Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne Muscular Dystrophy Vamorolone
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 121
Healthy volunteers: no

Brief summary:
Brief Summary: This Phase IIb study is a randomized, double-blind, parallel group, placebo and active-controlled study to evaluate the efficacy, safety, PD, and population PK of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg versus prednisone 0.75 mg/kg/day and placebo over a Treatment Period of 24 weeks, and to evaluate persistence of effect over a Treatment Period of 48 weeks in ambulant boys ages 4 to \<7 years with DMD.

Detailed description:
This Phase IIb study is a randomized, double-blind, parallel group, placebo and active-controlled study to evaluate the efficacy, safety, PD, and population PK of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg versus prednisone 0.75 mg/kg/day and placebo over a Treatment Period of 24 weeks, and to evaluate persistence of effect over a Treatment Period of 48 weeks in ambulant boys ages 4 to \<7 years with DMD.

The study is comprised of a 5-week Pretreatment Screening Period, a 1-day Pretreatment Baseline Period, a 24-week Treatment Period #1 (Weeks 1-24), a 4-week Transition Period (Weeks 25-28), a 20-week Treatment Period #2 (Weeks 28 + 1 day to 48), and a 4-week Dose-tapering Period (Weeks 49-52).

Subjects will be randomized to one of six treatment groups in a 2:2:1:1:1:1 ratio, where the two prednisone groups in Treatment Period #1 (Groups 3 and 4) will be combined and the two placebo groups in Treatment Period #1 (Groups 5 and 6) will be combined, effectively resulting in a 1:1:1:1 randomization (vamorolone 2.0 mg/kg/day : vamorolone 6.0 mg/kg/day : prednisone 0.75 mg/kg/day : placebo) for Treatment Period #1.

Subjects will be stratified based on age at study entry (\<6 vs. ≥ 6 years). During the 4-week Transition Period between Treatment Period #1 and Treatment Period #2, all subjects will continue on the same oral suspension (vamorolone 2.0 mg/kg or 6.0 mg/kg, or matching placebo) they received during Treatment Period #1 and all subjects will have their tablet dose tapered to zero. Thus, subjects randomized to receive vamorolone during Treatment Period #1 (Groups 1 and 2) will continue to receive vamorolone at the same dose, while subjects randomized to receive prednisone will have their dose tapered to zero, and subjects randomized to placebo will continue to receive placebo.

The prednisone group will be used as an active control comparison for safety and efficacy endpoints as requested by the European Medicines Agency (EMA). The placebo group will be used as comparator for efficacy endpoints (superiority model) as requested by the EMA and Food and Drug Administration (FDA) protocol advisory board. Although glucocorticoids are part of the care recommendations for DMD, their adverse effect profile has limited their use. The age at which glucocorticoids should be started in DMD boys is uncertain, ranging from 4 to 7 years, based on a balance between benefits and side effects. In view of the age inclusion criteria and duration of the placebo-controlled study period (6 months), the use of a placebo group has been considered acceptable as in clinical practice it will not cause a real delay in prescription of an accepted treatment for this condition. Any exposure of placebo longer than 6 months was considered unethical.

At the end of the Treatment Period #2, subjects may be given access to vamorolone through an additional study or general access program, or given the option to transition to standard of care treatment for DMD (may include glucocorticoids). Subjects completing VBP15-004 and enrolling directly into an additional vamorolone study or general access program to receive vamorolone will not need to taper their vamorolone dose prior to enrollment. All other subjects will begin a 4-week double-blind Dose-tapering Period during which the dose of study medication will be progressively reduced and discontinued.

Arms:
arm 1: Patients enrolled in Treatment Group 1 (experimental group) will receive vamorolone 2.0 mg/kg/day for the duration of the study. arm 2: Patients enrolled in Treatment Group 2 (experimental group) will receive vamorolone at 6.0 mg/kg/day for the duration of the study. arm 3: Patients enrolled in Treatment Group 3 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by 20 weeks of treatment with 2.0 mg/kg/day vamorolone. arm 4: Patients enrolled in Treatment Group 4 (active comparator group) will receive prednisone 0.75 mg/kg/day for 24 weeks followed by 20 weeks treatment with 6.0 mg/kg/day vamorolone. arm 5: Patients enrolled in Treatment Group 5 (placebo comparator group) will receive placebo daily for 24 weeks followed by 20 weeks treatment with 2.0 mg/kg/day vamorolone. arm 6: Patients enrolled in Treatment Group 6 (placebo comparator group) will receive placebo daily for 24 weeks followed by 20 weeks treatment with 6.0 mg/kg/day vamorolone.

Interventions: intervention 1: Vamorolone intervention 2: Prednisone intervention 3: Placebo intervention 4: Vamorolone intervention 5: Prednisone intervention 6: Placebo intervention 7: Vamorolone intervention 8: Vamorolone
Intervention descriptions: intervention 1: Oral administration of 2.0 mg/kg/day for the duration of the study. intervention 2: Oral administration of 0.75 mg/kg/day for 24 weeks. intervention 3: Oral administration of placebo daily for 24 weeks. intervention 4: Oral administration of 6.0 mg/kg/day for the duration of the study. intervention 5: Oral administration of 0.75 mg/kg/day for 24 weeks. intervention 6: Oral administration of placebo daily for 24 weeks. intervention 7: Oral administration of 2.0 mg/kg/day for 20 weeks. intervention 8: Oral administration of 6.0 mg/kg/day for 20 weeks.

Protocol document:
Prot_002.pdf: 
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Vam.orolone 
Amendment #4 
Protocol No.: VBP15--004 
28 August 2020 
Document No. VBPE5-004-A4 (Version 1.4) 
IND 118.942 
SIGNATURES O:F AGREEMENT FOR VBP15-004-A4 (Version 1.4) 
Amendment #4 for a Pha5e IIb Randomized, Double-blind, Parallel Group, Placebo-
and Active-c.ontrolled Study "ith Double-Blind Extension to Assess the Efficacy and 
Safety ofVamorolone in Ambulant Boys with Duchenne Muscular Dystrophy 
(DMD) 
Re,iewed and Approved by: 
_/-dlJ--_ 
~.....,..,,h,_ 
~"".Z."!it :.ia:o,oouor 
Eric Hoffman, Ph.D. 
Date 
Chief E.'tecutive Officer 
ReveraGen BioPhanua, Inc. 
.. --ty-
0 .... 
/U;t~d.!~~-:::;:: 
Michela Guglieri, M.D. 
Date 
Study Chair 
John Walton Muscttlar Dystrophy Research Centre 
Pa11/a R Cl(}rn&ns 
Pattla R. Clemens, M D. 
Date 
Study Vice Chair 
University of Pittsburgh School of Medicine 
John van den Anker, M.D., Ph.D. 
Medical Monitor 
Chief Medical Officer 
ReveraGenBioPhanua, Inc. 
Date 
Benjamin D. Schwartz, M.D., iPh.D. 
Date 
Consulting Medical Monitor 
The Camden Group, llC 
~_,.,._.,.u-,.~ 
/./wet J #elt.;te-ww't:.~'1;' .,,,,.,..,. 
Laurel J. Mengle-Gaw, Ph.D. 
Date 
Consulting Clinical Monitor 
The Camden Group, llC 
~.-.,. ...... ..,_ 
MArk;.JttrtH-
~~t':io;i,::"=,-, 
Mark J. Jaros, Ph.D. 
Date 
Consulting Statistician 
Sunnnit Analytical, llC 
Re:veraGe.n BioPhanna, Inc.. - CONFIDENTIAL 
Page 2 of232 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 3 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
INVESTIGATOR PROTOCOL AGREEMENT 
________________________________________________________________________ 
Amendment #4 for a Phase IIb Randomized, Double-blind, Parallel Group, Placebo- 
and Active-controlled Study with Double-Blind Extension to Assess the Efficacy and 
Safety of Vamorolone in Ambulant Boys with Duchenne Muscular Dystrophy 
(DMD) 
PROTOCOL NUMBER: 
VBP15-004 
DOCUMENT NUMBER: VBP15-004-A4 (Version 1.4) 
SPONSOR: 
ReveraGen BioPharma, Inc. 
DOCUMENT DATE: 
28 August 2020 
____________________________________________________________________________________________________________ 
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 set out in the 
Declaration of Helsinki listed in 21 CFR part 312, and ICH principles of Good 
Clinical Practice (GCP) and in accordance with all applicable laws, guidances and 
directives of the jurisdiction where the study is being conducted.  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, 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): 
 
RETAIN THE ORIGINAL SIGNED AGREEMENT AT YOUR SITE AND RETURN AN 
ELECTRONIC SIGNED COPY TO REVERAGEN BIOPHARMA, INC., OR DESIGNEE 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 4 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
SERIOUS ADVERSE EVENT CONTACT INFORMATION 
In the event of a serious adverse event (SAE) (see Section 7.5), 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:  
In United States and Canada: 
 
Email: CHOSafety@prahs.com 
 
Drug Safety Fax: 1 888 772 6919 or 1 434 951 3482 
 
SAE Questions: Drug Safety Helpline: 1 800 772 2215  
In Europe, Asia, Pacific, Africa and Australia: 
  
 
Email: MHGSafety@prahs.com 
 
Drug Safety Fax: +44 1792 525720 
 
SAE Questions: Drug Safety Helpline: +49 621 878 2154 
 
 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 5 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
PROTOCOL AMENDMENT TRACKING 
Document 
Document Number 
Approval Date 
Original Protocol 
VBP15-004 
15 December 2017 
Amendment #1 
VBP15-004-A1 (Version 1.1) 
04 May 2018 
Amendment #2 
VBP15-004-A2 (Version 1.2) 
05 March 2019 
Amendment #3 
VBP15-004-A3 (Version 1.3) 
21 May 2019 
Amendment #4 
VBP15-004-A4 (Version 1.4) 
28 August 2020 
Reasons for Protocol Amendment #4: 
1. To revise one of the primary objectives of the study to compare the efficacy of 
vamorolone administered orally at a dose of 6.0 mg/kg/day vs. placebo over a 24-
week treatment period; 
2. To revise the primary efficacy endpoint to TTSTAND velocity, comparison of 
vamorolone 6.0 mg/kg/day vs. placebo in change from baseline to Week 24, to 
align with the primary objective; 
3. To add an additional secondary objective of the study to compare the efficacy of 
vamorolone administered orally at a dose of 2.0 mg/kg/day vs. placebo over a 24-
week treatment period; 
4. To delete a secondary objective of the study comparing the efficacy of vamorolone 
2.0 mg/kg/day vs. 6.0 mg/kg/day over 24 weeks; 
5. To revise the list of safety endpoints to include linear growth velocity, and to clarify 
the endpoints for BMI z-score and ACTH Stimulation Test; 
6. To revise the secondary efficacy endpoints for Treatment Period #1; 
7. To add exploratory efficacy endpoints for Treatment Period #1; 
8. To add comparison of each vamorolone group to the placebo group for PARS III; 
9. To clarify Ease of Study Drug Administration exploratory endpoint; 
10. To revise the methodology for sample size calculation, in consideration of the 
revised primary efficacy endpoint; 
11. To add a Per Protocol Population for statistical analyses; 
12. To revise the multiple testing procedures for the efficacy endpoints; 
13. To revise the statistical methodology for efficacy and safety analyses; 
14. To clarify the circumstances under which hospitalizations should be considered 
serious adverse events; 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 6 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
15. To add assessment of suicidality and abuse potential associated with treatment from 
examination of adverse event data; 
16. To clarify that demographic and baseline characteristics summary tables will not be 
presented by age stratification; 
17. To update the safety information presented in Section 1.5 Overall Benefit/Risk and 
the serious adverse event information presented in Section 5.4 Rationale for Dose 
Selection to include current data from the vamorolone program;  
18. To remove analysis of biomarkers of immune suppression;  
19. To clarify that levels, not ratios, of serum osteocalcin and CTX1 will be reported;  
20. To clarify that analyses of candidate genetic modifiers of DMD will be presented in 
an addendum report;  
21. To clarify that spine x-ray data will be analyzed in an addendum report; 
22. To remove BMD z-score from the list of parameters assessed by DXA scan;  
23. To add an endpoint for the assessment of tolerability; and 
24. To correct typographical errors. 
The Sections changed by Amendment #4 are listed in was/is format in Appendix 15.1. 
 
Additionally, a protocol clarification letter (Protocol Clarification Letter #2.1, 27 March 
2020) was issued to outline modifications that could be made to study conduct due to 
COVID-19.  The main reasons for the Protocol Clarification Letter were as follows: 
1. To detail the modifications to study conduct and site monitoring to be implemented 
during the global COVID-19 pandemic.  Modifications are allowed to informed 
consent process; visit schedule and on-site study visits; collection of clinical 
laboratory assessments, weight, vital signs, efficacy assessments, adverse events 
and concomitant medications; dispense, return, and review of subject diaries; 
investigational product dispensing, administration, and compliance measurement; 
recording of COVID-19-related protocol deviations; transition to vamorolone 
general access program; and site monitoring.  The key modifications to be made on 
a visit-, site-, or subject-specific basis are: 
a. to allow for scheduled assessments to be performed remotely, with the 
exception of Screening assessments, which must be performed at the study 
site; 
b. for critical safety assessments (i.e., clinical laboratory tests, collection of 
adverse events and concomitant medications), intervals between 
assessments should be no longer than 12 weeks; 
c. in cases where on-site study visits are not possible for the completion of 
scheduled efficacy assessments, the Time to Stand Test (TTSTAND) will 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 7 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
be conducted remotely by a trained clinical evaluator by 
videoconferencing interface; assessment of TTSTAND must be completed 
at the Baseline, Week 24, and Week 48 assessment time points; 
d. to allow for investigational product sufficient for 12 weeks of dosing to be 
shipped directly from the site to subjects’ homes. 
 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 8 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
STUDY SYNOPSIS 
Protocol Title 
A Phase IIb Randomized, Double-blind, Parallel Group, Placebo- and Active-
controlled Study with Double-Blind Extension to Assess the Efficacy and Safety 
of Vamorolone in Ambulant Boys with Duchenne Muscular Dystrophy (DMD) 
Name of Sponsor 
ReveraGen BioPharma, Inc. 
Protocol Number 
VBP15-004 
Drug Substance 
delta-1,4,9(11)-pregnatriene-17-alpha,21-dihydroxy-16-alpha-methyl-3,20-dione 
Investigational 
Drug Product 
Vamorolone, 1.33% and 4.0% wt/wt suspension for oral dosing 
Phase of 
Development 
Phase IIb 
Indication 
Treatment of Duchenne muscular dystrophy (DMD) 
Primary Objectives 
1. To compare the efficacy of vamorolone administered orally at daily doses of 
6.0 mg/kg over a 24-week treatment period vs. placebo in ambulant boys 
ages 4 to <7 years with DMD; and  
2. To evaluate the safety and tolerability of vamorolone administered orally at 
daily doses of 2.0 mg/kg and 6.0 mg/kg in ambulant boys ages 4 to <7 years 
with DMD.  
Secondary 
Objectives 
1. To compare the efficacy of vamorolone administered orally at daily doses of 
2.0 mg/kg over a 24-week treatment period vs. placebo in ambulant boys 
ages 4 to <7 years with DMD; 
2. To compare the safety of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily 
prednisone 0.75 mg/kg in ambulant boys ages 4 to <7 years with DMD; 
3. To compare the efficacy of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily 
prednisone 0.75 mg/kg in ambulant boys ages 4 to <7 years with DMD;  
4. To compare the efficacy of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 48-week treatment period in ambulant boys 
ages 4 to <7 years with DMD vs. untreated DMD historical controls;  
5. To compare the safety of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 48-week treatment period in ambulant boys 
ages 4 to <7 years with DMD vs. prednisone-treated DMD historical 
controls; and 
6. To evaluate the population pharmacokinetics (PK) of vamorolone 
administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg in ambulant 
boys ages 4 to <7 years with DMD. 
Exploratory 
Objectives 
1. To evaluate the satisfaction with treatment of vamorolone administered 
orally at daily doses of 2.0 mg/kg and 6.0 mg/kg over a 24-week treatment 
period vs. daily prednisone 0.75 mg/kg in ambulant boys ages 4 to <7 years 
with DMD;  
2. To evaluate the effect of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 9 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
prednisone 0.75 mg/kg on behavior and neuropsychology;  
3. To evaluate the effect of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. placebo on 
physical functioning; 
4. To assess the ease of administration of the study medication suspension to 
ambulant boys ages 4 to <7 years with DMD; 
5. To compare the effects of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. placebo on 
potential serum pharmacodynamics (PD) biomarkers of safety and efficacy 
in ambulant boys ages 4 to <7 years with DMD;  
6. To compare the effects of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily 
prednisone 0.75 mg/kg on potential serum PD biomarkers of safety and 
efficacy in ambulant boys ages 4 to <7 years with DMD; and 
7. To determine if candidate genetic modifiers of DMD (gene polymorphisms 
associated with disease severity, or response to glucocorticoid treatment) are 
similarly associated with vamorolone-treated DMD subjects (baseline 
disease severity, or response to vamorolone or prednisone treatment). 
Study Design 
This Phase IIb study is a randomized, double-blind, parallel group, placebo and 
active-controlled study to evaluate the efficacy, safety, PD, and population PK of 
vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg 
versus prednisone 0.75 mg/kg/day and placebo over a Treatment Period of 
24 weeks, and to evaluate persistence of effect over a Treatment Period of 
48 weeks in ambulant boys ages 4 to <7 years with DMD. 
The study is comprised of a 5-week Pretreatment Screening Period, a 1-day 
Pretreatment Baseline Period, a 24-week Treatment Period #1 (Weeks 1-24), a 
4-week Transition Period (Weeks 25-28), a 20-week Treatment Period #2 
(Weeks 28 + 1 day to 48), and a 4-week Dose-tapering Period (Weeks 49-52). 
Subjects will be randomized to one of six treatment groups in a 2:2:1:1:1:1 ratio, 
where the two prednisone groups in Treatment Period #1 (Groups 3 and 4) will 
be combined and the two placebo groups in Treatment Period #1 (Groups 5 and 
6) will be combined, effectively resulting in a 1:1:1:1 randomization 
(vamorolone 2.0 mg/kg/day : vamorolone 6.0 mg/kg/day : prednisone 
0.75 mg/kg/day : placebo) for Treatment Period #1: 
Study Randomization Schedule 
Group 
# 
Treatment Period #1 
Treatment Period #2 
1 
30 
Vamorolone, 2.0 mg/kg/day ® 
Vamorolone, 2.0 mg/kg/day 
2 
30 
Vamorolone, 6.0 mg/kg/day ® 
Vamorolone, 6.0 mg/kg/day 
3 
15 
Prednisone, 0.75 mg/kg/day ® 
Vamorolone, 2.0 mg/kg/day 
4 
15 
Prednisone, 0.75 mg/kg/day ® 
Vamorolone, 6.0 mg/kg/day 
5 
15 
Placebo ® 
Vamorolone, 2.0 mg/kg/day 
6 
15 
Placebo ® 
Vamorolone, 6.0 mg/kg/day 
# = number of planned randomized subjects in each group 
Subjects will be stratified based on age at study entry (<6 vs. ≥ 6 years).  During 
the 4-week Transition Period between Treatment Period #1 and Treatment 
Period #2, all subjects will continue on the same oral suspension (vamorolone 
2.0 mg/kg or 6.0 mg/kg, or matching placebo) they received during Treatment 
Period #1 and all subjects will have their tablet dose tapered to zero.  Thus, 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 10 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
subjects randomized to receive vamorolone during Treatment Period #1 (Groups 
1 and 2) will continue to receive vamorolone at the same dose, while subjects 
randomized to receive prednisone will have their dose tapered to zero, and 
subjects randomized to placebo will continue to receive placebo. 
The prednisone group will be used as an active control comparison for safety and 
efficacy endpoints as requested by the European Medicines Agency (EMA).  
The placebo group will be used as comparator for efficacy endpoints (superiority 
model) as requested by the EMA and Food and Drug Administration (FDA) 
protocol advisory board.  Although glucocorticoids are part of the care 
recommendations for DMD, their adverse effect profile has limited their use.  
The age at which glucocorticoids should be started in DMD boys is uncertain, 
ranging from 4 to 7 years, based on a balance between benefits and side effects.  
In view of the age inclusion criteria and duration of the placebo-controlled study 
period (6 months), the use of a placebo group has been considered acceptable as 
in clinical practice it will not cause a real delay in prescription of an accepted 
treatment for this condition.  Any exposure of placebo longer than 6 months was 
considered unethical. 
At the end of the Treatment Period #2, subjects may be given access to 
vamorolone through an additional study or general access program, or given the 
option to transition to standard of care treatment for DMD (may include 
glucocorticoids).  Subjects completing VBP15-004 and enrolling directly into an 
additional vamorolone study or general access program to receive vamorolone 
will not need to taper their vamorolone dose prior to enrollment.  All other 
subjects will begin a 4-week double-blind Dose-tapering Period during which 
the dose of study medication will be progressively reduced and discontinued. 
Planned Sample 
Size 
A total of approximately 120 subjects will be randomized (2:2:1:1:1:1) to 
treatment as follows (treatment assignment in Treatment Period #1 ® treatment 
assignment in Treatment Period #2): 
Vamorolone 2.0 mg/kg/day ® Vamorolone 2.0 mg/kg/day (n=30);  
Vamorolone 6.0 mg/kg/day ® Vamorolone 6.0 mg/kg/day (n=30); 
Prednisone 0.75 mg/kg/day ® Vamorolone 2.0 mg/kg/day (n=15);  
Prednisone 0.75 mg/kg/day ® Vamorolone 6.0 mg/kg/day (n=15); 
Placebo ® Vamorolone 2.0 mg/kg/day (n=15); or  
Placebo ® Vamorolone 6.0 mg/kg/day (n=15). 
Inclusion Criteria 
1. Subject’s parent(s) or legal guardian(s) has (have) provided written 
informed consent and Health Insurance Portability and Accountability Act 
(HIPAA) authorization, where applicable, prior to any study-related 
procedures; participants will be asked to give written or verbal assent 
according to local requirements 
2. Subject has a centrally confirmed (by TRiNDS central genetic counselor[s]) 
diagnosis of DMD as defined as: 
• 
Dystrophin immunofluorescence and/or immunoblot showing complete 
dystrophin deficiency, and clinical picture consistent with typical 
DMD, OR 
• 
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 
• 
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 clinical picture consistent 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
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ReveraGen BioPharma, Inc. – CONFIDENTIAL 
with typical DMD; 
3. Subject is ≥ 4 years and <7 years of age at time of enrollment in the study; 
4. Subject weighs >13.0 kg and ≤ 39.9 kg at the Screening Visit; 
5. Subject is able to walk independently without assistive devices; 
6. Subject is able to complete the Time to Stand Test (TTSTAND) without 
assistance in <10 seconds, as assessed at the Screening Visit; 
7. 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. [Notes: Serum gamma glutamyl transferase (GGT), creatinine, 
and total bilirubin all must be ≤ upper limit of the normal range at the 
Screening Visit.  An abnormal vitamin D level that is considered clinically 
significant will not exclude a subject from randomization]; 
8. 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 local laboratory from blood collected during the 
Screening Period, OR 
• 
Documentation, provided at the Screening Visit, that the subject has 
had 2 doses of varicella vaccine, with or without serologic evidence of 
immunity; the second of the 2 immunizations must have been given at 
least 14 days prior to randomization.  
9. Subject is able to swallow tablets, as confirmed by successful test 
swallowing of placebo tablets during the Screening Period; and 
10. Subject and parent(s)/guardian(s) 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 a history of primary hyperaldosteronism; 
6. Subject has evidence of symptomatic cardiomyopathy [Note: Asymptomatic 
cardiac abnormality on investigation would not be exclusionary]; 
7. 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 1 month 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, unless discontinued for intolerance.  Inhaled and/or topical 
glucocorticoids are permitted if last use is at least 4 weeks prior to first dose 
of study medication or if administered at stable dose beginning at least 4 
weeks prior to first dose of study medication and anticipated to be used at 
the stable dose regimen for the duration of the study]; 
8. Subject has an allergy or hypersensitivity to the study medication or to any 
of its constituents; 
9. Subject has used idebenone within 4 weeks prior to the first dose of study 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 12 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
medication; 
10. Subject has severe behavioral or cognitive problems that preclude 
participation in the study, in the opinion of the Investigator; 
11. 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; 
12. Subject is taking (or has taken within 4 weeks prior to the first dose of study 
medication) herbal remedies and supplements which can impact muscle 
strength and function (e.g., Co-enzyme Q10, creatine, etc);  
13. Subject is taking (or has taken within 3 months prior to the first dose of 
study medication) any medication indicated for DMD, including Exondys51 
and Translarna;  
14. Subject has been administered a live attenuated vaccine within 14 days prior 
to the first dose of study medication; 
15. Subject is currently taking any other investigational drug or has taken any 
other investigational drug within 3 months prior to the first dose of study 
medication;  
16. Subject has a sibling who is currently enrolled in any vamorolone study or 
Expanded Access Program, or who intends to enroll in any vamorolone 
study or Expanded Access Program during the subject’s participation in the 
VBP15-004 study; or 
17. Subject has previously been enrolled in the study. 
Note: Any parameter/test may be repeated at the Investigator’s discretion during 
Screening to determine 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 injury, or if 
ineligible due to negative anti-varicella IgG antibody test result.  
Number of Centers 
The study will be conducted at approximately 30 study sites in approximately 
15 countries, predominantly in the European Union (EU). 
Study Period 
First subject screened: 1Q 2018 
Last subject last visit: 2Q 2020 
Study Duration  
Up to approximately 36 months total duration 
Individual Subject 
Study Duration 
Up to approximately 57 weeks: 
• 
Screening Period: up to 5 weeks 
• 
Treatment Period #1: 24 weeks 
• 
Transition Period: 4 weeks 
• 
Treatment Period #2: 20 weeks 
• 
Dose-tapering Period: 4 weeks (only for subjects who will transition off 
vamorolone at the end of the study) 
Subjects who complete the Treatment Period Week 48 assessments may be given 
the option of continuing vamorolone treatment in an additional vamorolone 
study or general access program under separate protocol.  Subjects who continue 
directly with vamorolone treatment in the additional vamorolone study or 
general access program will be discharged from the VBP15-004 study following 
completion of all Week 48 assessments and the Week 48 Follow-up Visit ACTH 
Stimulation Test, and will not participate in the Dose-tapering Period. 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 13 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
Study Drug 
Formulation, 
Dosage & 
Administration 
Treatment Period #1 
Vamorolone 
1.33% 
and 
vamorolone 
4.0% 
wt/wt 
oral 
suspensions 
(investigational medicine), prednisone (active-control) or placebo will be 
administered once daily over the 24-week Treatment Period #1.  Subjects 
receiving 2.0 mg/kg/day will be administered the vamorolone 1.33% wt/wt oral 
suspension, and subjects receiving 6.0 mg/kg/day will be administered the 
vamorolone 4.0% wt/wt oral suspension.  To maintain the blind, matched 
suspension (vamorolone or placebo) and matched tablets (prednisone or placebo) 
will be administered.  Each subject will receive a dose of suspension 
(vamorolone or placebo) and tablets (prednisone or placebo) each day.  The 
number of tablets of prednisone 5 mg or matching placebo to be administered, 
based on subject weight and a prednisone dose of 0.75 mg/kg, is shown in the 
table below: 
Prednisone and Placebo Tablet Dosing 
Band 
Weight 
range in kg 
Weight used 
for calculation 
of dose per kg 
Dose in mg 
based on 
0.75 mg/kg 
prednisone 
Number tablets of 
prednisone (5 mg) or 
matching placebo for 
given weight range 
A 
13-19.9 
13.33 kg 
10 mg 
2 
B 
20-25.9 
20.00 kg 
15 mg 
3 
C 
26-32.9 
26.67 kg 
20 mg 
4 
D 
33-39.9 
33.33 kg 
25 mg 
5 
Study drugs will be administered in the study unit on Day 1, and at the Week 2, 
Week 12 and Week 24 study visits; all other doses will be administered at home.  
Study drug oral suspensions will be administered by mouth using a volumetric 
syringe.  Following administration of the dose of study drug suspension, the 
syringe will be filled once with water and the water will be administered by 
mouth using the volumetric syringe.  Prednisone or matching placebo tablets will 
be taken either immediately before or immediately after the dose of suspension.  
The subject will then drink approximately 50 mL (approximately 2 ounces) of 
water to ensure the full dose has been ingested.   
The daily dose of study medication should be taken with breakfast including at 
least 8 g of fat (approximately 8 ounces [240 mL] of full-fat milk or equivalent 
high-fat food portion).  There are no other food or drink restrictions before or 
after dosing.  
Transition Period 
Vamorolone 1.33% wt/wt or 4.0% wt/wt (investigational medicine) or placebo 
oral suspension will continue to be administered once daily over the 4-week 
Transition Period.  Prednisone (active control) and placebo tablets will be 
tapered over the 4-week Transition Period.  All study medication will be 
administered once daily, in the same manner as during Treatment Period #1.  
Treatment Period #2 and Dose-tapering Period 
Vamorolone 1.33% wt/wt or 4.0% wt/wt oral suspension (investigational 
medicine) will be administered once daily over the 20-week Treatment 
Period #2, and during the 4-week Dose-tapering Period, as applicable.  No study 
drug tablets are administered during Treatment Period #2 or the Dose-tapering 
Period.  The oral suspension study medication will be administered once daily, 
in the same manner as during Treatment Period #1.  


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 14 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
Study Summary 
This Phase IIb study is a randomized, double-blind, parallel group, placebo- and 
active-controlled study with double-blind extension to evaluate the long-term 
efficacy, safety, tolerability, PD, and population PK of vamorolone (the 
investigational medicine) compared to prednisone (active control) and placebo 
over a Treatment Period of 24 weeks in boys ages 4 to <7 years with DMD, and 
determine the persistence of effect over a total Treatment Period of 48 weeks.   
Study drug dosing will occur from Day 1 until the Week 48 Visit.  Study drug 
dosing will occur at home on all days except the Day 1, Week 2, Week 12, 
Week 24, Week 28, Week 30, Week 40, and Week 48 study visits, when dosing 
will occur at the study site.   
Subjects will be assessed for safety and tolerability, clinical efficacy, PD, and 
population PK at scheduled visits throughout the study.  Treatment Period #1, 
Transition Period, and Treatment Period #2 study visits will occur at Day 1, 
Week 2, Week 6, Week 12, Week 18, Week 24, Week 28, Week 30, Week 34, 
Week 40 and Week 48; all subjects will return to the clinical site for a Week 24 
Follow-up Visit and for a Week 48 Follow-up Visit, 48 ± 3 hours after 
administration of the final dose of Treatment Period #1 and Treatment Period #2 
study medication, respectively, for ACTH Stimulation testing.  Adverse events, 
including SAEs, and concomitant medications will be recorded throughout the 
study.   
Subject diaries will be dispensed at the Day 1 Visit and at each study visit 
thereafter through Week 48 to record AEs, changes to concomitant medications 
taken during the study, and any missed or incomplete doses of study medication. 
There is flexibility in the timing of completion of some of the scheduled 
Week 24 and Week 48 assessments.  The scheduled physical examination, 
weight, vital signs, clinical laboratory tests, blood draws for PD biomarker 
analysis, blood draw for DNA testing (Week 24 only), Ease of Study Medication 
Administration Assessment, PODCI, PARS III, and functional assessments 
(TTSTAND, TTCLIMB, TTRW, NSAA, 6MWT, hand-held myometry, ROM) 
must all be performed on the date of the Week 24 or Week 48 dose of study 
medication.  The 12-lead ECG may be performed on the date of the Week 24 or 
Week 48 dose of study medication, the day following the Week 24 or Week 48 
dose of study medication, or the day of the Week 24 or Week 48 Follow-up 
Visit.  For the Week 24 assessments, completion of the DXA scan, spine X-rays, 
Fracture Questionnaire, 2-D echocardiography, eye examination, TSQM, and 
Blindedness Assessment may be performed up to 7 days following the date of 
the Week 24 dose of study medication to accommodate need for additional 
scheduling flexibility.  For the Week 48 assessments, completion of the DXA 
scan, Fracture Questionnaire, 2-D echocardiography, eye examination, and 
TSQM may be performed on the date of the final Week 48 dose of study 
medication, the day following the Week 48 dose of study medication, or the day 
of the Week 48 Follow-up Visit for subjects who will receive additional 
vamorolone therapy by enrolling directly into an additional vamorolone study or 
general access program, or up to 7 days following the date of the final Week 48 
dose of study medication for subjects participating in the Dose-tapering Period.  
A Transition Period of 4 weeks in duration follows the end of Treatment Period 
#1 for all subjects.  During this Transition Period, all subjects will continue to 
receive the liquid formulation (vamorolone 2.0 mg/kg or 6.0 mg/kg, or matching 
placebo) they received during Treatment Period #1 and will be tapered off their 
study medication tablets (prednisone or matching placebo).  Site study staff will 
contact the parent(s)/guardian(s) by telephone at Week 26 to ensure that the 
tablet tapering is proceeding according to protocol, to assess potential signs or 
symptoms indicative of adrenal suppression, and to address any questions the 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 15 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
parent(s)/guardian(s) may have.  All subjects will return to the clinical site for 
the Week 28 assessments, prior to receiving their first dose of Treatment Period 
#2 study medication on the day after the Week 28 Visit (Week 28 + 1 day).   
Subjects who complete the VBP15-004 study assessments through the Week 48 
Visit and Week 48 Follow-up Visit may be given access to vamorolone through 
an additional study or general access program, or given the option to transition to 
standard of care treatment (including glucocorticoids) for DMD.  Standard of 
care treatment for DMD may be offered to the subject following completion of 
the Phase IIb VBP15-004 study, if the subject’s parent or guardian does not wish 
to enroll the subject in the additional vamorolone study or general access 
program and/or the Investigator feels it to be in the best interest of the subject.   
Subjects who complete the VBP15-004 study and will enroll directly into an 
additional vamorolone study or general access program to continue vamorolone 
treatment will be discharged from the VBP15-004 study following completion of 
all Week 48 assessments and the Week 48 Follow-up Visit ACTH Stimulation 
Test.  Subjects who will not continue vamorolone treatment in an additional 
vamorolone study or general access program, including those subjects who will 
transition to standard of care treatment for DMD, will have their vamorolone 
dose tapered during a 4-week Dose-tapering Period, prior to discharge from the 
study.  Site study staff will contact the parent(s)/guardian(s) by telephone at 
Week 50 to ensure that the dose tapering is proceeding according to protocol, to 
assess potential signs or symptoms of adrenal suppression, and to address any 
questions the parent(s)/guardian(s) may have.  
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.   
Any subject who discontinues the study prior to the Week 24 Visit should return 
to the study unit for scheduled Week 24 assessments and the Week 24 Follow-up 
Visit ACTH Stimulation Test at the time of early withdrawal, whenever 
possible; any subject who prematurely discontinues the study after Week 24 but 
prior to Week 28 should complete the scheduled Week 28 assessments at the 
time of early withdrawal, whenever possible; and any subject who prematurely 
discontinues the study after Week 28 but prior to Week 48 should complete the 
scheduled Week 48 assessments and the Week 48 Follow-up Visit ACTH 
Stimulation Test at the time of early withdrawal, whenever possible, assuming 
the subject has not withdrawn consent.  Any subject who withdraws early from 
the study should undergo Early Discontinuation Dose-tapering. 
Safety Measures  
• 
Body Mass Index (BMI) 
• 
Weight and Height 
• 
Vital signs (sitting blood pressure, heart rate, respiratory rate, and body 
temperature [modality for determining temperature should be consistent for 
each subject at all assessment time points throughout the study]) 
• 
Physical examination 
• 
Cushingoid features 
• 
Clinical laboratory tests: 
• 
Hematology and clinical chemistry 
• 
Urinalysis 
• 
Lipid profile (triglycerides, total cholesterol, low density 
lipoprotein [LDL], high density lipoprotein [HDL]) 
• 
Vitamin D level 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 16 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
• 
ACTH Stimulation Test 
• 
12-lead electrocardiogram (ECG) 
• 
2-D echocardiography 
• 
Eye examination 
• 
Dual-energy x-ray absorptiometry (DXA) scan 
• 
Spine X-ray 
• 
Fracture Questionnaire 
• 
Clinical signs and symptoms (AEs and SAEs) 
• 
Grading of clinical and clinical laboratory AEs will be according to the 
Common Terminology Criteria for Adverse Events (CTCAE), v.4.03 
Pharmacodynamic 
Measures 
• 
Blood will be collected for serum PD biomarker testing to explore effects of 
vamorolone on biomarkers of muscle cellular pathology, and biomarkers 
associated with acute and chronic glucocorticoid treatment (aspects of both 
safety and efficacy).  Secondary outcomes are serum biomarkers bridged to 
clinical outcomes of safety, including adrenal suppression, insulin 
resistance, and bone turnover.  Exploratory outcomes are serum biomarkers 
that have been shown to be glucocorticoid-responsive in DMD patients, but 
not yet bridged to clinical outcomes (safety and efficacy).  Samples for 
analysis of acute and chronic PD biomarker response will be collected at 
Day 1, Week 12, and Week 24, Week 28, Week 40, and Week 48 (pre-
dose), and final Dose-tapering Period Visit.  Blood remaining from collected 
samples may be stored for future exploratory biomarker studies.  Blood 
samples for PD biomarkers, including insulin and glucose, will be collected 
after subjects have fasted for ≥ 6 hours, and prior to the daily dose of study 
medication where applicable.  
Pharmacokinetic 
Measures 
• 
Blood will be collected from all subjects at the Week 30 Visit, at 2 hours 
post-dose, for vamorolone population PK analysis.   
Clinical Efficacy 
Measures 
• 
Time to Stand Test (TTSTAND) 
• 
Time to Climb 4 steps (TTCLIMB) 
• 
Time to Run/Walk 10 meters Test (TTRW) 
• 
North Star Ambulatory Assessment (NSAA) 
• 
Six-minute Walk Test (6MWT) 
• 
Hand-held Myometry (elbow flexors/knee extensors) 
• 
Range of Motion (ROM) in the ankles 
Exploratory 
Measures  
• 
Treatment satisfaction questionnaire (TSQM) 
• 
Pediatric Outcome Data Collection Instrument (PODCI) 
• 
PARS III questionnaire 
• 
Ease of Study Medication Administration Assessment 
• 
Blindedness Assessment 
• 
DNA testing for candidate genetic modifiers of DMD 
Statistical Methods 
Sample Size: 
This is a randomized, double-blind, parallel group, placebo- and active-
controlled study.  Study medication is administered daily in this Phase IIb trial.  
Data for untreated subjects from the Cooperative International Neuromuscular 
Research Group (CINRG) Duchenne Natural History Study and data for 
prednisone-treated subjects from the CINRG Prednisone study were used to help 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 17 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
estimate sample sizes for this study.  
In the vamorolone VBP15-003 study and the interim analysis of the VBP15-LTE 
study, doses of 0.25 and 0.75 mg/kg/day showed little evidence of clinical 
benefit, whereas doses of 2.0 and 6.0 mg/kg/day both showed clear evidence of 
clinical benefit comparable to that seen with glucocorticoids (prednisone and 
deflazacort). 
In consideration of the primary efficacy endpoint in the current study, 
comparison of 6.0 mg/kg/day vamorolone versus placebo, sample size 
calculations were performed using data from vamorolone-treated subjects from 
the VBP15-002/VBP15-003 24-week treatment period.  The analysis compared 
TTSTAND velocity from the combined 2.0 and 6.0 mg/kg/day groups 
(Treatment Group) to the combined 0.25 and 0.75 mg/kg/day groups (Pseudo-
Placebo Group).   
Least squares (LS) means from the mixed model for repeated measures 
(MMRM) modeling of VBP15-002/VBP15-003 24-week data were used as 
parameter estimates of the population means in the sample size calculations for 
the comparison of the Treatment Group (2.0 + 6.0 mg/kg/day) vs. the Pseudo-
Placebo Group (0.25 + 0.75 mg/kg/day) on the mean change from baseline at 
Week 24.  For the estimates of standard deviations within each comparison 
group, simple descriptive statistics from the VBP15-002/VBP15-003 24-week 
data were used.  Power was estimated using two-sided t-tests assuming unequal 
variance, with alpha =0.05.  
The following table shows the resultant estimated power for various sample sizes 
per comparison group for comparing the Treatment Group (2.0 + 6.0 mg/kg/day) 
vs. the Pseudo-Placebo Group (0.25 + 0.75 mg/kg/day) on the mean change from 
baseline at Week 24 for the alternative hypothesis that H1: μ1 ≠ μ2 assuming an 
alpha level of 0.05 and parameter estimates from the analyses described above 
for TTSTAND velocity: 
 
Sample Size 
per 
Comparison 
Group 
μ1 
(Pseudo-
Placebo) 
μ2 
(Treatment 
Group) 
σ1 
(Pseudo-
Placebo) 
σ2 
(Treatment 
Group) 
Estimated 
Power 
25 
-0.0052 
0.0450 
0.0628 
0.0530 
84.89% 
28 
-0.0052 
0.0450 
0.0628 
0.0530 
88.76% 
30 
-0.0052 
0.0450 
0.0628 
0.0530 
90.81% 
The sample size of 25 per treatment group for 2.0 mg/kg/day, 6.0 mg/kg/day, 
prednisone, and placebo will result in a total enrollment of 100 subjects which 
will provide approximately 85% power at alpha level 0.05 to detect a statistically 
significant difference between 6.0 mg/kg/day and placebo on TTSTAND 
velocity at Week 24.  Similarly, a total enrollment of 120 subjects (30 per 
treatment group) will provide approximately 91% power at alpha level 0.05 to 
detect a statistically significant difference between 6.0 mg/kg/day and placebo 
on TTSTAND velocity at Week 24. 
Note that subjects in the prednisone and placebo groups will actually be 
randomized into two groups each: 
• 
Prednisone 0.75 mg/kg/day ® Vamorolone 2.0 mg/kg/day (n=15);  
• 
Prednisone 0.75 mg/kg/day ® Vamorolone 6.0 mg/kg/day (n=15); 
• 
Placebo ® Vamorolone 2.0 mg/kg/day (n=15); or  
• 
Placebo ® Vamorolone 6.0 mg/kg/day (n=15). 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
Page 18 of 232 
ReveraGen BioPharma, Inc. – CONFIDENTIAL 
These groups will be pooled by initial treatment (prednisone or placebo) for the 
Treatment Period #1 analyses. 
If the number of subjects who withdraw early from the study is high, additional 
subjects may be enrolled to achieve approximately 120 subjects completing the 
Week 24 Visit assessments. 
Analysis Populations:   
Four populations will be defined for data analysis: the Safety Population, the 
modified Intent-to-Treat Population, the Per Protocol Population (PPP), and the 
Pharmacokinetic (PK) Population. 
Safety Population 
All subjects who receive at least one dose of study medication will be included 
in the Safety Population.  The Safety Population is the primary analysis 
population for safety and PD assessments.  Results will be presented “as 
treated.” 
Modified Intent-to-Treat (mITT) Population 
All subjects who receive at least one dose of study medication and have at least 
one post-baseline assessment will be included in the mITT Population.  The 
mITT Population is the primary analysis population for clinical efficacy.  
Subjects who receive at least one dose of study medication but never have post-
baseline assessments will be excluded.  Results will be presented “as 
randomized.” 
Per Protocol Population 
The PPP will be those subjects in the mITT Population who had no major 
protocol deviations and will be the secondary analysis population for analysis of 
the efficacy data.  The PPP will also exclude some subjects because of missed 
assessments due to the COVID-19 pandemic.  Exclusion of subjects from the 
PPP will be made on a subject-by-subject basis prior to database hard lock. 
 
