post-hoc subgroups will be fully detailed in the final CSR. 
 
7.3. 
Management of Analysis Data 
7.3.1. 
Data Handling 
For the summary of continuous values and laboratory shift tables, unscheduled tests will be 
included with the time of the nearest regularly scheduled test.  If there is a scheduled test and 
one or more unscheduled tests assigned to the same time point, the most conservative test 
(i.e., a test with low or high results) will be used.  Repeated tests will be included only if they 
reflect abnormal (low or high) results and the corresponding original results are normal. All 
laboratory values, for all visits, will be provided in by-subject listings. 
7.3.2. 
Missing Data 
Every effort will be made to collect all data. However, despite best efforts, missing or 
incomplete data may be reported. All missing or partial data will be presented in the subject 
data listing, as they are recorded on the eCRF. 
Subjects lost to follow-up or withdrawn will be included in statistical presentations up to the 
point of their last evaluation. Unless otherwise specified, in general no imputation of values 
for missing data will be performed. 


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7.3.2.1. 
Handling of Missing Date Values 
Partial or Missing Dates/Times 
The following conventions will be used to impute missing portions of dates for adverse events 
and concomitant medications, if warranted.  Note that the imputed values outlined here may 
not always provide the most conservative date.  In those circumstances, the imputed value may 
be replaced by a date that will lead to a more conservative analysis. 
A. 
Start Dates 
1) 
If the year is unknown, then the date will not be imputed and will 
be assigned a missing value.  
2) 
If the month is unknown, then: 
i) If the year matches the first dose date year, then impute 
the month and day of the first dose date. 
ii) Otherwise, assign ‘January.’  
3) 
 If the day is unknown, then: 
i) If the month and year match the first dose date month 
and year, then impute the day of the first dose date. 
ii) Otherwise, assign the first day of the month. 
B. 
Stop Dates 
1) 
If the year is unknown, then the date will not be imputed and will 
be assigned a missing value. 
2) 
If the month is unknown, then assign ‘December.’ 
3) 
If the day is unknown, then assign the last day of the month. 
 
For AEs, partial or missing times will be imputed in the following manner: 
A. 
Start Times 
1) 
Day 1:  
i) If hour is missing on the CRF, hour will be imputed as 
hour of the first dose.  
ii) If minute is missing on the CRF, minute will be 
imputed as minute of the first dose.  
iii) If hour is missing for both start of the AE and for the 
time of the first dose on the CRF, hour will be imputed 
as 23.  
iv) If minute is missing for both start of the AE and for the 
time of the first dose on the CRF, minute will be 
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2) 
 Study days other than Day 1: 
i) If hour is missing on the CRF, hour will be imputed as 
00. 
ii) If minute is missing on the CRF, minute will be 
imputed as 00. 
B. 
Stop Times 
1) 
If hour is missing on the CRF, hour will be imputed as 23.  
2)  
If minute is missing on the CRF, minute will be imputed as 59. 
 
7.3.2.2. 
Imputation Methods 
No data will be imputed for this study. All data will be observed cases, without imputation.  
7.3.3. 
Handling of Early Termination Visit Information 
In the event that a subject is terminated early from this study the early termination visit data 
will be analyzed at the closest scheduled visit.  If the closest visit has valid data, the early 
termination data will be assigned to the next available visit. 
7.3.4. 
Pooling of Investigational Sites 
The data from all study centers will be pooled together for analyses. 
7.3.5. 
Coding Conventions for Events and Medications 
All adverse events, and medical history will be mapped to the Medical Dictionary for 
Regulatory Activities (MedDRA version 19.0) system for reporting (preferred term and body 
system). 
Prior and Concomitant medications will be coded using World Health Organization (WHO) 
Drug classification (Version 4.3). 
7.3.6. 
Baseline Visits  
Baseline for the following endpoints is defined as the last response during Screening prior to 
Study Day -1:  physical exam; blood for chemistry, hematology, lipids; urinalysis by dipstick 
and microscopic analysis; 12-lead ECG; serum PD biomarkers (cortisol (daytime), cortisone, 
17- hydroxyprogesterone, ACTH, testosterone, corticosterone, 11- deoxycortisol, 
androstenedione, progesterone, DHEA, osteocalcin, serum aminoterminal propeptide of type 
I collagen (P1NP), carboxy-terminal telopeptide (CTX), HbA1c); and SOMAscan aptamers.   