Pharmacokinetic (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. 
General Statistical Considerations:   
All measurements will be analyzed based upon the type of distribution and 
descriptive statistics presented by treatment group and time point, as appropriate.  
No formal interim statistical analyses are planned, apart from the interim 
unblinded safety data views and presentations to be created for the Data and 
Safety Monitoring Board (DSMB).  The Week 24 analyses are the primary 
analyses for this study and will be performed after all subjects have completed 
Week 24 of Treatment Period #1.  The Week 48 analyses (vamorolone versus 
untreated historical controls and vamorolone versus prednisone-treated historical 
controls) will be performed after all subjects have completed Treatment 
Period #2.  Missing values for safety outcomes will be treated as missing, unless 
stated otherwise.   
Baseline measurement is defined as the last non-missing value prior to the first 
dose of study drug.  
Treatment Period #1 analyses will be summarized by four treatment groups: 
• 
Vamorolone 2.0 mg/kg/day (n=30);  
• 
Vamorolone 6.0 mg/kg/day (n=30); 
• 
Prednisone 0.75 mg/kg/day (n=30); and 


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• 
Placebo (n=30). 
Treatment Period #2 analyses (besides historical control comparison data) will 
be summarized by six treatment groups: 
• 
Vamorolone 2.0 mg/kg/day ® Vamorolone 2.0 mg/kg/day (n=30);  
• 
Vamorolone 6.0 mg/kg/day ® Vamorolone 6.0 mg/kg/day (n=30); 
• 
Prednisone 0.75 mg/kg/day ® Vamorolone 2.0 mg/kg/day (n=15);  
• 
Prednisone 0.75 mg/kg/day ® Vamorolone 6.0 mg/kg/day (n=15); 
• 
Placebo ® Vamorolone 2.0 mg/kg/day (n=15); and  
• 
Placebo ® Vamorolone 6.0 mg/kg/day (n=15). 
Adjustment for Multiple Comparisons: 
The primary efficacy endpoint tests vamorolone 6.0 mg/kg/day vs. placebo using 
TTSTAND velocity at Week 24 and occurs during Treatment Period #1 of the 
study.  The primary efficacy endpoint supports the primary objective of this 
study.  The study is thus powered for the efficacy comparison using an alpha 
level of 0.05 for success.   
The secondary efficacy endpoints will be tested at Week 24 along with the 
primary efficacy endpoint using a fixed sequential testing process where the 
fixed sequence of testing will be done in the following order: 
1. TTSTAND velocity, vamorolone 2.0 mg/kg/day vs placebo 
2. 6 Minute Walk Test (6MWT) meters walked, vamorolone 6.0 
mg/kg/day vs. placebo 
3. 6 Minute Walk Test (6MWT) meters walked, vamorolone 2.0 
mg/kg/day vs. placebo 
4. Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 6.0 
mg/kg/day vs. placebo 
5. Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 2.0 
mg/kg/day vs. placebo 
6. 6MWT meters walked, vamorolone 6.0 mg/kg/day vs. prednisone 
7. 6MWT meters walked, vamorolone 2.0 mg/kg/day vs. prednisone 
Each test in the sequence will be carried out using a two-sided alpha level of 
0.05.  Statistical testing of the primary/secondary efficacy endpoints will stop if 
a p-value >0.05 occurs or if a p-value ≤ 0.05 occurs in the wrong direction.  In 
case the fixed sequential testing process stops, the results of the subsequent tests 
will be reported with nominal p-values, but p-values ≤ 0.05 in the right direction 
will not be considered proof of statistical testing success in these subsequent 
tests. 
All other analyses will not be corrected for multiple comparisons (tests will be 
performed at the 0.05 alpha level), as they will be viewed and handled in the 
perspective of not testing a formal hypothesis. 
Efficacy Analyses: 
All evaluations of clinical efficacy will be listed and presented using descriptive 
statistics per treatment group and time point.  The primary efficacy outcome is 
TTSTAND (velocity), comparison of vamorolone 6.0 mg/kg/day vs placebo.  
Secondary and exploratory efficacy outcomes are TTSTAND (velocity), 
comparison of vamorolone 2.0 mg/kg/day vs placebo; the NSAA assessment; 
TTCLIMB (velocity); TTRW (velocity); 6MWT; hand-held myometry (elbow 
flexors and knee extensors); and ROM.   
The primary efficacy outcome TTSTAND (velocity) change from baseline to 
Week 24 will be compared between the 6.0 mg/kg/day vamorolone dose group 


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and the placebo group using a restricted maximum likelihood (REML)-based 
mixed model for repeated measures (MMRM).  This model includes fixed 
effects for treatment (vamorolone 2.0 mg/kg/day, vamorolone 6.0 mg/kg/day, 
prednisone 0.75 mg/kg/day, and placebo), week, baseline TTSTAND, age group 
(per stratification), and the treatment-by-week interaction.  Study week will be 
included in the model as a categorical variable (Weeks 6, 12, and 24) along with 
the treatment-by-week interaction.  Within this model, pairwise comparisons 
(using least squares [LS] mean contrasts) will be made to compare TTSTAND 
velocity at 24 weeks for the vamorolone 6.0 mg/kg/day dose level with placebo 
(primary efficacy outcome).  
For secondary outcomes, the same models will be used as for the primary 
outcome (REML-based MMRM including fixed effects for treatment 
[vamorolone 2.0 mg/kg/day, vamorolone 6.0 mg/kg/day, prednisone 0.75 
mg/kg/day, and placebo], age group [<6 years; ≥ 6 years], week, baseline, and 
treatment-by-week interaction). 
An unstructured covariance matrix will be used, and underlying modelling 
assumptions will be checked.  If differences between baseline characteristics 
exist between the treatment groups, it will be investigated if adjustment for these 
characteristics is clinically relevant and necessary.  The secondary outcome 
measures will be compared using similar models. 
Sensitivity analyses will be performed to assess the impact of COVID-19 on the 
primary endpoint.  Additional sensitivity and supportive analyses will be 
performed on the primary and secondary outcomes.  Full details will be provided 
in the SAP. 
Subjects who are randomized to receive vamorolone 2.0 mg/kg/day or 
vamorolone 6.0 mg/kg/day for both treatment periods will have TTSTAND 
velocity change from baseline data captured over 48 weeks compared with 
untreated DMD historical control data.  Full details will be provided in the 
Statistical Analysis Plan (SAP). 
 
Patient Reported Outcome Analyses: 
Patient Reported Outcomes including the TSQM, PODCI, PARS III, Ease of 
Study Medication Administration Assessment, and the Blindedness Assessment 
will be listed and presented using descriptive statistics by treatment and time 
point.  In addition, comparison will be made for each vamorolone dose group 
with placebo for the PODCI and for each vamorolone dose group with 
prednisone and placebo for the PARS III, with p values computed for the 
comparisons.  Full details will be provided in the SAP. 
Safety Analyses: 
All evaluations of clinical safety will be listed and presented using descriptive 
statistics per treatment group and time point.  For the safety analyses during 
Treatment Period #1, the vamorolone dose levels will be compared to 
prednisone, as specified in the SAP.   
Safety data will include BMI, weight, vital signs, 2D-echocardiogram, DXA 
scan, spine x-ray, eye examination results, ACTH Stimulation Test results, and 
ECG results, and these will be presented using descriptive statistics.  Safety 
laboratory data will be summarized using descriptive statistics, and out-of-range 
values will be listed.  Adverse events will be summarized overall and by 
treatment group, system organ class (SOC) and preferred term (using the 
Medical Dictionary for Regulatory Activities [MedDRA]); by treatment group 
and relationship to study medication; and by treatment group and intensity 
(CTCAE grade).  Suicidality and abuse potential associated with treatment will 


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be assessed by examination of adverse event data.  Full details will be provided 
in the SAP. 
In Treatment Period #1, BMI z-score change from baseline results will be 
compared between treatment groups using an REML-based MMRM analysis 
with treatment group, week of the visit, and the treatment-by-week interaction as 
factors, and baseline BMI z-score and age group as a covariate.  Week will be 
included in the model as a categorical variable (Week 12 and 24) along with the 
treatment-by-week interaction.  An unstructured within-subject covariance 
matrix will be used.  If this analysis fails to converge, Akaike’s information 
criterion will be used to select the best covariance structure from compound 
symmetry and autoregressive-1 (AR(1)).  The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom. 
Change from baseline in all continuous clinical laboratory test results will be 
tested using one sample t-tests with p-values presented along with the descriptive 
statistics at each assessment visit within each treatment group. 
Pharmacodynamics Analyses: 
Serum PD biomarkers of adrenal axis suppression, insulin resistance, and bone 
turnover will be assessed.  PD biomarkers will be analyzed using MMRMs 
similar to the primary efficacy model.  Plots will be created.  Additional 
exploratory PD biomarkers of both safety and efficacy may be assessed.  
Vamorolone-treated groups will be compared to both prednisone-treated and 
placebo groups. 
Pharmacokinetic Analyses: 
The 2-hr post-dose plasma concentration measurements of vamorolone at 
Week 30 will be used for comparison of drug exposures between the two dosing 
groups.  They will be added to PK data from previous studies in DMD boys for 
comparison with measurements obtained in healthy adult male subjects.  All PK 
data will be combined in a population assessment of plasma concentrations in 
relation to dose and age of subjects.  


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TABLE OF CONTENTS 
SERIOUS ADVERSE EVENT CONTACT INFORMATION .....................................4 
PROTOCOL AMENDMENT TRACKING ...................................................................5 
STUDY SYNOPSIS ...........................................................................................................8 
LIST OF TABLES ...........................................................................................................30 
LIST OF FIGURES .........................................................................................................31 
LIST OF ABBREVIATIONS .........................................................................................32 
1 
INTRODUCTION ..................................................................................................36 
1.1 
BACKGROUND AND UNMET NEED ......................................................................36 
1.2 
NONCLINICAL EXPERIENCE ...............................................................................38 
1.2.1 
Safety Pharmacology ...............................................................................39 
1.2.2 
Pharmacokinetics and Metabolism ........................................................40 
1.2.3 
Toxicology .................................................................................................44 
1.3 
CLINICAL EXPERIENCE ......................................................................................57 
1.3.1 
Phase I Study in Healthy Adult Male Volunteers (VBP15-001) ..........57 
1.3.2 
Pharmacokinetics in Phase IIa Study in 4 to 7 years Duchenne 
Muscular Dystrophy Boys (VBP15-002) ................................................69 
1.3.3 
Safety in Phase II Studies in 4 to7 years Duchenne Muscular 
Dystrophy Boys (VBP15-002 and VBP15-003) .....................................72 
1.4 
RATIONALE FOR STUDY DESIGN ........................................................................74 
1.5 
OVERALL BENEFIT/RISK ....................................................................................78 
2 
STUDY OBJECTIVES AND ENDPOINTS .........................................................79 
2.1 
STUDY OBJECTIVES ............................................................................................79 
2.1.1 
Primary Objectives ..................................................................................79 


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2.1.2 
Secondary Objectives ...............................................................................80 
2.1.3 
Exploratory Objectives ............................................................................81 
2.2 
STUDY ENDPOINTS ..............................................................................................82 
2.2.1 
Safety Endpoints ......................................................................................82 
2.2.2 
Clinical Efficacy Endpoints .....................................................................83 
2.2.3 
Additional Exploratory Endpoints .........................................................86 
2.2.4 
Pharmacodynamic Endpoints .................................................................86 
2.2.5 
Endpoints for Patient-Reported Outcomes ...........................................87 
3 
STUDY DESIGN .....................................................................................................88 
3.1 
OVERALL STUDY DESIGN ...................................................................................88 
3.2 
RANDOMIZATION ................................................................................................91 
3.3 
BLINDING 92 
3.4 
UNBLINDING .......................................................................................................93 
4 
SELECTION AND WITHDRAWAL OF STUDY SUBJECTS .........................95 
4.1 
SUBJECT ENROLLMENT AND IDENTIFICATION LOG .........................................95 
4.2 
INCLUSION CRITERIA .........................................................................................95 
4.3 
EXCLUSION CRITERIA ........................................................................................97 
4.4 
WITHDRAWAL OF SUBJECTS FROM STUDY .......................................................99 
4.5 
TERMINATION OF STUDY .................................................................................100 
5 
TREATMENT OF STUDY SUBJECTS ............................................................101 
5.1 
STUDY MEDICATIONS ADMINISTERED ............................................................101 
5.1.1 
Study Medications Administered During Treatment Period #1 ........101 
5.1.2 
Study Medications Administered During Transition Period .............102 


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5.1.3 
Study Medications Administered During Treatment Period #2 and 
the Dose-tapering Period .......................................................................103 
5.2 
IDENTITY OF INVESTIGATIONAL PRODUCT .....................................................104 
5.3 
DOSAGE SCHEDULE AND ADMINISTRATION OF STUDY MEDICATION ............105 
5.4 
RATIONALE FOR DOSE SELECTION ..................................................................108 
5.5 
TREATMENT COMPLIANCE ..............................................................................110 
5.6 
STUDY DRUG DOSE INTERRUPTION OR DISCONTINUATION ...........................110 
5.7 
PRIOR AND CONCOMITANT MEDICATIONS AND THERAPIES ..........................111 
5.7.1 
Prior Therapy .........................................................................................111 
5.7.2 
Concomitant Therapies .........................................................................111 
5.7.3 
Prohibited Therapies .............................................................................112 
5.7.4 
Permitted Therapies ..............................................................................113 
5.7.5 
Hydrocortisone .......................................................................................113 
5.7.6 
Vitamin D ................................................................................................114 
5.8 
STUDY MEDICATION MANAGEMENT ...............................................................114 
5.8.1 
Packaging and Labeling of Study Medication ....................................114 
5.8.2 
Storage of Study Medication .................................................................116 
5.8.3 
Study Medication Shipping and Handling ..........................................116 
5.8.4 
Study Medication Accountability .........................................................117 
5.9 
PROCEDURES FOR ASSIGNING SUBJECT STUDY NUMBERS .............................118 
6 
STUDY SCHEDULE ............................................................................................118 
6.1 
TIME AND EVENTS SCHEDULE .........................................................................118 
6.2 
INFORMED CONSENT AND ASSENT PROCEDURES ............................................126 
6.2.1 
HIPAA and Protected Health Information .........................................127 


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6.3 
VISIT SCHEDULE AND PROCEDURES ................................................................127 
6.3.1 
Screening Period (Day -33 to -2) ...........................................................128 
6.3.2 
Baseline Period (Day -1) Visit ...............................................................130 
6.3.3 
Treatment Period #1 Day 1 Visit ..........................................................131 
6.3.4 
Treatment Period #1 (Weeks 1-24) .......................................................133 
6.3.5 
Transition Period (Weeks 25-28) ..........................................................135 
6.3.6 
Treatment Period #2 (Week 28 + 1 Day through Week 48) ...............137 
6.3.7 
Dose-tapering Period (Weeks 49-52) ....................................................140 
6.4 
SUBJECT DISCONTINUATION ............................................................................141 
6.4.1 
Early Discontinuation Prior to Week 24 ..............................................143 
6.4.2 
Early Discontinuation After Week 24 and Prior to Week 28 ............144 
6.4.3 
Early Discontinuation After Week 28 and Prior to Week 48 ............144 
6.5 
SUBJECT AND STUDY COMPLETION .................................................................145 
7 
STUDY ASSESSMENTS AND MEASUREMENTS ........................................145 
7.1 
DEMOGRAPHIC ASSESSMENTS .........................................................................145 
7.1.1 
Genetic Modifiers of DMD ....................................................................145 
7.2 
SAFETY AND TOLERABILITY ASSESSMENTS ....................................................145 
7.2.1 
Medical History ......................................................................................145 
7.2.2 
Physical Examination, Cushingoid Features, Weight, and Height ...146 
7.2.3 
Vital Signs ...............................................................................................147 
7.2.4 
Clinical Laboratory Tests ......................................................................147 
7.2.5 
Chicken Pox Immunity ..........................................................................151 
7.2.6 
Pharmacodynamic Biomarker Panel ...................................................151 
7.2.7 
ACTH Stimulation Test .........................................................................152 


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7.2.8 
Population PK Assessment ....................................................................154 
7.2.9 
Total Blood Volume Required ..............................................................154 
7.2.10 
12-Lead ECG ..........................................................................................156 
7.2.11 
2D-echocardiography ............................................................................156 
7.2.12 
Eye Examination ....................................................................................157 
7.2.13 
Bone Health and DXA Scan (total body and spine) ............................157 
7.2.14 
Spine X-rays ...........................................................................................158 
7.3 
ASSESSMENT OF MUSCLE STRENGTH AND FUNCTION ....................................158 
7.3.1 
Time to Stand Test (TTSTAND) ..........................................................158 
7.3.2 
Time to Climb Test (TTCLIMB) ..........................................................159 
7.3.3 
Time to Run/Walk Test (TTRW) .........................................................159 
7.3.4 
North Star Ambulatory Assessment (NSAA) ......................................159 
7.3.5 
Six-minute Walk Test (6MWT) ............................................................160 
7.3.6 
Hand-Held Myometry (elbow flexors and knee extensors) ................160 
7.3.7 
Range of Motion (ROM) .......................................................................160 
7.4 
PATIENT-REPORTED OUTCOME MEASURES ...................................................161 
7.4.1 
Pediatric Outcomes Data Collection Instrument (PODCI) ...............161 
7.4.2 
Treatment Satisfaction Questionnaire (TSQM) ..................................161 
7.4.3 
Behavioral Assessment ..........................................................................161 
7.4.4 
Ease of Study Medication Administration Assessment ......................162 
7.4.5 
Blindedness Assessment ........................................................................162 
7.4.6 
Subject Diary ..........................................................................................162 
7.5 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................163 
7.5.1 
Intensity ..................................................................................................164 


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7.5.2 
Relationship ............................................................................................164 
7.5.3 
Clinical Laboratory Test Abnormalities ..............................................166 
7.5.4 
Follow-Up of Adverse Events ................................................................167 
7.5.5 
Dosing Error ...........................................................................................167 
7.5.6 
Serious Adverse Events .........................................................................168 
8 
STUDY COMMITTEES ......................................................................................171 
8.1 
STUDY STEERING COMMITTEE ........................................................................171 
8.2 
DATA AND SAFETY MONITORING BOARD .......................................................171 
9 
DATA COLLECTION .........................................................................................172 
9.1 
SOURCE DOCUMENTS .......................................................................................172 
9.2 
ELECTRONIC CASE REPORT FORM COMPLETION ..........................................173 
9.3 
DATA PROCESSING ...........................................................................................173 
9.4 
SUBJECT DIARIES .............................................................................................174 
10 
STATISTICAL METHODS AND PLANNED ANALYSES ............................174 
10.1 SAMPLE SIZE DETERMINATION .......................................................................174 
10.2 STATISTICAL AND ANALYTICAL PLAN (SAP) ..................................................176 
10.2.1 
Deviations from the Statistical Analysis Plan ......................................176 
10.3 ANALYSIS POPULATIONS ..................................................................................176 
10.3.1 
Safety Population ...................................................................................176 
10.3.2 
Modified Intent-to-Treat (mITT) Population .....................................176 
10.3.3 
Per Protocol Population ........................................................................177 
10.3.4 
Pharmacokinetic (PK) Population ........................................................177 
10.4 MEASURES TAKEN TO AVOID/MINIMIZE BIAS ...............................................177 
10.5 INTERIM ANALYSIS ...........................................................................................177 


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10.6 WEEK 24 ANALYSIS ..........................................................................................177 
10.7 WEEK 48 ANALYSIS ..........................................................................................177 
10.8 MISSING, UNUSED, AND SPURIOUS DATA ........................................................178 
10.9 STATISTICAL ANALYSIS ...................................................................................178 
10.9.1 
General Considerations .........................................................................178 
10.9.2 
Adjustment for Multiple Comparisons ................................................179 
10.9.3 
Subject Disposition, Demographics, and Baseline Characteristics ...180 
10.9.4 
Efficacy Analyses ...................................................................................181 
10.9.5 
Safety Analyses .......................................................................................182 
10.9.6 
Pharmacodynamic Analyses .................................................................183 
10.9.7 
Patient-Reported Outcome Exploratory Analyses .............................184 
10.9.8 
Pharmacokinetic Analyses ....................................................................184 
10.9.9 
Concurrent Medications ........................................................................184 
11 
STUDY MANAGEMENT AND ETHICAL AND REGULATORY 
REQUIREMENTS ...............................................................................................185 
11.1 REGULATORY APPROVAL AND GOOD CLINICAL PRACTICE ..........................185 
11.2 INVESTIGATOR RESPONSIBILITIES ...................................................................185 
11.2.1 
Subject Information and Informed Consent .......................................185 
11.2.2 
Institutional Review Board/Independent Ethics Committee 
Approval and Other Institutional Requirements ...............................186 
11.2.3 
Study Documentation ............................................................................187 
11.2.4 
Delegation of Investigator Responsibilities ..........................................189 
11.3 PROTOCOL DEVIATIONS ...................................................................................189 
11.3.1 
Protocol Deviation Definitions ..............................................................189 


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11.3.2 
Reporting Important Protocol Deviations ...........................................190 
11.4 STUDY RECORDS RETENTION AND DIRECT ACCESS TO SOURCE 
DOCUMENTS .....................................................................................................190 
11.5 STUDY MONITORING ........................................................................................191 
11.6 QUALITY ASSURANCE ......................................................................................192 
11.7 STUDY TERMINATION AND SITE CLOSURE ......................................................193 
11.8 SITE TERMINATION ..........................................................................................193 
11.9 DISCONTINUATION OF STUDY ..........................................................................194 
12 
DISCLOSURE OF DATA ....................................................................................194 
12.1 CONFIDENTIALITY ............................................................................................194 
12.2 PUBLICATION ....................................................................................................195 
13 
INVESTIGATOR PROTOCOL AGREEMENT ..............................................196 
14 
REFERENCES ......................................................................................................197 
15 
APPENDICES .......................................................................................................202 
APPENDIX 15.1 
PROTOCOL AMENDMENT #4 COMPLETE LIST OF CHANGES ........203 
 


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LIST OF TABLES 
Table 1. 
AUC0-24hr in Mice after 179 Days Treatment with 3 Dose Levels (5, 15 
and 45 mg/kg/day) ..........................................................................................50 
Table 2. 
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 ............................................58 
Table 3. 
Summary of Pharmacokinetic Parameters for Vamorolone After 
Single Dose Oral Administration of 8 mg/kg to Healthy Subjects Under 
Fed and Fasted Conditions ............................................................................60 
Table 4. 
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 ...................................62 
Table 5. 
Summary of Pharmacokinetic Parameters for Vamorolone after Once 
Daily Oral Administration of 0.25, 0.75, 2.0 and 6.0 mg/kg Doses to 
DMD Boys .......................................................................................................71 
Table 6. 
Study Randomization Schedule ....................................................................75 
Table 7. 
Study Medications for the Six Treatment Groups During Treatment 
Period #1 .......................................................................................................101 
Table 8. 
Study Medications for the Six Treatment Groups During the 
Transition Period .........................................................................................102 
Table 9. 
Study Medications for the Six Treatment Groups During Treatment 
Period #2 and the Dose-tapering Period ....................................................103 
Table 10 Weight Bands for Prednisone or Matching Tablet Dosing ......................105 
Table 11 Schedule of Study Activities ........................................................................121 
Table 12. Tablet Dose Tapering ..................................................................................136 
Table 13. Suspension Dose Tapering ..........................................................................140 
Table 14. Tablet Dose Tapering for Subjects Discontinuing Prior to Week 24 ......143 
Table 15. Suspension Dose Tapering for Subjects Discontinuing Prior to 
Week 24 .........................................................................................................144 
Table 16. Suspension Dose-Tapering for Subjects Discontinuing After Week 24 
and Prior to Week 28 ...................................................................................144 
Table 17. Hematology, Chemistry, and Lipids Clinical Laboratory Tests .............149 
Table 18. Urinalysis Clinical Laboratory Tests .........................................................150 
Table 19. Pharmacodynamic Biomarkers – Secondary Safety Outcomes ..............152 
Table 20. Blood Sample Number and Volume by Study Visit ..................................155 


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 LIST OF FIGURES 
Figure 1 Liver Function Enzymes in GLP Chronic Toxicology Study in Mice 
(26 weeks) ........................................................................................................51 
Figure 2. 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 .................................................58 
Figure 3. 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 ............................59 
Figure 4. Plasma Concentrations of Vamorolone (VBP15) After Single Dose 
Oral Administration of 8 mg/kg to Healthy Subjects Under Fed and 
Fasted Conditions ..........................................................................................60 
Figure 5. 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 ........................63 
Figure 6. Morning Cortisol Measurements in the Vamorolone Phase I Healthy 
Subjects ...........................................................................................................66 
Figure 7. Fasting Serum Glucose During the Phase I MAD Period (Two Weeks 
Daily Treatment) ............................................................................................67 
Figure 8 Mean Plasma Concentrations of Vamorolone after Once Daily Oral 
Administration of 0.25, 0.75, 2.0, and 6.0 mg/kg Doses ..............................70 
Figure 9 Regression Analysis of Cmax and AUCinf versus Dose .................................72 


Vamorolone 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition/Term 
 
 
%CV 
percent coefficient of variation 
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 
AUC(0-t) 
area under the concentration-time curve from time 0 to time t 
AUC(inf) 
area under the concentration-time curve from time 0 to infinity 
AUClast 
area under the plasma concentration-time curve from time 0 to 
the last observed measurable concentration 
BMI 
body mass index 
BUN 
blood urea nitrogen 
C 
Celsius 
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 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTM 
Clinical Trial Material 
CTMS 
Clinical Trial Management Software 
CTX1 
C-terminal peptide fragment of collagen 1 
CYP 
cytochrome P450 
dL 
deciliter 
DMD 
Duchenne muscular dystrophy 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
DXA 
dual-energy x-ray absorptiometry 


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Abbreviation 
Definition/Term 
 
 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EU 
European Union 
F% 
percent bioavailability 
FDA 
Food and Drug Administration 
GALT 
gut-associated lymphoid tissue 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GLDH 
glutamate dehydrogenase 
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 
ID 
identification 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web Response System 
kg 
kilogram 
L 
liter 
LLC 
Limited Liability Company 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
LS 
least squares 
µg 
microgram 
m 
meter 
m2 
square meter 
MAD 
multiple ascending dose (study) 
MCMC 
Markov Chain Monte Carlo 


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Abbreviation 
Definition/Term 
 
 
MD 
Medical Doctor (physician) 
Mdx 
mouse model lacking dystrophin 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
Min 
minute 
mITT 
modified Intent-to-Treat 
mL 
milliliter 
MMRM 
mixed model for repeated measures  
MTD 
maximum tolerated dose 
N, No. 
number 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NCA 
non-compartmental analysis 
NF-κB 
nuclear factor kappa-light-chain-enhancer of activated B cells 
ng 
nanogram 
nM 
nanomolar 
nmol 
nanomole 
NOAEL 
no observed adverse effect level 
NSAA 
North Star Ambulatory Assessment 
OTC 
over-the-counter (non-prescription medication) 
oz 
ounce 
P1NP 
serum aminoterminal propeptide of type I collagen 
PARS III 
Personal Adjustment and Role Skills Scale III 
PBL 
peripheral blood leukocytes 
PD 
pharmacodynamics 
PHI 
Protected Health Information 
PK 
pharmacokinetics 
PODCI 
Pediatric Outcomes Data Collection Instrument 
PPP 
Per Protocol Population 
PR [PQ] 
time from onset of P wave to start of the QRS complex 
QD 
once daily (dosing) 
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 


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Abbreviation 
Definition/Term 
 
 
RBC 
Red Blood Cell 
REML 
restricted maximum likelihood  
ROM 
Range of Motion  
RR 
in electrocardiography, the interval between successive Rs 
(peaks of QRS complexes) 
6MWT 
Six-minute Walk Test 
SAD 
single ascending dose (study) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedures 
SSC 
Study Steering Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum observed plasma concentration 
TRiNDS 
Therapeutic Research in Neuromuscular Disorders Solutions 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
TTCLIMB 
Time to Climb (Test) 
TTSTAND 
Time to Stand (Test) 
TTRW 
Time to Run/Walk (Test) 
ULN 
upper limit of normal 
US 
United States 
vol 
volume 
vs. 
versus 
Vss 
volume of distribution at steady state 
WBC 
White Blood Cell 
WHO 
World Health Organization 
wt 
weight 


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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.  
Duchenne muscular dystrophy 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 until recently treatment options were medications used “off-
label” to alleviate the symptoms of DMD.  Despite scientific advances, only 
glucocorticoids, such as prednisone or deflazacort, have consistently demonstrated 
efficacy in clinical trials.10  Indeed, the United States Food and Drug Administration (US 
FDA) recently approved deflazacort as a treatment for DMD.  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 


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these compounds for maximum effect and glucocorticoids have extensive side effect 
profiles, often limiting long-term administration.  The current 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 glucocorticoids 
prednisone, prednisolone, methylprednisolone, 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 DMD12 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 adverse 
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 adverse 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 adverse effect profile, thereby improving the 


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quality of life for DMD patients.  This profile would enable use of vamorolone in DMD 
boys 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-kB 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 
prednisolone 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. 
All Good Clinical Laboratory (GLP) studies were conducted in, or inspected by, a 
country that has implemented the Organisation for Economic Cooperation and 
Development (OECD) Mutual Acceptance of Data (MAD) system. 


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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 prednisolone 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 counts in a dose-dependent manner.  This finding is attributed to a reduction in 


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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 
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 
bioavailability (F%) was 74.5%.  Following oral administration of 15 mg/kg via cherry 


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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). 
Multiple Dose 
Crl:CD1(ICR) mice were administered vamorolone or vehicle once daily (QD) for 
28 consecutive days.  Vamorolone exposure (as assessed by the Cmax and area under the 
plasma concentration-time curve from time 0 to the last observed measurable 
concentration [AUClast]) 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 QD 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). 
Beagle dogs were administered vehicle or vamorolone at doses of 2 mg/kg/day, 
10 mg/kg/day, or 50 mg/kg/day for 39 weeks.  Systemic exposure (area under the plasma 
concentration-time curve from time 0 to 24 hours [AUC0-24hr]) to vamorolone appeared to 
be independent of sex.  Mean AUC0-24hr and Cmax values for vamorolone increased with 
increasing dose in an approximately dose proportional manner on Days 1 and 270.  Mean 
systemic exposure (AUC0-24hr) to vamorolone appeared to increase following repeated 
administration of vamorolone.  Due to the alterations in the feeding regimen, changes in 
systemic exposure following repeated administration should be viewed with caution due 
the influence of feeding on exposure.  For the 2 and 10 mg/kg/day dose groups, exposure 
on Day 270 was generally higher than on Day 1, indicating possible inhibition of 
metabolism of vamorolone at these dose levels.  On Day 270, mean AUC0-24hr values 
were 2.34-fold and 2.98-fold 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 270 was 
2.07-fold higher compared to that on Day 1 (ReveraGen Report No. 1998-014). 
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 


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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). 
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 
concentrations of vamorolone were higher than brain concentrations with the area under 
the plasma concentration-time curve (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). 
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 


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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). 
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 
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 
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.  However, a slight 
decrease in body weight related to vamorolone was observed in 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.  There were no other clinical 
observations (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 


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(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 clinical observations (ReveraGen Report No. 1998-001). 
Multiple Dose 
Acute Toxicity Studies 
Vamorolone or vehicle was administered to Crl:CD1(ICR) mice QD 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) 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 on clinical observations, food 
consumption, ophthalmic examination, or urinalysis during the study.  A 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.  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.  


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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). 
Vamorolone or vehicle was administered to beagle dogs QD 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 body weight, body temperature, food 
consumption, ophthalmology, electrocardiography, macroscopic, or urinalysis parameters 
at necropsy.  A dose-dependent decrease in body weight gain was observed at all doses 
but weights generally returned to normal during the recovery period. 
Adrenal gland weights decreased 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 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). 
Non-naive cynomolgus monkeys were administered vamorolone or vehicle QD 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. 


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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 non-significant 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). 
Chronic toxicity studies 
26-week chronic toxicity study in mice 
A 26-week chronic toxicity study was carried out in Crl:CD1®(ICR) mice to evaluate the 
reversibility, progression, or delayed appearance of any observed changes following a 
4-week postdose observation period.  Doses of vamorolone tested were 5, 15, and 
45 mg/kg/day.  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. 
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 


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spontaneous background finding.  The death of one male at 5 mg/kg/day 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 45 mg/kg/day.  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 
with 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 ≥ 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 
lymphoid depletion, although 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 ≥ 5 mg/kg/day 
and females at ≥ 15 mg/kg/day that lacked correlative findings among other study 
endpoints; resolution for this endpoint could not be determined. 


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A mild vamorolone-related increase in albumin was observed in males at ≥ 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 
45 mg/kg/day and females at 15 mg/kg/day 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 45 mg/kg/day.  
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; 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 
45 mg/kg/day.  Decreased anagen hair follicles was documented for individual animals 
when there were no anagen hair follicles in the section of skin.  Incidence in controls and 
mice at 5 and 15 mg/kg/day were similar.  A severity score was 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 were no meaningful differences 
between treated 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.  


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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, did not appear to change following 
repeated administration of vamorolone at 15 mg/kg, and appeared to decrease following 
repeated administration of vamorolone at 45 mg/kg.  Systemic exposure to vamorolone in 
males appeared to decrease following repeated administration of vamorolone (Table 1). 
Table 1. 
AUC0-24hr in Mice after 179 Days Treatment with 3 Dose Levels (5, 15 
and 45 mg/kg/day) 
Average AUC0-24hr (hr*ng/mL) 
Dose 
(mg/kg/day) 
Male 
Female 
Day 1 
Day 179 
Day 1 
Day 179 
5 
5700 
1150 
159 
991 
15 
11600 
3710 
3450 
4240 
45 
50700 
10200 
27000 
12700 
 
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 No-
Observable-Adverse-Effect Level (NOAEL) is considered to be 45 mg/kg/day under the 
conditions of this study. 
As liver is considered a primary target organ, the liver enzymes (aspartate 
aminotransferase [AST], alanine aminotransferase [ALT]) of mice in this study were 
studied at study termination (Figure 1). 


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Figure 1 
Liver Function Enzymes in GLP Chronic Toxicology Study in Mice 
(26 weeks) 
 
There were no differences between male and female mice regarding liver function 
enzymes.  There were no drug-related elevations of AST at any dose.  The highest dose 
tested (45 mg/kg/day) showed mild elevations of ALT with about half of values above 
the upper limit of normal range.  The mild elevations of ALT were reversible, returning 
to within normal range after cessation of drug. 
The Study Director concluded that 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 No-Observable-Adverse-Effect Level (NOAEL) is considered to 
be 45 mg/kg/day under the conditions of this study. 
39-week chronic toxicity study in beagle dogs 
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 that 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. 


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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 
(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 were observed relative to controls 
over the course of the 39-week dose phase 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. 


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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. 
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 


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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 
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 considered 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. 


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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. 
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).  
7-day study in cynomolgus monkeys 
Non-naive cynomolgus monkeys were administered vamorolone or vehicle QD 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.  These decreases 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). 
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. 


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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). 
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]”). 


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Taken together, these data indicate vamorolone is negative for any mutagenic signal. 
1.3 
Clinical Experience 
Clinical experience with vamorolone is comprised of a completed Phase I clinical trial of 
vamorolone in healthy adult volunteers (VBP15-001), completed Phase IIa (VBP15-002) 
and Phase II extension (VBP15-003) trials in DMD boys, and an ongoing long-term 
extension (VBP15-LTE) trial in DMD boys.   
1.3.1 
Phase I Study in Healthy Adult Male Volunteers (VBP15-001) 
Study Design and Objectives 
The safety, tolerability, and PK of vamorolone were initially evaluated 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 of 8 subjects each; six subjects in each cohort 
received 14 daily doses of vamorolone (1.0, 3.0, 9.0 and 20.0 mg/kg/day) and two 
subjects in each cohort received placebo. 
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. 
Pharmacokinetics  
SAD Cohorts – Pharmacokinetics (Fasted) 


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Vamorolone PK data shows strong adherence to dose linearity and dose proportionality, 
with relatively little subject-subject variation (Figure 2, Table 2, Figure 3).  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, 3.3 and 4.3 hours, respectively (Figure 2, 
Table 2). 
Figure 2. 
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  
 
Data presented as arithmetic mean ± standard error 
Table 2. 
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 
 
*Geometric mean (%CV) (N) except Tmax for which the median (N) [Range] is reported.  
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 


Vamorolone 
28 August 2020 
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Protocol No.: VBP15-004 
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to infinity; lz = elimination rate constant; t½ = terminal half-life; CL/F = apparent total clearance from plasma; Vz/F = 
apparent volume of distribution during terminal phase. 
Figure 3. 
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 
 
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 4, Table 3). 