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Baseline for the following endpoints is defined as Study Day -1:  weight; blood for serum 
PK; and strength and flexibility testing (QMT, TTRW, TTSTAND, TTCLIMB, NSAA, and 
6MWT). 
Baseline for the following endpoints is defined as the last response prior to dosing on Study 
Day 1:  vital signs, and PD biomarkers fasting insulin and glucose. 
7.3.7. 
Analysis Software 
Data manipulation, tabulation of descriptive statistics, and graphical representations will be 
performed primarily using SAS (release 9.2 or higher) for Windows.  If the use of other 
software is warranted, the final clinical study report will detail what software was used and 
for what purposes. 
7.3.8. 
Study Data 
Study data identified in the schedule for time and events (Table 2) are collected, and source 
verified, on the electronic data capture tool OpenClinica v3.12.2.  Laboratory data, including 
PK and PD test results, are not collected in the EDC tool and are provided from external 
laboratories.  
All study data will be formulated into regulatory compliant data sets to provide transparency, 
traceability, and integrity of trial analysis results from the collection source. Observed study 
data will be mapped to the CDISC Study Data Tabulation Model (SDTM) and serve as the 
source data from the trial.  All study analyses will be completed using analysis data sets that 
are derived from the SDTM and follow the CDISC Analysis Data Model (ADaM) 
architecture.  
The methods for programming the CDISC SDTM and ADaM data sets are described in 
Figure 1. 


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Figure 1 
SDTM, ADaM, and TFL Development and Validation 
 
Where: 
1. Development, Validation, and Maintenance of SDTM domains 
2. Development and Validation of Analysis Data Sets (ADaM), with input source the 
appropriate SDTM domains. 
3. Development and Validation of draft and then final Tables, Figures, and Listings 
(TFL), with input data source the SDTM domains and analysis specific ADaM data 
sets and randomization code (RC) applied. 
 
7.4. 
Planned Study Analyses 
7.4.1. 
Statistical Summaries: Descriptive and Inferential 
All statistical tests will be two-sided and a resultant p-value of less than or equal to 0.05 will 
be considered statistically significant.  All p-values will be rounded to and displayed in four 
decimals.  If a p-value less than 0.0001 occurs it will be shown in tables as <0.0001. 
Descriptive summaries of variables will be provided where appropriate.  In general, for 
continuous variables, the number of non-missing values (n) and the mean, standard deviation, 
median, minimum, and maximum will be tabulated.  For categorical variables, the counts and 
proportions of each value will be tabulated.   


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All collected data will be presented in listings.  Data not subject to analysis according to this 
plan will not appear in any tables or graphs but will be included in the data listings. 
7.4.2. 
Interim Analyses and Data Monitoring 
No interim analyses are planned for this study. 
The independent Data and Safety Monitoring Board (DSMB) will be consulted to review the 
safety data from each dose level group.  The DSMB will receive reports when it is assessed 
that a dose level group is completed and no more de-escalations to that dose are expected, but 
no less frequently than every 6 months.  The DSMB will meet at regular intervals to review 
all pertinent safety data.  The DSMB will also be notified at any point where a dose de-
escalation occurs and the dose is deemed to have unacceptable toxicity.  The DSMB may 
request summaries at other points in time.  In addition, the Medical Monitor may request at 
any time that the DSMB review safety data if the Medical Monitor has specific concerns. 
In all cases, data will be compiled by the Coordinating Center and presented to the DSMB in 
a format that allows for complete review of all compiled safety data.  The DSMB can 
recommend to the Sponsor altering or terminating the trial for safety or other study integrity-
related issues. 
The primary safety endpoints that the DSMB will review are safety labs and adverse events.  
Refer to the DSMB charter for complete details. Analysis and reporting of safety endpoint 
information is specified in the DSMB Charter, and not repeated herein. Note that all DSMB 
reports will be included in the final CSR. 
7.4.3. 
Final Analysis 
The final study analysis will be completed following complete enrollment and the database 
locked after all subjects have completed their final follow-up assessments.  Subjects who 
prematurely discontinue from the study prior to Week 2 (Day 14) should complete the Week 
2 (Days 13 and 14) procedures at the time of early discontinuation and enter the 14-day 
Follow-up Period.  Subjects who prematurely discontinue from the study after Week 2 (Day 
14) but prior to the scheduled Week 4 (Day 28) Follow-up Visit should return to the study 
site for Week 4 (Day 28) procedures.   
7.5. 
Multiple Testing Procedures 
No adjustments for multiplicity on inferential statistics will be presented in this SAP. 
 


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8. 
SUMMARY OF STUDY DATA 
8.1. 
Subject Summary Grouping 
In general, and unless otherwise noted, data summaries will be presented by study cohort: 
Dose Level Group 1, Dose Level Group 2, Dose Level Group 3, or Dose Level Group 4.     
8.2. 
Patient Disposition 
The number of subjects at each cohort dose level, and the compliance and completion rates of 
dosing at each dose level will be summarized.  The number of discontinuations (if any) and 
reason for discontinuation and whether they occurred before the Week 2 visit or after the Week 
2 visit but before the Week 4 visit and whether the Week 4 visit assessments were completed 
will be summarized by dose level group. 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented. 
8.3. 
Protocol Deviations/Violations 
A summary listing of protocol deviations and of protocol violations will be provided by dose 
level group and by study site.  
All protocol deviations and violations will be presented in a by-subject data listing.  
8.4. 
Demographics and Baseline Characteristics  
Subject demographics (age, race, and ethnicity) and baseline characteristics (height, weight, 
body mass index [BMI] and BMI percentile (see Appendix13.4 for a description and example 
of BMI percentile calculation given BMI score; see Centers for Disease Control and 
Prevention [CDC] webpage https://www.cdc.gov/growthcharts/percentile_data_files.htm for 
a detailed discussion on the derivation of the computational algorithm), and months/years 
since DMD diagnosis) will be summarized descriptively, either continuously or categorically.  
The summaries will be compared visually by cohort dose level group and reviewed for any 
differences among the dose level groups. 
All demographic and baseline information will be listed by subject. 
8.5. 
Medical History 
Subject medical, surgical, medication and treatment history will be collected during the 
screening phase and reviewed throughout the study. The dates and descriptions of past events 
will be documented in source documents and captured in the relevant eCRF.  Medical history 
will be coded using the MedDRA (version 19.0).  