Vamorolone 
28 August 2020 
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Protocol No.: VBP15-004 
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Figure 4. 
Plasma Concentrations of Vamorolone (VBP15) After Single Dose Oral 
Administration of 8 mg/kg to Healthy Subjects Under Fed and Fasted 
Conditions  
 
Data presented as arithmetic mean ± standard error 
Table 3. 
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; lz = elimination rate constant; t½ = terminal half-life; CL/F = apparent total clearance from plasma; Vz/F = 
apparent volume of distribution during terminal phase: . 


Vamorolone 
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Protocol No.: VBP15-004 
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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 
dosing schedule.  Safety and tolerability are additional goals of the MAD study, and these 
remain important endpoints independent of the PK studies. 
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 4).    


Vamorolone 
28 August 2020 
Amendment #4 
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Protocol No.: VBP15-004 
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Table 4. 
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) 
lz (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) 
lz (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; lz = elimination rate constant; t½ = 
terminal half-life; CL/F = apparent total clearance from plasma; Vz/F = apparent volume of distribution during terminal 
phase. 
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 (~2-4 hours) and dosing interval (24 hours) (Figure 5; 
Table 4).  


Vamorolone 
28 August 2020 
Amendment #4 
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Protocol No.: VBP15-004 
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Figure 5. 
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  
 
Data presented as arithmetic mean ± standard error 
Safety 
SAD Cohorts 
In the SAD part, overall, 6 subjects (11%) administered vamorolone experienced a total 
of 10 treatment-emergent adverse events (TEAEs); no subject in the placebo group 
experienced any TEAEs.  There was no dose-related trend in the incidence or severity of 
TEAEs; the dose group with the highest number of subjects reporting TEAEs was the 
0.1 mg/kg dose group (2 subjects, 33%), and the highest number of TEAEs (3 events) 
was reported by 1 subject in the 1.0 mg/kg vamorolone dose group.  In the 0.3 and 
3.0 mg/kg vamorolone fasted and the 8.0 mg/kg fed dose groups, 1 subject per group 
(17%) experienced TEAEs, and no subjects in the 8.0 mg/kg and 20 mg/kg, fasted, dose 
groups experienced any TEAEs.  The most common TEAEs were dizziness and 
headache, each reported by 2 subjects overall (4%); all other TEAEs were reported by 
only 1 subject (2%) and included ear pain, nausea, non-cardiac chest pain, and blood 
bilirubin increased.  Three subjects (6%) had TEAEs that were considered possibly 
related to treatment.  Possibly related TEAEs included nausea (1 subject, 2%), dizziness 
(2 subjects, 4%), and headache (2 subjects, 4%).  One subject (2%) had a moderate 


Vamorolone 
28 August 2020 
Amendment #4 
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Protocol No.: VBP15-004 
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ReveraGen BioPharma, Inc. – CONFIDENTIAL 
TEAE of blood bilirubin increased, which was considered unrelated to study drug.  All 
other TEAEs were mild in severity. 
MAD Cohorts 
In the MAD part, overall, a total of 6 subjects (19%) administered vamorolone or placebo 
experienced a total of 10 TEAEs: 2 subjects each in the 1.0 mg/kg vamorolone, 20 mg/kg 
vamorolone, and placebo groups, and none in the 3.0 mg/kg and 9.0 mg/kg dose groups.  
There was no dose-related trend in the incidence or severity of TEAEs.  The most 
common TEAE was headache (2 subjects, 6%); all other TEAEs occurred in only 
1 subject (3%) per group, and included nausea, toothache, vomiting, ALT increased, 
hepatic enzyme increased, arthralgia, dizziness, and syncope.  TEAEs were considered 
possibly related in 2 subjects (6%) and remotely related in 1 subject (3%).  Possibly 
related AEs were ALT increased and hepatic enzyme increased, occurring in 1 subject in 
the 20 mg/kg vamorolone and placebo groups, respectively.  The remotely related TEAEs 
were dizziness and syncope, both occurring in the same subject (1.0 mg/kg vamorolone).  
All TEAEs were mild in severity. 
With the exception of the AEs related to hepatic enzymes, there were no other 
meaningful changes in clinical laboratory parameters.  Of note, glucose levels remained 
stable at all doses of vamorolone in both the SAD and MAD parts, suggesting that 
vamorolone does not induce insulin resistance at the doses and dosing duration studied; 
in addition, no changes in the white blood cell count differential were observed, 
suggesting that vamorolone did not induce immunosuppressive effects in this study 
population. 
Pharmacodynamic Safety Biomarkers 
Vamorolone has shown improved safety profiles relative to prednisone in nonclinical 
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. 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
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ReveraGen BioPharma, Inc. – CONFIDENTIAL 
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 µg/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 6).  Active substance volunteers at four MAD 
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).  


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
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ReveraGen BioPharma, Inc. – CONFIDENTIAL 
Figure 6. 
Morning Cortisol Measurements in the Vamorolone Phase I Healthy 
Subjects 
Note: 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. 
Vamorolone thus shows approximately a 10-fold improvement in safety window 
compared to prednisone on a mg/kg comparative basis.  These data are consistent with 
in vitro and ex vivo nonclinical mouse data comparing 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 


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Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
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ReveraGen BioPharma, Inc. – CONFIDENTIAL 
(15 mg/kg/day; 30 mg/kg/day) showed development of insulin resistance with 
prednisolone, but not vamorolone.29 
Summary of Phase I Data 
Pharmacokinetics 
• 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, 
showing little if any drug accumulation, consistent with the short half-life and daily 
dosing schedule. 
• There were no apparent relationships between CL/F and body size, either in terms 
of body weight or BMI. 
• 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.  Comparison of the data from 
the high fat meal with the fasted 8.0 mg/kg cohort data showed that absorption was 
increased by 2.5-fold by the high fat meal, consistent with the lipophilic character 
of vamorolone (steroidal compound). 
Safety 
• Single and multiple daily doses of vamorolone up to 20 mg/kg were well tolerated 
by healthy subjects, and a maximum tolerated dose (MTD) was not identified. 
• Regarding the primary target organ, liver, one subject in the 20 mg/kg vamorolone 
MAD dose group who had an elevation of serum bilirubin at baseline (pre-dose) 
experienced an AE of ALT increased after 9 days of dosing; this AE was judged to 
be possibly related to vamorolone and drug dosing was halted.  No other subjects in 
the vamorolone dose groups experienced AEs related to liver function. 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
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• Results of post-dose morning cortisol levels suggest that vamorolone causes acute 
adrenal suppression after single dosing and chronic adrenal suppression after 
multiple dosing, but only at the higher (≥ 8.0 mg/kg) single and multiple doses 
studied. 
• Safety PD biomarker studies showed that vamorolone had an improved safety 
window for adrenal axis suppression (100-fold increase in therapeutic window), no 
evidence of insulin resistance, no changes in bone turnover markers (osteocalcin, 
C-terminal peptide fragment of collagen 1[CTX1]), compared to prednisone studies 
reported in the literature25,30 
• There were no clinically significant changes in vital signs, ECGs, or physical 
examinations. 
1.3.2 
Pharmacokinetics in Phase IIa Study in 4 to 7 years Duchenne Muscular 
Dystrophy Boys (VBP15-002) 
Forty-eight boys with DMD received oral doses of vamorolone once daily for 14 days at 
doses of 0.25 mg/kg/day, 0.75 mg/kg/day, 2.0 mg/kg/day, and 6.0 mg/kg/day, 12 subjects 
receiving vamorolone at each dose level.  The drug was administered with a glass of 
whole milk or other high-fat food.  Six blood samples were collected on Day 1 and Day 
14 at 0, 1, 2, 4, 6, and 8 hours post-dose and plasma was analyzed for vamorolone.  The 
time-course of plasma drug concentrations was assessed using noncompartmental 
analytical (NCA) methods using the WinNonlin software (Certara).   
Of the 48 DMD subjects enrolled in the study (12 at each dosing level), 47 had evaluable 
PK data.  The average Day 1 and Day 14 vamorolone concentration versus time profiles 
are shown in Figure 8 for the four dose levels.  Overall, as expected, higher doses 
resulted in higher plasma concentrations of vamorolone.  In particular, plasma 
vamorolone concentrations versus time showed a rapid to moderate rate of absorption, a 
maximum concentration (Cmax) at a Tmax of 2 to 4 hours, and a decline phase with a 
typical half-life (t1/2) of 2 hours.  For all 4 doses, the mean PK profiles on Day 1 and 
Day14 appear similar.  Many individual subjects had closely matching Day 1 and Day 14 


Vamorolone 
28 August 2020 
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Protocol No.: VBP15-004 
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profiles, but several did not.  There was no accumulation of drug owing to the relatively 
short half-life and once-daily (morning) dosing. 
Figure 8 
Mean Plasma Concentrations of Vamorolone after Once Daily Oral 
Administration of 0.25, 0.75, 2.0, and 6.0 mg/kg Doses  
 
Vamorolone concentrations shown as mean ± standard deviation on linear (top panel) and semi-logarithmic 
(bottom panel) graphs. 
A summary of the observed (Cmax and Tmax) and calculated (AUC, t1/2, and CL) PK 
parameters for all doses on Day 1 and Day 14 is provided in Table 5.  Even with only 6 
blood samples collected from each subject, the PK profiles adequately capture the overall 
exposures, but must be considered approximate.  This particularly applies to the peak 
values and the half-lives.  Nevertheless, there is good consistency in the data with 
moderate variability as SD values are reasonable and the coefficient of variation values 
are typically less than 50%.  
The drug is absorbed at a moderate rate with peak concentrations typically occurring at 2 
to 4 hours on both Days 1 and 14.  The median Tmax across all doses is typically 2 or 4 
hours.  The half-lives were similar on both days, averaging about 2 hours, although some 
subjects had irregular profiles without a clear decline phase.  The apparent clearance (CL 


Vamorolone 
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Protocol No.: VBP15-004 
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and CL/F) values were consistent across the dose levels for Day 1 as well as for Day 14, 
but the latter tended to average slightly lower (about 2400 mL/hr/kg on Day 1 and 
1900 mL/hr/kg on Day 14).  
Table 5. 
Summary of Pharmacokinetic Parameters for Vamorolone after Once 
Daily Oral Administration of 0.25, 0.75, 2.0 and 6.0 mg/kg Doses to DMD 
Boys  
Parameters 
Day 1 
 
Dose, mg/kg/day 
Day 14 
 
Dose, mg/kg/day 
0.25 
0.75 
2.0 
6.0 
0.25 
0.75 
2.0 
6.0 
Cmax [ng/ml] 
22.9 (13.4) 75.9 (25.9) 199 (111) 
855.6 (471) 32.2 (15.2) 124.7 (42.5) 252.5 (96) 
970 (270) 
Tmax [h] 
3.6 [4] (1.2) 4.6 [4] (2.1) 2.5 [2] (1.3) 2.7 [2] (1.3) 3.8 [4] (1.8) 3.8 [4] (2.2) 2.8 [2] (1) 
2.3 [2] (0.86) 
AUCinf [hr∙ng/ml] 
118 (48) 
379 (117) 
761 (352) 
3279 (1693) 164 (61) 
544 (155) 
1138 (467) 3606 (897) 
t1/2 [h] 
2.1 (0.85) 
1.8 (0.43) 
1.9 (0.79) 
1.9 (0.95) 
1.9 (0.96) 
2.1 (0.8) 
1.9 (1.02) 
1.4 (0.35) 
CL [ml/hr/kg] 
2459 (897) 2285 (1103) 2697 (1285) 2320 (1375) 1828 (919) 1509 (482) 2047 (771) 1777 (476) 
Values are mean (standard deviation) and for Tmax, which are shown as mean [median] (standard deviation). 
An assessment of the linearity of the PKwith dose using Cmax and AUC is shown in 
Figure 9.  Data for all individual subjects were used which also depict the variability for 
each dose level.  While larger doses appear to present greater variability, this is a visual 
size distortion as the standard deviation is similar at each dose level (Table 5).  Fitting 
the power equation of the form (Cmax , AUCinf  = a x·Doseb) resulted in 95% confidence 
intervals for b values that include 1.0 for Cmax and AUCinf for both Days 1 and 14 
indicative of linear relationships across this range of dose levels.  


Vamorolone 
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Figure 9 
Regression Analysis of Cmax and AUCinf versus Dose  
 
Regression was performed by fitting the indicated power equations to the data for Day 1 and Day 14.  The 
fitted parameters are shown in the figure boxes. 
Compared with fasting healthy adult volunteers (Section 1.3.1), the boys with DMD 
showed lower Cmax values  and more variation in the time to reach the maximal 
concentration of vamorolone for any given dose.  This observation might be due to the 
fact that the boys with DMD received vamorolone after 8 ounces of whole milk or other 
high fat food and a so-called food effect might have played a role.  The apparent 
clearance of vamorolone seems higher in the boys with DMD but this finding is not 
significant.  
1.3.3 
Safety in Phase II Studies in 4 to7 years Duchenne Muscular Dystrophy Boys 
(VBP15-002 and VBP15-003)  
Adverse events: There were no serious adverse events (SAEs) reported over the 14-day 
treatment in the Phase I clinical trial in healthy adult volunteers, nor in the four cohorts 
(0.25 mg/kg, 0.75 mg/kg, 2.0 mg/kg, and 6.0 mg/kg) of the Phase IIa study (VBP15-002; 
14-day treatment) in boys ages 4 to <7 years with DMD.  There were a total of 4 SAEs in 


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the Phase II VBP15-003 study and three SAEs to date in the VBP15-LTE extension 
study: two SAEs of pneumonia in two different subjects (both subjects receiving 
vamorolone 0.75 mg/kg/day), one SAE of bilateral testicular torsion and one SAE of 
hypoxia in the same subject receiving 6.0 mg/kg/day, one SAE of influenza associated 
dehydration in a subject receiving 6.0 mg/kg/day, and two SAEs of acute myoglobinuria 
in the same subject receiving 6.0 mg/kg/day.  Each of these SAEs was considered 
unrelated to study drug, and none of them resulted in discontinuation from the study.  In 
the VBP15-003 study, there were a total of 218 TEAEs among 42 of the 48 subjects 
(87.5%).  In VBP15-003 study, the TEAEs with the highest incidence were viral upper 
respiratory tract infection (41.7%); pyrexia (35.4%); cough (18.8%); vomiting (14.6%); 
and diarrhea (10.4%).   
Body Mass Index (BMI): Body Mass Index was measured throughout the VBP15-003 
study.  The mean change from baseline to Week 24 for BMI was 0.03, 0.20, 0.23, and 
1.15 for the 0.25, 0.75, 2.0, and 6.0 mg/kg/day dose level groups, respectively.  Body 
Mass Index increases generally reflect an increase in weight.  Body Mass Index z-score 
was monitored in the VBP15-003 study.  The mean change from baseline to Week 24 for 
BMI z-score for the 6.0 mg/kg/day group showed a statistically significant increase 
compared to the mean change from baseline to Week 24 for the 0.25 mg/kg/day and 
0.75 mg/kg/day dose level groups.  In contrast, the mean change from baseline to 
Week 24 for the 2.0 mg/kg/day dose level group in BMI z-score was minimal and 
comparisons with the other vamorolone dose level groups lacked statistical significance.  
The mean increase from baseline to Week 24 for BMI z-score was similar for the 
6.0 mg/kg/day group and a daily prednisone-treated historical control group.   
Potential liver toxicity: In the Phase I clinical trial in adult volunteers, vamorolone 
showed mild elevations of liver enzymes in one subject receiving 20.0 mg/kg in the 
fasted state, and dosing was halted.  All DMD subjects have elevated serum ALT and 
AST enzymes because of the muscle condition.  For that reason, two enzymes, glutamate 
dehydrogenase (GLDH) and gamma glutamyl transferase (GTT), that are preferentially 
expressed in liver were evaluated in the VBP15-003 study.  None of the mean changes in 
GLDH from baseline to any of the VBP15-003 on-treatment assessment time points were 


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statistically significant for any dose level group.  Although the mean changes from 
baseline to Week 8, Week 16, and Week 24 in GLDH levels did not show a dose 
response, shift analysis of GLDH levels did suggest a possible dose-related shift to higher 
GLDH levels at 2.0 mg/kg/day and 6.0 mg/kg/day at Weeks 16 and 24.  Mean GGT 
levels and individual subject values at each VBP15-003 assessment time point across the 
four dose level groups remained at or below the normal range. On the basis of these mean 
GLDH and GGT data, vamorolone at dose levels up to 6.0 mg/kg/day does not appear to 
induce liver toxicity over a 24-week treatment period. 
Adrenal suppression: In the VBP15-003 study, after 24 weeks of treatment, 0 of 8 tested 
participants (0.25 mg/kg/day), 1 of 12 (8.3%) tested participants (0.75 mg/kg/day), 5 of 
12 (41.7%) tested participants (2.0 mg/kg/day), and 8 of 9 (88.9%) tested participants 
(6.0 mg/kg/day) had a depressed morning cortisol (<3.6 μg/dL [100 nM]) consistent with 
chronic adrenal suppression.29  
Insulin resistance: In the VBP15-003 study, mean changes from baseline for fasting 
insulin showed dose-and time-related changes for all dose level groups at Week 12 and 
Week 24.  Statistical significance was observed for mean increase from baseline for the 
6.0 mg/kg/day dose level group at Week 12 and Week 24.  
Bone Turnover: In the VBP15-003 study, pharmacodynamic biomarker testing for bone 
turnover markers suggested that vamorolone does not have the detrimental bone effects 
observed with prednisone and deflazacort. 
1.4 
Rationale for Study Design 
The proposed Phase IIb clinical trial (VBP15-004) is designed as a pivotal study to show 
that vamorolone treatment over a Treatment Period of 24 weeks leads to superior 
improvements in strength and mobility versus placebo (efficacy), with a reduced adverse 
effect profile versus prednisone treatment (safety), and to demonstrate persistence of 
effect over a Treatment Period of 48 weeks.  To determine efficacy, functional outcomes 
in DMD patient groups receiving one of two doses of vamorolone over 24 weeks will be 
compared to functional outcomes of DMD patients receiving placebo.  To determine 
safety, body mass index (BMI) and PD safety biomarker findings in DMD patients 


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receiving one of two dose levels of vamorolone over 24 weeks will be compared to DMD 
patients receiving prednisone.  The two dose levels of vamorolone to be studied have 
been chosen based upon data obtained in the Phase IIa and Phase II extension studies 
(VBP15-002; VBP15-003). 
This Phase IIb study is a double-blind study of two dose levels of vamorolone, with 
placebo and prednisone-treated control arms.   
Subjects who meet all eligibility criteria in this study (VBP15-004) will be randomized to 
one of six treatment groups as shown in Table 6. 
Table 6. 
Study Randomization Schedule 
Group 
Planned Number 
of Subjects 
Treatment Period #1 
(24 Weeks) 
Treatment Period #2 
(20 Weeks)  
1 
30 
Vamorolone, 2.0 mg/kg/day ® 
Vamorolone, 2.0 mg/kg/day 
2 
30 
Vamorolone, 6.0 mg/kg/day ® 
Vamorolone, 6.0 mg/kg/day 
3 
15 
Prednisone, 0.75 mg/kg/day ® 
Vamorolone, 2.0 mg/kg/day 
4 
15 
Prednisone, 0.75 mg/kg/day ® 
Vamorolone, 6.0 mg/kg/day 
5 
15 
Placebo ® 
Vamorolone, 2.0 mg/kg/day 
6 
15 
Placebo ® 
Vamorolone, 6.0 mg/kg/day 
Evaluation of the two dose levels of vamorolone, prednisone, and placebo during the 24-
week Treatment Period #1 in this study will allow comparison of change from baseline in 
safety parameters, muscle strength and functional efficacy parameters, and PD biomarker 
levels over 24 weeks of treatment as compared to no treatment (placebo) or standard of 
care treatment (prednisone).  In particular, evaluation of change of the PD biomarkers 
from baseline over a longer (24-week) period may aid in the clinical validation of 
biomarkers which exhibit small changes over time.  In addition, evaluation of the two 
dose levels of vamorolone over the total 48-week period of the study will allow 
assessment of the persistence of effect. 
The primary efficacy outcome is the Time to Stand (TTSTAND) from the floor 
(velocity), and comparison will be made between the 6.0 mg/kg/day dose level of 
vamorolone and the placebo group at Week 24.  Multiple secondary and exploratory 
efficacy outcomes will be measured, including TTSTAND, Time to Run/Walk 10 meters 
(TTRW), Time to Climb four stairs (TTCLIMB), North Star Ambulatory Assessment 


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(NSAA), 6-Minute Walk Test (6MWT), Range of Motion test (ROM), and hand-held 
myometry (elbow flexors and knee extensors).  Additional exploratory measures of 
efficacy include PD biomarkers that have previously been shown to be glucocorticoid-
responsive in DMD boys and inflammatory bowel disease in children.31  Moreover, 
physical functioning, behavior, neuropsychology, and satisfaction with treatment will be 
measured as exploratory outcomes using the parent proxy-report of Pediatric Outcomes 
Data Collection Instrument (PODCI), PARS III, Treatment Satisfaction Questionnaire 
(TSQM), and Ease of Study Medication Administration Assessment for the study 
medication suspension, respectively.   
For the safety measure of body mass index (BMI) z-score, comparisons will be made 
between each dose level of vamorolone and the prednisone-treated group.  Additional 
secondary safety measures are serum biomarkers bridged to later clinical safety concerns.  
These include: 
1. Adrenal suppression.  Pharmacological doses of glucocorticoids cause 
suppression of the hypothalamo-pituitary-adrenal axis, leading to low 
concentration of endogenous cortisol and other steroidal hormones in serum.  
Adrenal suppression is directly associated with risk of adrenal crisis, delay of 
puberty and stunting of growth.  Measurement of morning cortisol concentrations 
will reflect the degree of adrenal suppression.  Plasma cortisol secretion typically 
follows a circadian pattern with the highest concentrations early in the morning; a 
morning serum cortisol concentration less than 3.6 µg/dL (or 100 nM) is highly 
suggestive of adrenal suppression.  A single cortisol measurement at other times 
of the day is of limited value and dynamic testing with Cosyntropin (a synthetic 
peptide of ACTH, also known as tetracosactide) is a standard approach to the 
assessment of endogenous cortisol production.32  Serum cortisol levels less than 
18 µg/dL (500 nM) 30 or 60 minutes after stimulation with Cosyntropin (250 µg) 
are considered diagnostic of adrenal suppression.  
2. Bone turnover.  Pharmacological doses of glucocorticoids cause an imbalance of 
bone formation and bone resorption, leading to later osteopenia and bone 


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fragility.33  Bone fragility is a significant adverse effect of chronic pharmacologic 
glucocorticoids in DMD as this can lead to fracture, which increases the 
likelihood of premature loss of ambulation.  Serum biomarkers that have been 
bridged to later clinical outcomes of osteopenia are osteocalcin (bone formation; 
glucocorticoids decrease serum levels), and CTX1 (bone resorption; 
glucocorticoids increase serum levels).  Decreases of osteocalcin and increases of 
CTX1 are reflective of abnormal bone turnover, a risk factor bridged to later 
bone fragility. 
3. Insulin resistance.  Insulin resistance is the term where increased blood glucose 
triggers increased insulin secretion from the pancreatic islet cells, but the 
elevated serum insulin fails to sufficiently trigger glucose uptake by muscle 
and/or liver.  Thus, peripheral tissues are resistant to insulin signaling (insulin 
resistance).  Insulin resistance has been bridged to later clinical outcomes, 
including heart disease, type 2 diabetes, and vascular disease.  Serum biomarkers 
that are accepted as measures of insulin resistance are increased serum glucose 
and insulin.  This can be measured after acute (hours after first dose) or chronic 
(after weeks or months of dosing) glucocorticoid treatment. 
Additional exploratory safety outcomes are measures of additional serum safety 
biomarkers that have been defined in glucocorticoid-treated DMD and inflammatory 
bowel disease patients. 
This trial will be conducted in compliance with this protocol, and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki, and that are 
consistent with Good Clinical Practice (GCP) and the applicable regulatory requirements, 
and the recently issued FDA guidance on developing drugs for treatment for DMD and 
related dystrophinopathies.34 
It is obligatory that the Investigator become familiar with all sections of the vamorolone 
Investigator’s Brochure.29 


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1.5 
Overall Benefit/Risk 
It is anticipated that the adverse effect profile of the investigational product will be more 
favorable than standard of care glucocorticoids in the long term.  There has been a total 
of 11 SAEs in the vamorolone program to date: a total of 4 SAEs in the VBP15-003 
study, a total of 3 SAEs in the VBP15-LTE study, a total of 3 SAEs in the VBP15-004 
study, and 1 SAE in the VBP15-EAP program.  There have been two SAEs of pneumonia 
in two different subjects (both subjects receiving vamorolone 0.75 mg/kg/day); one SAE 
of bilateral testicular torsion and one SAE of hypoxia in the same subject receiving 6.0 
mg/kg/day; one SAE of influenza associated dehydration in a subject receiving 6.0 
mg/kg/day; two SAEs of acute myoglobulinemia in the same subject receiving 6.0 
mg/kg/day; one SAE of viral gastroenteritis with secondary dehydration in a subject 
receiving blinded study drug; one SAE of asthma exacerbation in the setting of 
respiratory syncytial virus and bronchiolitis in a subject receiving vamorolone at either 
2.0 mg/kg/day or 6.0 mg/kg/day; one SAE of perforated appendicitis occurring with 30 
days after the subject completed the VBP15-004 study, and one SAE of viral 
gastroenteritis requiring hospitalization for hydration.  Each of these SAEs was 
considered unrelated to study drug, and none of them resulted in discontinuation from the 
study.   
In the Phase I clinical trial in adult volunteers, vamorolone showed mild elevations of 
liver enzymes in one subject receiving 20.0 mg/kg in the fasted state.  One subject 
participating in VBP15-004 developed an AE of acute cholestatic hepatitis manifested by 
elevated transaminases, direct bilirubin, ALP and GGT during Treatment Period #1 and 
after study drug interruption and restart, redeveloped acute cholestatic hepatitis in 
Treatment Period #2.  Unblinding of the treatment assignment for this subject, to 
facilitate decisions regarding subsequent standard of care corticosteroid therapy, 
indicated that the subject had been on vamorolone 6.0 mg/kg/day in both Treatment 
Period #1 and Treatment Period #2.   
In the VBP15-002 study, after 2 weeks of treatment, 0 of 11 tested participants who 
received vamorolone 0.25 mg/kg/day, 0 of 11 tested participants who received 


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vamorolone 0.75 mg/kg/day, 2 of 11 (18.2%) tested participants who received 
vamorolone 2 mg/kg/day, and 6 of 10 (60.0%) tested participants who received 
vamorolone 6 mg/kg/day had a depressed morning cortisol (<3.6 μg/dL [100 nmol/L]) 
consistent with chronic adrenal suppression.  In the VBP15-003 study, after 24 weeks of 
treatment, 0 of 8 tested participants (0.25 mg/kg/day), 1 of 12 (8.3%) tested participants 
(0.75 mg/kg/day), 5 of 12 (41.7%) tested participants (2.0 mg/kg/day), and 8 of 9 (88.9%) 
tested participants (6.0 mg/kg/day) had a depressed morning cortisol (<3.6 μg/dL 
[100 nM]) consistent with chronic adrenal suppression.  Instructions for detecting adrenal 
crisis and the circumstances in which stress dose steroids should be provided will be 
included in the Informed Consent Form (ICF) and Manual of Operations, and 
Investigators should monitor clinical study participants closely to identify elevations in 
liver-specific enzymes.   
Potential Health Benefits: Subjects may or may not receive direct health benefit from 
participating in the study.  Some subjects will be randomly assigned to vamorolone at one 
of two planned dose levels (2.0 mg/kg/day and 6.0 mg/kg/day) over the course of the 
48-week trial.  In the VBP15-003 study, clinical efficacy was assessed by Timed 
Function Tests.  Improvement in Time to Stand, Time to Climb, Time to Run/Walk 
10 Meters, and 6-Minute Walk Test were seen predominantly for the 2.0 and 
6.0 mg/kg/day dose level groups, with many of the improvements showing statistical 
significance compared to an untreated Duchenne Natural History Group.  In view of the 
initial clinical evidence of safety, the improvements observed in the assessments of 
efficacy, and the nature of potential adverse effects that can be monitored, the data 
support an acceptable benefit/risk profile for vamorolone.  
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 Primary Objectives 
The primary objectives of this study are: 


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1. To compare the efficacy of vamorolone administered orally at daily doses of 
6.0 mg/kg over a 24-week treatment period vs. placebo in ambulant boys ages 4 to 
<7 years with DMD; and  
2. To evaluate the safety and tolerability of vamorolone administered orally at daily 
doses of 2.0 mg/kg and 6.0 mg/kg in ambulant boys ages 4 to <7 years with 
DMD. 
2.1.2 Secondary Objectives 
The secondary objectives of this study are: 
1. To compare the efficacy of vamorolone administered orally at daily doses of 
2.0 mg/kg over a 24-week treatment period vs. placebo in ambulant boys ages 4 to 
<7 years with DMD; 
2. To compare the safety of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily prednisone 
0.75 mg/kg in ambulant boys ages 4 to <7 years with DMD; 
3. To compare the efficacy of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily prednisone 
0.75 mg/kg in ambulant boys ages 4 to <7 years with DMD;  
4. To compare the efficacy of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 48-week treatment period in ambulant boys ages 
4 to <7 years with DMD vs. untreated DMD historical controls;  
5. To compare the safety of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 48-week treatment period in ambulant boys ages 
4 to <7 years with DMD vs. prednisone-treated DMD historical controls; and 
6. To evaluate the population pharmacokinetics of vamorolone administered orally 
at daily doses of 2.0 mg/kg and 6.0 mg/kg in ambulant boys ages 4 to <7 years 
with DMD. 


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2.1.3 Exploratory Objectives 
The exploratory objectives of this study are:  
1. To evaluate the satisfaction with treatment of vamorolone administered orally at 
daily doses of 2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily 
prednisone 0.75 mg/kg in ambulant boys ages 4 to <7 years with DMD;  
2. To evaluate the effect of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily prednisone 
0.75 mg/kg on behavior and neuropsychology;  
3. To evaluate the effect of vamorolone administered orally at daily doses of 2.0 
mg/kg and 6.0 mg/kg over a 24-week treatment period vs. placebo on physical 
functioning; 
4. To assess the ease of administration of the study medication suspension to 
ambulant boys ages 4 to <7 years with DMD; 
5. To compare the effects of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. placebo on 
potential serum PD biomarkers of safety and efficacy in ambulant boys ages 4 to 
<7 years with DMD;  
6. To compare the effects of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily prednisone 
0.75 mg/kg on potential serum PD biomarkers of safety and efficacy in ambulant 
boys ages 4 to <7 years with DMD; and 
7. To determine if candidate genetic modifiers of DMD (gene polymorphisms 
associated with disease severity, or response to glucocorticoid treatment) are 
similarly associated with vamorolone-treated DMD subjects (baseline disease 
severity, or response to vamorolone or prednisone treatment). 


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2.2 
Study Endpoints 
2.2.1 Safety Endpoints 
1. BMI z-score: Change from baseline to each of the scheduled on-treatment and 
post-treatment assessment time points; 
2. Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) 
by system organ class (SOC): Overall by treatment, by treatment and relationship, 
and by treatment and intensity (see Section 7.5);  
3. Vital signs (sitting blood pressure, heart rate, respiratory rate, and body 
temperature): Change from baseline to each of the scheduled on-treatment and 
post-treatment assessment time points;   
4. Body weight and height: Change from baseline to each of the scheduled 
on-treatment and post-treatment assessment time points; 
5. Cushingoid features: Change from baseline to each of the scheduled on-treatment 
and post-treatment assessment time points (changes from baseline will be 
recorded as AEs); 
6. Clinical laboratory values: Change from baseline to each of the scheduled 
on-treatment and post-treatment assessment time points in: 
• 
Hematology and clinical chemistry 
• 
Lipid profile (triglycerides, total cholesterol, low density lipoprotein [LDL], 
high density lipoprotein [HDL]) 
• 
Vitamin D level 
• 
Urinalysis; 
7. 12-lead electrocardiogram (ECG): Change from baseline to each of the scheduled 
on-treatment and post-treatment assessment time points; 
8. 2D-echocardiogram: Change from baseline to Week 24 and Week 48; 


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9. Dual-energy x-ray absorptiometry (DXA) scan: Change from baseline to Week 24 
and Week 48 in spine BMD, total body BMD, spine and total body bone mass, 
and total body composition (lean mass, fat mass, fat-free mass, Lean Mass Index, 
and Fat Mass Index); 
10. Spine x-rays: Change from baseline to Week 24 assessment; 
11. Eye examination for detection of clinically significant abnormalities (cataracts 
and/or glaucoma) at Week 24 and Week 48 assessments compared to baseline; 
12. ACTH Stimulation Test: measure of adrenal suppression at Week 24 and 
Week 48.  Percentage of subjects in each treatment group with cortisol levels <18 
µg/dL (or 500 nM) 30 or 60 minutes after stimulation with Cosyntropin;  
13. Linear growth velocity: Change from baseline to each of the scheduled 
on-treatment and post-treatment assessment time points in height percentile for 
age.  
Data for the following additional safety outcomes will be listed only: 
1. Physical examination findings at each of the pretreatment, on-treatment, and 
post-treatment assessment time points. 
2. Fracture Questionnaire results at pretreatment, Week 24, and Week 48.  
Tolerability Endpoint 
1. Premature discontinuations of study treatment due to adverse events. 
2.2.2 Clinical Efficacy Endpoints 
Primary Clinical Efficacy Endpoint 
1. Time to Stand Test (TTSTAND) velocity (rise/second): Comparison of the 
vamorolone 6.0 mg/kg/day dose level group versus the placebo group in change 
from baseline to the Week 24 assessment. 
Secondary Efficacy Endpoints 
1. Change from baseline to Week 24 for the following comparisons: 


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• TTSTAND velocity, vamorolone 2.0 mg/kg/day vs placebo 
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 6.0 mg/kg/day vs. 
placebo 
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 2.0 mg/kg/day vs. 
placebo 
• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 6.0 mg/kg/day 
vs. placebo 
• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 2.0 mg/kg/day 
vs. placebo 
• 6MWT meters walked, vamorolone 6.0 mg/kg/day vs. prednisone 
• 6MWT meters walked, vamorolone 2.0 mg/kg/day vs. prednisone 
2. Change from baseline to each of the scheduled study assessment time points for 
each treatment group up to Week 48 for: 
• Time to Stand Test (TTSTAND) velocity (rise/second); 
• Time to Climb (4 Steps) Test (TTCLIMB) velocity (tasks/second); 
• Time to Run/Walk Test (TTRW) velocity (meters/second) to complete 
10 meters of a 14 meter course; 
• Total distance traveled, in meters, in completing the Six-minute Walk Test 
(6MWT);  
• North Star Ambulatory Assessment (NSAA);  
• Hand-held myometry (elbow flexors and knee extensors); and 
• Range of motion in the ankles (ROM).  
Exploratory Efficacy Endpoints 
1. Change from baseline to each of the scheduled study assessment time points up to 
and including Week 24 for the following comparisons: 


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• TTSTAND velocity, vamorolone 6.0 mg/kg/day vs placebo (Week 6 and 12 
only) 
• TTSTAND velocity, vamorolone 2.0 mg/kg/day vs placebo (Week 6 and 12 
only) 
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 6.0 mg/kg/day vs. 
placebo (Week 12 only) 
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 2.0 mg/kg/day vs. 
placebo (Week 12 only) 
• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 6.0 mg/kg/day 
vs. placebo (Week12 only) 
• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 2.0 mg/kg/day 
vs. placebo (Week12 only) 
• 6MWT meters walked, vamorolone 6.0 mg/kg/day vs. prednisone (Week 12 
only) 
• 6MWT meters walked, vamorolone 2.0 mg/kg/day vs. prednisone (Week 12 
only) 
• NSAA total score, vamorolone 6.0 mg/kg/day vs. placebo 
• NSAA total score, vamorolone 2.0 mg/kg/day vs. placebo 
• Hand-held Myometry knee extensors, vamorolone 6.0 mg/kg/day vs. placebo 
• Hand-held Myometry knee extensors, vamorolone 2.0 mg/kg/day vs. placebo 
• Hand-held Myometry elbow extensors, vamorolone 6.0 mg/kg/day vs. placebo 
• Hand-held Myometry elbow extensors, vamorolone 2.0 mg/kg/day vs. placebo 
• TTCLIMB velocity, vamorolone 6.0 mg/kg/day vs. placebo 
• TTCLIMB velocity, vamorolone 2.0 mg/kg/day vs. placebo 
• ROM in the ankles, vamorolone 6.0 mg/kg/day vs. placebo 
• ROM in the ankles, vamorolone 2.0 mg/kg/day vs. placebo 


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2.2.3 Additional Exploratory Endpoints 
1. Treatment satisfaction questionnaire (TSQM): Comparison of each vamorolone 
dose level group to the prednisone group at the Week 24 visit; comparison of each 
treatment group at the Week 48 visit; 
2. Pediatric Outcomes Data Collection Instrument (PODCI): Comparison of each 
vamorolone dose level group to the placebo group for change from baseline to the 
Week 24 assessment; comparison of each treatment group for change from 
baseline to the Week 48 assessment; 
3. Behavioral changes (PARS III): Comparison of each vamorolone dose level group 
to the prednisone group and to the placebo group for change from baseline to each 
of the scheduled study assessment time points up to the Week 24 assessment; 
comparison of each treatment group for change from baseline to the Week 48 
assessment; 
4. Ease of study medication administration (Question 1 only: tablet vs liquid) 
assessed at each of the scheduled study assessment time points;  
5. Blindedness Assessment at each of the scheduled study assessment time points; 
and 
6. DNA testing for candidate genetic modifiers of DMD. 
2.2.4 Pharmacodynamic Endpoints 
1. The following pharmacodynamic biomarkers are considered secondary outcome 
measures focusing on safety outcomes.  In each case, the biomarkers studied 
reflect safety concerns of glucocorticoids: 
a. Adrenal suppression.  First-in-morning serum cortisol levels will be 
measured.  Cortisol measures falling below 3.6 µg/dL (or 100 nM) will be 
considered to be indicative of the development of adrenal suppression.  
ACTH Stimulation Test will be performed at the Screening Visit and at 
the Week 24 Follow-up Visit (48 ± 3 hours after the final dose of 
Treatment Period #1 study medication) and at the Week 48 Follow-up 


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Visit (48 ± 3 hours after the final dose of Treatment Period #2 study 
medication): cortisol levels <18 µg/dL (or 500 nM) 30 or 60 minutes after 
stimulation with Cosyntropin (250 µg) will be considered to be indicative 
of adrenal suppression.   
b. Bone turnover.  Measures of serum osteocalcin are reflective of bone 
formation, and measures of serum CTX1 are reflective of bone 
reabsorption.  Levels of osteocalcin and CTX1 predict later clinical safety 
concerns of osteopenia and bone fragility. 
c. Insulin resistance.  Glucocorticoids cause both acute and chronic insulin 
resistance, with serum elevations of both insulin and glucose.  Measures of 
hyperinsulinemia and hyperglycemia are accepted measures of insulin 
resistance. 
2. Exploratory biomarkers for aspects of safety and efficacy31 
2.2.5 
Endpoints for Patient-Reported Outcomes 
Safety endpoints based on subject reports of AEs are listed in Section 2.2.1.   
The parent/legal guardian of each subject will be asked to assess the ease of 
administration of the study medication suspension (see Section 7.4.4).   
Additionally, subjects’ parents/legal guardians will be asked to complete the PODCI (see 
Section 7.4.1).  Satisfaction with treatment will be measured using the Treatment 
Satisfaction Questionnaire (TSQM) which also will be completed by the parent/legal 
guardian (see Section 7.4.2).  Additionally, the PARS III behavioral assessment will be 
completed by the parent/guardian (see Section 7.4.3).  Finally, the subject’s parent/legal 
guardian will complete a Blindedness Assessment at the Week 24 Visit (see Section 
7.4.5). 
No other patient-reported outcomes are planned.   


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3 
STUDY DESIGN 
3.1 
Overall Study Design 
This Phase IIb study is a randomized, double-blind, parallel group, placebo- and active-
controlled study with double-blind extension to evaluate the long-term efficacy, safety, 
tolerability, PD, and population PK of vamorolone (the investigational medicine) 
compared to prednisone (active control) and placebo over a Treatment Period of 
24 weeks in boys ages 4 to <7 years with DMD, and determine the persistence of effect 
over a total Treatment Period of 48 weeks.  Six treatment groups will receive either 
vamorolone at one of two doses (2.0 mg/kg or 6.0 mg/kg), prednisone (0.75 mg/kg), or 
placebo once daily for 24 weeks, and will receive vamorolone at one of two doses 
(2.0 mg/kg or 6.0 mg/kg) daily for an additional 20 weeks.  A total of approximately 
120 subjects will be randomized into the study as shown in Table 6.  
To maintain the blind during Treatment Period #1, matched suspension (vamorolone or 
placebo) and matched tablets (prednisone or placebo) will be administered.  Each subject 
will receive a dose of suspension (vamorolone or placebo) and tablets (prednisone and 
placebo) once daily during Treatment Period #1.  The number of tablets and volume of 
suspension per dose will be determined by body weight.  
The study is comprised of a Pretreatment Screening Period of up to 32 days duration, a 
1-day Pretreatment Baseline Period, a 24-week Treatment Period #1, a 4-week Transition 
Period, a 20-week Treatment Period #2, and a 4-week Dose-tapering Period.  Subjects 
will be enrolled into this study at the time written informed consent is given, and 
randomized to treatment only after completion of all Pretreatment Screening assessments. 
Study drug dosing will occur from Day 1 until the Week 48 Visit (Section 5.3).  Study 
drug dosing will occur at home on all days except the Day 1, Week 2, Week 12, Week 
24, Week 28, Week 30, Week 40, and Week 48 study visits, when dosing will occur at 
the study site.   
Subjects will be assessed for safety and tolerability, clinical efficacy, PD, and population 
PK at scheduled visits throughout the study (see Section 6 for a schedule of study 
assessments).  Treatment Period #1, Transition Period, and Treatment Period #2 study 


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visits will occur at Day 1, Week 2, Week 6, Week 12, Week 18, Week 24, Week 28, 
Week 30, Week 34, Week 40 and Week 48 (Table 11); all subjects will return to the 
clinical site for a Week 24 Follow-up Visit and for a Week 48 Follow-up Visit, 48 ± 3 
hours after administration of the final dose of Treatment Period #1 and Treatment Period 
#2 study medication, respectively, for ACTH Stimulation testing.  Adverse events, 
including SAEs, and concomitant medications will be recorded throughout the study.   
Subject diaries will be dispensed at the Day 1 Visit and at each study visit thereafter 
through Week 48 to record AEs, changes to concomitant medications taken during the 
study, and any missed or incomplete doses of study medication. 
There is flexibility in the timing of completion of some of the scheduled Week 24 and 
Week 48 assessments.  The scheduled physical examination, weight, vital signs, clinical 
laboratory tests, blood draws for PD biomarker analysis, blood draw for DNA testing 
(Week 24 only), Ease of Study Medication Administration Assessment, PODCI, PARS 
III, and functional assessments (TTSTAND, TTCLIMB, TTRW, NSAA, 6MWT, hand-
held myometry, ROM) must all be performed on the date of the Week 24 or Week 48 
dose of study medication.  The 12-lead ECG may be performed on the date of the Week 
24 or Week 48 dose of study medication, the day following the Week 24 or Week 48 
dose of study medication, or the day of the Week 24 or Week 48 Follow-up Visit.  For 
the Week 24 assessments, completion of the DXA scan, spine X-rays, Fracture 
Questionnaire, 2-D echocardiography, eye examination, TSQM, and Blindedness 
Assessment may be performed up to 7 days following the date of the Week 24 dose of 
study medication to accommodate need for additional scheduling flexibility.  For the 
Week 48 assessments, completion of the DXA scan, Fracture Questionnaire, 2-D 
echocardiography, eye examination, and TSQM may be performed on the date of the 
final Week 48 dose of study medication, the day following the Week 48 dose of study 
medication, or the day of the Week 48 Follow-up Visit for subjects who will receive 
additional vamorolone therapy by enrolling directly into an additional vamorolone study 
or general access program, or up to 7 days following the date of the final Week 48 dose 
of study medication for subjects participating in the Dose-tapering Period.   


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A Transition Period of 4 weeks in duration follows the end of Treatment Period #1 for all 
subjects.  During this Transition Period, all subjects will continue to receive the liquid 
formulation (vamorolone 2.0 mg/kg or 6.0 mg/kg, or matching placebo) they received 
during Treatment Period #1 and will be tapered off their study medication tablets 
(prednisone or matching placebo).  Site study staff will contact the parent(s)/guardian(s) 
by telephone at Week 26 to ensure that the tablet tapering is proceeding according to 
protocol, to assess potential signs or symptoms indicative of adrenal suppression, and to 
address any questions the parent(s)/guardian(s) may have.  All subjects will return to the 
clinical site for the Week 28 assessments, prior to receiving their first dose of Treatment 
Period #2 study medication on the day after the Week 28 Visit (Week 28 + 1 day) (see 
Section 6.3.6).   
Subjects who complete the VBP15-004 study assessments through the Week 48 Visit and 
Week 48 Follow-up Visit may be given access to vamorolone through an additional study 
or general access program, or given the option to transition to standard of care treatment 
(including glucocorticoids) for DMD.  Standard of care treatment for DMD may be 
offered to the subject following completion of the Phase IIb VBP15-004 study, if the 
subject’s parent or guardian does not wish to enroll the subject in the additional 
vamorolone study or general access program and/or the Investigator feels it to be in the 
best interest of the subject.   
Subjects who will enroll directly into the additional vamorolone study or general access 
program to continue vamorolone treatment will be discharged from the VBP15-004 study 
following completion of all Week 48 assessments and the Week 48 Follow-up Visit 
ACTH Stimulation Test.  Subjects who will not continue vamorolone treatment in the 
additional vamorolone study or general access program, including those subjects who 
will transition to standard of care treatment for DMD, will have their vamorolone dose 
tapered during a 4-week Dose-tapering Period, prior to discharge from the study.  Site 
study staff will contact the parent(s)/guardian(s) by telephone at Week 50 to ensure that 
the dose tapering is proceeding according to protocol (see Section 6.3.7), to assess 
potential signs or symptoms of adrenal suppression, and to address any questions the 
parent(s)/guardian(s) may have.  


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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.   
Any subject who discontinues the study prior to the Week 24 Visit should return to the 
study unit for scheduled Week 24 assessments and the Week 24 Follow-up Visit ACTH 
Stimulation Test at the time of early withdrawal, whenever possible; any subject who 
prematurely discontinues the study after Week 24 but prior to Week 28 should complete 
the scheduled Week 28 assessments at the time of early withdrawal, whenever possible; 
and any subject who prematurely discontinues the study after Week 28 but prior to Week 
48 should complete the scheduled Week 48 assessments and the Week 48 Follow-up 
Visit ACTH Stimulation Test at the time of early withdrawal, whenever possible, 
assuming the subject has not withdrawn consent.  Any subject who withdraws early from 
the study should undergo Early Discontinuation Dose-tapering (see Section 6.4). 
3.2 
Randomization 
Following consent and review of study entry criteria to confirm subject eligibility for the 
study, the subject can be randomized to treatment.  Randomization should be performed 
at least 10 days prior to the baseline visit and will be achieved via the Interactive 
Voice/Web Response System (IXRS) system with user name and password access.  
Randomization will be stratified by participant’s age (<6 vs. ≥ 6 years).  Randomization 
will be stratified only by age; randomization will not be stratified by investigational site.  
Randomization will require the site investigator, or designee, to verify that the subject 
meets the inclusion/exclusion criteria of the study, and to verify that the child has not 
previously been randomized.  The following information will need to be entered into the 
IXRS system in order to assign the subject to a treatment group and the appropriate age 
stratification group: 
• 
Participant’s Study Subject Identification Number 
• 
Participant’s Date of Birth  
• 
Participant’s weight, as recorded at the Screening Visit. 


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When the site investigator/designee completes the randomization procedures via the 
IXRS system, an e-mail report with the randomization number and age stratification 
group will be generated and sent to the clinical trials supply company confirming 
randomization into the trial.  
The randomization number will be assigned by the IXRS system and will only be used 
for study drug supply and shipment.  Once the information has been received, the clinical 
trials supply company will prepare a subject-specific kit of study medication and ship it 
to the pharmacy at the study site. 
Randomization procedures should be completed at least 10 days prior to the Baseline 
Visit in order to allow study drug supply to be shipped to the site in time to be 
dispensed to the participant by the site investigator for Day 1 dosing. 
3.3 
Blinding 
To achieve double-blinding, the supplies company will manufacture identical liquid 
formulations for vamorolone and placebo, and identical tablet formulation for prednisone 
and placebo.  Each dose of study medication will consist of doses of both a liquid 
formulation (vamorolone or placebo) and tablets (prednisone or placebo) through Week 
28, and liquid formulation only following Week 28 through Week 48 (see Table 7).  
To blind the liquid formulation, the supplies company will manufacture 1.33% and 4.0% 
wt/wt vamorolone suspension formulations, and placebo suspension formulation, 
identical in appearance.  Subjects who are randomized to receive vamorolone 2.0 mg/kg 
will receive the 1.33% vamorolone suspension, and subjects who are randomized to 
receive vamorolone 6.0 mg/kg will receive the 4.0% vamorolone suspension.  Study 
medication will be shipped to the sites in 100 mL bottles labeled with subject-specific 
identifiers.  Trained site study staff will calculate study medication dose volume based on 
subject body weight for all subjects as 0.15 mL/kg, regardless of treatment assignment. 
Subjects, parents/guardians, site investigators and all other site study staff will not know 
to which treatment group the subject has been assigned and will remain blinded to the 
identity of the treatment assignment until the end of the study (last subject last visit) and 
the database has been locked.  


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3.4 
Unblinding 
Every attempt should be made to preserve the integrity of study drug blinding.  All 
subjects will be provided with a card, to be carried at all times, stating “I am taking part 
in a clinical trial” (in the local language) to be presented to medical staff in the event of 
routine treatment or a medical emergency.  Investigational medications can usually be 
withdrawn without the need for unblinding in a subject experiencing an AE that requires 
study medication withdrawal.  In this case, the site investigator should provide adequate 
and necessary support to the subject without unblinding study treatment.   
Subjects who experience a medical emergency, whether their treatment remains blinded 
or is unblinded, should be covered with stress steroids, except for unblinded subjects who 
were receiving placebo.   
All subjects who have study medication withdrawn without unblinding will need to 
undergo dose-tapering according to the schedule in Section 6.4. 
In the event that unblinding is necessary, an emergency unblinding procedure is provided 
to allow site investigators to disclose a treatment assignment for an individual subject if 
clinical circumstances should require this.   
Unblinding will be performed and treatment assignment obtained through the IXRS 
system with username and password code.  The expectation is that emergency unblinding 
will occur only very rarely; for example, when the subject needs emergency surgery and 
information about all treatment interventions is required.  In the exceptional circumstance 
that knowledge of the study drug assignment appears essential for providing appropriate 
medical management, the site investigator should make every effort to contact the study 
chair or the independent Medical Monitor to discuss the rationale for breaking the blind.  
If the site investigator still believes that unblinding is needed, or the study chair and 
independent Medical Monitor are not available for contact, the site investigator will 
follow the IXRS unblinding procedures for unblinding the subject in question (see the 
Manual of Operations for details on how to unblind a subject using the IXRS system).   
After breaking the blind, the site staff should record details regarding the reasons for 
breaking the blind, including any AEs leading to the unblinding, in the source documents 


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and electronic case report form (eCRF).  Once the blind is broken for a given subject, 
study drug will be discontinued and the subject will be withdrawn from the study.  
Furthermore, as the subject might have received glucocorticoids (prednisone) as part of 
the study and as vamorolone appears to affect the adrenal axis, prednisone and 
vamorolone cannot be discontinued without a proper dose-tapering period.   
Any subject whose treatment is unblinded prior to the Week 24 Visit should return to the 
clinic for Week 24 assessments at the time of unblinding, whenever possible, assuming 
the subject has not withdrawn consent; any subject whose treatment is unblinded after 
Week 24 and prior to the Week 28 Visit should return to the clinic for Week 28 
assessments at the time of unblinding, whenever possible, assuming the subject has not 
withdrawn consent; any subject whose treatment is unblinded after Week 28 and prior to 
the Week 48 Visit should return to the clinic for Week 48 assessments at the time of 
unblinding, whenever possible, assuming the subject has not withdrawn consent.  Since 
all subjects will receive vamorolone at one of two dose levels during Treatment Period #2 
(Weeks 28 – 48), the identification, through unblinding, of the vamorolone dose level to 
which a given subject is assigned is unlikely to give additional useful information, and 
thus the need to unblind treatment assignment is remote during this study period.  Any 
subject whose treatment, upon unblinding, is revealed to be either vamorolone or 
prednisone, will need to follow the dose-tapering protocol (Section 6.4 specific to the 
time of unblinding); these subjects will also be asked to return to the clinic at the end of 
the tapering period for final Dose-tapering Period assessments, whenever possible.  If the 
subject was taking placebo prior to unblinding, study drug tapering will not be required; 
however, the subject should return for final Week 24 assessments at the time of 
unblinding and withdrawal from the study.  After unblinding, a subject may be prescribed 
standard of care glucocorticoids, if clinically indicated.    
Subjects who discontinue the study for any reason other than a medical emergency 
will not be unblinded.  


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4 
SELECTION AND WITHDRAWAL OF STUDY SUBJECTS 
4.1 
Subject Enrollment and Identification Log 
Subjects will be recruited through the clinics of participating site investigators and other 
mechanisms including patient registries, national and international networks and patient 
foundations.  After identification of a possible subject, the site investigator will discuss 
the study with the subject’s parent(s) or legal guardian(s).  The subject’s parent(s) or 
guardian(s) will be provided with a copy of the study subject information sheet 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 to <7 years of age. 
A subject enrollment log will be maintained at each investigational site for all subjects 
who are screened for the study, including those not randomized to treatment.  Limited 
data will be collected for these subjects, including date of birth, and reason for exclusion 
from the study.  Subject enrollment logs will be maintained for all subjects enrolled in the 
study.  This record will also include the dates of subject enrollment and 
completion/termination.   
The Site Investigator will keep a record relating the names of the subjects to their 
enrollment numbers (subject identification log) to permit efficient verification of data 
subject files, when required.  These logs will be reviewed during routine monitoring calls 
and/or visits. 
4.2 
Inclusion Criteria 
To qualify for randomization in this study, the subject must satisfy the following 
inclusion criteria: 
1. Subject’s parent(s) or legal guardian(s) has (have) provided written informed 
consent and Health Insurance Portability and Accountability Act (HIPAA) 
authorization, where applicable, prior to any study-related procedures; 


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participants will be asked to give written or verbal assent according to local 
requirements; 
2. Subject has a centrally confirmed (by TRiNDS central genetic counselor[s]) 
diagnosis of DMD, as defined as: 
• 
Dystrophin immunofluorescence and/or immunoblot showing complete 
dystrophin deficiency, and clinical picture consistent with typical DMD, OR 
• 
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 
• 
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 clinical picture consistent with typical DMD; 
3. Subject is ≥ 4 years and <7 years of age at time of enrollment in the study; 
4. Subject weighs >13.0 kg and ≤ 39.9 kg at the Screening Visit; 
5. Subject is able to walk independently without assistive devices; 
6. Subject is able to complete the Time to Stand Test (TTSTAND) without 
assistance in <10 seconds, as assessed at the Screening Visit; 
7. 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. 
[Notes: Serum gamma glutamyl transferase (GGT), creatinine, and total bilirubin 
all must be ≤ upper limit of the normal range at the Screening Visit.  An abnormal 
vitamin D level that is considered clinically significant will not exclude a subject 
from randomization]; 
8. 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 local laboratory from blood collected during the Screening 
Period, OR 


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• 
Documentation, provided at the Screening Visit, that the subject has had 2 
doses of varicella vaccine, with or without serologic evidence of immunity; 
the second of the 2 immunizations must have been given at least 14 days 
prior to randomization. 
9. Subject is able to swallow tablets, as confirmed by successful test swallowing of 
placebo tablets during the Screening Period; and  
10. Subject and parent(s)/guardian(s) 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 randomization in this study if he 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 a history of primary hyperaldosteronism; 
6. Subject has evidence of symptomatic cardiomyopathy [Note: Asymptomatic 
cardiac abnormality on investigation would not be exclusionary]; 
7. 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 1 
month 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, unless 


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discontinued for intolerance.  Inhaled and/or topical glucocorticoids are permitted 
if last use is at least 4 weeks prior to first dose of study medication or if 
administered at stable dose beginning at least 4 weeks prior to first dose of study 
medication and anticipated to be used at the stable dose regimen for the duration 
of the study]; 
8. Subject has an allergy or hypersensitivity to the study medication or to any of its 
constituents; 
9. Subject has used idebenone within 4 weeks prior to the first dose of study 
medication; 
10. Subject has severe behavioral or cognitive problems that preclude participation in 
the study, in the opinion of the Investigator; 
11. 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; 
12. Subject is taking (or has taken within 4 weeks prior to the first dose of study 
medication) herbal remedies and supplements which can impact muscle strength 
and function (e.g., Co-enzyme Q10, Creatine, etc);  
13. Subject is taking (or has taken within 3 months prior to the first dose of study 
medication) any medication indicated for DMD, including Exondys51 and 
Translarna;  
14. Subject has been administered a live attenuated vaccine within 14 days prior to 
the first dose of study medication; 
15. Subject is currently taking any other investigational drug or has taken any other 
investigational drug within 3 months prior to the first dose of study medication;  
16. Subject has a sibling who is currently enrolled in any vamorolone study or 
Expanded Access Program, or who intends to enroll in any vamorolone study or 
Expanded Access Program during the subject’s participation in the VBP15-004 
study; or 


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17. Subject has previously been enrolled in the study. 
Note: Any parameter/test may be repeated at the Investigator’s discretion during 
Screening to determine 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 injury, or if ineligible due to negative 
anti-varicella IgG antibody test result. 
4.4 
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:  
• 
The subject’s parent/legal guardian is uncooperative/noncompliant and does not 
adhere to study responsibilities, including failure to attend 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, and may jeopardize the subject’s health; 
• 
The Sponsor terminates the study; 
• 
Any other reason relating to subject safety or integrity of the study data; 
• 
The subject is unblinded to study treatment. 
In the event a subject is withdrawn from the study, the Sponsor or designee (e.g., 
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. 
All subjects who withdraw from the study prior to the Week 24 Visit should return to 
the study site for Week 24 assessments and the Week 24 Follow-up Visit ACTH 
Stimulation Test at the time of early withdrawal and undergo Dose-tapering, where 


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possible (see Section 6.4.1 and Section 7.2.7), subjects who prematurely discontinue 
from the study after Week 24 but prior to Week 28 should complete the Week 28 
assessments at the time of early withdrawal and undergo Dose-tapering, where 
possible (see Section 6.4.2), and subjects who prematurely discontinue from the study 
after Week 28 but prior to Week 48 should complete the Week 48 assessments and 
the Week 48 Follow-up Visit ACTH Stimulation Test at the time of early withdrawal 
and undergo Dose-tapering, where possible (see Section 6.3.7 and Section 7.2.7), 
assuming the subject has not withdrawn consent.  Subjects will also be asked to come 
back at the end of the tapering period for a follow up visit.  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 
of informed consent may be used by the Sponsor. 
4.5 
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 participants.   
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
site Investigators and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension.  The Institutional Review Board(s) 
(IRB[s])/Independent Ethics Committee(s) (IEC[s]) will also be informed promptly by 
the Investigator/institution or the Sponsor and provided the reason(s) for the termination 
or suspension. 
Subject enrollment at a given site may be terminated by the Sponsor.  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. 


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Subjects who are participating at a given site at the time it is terminated by the Sponsor 
will be offered the opportunity to continue to participate in the study at an alternative 
active site.  Subjects who decline the offer to participate at an alternative active site will 
need to undergo dose tapering at the time the original site is terminated according to the 
dose-tapering schedule (see Section 6.4). 
5 
TREATMENT OF STUDY SUBJECTS 
5.1 
Study Medications Administered 
5.1.1 Study Medications Administered During Treatment Period #1 
Vamorolone 1.33% wt/wt or 4.0% wt/wt oral suspension (investigational medicine), 
prednisone (active control) or placebo will be administered once daily over the 24-week 
Treatment Period #1. 
There are six treatment groups in this study.  The oral suspensions and tablets for 
Treatment Period #1 are shown in Table 7 for subjects who will be randomly assigned 
(2:2:1:1:1:1) to the following six treatment groups.  
Table 7. 
Study Medications for the Six Treatment Groups During Treatment 
Period #1 
Treatment Group 
Study Medications 
Oral Suspension 
Tablets 
Treatment Group 1 
2.0 mg/kg vamorolone  
placebo 
Treatment Group 2 
6.0 mg/kg vamorolone  
placebo 
Treatment Group 3 
placebo  
0.75 mg/kg prednisone 
Treatment Group 4 
placebo  
0.75 mg/kg prednisone 
Treatment Group 5 
placebo  
placebo 
Treatment Group 6 
placebo  
placebo  
 
Vamorolone will be administered as a 1.33% wt/wt suspension for oral dosing at the 
planned dose level of 2.0 mg/kg and as a 4.0% wt/wt suspension for oral dosing at the 
planned dose level of 6.0 mg/kg.  Prednisone will be administered as tablets for oral 
dosing at a dose of 0.75 mg/kg.  Prednisone tablets will be dispensed at a dosage strength 


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of 5 mg/tablet.  To maintain the blind, matched suspension (vamorolone or placebo) and 
tablets (prednisone or placebo) have been produced.  Each subject will receive a dose of 
suspension (0.15 mL/kg of vamorolone [1.33% oral suspension for the 2.0 mg/kg dose 
level or 4.0% oral suspension for the 6.0 mg/kg dose level] or placebo) and tablets 
(prednisone or placebo) each day (see Section 3.3).  The number of tablets per dose will 
be determined by body weight (see Table 10).   
The clinical trials supplies companies will manufacture identical liquid formulation of 
vamorolone and placebo and identical tablets for prednisone and placebo to maintain the 
blind.  Liquid solution of prednisone could not have been matched for color and flavor 
with vamorolone to maintain the blind.  Therefore, a double-dummy design is being used 
in this study.  
5.1.2 Study Medications Administered During Transition Period 
Vamorolone 1.33% wt/wt or 4.0% wt/wt oral suspension (investigational medicine), 
prednisone (active control) or placebo will be administered once daily over the 4-week 
Transition Period.  Prednisone and placebo tablets will be tapered over the 4-week 
Transition Period (see Table 12). 
The oral suspensions and tablets for the Transition Period are shown in Table 8 for 
subjects in each of the six treatment groups.  
Table 8. 
Study Medications for the Six Treatment Groups During the Transition 
Period 
Treatment Group 
Study Medications 
Oral Suspension 
Tablets (Tapering Doses) 
Treatment Group 1 
2.0 mg/kg vamorolone  
placebo 
Treatment Group 2 
6.0 mg/kg vamorolone  
placebo 
Treatment Group 3 
placebo  
prednisone 
Treatment Group 4 
placebo  
prednisone 
Treatment Group 5 
placebo  
placebo 
Treatment Group 6 
placebo  
placebo  
 


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Vamorolone will continue to be administered as a 1.33% wt/wt suspension for oral 
dosing at the planned dose level of 2.0 mg/kg and as a 4.0% wt/wt suspension for oral 
dosing at the planned dose level of 6.0 mg/kg.  Prednisone will be administered as tablets 
for oral dosing with decreasing number of tablets over the 4-week Transition Period 
(Table 12).  Prednisone tablets will be dispensed at a dosage strength of 5 mg/tablet.  To 
maintain the blind, each subject will receive a dose of suspension (0.15 mL/kg of 
vamorolone [1.33% oral suspension for the 2.0 mg/kg dose level or 4.0% oral suspension 
for the 6.0 mg/kg dose level] or placebo) and tablets (prednisone or placebo) each day 
(see Section 3.3).  The number of tablets per dose will be tapered to zero (0) over the 
4-week Transition Period (see Table 12).   
5.1.3 Study Medications Administered During Treatment Period #2 and the 
Dose-tapering Period 
Vamorolone 1.33% wt/wt or 4.0% wt/wt oral suspension (investigational medicine) will 
be administered once daily over the 20-week Treatment Period #2, and during the 4-week 
Dose-tapering Period, as applicable.  No study drug tablets are administered during 
Treatment Period #2 or the Dose-tapering Period. 
The oral suspensions for Treatment Period #2 are shown in Table 9 for subjects in each 
of the six treatment groups. 
Table 9. 
Study Medications for the Six Treatment Groups During Treatment 
Period #2 and the Dose-tapering Period 
Treatment Group 
Study Medications 
Oral Suspension 
Treatment Group 1 
2.0 mg/kg vamorolone  
Treatment Group 2 
6.0 mg/kg vamorolone  
Treatment Group 3 
2.0 mg/kg vamorolone  
Treatment Group 4 
6.0 mg/kg vamorolone  
Treatment Group 5 
2.0 mg/kg vamorolone  
Treatment Group 6 
6.0 mg/kg vamorolone  
 


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Vamorolone will be administered as a 1.33% wt/wt suspension for oral dosing at the 
planned dose level of 2.0 mg/kg and as a 4.0% wt/wt suspension for oral dosing at the 
planned dose level of 6.0 mg/kg.  During Treatment Period #2, each subject will receive a 
dose of suspension (0.15 mL/kg of vamorolone [1.33% oral suspension for the 2.0 mg/kg 
dose level or 4.0% oral suspension for the 6.0 mg/kg dose level] each day (see 
Section 3.3).  The dose of suspension study medication will be tapered according to the 
schedule outlined in Section 6.3.7 during the Dose-tapering Period. 
5.2 
Identity of Investigational Product 
ReveraGen BioPharma, Inc. will supply the following investigational study medications: 
Vamorolone 
Active Substance: 
 Vamorolone 
Strength: 
 1.33% wt/wt and 4.0% wt/wt 
Dosage Form: 
 Oral suspension 
Manufacturer: 
 Velesco Pharmaceutical Services 
Prednisone 
Active Substance: 
 Prednisone 
Strength: 
 5 mg 
Dosage Form: 
 Tablet 
Manufacturer: 
 Piramal Healthcare UK Limited 
Placebo to Match Vamorolone 
Dosage Form: 
 Oral suspension 
Manufacturer: 
 Velesco Pharmaceutical Services 
Placebo to Match Prednisone 
Dosage Form: 
 Tablet 
Manufacturer: 
 Piramal Healthcare UK Limited 


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5.3 
Dosage Schedule and Administration of Study Medication 
The site pharmacist or designated site study staff will dispense blinded study medication 
to each subject randomized in the study (see Section 5.8).  Subjects will receive one of 
six study medication combinations depending on their treatment group assignment 
(Table 7).   
To maintain the study blind, matched suspension (vamorolone or placebo) and tablets 
(prednisone or placebo) have been produced (see Section 3.3).  Vamorolone will be 
administered as a suspension for oral dosing (1.33% wt/wt suspension for the 2.0 mg/kg 
dose level or as a 4.0% wt/wt suspension for the 6.0 mg/kg dose level) (see Pharmacy 
Manual for instructions on calculation of suspension dose volume).  Prednisone will be 
administered as 5 mg tablets for oral dosing. 
Each subject will receive a dose of suspension (vamorolone or placebo) and tablets 
(prednisone or placebo) each day during Treatment Period #1, and a dose of suspension 
(vamorolone or placebo) each day during Treatment Period #2.  The number of 
prednisone or matching placebo tablets per dose will depend upon body weight, as 
indicated below (Table 10).  All subjects will receive 0.15 mL/kg per dose of a 
vamorolone or placebo suspension (Table 7).   
Table 10 
Weight Bands for Prednisone or Matching Tablet Dosing 
Band 
Weight 
range in kg 
Weight used 
for 
calculation 
of dose per 
kg 
Prednisone 
dose in mg 
based on 
0.75 mg/kg  
Number tablets of 
prednisone (5 mg) or 
matching placebo per 
dose for given weight 
range 
A 
13-19.9 
13.33 kg 
10 mg 
2 
B 
20-25.9 
20.00 kg 
15 mg 
3 
C 
26-32.9 
26.67 kg 
20 mg 
4 
D 
33-39.9 
33.33 kg 
25 mg 
5 
 
Subjects will receive study medication, administered orally once daily for 48 weeks, from 
Study Day 1 to the Week 48 Visit.  At the end of the 24-week Treatment Period #1, all 


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subjects will be tapered off the tablet study medication over a 4-week Transition Period.  
Those subjects randomized to receive placebo will also undergo tablet dose-tapering to 
maintain the study blind.  At the end of the 20-week Treatment Period #2, subjects who 
will transition off vamorolone treatment at the end of the study will be tapered off 
suspension study medication over a 4-week Dose-tapering Period, prior to discharge from 
the study (see Section 6.3.7). 
Study medication sufficient for 4, 6, or 8 weeks of dosing (plus overage), depending upon 
the dispensing interval, will be dispensed by trained study staff at the Day 1 Visit, just 
prior to dosing, and at Week 6, Week 12, Week 18, Week 24 Follow-up, Week 28, 
Week 34, Week 40, and Week 48 Follow-up.  Each subject’s dose (in mL for suspension 
formulation; in number of tablets for tablet formulation) will be calculated and written on 
the labels of the bottles and blisters to be dispensed at a given visit by trained site staff 
based on the weight of the subject (in kg) recorded at the previous visit: weight at 
Screening will be used to calculate dose of suspension and tablets for drug supply 
dispensed at Day 1; weight at the Week 2 Visit will be used to calculate dose of 
suspension and tablets for drug supply dispensed at Week 6; weight at the Week 6 Visit 
will be used to calculate dose of suspension and tablets for drug supply dispensed at 
Week 12; weight at the Week 12 Visit will be used to calculate dose of suspension and 
tablets for drug supply dispensed at Week 18; weight at the Week 18 Visit will be used to 
calculate dose of suspension and tablets for drug supply dispensed at Week 24 Follow-up 
for the Transition Period; weight at the Week 24 Visit will be used to calculate dose of 
suspension for drug supply dispensed at Week 28; weight at the Week 30 Visit will be 
used to calculate dose of suspension for drug supply dispensed at Week 34; weight at the 
Week 34 Visit will be used to calculate dose of suspension for drug supply dispensed at 
Week 40; and weight at the Week 40 Visit will be used to calculate dose of suspension 
and tablets for drug supply dispensed at the Week 48 Follow-up Visit for the Dose-
tapering Period.  The dispensed study medication bottle(s) and blister(s) will be returned 
to the study site at each subsequent scheduled study visit.  Study medication suspension 
and tablets dispensed at the Day 1 Visit should be brought in with the subject to the 
Week 2 Visit, for Week 2 dosing in-clinic and compliance monitoring; this study 


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medication will be returned to the subject at the end of the Week 2 Visit for continued 
dosing through the Week 6 Visit: new study medication will not be dispensed at the 
Week 2 Visit.  In a similar manner, study medication dispensed at the Week 28 Visit 
should be brought in with the subject to the Week 30 Visit, for Week 30 dosing in-clinic 
and compliance monitoring; this study medication will be returned to the subject at the 
end of the Week 30 Visit for continued dosing through the Week 34 Visit: new study 
medication will not be dispensed at the Week 30 Visit. 
Randomized subjects will receive all doses under the supervision of parents or legal 
guardians or trained study staff.  Study drugs will be administered in the study unit at the 
Day 1, Week 2, Week 12, Week 24, Week 28, Week 30, Week 40, and Week 48 study 
visits; all other doses will be administered at home.  Subjects should receive each dose of 
study medication in the morning and at approximately the same time of day.   
Vamorolone or matching placebo suspension will be administered orally using a 
volumetric syringe supplied by the site.  Following administration of the dose of study 
drug suspension, the syringe will be filled once with water and the water will be 
administered by mouth using the volumetric syringe.  Prednisone or matching placebo 
tablets will be taken either immediately before or immediately after the dose of 
suspension.  The subject will then drink approximately 50 mL (approximately 2 ounces) 
of water to ensure the full dose has been ingested.  The dose of study medication should 
be taken with breakfast, including at least 8 g of fat (approximately 8 ounces [240 mL] of 
full-fat milk or equivalent high-fat food portion).  There are no other food or drink 
restrictions before or after dosing.   
At the Day 1, Week 2, Week 12, Week 24, Week 28, Week 30, Week 40, and Week 48 
study visits, subjects will arrive at the study clinic after having fasted for ≥ 6 hours, and 
will eat breakfast at the study site within 30 minutes prior to administration of the dose of 
study medication; breakfast at the site will include at least 8 g of fat (8 ounces [240 mL] 
of full-fat milk or equivalent high-fat food portion).   
Any missed or incomplete doses of study medication should be recorded in the Subject 
Diary and reported immediately to the site Investigator. 


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5.4 
Rationale for Dose Selection 
Dose levels of the investigational medication were chosen for this study to ensure the 
safety of subjects participating in the study, and to allow demonstration of efficacy and 
PD effects.  The prednisone (active control) dose was selected based on current standard 
of care practice in boys with DMD.   
All doses of study medication will be administered in the morning with breakfast, 
including at least 8 g of fat (approximately 8 ounces [240 mL] of full-fat milk or 
equivalent high-fat food portion).   
Based on the comparison between the PK parameters in DMD boys receiving 0.25 mg/kg 
or 0.75 mg/kg vamorolone with a glass of full-fat milk or equivalent fat-containing food 
and the PK parameters in healthy adult males receiving similar doses of vamorolone 
fasted, it appears that the 2.5-fold increase in exposure observed between the fasted and 
fed conditions in the healthy adult males (Section 1.3.1) is not reproduced in the DMD 
boys (see Section 1.3.2).  The rationale for the lowest vamorolone dose of 2.0 mg/kg/day, 
administered with a glass of full-fat milk or equivalent fat-containing food is as follows: 
A starting dose of 2.0 mg/kg/day with a glass of milk is approximately 10% of the 
highest safe dose tested in adults (20.0 mg/kg/day fasted). 
The highest vamorolone dose to be administered, 6.0 mg/kg/day, will similarly be 
administered with a glass of full-fat milk or equivalent fat-containing food.  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 to 7 year-old children is approximately 
30% 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 either of the planned dose levels.  Also based on the Phase I data, 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.   


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Vamorolone at doses of 0.25 mg/kg/day, 0.75 mg/kg/day, 2.0 mg/kg/day and 
6.0 mg/kg/day has been demonstrated to be safe and well-tolerated in a 2-week Phase IIa 
study (VBP15-002) in 4 to <7 years DMD boys.  There has been a total of 11 SAEs in the 
vamorolone program to date: a total of 4 SAEs in the VBP15-003 study, a total of 3 SAEs 
in the VBP15-LTE study, a total of 3 SAEs in the VBP15-004 study, and 1 SAE in the 
VBP15-EAP program.  There have been two SAEs of pneumonia in two different 
subjects (both subjects receiving vamorolone 0.75 mg/kg/day); one SAE of bilateral 
testicular torsion and one SAE of hypoxia in the same subject receiving 6.0 mg/kg/day; 
one SAE of influenza associated dehydration in a subject receiving 6.0 mg/kg/day; two 
SAEs of acute myoglobulinemia in the same subject receiving 6.0 mg/kg/day; one SAE 
of viral gastroenteritis with secondary dehydration in a subject receiving blinded study 
drug; one SAE of asthma exacerbation in the setting of respiratory syncytial virus and 
bronchiolitis in a subject receiving vamorolone at either 2.0 mg/kg/day or 6.0 mg/kg/day; 
one SAE of perforated appendicitis occurring with 30 days after the subject completed 
the VBP15-004 study, and one SAE of viral gastroenteritis requiring hospitalization for 
hydration.  Each of these SAEs was considered unrelated to study drug, and none of them 
resulted in discontinuation from the study.  One subject receiving vamorolone 6.0 mg/kg 
in the Phase II extension study (VBP15-003) who had an incidental early morning 
cortisol drawn following an AE of presyncope had evidence of adrenal suppression.  In 
the VBP15-003 study, after 24 weeks of treatment, 0 of 8 tested participants 
(0.25 mg/kg/day), 1 of 12 (8.3%) tested participants (0.75 mg/kg/day), 5 of 12 (41.7%) 
tested participants (2.0 mg/kg/day), and 8 of 9 (88.9%) tested participants 
(6.0 mg/kg/day) had a depressed morning cortisol (<3.6 μg/dL [100 nM]) consistent with 
chronic adrenal suppression.29  Thus, based on the available data in the Phase I and Phase 
II studies regarding the safety signal of suppression of the adrenal axis, the possibility of 
adrenal suppression is present in subjects at the 2.0 and 6.0 mg/kg/day dose levels.    
The dose of prednisone has been selected according to the Care Recommendation for 
DMD (daily prednisone 0.75 mg/kg/day).  The weight-dose bands (Table 10) have been 
selected to ensure that subjects will not be overdosed in view of the potential side effects.  


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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 incomplete 
or missed doses by completion of a diary by the subject’s parent or guardian.  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 the days of the Day 1, Week 2, Week 12, and Week 24 Visits 
(Treatment Period #1), Week 28 (Transition Period), and Week 30, Week 40, and 
Week 48 (Treatment Period #2) will be administered at the participating study site by a 
trained investigational staff member.  All incomplete or missed doses are to be 
documented in the source document and on the appropriate eCRF page.  The volume of 
unused study medication remaining in each bottle returned, as well as the number of 
unused tablets, will be documented in the source documents and on the appropriate eCRF 
page. 
5.6 
Study Drug Dose Interruption or Discontinuation 
Subjects whose study medication is interrupted should continue to follow the original 
schedule and timing of study visits.  Study staff should contact the Study Chair or 
Medical Monitor at the time of dose interruption for any additional instructions for 
visit-specific assessments.  If the study medication is interrupted during the scheduled 
Week 24 F/U or Week 48 F/U Visit, the scheduled ACTH Stimulation Test should be 
performed, but the site should contact the Study Chair or Medical Monitor prior to the 
Week 24 or Week 48 Visit to discuss whether the dose of hydrocortisone scheduled for 
one day prior to the ACTH Stimulation Test should be given. 
In the event any clinical observation suggests an intolerability of an individual subject to 
the study medication, in the opinion of the Investigator, the case should be discussed with 
the Study Chair and the Independent Medical Monitor within 24 hours and study drug 
discontinuation should be considered.  In view of the potential effect of the study drugs 


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on adrenal glands, the study drugs cannot be discontinued suddenly.  In case study drug 
needs to be discontinued, for whatever reason, the dose tapering process described for the 
end of the treatment period should be followed.  If a subject discontinues study drug due 
to intolerability, the subject will be withdrawn from the study.  Study drug 
discontinuation due to intolerability will not usually require unblinding (see Section 3.4).  
The subject should return to the study site for completion of Week 24 assessments and 
the Week 24 Follow-up Visit ACTH Stimulation Test at the time of early withdrawal (if 
withdrawal is prior to the Week 24 Visit), or Week 48 assessments and the Week 48 
Follow-up Visit ACTH Stimulation Test (if withdrawal is after Week 24 and prior to the 
Week 48 Visit), prior to participation in the Dose-tapering Period.  Any AE still ongoing 
at the time of study drug discontinuation will be monitored until it has returned to 
baseline status, stabilized, or the Investigator, Study Chair, Medical Monitor and Sponsor 
agree that follow-up is no longer needed.  
5.7 
Prior and Concomitant Medications and Therapies 
5.7.1 Prior Therapy 
All medications (prescription and over-the-counter [OTC]) taken within 3 months prior to 
the Screening Visit through Baseline Day -1 (until just prior to administration of the first 
dose of study medication) will be captured as prior medications (Medication History) in 
the source document and 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.   
5.7.2 Concomitant Therapies 
Any medications that are taken after administration of the first dose of study medication 
will be recorded as concomitant medications on the appropriate eCRF page.  Subject 
diaries will be provided to subjects to record any concomitant medication changes during 
the study (see Section 7.4.6).  
All medications (prescription and OTC) taken during the study must be recorded in the 
source documents and in the eCRF, including the name of the medication, dosage and 
regimen, reason for therapy, and treatment start and stop dates.  Furthermore, each 


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change in concomitant medication (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, 
reason for therapy (i.e., DMD or non-DMD), and dates of therapy will also be recorded.  
Site personnel will review the information with the subject and/or his parent or guardian, 
if applicable, for completeness and accuracy at each study visit. 
5.7.3 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 glucocorticoids or other immunosuppressive agents.  Subjects who have 
received prior treatment with immunosuppressive agents are ineligible for study 
entry.  [Notes: Inhaled and/or topical glucocorticoids are permitted but must be 
administered at stable dose beginning at least 4 weeks prior to first dose of study 
medication, and are anticipated to be used at the stable dose regimen for the 
duration of the study; past transient use of oral or inhaled glucocorticoids or other 
oral immunosuppressive agents for no longer than 1 month cumulative, with last 
use at least 3 months (or last use at least one month prior for inhaled 
glucocorticoids) prior to first dose of study medication, will be considered for 
eligibility on a case-by-case basis.] 
• 
Idebenone: use must be discontinued at least 4 weeks prior to the first dose of 
study medication 
• 
Live attenuated vaccines: use must be avoided within 14 days prior to first dose of 
study medication and for the duration of participation in the study 


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Protocol No.: VBP15-004 
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• 
Any investigational medications other than vamorolone: use must be discontinued 
at least 3 months prior to the first dose of study medication 
• 
Other medications indicated for the treatment of DMD, including Exondys 51 and 
Translarna: use must be discontinued at least 3 months prior to the first dose of 
study medication. 
• 
Any approved medications or herbal remedies which can impact strength and 
function (including, but not limited to, Co-enzyme Q10, creatine): use must be 
discontinued at least 4 weeks prior to the first dose of study medication. 
In addition, vamorolone should be used with caution with any drug metabolized by 
cytochrome P450 3A4 (CYP3A4). 
The Investigator should contact the Study Chair and Medical Monitor concerning 
individual medications or therapies not listed that may be of concern. 
5.7.4 Permitted Therapies 
Every effort should be made NOT to start any prescription or OTC medications during 
the study.  Concomitant medications should be maintained on 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 documents and in the eCRF.  
5.7.5 Hydrocortisone 
All subjects will be given a single dose of hydrocortisone (5 mg or 10 mg) 24 hours after 
the final dose of Treatment Period #1 study medication at the Week 24 Visit, and 
24 hours after the final dose of Treatment Period #2 study medication at the Week 48 
Visit.  The hydrocortisone dose will be approximately 8 mg/m2, rounded up to either 5 
mg or 10 mg; subjects will be provided with either a single 5 mg or 10 mg hydrocortisone 
tablet which will be dispensed by the site staff at the Week 24 and Week 48 Visits. 
In addition, all subjects should be covered with “stress dosing” of hydrocortisone (or 
prednisone) during times of illness, injury, or surgery (see Section 7.2.7). 