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Subject medical history data will be presented in a by-subject listing. 
8.6. 
Prior and Concomitant Medications  
A categorical summary of all prior and concomitant medications taken during the course of 
the study will be presented in tabular form by therapeutic drug class and generic drug name 
(brand name where generic name is unavailable) using the World Health Organization 
(WHO) Drug classification (Version 4.3).   
All prior and concomitant medications will be detailed in the subject data listings. 
A concomitant medication is defined as any medication taken on or after the day of first 
exposure to study drug up until Week 4 treatment follow-up. 
Prior medications are defined as any medication that is taken prior to the day of first 
exposure to any study drug, collected from up to 30 days prior to Screening. 
All prior and concomitant medications will be presented in by-subject listings. 
8.7. 
Treatment Compliance  
Continuous descriptive summaries will be presented for the Safety Population by dose level 
and will include number of doses, number of doses missed, and total exposure to study drug.   
9. 
EFFICACY ANALYSES  
Unless otherwise noted, all efficacy analyses will be exploratory and be completed using the 
Safety Population. All efficacy analyses will be completed using the planned dose that the 
subject received.  
In general, and unless otherwise noted, data summaries will be presented by study cohort: 
Dose Level Group 1, Dose Level Group 2, Dose Level Group 3, or Dose Level Group 4.  If, 
due to dose limiting toxicity, 2 or more study cohorts are dosed at the same level, then 
summaries will also be grouped by treatment dose level. 
Since change in strength is not expected from a two-week treatment period, the main purpose 
of collecting these strength and mobility data is to provide baseline responses for the VBP15-
003 six month extension study as well as potentially provide coefficients of variation to 
assess reliability in this age group. 
9.1. 
Clinical Efficacy   
The evaluations of exploratory clinical efficacy will be performed using the Safety 
Population.  The last non-missing value prior to the first dose of study medication will be 
used as the baseline value for analyses.  Data will be summarized by planned treatment. 


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The QMT measurements will be done unilaterally using the dominant side, if known. For 
each muscle group (knee extension/flexion, elbow extension/flexion) the better of two 
collected test results at each visit will be summarized.   
The descriptive summaries will include continuous descriptive statistics and box and whisker 
plots on observed and change from baseline responses at each time point by dose level.    
Subject data reliability over testing visits may be explored if necessary by examining plots of 
the coefficient of variation and would be presented in the CSR as post hoc.      
All QMT data will be presented in a listing. 
The same approach described for QMT will be taken for all timed function tests (TTRW, 
TTSTAND, TTCLIMB, 6MWT) and the NSAA total score (note that NSAA total score is 
only calculated if all subscores are non-missing). 
For TTRW, TTSTAND, and TTCLIMB, results will also be converted to velocities and 
analyzed as described above using the following transformation formulas: 
• TTSTAND velocity = 1 / TTSTAND and is expressed as rises/sec. 
 
• TTCLIMB velocity = 1 / TTCLIMB and is expressed as tasks/sec. 
• TTRW velocity = 10 / TTRW and is expressed as meters/sec. 
Note that serum creatine kinase is considered an exploratory efficacy endpoint.  However, for 
convenience, it is presented with the other chemistry laboratory results described in Section 
10.2.   
10. 
SAFETY ANALYSES 
Safety analyses will be performed using the Safety Population and will be completed using 
the actual treatment a subject received and will address the primary objective of the study. 
All safety data will be presented in by-subject listings as well as in tables and figures as 
described below. 
10.1. 
Adverse Events  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 19.0.   
Treatment-emergent adverse events (TEAEs) are defined as any adverse event or worsening 
of an existing condition after initiation of the investigational product and through the 
subject’s last study visit (study completion or early termination).  Serious adverse events will 


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be recorded from the date of informed consent, throughout the clinical trial, and for up to 30 days 
after the final administration of study drug.  If the onset of an AE is on Day 1, then the time of 
first dose, collected from the vitals CRF or PK CRF, will be compared to the time of onset to 
determine if the AE is treatment-emergent. 
The number and percent of subjects with any TEAEs will be summarized by system organ 
class and preferred term by dose level (and overall).  At each level of tabulation (ex. at the 
preferred term level) subjects will be counted only once if they had more than one such event 
reported during the AE collection period. 
 