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28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
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5.7.6 Vitamin D 
Serum Vitamin D levels will be measured at Screening and at the Weeks 12, 24, 40, and 
48 Visits.  Vitamin D insufficiency and deficiency (serum 25[OH] D concentration less 
than 20 ng/mL or less than 50 nmol/L) will be treated with high doses of Vitamin D 
supplement according to local site guidelines.  Vitamin D supplements will be recorded 
in the source document and in the eCRF.  
5.8 
Study Medication Management 
5.8.1 Packaging and Labeling of Study Medication 
When all entry criteria are met, and at least 10 days prior to the Baseline Day -1 Visit, 
subjects will be randomized to treatment via the IXRS system.  Subject-specific 
suspension and tablet study drug supplies sufficient for the first six weeks of Treatment 
Period #1 will be packaged, labeled (with MED ID number and other protocol-specific 
information) and couriered to the pharmacy at the recruiting site prior to the Baseline 
Visit for the subject.  
Investigational medication suspension and matching placebo suspension will be packaged 
in sterile 120 mL (4 oz) amber bottles with a 100 mL fill volume with child-resistant cap 
with a 24 mm bottle press-in adapter.  Bottles are filled with 110 mL of suspension in 
order to guarantee a delivery of 100 mL.   
Bottles of investigational medication suspension will contain either 1.33 grams of 
vamorolone/100 mL (1.33% orange-flavored suspension) or 4.0 grams of 
vamorolone/100 mL (4.0% orange-flavored suspension).  The matching placebo 
suspension will be identical in appearance and taste to the vamorolone suspensions.  The 
volume per dose to be administered to each subject depends on the subject’s weight (in 
kg) recorded at the visit prior to each study drug dispensing visit.  Each subject will 
receive a volume of 0.15 mL/kg of a vamorolone suspension or matching placebo 
suspension (Table 7).  Instructions for the calculation of each dose of liquid formulation 
are given in the Pharmacy Manual. 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
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Prednisone 5 mg tablets and matching placebo will be dispensed in blister packs, each 
containing 15 tablets.  The number of tablets to be administered per dose to each subject 
depends on the subject body weight calculated at the visit prior to each study drug 
dispensing visit (Table 10).   
Drug supplies will be labeled with the Sponsor name, protocol number, lot number, 
expiration or retest date, and other appropriate study information.  Carton, bottle, and 
blister pack labels will be written in accordance with all applicable laws, guidance and 
directives of the jurisdiction where the study is being conducted.  
Trained site staff will write the dose in mL (suspension) and number of tablets (tablets) 
on the bottle and blister pack labels, respectively, prior to bottle and blister pack 
dispensing to subjects. 
At the Screening Visit, a test packet containing placebo tablets will be provided by the 
site investigator to confirm the subject’s ability to swallow tablets.  The test of 
swallowing ability will take place at the Screening Visit.  At the beginning of the trial, the 
clinical trials supply company will provide each site with sufficient test packets for their 
anticipated recruitment numbers.  These test packets will be stored in a locked cupboard, 
at ambient room temperature. 
Study medication will be dispensed to the subject’s parent or legal guardian for 
Treatment Period #1 dosing at the Day 1 Visit and at the Week 6, Week 12 and Week 18 
Visits.  At the Week 24 Follow-up Visit, a 4-week supply of study medication for the 
Week 25 to Week 28 Transition Period will be dispensed.  Study medication will be 
dispensed to the subject’s parent or legal guardian for Treatment Period #2 dosing at the 
Week 28, Week 34, and Week 40 Visits.  At the Week 48 Follow-up Visit, study 
medication for the Dose-tapering Period will be dispensed.  Dispensed bottles and unused 
tablets of study medication will be returned at each subsequent study visit, prior to 
dispensing bottle(s)/blister pack(s) for the next dispensing interval (see Section 5.3).  
Each study medication bottle and blister pack may be used for a single subject only.   


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
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Clinical supplies dispensed by the study site staff and ready for administration to subjects 
will be labeled with the dispense date, protocol number, MED ID number, and volume 
(suspension) or number of tablets to be administered per dose.   
5.8.2 Storage of Study Medication 
All Clinical Trial Materials (CTM) for use in the trial must be stored in a locked 
container/cabinet free from environmental extremes, under the responsibility of the 
institutional pharmacist or Principal Investigator.  Study medication suspensions should 
be stored at refrigerated temperature (2oC – 8oC; 36oF – 46oF).  Excursions to ambient 
temperature are allowed (see Pharmacy Manual for details).  Study medication tablets 
will be stored in a locked cupboard, at ambient room temperature. 
Access to study medication stored at the study site must be limited to authorized clinic 
personnel. 
5.8.3 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.   
When all entry criteria are met, at least 10 days prior to the Baseline Visit, subjects will 
be randomized to treatment via the IXRS system.  Subject-specific suspension and tablet 
drug supplies will be packaged, labeled (with MED ID number and other 
protocol-specific information) and couriered to the pharmacy at the study site prior to the 
Baseline Visit for the subject.  At the Day 1 Visit, the trained site staff will record the 
volume in mL per suspension dose (bottles) and number of tablets per dose (blister packs) 
on the bottle and blister pack labels, respectively.  Labeled study drug supplies sufficient 
to last until the Week 6 Visit will be dispensed to each subject.  The first dose of study 
medication will be administered in clinic on Study Day 1.  The initial drug supply will be 
sufficient to allow for the Week 6 Visit to occur on the latest date permissible within the 
protocol-specified visit window (6 weeks ± 3 days).  No additional study drug supplies 
will be dispensed at the Week 2 Visit. 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
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Prior to the subsequent study drug dispensing visits (i.e., Week 6, Week 12, Week 18, 
Week 24 Follow-up, Week 28, Week 34, Week 40, Week 48 Follow-up), additional study 
drug supplies will be ordered using the IXRS system.  Study drug dispensed at the 
Week 28, Week 34, Week 40, and Week 48 Follow-up Visits for dosing during 
Treatment Period #2 and the Dose-tapering Period will consist of liquid suspension only 
(no tablets).  The new subject-specific drug supply will be packaged, labeled (as 
described above) and couriered to the site.  Study drug will be ordered at least 10 days 
prior to the next scheduled study drug dispensing visit to allow time for the new supplies 
to be shipped to the site in time for the next scheduled dispensing visit.   
It is essential to this study that all CTM be accounted for during the study period.  All 
unused (i.e., undispensed; dispensed and returned) study medication will be retained at 
the study site for reconciliation by the Sponsor's study monitors (or designees) during 
routine monitoring visits.  Final disposition of all unused CTM will be coordinated by the 
Sponsor's study monitors (or designees) throughout and at the end of the study (see 
Section 5.8.4).   
Clinical trial material must be dispensed and administered according to the procedures 
described in this protocol.  Only subjects randomized in the study may receive study 
medication, in accordance with all applicable regulatory requirements.  Only authorized 
study personnel may supply CTM.  Authorized study personnel refers to the Investigator 
(or designee) and hospital pharmacists, in accordance with all applicable regulatory 
requirements and the Site Signature Log/Delegation of Authority.  Only authorized study 
personnel or the subject’s parent or legal guardian may administer CTM. 
5.8.4 Study Medication Accountability 
The 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 Subject ID number of the subject to whom the study drug was dispensed 
• 
The MED ID number of the dispensed kit 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
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ReveraGen BioPharma, Inc. – CONFIDENTIAL 
• 
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 Study Monitor at 
every monitoring visit.  Unused medication will be returned to ReveraGen Inc. or its 
designee or destroyed on site at the end of the study or at a specific time in agreement 
with the Sponsor, as coordinated between the site and ReveraGen or its designee.  The 
completed Drug Dispensing Log and Drug Return Record(s) will be returned to 
ReveraGen Inc or its designee.  The Investigator’s copy of the Drug Return Record(s) 
must accurately document the return of all study drug supplies to ReveraGen Inc. or its 
designee. 
5.9 
Procedures for Assigning Subject Study Numbers 
All data for all subjects whose parent(s) or guardian(s) sign the Informed Consent Form 
(ICF) for the study will be identified using the unique subject identification number.  
Subjects are considered to be enrolled in the study when the parent(s) or guardian(s) signs 
the study-specific ICF at Screening.  The Site Investigator will keep a record relating the 
names of the subjects to their ID numbers (subject identification log) to permit efficient 
verification of data subject files, when required.  A subject enrollment log will include 
the dates of subject enrollment and completion/termination.   
6 
STUDY SCHEDULE 
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:  The up to 32-day interval, from subject’s 
parent or guardian signing of the Informed Consent/HIPAA authorization until 
completion of all designated screening procedures, 24 hours prior to the first dose 
of study medication.  All screening procedures must be completed by Day -11.  
Subjects meeting all eligibility criteria will be randomized by Day -11, at least 
10 days prior to the Baseline Day -1 Visit. 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
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• Pretreatment Baseline Period:  The 24-hour period immediately prior to 
administration of the first dose of study medication (Baseline Day -1). 
• Treatment Period #1:  The 24-week interval starting with administration of the 
first dose of study medication on Study Day 1 and continuing through the time of 
the Week 24 Follow-up Visit.  Treatment Period #1 includes administration of the 
final dose of Treatment Period #1 study medication at the Week 24 Visit, and 
ACTH Stimulation testing at the Week 24 Follow-up Visit, 48 ± 3 hours after the 
final dose of Treatment Period #1 study medication.   
• Transition Period: The 4-week interval following the end of the 24-week 
Treatment Period #1 during which subjects will continue on their suspension 
study medication at the same dose they received during the Treatment Period #1 
and have their tablet study medication dose tapered to zero (0) tablets/day (see 
Section 6.3.5).  Once subjects have completed all study assessments for the 
Transition Period, they will enter Treatment Period #2.  
• Treatment Period #2:  The 20-week interval starting with administration of the 
first dose of Treatment Period #2 study medication on the day after the Week 28 
Visit (Week 28 + 1 day) and continuing through the time of the Week 48 
Follow-up Visit.  Treatment Period #2 includes administration of the final dose of 
Treatment Period #2 study medication at the Week 48 Visit, and ACTH 
Stimulation testing at the Week 48 Follow-up Visit, 48 ± 3 hours after the final 
dose of Treatment Period #2 study medication.  Subjects who will not participate 
in the Dose-tapering Period will be discharged from the study following 
completion of the Week 48 assessments and the ACTH Stimulation Test at the 
Week 48 Follow-up Visit.   
• Dose-tapering Period: The 4-week interval following the end of the 20-week 
Treatment Period #2 during which subjects will have their suspension study 
medication dose tapered to 0 mg/kg/day (see Section 6.3.7).  Once subjects have 
completed the Dose-tapering Period, they will be discharged from the study 
following completion of all final Dose-tapering Period assessments.   


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
IND 118,942 
 
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The procedures to be completed at each visit during each study period are presented in 
the Schedule of Study Activities in Table 11 and in the sections that follow.  (Note: In 
Table 11, each visit with the acceptable time window around the planned visit date, 
where applicable, is provided.)  Detailed descriptions of the assessments and the 
definitions of study endpoints are provided in Section 7 and Section 2, respectively.  Any 
deviation from study procedures should be noted in the source documents and in the 
Clinical Trial Management Software (CTMS), and significant deviations should be 
reported immediately to the Sponsor.   
Overall, up to approximately 57 weeks are allocated for each subject to complete the 
study, including a 32-day Pretreatment Screening Period, a one-day Pretreatment 
Baseline Period, a 24-week Treatment Period #1, a 4-week Transition Period, a 20-week 
Treatment Period #2, plus a 4-week Dose-Tapering Period, as applicable.  Upon the 
completion of the study, subjects may have the option to enroll in an additional 
vamorolone study or general access program. 
Subjects electing to enroll directly into an additional vamorolone study or general access 
program to continue vamorolone therapy will be discharged from the VBP15-004 study 
following completion of all final Week 48 assessments and ACTH Stimulation testing at 
the Week 48 Follow-up Visit, and will be enrolled in the additional vamorolone study or 
general access program (separate written protocol and ICF).   
Subjects completing the VBP15-004 study and enrolling directly into the additional 
vamorolone study or general access program to continue vamorolone treatment do not 
need to dose taper in VBP15-004. 


Vamorolone 
28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
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Table 11 
Schedule of Study Activities 
 
Pretreatment 
Period 
Treatment Period #1 
Transition 
Period 
Treatment Period #2 
Dose-tapering 
Period 
SCR 
BL 
Day 
Week 
Study Day or Week/Visit 
-33 
to -2a 
-1b 
1c 
2 
(±1d)d 
6 
(±3d)d 
12 
(±1w)d 
18 
(±1w)d 
24e 
(±1w)d 
24 
(F/U)e 
26 
28f 
(±1d)d 28+1d 
30 
(±1d)d 
34 
(±3d)d 
40 
(±1w)d 
48g 
(±1w)d 
48  
F/Ug 
50 
52h 
(±1d)d 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollmenti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
 
X 
Cushingoid features 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
 
X 
Height 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Weight 
X 
X 
 
X 
X 
X 
Xl 
X 
 
 
X 
 
X 
X 
Xl 
X 
 
 
X 
Vital signsm 
X 
X 
Xn 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
X 
Blood for clinical labso 
X 
 
Xp 
Xp 
X 
Xp 
X 
Xp 
 
 
Xp 
 
Xp 
X 
Xp 
Xp 
 
 
Xp 
Blood for HbA1co 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Blood for vitamin Do 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Confirmation of varicella 
immunity 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisq 
X 
 
Xp 
Xp 
X 
Xp 
X 
Xp 
 
 
Xp 
 
Xp 
X 
Xp 
Xp 
 
 
Xp 
Blood for serum PD 
biomarker panelr,s 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
X 
Fasting blood for insulin, 
glucoses 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
X 
Blood for DNA Testing 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ACTH Stimulation Test 
X 
 
 
 
 
 
 
 
Xt 
 
 
 
 
 
 
 
Xt 
 
 
Blood for Plasma PK 
 
 
 
 
 
 
 
 
 
 
 
 
Xu 
 
 
 
 
 
 
12-lead ECGv 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
2D-echocardiogram 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 


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Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
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Pretreatment 
Period 
Treatment Period #1 
Transition 
Period 
Treatment Period #2 
Dose-tapering 
Period 
SCR 
BL 
Day 
Week 
Study Day or Week/Visit 
-33 
to -2a 
-1b 
1c 
2 
(±1d)d 
6 
(±3d)d 
12 
(±1w)d 
18 
(±1w)d 
24e 
(±1w)d 
24 
(F/U)e 
26 
28f 
(±1d)d 28+1d 
30 
(±1d)d 
34 
(±3d)d 
40 
(±1w)d 
48g 
(±1w)d 
48  
F/Ug 
50 
52h 
(±1d)d 
Eye examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
DXA scan 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Spine X-ray 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Fracture Questionnaire 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Dispense study medication 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
Return study medication/ 
compliance monitoring 
 
 
 
Xw 
X 
X 
X 
X 
 
 
X 
 
Xw 
X 
X 
X 
 
 
X 
Study medication dosingx 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Study medication dose 
tapering 
 
 
 
 
 
 
 
 
Xy 
 
X 
 
 
 
 
 
X 
 
X 
Telephone call to subjectz 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Time to Stand Test 
(TTSTAND) 
X 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
Time to Climb Test 
(TTCLIMB) 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Time to Run/Walk Test 
(TTRW) 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
NSAAaa 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Myometry (elbow flexors, 
knee extensors) 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Six-minute Walk Test 
(6MWT) 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Range of Motion (ROM) - 
ankles 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Pediatric Outcomes Data 
Collection Instrument 
(PODCI) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Treatment Satisfaction 
Questionnaire (TSQM) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 


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28 August 2020 
Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
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Pretreatment 
Period 
Treatment Period #1 
Transition 
Period 
Treatment Period #2 
Dose-tapering 
Period 
SCR 
BL 
Day 
Week 
Study Day or Week/Visit 
-33 
to -2a 
-1b 
1c 
2 
(±1d)d 
6 
(±3d)d 
12 
(±1w)d 
18 
(±1w)d 
24e 
(±1w)d 
24 
(F/U)e 
26 
28f 
(±1d)d 28+1d 
30 
(±1d)d 
34 
(±3d)d 
40 
(±1w)d 
48g 
(±1w)d 
48  
F/Ug 
50 
52h 
(±1d)d 
PARS III 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Ease of Study Medication 
Administration 
Assessmentbb 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
 
Blindedness Assessment 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense subject diariescc 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
Return subject diaries 
 
 
 
X 
X 
X 
X 
X 
Xdd 
 
X 
 
X 
X 
X 
X 
Xee 
 
X 
AE/SAE recordingff 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xgg 
Concomitant medications 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Discharge from study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xhh 
 
Xii 
BL = Baseline; d = day(s); F/U = Follow-up; SCR = Screening; w = week.  
a. 
The Pretreatment Screening Period spans Day -33 through Day -2, but all screening procedures must be completed by Day -11.  Subjects meeting all eligibility criteria will be randomized by 
Day -11, at least 10 days prior to the Baseline Day -1 Visit. 
b. 
Baseline Day -1, within 24 hours prior to administration of the first dose of study drug.   
c. 
Treatment Day 1 begins at the time of administration of the first dose of study medication in the clinic. 
d. 
Time windows around the Week 2, Week 6, Week 12, Week 18, and Week 24 Visits are allowances from date of Day 1 Visit.  Time window around the Week 28 Visit is allowance from 
date of Week 24 F/U Visit.  Time windows around the Week 30, Week 34, Week 40, and Week 48 Visits are allowances from date of Week 28+1d Visit.  Time window around the Week 52 
Visit is allowance from date of Week 48 F/U Visit. 
e. 
Subjects who prematurely discontinue from the study prior to Week 24 should complete the Week 24 assessments and the Week 24 Follow-up Visit ACTH Stimulation Test at the time of 
early withdrawal and undergo Early Discontinuation Dose-tapering, where possible (see Section 6.4.1 and Section 7.2.7).  The Week 24 Follow-up Visit must occur to allow the ACTH 
Stimulation Test to be performed 48 ± 3 hours after the final dose of Treatment Period #1 study medication.  
f. 
Subjects who prematurely discontinue from the study after Week 24 but prior to Week 28 should complete the Week 28 assessments, and undergo Early Discontinuation Dose-tapering, 
where possible (see Section 6.4.2).   
g. 
Subjects who prematurely discontinue from the study after Week 28 but prior to Week 48 should complete the Week 48 assessments and the Week 48 Follow-up Visit ACTH Stimulation 
Test at the time of early withdrawal and undergo Dose-tapering, where possible (see Section 6.4.3 and Section 7.2.7).  The Week 48 Follow-up Visit must occur to allow the ACTH 
Stimulation Test to be performed 48 ± 3 hours after the final dose of Treatment Period #2 study medication.  
h. 
Subjects will have one study site visit during the Dose-tapering Period, at one week after the dose of liquid formulation has been discontinued (Week 52) (see Section 6.3.7).  
i. 
Subjects are considered to be enrolled in the study at the time written informed consent is obtained. 


Vamorolone 
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Amendment #4 
Document No. VBP15-004-A4 (Version 1.4) 
Protocol No.: VBP15-004 
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j. 
Study eligibility should be rechecked and confirmed at Baseline Day -1 Visit. 
k. 
Randomization occurs by Interactive Voice/Web Response System (IXRS) after subjects are confirmed to have met all study entry criteria, at least 10 days prior to the Baseline Day -1 Visit. 
l. 
Weight recorded at the Week 18 Visit and the Week 40 Visit will be used to calculate doses for study drug dispensed at the Week 24 Follow-up and Week 48 Follow-up Visits, respectively. 
m. Sitting blood pressure, body temperature, respiratory rate, and heart rate. 
n. 
Vital signs recorded prior to administration of the first dose of study drug at the Day 1 Visit. 
o. 
Blood for hematology, chemistry, and lipids, including HbA1c and Vitamin D where applicable. 
p. 
Blood samples (collected after subjects have fasted for ≥ 6 hours) and urine collected at scheduled visit, and prior to dose of study drug where applicable.   
q. 
Urinalysis by dipstick and microscopic analysis. 
r. 
Blood collected for PD biomarkers includes secondary safety outcomes (morning cortisol, osteocalcin, CTX1, P1NP), and exploratory safety and efficacy PD biomarkers.  
s. 
Blood samples for PD biomarkers and fasting glucose and insulin determination will be collected after subjects have fasted for ≥ 6 hours, prior to the daily dose of study medication where 
applicable. 
t. 
Subjects will return to the study site for the Week 24 Follow-up Visit for an ACTH Stimulation Test 48 hours ± 3 hours after administration of the final dose of Treatment Period #1 study 
medication, and for the Week 48 Follow-up Visit for an ACTH Stimulation Test 48 hours ± 3 hours after administration of the final dose of Treatment Period #2 study medication (see 
Section 7.2.7). 
u. 
Blood sample for population PK analysis will be collected 2 hours after administration of the daily dose of study medication. 
v. 
12-lead ECG recorded after subject has rested quietly in a supine position for at least 5 minutes. 
w. Study medication brought by subjects to the Week 2 Visit and Week 30 Visit for dosing and compliance assessment will be redispensed to subjects at the end of the visit. 
x. 
The dose of study medication on the days of the Day 1, Week 2, Week 12, Week 24, Week 28, Week 30, Week 40, and Week 48 Visits will be administered after 1) fasting blood draws; and 
2) breakfast provided by the study site.  All other doses will be taken at home.  See Section 6.3.3 for other Day 1 pre-dose safety assessments. 
y. 
Doses of tablet study drug will be tapered and suspension study drug will be continued, during Weeks 24-28.  
z. 
Site study staff will contact the parent(s)/guardian(s) by telephone at Weeks 26 and 50 to ensure that the study drug tapering is proceeding according to protocol, to assess potential signs or 
symptoms indicative of adrenal suppression, and to address any questions the parent(s)/guardian(s) may have.  
aa. North Star Ambulatory Assessment; includes the Time to Stand Test (TTSTAND). 
bb. Ease of Study Medication Administration assessed at the Weeks 2, 12, and 24, 30, 40, and 48 Visits.  
cc. Subject diaries used to record any changes in concomitant medications taken, any AEs experienced during the study, and any incomplete or missed doses of study medication. 
dd. Subject diaries dispensed at the Week 24 Visit will be returned and redispensed at the Week 24 F/U Visit; final return will occur at the Week 28 Visit. 
ee. Subject diaries dispensed at the Week 48 Visit will be returned at the Week 48 F/U Visit, and will be redispensed to subjects participating in the Dose-tapering Period for final return at the Week 
52 Visit. 
ff. All AEs and SAEs must be recorded in the source documents and eCRF from the date of the subject’s written informed consent until the final Week 52 Visit or the subject’s participation in the 
study is completed (SAEs through 30 days after final study drug dose).  Ongoing AEs will be followed to resolution, stabilization, or until such time the Investigator agrees follow-up is not 
necessary. 
gg. For subjects who do not continue to receive vamorolone through an additional vamorolone study or general access program, site staff will make a phone call to the home 31-35 days after the final 
dose of study medication in VBP15-004 Dose-tapering Period to confirm the final SAE status of the subject. 


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hh. Subjects who elect to continue vamorolone therapy by enrolling directly into an additional vamorolone study or general access program may be discharged from the study following completion 
of all final Week 48 assessments, including the Week 48 Follow-up Visit ACTH Stimulation Test. 
ii. 
Subjects who participate in the Dose-tapering Period may be discharged from the study following completion of all final Dose-Tapering Visit assessments (Week 52) (see Section 6.3.7). 
 


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6.2 
Informed Consent and Assent Procedures  
Subjects are considered to be enrolled in the study at the time written informed consent is 
obtained. 
The parent(s) or guardian(s) of all subjects are to give informed consent in accordance 
within the Declaration of Helsinki, US 21 Code of Federal Regulations (CFR) Part 50, 
International Conference on Harmonisation [ICH] guidelines on GCP and all applicable 
laws, guidances, and directives of the jurisdiction where the study is being conducted. 
The parent(s) or guardian(s) of subjects who choose to enroll in this study will give 
written informed consent at the Screening Visit, Day -33 to Day -11.  The Investigator (or 
designated staff) will obtain the written informed consent from the subject’s parent(s) or 
guardian(s) prior to any study-specific procedures.  Each subject’s parent(s) or 
guardian(s) will receive an explanation of the nature and purposes of the study from the 
Investigator or designee.  Time will be given to the parent(s)/guardian(s) to ask questions 
and make their decision on whether they would like for their child to participate.  The 
Investigator or designee will ensure the study is appropriate for the subject.  Reasons for 
exclusion will be documented for subjects found ineligible during the Pretreatment 
Period.  The subject’s parent(s) or guardian(s) will be asked if s/he understands that the 
study is for research purposes only and that it may not provide any therapeutic benefit to 
the subject.  Each subject’s parent(s) or guardian(s) will be asked if s/he understands that 
the subject is free to withdraw from the study at any time without prejudice.  Each 
subject’s parent(s) or guardian(s) will be required to sign a study ICF (and HIPAA 
authorization, if applicable) before any procedures are performed for the study; both 
parents or guardians will sign the ICF in jurisdictions where this is required.   
If applicable, the assent of the child himself will also be obtained, if possible in writing 
per individual where a child is intellectually capable of assenting (and in accordance with 
local regulations), and with the permission of the parent(s)/guardian(s). 
The Investigator or designee will obtain written informed consent from each subject’s 
parent(s) or guardian(s) prior to subject’s participation in the study using ICFs approved 
by the appropriate IRB/IEC at each site.  Consent must be obtained in accordance with 


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the principles outlined in the current version of the Declaration of Helsinki.  Informed 
Consent Forms must be dated and signed by the Investigator or designee and the subject’s 
legal representative(s) and the original signed consent form must be kept by the 
Investigator in the study subject’s file.  “Legal representative” means an individual whom 
a 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 Monitor will ensure that the ICF has been signed by the subject’s 
legal representative(s).  The study subject’s legal representative(s) will receive a copy of 
the signed consent form. 
6.2.1 HIPAA and Protected Health Information  
In the applicable countries, during the informed consent procedure, the Investigator or 
designee will review the elements of the HIPAA and Protected Health Information (PHI) 
with each subject’s parent(s) or guardian(s), and each subject’s parent or guardian will 
confirm that s/he understands HIPAA authorization and PHI.  The Investigator (or 
designated staff) will obtain HIPAA authorization from the subject’s parent(s) or 
guardian(s) on the appropriate IRB/IEC-approved form at each site, prior to any 
study-related procedures.  
6.3 
Visit Schedule and Procedures 
During the study, there will be a total of up to 16 study site visits: Pretreatment Screening 
Visit (screening procedures can be performed on more than one day if necessary); 
Pretreatment Baseline Day -1 Visit; Treatment Period #1 Day 1 and Weeks 2, 6, 12, 18, 
and 24 Visits, and Week 24 Follow-up Visit; Transition Period Week 28 Visit; Treatment 
Period #2 Weeks 30, 34, 40, 48 Visits, and Week 48 Follow-up Visit; and final Dose-
tapering Period Week 52 Visit.  In addition, to facilitate completion of all required 
Week 24 and Week 48 assessments, some of the assessments scheduled for the Week 24 
and Week 48 Visits may be completed on the day following the Week 24 (Week 48) dose 
of study medication, the day of the Week 24 (Week 48) Follow-up Visit, or in some cases 
up to 7 days following the date of the Week 24 (Week 48) dose of study medication, if 
needed (see Section 6.3.4 and Section 6.3.6). 


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Each subject will receive the double-blind study medication at stable daily dose for an 
initial period of 24 weeks (Treatment Period #1).  Following completion of the 24-week 
Treatment Period #1, all subjects will continue to receive the suspension formulation 
(vamorolone or matching placebo) at the same dose they received during the Treatment 
Period #1, while tapering the number of tablets (prednisone or matching placebo) during 
the 4-week double-blind Transition Period, and will return to the study site for study 
assessments at the end of the Transition Period (Week 28), prior to receiving the first 
dose of study medication for Treatment Period #2 at home on Week 28 + 1 day.   
Each subject will receive double-blind study medication at stable daily dose for a period 
of 20 weeks (Treatment Period #2).  Following completion of the 20-week Treatment 
Period #2, all subjects who will not be continuing to receive vamorolone in an additional 
vamorolone study or general access program (separate protocol) will taper their liquid 
formulation study medication during the 4-week double-blind Dose-Tapering Period, and 
will return to the study site for study assessments at the end of the Dose-Tapering Period 
(Week 52).  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 -33 to -2) 
The Investigator or study staff will discuss with each subject and the subject’s parent(s) 
or legal guardian(s) 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) for confirmation that the subject meets the DMD diagnostic 
inclusion criteria.   
Following the signing of the written ICF, subjects will be considered to be enrolled in the 
study, and 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 


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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.  The Coordinating Center will not collect names or other 
identifiers except dates (diagnosis, study visits), date of birth, and the subject study 
number. 
Subjects will undergo the procedures in the bulleted list below during the Screening 
Period.  The procedures may be completed over the course of several visits, if necessary, 
but all scheduled Screening procedures must be completed within the timeframe of 
Day -33 to Day -11, 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 to determine 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. 
Subjects meeting all Screening eligibility tests will be randomized to treatment during the 
Screening Period. 
• Review of the Inclusion and Exclusion Criteria (see Sections 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 prior medications (Medication History) (see Section 5.7.1) 
• Complete physical examination, including weight (in kilograms) and height 
(in cm) (see Section 7.2.2) 
• Recording of vital signs (sitting blood pressure, heart rate, body temperature, 
respiratory rate) (see Section 7.2.3) 
• Collection of blood for clinical laboratory testing (hematology, clinical 
chemistry, lipids, HbA1c, and vitamin D) and collection of urine for urinalysis 
(see Section 7.2.4) 
• Testing for chicken pox immunity (see Section 7.2.5) 


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• 12-lead ECG (see Section 7.2.10) 
• 2D-echocardiogram (see Section 7.2.11) 
• Time to Stand Test (TTSTAND) (see Section 7.3.1) 
• Time to Climb Test (TTCLIMB) (see Section 7.3.2) 
• Time to Run/Walk Test (TTRW) (see Section 7.3.3) 
• North Star Ambulatory Assessment (NSAA) (see Section 7.3.4) 
• Six-minute Walk Test (6MWT) (see Section 7.3.5) 
• Hand-held myometry (elbow flexors and knee extensors) (see Section 7.3.6) 
• Range of Motion (ROM) in the ankles (see Section 7.3.7)  
• Eye exam (see Section 7.2.12) 
• DXA scan (see Section 7.2.13) 
• Spine X-rays (see Section 7.2.14) 
• ACTH Stimulation Test (see Section 7.2.7) 
• Pediatric Outcomes Data Collection Instrument questionnaire (PODCI) (see 
Section 7.4.1)  
• PARS III questionnaire (see Section 7.4.3) 
• Recording of AEs and SAEs beginning at the time written informed consent is 
obtained (see Section 7.5) 
• Randomization (see Section 3.2) 
6.3.2 Baseline Period (Day -1) Visit 
Subjects who have met all study eligibility criteria and been randomized to treatment via 
IXRS during the Screening Period, and for whom subject-specific blinded study 
medication has been shipped to and received by the study site will return to the study site 
during the Pretreatment Baseline Period (Day -1, the 24-hour interval immediately 


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preceding administration of the first dose of study medication) for baseline assessments.  
Subjects will retain their 6-digit study identification number which was assigned during 
the Screening Period. 
The following procedures will be completed at the Baseline Day -1 Visit: 
• Physical examination including weight (in kilograms) and assessment of 
cushingoid features (see Section 7.2.2)  
• Recording of vital signs (sitting blood pressure, heart rate, body temperature, 
respiratory rate) (see Section 7.2.3)  
• Time to Stand Test (TTSTAND) (see Section 7.3.1)  
• Time to Climb Test (TTCLIMB) (see Section 7.3.2)  
• Time to Run/Walk Test (TTRW) (see (see Section 7.3.3) 
• North Star Ambulatory Assessment (NSAA) (see Section 7.3.4)  
• Six-minute Walk Test (6MWT) (see Section 7.3.5) 
• Hand-held myometry (elbow flexors and knee extensors) (see Section 7.3.6)  
• Range of Motion (ROM) in the ankles (see Section 7.3.7) 
• Recording of AEs and SAEs; review of all AEs for resolution status and date 
(see Section 7.5) 
• Recording of prior medications (Medication History) (see Section 5.7.1) 
6.3.3 Treatment Period #1 Day 1 Visit 
At the Treatment Period #1 Day 1 Visit, certain procedures will be performed prior to 
administration of the first dose of study drug and are listed in this section.  Treatment 
Period #1 Day 1, for purposes of the study analyses, begins with administration of the 
first dose of study medication.   
Subjects will take the first dose of study medication in clinic on the day after the 
Pretreatment Baseline Visit.  Subjects must have fasted ≥ 6 hours prior to arrival at the 


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study site for the Day 1 Visit.  Breakfast, including at least 8 g of fat (8 ounces [240 mL] 
of full-fat milk or equivalent high-fat food portion) will be served at the study site after 
the blood and urine collections for clinical laboratory tests and the blood draw for PD 
biomarkers, including insulin and glucose, and within 30 minutes prior to administration 
of the dose of study medication.   
Subjects will receive a medical “alert” card stating that participation in the study may 
increase the subjects’ risk of adrenal suppression.  The card will include instructions for 
families and clinicians regarding management of possible adrenal suppression during 
emergencies, including coverage with “stress doses” of hydrocortisone (or prednisone) 
during times of illness, injury, or surgery. 
The following procedures will be completed at the Treatment Period #1 Day 1 Visit: 
• Recording of vital signs (sitting blood pressure, heart rate, body temperature, 
respiratory rate) prior to administration of first dose of study drug (see 
Section 7.2.3)  
• Clinical laboratory evaluation including hematology, clinical chemistry, lipids, 
and urinalysis tests, prior to administration of first dose of study drug (see 
Section 7.2.4) 
• Blood samples for fasted glucose and insulin, prior to administration of first dose 
of study drug (see Section 7.2.6) 
• Blood samples for PD biomarkers including osteocalcin, CTX1, serum 
aminoterminal propeptide of type I collagen (P1NP), and cortisol, prior to 
administration of first dose of study drug (see Section 7.2.6).  Blood remaining 
from collected samples not needed for protocol-specified analyses may be stored 
for future exploratory biomarker studies. 
• Dispensing of study medication and administration of first dose (see Section 5.8.1 
and Section 5.3, respectively) 
• Dispensing of subject diary (see Section 7.4.6) 


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• Recording of AEs and SAEs; review of all AEs for resolution status and date 
(see Section 7.5) 
• Recording of concomitant medications (see Section 5.7) 
On Day 1, the subject will be discharged from the clinic after completion of all scheduled 
assessments.  
6.3.4 Treatment Period #1 (Weeks 1-24) 
Subjects will return to the study site for safety, efficacy, and PD assessments beginning at 
Week 2 and continuing through the Week 24 Follow-up Visit, according to the schedule 
of visits in Table 11.   
Subjects will continue to receive daily oral administration of vamorolone/placebo 
suspension and prednisone/placebo tablets throughout the 24-week Treatment Period #1.  
The daily dose of study medication should be taken with breakfast, including at least 8 g 
of fat (8 ounces [240 mL] of full-fat milk or equivalent high-fat food portion).  
Dosing is to occur at home throughout the 24-week Treatment Period #1, except at the 
Weeks 2, 12 and 24 study visits when dosing will occur at the study site.  Subjects must 
have fasted ≥ 6 hours prior to arrival at the study site for the Weeks 2, 12, and 24 study 
visits.  Breakfast, including at least 8 g of fat (8 ounces [240 mL] of full-fat milk or 
equivalent high-fat food portion) will be served at the study site after the blood and urine 
collections for clinical laboratory tests and the blood draws for PD biomarkers, including 
insulin and glucose (Weeks 12 and 24 only), and within 30 minutes prior to 
administration of the dose of study medication.  Ease of administration of the suspension 
study medication will be assessed at the Weeks 2, 12, and 24 Visits.  Apart from blood 
and urine sample collections, all other scheduled assessments should be performed after 
administration of the study medication in clinic.    
Study medication will be dispensed at Weeks 6, 12, 18, and at the Week 24 Follow-up 
Visit, and returned at Weeks 2 (compliance monitoring only; will be redispensed at end 
of visit), 6, 12, 18, and 24 for all subjects.  Subjects will receive subject diaries at each 
study visit and return the diaries at each subsequent visit.  Diaries will be reviewed with 


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the subject’s parent or guardian by the study staff to assess AEs, changes to concomitant 
medications/therapies, and any missed or incomplete doses of study medication.   
Limited safety assessments will be conducted at the Week 2 Visit. 
Clinical efficacy assessments (TTSTAND, TTRW, TTCLIMB, NSAA, 6MWT, 
hand-held myometry, and ROM) and the subject reported outcomes (TSQM, PODCI, 
Ease of Study Medication Administration Assessment, and PARS III) will be conducted 
as specified in the schedule of study activities (Table 11).  Weight will be recorded at 
every visit and height will be measured at 12-week intervals.  Vital signs will be recorded 
at each study visit.  A physical examination including assessment of cushingoid features 
will be performed every 6 weeks.  A 12-lead ECG will be recorded at Weeks 12 and 24.  
2D-echocardiography will be performed at Week 24.  Blood and urine samples for 
clinical laboratory tests and blood for the serum PD biomarker panel will be collected at 
scheduled visits throughout the study (Table 11).  Blood will be collected at Week 24 for 
DNA testing for candidate genetic modifiers of DMD.  An eye examination to exclude 
cataracts and glaucoma will be performed at Week 24.  A DXA scan and spine X-ray will 
be performed at Week 24.  A Blindedness Assessment will be completed by the 
parent(s)/guardian(s) at the Week 24 Visit.  Adverse events, including SAEs, and 
concomitant medications will be assessed at each study visit and recorded throughout the 
study.  
There is flexibility in the timing of completion of some of the scheduled Week 24 
assessments.  The scheduled physical examination, weight, vital signs, clinical laboratory 
tests, blood draws for PD biomarker analysis and DNA testing, Ease of Study Medication 
Administration Assessment, PODCI, PARS III, and functional assessments (TTSTAND, 
TTCLIMB, TTRW, NSAA, 6MWT, hand-held myometry, ROM) must all be performed 
on the date of the final Week 24 dose of Treatment Period #1 study medication.  The 
12-lead ECG may be performed on the date of the final Week 24 dose of study 
medication, the day following the final Week 24 dose of study medication, or the day of 
the Week 24 Follow-up Visit.  Completion of the DXA scan, spine X-ray, Fracture 
Questionnaire, 2-D echocardiography, eye examination, TSQM, and Blindedness 


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Assessment may be performed on the date of the final Week 24 dose of study medication 
or up to 7 days following the date of the final Week 24 dose of study medication to 
accommodate need for additional scheduling flexibility.   
At the Week 24 Visit, all subjects will be dispensed a single dose of oral hydrocortisone 
(5 mg or 10 mg) to be administered 24 hours after administration of the final dose of 
study medication at the Week 24 Visit.  The hydrocortisone dose will be approximately 
8 mg/m2, rounded up to either 5 mg or 10 mg; subjects will be provided with either a 
single 5 mg or 10 mg hydrocortisone tablet which will be dispensed by the site staff at the 
Week 24 Visit (see Manual of Operations for details).   
Subjects will return to the study site approximately 48 hours after administration of the 
Week 24 dose of Treatment Period #1 study medication (and approximately 24 hours 
after the oral hydrocortisone) for ACTH Stimulation testing.  The ACTH Stimulation 
Test will be performed in the morning, before 12 noon local time, 48 ± 3 hours after 
administration of the final dose of Treatment Period #1 study medication, and prior to 
administration of the first dose of study drug in the Transition Period (see Manual of 
Operations for details).   
At the end of the 24-week Treatment Period, including the Week 24 Follow-up Visit for 
the ACTH Stimulation Test, all subjects will begin a 4-week double-blind Transition 
Period during which the doses of the tablet study medication will be progressively 
reduced and discontinued (see Section 6.3.5).  Subjects will take the first doses of study 
medication in the Transition Period with a high-fat meal on the same day as the Week 24 
Follow-up Visit ACTH Stimulation Test, as soon as possible after ACTH Stimulation 
testing has been completed. 
6.3.5 Transition Period (Weeks 25-28) 
All subjects will participate in the 4-week double-blind dose Transition Period.  During 
this period, all subjects will continue on the same dose of their liquid formulation (either 
vamorolone or matching placebo) as they were administered during Treatment Period #1 
and will have dose-tapering of their prednisone or matching placebo tablets as outlined in 


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Table 12.  This tapering is to aid in re-establishment of adrenal function if adrenal 
suppression has occurred in the prednisone-treated patients.   
Table 12. Tablet Dose Tapering 
Treatment Period Dose  
(No. tabs) 
Week 25 Dose  
(No. tabs) 
Week 26 Dose  
(No. tabs) 
Week 27 Dose 
(No. tabs)  
Week 28 Dose  
(No. tabs) 
2 
1 
0 
 
 
3 
2 
1 
0 
 
4 
3 
2 
1 
0 
5 
3 
2 
1 
0 
No. = number; tabs = tablets. 
Subjects will take the first doses of study medication in the Transition Period with a high-
fat meal on the same day as the Week 24 Follow-up Visit ACTH Stimulation Test, as 
soon as possible after ACTH Stimulation testing has been completed. 
Site study staff will contact the parent(s)/guardian(s) by telephone at Week 26 to ensure 
that the tablet tapering is proceeding according to protocol, to assess potential signs or 
symptoms indicative of adrenal suppression, and to address any questions the 
parent(s)/guardian(s) may have.  In addition, subjects will be assessed promptly for 
adrenal suppression if unwell at any time during the Transition Period.  There will be a 
low threshold for recommending commencement of daily oral prednisone or 
hydrocortisone, or intravenous hydrocortisone if hospitalization occurs in these 
circumstances. 
Each subject will return to the study site for Week 28 safety study assessments.   
Subjects must have fasted ≥ 6 hours prior to arrival at the study site for the Week 28 
Visit.  Breakfast will be served at the study site after the blood and urine collection for 
clinical laboratory tests and the blood draw for PD biomarkers, including fasting glucose 
and insulin.  At the Week 28 Visit, subjects will also have a physical examination with 
weight, assessment of cushingoid features and vital signs recorded.  Study medication 
will be returned for compliance monitoring.  Adverse events, including SAEs, and 
concomitant medications will be assessed.  Subject diaries will be returned and reviewed 
with site staff.   


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6.3.6 Treatment Period #2 (Week 28 + 1 Day through Week 48)  
Subjects will take the first dose of study medication in Treatment Period #2 at home on 
the day after the Week 28 Visit (Week 28 + 1 day).  There is no scheduled study visit at 
Week 28 + 1 day.   
Subjects will return to the study site for safety, efficacy, and PD assessments beginning at 
Week 30 and continuing through the Week 48 Follow-up Visit, according to the schedule 
of visits in Table 11.  Population PK assessments will be performed on blood collected at 
the Week 30 Visit only. 
Subjects will receive daily oral administration of vamorolone suspension throughout the 
20-week Treatment Period #2, from Week 28+ 1 day through the day of the Week 48 
Visit.  The daily dose of study medication should be taken with breakfast, including at 
least 8 g of fat (8 ounces [240 mL] of full-fat milk or equivalent high-fat food portion).  
Dosing is to occur at home throughout the 20-week Treatment Period #2 except at the 
Weeks 30, 40, and 48 study visits when dosing will occur at the study site.  Subjects must 
have fasted ≥ 6 hours prior to arrival at the study site for the Weeks 30, 40, and 48 study 
visits.  Breakfast, including at least 8 g of fat (8 ounces [240 mL] of full-fat milk or 
equivalent high-fat food portion) will be served at the study site after the blood and urine 
collections for clinical laboratory tests and the blood draws for PD biomarkers, including 
insulin and glucose (Weeks 40 and 48 only), and within 30 minutes prior to 
administration of the dose of study medication.  Ease of suspension study medication 
administration will be assessed at the Weeks 30, 40, and 48 Visits.  Apart from blood and 
urine sample collections, all other scheduled assessments should be performed after 
administration of the study medication in clinic.   
Study medication will be dispensed at Weeks 34, 40, and at the Week 48 Follow-up Visit 
(for subjects participating in the Dose-tapering Period only), and returned at Weeks 30 
(compliance monitoring only; will be redispensed at end of visit), 34, 40, and 48 for all 
subjects.  Subjects will receive subject diaries at each study visit and return the diaries at 
each subsequent visit.  Diaries will be reviewed with the subject’s parent or guardian by 


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the study staff to assess AEs, changes to concomitant medications/therapies, and any 
missed or incomplete doses of study medication.   
Limited safety assessments and blood draw for population PK analysis will be conducted 
at the Week 30 Visit.  
Clinical efficacy assessments (TTSTAND, TTRW, TTCLIMB, NSAA, 6MWT, 
hand-held myometry, and ROM) and the subject reported outcomes (TSQM, PODCI, 
Ease of Study Medication Administration Assessment, and PARS III) will be conducted 
as specified in the schedule of study activities (Table 11).  Weight will be recorded at 
every visit and height will be measured at Weeks 34 and 48.  Vital signs will be recorded 
at each study visit.  A physical examination including assessment of cushingoid features 
will be performed at Weeks 34, 40, and 48.  A 12-lead ECG will be recorded at Weeks 40 
and 48.  2D-echocardiography will be performed at Week 48.  Blood and urine samples 
for clinical laboratory tests and blood for the serum PD biomarker panel will be collected 
at scheduled visits throughout Treatment Period #2 (Table 11).  A blood sample for 
plasma PK will be collected at Week 30, two hours following dosing.  An eye 
examination to exclude cataracts and glaucoma will be performed at Week 48.  A DXA 
scan will be performed at Week 48.  Adverse events, including SAEs, and concomitant 
medications will be assessed at each study visit and recorded throughout the study.  
There is flexibility in the timing of completion of some of the scheduled Week 48 
assessments.  The scheduled physical examination, weight, vital signs, clinical laboratory 
tests, blood draws for PD biomarker analysis, Ease of Study Medication Administration 
Assessment, PODCI, PARS III, and functional assessments (TTSTAND, TTCLIMB, 
TTRW, NSAA, 6MWT, hand-held myometry, ROM) must all be performed on the date 
of the final Week 48 dose of Treatment Period #2 study medication.  The 12-lead ECG 
may be performed on the date of the final Week 48 dose of study medication, the day 
following the final Week 48 dose of study medication, or the day of the Week 48 Follow-
up Visit.  Completion of the DXA scan, Fracture Questionnaire, 2-D echocardiography, 
eye examination, and TSQM, may be performed on the date of the final Week 48 dose of 
study medication, the day following the Week 48 dose of study medication, or the day of 


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the Week 48 Follow-up Visit (for subjects receiving vamorolone therapy by enrolling 
directly into an additional vamorolone study or general access program), or up to 7 days 
following the date of the final Week 48 dose of study medication (for subjects 
participating in the Dose-tapering Period) to accommodate need for additional scheduling 
flexibility. 
At the Week 48 Visit, all subjects will be dispensed a single dose of oral hydrocortisone 
(5 mg or 10 mg) to be administered 24 hours after administration of the final dose of 
study medication at the Week 48 Visit.  The hydrocortisone dose will be approximately 
8 mg/m2, rounded up to either 5 mg or 10 mg; subjects will be provided with either a 
single 5 mg or 10 mg hydrocortisone tablet which will be dispensed by the site staff at the 
Week 48 Visit (see Manual of Operations for details).   
Subjects will return to the study site approximately 48 hours after administration of the 
final (Week 48) dose of Treatment Period #2 study medication (and approximately 24 
hours after the oral hydrocortisone) for ACTH Stimulation testing.  The ACTH 
Stimulation Test will be performed in the morning, before 12 noon local time, 48 ± 3 
hours after administration of the final Treatment Period #2 dose of study medication, and 
prior to administration of the first dose of study drug in the Dose-tapering Period if the 
subject is to taper, or prior to the first dose of study medication in the additional 
vamorolone study or general access program for subjects transitioning directly to that 
protocol (see Manual of Operations for details).   
At the end of the 20-week Treatment Period #2, including the Week 48 Follow-up Visit 
for the ACTH Stimulation Test, subjects may be given the option of continuing 
vamorolone therapy by enrolling into an additional vamorolone study or general access 
program.  Subjects enrolling directly into an additional vamorolone study or general 
access program will not need to taper their vamorolone dose prior to enrollment.  All 
other subjects will begin a 4-week double-blind Dose-tapering Period during which the 
doses of suspension study medication will be progressively reduced and discontinued 
(see Section 6.3.7). 


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Subjects who will not participate in the Dose-tapering Period (see Section 6.3.7) will be 
discharged from the study following completion of all Week 48 assessments, including 
the Week 48 Follow-up Visit ACTH Stimulation Test.  Subjects who do participate in the 
Dose-tapering Period will be dispensed vamorolone at the Week 48 Follow-up Visit, as 
well as instructions for tapering the dose of vamorolone during the Dose-tapering Period.  
Subjects will take the first dose of study medication in the Dose-tapering Period with a 
high-fat meal on the same day as the Week 48 Follow-up Visit ACTH Stimulation Test, 
as soon as possible after ACTH Stimulation testing has been completed. 
6.3.7 Dose-tapering Period (Weeks 49-52) 
All subjects who complete the study and opt not to continue vamorolone therapy by 
enrolling into an additional vamorolone study or general access program will participate 
in a 4-week double-blind Dose-tapering Period during which the doses of suspension 
study medication will be progressively reduced and discontinued.  In addition, subjects 
who discontinue study medication after Week 28 and prior to Week 48 will also 
participate in the Dose-tapering Period if possible and if, in the opinion of the 
Investigator, it is safe to do so.  The purpose of dose-tapering is to aid in re-establishment 
of adrenal function if adrenal suppression has occurred during vamorolone treatment.  
Dose tapering will be performed in a stepwise manner, according to the subject’s most 
recent calculated liquid formulation dose during the 20-week Treatment Period #2.  
Dose tapering for the liquid formulation (vamorolone) will be performed as outlined in 
Table 13.  For subjects who have completed Treatment Period #2, the subject’s weight 
recorded at the Week 40 Visit will be used to calculate dose volume for all dose 
de-escalations during the Dose-tapering Period. 
Table 13. Suspension Dose Tapering 
Treatment Period #2 
Dose Level 
Week 49 
Dose Level 
Week 50 
Dose Level 
Week 51 
Dose Level 
Week 52 
Dose Level 
Formulation: 100% 
50% 
25% 
10% 
0% 
 


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Subjects will take the first dose of study medication in the Dose-tapering Period with a 
high-fat meal on the same day as the Week 48 Follow-up Visit ACTH Stimulation Test, 
as soon as possible after ACTH Stimulation testing has been completed. 
Site study staff will contact the parent(s)/guardian(s) by telephone at Week 50 to ensure 
that the dose tapering is proceeding according to protocol, to assess potential signs or 
symptoms indicative of adrenal suppression, and to address any questions the 
parent(s)/guardian(s) may have.  In addition, subjects will be assessed promptly for 
adrenal suppression if unwell at any time during the Dose-Tapering Period.  There will be 
a low threshold for recommending commencement of daily oral prednisone or 
hydrocortisone, or intravenous hydrocortisone if hospitalization occurs in these 
circumstances. 
The final end-of-study visit will be scheduled approximately one week after the final 
dose de-escalation.  Each subject will return to the study site for final study assessments 
when he has received no suspension study medication for one week (Study Week 52).   
Subjects must have fasted ≥ 6 hours prior to arrival at the study site for the final Week 52 
Dose-tapering Visit.  Breakfast will be served at the study site after the blood and urine 
collection for clinical laboratory tests and the blood draw for PD biomarkers, including 
fasting glucose and insulin.  At the final Week 52 Visit, subjects will also have a physical 
examination with weight, assessment of cushingoid features and vital signs recorded.  
Study medication will be returned for compliance monitoring.  Adverse events, including 
SAEs, and concomitant medications will be assessed.  Subject diaries will be returned 
and reviewed with site staff.   
Subjects participating in the Dose-tapering Period will be discharged from the study 
following completion of all Dose-tapering Period assessments. 
6.4 
Subject Discontinuation 
In the event that a subject withdraws early from the study prior to the Week 48 Visit, the 
reason for discontinuation must be fully documented in the source documents and the 
eCRF.   


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Any subject who withdraws from the study prior to the Week 24 Visit should return to 
the study site for Week 24 assessments and the Week 24 Follow-up Visit ACTH 
Stimulation Test at the time of early withdrawal, whenever possible (see Section 6.3.4); 
any subject who prematurely discontinues from the study after Week 24 but prior to 
Week 28 should complete the Week 28 assessments at the time of early withdrawal, 
whenever possible (see Section 6.3.5); and any subject who prematurely discontinues 
from the study after Week 28 but prior to Week 48 should complete the Week 48 
assessments and the Week 48 Follow-up Visit ACTH Stimulation Test at the time of 
early withdrawal, whenever possible (see Section 6.3.6), assuming the subject has not 
withdrawn consent.  Site personnel will document all assessments, including any AEs, in 
the source documents and eCRF.   
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 of informed consent may be used by the Sponsor.  Every effort will be 
made to ensure that subjects who withdraw consent undergo dose-tapering, as 
appropriate, prior to the date of withdrawal of consent.  Subjects who withdraw early 
from the study may be replaced, at the discretion of the Sponsor. 
Subjects who discontinue study medication should follow the procedures for the 
applicable Early Discontinuation Dose-tapering Period described below and detailed in 
the Manual of Operations, whenever possible.  Dose tapering for subjects who 
discontinue the study early is to aid in re-establishment of adrenal function if adrenal 
suppression has occurred in the prednisone and/or vamorolone treated patients.   
Subjects will be assessed promptly if unwell during the tapering phase or in the weeks 
following study medication cessation due to the risk of adrenal suppression.  There will 
be a low threshold for recommending commencement of daily oral prednisone or 
hydrocortisone, or intravenous hydrocortisone if hospitalization occurs in these 
circumstances. 


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The final end-of-study visit will be scheduled approximately one week after the final 
dose de-escalation.  Each subject will return to the study site for final study assessments 
when he has received no suspension and/or tablet study medication for one week.   
Subjects must have fasted ≥ 6 hours prior to arrival at the study site for the final Early 
Discontinuation Dose-tapering Visit.  Breakfast will be served at the study site after the 
blood and urine collection for clinical laboratory tests and the blood draw for PD 
biomarkers, including fasting glucose and insulin.  At the final Study Visit, subjects will 
also have a physical examination with weight, assessment of cushingoid features and 
vital signs recorded.  Study medication will be returned for compliance monitoring.  
Adverse events, including SAEs, and concomitant medications will be assessed.  Subject 
diaries will be returned and reviewed with site staff.   
6.4.1 Early Discontinuation Prior to Week 24 
Any subject who discontinues the study after Day 1 and prior to the Week 24 Visit should 
return to the study site for Week 24 assessments and the Week 24 Follow-up ACTH 
Stimulation Test at the time of early withdrawal, and will participate in a 4-week Early 
Discontinuation Dose Tapering Period, whenever possible.  Dose tapering will be 
performed in a stepwise manner, according to the subject’s most recently calculated 
liquid and tablet formulation doses during the 24-week Treatment Period #1.  
Dose tapering for tablets (prednisone and matching placebo) will be performed as 
outlined in Table 14.   
Table 14. Tablet Dose Tapering for Subjects Discontinuing Prior to Week 24 
Treatment Period Dose  
(No. tabs) 
Week 25 Dose  
(No. tabs) 
Week 26 Dose  
(No. tabs) 
Week 27 Dose 
(No. tabs)  
Week 28 Dose  
(No. tabs) 
2 
1 
0 
 
 
3 
2 
1 
0 
 
4 
3 
2 
1 
0 
5 
3 
2 
1 
0 
No. = number; tabs = tablets. 
Dose tapering for the liquid formulation (vamorolone and matching placebo) will be 
performed as outlined in Table 15. 


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Table 15. Suspension Dose Tapering for Subjects Discontinuing Prior to Week 24 
Treatment Period Dose 
Level 
Week 25 
Dose Level 
Week 26 
Dose Level 
Week 27 
Dose Level 
Week 28 
Dose Level 
Formulation: 100% 
50% 
25% 
10% 
0% 
 
As soon as possible after ACTH Stimulation testing has been completed at the Week 24 
Follow-up/Early Termination Visit, subjects will take the first doses of study medication 
in the Early Discontinuation Dose Tapering Period with a high-fat meal on the same day. 
6.4.2 Early Discontinuation After Week 24 and Prior to Week 28 
Subjects who discontinue from the study after Week 24 and prior to Week 28 will 
continue on the same schedule for dose tapering of tablets they are already following for 
Transition Period dosing, and will begin the 4-week suspension dose tapering schedule 
shown in Table 16. 
Table 16. Suspension Dose-Tapering for Subjects Discontinuing After Week 24 
and Prior to Week 28 
 
Formulation Dose Level (% of Volume Administered During Treatment 
Period #1) at Each Week Following Discontinuation 
Time of Early 
Discontinuation 
100% 
50% 
25% 
10% 
0% 
 
Week 25 
Week 25  
Week 26 
Week 27  
Week 28 
Week 29  
 
Week 26 
Week 26  
Week 27 
Week 28 
Week 29 
Week 30  
 
Week 27 
Week 27  
Week 28 
Week 29  
Week 30 
Week 31  
 
 
Each subject will return to the study site for final study assessments when he has received 
no suspension or tablet study medication for one week (Study Week 29, Week 30, or 
Week 31, depending on when the subject discontinued [see Table 16]).   
6.4.3 Early Discontinuation After Week 28 and Prior to Week 48 
Subjects who discontinue from the study after Week 28 and before the Week 48 Visit 
will follow the same schedule for dose tapering of suspension as described in 
Section 6.3.7. 


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6.5 
Subject and Study Completion 
A completed subject is defined as a subject who has completed Treatment Period #1 and 
Treatment Period #2, through the Week 48 and Week 48 Follow-up Visit assessments, 
and Dose-tapering Period, if applicable, and has not prematurely withdrawn from the 
study for any reason.  The study will be completed when the final subject has completed 
his final study visit (“last subject, last visit”). 
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 page. 
7.1.1 Genetic Modifiers of DMD 
Approximately 6 mL of blood will be collected at the Week 24 Visit for DNA testing to 
determine if candidate genetic modifiers of DMD (gene polymorphisms associated with 
disease severity or response to glucocorticoid treatment) are similarly associated with 
vamorolone-treated DMD patients (baseline disease severity or response to vamorolone 
or prednisone treatment).   
DNA testing will be performed by a certified central laboratory. 
The procedures for the collection, handling, and shipping of blood samples for DNA 
testing will be specified in the Laboratory Manual(s) provided to the clinical center.  
Results will be presented in an addendum report. 
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 


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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 
page. 
7.2.2 Physical Examination, Cushingoid Features, Weight, and Height 
A complete physical examination will be performed at Screening, Baseline Day -1 and 
every 6 weeks thereafter through Treatment Period #1, at the Week 28 Transition Period 
Visit, at Weeks 34, 40, and 48 of Treatment Period #2, and at the final Week 52 
Dose-tapering Period Visit, 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.  Clinically significant changes from baseline should be 
recorded as AEs.  Particular attention will be paid in identifying any sign of cushingoid 
features, which should also be recorded as AEs if they first appear or worsen during the 
study.  
Additional unscheduled symptom-directed physical examinations may be conducted at 
any time at the Investigator’s discretion.   
Height (in cm) will be recorded at Screening, and Weeks 12, 24, 34, and 48.  Weight 
(in kg) will be recorded at Screening, Baseline Day -1, Week 2, Week 6, Week 12, 
Week 18, Week 24, Week 28, Week 30, Week 34, Week 40, and Week 48, and at the 
final Week 52 Dose-tapering Visit (Table 11).  Weight recorded at the previous visit will 
be used to calculate the study medication (suspension and tablets) dose for the subsequent 
dispensing interval (see Section 5.3).   
Results will be recorded in the source documents and on the appropriate eCRF page. 


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7.2.3 Vital Signs 
Vital signs (sitting blood pressure, heart rate, respiration rate, and body temperature) will 
be recorded at Screening, Baseline Day -1, Day 1, Week 2, Week 6, Week 12, Week 18, 
Week 24, Week 28, Week 30, Week 34, Week 40, and Week 48, and at the final Week 52 
Dose-tapering Visit.  Vital signs should be recorded after the subject has been resting for 
at least 5 minutes.  Body temperature may be measured using oral, tympanic, or temporal 
recording devices; however, the same methodology must be used for all assessments of a 
given subject. 
Results will be recorded in the source documents and on the appropriate eCRF page. 
If vital signs are recorded at the same study visit as blood sampling and ECG recording, 
at least 15 minutes should elapse after collection of blood samples and before performing 
ECG and recording vital signs. 
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 17 and Table 18, below, 
during the Screening Period, at the Day 1 Visit, and at each of the subsequent study visits 
specified in Table 11.  Blood for vitamin D and HbA1c are collected at specific visits 
only (Table 17).  Fasted blood and urine samples for clinical laboratory tests will be 
collected pre-dose at the Day 1 and Weeks 2, 12, 24, 28, 30, 40, and 48 Visits, and fasted 
samples will be collected at the final Week 52 Dose-tapering Period Visit.  Non-fasted 
blood and urine samples for clinical laboratory tests will be collected at the Screening, 
and Weeks 6, 18, and 34 Visits.  Details of blood draws can be found in the Laboratory 
Manual. 
All blood and urine samples will be sent to the designated central laboratory for testing. 
For the hematology, chemistry, and lipids laboratory tests, blood will be collected by 
direct venipuncture of peripheral veins.  A total of approximately 140 mL of blood will 
be collected over the course of this study for clinical safety laboratory evaluation (see 
Section 7.2.9 for details of blood volumes to be collected).   


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If blood sampling is performed at the same study visit as vital signs assessment and ECG 
recording, at least 15 minutes should elapse after collection of blood samples and before 
performing ECG and recording vital signs. 
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.   
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 17. Hematology, Chemistry, and Lipids Clinical Laboratory Tests 
Hematology 
Red Blood Cells (RBC) 
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 
Glutamate dehydrogenase (GLDH) 
Inorganic Phosphorus 
Alkaline phosphatase (ALP) 
Blood Urea Nitrogen (BUN) 
Gamma Glutamyl Transferase (GGT) 
Creatinine 
Aspartate aminotransferase (AST) 
Total Protein 
Alanine aminotransferase (ALT) 
Albumin 
Creatine kinase (CK) 
Bicarbonate 
Lipase  
Lactate Dehydrogenase (LDH) 
Amylase  
Cystatin C 
Vitamin Db  
HbA1cc 
 
 
Lipids 
Triglycerides 
Low Density Lipoprotein (LDL) 
Total cholesterol 
High density Lipoprotein (HDL) 
a. If outside normal range, direct bilirubin will be measured and reported. 
b. Vitamin D levels measured at Screening, Weeks 12, 24, 40, and 48 only. 
c. HbA1c levels measured at Screening, Week 24, and Week 48 only. 
Urine will be collected for routine analysis, by dipstick and microscopic analysis, for the 
tests described in Table 18.   


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Table 18. Urinalysis Clinical Laboratory Tests 
Urinalysis (including microscopic examination) 
Dipsticka 
Microscopic Analysis 
Protein 
WBC/hpf 
Glucose 
RBC/hpf  
Ketones 
Casts 
pH 
Bacteria 
Leukocyte esterase 
 
Blood 
 
a. A midstream clean-catch urine specimen will be collected for dipstick analysis.   
Blood for hemoglobin A1c (HbA1c) determination is collected at the scheduled 
Screening, Week 24 and Week 48 Visits, and should also be collected if urine glucose is 
positive and/or fasted glucose levels are above normal limits (see Section 7.2.6 and 
Laboratory Manual).  
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 provided to the clinical center. 
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 documents and eCRF.  The clinical laboratory will clearly mark all laboratory 
test values that are outside the normal range and the 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, in the Investigator’s opinion, will be indicated (see Section 7.5). 


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7.2.5 Chicken Pox Immunity 
Subjects must provide evidence of immunity to varicella zoster virus to be eligible for 
randomization to treatment.  Evidence of immunity may be determined by either a 
positive anti-varicella IgG antibody test result obtained during the Screening Period, or 
documentation, provided at the Screening Visit, that the subject has had 2 doses of 
varicella vaccine, with or without serologic immunity, with the second of the 2 doses 
given at least 14 days prior to randomization.  For subjects whose anti-varicella antibody 
titer will be measured at Screening, a 2 mL blood sample will be collected for antibodies 
(IgG) to Varicella Zoster virus to confirm immunity.  The blood sample will be sent to 
the local laboratory for testing.  
If antibodies are not detected in the blood sample sent to the local laboratory, and 
documentation of two previous vaccinations against varicella cannot be provided, 
immunization before starting the trial will be advised and the immunization status must 
be re-checked prior to randomization (see Manual of Operations for details).  Lack of 
willingness to immunize a child who is not already immune to chicken pox will be a 
reason for exclusion of the child from the trial.  
7.2.6 Pharmacodynamic Biomarker Panel 
Blood samples will be collected to explore the effect of vamorolone on biomarkers 
associated with glucocorticoid safety concerns (secondary outcomes for adrenal 
suppression, insulin resistance, and bone turnover), as listed in Table 19.   
Blood samples will be collected pre-dose at the Day 1 and Weeks 12, 24, 28, 40, and 48 
Visits, and at the final Week 52 Dose-tapering Period Visit for analysis of biomarkers for 
secondary outcome measures of adrenal suppression, bone turnover, and insulin 
resistance.  Approximately 2 mL of blood will be collected for the PD biomarker panel 
(osteocalcin, P1NP, and CTX bone turnover markers) at each scheduled collection time 
point; blood samples for analysis of morning cortisol levels (adrenal suppression 
biomarker) and fasting glucose and insulin (insulin resistance biomarkers) will be 
collected as part of the clinical laboratory tests and require no additional blood volume.  
All samples will be collected after the subject has fasted for ≥ 6 hours and prior to 


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administration of the daily dose of study medication at dosing visits.  Blood remaining 
from collected samples not needed for protocol-specified analyses at each of these time 
points may be stored for future exploratory biomarker studies for aspects of safety and 
efficacy.  These remaining blood samples may be released to scientists worldwide for 
research purposes, including research on biomarkers in DMD.  Any released samples will 
have no identifying subject information.   
Blood for HbA1c determination should be collected if urine glucose is positive and/or 
fasted glucose levels are above normal limits at any of the scheduled assessment time 
points (see Section 7.2.4 and Laboratory Manual).  
A total of approximately 14 mL of blood will be collected for the PD biomarker panel 
(osteocalcin, P1NP, and CTX bone turnover markers) over the course of the 57-week 
study (see Section 7.2.9).   
Table 19. Pharmacodynamic Biomarkers – Secondary Safety Outcomes 
Adrenal Suppression 
Cortisol - morning 
Insulin Resistance 
Glucose – fasting 
Insulin - fasting 
Bone Turnover 
Osteocalcin 
CTX1 
P1NP 
7.2.7 ACTH Stimulation Test 
The ACTH Stimulation Test will be performed in the morning during the Screening Visit, 
in the morning of the Week 24 Follow-up Visit (48 ± 3 hours after the final dose of 
Treatment Period #1 study medication), and in the morning of the Week 48 Follow-up 
Visit (48 ± 3 hours after the final dose of Treatment Period #2 study medication) to assess 
the adrenal gland stress response.   
All subjects will be given a single dose of hydrocortisone (5 mg or 10 mg) 24 hours after 
the dose of study medication at the Week 24 Visit and 24 hours after the dose of study 
medication at the Week 48 Visit.  The hydrocortisone dose will be approximately 


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8 mg/m2, rounded up to either 5 mg or 10 mg; subjects will be provided with either a 
single 5 mg or 10 mg hydrocortisone tablet which will be dispensed by the site staff at the 
Week 24 or Week 48 Visit (see Manual of Operations for details).  
Subjects will return to the study site approximately 48 hours after administration of the 
final (Week 24) dose of Treatment Period #1 study medication (and approximately 
24 hours after the dose of oral hydrocortisone), and approximately 48 hours after 
administration of the final (Week 48) dose of Treatment Period #2 study medication (and 
approximately 24 hours after the dose of oral hydrocortisone) for ACTH Stimulation 
testing.  The ACTH Stimulation Test will be initiated as close to 8 AM local time as 
possible, but in any case completed in the morning, before 12 noon local time, 48 ± 3 
hours after administration of the final Treatment Period #1 or Treatment Period #2 dose 
of study medication, and prior to administration of the first dose of study drug in the 
Transition Period (Week 24) or Dose-Tapering Period (Week 48) (see Manual of 
Operations for details).   
The ACTH Stimulation Test involves insertion of a saline lock and then administration of 
250 µg of Cosyntropin at time zero.  Blood samples for cortisol measurement are 
collected at time 0 immediately prior to Cosyntropin administration, and at 30 ± 5 
minutes and 60 ± 5 minutes after Cosyntropin administration.  
The potential side effects of ACTH Stimulation testing (nausea, sweating, dizziness, 
palpitations, facial flushing) will be discussed with the subject and the family before 
starting the test.  Cortisol levels below 18 µg/dL (equivalent to 500 nM) 30 or 60 minutes 
after stimulation with Cosyntropin will be considered indicative of adrenal suppression. 
Approximately 2 mL of blood will be collected at each time point for cortisol 
measurement; a total of approximately 6 mL of blood will be collected during each of the 
Screening Visit, the Week 24 Follow-up Visit (48 ± 3 hours following the final dose of 
Treatment Period #1 study medication), and the Week 48 Follow-up Visit (48 ± 3 hours 
following the final dose of Treatment Period #2 study medication) for the ACTH 
Stimulation Test (see Section 7.2.9). 


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Blood samples will be sent to a central laboratory, and results centrally interpreted 
(Children’s Hospital of Eastern Ontario).  Results of the Week 24 analysis will not be 
reported to the study sites. 
7.2.8 Population PK Assessment 
At the Week 30 Visit, all subjects will have blood collected for PK assessments at 
2 hours post-dose.  Approximately 2 mL of blood will be collected into K2-EDTA tubes 
at the single assessment time point.   
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 time 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. 
7.2.9 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 57-week study are summarized in Table 20.  
A total of 182 mL of blood will be collected from each subject over the course of the 
up-to-57-week study.  


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Table 20. Blood Sample Number and Volume by Study Visit 
 
Total mL of Blood 
Test 
SCR 
Day 1 Week 
2 
Week 
6 
Week 
12 
Week 
18 
Week 
24 
Week 
24 F/U 
Week 
28  
Week 
30 
Week 
34 
Week 
40 
Week 
48 
Week 
48 F/U 
Week 
52 
Total 
Volume 
Clinical Safety Labsa 
12b 
10c 
10c 
10 
12c 
10 
12b,c 
 
10c 
10c 
10 
12c 
12b,c 
 
10c 
140b 
Varicella Zoster IgG 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
PD Biomarker Paneld 
 
2 
 
 
2 
 
2 
 
2 
 
 
2 
2 
 
2 
14 
PD Insulin/Glucosec 
 
From 
Clinical 
Safety 
Lab 
Sample 
 
 
From 
Clinical 
Safety 
Lab 
Sample 
 
 From 
Clinical 
Safety 
Lab 
Sample 
 
 From 
Clinical 
Safety 
Lab 
Sample 
 
 
 From 
Clinical 
Safety 
Lab 
Sample 
 From 
Clinical 
Safety 
Lab 
Sample 
 
 From 
Clinical 
Safety 
Lab 
Sample 
 
DNA Testing 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
6 
ACTH Stimulation 
Teste 
6 
 
 
 
 
 
 
6 
 
 
 
 
 
6 
 
18 
PKf 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
2 
Total Volume by 
Visit (mL) 
20 
12 
10 
10 
14 
10 
20 
6 
12 
12 
10 
14 
14 
6 
12 
182 
Total Volume: 182 mL 
F/U = Follow-up; SCR = Screening 
a Hematology, Chemistry, Lipids; GLDH; volume includes blood for vitamin D testing, fasting insulin and glucose, cortisol, and exploratory PD biomarkers, 
where applicable. 
b Includes blood for HbA1c testing. 
c Subjects must have fasted ≥ 6 hours prior to blood draws. 
d Osteocalcin, CTX1, P1NP, pre-dose on dosing days; subjects must have fasted ≥ 6 hours prior to pre-dose and Week 52 blood draws.   
e ACTH Stimulation Test performed at Screening, Week 24 Follow-up Visit, 48 ± 3 hours after the final dose of Treatment Period #1 study medication and prior 
to first dose of study medication in the Transition Period, and Week 48 Follow-up Visit, 48 ± 3 hours after the final dose of Treatment Period #2 study 
medication and prior to first dose of study medication in the Dose-Tapering Period. 
f Blood drawn for population PK at 2 hours post-dose at the Week 30 Visit.   
 
 


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7.2.10 12-Lead ECG 
12-lead ECGs will be recorded at the Screening, Week 12, Week 24, Week 40, and 
Week 48 Visits.  All ECG recordings 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.  
If blood sampling, vital signs assessment, and ECG recordings are scheduled at the same 
study visits, at least 15 minutes should elapse between collection of blood samples and 
before performing ECG and recording vital signs. 
ECG results will be read locally.  Results must be interpreted and recorded on the 
appropriate eCRF page. 
7.2.11 2D-echocardiography 
Standard trans-thoracic echocardiogram will be performed at Screening, Week 24, and 
Week 48 to assess cardiac status.  The echocardiograms must be manually reviewed and 
interpreted locally by medically qualified personnel.  No central reading of 
echocardiography results is planned.  The findings will be categorized as: normal; 
abnormal but not clinically significant; abnormal and clinically significant.  An 
echocardiogram result that is abnormal and clinically significant will be recorded in 
medical history if detected during the Screening Period and will be considered as an AE 
if detected after the first dose of study medication.  Adequate management should be 
initiated if any abnormalities of clinical significance are detected.  
Echocardiographic parameters to be recorded will be described in the Manual of 
Operations.  Results must be interpreted and recorded on the appropriate eCRF page. 


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7.2.12 Eye Examination 
An eye examination will be performed by a certified and appropriately trained 
optometrist or ophthalmologist at Screening, Week 24, and Week 48 to assess for 
presence and degree of cataracts and glaucoma.  Number and severity of cataracts, if 
present, will be recorded.  Ocular pressure and presence/absence of glaucoma will be 
recorded. 
Results must be interpreted and recorded in the source document and on the appropriate 
eCRF page. 
7.2.13 Bone Health and DXA Scan (total body and spine) 
Data on bone mass, density, and total body composition (fat mass, fat-free mass, lean 
mass, Lean Mass Index, and Fat Mass Index) will be collected by DXA during the 
Screening Period (depending on local facilities, this may require an additional visit but 
should be completed prior to starting study medication), and at Week 24 and Week 48.   
Antero-posterior spine (L1-L4) and total body (without head) bone mineral density 
(BMD) by DXA scan will be collected.  DXA quality control will be performed as 
described in the Manual of Operations.  DXA scans will be analyzed centrally by a 
certified medical radiation technologist at Children’s Hospital of Ottawa in Ottawa, 
Canada.  The Screening result will represent a baseline assessment for long-term follow 
up.  Additional DXA scanning may be arranged if clinically indicated throughout the 
study.  
Vitamin D deficiency and insufficiency will be treated with Vitamin D supplements (see 
Section 5.7.6). 
Vertebral and non-vertebral fractures will be assessed and recorded at Screening, 
Week 24, and Week 48 using a Fracture Questionnaire.  Fractures will be recorded as 
medical history if reported during the Screening Period and as AEs if detected following 
the first dose of study medication and confirmed by radiologic investigation.  The 
Fracture Questionnaires completed at the Weeks 24 and 48 Visits will document all 


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radiographically confirmed fractures which occurred during the course of the study, 
following the first dose of study medication. 
7.2.14 Spine X-rays 
Data on bone health will also be collected by lateral spine X-ray (T4-L5) during the 
Screening Period (depending on local facilities, this may require an additional visit but 
should be completed prior to starting study medication) and at the Week 24 Visit.  Lateral 
spine X-ray will be analyzed centrally by two certified pediatric radiologists at Children’s 
Hospital of Ottawa in Ottawa, Canada, who are blinded to the results of one another; a 
third radiologist will resolve any discrepancies arising from the first two readings.  
Quantification of any vertebral fractures detected will be performed.  The Screening 
result will represent a baseline assessment for long-term follow up.  Additional spine 
X-rays may be arranged if clinically indicated throughout the study.  
Spine x-ray data will be analyzed in an addendum report. 
Fractures will be recorded as medical history if detected during the Screening Period and 
as AEs if detected following the first dose of study medication.  
7.3 
Assessment of Muscle Strength and Function 
Muscle strength and function assessments should be performed in the morning and at 
approximately the same time of day, whenever possible. 
7.3.1 Time to Stand Test (TTSTAND) 
The Time to Stand Test (TTSTAND) will be assessed at the Screening, Baseline Day -1, 
Week 6, Week 12, Week 24, Week 34, Week 40 and Week 48 Visits.   
The TTSTAND measures the time (in seconds) required for the subject to stand to an 
erect position from a supine position (floor), and is assessed as part of the NSAA (see 
Section 7.3.4).  Complete instructions for administering and scoring the TTSTAND are 
given in the Clinical Evaluator Manual to be supplied to the sites prior to study start. 
Results will be recorded in the source documents and in the eCRF. 