Level of intensity will be assessed using the CTCAE grading.  
The following summary tables and subject level listings will be presented for TEAE data:  
• 
Overall summary of TEAEs  
• 
Summary table of TEAE descending incidence by PT 
• 
Summary table of TEAEs by SOC and PT  
• 
Summary table of serious TEAEs by SOC and PT  
• 
Summary table of TEAEs by highest relationship level to study drug by SOC and PT  
• 
Summary table of TEAEs by maximum intensity by SOC and PT 
• 
Summary table of TEAEs leading to study discontinuation by SOC and  PT 
• 
Summary table of TEAEs by worst outcome (recovered/resolved vs. 
recovering/resolving vs. not recovered/not resolved vs. recovered/resolved with 
sequelae vs. fatal vs. unknown) by SOC and PT   
• 
Table listing of SAEs 
• 
Table listing of related SAEs 
• 
Table listing of all AEs leading to death 
• 
Table listing of all AEs leading to study discontinuation 
 
10.2. 
Vital Signs, 12-Lead ECG, and Laboratory Outcomes  
Vital signs, including weight and BMI, clinical laboratory test results, and other laboratory 
test results not detailed elsewhere in this SAP will be summarized at each time point by dose 
level (and overall) using descriptive statistics and presented for observed response as well as 
change from baseline.  Descriptive statistics will include the typical statistics for continuous 
endpoints described in this SAP as well as interquartile range.  BMI observed and change 
from baseline will also be presented using box and whisker plots. 
Paired t-tests will be used to statistically test the change from Baseline to Week 2 and the 
change from Week 2 to Week 4 within each dose level (and overall) for all lab parameters, 
where applicable.  


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Note that vital signs will be gathered before and after dosing at Day 1.  All change from 
baseline calculations for all time points following will be relative to the pre-dose vital signs 
response at Day 1. 
Clinical laboratory test results will also be presented in shift tables for all laboratory 
parameters where low/normal/high or abnormal/normal status can be ascertained. 
Abnormal clinical lab test results will be presented in a table listing where low/normal/high 
or abnormal/normal status can be ascertained 
Except for lab results, data gathered at unscheduled visits will not be summarized but will be 
included in by-subject data listings.  See Section 7.3.1 for unscheduled or repeated lab tests. 
Lab results will be presented using U.S. conventional units.  
12-lead ECG interval parameters will only be presented in subject listings.  Overall ECG 
assessment will be summarized via shift table presenting Normal/Abnormal Not Clinically 
Significant/Abnormal Clinically Significant, and will be presented in subject listings also. 
10.3. 
Physical Exam  
CRF physical exam results will be presented in by-subject listings. 
 
10.4. 
Other Safety Measures 
Drug acceptability will be summarized descriptively as a continuous endpoint by study 
cohort at each time point collected, and presented in a by-subject listing. 
11. 
PHARMACOKINETIC (PK) ANALYSES  
All PK and MIST analyses will be detailed in a separate PK analysis plan.  
12. 
PHARMACODYNAMIC (PD) SERUM AND OTHER 
BIOMARKERS 
The evaluations of PD will be performed using the Safety Population.  The last non-missing 
value prior to the first dose of study medication will be used as the baseline value for 
analyses.  Data will be summarized by planned treatment.   
The descriptive summaries will include continuous descriptive statistics and box and whisker 
plots on observed and change from baseline responses at each time point by dose level.  


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Paired t-tests will be used to statistically test the change from Baseline to Week 2 and the 
change from Week 2 to Week 4 within each dose level (and overall), where applicable (note 
that the insulin resistance endpoints fasting glucose and fasting insulin are collected at 
Screening, Day 1, and Week 2, but will only have a paired t-test performed to test change 
from baseline at Week 2). 
A single time series plot will be created presenting individual subject’s change from baseline 
response over time by dose level.  Each dose level will be presented on a separate figure.   
Percentage change from baseline in serum PD biomarker concentrations will also be 
summarized in a table over time by dose level.  Continuous descriptive statistics will be 
provided along with interquartile range.  Percentage change is defined as 100*(change from 
baseline/baseline). 
Note that adrenal suppression immunoassay (first in-morning cortisol) endpoint will only be 
collected at Week 2 and will only be summarized as count data.  The summary table will 
tabulate the number and percentage of subjects with less than 100 nmol/L (3.6 
micrograms/dL) at 002 Week 2 pre-dose. 
All PD biomarker data will be presented in by-subject listings.  The listings will include 
normal range data, where available.  Furthermore, a listing of out of range observations will 
be presented. 
SomaScan data will be presented in an addendum report. 
Proteomics profiling data will be collected for potential analysis in future studies. These data 
will not be included in any by subject listing or in the CSR for this study. Any analysis of the 
proteomics profiling information will be reported in separate reports. 
13. 
REPORTING CONVENTIONS 
The following reporting conventions will be adopted for the presentation of study data.  
These conventions will enhance the review process and help to standardize presentation with 
common notations 
13.1. 
General Reporting Conventions  
• 
All tables and data listings will be developed in Landscape Orientation, unless 
presented as part of the text in a CSR. 
• 
Figures will be presented in Landscape Orientation, unless presented as part of 
the text in a CSR. 
• 
Legends will be used for all figures with more than one variable or item 
displayed. 


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• 
Figures will be in presented in color with treatment groups distinguished by 
different symbols and colors.  Lines in figures should be wide enough to view 
the line after being photocopied.  
• 
Specialized text styles, such as bolding, italics, borders, shading, superscripted 
and subscripted text will not be used in tables, figures, and data listings unless 
they add significant value to the table, figure, or data listing.  
• 
Only standard keyboard characters should be used in tables and data listings. 
Special characters, such as non-printable control characters, printer specific, 
or font specific characters, will not be used on a table, figure, or data listing.  
Hexadecimal character representations are allowed (e.g.,µ,α,β). 
• 
All titles will be centered on a page.  The ICH numbering convention is to be 
used for all tables, figures, and data listings. 
• 
All footnotes will be left justified and the bottom of a page.  Footnotes must 
be present on the page where they are first referenced.  Footnotes should be 
used sparingly and must add value to the table, figure, or data listing.  If more 
than four footnote lines are planned then a cover page may be used to display 
footnotes. 
• 
Missing values for both numeric and character variables will be presented as 
blanks in a table or data listing.  A zero (0) may be used if appropriate to 
identify when the frequency of a variable is not observed. 
• 
All date values will be presented as YYYY-MM-DD (e.g., 2013-05-17) ISO 
8601 format. 
• 
All observed time values will be presented using a 24-hour clock HH:MM:SS 
format (e.g., 01:35:45 or 11:26).  Seconds should only be reported if they 
were measured as part of the study, also in ISO 8601 format. 
• 
Time durations will be reported in mixed HHh MMm SSs notation (e.g., 5h 
32m, or 27h 52m 31s).  The use of decimal notation to present (display) time 
durations should be avoided (e.g. 0.083h = 5m) unless it is necessary to show 
the computation of time differences in a table, figure, or data listing, in which 
case both notations may be used to display the time duration.  
• 
All tables, figures, and data listings will have the Table, Listing, or Graph 
status (DRAFT, FINAL), and a date/time stamp on the bottom of each output.  
• 
All analysis programs developed for a table, figure, or data listing display will 
be self-contained to facilitate transfer of programs to multiple computing 
environments and transfer to a regulatory agency (if requested).  
11.1 
Population Summary Conventions 
• 
Population(s) represented on the tables or data listings will be clearly 


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identified in the last title of the Table as “Population: <name of population>” 
and will be identical in name to that identified in the protocol or SAP. 
• 
Consistent terminology will be used to define and identify a population.   
• 
Sub-population(s) or special population(s) descriptions will provide sufficient 
detail to ensure comprehension of the population (e.g., FAS Females, Per-
Protocol Males >60 years of age) used for analysis in a table or figure. 
• 
Population sizes may be presented for each treatment or dosing category as 
totals in the column header as (N=xxxx), where appropriate.  
• 
Population sizes shown with summary statistics are the samples sizes (n) of 
subjects with non-missing values.  
• 
All population summaries for categorical variables will include all categories 
that were planned and for which the subjects may have had a response. 
Percentages corresponding to null categories (cells) will be suppressed.    
• 
All population summaries for continuous variables will include: N, mean, SD, 
median, minimum, and maximum.  Other summaries (e.g. number missing, 
quartiles, 5%, 95% intervals, CV or %CV) may be used as appropriate. 
• 
All percentages are rounded and reported to xx.x%. A percentage of 100% 
will be reported as 100%.  For categorical summaries presenting “n (%)”, a 
count of 0 will be presented as “0”.  For continuous results an estimated % of 
0 will be presented as “0%”.  
• 
Population summaries that include p-values will report the p-value to 
four decimal places with a leading zero (0.0001).  All p-values reported on 
default output from statistical software (i.e., SAS® Software version 9.2 or 
later) may be reported at the default level of precision.  P-values <0.0001 
should be reported as <0.0001 not 0.0000. 
 
12 
REFERENCES 
ICH E9 Expert Working Group. Statistical Principles for Clinical Trials: ICH Harmonized 
Tripartite Guideline, September 1998 
 
 