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7.3.2 Time to Climb Test (TTCLIMB) 
The Time to Climb Test (TTCLIMB) will be assessed at Screening, Baseline Day -1, 
Week 12, Week 24, Week 40, and Week 48 Visits.   
The 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.35  
Complete instructions for administering the TTCLIMB are given in the Clinical 
Evaluator Manual to be supplied to the sites prior to study start. 
Results will be recorded in the source documents and in the eCRF. 
7.3.3 Time to Run/Walk Test (TTRW) 
The Time to Run/Walk Test (TTRW) will be assessed at Screening, Baseline Day -1, 
Week 12, Week 24, Week 40, and Week 48 Visits.   
The TTRW measures the time (in seconds) that it takes a subject to run or walk 10 meters 
and is assessed as part of the NSAA (see Section 7.3.4).  Complete instructions for 
administering and scoring the TTRW are given in the Clinical Evaluator Manual to be 
supplied to sites prior to study start. 
Results will be recorded in the source documents and in the eCRF. 
7.3.4 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.36  The 
NSAA consists of 17 scored items and 2 timed tests, including the TTRW and the 
TTSTAND (see Section 7.3.1).  The NSAA will be conducted at Screening, Baseline 
Day -1, Week 12, Week 24, Week 40, and Week 48 Visits.   
Subjects should be barefoot and wear comfortable clothing.  Complete instructions for 
administering and scoring the NSAA are given in the Clinical Evaluator Manual to be 
supplied to the sites prior to study start. 
The NSAA should be assessed BEFORE the 6MWT at study visits where both tests are 
performed.    


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Results will be recorded in the source documents and in the eCRF. 
7.3.5 Six-minute Walk Test (6MWT) 
Functional exercise capacity and mobility will be assessed in all subjects by means of the 
Six-minute Walk Test (6MWT) at Screening, Baseline Day -1, Week 12, Week 24, 
Week 40, and Week 48 Visits.  This evaluation is a modified version of the 6MWT, 
adapted for use in DMD patients.37 
The total distance traveled, in meters, should be recorded along with the validity of the 
test as assessed by the test administrator in the source documents and in the eCRF.  If a 
subject cannot complete 6 minutes of walking, the total meters and the time until 
discontinuation of the test should be recorded.  Subjects should wear comfortable shoes 
(trainers) and clothing.  Complete instructions for administering the 6MWT are given in 
the Clinical Evaluator Manual to be supplied to the sites prior to study start. 
The 6MWT should be assessed AFTER the NSAA at study visits where both tests are 
performed.   
Results will be recorded in the source documents and in the eCRF. 
7.3.6 Hand-Held Myometry (elbow flexors and knee extensors) 
Muscle strength will be measured with hand-held myometry.  Elbow flexor muscles will 
be measured in the upper limbs and quadriceps muscle will be used for the lower limbs.  
Measurements will be performed unilaterally on the elbow and knee muscles, on the 
same side as the dominant hand (see Clinical Evaluator Manual for details).  Muscle 
strength will be measured at Screening, Baseline Day -1, Week 12, Week 24, Week 40, 
and Week 48 Visits.  
Results will be recorded in the source documents and eCRF. 
7.3.7 Range of Motion (ROM) 
Range of motion (ROM) at the ankle joint will be measured using a standard goniometer 
at the Screening, Baseline Day -1, Week 12, Week 24, Week 40, and Week 48 Visits.  
Measurements will be performed on both the right and left ankle joints. 


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Training will be given to study staff and specific detailed instructions are included in the 
Clinical Evaluator Manual. 
Results will be recorded in the source documents and eCRF. 
7.4 
Patient-Reported Outcome Measures 
7.4.1 Pediatric Outcomes Data Collection Instrument (PODCI) 
Physical functioning will be assessed by completion of the Pediatric Outcomes Data 
Collection Instrument (PODCI).  The subject parent/legal guardians will be asked to 
complete this instrument at the Screening, Week 24, and Week 48 Visits.   
The completed Instrument is considered the source documentation for this assessment.  
Results will be recorded in the eCRF. 
7.4.2 Treatment Satisfaction Questionnaire (TSQM) 
Satisfaction with treatment will be measured at the Week 24 and Week 48 Visits using 
the Treatment Satisfaction Questionnaire for Medication (TSQM).  The TSQM consists 
of 14 Likert-scale items that yield four subscale scores: Effectiveness, Side Effects, 
Convenience, and Global Satisfaction (the latter being a component of the primary 
outcome variable for the proposed trial).  A child-report version of the TSQM is not 
available.  Therefore, the parent (s)/guardian(s) will be asked to report from their 
perspective of the boy’s treatment.  TSQM is available in all primary languages spoken at 
sites for this study.  
The completed Questionnaire is considered the source documentation for this assessment.  
Results will be recorded in the eCRF. 
7.4.3 Behavioral Assessment 
One instrument, for completion by the parent(s)/guardian(s), will be used for behavior 
assessment screening and evaluation of behavior change.  This is the PARS III, a scale 
designed to measure psychosocial adjustment of children with chronic physical illnesses.  
The instrument will be completed by the parent(s)/guardian(s) at the Screening Visit and 


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at the Weeks 12, 24, and 48 Visits.  The PARS III is available in all primary languages 
spoken at sites for this study. 
The completed assessment is considered the source documentation.  Results will be 
recorded in the eCRF. 
7.4.4 Ease of Study Medication Administration Assessment 
Ease of administration of the suspension study medication will be assessed by the 
parent(s)/guardian(s) at the Weeks 2, 12, 24, 30, 40, and 48 Visits.  Results will be 
recorded in the source documents and eCRF. 
7.4.5 Blindedness Assessment 
The subject’s parent(s)/guardian(s), the site Principal Investigator, and the Clinical 
Evaluator will each complete a Blindedness Assessment at the Week 24 Visit.  This is a 
brief questionnaire which asks each evaluator to predict the identity of the study 
medication (vamorolone, prednisone, or placebo) the subject was taking during 
Treatment Period #1, and to rate on a 4-point scale his/her level of certainty and the 
reason for the chosen level of certainty. 
Results will be recorded in the source documents and in the eCRF. 
7.4.6 Subject Diary 
The parent or legal guardian of each subject will be given a subject diary at the Day 1 
Visit in which to record any new concomitant medications and any changes to existing 
concomitant medications taken during the study, any AEs experienced by the subject 
during the study, and any missed or incomplete doses of study medication.  Parents/legal 
guardians will be instructed in how to record information in the diary and will be 
instructed to bring the diary with them to each study visit for review by study staff for 
completeness and accuracy.  A new diary will be dispensed at each visit for use through 
the time of the next scheduled visit.  Collection of final diaries will occur at the Week 52 
Visit, at the end of the Dose-tapering Period.   


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7.5 
Adverse Events and Serious Adverse Events 
The condition of the subjects will be monitored throughout the duration of the study by 
the clinical site study team and by recording of AEs in subject diaries.  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 drug.  Pre-existing conditions that worsen during a study are to 
be reported as AEs.  Signs and symptoms of DMD should not be recorded as AEs, unless 
their nature or severity is unexpected for the course of the disease. 
The Investigator is responsible for reporting AEs and SAEs to the Sponsor or designee.  
For reported death of a participant, the Investigator shall supply the Sponsor and the 
IRB/IEC with any additional information requested. 
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.  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 
documents and in the subject’s eCRF.  The date 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 page.  The details 
recorded shall include the nature, date of onset, final outcome and its date, intensity 
assessment (Common Terminology Criteria for Adverse Events [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 on the appropriate eCRF page. 


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7.5.1 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 CTCAE, 
version 4.03, 5-point scale, and reported in detail as indicated in 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. 
7.5.2 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 


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do not meet the criteria for study drug relationship listed under remote, possible, or 
probable. 
7.5.3 Clinical Laboratory Test Abnormalities 
Clinical laboratory test results will be recorded on the designated eCRF page.  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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7.5.4 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 documents 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 
further 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. 
7.5.5 Dosing Error 
For the purposes of this study, a dosing error is defined as a dose exceeding or less than 
the scheduled dose of liquid formulation, tablet formulation, or both.  Such occurrences 
will 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 will 
not be recorded as an AE unless there are associated signs or symptoms. 
• 
A dosing error with associated non-serious AEs will be recorded as AEs on the 
relevant AE forms in the eCRF. 
• 
A dosing error with an associated SAE will be recorded as an SAE. 
• 
Details of all dosing errors, including actual dose administered, will be 
documented in the source documents and recorded in the appropriate 
documentation. 


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7.5.6 Serious Adverse Events 
Serious adverse events 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.  For subjects who do not continue 
into an additional vamorolone study or general access program, site staff will make a 
phone call to the home 31-35 days after the final dose of study medication in the 
VBP15-004 Dose-tapering Period to confirm the final SAE status of the subject. 
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.  All SAEs, both related and unrelated, that begin within 
30 days after the subject’s final dose of study medication will be reported to the Sponsor 
within 24 hours of discovery by the Investigator.   
During the SAE collection period, the Investigator or clinical site personnel should notify 
the Coordinating Center of all SAEs, regardless of relationship to the investigational 
drug, within 24 hours of clinical staff becoming aware of the event; notification to the 
Coordinating Center will trigger alerts to the Study Chair, the Sponsor, and the Medical 
Monitor.  The Investigator will provide the initial notification by completing the SAE 
Report Form in the electronic data capture (EDC) system, which must include the 
Investigator’s assessment of the relationship of the event to investigational drug, and 
must be signed by the Investigator. 
In addition, notification is sent by the Investigator to the IRB/IEC and the subject’s 
Primary Care Physician. 
Follow-up information, or new information regarding an ongoing SAE, must be provided 
promptly to the Coordinating Center within 24 hours of knowledge of the new or 
follow-up information, which will forward the information to the Study Chair, the 
Sponsor, and the Medical Monitor. 
All SAE reports should be completed within the EDC. 


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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 terms death and sudden death are clearly distinct and must not be used 
interchangeably. 
Hospital admissions scheduled prior to the study are not considered SAEs unless the 
hospitalization is prolonged due to an adverse event.  Planned admissions as part of the 
study, hospitalizations for scheduled treatment of a preexisting condition that has not 
worsened, and hospitalization for an elective procedure are not considered SAEs.  
Hospitalizations for fewer than 24 hours and emergency room/department visits are not 
considered SAEs. 
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 Coordinating Center, who will notify the 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 Coordinating Center, who will notify the Study 
Chair, the Sponsor and the Medical Monitor within 24 hours of the Investigator becoming 
aware of the new information. 


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All 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.  All SAEs, related and 
unrelated, must be reported to the Sponsor within 24 hours of first awareness. 
If, at any time during the study, a subject experiences an SAE, appropriate care should be 
instituted. 
In the event of a serious adverse event (SAE), 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:  
In United States and Canada: 
 
Email: CHOSafety@prahs.com 
 
Drug Safety Fax: 1 888 772 6919 or 1 434 951 3482 
 
SAE Questions: Drug Safety Helpline: 1 800 772 2215  
In Europe, Asia, Pacific, Africa and Australia: 
 
Email: MHGSafety@prahs.com 
 
Drug Safety Fax: +44 1792 525720 
 
SAE Questions: Drug Safety Helpline: +49 621 878 2154 
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. 


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Suspected Unexpected Serious Adverse Reaction (SUSAR) Identification and Reporting 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is a suspected adverse 
reaction that is both serious and unexpected (not identified in the Investigator’s 
Brochure29).  Sponsor will inform Investigators of SUSARs in a manner and timeframe 
consistent with applicable national regulatory requirements. 
The study will comply with all local regulatory requirements.  This study adheres to the 
definition and reporting requirements of ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting. 
8 
STUDY COMMITTEES 
8.1 
Study Steering Committee 
A study steering committee (SSC – VISION-DMD) will be responsible for protocol 
development, review of any study amendments, and coordination of study conduct and 
interpretation of study results.  The SSC comprises the Sponsor, study chairs and medical 
monitors for the VBP15-003, VBP15-LTE, VBP15-004, and other studies, as applicable, 
the project managers, and the patient representatives.   
8.2 
Data and Safety Monitoring Board 
An unblinded Data and Safety Monitoring Board (DSMB), operating autonomously from 
the SSC and the site investigators, will be responsible for providing independent 
recommendations to the SSC about risk-benefit of the study and for any modification 
affecting safety or data integrity required during the course of the study.  The DSMB 
members must not be actively involved in study design, conduct or daily management of 
this study and must not have financial, propriety, professional, or other interests that may 
affect impartial, independent decision-making.  
Specialists may be invited to participate as non-voting members at any time if additional 
expertise is desired.  The DSMB will formally interact with the SSC through the sharing 
of blinded DSMB meeting minutes.  
The DSMB will be responsible for: 


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• 
Examining accumulating safety and other relevant data at pre-specified points 
during the course of the study in order to make recommendations concerning 
continuation, termination, or modification of the study; 
• 
Reviewing important protocol deviations; 
• 
Providing expert advice to the SSC on an ad hoc basis regarding matters such as 
safety concerns or diagnostic evaluations in individual subjects; 
• 
Based on the results of its deliberations, the DSMB can recommend continuation 
of the studies unchanged, study interruption, study termination, modification of 
the studies, or alteration in the DSMB monitoring plan. 
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, 
and/or x-rays.  Data collected during this study must be recorded in the appropriate 
source documents. 
Investigators will keep a record relating the names of the subjects to their enrollment 
numbers (subject identification log) to permit efficient verification of data subject files, 
when required. 
A subject enrollment log is to be completed at each study site.  Data recorded on the 
enrollment log are to include a subject identifier, the dates of enrollment and 
completion/termination, and the reason the subject was not entered (if applicable).   
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. 


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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 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 database 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).   
The Coordinating Center data management team will monitor the eCRFs for 
completeness and acceptability throughout the course of the study.  ReveraGen personnel 
(or their representatives) will be allowed read-only 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 10.9 and the Statistical 
Analysis Plan (SAP).  


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9.4 
Subject Diaries 
The information recorded in the diary will be considered source documentation, and any 
relevant requested information recorded in the diary should be transcribed by study staff 
to the appropriate eCRF page. 
10 STATISTICAL METHODS AND PLANNED ANALYSES 
10.1 Sample Size Determination 
This is a randomized, double-blind, parallel group, placebo- and active-controlled study.  
Study medication is administered daily in this Phase IIb trial.  Data for untreated subjects 
from the Cooperative International Neuromuscular Research Group (CINRG) Duchenne 
Natural History Study38,39,40,41 and data for prednisone treated subjects from the CINRG 
Prednisone study42 were used to help estimate sample sizes for this study.  
In the vamorolone VBP15-003 study and the interim analysis of the VBP15-LTE study, 
doses of 0.25 and 0.75 mg/kg/day showed little evidence of clinical benefit, whereas 
doses of 2.0 and 6.0 mg/kg/day both showed clear evidence of clinical benefit 
comparable to that seen with glucocorticoids (prednisone and deflazacort). 
In consideration of the primary efficacy endpoint, comparison of 6.0 mg/kg/day 
vamorolone versus placebo, sample size calculations were performed using data from 
vamorolone-treated subjects from the VBP15-002/VBP15-003 24-week treatment period.  
The analysis compared TTSTAND velocity from the combined 2.0 and 6.0 mg/kg/day 
groups (Treatment Group) to the combined 0.25 and 0.75 mg/kg/day groups (Pseudo-
Placebo Group).   
Least squares (LS) means from the mixed model for repeated measures (MMRM) 
modeling of VBP15-002/VBP15-003 24-week data were used as parameter estimates of 
the population means in the sample size calculations for the comparison of the Treatment 
Group (2.0 + 6.0 mg/kg/day) vs. the Pseudo-Placebo Group (0.25 + 0.75 mg/kg/day) on 
the mean change from baseline at Week 24.  For the estimates of standard deviations 
within each comparison group, simple descriptive statistics from the 


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VBP15-002/VBP15-003 24-week data were used.  Power was estimated using two-sided 
t-tests assuming unequal variance, with alpha =0.05.  
The following table shows the resultant estimated power for various sample sizes per 
comparison group for comparing the Treatment Group (2.0 + 6.0 mg/kg/day) vs. the 
Pseudo-Placebo Group (0.25 + 0.75 mg/kg/day) on the mean change from baseline at 
Week 24 for the alternative hypothesis that H1: μ1 ≠ μ2 assuming an alpha level of 0.05 
and parameter estimates from the analyses described above for TTSTAND velocity: 
Sample Size per 
Comparison Group 
μ1 
(Pseudo-
Placebo) 
μ2 
(Treatment 
Group) 
σ1 
(Pseudo-
Placebo) 
σ2 
(Treatment 
Group) 
Estimated 
Power 
25 
-0.0052 
0.0450 
0.0628 
0.0530 
84.89% 
28 
-0.0052 
0.0450 
0.0628 
0.0530 
88.76% 
30 
-0.0052 
0.0450 
0.0628 
0.0530 
90.81% 
 
The sample size of 25 per treatment group for 2.0 mg/kg/day, 6.0 mg/kg/day, prednisone, 
and placebo will result in a total enrollment of 100 subjects which will provide 
approximately 85% power at alpha level 0.05 to detect a statistically significant 
difference between 6.0 mg/kg/day and placebo on TTSTAND velocity at Week 24.  
Similarly, a total enrollment of 120 subjects (30 per treatment group) will provide 
approximately 91% power at alpha level 0.05 to detect a statistically significant 
difference between 6.0 mg/kg/day and placebo on TTSTAND velocity at Week 24. 
Note that subjects in the prednisone and placebo groups will actually be randomized into 
two groups each: 
• Prednisone 0.75 mg/kg/day ® Vamorolone 2.0 mg/kg/day (n=15);  
• Prednisone 0.75 mg/kg/day ® Vamorolone 6.0 mg/kg/day (n=15); 
• Placebo ® Vamorolone 2.0 mg/kg/day (n=15); or  
• Placebo ® Vamorolone 6.0 mg/kg/day (n=15). 
These groups will be pooled by initial treatment (prednisone or placebo) for the 
Treatment Period #1 analyses. 


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If the number of subjects who withdraw early from the study is high, additional subjects 
may be enrolled to achieve approximately 120 subjects completing the Week 24 Visit 
assessments. 
10.2 Statistical and Analytical Plan (SAP) 
The sections below summarize the intended statistical methods and analyses for this 
study.  A more detailed SAP will be written and finalized prior to any lock of the study 
database (final or interim, if applicable) and any analysis performed.  The SAP will give 
a detailed description of the summaries and analyses that will be performed and will 
clearly describe when these analyses will take place.   
10.2.1 Deviations from the Statistical Analysis Plan 
Any deviation(s) from the original SAP will be described and justified in the clinical 
study report. 
10.3 Analysis Populations 
Four populations will be defined for data analysis: the Safety Population, the modified 
Intent-to-Treat Population, the Per Protocol Population (PPP), and the Pharmacokinetic 
Population.   
10.3.1 Safety Population  
All subjects who receive at least one dose of study medication will be included in the 
Safety Population.  The Safety Population is the primary analysis population for safety 
and PD assessments.  Results will be presented “as treated.” 
10.3.2 Modified Intent-to-Treat (mITT) Population  
All subjects who receive at least one dose of study medication and have at least one post-
baseline assessment will be included in the mITT Population.  The mITT Population is 
the primary analysis population for clinical efficacy.  Subjects who receive at least one 
dose but never have post-baseline assessments will be excluded.  Results will be 
presented “as randomized.” 


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10.3.3 Per Protocol Population 
The Per Protocol Population (PPP) will be those subjects in the mITT Population who 
had no major protocol deviations and will be the secondary analysis population for 
analysis of the efficacy data.  The PPP will also exclude some subjects because of missed 
assessments due to the COVID-19 pandemic.  Exclusion of subjects from the PPP will be 
made on a subject-by-subject basis prior to database hard lock 
10.3.4 Pharmacokinetic (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. 
10.4 Measures Taken to Avoid/Minimize Bias 
Not applicable. 
10.5 Interim Analysis 
No formal interim statistical analyses are planned; however, interim safety data and 
overviews will be supplied to the DSMB.  Since this is a blinded study, an unblinded and 
independent statistician will be involved in preparing the overviews for the DSMB.  
These overviews will not be shared outside the unblinded and independent statistician 
and the unblinded DSMB members. 
10.6 Week 24 Analysis 
The primary analyses for this study are the analyses which will be performed after all 
subjects complete Week 24 of Treatment Period #1.  The results from these analyses will 
be provided to regulatory authorities.  Investigators, study subjects, study staff, and 
monitors will remain blinded throughout the duration of the 52-week study.  The 
Sponsor, including data management and statistical personnel, will be unblinded after the 
Week 24 analyses.   
10.7 Week 48 Analysis 
The Week 48 analyses will be performed after all subjects complete Week 48 of 
Treatment Period #2.  The results from these analyses will be provided to regulatory 


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authorities.  All study staff may be unblinded after database lock of Treatment Period #2 
data. 
10.8 Missing, Unused, and Spurious Data 
The primary analyses for the primary and secondary efficacy variables will be conducted 
on observed data only; the MMRMs will employ appropriate covariance structures to 
accommodate missing data, as described in Section 10.9.4.  Missing efficacy data will be 
imputed for supportive sensitivity analyses on the primary and secondary efficacy 
endpoints using the following methods: 
• Multiple Imputations using Markov Chain Monte Carlo (MCMC); and 
• Multiple Imputations using a Control-based Pattern Mixture Model. 
Full details will be provided in the SAP. 
10.9 Statistical Analysis 
10.9.1 General Considerations 
Statistical analyses will be performed using SAS® version 9.4 or later. 
All measurements will be analyzed based upon the type of distribution, and descriptive 
statistics will be presented by treatment group and assessment time point, as appropriate.  
Descriptive statistics for continuous variables (number [N], mean, median, standard 
deviation [SD], minimum, and maximum), descriptive statistics for categorical variables 
(N and percentage), and individual subject profiles will be presented, as appropriate.   
No formal interim statistical analyses are planned, apart from the interim data views and 
presentations to be created for the DSMB.  Missing values for safety and exploratory 
outcomes will be treated as missing, unless stated otherwise. 
Baseline measurement is defined as the last non-missing value prior to the first dose of 
study drug in the study.  
Treatment Period #1 analyses will be summarized by four treatment groups: 
• Vamorolone 2.0 mg/kg/day (n=30);  
• Vamorolone 6.0 mg/kg/day (n=30); 


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• Prednisone 0.75 mg/kg/day (n=30); and 
• Placebo (n=30). 
 
Treatment Period #2 analyses (besides historical control comparison data) will be 
summarized by six treatment groups: 
• Vamorolone 2.0 mg/kg/day ® Vamorolone 2.0 mg/kg/day (n=30);  
• Vamorolone 6.0 mg/kg/day ® Vamorolone 6.0 mg/kg/day (n=30); 
• Prednisone 0.75 mg/kg/day ® Vamorolone 2.0 mg/kg/day (n=15);  
• Prednisone 0.75 mg/kg/day ® Vamorolone 6.0 mg/kg/day (n=15); 
• Placebo ® Vamorolone 2.0 mg/kg/day (n=15); and  
• Placebo ® Vamorolone 6.0 mg/kg/day (n=15). 
TTSTAND, TTCLIMB, and TTRW will be analyzed using raw scores and velocity.  
Velocity will be calculated as follows: 
• 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 
Sensitivity analyses will be performed and will be described in the SAP. 
10.9.2 Adjustment for Multiple Comparisons 
The primary efficacy endpoint tests vamorolone 6.0 mg/kg/day vs. placebo using 
TTSTAND velocity at Week 24 and occurs during Treatment Period #1 of the study.  The 
primary efficacy endpoint supports the primary objective of this study.  The study is thus 
powered for the efficacy comparison using an alpha level of 0.05 for success.   
The secondary efficacy endpoints will be tested at Week 24 along with the primary 
efficacy endpoint using a fixed sequential testing process where the fixed sequence of 
testing will be done in the following order: 
1. TTSTAND velocity, vamorolone 2.0 mg/kg/day vs placebo 
2. 6 Minute Walk Test (6MWT) meters walked, vamorolone 6.0 mg/kg/day vs. 
placebo 


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3. 6 Minute Walk Test (6MWT) meters walked, vamorolone 2.0 mg/kg/day vs. 
placebo 
4. Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 6.0 mg/kg/day vs. 
placebo 
5. Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 2.0 mg/kg/day vs. 
placebo 
6. 6MWT meters walked, vamorolone 6.0 mg/kg/day vs. prednisone 
7. 6MWT meters walked, vamorolone 2.0 mg/kg/day vs. prednisone 
Each test in the sequence will be carried out using a two-sided alpha level of 0.05.  
Statistical testing of the primary/secondary efficacy endpoints will stop if a p-value >0.05 
occurs or if a p-value ≤ 0.05 occurs in the wrong direction.  In case the fixed sequential 
testing process stops, the results of the subsequent tests will be reported with nominal 
p-values, but p-values ≤ 0.05 in the right direction will not be considered proof of 
statistical testing success in these subsequent tests. 
All other analyses will not be corrected for multiple comparisons (tests will be performed 
at the 0.05 alpha level), as they will be viewed and handled in the perspective of not 
testing a formal hypothesis. 
10.9.3 Subject Disposition, Demographics, and Baseline Characteristics 
Subject disposition will be summarized by analysis population.  The number of subjects 
enrolled, the number in each population, and the reason for discontinuation from the 
study will be summarized and listed. 
Subject demographics (e.g., age, race, and ethnicity) and baseline characteristics (e.g., 
height, weight, and months/years since DMD diagnosis) will be summarized 
descriptively by treatment group and overall, per analysis population.  Baseline 
characteristics between groups presented in these summary tables will be reviewed for 
any clinically relevant differences among the treatment groups, and may be accounted for 
in the statistical models for the endpoints. 


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10.9.4 Efficacy Analyses  
The evaluations of clinical efficacy will be performed using the mITT Population and 
PPP.  Analyses will be done as per randomized treatment. 
All efficacy will be summarized and listed.  Where considered relevant, plots will be 
created. 
The primary efficacy outcome is Time to Stand (TTSTAND) from supine (velocity), 
comparison of vamorolone 6.0 mg/kg/day vs. placebo.  Secondary and exploratory 
efficacy outcomes are TTSTAND (velocity), comparison of vamorolone 2.0 mg/kg/day 
vs. placebo; the NSAA assessment; Time to Climb four stairs (TTCLIMB) (velocity); 
Time to Run/Walk 10 meters (TTRW) (velocity); the distance walked in 6 minutes 
(6MWT); hand-held myometry (elbow flexors and knee extensors); and ROM.  
The primary efficacy outcome TTSTAND (velocity) change from baseline to Week 24 
will be compared between the 6.0 mg/kg/day vamorolone dose group and the placebo 
group using a restricted maximum likelihood (REML)-based mixed model for repeated 
measures (MMRM).  This model includes fixed effects for treatment (vamorolone 2.0 
mg/kg/day, vamorolone 6.0 mg/kg/day, prednisone 0.75 mg/kg/day, and placebo), week, 
baseline TTSTAND, age group (per stratification), and the treatment-by-week 
interaction.  Study week will be included in the model as a categorical variable (Weeks 6, 
12, and 24) along with the treatment-by-week interaction.  Within this model, pairwise 
comparisons (using least squares [LS] mean contrasts) will be made to compare 
TTSTAND velocity at 24 weeks for the vamorolone 6.0 mg/kg/day dose level with 
placebo (primary efficacy outcome).   
For secondary outcomes, the same models will be used as for the primary outcome 
(REML-based MMRM including fixed effects for treatment [vamorolone 2.0 mg/kg/day, 
vamorolone 6.0 mg/kg/day, prednisone 0.75 mg/kg/day, and placebo], age group 
[<6 years; ≥ 6 years], week, baseline, and treatment-by-week interaction). 
An unstructured covariance matrix will be used, and underlying modelling assumptions 
will be checked.  If differences between baseline characteristics exist between the 
treatment groups, it will be investigated if adjustment for these characteristics is clinically 


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relevant and necessary.  The secondary outcome measures will be compared using similar 
models.  Full details will be provided in the SAP. 
The following sensitivity analyses will be performed (see SAP for full details) for the 
primary efficacy and secondary efficacy endpoints: 
• Multiple imputations using MCMC methods for missing data; 
• Multiple imputations using a Control-based Pattern-Mixture Model for missing 
data. 
Additional sensitivity analyses will be performed to assess the impact of COVID-19 on 
the primary endpoint.  Supportive analyses will also be performed on the primary 
endpoint.  Full details will be provided in the SAP. 
Subjects who are randomized to receive vamorolone 2.0 mg/kg/day or vamorolone 
6.0 mg/kg/day for both treatment periods will have TTSTAND velocity change from 
baseline data captured over 48 weeks compared with untreated DMD historical control 
data.  Full details will be provided in the SAP. 
10.9.5 Safety Analyses 
The Safety Population will be used for presentations and analyses of the safety 
parameters.  Analyses will be done as per actual treatment received.  
In general, descriptive statistics for each safety endpoint will be presented by time point 
and treatment group.  In addition, individual subject listings of all safety data will be 
created and sorted by treatment group and time point, and will be reviewed for any 
evidence of dose-related differences or trends in the safety profile of vamorolone.  Where 
considered relevant, plots will be created. 
Safety data will include BMI, weight, vital signs, 2D-echocardiogram, DXA scan, spine 
X-ray, eye examination results, and ACTH Stimulation Test results, and ECG results, and 
these will be presented using descriptive statistics.  Safety laboratory data will be 
summarized using descriptive statistics, and out-of-range values will be listed.  For safety 
analyses, the vamorolone doses during Treatment Period #1 will be compared to 
prednisone, as specified in the SAP.   


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In Treatment Period #1, BMI z-score change from baseline results will be compared 
between treatment groups using an REML-based MMRM analysis with treatment group, 
week of the visit, and the treatment-by-week interaction as factors, and baseline BMI 
z-score and age group as a covariate.  Week will be included in the model as a categorical 
variable (Week 12 and 24) along with the treatment-by-week interaction.  An 
unstructured within-subject covariance matrix will be used.  If this analysis fails to 
converge, Akaike’s information criterion will be used to select the best covariance 
structure from compound symmetry and autoregressive-1 (AR(1)).  The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. 
Change from baseline in all continuous clinical laboratory test results will be tested using 
one sample t-tests with p-values presented along with the descriptive statistics at each 
assessment visit within each treatment group (note that pharmacodynamic biomarkers - 
CK for efficacy, fasting glucose and insulin for insulin resistance, and GLDH for safety - 
will be of special interest). 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 20.  The incidence of AEs will be summarized overall and by 
treatment group, SOC and preferred term; treatment group, SOC, preferred term, and 
intensity (CTCAE v 4.03 grade); and treatment group, SOC, preferred term, and 
relationship to study drug.  Additional AE analyses will be at the subject level: the 
number of subjects who had any AE, the distribution of number of AEs per subject within 
a treatment group, worst intensity in a subject within a treatment group, highest level of 
relationship to study treatment for each subject within a treatment group.  Adverse events 
associated with suicidality and abuse potential will be listed.  Full details will be provided 
in the SAP. 
Physical examination results will be listed only.   
10.9.6 Pharmacodynamic Analyses 
The evaluations of PD biomarkers will be performed using the Safety Population. 
Analyses will be done as per actually received treatment. 
All PD biomarker results will be summarized and listed.  


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Serum PD biomarkers of adrenal axis suppression, insulin resistance, and bone turnover 
will be assessed.  PD biomarkers will be analyzed using MMRMs similar to the primary 
efficacy model.  Plots will be created.  Additional exploratory PD biomarkers of both 
safety and efficacy may be assessed.  Vamorolone-treated groups will be compared to 
both prednisone-treated and placebo groups. 
10.9.7 Patient-Reported Outcome Exploratory Analyses 
Patient Reported Outcomes including the TSQM, PODCI, PARS III, Ease of Study 
Medication Administration Assessment, and the Blindedness Assessment will be listed 
and presented using descriptive statistics by treatment and time point.  In addition, 
comparison will be made for each vamorolone dose group with placebo for the PODCI 
and for each vamorolone dose group with prednisone and placebo for the PARS III, with 
p values computed for the comparisons.  Full details will be provided in the SAP. 
10.9.8 Pharmacokinetic Analyses 
The 2-hr post-dose plasma concentration measurements of vamorolone at Week 30 will 
be used for comparison of drug exposures between the two dosing groups.  They will be 
added to PK data from previous studies in DMD boys for comparison with measurements 
obtained in healthy adult male subjects.  All PK data will be combined in a population 
assessment of plasma concentrations in relation to dose and age of subjects.  The PK 
population will be used for these analyses.  A separate PK Analysis Plan will be created 
to further discuss these analyses. 
10.9.9 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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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 and ICH E6 Guideline for Good Clinical 
Practice (GCP). 
Further, the trial will be conducted in accordance with all applicable laws, guidances and 
directives of the jurisdiction where the study is being conducted 
11.2 Investigator Responsibilities 
11.2.1 Subject Information and Informed Consent 
It is the Investigator’s responsibility to ensure that parent(s)/guardian(s) give(s) informed 
consent before the subject is admitted to the study, in accordance with ICH guidelines on 
GCP and all applicable laws, guidances and directives of the jurisdiction where the study 
is being conducted. 
If applicable, 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 written in a language they 
understand. 
The Investigator or designee will review the study with the parent(s)/guardian(s) 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(s)/guardian(s) of the subject.  The 
Investigator or designee and the parent(s)/guardian(s) of the subject must both sign and 
date the ICF after review and before the subject can participate in the study.  The 
parent(s)/guardian(s) of the subject will receive a copy of the signed and dated form, and 


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the original will be retained in the site study files.  The Investigator or designee must 
emphasize to the parent(s)/guardian(s) 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 relevant 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, 
as per ICH guidelines on GCP and all applicable laws, guidances and directives of the 
jurisdiction where the study is being conducted.  The Investigator will also keep 
documentation of study approval by internal committees per institutional requirements.  
It is the responsibility of the Sponsor to notify the competent authority of the Member 
State concerned and/or the IEC of any substantial amendment(s) to the protocol. 
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 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 


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approval, except when required to eliminate apparent immediate hazards to the subjects.  
In cases where any implemented deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial participants is implemented without prior IRB/IEC 
approval, the implemented deviation should be notified as soon as possible not only to 
the IRB/IEC for review and approval/favorable opinion but also to the regulatory 
authority(ies). 
While the study is ongoing and at study completion/discontinuation, the Investigator must 
submit to the IRB/IEC the following information in accordance with applicable 
regulatory requirements where the study is being conducted: 
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. 
11.2.3 Study Documentation 
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 
• 
Investigator Protocol Agreement form signed by the Investigator 
• 
IRB/IEC-approved copy of the ICF 


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• 
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 
• 
Investigator/site study contract. 
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 (see Before the Start of the 
Study) 
• 
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. 
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 


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• 
Subject enrollment log 
• 
Subject identification log 
• 
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  
11.3.1 Protocol Deviation Definitions 
Protocol deviations should be documented in accordance with the Manual of Operations. 
Protocol Deviation 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol 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. 
Important Protocol Deviation 
An important protocol deviation is a deviation from the IRB/IEC-approved protocol that 
may significantly 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. 


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11.3.2 
Reporting Important Protocol Deviations 
Upon discovery of an important protocol deviation, the Investigator is responsible for 
reporting the important protocol deviation to the IRB/IEC and Sponsor or designee 
(Coordinating Center) within 24 hours of discovery, or according to local site 
requirements. 
All deviations must be recorded in the CTMS. 
11.4 Study Records Retention and Direct Access to Source Documents 
Following completion of the clinical study, the medical files of trial subjects as well as 
other essential documents shall be retained by the Sponsor and the Investigator for at 
least 10 years after completion of the clinical trial, or for a period of time as required by 
the applicable regulatory authority. 
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 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. 
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 identification log 
3. Subject enrollment log 
4. Record of all relevant communications between the Investigator and the IRB/IEC 
5. Composition of the IRB/IEC 


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6. Record of all relevant communications between the Investigator and the Sponsor 
(or designee) 
7. 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 
8. Drug accountability records (See Section 5.8.4) 
9. Record of any body fluids or tissue samples retained 
10. All other source documents (subject records, hospital records, laboratory records, 
etc.) 
11. 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: 
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. 


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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. 
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. 


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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. 
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  
2. Failure of the Investigator to comply with applicable laws and/or pertinent 
regulations 
3. Submission of knowingly false information from the research facility to the 
Sponsor, Study Monitor, or regulatory authorities 
4. Insufficient adherence to protocol requirements. 


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If participation of a study site 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 relevant 
regulations where the study is being conducted.  
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. 
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.  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 applicable data protection / privacy laws in the relevant countries. 
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 


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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. 
12.2 Publication 
ReveraGen BioPharma, Inc. 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 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 ReveraGen 
BioPharma, Inc. or another entity delegated by ReveraGen BioPharma, Inc. 
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 


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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. 
13 INVESTIGATOR PROTOCOL AGREEMENT 
The Investigator Protocol Agreement at the front of this document must be signed by the 
study site Principal Investigator.  The Investigator must retain the original and an 
electronic signed copy must be kept on file by the Sponsor.  The completed Protocol 
Agreement signifies review and acceptance of the protocol amendment by the Principal 
Investigator prior to initiation of the study. 


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28. Moon HJ, Choi KH, Lee SI, Lee OJ, Shin JW, and Kim TW. Changes in 
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32. Agwu, J.C., et al., Tests of adrenal insufficiency. Arch Dis Child, 1999. 80(4): 
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33. van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Oral 
corticosteroids and fracture risk: relationship to daily and cumulative doses. 
Rheumatology (Oxford). 2000 Dec; 39(12): 1383-9. 
34. FDA Draft Guidance for Industry: Duchenne muscular dystrophy and related 
dystrophinopathies: developing drugs for treatment. June 2015. 
35. 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. 
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37. 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. 
38. Bello L, Kesari A, Gordish-Dressman H, et al. Genetic modifiers of 
ambulation in the Cooperative International Neuromuscular Research Group 
Duchenne natural history study. Ann Neurol. 2015; 77(4):684-696. 
39. Spurney C, Shimizu R, Morgenroth LP, et al. Cooperative International 
Neuromuscular Research Group Duchenne Natural History Study 
demonstrates insufficient diagnosis and treatment of cardiomyopathy in 
Duchenne muscular dystrophy. Muscle Nerve. 2014; Aug; 50(2):250-256.  
40. McDonald CM, Henricson EK, Abresch RT, et al. The Cooperative 
International Neuromuscular Research Group Duchenne natural history study 
– a longitudinal investigation in the era of glucocorticoid therapy: design of 
protocol and the methods used. Muscle Nerve. 2013; 48(1):32-54.  
41. Henricson EK, Abresch RT, Cnaan A, et al. The Cooperative International 
Neuromuscular Research Group Duchenne natural history study: 
glucocorticoid treatment preserves clinically meaningful function milestones 
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and other commonly used clinical trial outcome measures. Muscle Nerve. 
2013; 48(1):55-67. 
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weekend vs. daily prednisone in Duchenne muscular dystrophy. Neurology. 
2011; 77(5):444-452. 
 