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13 
APPENDICES 
13.1 
List of Planned Tables 
This list of planned tables includes all of the main tables to be presented for the study.  Other 
tables may be presented and will be described in a TLF shell document. 
NUMBER 
TITLES 
14.1.1.1 
Subject Disposition \ All Subjects 
14.1.2 
Demographic and Baseline Characteristics \ Safety Population 
14.1.4.1 
Prior Medications \ Safety Population 
14.1.4.2 
Concomitant Medications\ Safety Population 
14.2.1 
Treatment Administration\ Safety Population 
14.3.1 
Summary of Study Drug Exposure\ Safety Population 
14.2.4.1 
Summary of Time to Stand (TTSTAND) in Seconds \ Safety Population 
14.2.4.1.1 
Summary of Time to Stand (TTSTAND) in Seconds by Age Group\ Safety 
Population 
14.2.4.2 
Summary of Time to Stand (TTSTAND) Velocity in Rises/Second \ Safety 
Population 
14.2.4.2.1 
Summary of Time to Stand (TTSTAND) Velocity in Rises/Second by Age 
Group\ Safety Population 
14.2.5.1 
Summary of Time to Climb (TTCLIMB) in Seconds\ Safety Population 
14.2.5.1.1 
Summary of Time to Climb (TTCLIMB) in Seconds by Age Group\ Safety 
Population 
14.2.5.2 
Summary of Time to Climb (TTCLIMB) Velocity in Tasks/Second \ Safety 
Population 
14.2.5.2.1 
Summary of Time to Climb (TTCLIMB) Velocity in Tasks/Second by Age 
Group\ Safety Population 
14.2.6.1 
Summary of Time to Run/Walk 10 Meters (TTRW) in Seconds\ Safety 
Population 
14.2.6.1.1 
Summary of Time to Run/Walk 10 Meters (TTRW) in Seconds by Age 
Group\ Safety Population 
14.2.6.2 
Summary of Time to Run/Walk 10 Meters (TTRW) Velocity in 
Meters/Second\ Safety Population 
14.2.6.2.1 
Summary of Time to Run/Walk 10 Meters (TTRW) Velocity in 
Meters/Second by Age Group\ Safety Population 
14.2.7.1 
Summary of 6 Minute Walk Test (6MWT) in Meters\ Safety Population 
14.2.7.1.1 
Summary of 6 Minute Walk Test (6MWT) in Meters by Age Group\ Safety 
Population 


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14.2.8.1  
Summary of Quantitative Muscle Testing (QMT) Elbow Flexors in Pounds\ 
Safety Population 
14.2.8.1.1 
Summary of Quantitative Muscle Testing (QMT) Elbow Flexors in Pounds 
by Age Group\ Safety Population 
14.2.8.2  
Summary of Quantitative Muscle Testing (QMT) Elbow Extensors in 
Pounds \ Safety Population 
14.2.8.2.1 
Summary of Quantitative Muscle Testing (QMT) Elbow Extensors in 
Pounds by Age Group\ Safety Population 
14.2.8.3 
Summary of Quantitative Muscle Testing (QMT) Knee Flexors in Pounds \ 
Safety Population 
14.2.8.3.1 
Summary of Quantitative Muscle Testing (QMT) Knee Flexors in Pounds 
by Age Group\ Safety Population 
14.2.8.4 
Summary of Quantitative Muscle Testing (QMT) Knee Extensors in 
Pounds \ Safety Population 
14.2.8.4.1 
Summary of Quantitative Muscle Testing (QMT) Knee Extensors in 
Pounds by Age Group\ Safety Population 
14.2.9.1  
Summary of North Star Ambulatory Assessment (NSAA) Total Score \ 
Safety Population 
14.2.9.1.1 
Summary of North Star Ambulatory Assessment (NSAA) Total Score by 
Age Group\ Safety Population 
14.2.10.1 
Summary of Pharmacodynamic Parameters - Bone Turnover\ Safety 
Population 
14.2.10.2 
Summary of Pharmacodynamic Parameters - Adrenal Axis Suppression 
Mass Spectrometry\ Safety Population 
14.2.10.3 
Summary of Pharmacodynamic Parameters - Insulin Resistance \ Safety 
Population 
14.2.10.4 
Adrenal Axis Suppression Immunoassay (Cortisol (First in Morning)  \ 
Safety Population 
14.3.1.1 
Overall Summary of Adverse Events \ Safety Population 
14.3.1.2 
Summary of Treatment Emergent Adverse Events by System Organ Class 
and Preferred Term\ Safety Population 
14.3.1.3 
Summary of Treatment Emergent Adverse Events by Descending Incidence 
of Preferred Term\ Safety Population 
14.3.1.4 
Summary of Serious Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term\ Safety Population 
14.3.1.5 
Summary of Treatment Emergent Adverse Events by Maximum 
Relatedness to Treatment by System Organ Class and Preferred Term\ 
Safety Population 
14.3.1.6 
Summary of Treatment Emergent Adverse Events by Maximum Severity 
by System Organ Class and Preferred Term\ Safety Population 
14.3.1.7 
Summary of Treatment Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term\ Safety 
Population 


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14.3.1.8 
Summary of Treatment Emergent Adverse Events by Worst Outcome by 
System Organ Class and Preferred Term\ Safety Population 
14.3.2.1 
Table Listing of Serious Treatment Emergent Adverse Events\ Safety 
Population 
14.3.2.2 
Table Listing of Related Serious Treatment Emergent Adverse Events \ 
Safety Population 
14.3.2.3 
Table Listing of Treatment Emergent Serious Adverse Events Leading to 
Death\ Safety Population 
14.3.2.4 
Table Listing of Treatment Emergent Adverse Events Leading to Study 
Discontinuation\ Safety Population 
14.3.3.1 
Summary of Laboratory Parameters: Hematology\ Safety Population 
14.3.3.2 
Laboratory Shift from Baseline: Hematology \ Safety Population 
14.3.3.3 
Summary of Laboratory Parameters: Chemistry\ Safety Population 
14.3.3.4 
Laboratory Shift from Baseline: Chemistry \ Safety Population 
14.3.3.5 
Summary of Laboratory Parameters: Urinalysis\ Safety Population 
14.3.3.6 
Laboratory Shift from Baseline: Urinalysis- Random Urine\ Safety 
Population 
14.3.3.7 
Summary of Laboratory Parameters: Lipid Profile\ Safety Population 
14.3.3.8 
Laboratory Shift from Baseline: Lipid Profile\ Safety Population 
14.3.3.9 
Table Listing of Abnormal Lab Results by Subject and Visit\ Safety 
Population 
14.3.3.10 
Table of Normal Laboratory Ranges 
14.3.3.11 
Table of Normal Biomarker Ranges 
14.3.4.1 
Summary of Vital Signs\ Safety Population 
14.3.4.2 
Summary of Anthropometrics\ Safety Population 
14.3.4.3 
Summary of 12-Lead ECG Interpretation\ Safety Population 
14.3.4.4 
12-Lead ECG Interpretation Shift from Baseline\ Safety Population 
14.3.4.5 
Summary of Study Medication Acceptability \ Safety Population  
 


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13.2 
List of Planned Listings 
This list of planned listings includes all of the main listings to be presented for the study.  
Other listings may be presented and will be described in a TLF shell document. 
NUMBER 
TITLES 
16.2.1 
Subject Disposition \ All Subjects 
16.2.2.1.1 
Inclusion/Exclusion Criteria 
16.2.2.1.2 
Inclusion/Exclusion Listing\ All Subjects 
16.2.2.2 
Protocol Deviations\ All Subjects 
16.2.4.1 
Demographic and Baseline Information\ All Subjects 
16.2.4.2 
Medical History\ All Subjects  
16.2.4.3 
DMD History\ All Subjects 
16.2.4.4 
Genetic Confirmation by Muscle Biopsy\ All Subjects 
16.2.4.5.1 
Genetic Confirmation by DNA\ All Subjects 
16.2.4.5.2 
Genetic Confirmation by DNA Continued\ All Subjects 
16.2.5.1 
Study Drug Administration\ All Subjects 
16.2.5.2 
Study Drug Exposure\ All Subjects 
16.2.5.3 
Study Medication Log\ All Subjects 
16.2.5.4 
Study Drug Accountability\ All Subjects 
16.2.6.1 
Timed Tests\ All Subjects 
16.2.6.2 
Time to Stand (TTSTAND)\ All Subjects 
16.2.6.3 
Time to Climb (TTCLIMB)\ All Subjects 
16.2.6.4 
Time to Run/Walk (TTRW)\ All Subjects 
16.2.6.5 
Quantitative Muscle Testing (QMT)\ All Subjects 
16.2.6.6 
6 Minute Walk Test (6MWT) Pre-Test\ All Subjects 
16.2.6.7 
6 Minute Walk Test (6MWT) \ All Subjects 
16.2.6.8 
6 Minute Walk Test (6MWT) Post-Test\ All Subjects 
16.2.6.9 
North Star Ambulatory Assessment (NSAA)\ All Subjects 
16.2.7.1 
Adverse Events\ All Subjects 
16.2.7.2 
Adverse Events by System Organ Class and Preferred Term\ All 
Subjects 
16.2.7.3 
Serious Adverse Events\ All Subjects 
16.2.7.4 
Serious Adverse Events Leading to Death\ All Subjects 
16.2.8.1 
Hematology Laboratory Evaluations by Subject and Visit\ All 
Subjects 
16.2.8.2 
Chemistry Laboratory Evaluations by Subject and Visit\ All 
Subjects 
16.2.8.3 
Urinalysis Laboratory Evaluations by Subject and Visit\ All 
Subjects 
16.2.8.4 
Biomarker Laboratory Evaluations by Subject and Visit\ All 
Subjects 
16.2.8.5 
Lipids Laboratory Evaluations by Subject and Visit\ All Subjects 


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16.2.9.1.1 
Prior and Concomitant Medications\ All Subjects 
16.2.9.1.2 
Prior and Concomitant Medications - Steroids\ All Subjects 
16.2.9.1.3 
Concurrent Assistive, Orthotic, Night Splint, and Respiratory 
Devices\ All Subjects 
16.2.9.1.4 
Concurrent Occupational and Physical Therapy\ All Subjects 
16.2.9.2 
Vital Signs\ All Subjects 
16.2.9.3 
Physical Examination\ All Subjects 
16.2.9.4.1 
12-Lead Electrocardiogram (ECG) Results\ All Subjects 
16.2.9.4.2 
12-Lead Electrocardiogram (ECG) Interpretation\ All Subjects 
16.2.10 
Study Drug Acceptability\ All Subjects 
 
 
 


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13.3 
List of Planned Figures 
This list of planned figures includes all of the main figures to be presented for the study.  
Other figures may be presented and will be described in a TLF shell document. 
NUMBER 
TITLES 
14.2.4.1.1 
Time to Stand (seconds) \ Safety Population 
14.2.4.1.2 
Time to Stand (seconds) Change from Baseline\ Safety 
Population 
14.2.4.2.1 
Time to Stand Velocity (rise/seconds) \ Safety Population 
14.2.4.2.2 
Time to Stand Velocity (rise/seconds) Change from Baseline\ 
Safety Population 
14.2.5.1.1 
Time to Climb (seconds) \ Safety Population 
14.2.5.1.2 
Time to Climb (seconds) Change from Baseline\ Safety 
Population 
14.2.5.2.1 
Time to Climb Velocity (tasks/seconds) \ Safety Population 
14.2.5.2.2 
Time to Climb Velocity (tasks/seconds) Change from Baseline\ 
Safety Population 
14.2.6.1.1 
Time to Run/Walk 10 Meters (seconds) \ Safety Population 
14.2.6.1.2 
Time to Run/Walk 10 Meters (seconds) Change from Baseline\ 
Safety Population 
14.2.6.2.1 
Time to Run/Walk 10 Meters Velocity (meters/second) \ Safety 
Population 
14.2.6.2.2 
Time to Run/Walk 10 Meters Velocity (meters/second) Change 
from Baseline\ Safety Population 
14.2.7.1.1 
6 Minute Walk Test (meters) \ Safety Population 
14.2.7.1.2 
6 Minute Walk Test (meters) Change from Baseline\ Safety 
Population 
14.2.8.1.1 
QMT Elbow Flexors \ Safety Population 
14.2.8.1.2 
QMT Elbow Flexors Change from Baseline\ Safety Population 
14.2.8.2.1  
QMT Elbow Extensors \ Safety Population 
14.2.8.2.2  
QMT Elbow Extensors Change from Baseline\ Safety Population 
14.2.8.3.1 
QMT Knee Flexors \ Safety Population 
14.2.8.3.2 
QMT Knee Flexors Change from Baseline\ Safety Population 
14.2.8.4.1 
QMT Knee Extensors \ Safety Population 
14.2.8.4.2 
QMT Knee Extensors Change from Baseline\ Safety Population 
14.2.9.1.1 
NSAA Total Score \ Safety Population 
14.2.9.1.2  
NSAA Total Score Change from Baseline\ Safety Population 
14.2.10.1.1 
Pharmacodynamic Parameters - Bone Turnover\ Safety 
Population 


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14.2.10.1.2 
Pharmacodynamic Parameters - Bone Turnover Change from 
Baseline\ Safety Population 
14.2.10.1.3 
Pharmacodynamic Parameters - Bone Turnover Change from 
Baseline by Subject\ Safety Population 
14.2.10.2.1 
Pharmacodynamic Parameters - Adrenal Axis Suppression Mass 
Spectrometry\ Safety Population 
14.2.10.2.2 
Pharmacodynamic Parameters - Adrenal Axis Suppression Mass 
Spectrometry Change from Baseline\ Safety Population 
14.2.10.2.3 
Pharmacodynamic Parameters - Adrenal Axis Suppression Mass 
Spectrometry Change from Baseline by Subject\ Safety 
Population 
14.2.10.3.1 
Pharmacodynamic Parameters - Insulin Resistance\ Safety 
Population 
14.2.10.3.2 
Pharmacodynamic Parameters - Insulin Resistance Change from 
Baseline\ Safety Population 
14.2.10.3.3 
Pharmacodynamic Parameters - Insulin Resistance Change from 
Baseline by Subject\ Safety Population 
14.3.3.3.1 
Serum Creatine Kinase\ Safety Population 
14.3.3.3.2 
Serum Creatine Kinase Change from Baseline\ Safety Population 
14.3.3.3.3 
Serum Creatine Kinase Change from Baseline by Subject\ Safety 
Population 
14.3.4.2.1 
Body Mass Index (kg/m2) \ Safety Population 
14.3.4.2.2 
Body Mass Index (kg/m2) Change from Baseline\ Safety 
Population 
 
 
 


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13.4 Calculating BMI Z-Scores 
The following example for computing BMI z-scores given age and sex for children aged 2 to 
20 years uses the computational algorithm presented on the Centers for Disease Control and 
Prevention (CDC) webpage “Percentile Data Files with LMS Values”.   For a detailed 
discussion on the derivation of the computational algorithm and reference materials, visit the 
webpage at https://www.cdc.gov/growthcharts/percentile_data_files.htm. 
To obtain the z-score (Z) for a given BMI measurement X, use the following equation: 
Z= [((X/M)^L) – 1] / (LS), where L≠0 
or 
Z = ln(X/M)/S, where L=0 
where L, M, and S are the values from the BMIAGE.xls reference table (growth chart 8  
linked to on the aforementioned CDC webpage). 
For example, for a 24 month old male (coded sex value = 1) who has a BMI of 17.2864, the 
BMIAGE.xls reference table presents values of L=-2.01118, M=16.57503, and S=0.080592.  
Plugging those parameter values into the Z formula above results in a Z-score of 0.5.  
 
 


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13.5 SAP Amendment Summary of Changes 
Page Number 
Section 
Description of Change