 


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15 APPENDICES 
 
 


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Appendix 15.1 
Protocol Amendment #4 Complete List of Changes 
The following changes have been incorporated into the protocol under this protocol 
amendment, as summarized in Protocol Amendment Tracking, Reasons for Protocol 
Amendment #4.  Protocol sections that have been changed are itemized below with the 
original and revised text.  Correction of typographical errors is not itemized. 
Sections Changed: 
Synopsis: Primary Objectives, #1 
Section 2.1.1: Primary Objectives, #1 
Original Text: 
1. To compare the efficacy of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg 
over a 24-week treatment period vs. placebo in ambulant boys ages 4 to <7 years with DMD; and  
Revised Text: 
1. To compare the efficacy of vamorolone administered orally at daily doses of 6.0 mg/kg over a 24-week 
treatment period vs. placebo in ambulant boys ages 4 to <7 years with DMD; and  
Sections Changed: 
Synopsis: Secondary Objectives, #1-3 
Section 2.1.2: Secondary Objectives, #1-3 
Original Text: 
1. To compare the safety of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg 
over a 24-week treatment period vs. daily prednisone 0.75 mg/kg in ambulant boys ages 4 to <7 years 
with DMD; 
2. To compare the efficacy of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg 
over a 24-week treatment period vs. daily prednisone 0.75 mg/kg in ambulant boys ages 4 to <7 years 
with DMD;  
3. To compare the efficacy of vamorolone administered orally at daily doses of 2.0 mg/kg vs. vamorolone 
administered orally at daily doses of 6.0 mg/kg over a 24-week treatment period in ambulant boys ages 
4 to <7 years with DMD; 
Revised Text: 
1. To compare the efficacy of vamorolone administered orally at daily doses of 2.0 mg/kg over a 24-week 
treatment period vs. placebo in ambulant boys ages 4 to <7 years with DMD; 
2. To compare the safety of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg 
over a 24-week treatment period vs. daily prednisone 0.75 mg/kg in ambulant boys ages 4 to <7 years 
with DMD; 
3. To compare the efficacy of vamorolone administered orally at daily doses of 2.0 mg/kg and 6.0 mg/kg 
over a 24-week treatment period vs. daily prednisone 0.75 mg/kg in ambulant boys ages 4 to <7 years 
with DMD; 


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Section Changed: 
Synopsis: Synopsis, Pharmacodynamic Measures, sentence #2 
Original Text: 
Secondary outcomes are serum biomarkers bridged to clinical outcomes of safety, including adrenal 
suppression, insulin resistance, bone turnover, and immune suppression.   
Revised Text: 
Secondary outcomes are serum biomarkers bridged to clinical outcomes of safety, including adrenal 
suppression, insulin resistance, and bone turnover.   
Sections Changed: 
Synopsis: Statistical Methods, Sample Size, paragraphs #2 and #3 
Section 10.1: Sample Size Determination, paragraphs #2 and #3 
Original Text: 
The primary efficacy outcome is TTSTAND (velocity) change from baseline to Week 24.  A sample size of 
30 subjects per treatment group (120 total subjects) will detect a 0.0674 point difference in mean change 
from baseline to Week 24 in TTSTAND (velocity) between a vamorolone dose level and placebo, 
assuming a common standard deviation of 0.08, a two-sided t test, and a Type-I error of 0.025 with 
approximately 83% power.  The Bonferroni adjustment method will be used to control the Type-I error rate 
at 0.05 due to the multiple comparisons (2 vamorolone dose levels will be tested against placebo). 
Based on this calculation, a total of approximately 120 subjects will be randomized to treatment with 
vamorolone 2.0 mg/kg/day (n=30), vamorolone 6.0 mg/kg/day (n=30), prednisone 0.75 mg/kg/day (n=30), 
or placebo (n=30). 
Revised Text: 
In the vamorolone VBP15-003 study and the interim analysis of the VBP15-LTE study, doses of 0.25 and 
0.75 mg/kg/day showed little evidence of clinical benefit, whereas doses of 2.0 and 6.0 mg/kg/day both 
showed clear evidence of clinical benefit comparable to that seen with glucocorticoids (prednisone and 
deflazacort). 
In consideration of the primary efficacy endpoint in the current study, comparison of 6.0 mg/kg/day 
vamorolone versus placebo, sample size calculations were performed using data from vamorolone-treated 
subjects from the VBP15-002/VBP15-003 24-week treatment period.  The analysis compared TTSTAND 
velocity from the combined 2.0 and 6.0 mg/kg/day groups (Treatment Group) to the combined 0.25 and 
0.75 mg/kg/day groups (Pseudo-Placebo Group).   
Least squares (LS) means from the mixed model for repeated measures (MMRM) modeling of VBP15-
002/VBP15-003 24-week data were used as parameter estimates of the population means in the sample size 
calculations for the comparison of the Treatment Group (2.0 + 6.0 mg/kg/day) vs. the Pseudo-Placebo 
Group (0.25 + 0.75 mg/kg/day) on the mean change from baseline at Week 24.  For the estimates of 
standard deviations within each comparison group, simple descriptive statistics from the VBP15-
002/VBP15-003 24-week data were used.  Power was estimated using two-sided t-tests assuming unequal 
variance, with alpha =0.05.  
The following table shows the resultant estimated power for various sample sizes per comparison group for 
comparing the Treatment Group (2.0 + 6.0 mg/kg/day) vs. the Pseudo-Placebo Group (0.25 + 0.75 
mg/kg/day) on the mean change from baseline at Week 24 for the alternative hypothesis that H1: μ1 ≠ μ2 


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assuming an alpha level of 0.05 and parameter estimates from the analyses described above for TTSTAND 
velocity: 
Sample Size 
per 
Comparison 
Group 
μ1 
(Pseudo-
Placebo) 
μ2 
(Treatment 
Group) 
σ1 
(Pseudo-
Placebo) 
σ2 
(Treatment 
Group) 
Estimated 
Power 
25 
-0.0052 
0.0450 
0.0628 
0.0530 
84.89% 
28 
-0.0052 
0.0450 
0.0628 
0.0530 
88.76% 
30 
-0.0052 
0.0450 
0.0628 
0.0530 
90.81% 
The sample size of 25 per treatment group for 2.0 mg/kg/day, 6.0 mg/kg/day, prednisone, and placebo will 
result in a total enrollment of 100 subjects which will provide approximately 85% power at alpha level 0.05 
to detect a statistically significant difference between 6.0 mg/kg/day and placebo on TTSTAND velocity at 
Week 24.  Similarly, a total enrollment of 120 subjects (30 per treatment group) will provide approximately 
91% power at alpha level 0.05 to detect a statistically significant difference between 6.0 mg/kg/day and 
placebo on TTSTAND velocity at Week 24. 
Section Changed: 
Synopsis: Statistical Methods, Analysis Populations 
Original Text: 
Three populations will be defined for data analysis: the Safety Population, the modified Intent-to-Treat 
Population, and the Pharmacokinetic Population. 
Safety Population 
All subjects who receive at least one dose of study medication will be included in the Safety Population.  
The Safety Population is the primary analysis population for safety and PD assessments.  Results will be 
presented “as treated.” 
Modified Intent-to-Treat (mITT) Population 
All subjects who receive at least one dose of study medication and have at least one post-baseline 
assessment will be included in the mITT Population.  The mITT Population is the primary analysis 
population for clinical efficacy.  Subjects who receive at least one dose of study medication but never have 
post-baseline assessments will be excluded.  Results will be presented “as randomized.” 
Pharmacokinetic (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. 
Revised Text: 
Four populations will be defined for data analysis: the Safety Population, the modified Intent-to-Treat 
Population, the Per Protocol Population (PPP), and the Pharmacokinetic (PK) Population. 
Safety Population 
All subjects who receive at least one dose of study medication will be included in the Safety Population.  
The Safety Population is the primary analysis population for safety and PD assessments.  Results will be 
presented “as treated.” 
Modified Intent-to-Treat (mITT) Population 
All subjects who receive at least one dose of study medication and have at least one post-baseline 
assessment will be included in the mITT Population.  The mITT Population is the primary analysis 
population for clinical efficacy.  Subjects who receive at least one dose of study medication but never have 
post-baseline assessments will be excluded.  Results will be presented “as randomized.” 


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Per Protocol Population 
The PPP will be those subjects in the mITT Population who had no major protocol deviations and will be 
the secondary analysis population for analysis of the efficacy data.  The PPP will also exclude some 
subjects because of missed assessments due to the COVID-19 pandemic.  Exclusion of subjects from the 
PPP will be made on a subject-by-subject basis prior to database hard lock. 
Pharmacokinetic (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. 
Sections Changed: 
Synopsis: Statistical Methods, Adjustment for Multiple Comparisons, paragraphs 
#1-4 
Section 10.9.2: Adjustment for Multiple Comparisons, paragraphs #1-4 
Original Text: 
The primary efficacy endpoint tests each dose of vamorolone vs. placebo using TTSTAND velocity at 
Week 24 and occurs during Treatment Period #1 of the study.  The primary efficacy endpoint supports the 
primary objective of this study.  The study is thus powered for the efficacy comparisons.   
A multi-branched gatekeeping procedure will be utilized for the primary efficacy endpoint.  The primary 
efficacy endpoint (TTSTAND velocity at Week 24) will be tested first using a Bonferroni adjustment.  Any 
dose that is significant for the primary efficacy endpoint will then have the secondary efficacy endpoints 
tested sequentially.  Further details are provided below. 
For primary efficacy (TTSTAND velocity), the two vamorolone dose levels will be compared with 
placebo.  To account for these comparisons (two vamorolone dose levels vs. placebo), Bonferroni multiple 
comparison adjustments will be utilized.  Each comparison will be conducted at the 0.025 (0.05/2) alpha 
level.  
Secondary efficacy endpoints will be tested sequentially on change from baseline to Week 24 values (each 
dose of vamorolone vs. placebo or prednisone [6MWT only]).  Only the doses that are significant for the 
primary efficacy endpoint (change in TTSTAND velocity at Week 24) will have the secondary endpoints 
tested.  A 0.025 alpha level will be used for the sequential testing.  Testing will stop once a p-value is 
>0.025 for one of the secondary efficacy endpoints.  The Week 24 change from baseline values will be 
tested using this sequential testing procedure.  The order of the secondary efficacy endpoints is as follows. 
1. Six-minute Walk Test (6MWT) vs. placebo 
2. Time to Run/Walk 10 meters Test (TTRW) velocity vs. placebo 
3. 6MWT vs. prednisone 
4. North Star Ambulatory Assessment (NSAA) vs. placebo 
5. Hand-held Myometry (knee extensors) vs. placebo 
6. Hand-held Myometry (elbow flexors) vs. placebo 
7. Time to Climb 4 Steps (TTCLIMB) velocity vs. placebo 
8. Range of Motion (ROM) in the ankles vs. placebo 
Revised Text: 
The primary efficacy endpoint tests vamorolone 6.0 mg/kg/day vs. placebo using TTSTAND velocity at 
Week 24 and occurs during Treatment Period #1 of the study.  The primary efficacy endpoint supports the 
primary objective of this study.  The study is thus powered for the efficacy comparison using an alpha level 
of 0.05 for success.   


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The secondary efficacy endpoints will be tested at Week 24 along with the primary efficacy endpoint using 
a fixed sequential testing process where the fixed sequence of testing will be done in the following order: 
1. TTSTAND velocity, vamorolone 2.0 mg/kg/day vs placebo 
2. 6 Minute Walk Test (6MWT) meters walked, vamorolone 6.0 mg/kg/day vs. placebo 
3. 6 Minute Walk Test (6MWT) meters walked, vamorolone 2.0 mg/kg/day vs. placebo 
4. Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 6.0 mg/kg/day vs. placebo 
5. Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 2.0 mg/kg/day vs. placebo 
6. 6MWT meters walked, vamorolone 6.0 mg/kg/day vs. prednisone 
7. 6MWT meters walked, vamorolone 2.0 mg/kg/day vs. prednisone 
Each test in the sequence will be carried out using a two-sided alpha level of 0.05.  Statistical testing of the 
primary/secondary efficacy endpoints will stop if a p-value >0.05 occurs or if a p-value ≤ 0.05 occurs in the 
wrong direction.  In case the fixed sequential testing process stops, the results of the subsequent tests will 
be reported with nominal p-values, but p-values ≤ 0.05 in the right direction will not be considered proof of 
statistical testing success in these subsequent tests. 
Section Changed: 
Synopsis: Statistical Methods, Efficacy Analysis, paragraphs #1 and #2 
Original Text: 
All evaluations of clinical efficacy will be listed and presented using descriptive statistics per treatment 
group and time point.  The primary efficacy outcome is TTSTAND (velocity).  Secondary efficacy 
outcomes are the NSAA assessment, TTCLIMB, TTRW, 6MWT, hand-held myometry (elbow flexors and 
knee extensors), and ROM.  TTSTAND, TTCLIMB, and TTRW will be analyzed using raw scores and 
velocity.   
The primary efficacy outcome TTSTAND (velocity) change from baseline to Week 24 will be compared 
between each of the two different vamorolone dose groups and the placebo group using a restricted 
maximum likelihood (REML)-based mixed model for repeated measures (MMRM).  This model includes 
fixed effects for treatment (vamorolone 2.0 mg/kg/day, vamorolone 6.0 mg/kg/day, prednisone 0.75 
mg/kg/day, and placebo), week, baseline TTSTAND, age group (per stratification), and the treatment-by-
week interaction.  Study week will be included in the model as a categorical variable (Weeks 6, 12, and 24) 
along with the treatment-by-week interaction.  Within this model, pairwise comparisons (using least 
squares [LS] mean contrasts) will be made to compare TTSTAND at 24 weeks for each vamorolone dose 
level with placebo separately (primary efficacy outcome), for each vamorolone dose level with prednisone 
separately (secondary analysis), and for the high vamorolone dose level with the low vamorolone dose 
level (secondary analysis).  Treatments will also be compared at other weeks as secondary analyses.  An 
unstructured covariance matrix will be used, and underlying modelling assumptions will be checked.  If 
differences between baseline characteristics exist between the three treatment groups in this comparison, it 
will be investigated if adjustment for these characteristics is clinically relevant and necessary.  The 
secondary outcome measures will be compared using similar models. 
Revised Text: 
All evaluations of clinical efficacy will be listed and presented using descriptive statistics per treatment 
group and time point.  The primary efficacy outcome is TTSTAND (velocity), comparison of vamorolone 
6.0 mg/kg/day vs placebo.  Secondary and exploratory efficacy outcomes are TTSTAND (velocity), 
comparison of vamorolone 2.0 mg/kg/day vs placebo; the NSAA assessment; TTCLIMB (velocity); TTRW 
(velocity); 6MWT; hand-held myometry (elbow flexors and knee extensors); and ROM.   
The primary efficacy outcome TTSTAND (velocity) change from baseline to Week 24 will be compared 
between the 6.0 mg/kg/day vamorolone dose group and the placebo group using a restricted maximum 
likelihood (REML)-based mixed model for repeated measures (MMRM).  This model includes fixed 


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effects for treatment (vamorolone 2.0 mg/kg/day, vamorolone 6.0 mg/kg/day, prednisone 0.75 mg/kg/day, 
and placebo), week, baseline TTSTAND, age group (per stratification), and the treatment-by-week 
interaction.  Study week will be included in the model as a categorical variable (Weeks 6, 12, and 24) along 
with the treatment-by-week interaction.  Within this model, pairwise comparisons (using least squares [LS] 
mean contrasts) will be made to compare TTSTAND velocity at 24 weeks for the vamorolone 6.0 
mg/kg/day dose level with placebo (primary efficacy outcome).  
For secondary outcomes, the same models will be used as for the primary outcome (REML-based MMRM 
including fixed effects for treatment [vamorolone 2.0 mg/kg/day, vamorolone 6.0 mg/kg/day, prednisone 
0.75 mg/kg/day, and placebo], age group [<6 years; ≥ 6 years], week, baseline, and treatment-by-week 
interaction). 
An unstructured covariance matrix will be used, and underlying modelling assumptions will be checked.  If 
differences between baseline characteristics exist between the treatment groups, it will be investigated if 
adjustment for these characteristics is clinically relevant and necessary.  The secondary outcome measures 
will be compared using similar models. 
Sensitivity analyses will be performed to assess the impact of COVID-19 on the primary endpoint.  
Additional sensitivity and supportive analyses will be performed on the primary and secondary outcomes.  
Full details will be provided in the SAP. 
Sections Changed: 
Synopsis: Statistical Methods, Patient Reported Outcome Analyses 
Section 10.9.7: Patient Reported Outcome Exploratory Analyses 
Original Text: 
Patient Reported Outcomes including the TSQM, PODCI, PARS III, Ease of Study Medication 
Administration Assessment, and the Blindedness Assessment will be listed and presented using descriptive 
statistics by treatment and time point.  In addition, comparison will be made for each vamorolone dose 
group with placebo for the PODCI and for each vamorolone dose group with prednisone for the PARS III, 
with p values computed for the comparisons.  Full details will be provided in the SAP. 
Revised Text: 
Patient Reported Outcomes including the TSQM, PODCI, PARS III, Ease of Study Medication 
Administration Assessment, and the Blindedness Assessment will be listed and presented using descriptive 
statistics by treatment and time point.  In addition, comparison will be made for each vamorolone dose 
group with placebo for the PODCI and for each vamorolone dose group with prednisone and placebo for 
the PARS III, with p values computed for the comparisons.  Full details will be provided in the SAP. 
Section Changed: 
Synopsis: Statistical Methods, Safety Analyses 
Original Text: 
All evaluations of clinical safety will be listed and presented using descriptive statistics per treatment group 
and time point.  For the safety analyses, the vamorolone dose levels will be compared to prednisone.   
Safety data will include BMI, weight, vital signs, 2D-echocardiogram, DXA scan, spine x-ray, eye 
examination results, ACTH Stimulation Test results, and ECG results, and these will be presented using 
descriptive statistics.  Safety laboratory data will be summarized using descriptive statistics, and out-of-
range values will be listed.  Adverse events will be summarized overall and by treatment group, system 
organ class (SOC) and preferred term (using the Medical Dictionary for Regulatory Activities [MedDRA]); 
by treatment group and relationship to study medication; and by treatment group and intensity (CTCAE 
grade).   


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In Treatment Period #1, BMI z-score change from baseline data captured over 24 weeks will be compared 
for subjects who are randomized to receive vamorolone 2.0 mg/kg/day or vamorolone 6.0 mg/kg/day vs. 
subjects randomized to receive prednisone.  The same MMRM that is used for the primary efficacy analysis 
will be used for BMI z-score.  The test for statistical significance will be performed at the 0.05 level.  
Subjects who are randomized to receive vamorolone 2.0 mg/kg/day or vamorolone 6.0 mg/kg/day for both 
treatment periods will have their BMI z-score change from baseline data captured over 48 weeks compared 
with prednisone-treated DMD historical control data.  Full details will be provided in the SAP.  
Revised Text: 
All evaluations of clinical safety will be listed and presented using descriptive statistics per treatment group 
and time point.  For the safety analyses during Treatment Period #1, the vamorolone dose levels will be 
compared to prednisone, as specified in the SAP.   
Safety data will include BMI, weight, vital signs, 2D-echocardiogram, DXA scan, spine x-ray, eye 
examination results, ACTH Stimulation Test results, and ECG results, and these will be presented using 
descriptive statistics.  Safety laboratory data will be summarized using descriptive statistics, and out-of-
range values will be listed.  Adverse events will be summarized overall and by treatment group, system 
organ class (SOC) and preferred term (using the Medical Dictionary for Regulatory Activities [MedDRA]); 
by treatment group and relationship to study medication; and by treatment group and intensity (CTCAE 
grade).  Suicidality and abuse potential associated with treatment will be assessed by examination of 
adverse event data.  Full details will be provided in the SAP. 
In Treatment Period #1, BMI z-score change from baseline results will be compared between treatment 
groups using an REML-based MMRM analysis with treatment group, week of the visit, and the treatment-
by-week interaction as factors, and baseline BMI z-score and age group as a covariate.  Week will be 
included in the model as a categorical variable (Week 12 and 24) along with the treatment-by-week 
interaction.  An unstructured within-subject covariance matrix will be used.  If this analysis fails to 
converge, Akaike’s information criterion will be used to select the best covariance structure from 
compound symmetry and autoregressive-1 (AR(1)).  The Kenward-Roger approximation will be used to 
estimate denominator degrees of freedom. 
Change from baseline in all continuous clinical laboratory test results will be tested using one sample t-tests 
with p-values presented along with the descriptive statistics at each assessment visit within each treatment 
group. 
Sections Changed: 
Synopsis: Statistical Methods, Pharmacodynamics Analyses, sentence #1 
Section 10.9.6: Pharmacodynamic Analyses, sentence #1 
Original Text: 
Serum PD biomarkers of adrenal axis suppression, insulin resistance, bone turnover, and immune 
suppression will be assessed.   
Revised Text: 
Serum PD biomarkers of adrenal axis suppression, insulin resistance, and bone turnover will be assessed.   
Section Changed: 
List of Abbreviations 
Original Text: 


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PK 
pharmacokinetics 
PODCI 
Pediatric Outcomes Data Collection Instrument 
PR [PQ] 
time from onset of P wave to start of the QRS complex 
QD 
once daily (dosing) 
Revised Text: 
PK 
pharmacokinetics 
PODCI 
Pediatric Outcomes Data Collection Instrument 
PPP 
Per Protocol Population 
PR [PQ] 
time from onset of P wave to start of the QRS complex 
QD 
once daily (dosing) 
Section Changed: 
Section 1.4: Rationale for Study Design, paragraph #5 
Original Text: 
The primary efficacy outcome is the Time to Stand (TTSTAND) from the floor 
(velocity), and comparisons will be made between each dose level of vamorolone and the 
placebo group at Week 24.  Multiple secondary efficacy outcomes will be measured, 
including Time to Run/Walk 10 meters (TTRW), Time to Climb four stairs (TTCLIMB), 
North Star Ambulatory Assessment (NSAA), 6-Minute Walk Test (6MWT), Range of 
Motion test (ROM), and hand-held myometry (elbow flexors and knee extensors).  
Exploratory measures of efficacy include PD biomarkers that have previously been 
shown to be glucocorticoid-responsive in DMD boys and inflammatory bowel disease in 
children.31  Moreover, physical functioning, behavior, neuropsychology, and satisfaction 
with treatment will be measured as exploratory efficacy outcomes using the parent proxy-
report of Pediatric Outcomes Data Collection Instrument (PODCI), PARS III, Treatment 
Satisfaction Questionnaire (TSQM), and Ease of Study Medication Administration 
Assessment for the study medication suspension, respectively.   
Revised Text: 
The primary efficacy outcome is the Time to Stand (TTSTAND) from the floor 
(velocity), and comparison will be made between the 6.0 mg/kg/day dose level of 
vamorolone and the placebo group at Week 24.  Multiple secondary and exploratory 


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efficacy outcomes will be measured, including TTSTAND, Time to Run/Walk 10 meters 
(TTRW), Time to Climb four stairs (TTCLIMB), North Star Ambulatory Assessment 
(NSAA), 6-Minute Walk Test (6MWT), Range of Motion test (ROM), and hand-held 
myometry (elbow flexors and knee extensors).  Additional exploratory measures of 
efficacy include PD biomarkers that have previously been shown to be glucocorticoid-
responsive in DMD boys and inflammatory bowel disease in children.31  Moreover, 
physical functioning, behavior, neuropsychology, and satisfaction with treatment will be 
measured as exploratory outcomes using the parent proxy-report of Pediatric Outcomes 
Data Collection Instrument (PODCI), PARS III, Treatment Satisfaction Questionnaire 
(TSQM), and Ease of Study Medication Administration Assessment for the study 
medication suspension, respectively.   
Section Changed: 
Section 1.4: Rationale for Study Design, paragraph #6, item #4  
Original Text: 
4. 
Immune suppression.  Glucocorticoids can cause immunosuppression.  The 
measure of differential lymphocyte percentage can be a biomarker for immune 
suppression. 
Revised Text: 
none 
Section Changed: 
Section 1.5: Overall Benefit/Risk, paragraph #1  
Original Text: 
It is anticipated that the adverse effect profile of the investigational product will be more 
favorable than standard of care glucocorticoids in the long term.  There were no serious 
adverse events (SAEs) reported over the 14-day treatment in the Phase I clinical trial in 
healthy adult volunteers, nor in the four cohorts (0.25 mg/kg, 0.75 mg/kg, 2.0 mg/kg, and 
6.0 mg/kg) of the Phase IIa study (VBP15-002; 14-day treatment) in boys ages 4 to 
<7 years with DMD.  There have been a total of 7 SAEs in the Phase II VBP15-003 and 


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VBP15-LTE extension studies in DMD boys: two SAEs of pneumonia in two different 
subjects (both subjects receiving vamorolone 0.75 mg/kg/day), one SAE of bilateral 
testicular torsion and one SAE of hypoxia in the same subject receiving 6.0 mg/kg/day, 
one SAE of influenza associated dehydration in a subject receiving 6.0 mg/kg/day, and 
two SAEs of acute myoglobinuria in the same subject receiving 6.0 mg/kg/day.  Each of 
these SAEs was considered unrelated to study drug, and none of them resulted in 
discontinuation from the study.  In the Phase I clinical trial in adult volunteers, 
vamorolone showed mild elevations of liver enzymes in one subject receiving 20.0 mg/kg 
in the fasted state.  On the basis of mean GLDH and GGT data, vamorolone at dose 
levels up to 6.0 mg/kg/day did not appear to induce liver toxicity over a 24-week 
treatment period in the VBP15-003 study.  In the VBP15-002 study, after 2 weeks of 
treatment, 0 of 11 tested participants who received vamorolone 0.25 mg/kg/day, 0 of 11 
tested participants who received vamorolone 0.75 mg/kg/day, 2 of 11 (18.2%) tested 
participants who received vamorolone 2 mg/kg/day, and 6 of 10 (60.0%) tested 
participants who received vamorolone 6 mg/kg/day had a depressed morning cortisol 
(<3.6 μg/dL [100 nmol/L]) consistent with chronic adrenal suppression.  In the 
VBP15-003 study, after 24 weeks of treatment, 0 of 8 tested participants 
(0.25 mg/kg/day), 1 of 12 (8.3%) tested participants (0.75 mg/kg/day), 5 of 12 (41.7%) 
tested participants (2.0 mg/kg/day), and 8 of 9 (88.9%) tested participants 
(6.0 mg/kg/day) had a depressed morning cortisol (<3.6 μg/dL [100 nM]) consistent with 
chronic adrenal suppression.  Instructions for detecting adrenal crisis and the 
circumstances in which stress dose steroids should be provided will be included in the 
Informed Consent Form (ICF) and Manual of Operations, and Investigators should 
monitor clinical study participants closely to identify elevations in liver-specific 
enzymes.   
Revised Text: 
It is anticipated that the adverse effect profile of the investigational product will be more 
favorable than standard of care glucocorticoids in the long term.  There has been a total 
of 11 SAEs in the vamorolone program to date: a total of 4 SAEs in the VBP15-003 
study, a total of 3 SAEs in the VBP15-LTE study, a total of 3 SAEs in the VBP15-004 


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study, and 1 SAE in the VBP15-EAP program.  There have been two SAEs of pneumonia 
in two different subjects (both subjects receiving vamorolone 0.75 mg/kg/day); one SAE 
of bilateral testicular torsion and one SAE of hypoxia in the same subject receiving 6.0 
mg/kg/day; one SAE of influenza associated dehydration in a subject receiving 6.0 
mg/kg/day; two SAEs of acute myoglobulinemia in the same subject receiving 6.0 
mg/kg/day; one SAE of viral gastroenteritis with secondary dehydration in a subject 
receiving blinded study drug; one SAE of asthma exacerbation in the setting of 
respiratory syncytial virus and bronchiolitis in a subject receiving vamorolone at either 
2.0 mg/kg/day or 6.0 mg/kg/day; one SAE of perforated appendicitis occurring with 30 
days after the subject completed the VBP15-004 study, and one SAE of viral 
gastroenteritis requiring hospitalization for hydration.  Each of these SAEs was 
considered unrelated to study drug, and none of them resulted in discontinuation from the 
study.   
In the Phase I clinical trial in adult volunteers, vamorolone showed mild elevations of 
liver enzymes in one subject receiving 20.0 mg/kg in the fasted state.  One subject 
participating in VBP15-004 developed an AE of acute cholestatic hepatitis manifested by 
elevated transaminases, direct bilirubin, ALP and GGT during Treatment Period #1 and 
after study drug interruption and restart, redeveloped acute cholestatic hepatitis in 
Treatment Period #2.  Unblinding of the treatment assignment for this subject, to 
facilitate decisions regarding subsequent standard of care corticosteroid therapy, 
indicated that the subject had been on vamorolone 6.0 mg/kg/day in both Treatment 
Period #1 and Treatment Period #2.   
In the VBP15-002 study, after 2 weeks of treatment, 0 of 11 tested participants who 
received vamorolone 0.25 mg/kg/day, 0 of 11 tested participants who received 
vamorolone 0.75 mg/kg/day, 2 of 11 (18.2%) tested participants who received 
vamorolone 2 mg/kg/day, and 6 of 10 (60.0%) tested participants who received 
vamorolone 6 mg/kg/day had a depressed morning cortisol (<3.6 μg/dL [100 nmol/L]) 
consistent with chronic adrenal suppression.  In the VBP15-003 study, after 24 weeks of 
treatment, 0 of 8 tested participants (0.25 mg/kg/day), 1 of 12 (8.3%) tested participants 
(0.75 mg/kg/day), 5 of 12 (41.7%) tested participants (2.0 mg/kg/day), and 8 of 9 (88.9%) 


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tested participants (6.0 mg/kg/day) had a depressed morning cortisol (<3.6 μg/dL 
[100 nM]) consistent with chronic adrenal suppression.  Instructions for detecting adrenal 
crisis and the circumstances in which stress dose steroids should be provided will be 
included in the Informed Consent Form (ICF) and Manual of Operations, and 
Investigators should monitor clinical study participants closely to identify elevations in 
liver-specific enzymes.   
Section Changed: 
Section 2.2.1: Safety Endpoints, #1, #9, and #12 
Original Text: 
1. BMI z-score: Comparison of each vamorolone dose level group with the prednisone 
group in change from baseline to each of the scheduled on-treatment and post-
treatment assessment time points. 
Original Text: 
9. Dual-energy x-ray absorptiometry (DXA) scan: Change from baseline to Week 24 
and Week 48 in spine BMD, spine BMD z-score, total body BMD, spine and total 
body bone mass, and total body composition (lean mass, fat mass, fat-free mass, Lean 
Mass Index, and Fat Mass Index); 
Original Text: 
12. ACTH Stimulation Test: measure of adrenal suppression at Week 24 and Week 48.  
Adrenal suppression is likely if cortisol levels <18 µg/dL (or 500 nM) 30 or 
60 minutes after stimulation with Cosyntropin.  
Revised Text: 
1. BMI z-score: Change from baseline to each of the scheduled on-treatment and post-
treatment assessment time points; 
Revised Text: 
9. Dual-energy x-ray absorptiometry (DXA) scan: Change from baseline to Week 24 
and Week 48 in spine BMD, total body BMD, spine and total body bone mass, and 


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total body composition (lean mass, fat mass, fat-free mass, Lean Mass Index, and Fat 
Mass Index); 
Revised Text: 
12. ACTH Stimulation Test: measure of adrenal suppression at Week 24 and Week 48.  
Percentage of subjects in each treatment group with cortisol levels <18 µg/dL (or 
500 nM) 30 or 60 minutes after stimulation with Cosyntropin.  
13. Linear growth velocity: Change from baseline to each of the scheduled on-treatment 
and post-treatment assessment time points in height percentile for age.  
Section Changed: 
Section 2.2.1: Safety Endpoints, paragraph #15 
Original Text: 
none 
Revised Text: 
Tolerability Endpoint 
1. Premature discontinuations of study treatment due to adverse events. 
Section Changed: 
Section 2.2.2: Clinical Efficacy Endpoints 
Original Text: 
Primary Clinical Efficacy Endpoint 
1. 
Time to Stand Test (TTSTAND) velocity (rise/second): Comparison of each 
vamorolone dose level group versus the placebo group in change from baseline 
to the Week 24 assessment. 
Secondary Efficacy Endpoints 
1. 
Change from baseline to each of the scheduled study assessment time points for 
each treatment group up to Week 48, with comparison of each vamorolone dose 
level group versus the placebo group at each of the scheduled study assessment 
time points up to and including Week 24 for: 


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• Time to Stand Test (TTSTAND) velocity (rise/second) (other than Week 24); 
• Time to Climb (4 Steps) Test (TTCLIMB) velocity (tasks/second); 
• Time to Run/Walk Test (TTRW) velocity (meters/second) to complete 
10 meters of a 14 meter course; 
• Total distance traveled, in meters, in completing the Six-minute Walk Test 
(6MWT);  
• North Star Ambulatory Assessment (NSAA);  
• Hand-held myometry (elbow flexors and knee extensors); and 
• Range of motion in the ankles (ROM).  
2. 
Change from baseline with comparison of each vamorolone dose level group 
versus the prednisone group at each of the scheduled study assessment time 
points up to and including Week 24 for: 
• Total distance traveled, in meters, in completing the Six-minute Walk Test 
(6MWT). 
Revised Text: 
Primary Clinical Efficacy Endpoint 
1. 
Time to Stand Test (TTSTAND) velocity (rise/second): Comparison of the 
vamorolone 6.0 mg/kg/day dose level group versus the placebo group in change 
from baseline to the Week 24 assessment. 
Secondary Efficacy Endpoints 
1. 
Change from baseline to Week 24 for the following comparisons: 
• TTSTAND velocity, vamorolone 2.0 mg/kg/day vs placebo 
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 6.0 mg/kg/day vs. 
placebo 
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 2.0 mg/kg/day vs. 
placebo 


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• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 6.0 mg/kg/day 
vs. placebo 
• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 2.0 mg/kg/day 
vs. placebo 
• 6MWT meters walked, vamorolone 6.0 mg/kg/day vs. prednisone 
• 6MWT meters walked, vamorolone 2.0 mg/kg/day vs. prednisone 
2. 
Change from baseline to each of the scheduled study assessment time points for 
each treatment group up to Week 48 for: 
• Time to Stand Test (TTSTAND) velocity (rise/second); 
• Time to Climb (4 Steps) Test (TTCLIMB) velocity (tasks/second); 
• Time to Run/Walk Test (TTRW) velocity (meters/second) to complete 
10 meters of a 14 meter course; 
• Total distance traveled, in meters, in completing the Six-minute Walk Test 
(6MWT);  
• North Star Ambulatory Assessment (NSAA);  
• Hand-held myometry (elbow flexors and knee extensors); and 
• Range of motion in the ankles (ROM).  
Exploratory Efficacy Endpoints 
1. 
Change from baseline to each of the scheduled study assessment time points up 
to and including Week 24 for the following comparisons: 
• TTSTAND velocity, vamorolone 6.0 mg/kg/day vs placebo (Week 6 and 12 
only) 
• TTSTAND velocity, vamorolone 2.0 mg/kg/day vs placebo (Week 6 and 12 
only) 
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 6.0 mg/kg/day vs. 
placebo (Week 12 only) 


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• 6 Minute Walk Test (6MWT) meters walked, vamorolone 2.0 mg/kg/day vs. 
placebo (Week 12 only) 
• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 6.0 mg/kg/day 
vs. placebo (Week12 only) 
• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 2.0 mg/kg/day 
vs. placebo (Week12 only) 
• 6MWT meters walked, vamorolone 6.0 mg/kg/day vs. prednisone (Week 12 
only) 
• 6MWT meters walked, vamorolone 2.0 mg/kg/day vs. prednisone (Week 12 
only) 
• NSAA total score, vamorolone 6.0 mg/kg/day vs. placebo 
• NSAA total score, vamorolone 2.0 mg/kg/day vs. placebo 
• Hand-held Myometry knee extensors, vamorolone 6.0 mg/kg/day vs. 
placebo 
• Hand-held Myometry knee extensors, vamorolone 2.0 mg/kg/day vs. 
placebo 
• Hand-held Myometry elbow extensors, vamorolone 6.0 mg/kg/day vs. 
placebo 
• Hand-held Myometry elbow extensors, vamorolone 2.0 mg/kg/day vs. 
placebo 
• TTCLIMB velocity, vamorolone 6.0 mg/kg/day vs. placebo 
• TTCLIMB velocity, vamorolone 2.0 mg/kg/day vs. placebo 
• ROM in the ankles, vamorolone 6.0 mg/kg/day vs. placebo 
• ROM in the ankles, vamorolone 2.0 mg/kg/day vs. placebo 
Section Changed: 
Section 2.2.3: Exploratory Endpoints, #3 and #4 
Original Text: 
2.2.3 Exploratory Endpoints 


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3. Behavioral changes (PARS III): Comparison of each vamorolone dose level group 
to the prednisone group for change from baseline to each of the scheduled study 
assessment time points up to the Week 24 assessment; comparison of each 
treatment group for change from baseline to the Week 48 assessment; 
4. Ease of study medication administration assessed at each of the scheduled study 
assessment time points;  
Revised Text: 
2.2.3 Additional Exploratory Endpoints 
3. Behavioral changes (PARS III): Comparison of each vamorolone dose level group 
to the prednisone group and to the placebo group for change from baseline to each 
of the scheduled study assessment time points up to the Week 24 assessment; 
comparison of each treatment group for change from baseline to the Week 48 
assessment; 
4. Ease of study medication administration (Question 1 only: tablet vs liquid) 
assessed at each of the scheduled study assessment time points;  
Section Changed: 
Section 2.2.4: Pharmacodynamic Endpoints, #1b and #1d 
Original Text: 
2.2.4 Exploratory Endpoints 
b. Bone turnover.  Measures of serum osteocalcin are reflective of bone 
formation, and measures of serum CTX1 are reflective of bone 
reabsorption.  Ratios of osteocalcin and CTX1 predict later clinical safety 
concerns of osteopenia and bone fragility. 
d. Immune suppression.  Glucocorticoids can cause immunosuppression.  
Measure of differential lymphocyte percentage can be a biomarker for 
immune suppression. 
Revised Text: 
2.2.4 Exploratory Endpoints 


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b. Bone turnover.  Measures of serum osteocalcin are reflective of bone 
formation, and measures of serum CTX1 are reflective of bone 
reabsorption.  Levels of osteocalcin and CTX1 predict later clinical safety 
concerns of osteopenia and bone fragility. 
Section Changed: 
Section 5.4: Rationale for Dose Selection, paragraph #5 
Original Text: 
Vamorolone at doses of 0.25 mg/kg/day, 0.75 mg/kg/day, 2.0 mg/kg/day and 
6.0 mg/kg/day has been demonstrated to be safe and well-tolerated in a 2-week Phase IIa 
study (VBP15-002) in 4 to <7 years DMD boys.  The safety of these four doses continued 
to be studied in the 24-week Phase II extension study (VBP15-003) in 4 to 7 year-old 
DMD boys, and continues to be studied in the ongoing VBP15-LTE long-term extension 
study.  There were a total of 4 SAEs in the Phase II VBP15-003 study and three SAEs to 
date in the VBP15-LTE extension study: two SAEs of pneumonia in two different 
subjects (both subjects receiving vamorolone 0.75 mg/kg/day), one SAE of bilateral 
testicular torsion and one SAE of hypoxia in the same subject receiving 6.0 mg/kg/day, 
one SAE of influenza associated dehydration in a subject receiving 6.0 mg/kg/day, and 
two SAEs of acute myoglobinuria in the same subject receiving 6.0 mg/kg/day.  Each of 
these SAEs was considered unrelated to study drug, and none of them resulted in 
discontinuation from the study.  One subject receiving vamorolone 6.0 mg/kg in the 
Phase II extension study (VBP15-003) who had an incidental early morning cortisol 
drawn following an AE of presyncope had evidence of adrenal suppression.  In the 
VBP15-003 study, after 24 weeks of treatment, 0 of 8 tested participants (0.25 
mg/kg/day), 1 of 12 (8.3%) tested participants (0.75 mg/kg/day), 5 of 12 (41.7%) tested 
participants (2.0 mg/kg/day), and 8 of 9 (88.9%) tested participants (6.0 mg/kg/day) had a 
depressed morning cortisol (<3.6 μg/dL [100 nM]) consistent with chronic adrenal 
suppression.29  Thus, based on the available data in the Phase I and Phase II studies 
regarding the safety signal of suppression of the adrenal axis, the possibility of adrenal 
suppression is present in subjects at the 2.0 and 6.0 mg/kg/day dose levels.    


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Revised Text: 
Vamorolone at doses of 0.25 mg/kg/day, 0.75 mg/kg/day, 2.0 mg/kg/day and 
6.0 mg/kg/day has been demonstrated to be safe and well-tolerated in a 2-week Phase IIa 
study (VBP15-002) in 4 to <7 years DMD boys.    There has been a total of 11 SAEs in 
the vamorolone program to date: a total of 4 SAEs in the VBP15-003 study, a total of 3 
SAEs in the VBP15-LTE study, a total of 3 SAEs in the VBP15-004 study, and 1 SAE in 
the VBP15-EAP program.  There have been two SAEs of pneumonia in two different 
subjects (both subjects receiving vamorolone 0.75 mg/kg/day); one SAE of bilateral 
testicular torsion and one SAE of hypoxia in the same subject receiving 6.0 mg/kg/day; 
one SAE of influenza associated dehydration in a subject receiving 6.0 mg/kg/day; two 
SAEs of acute myoglobulinemia in the same subject receiving 6.0 mg/kg/day; one SAE 
of viral gastroenteritis with secondary dehydration in a subject receiving blinded study 
drug; one SAE of asthma exacerbation in the setting of respiratory syncytial virus and 
bronchiolitis in a subject receiving vamorolone at either 2.0 mg/kg/day or 6.0 mg/kg/day; 
one SAE of perforated appendicitis occurring with 30 days after the subject completed 
the VBP15-004 study, and one SAE of viral gastroenteritis requiring hospitalization for 
hydration.  Each of these SAEs was considered unrelated to study drug, and none of them 
resulted in discontinuation from the study.  One subject receiving vamorolone 6.0 mg/kg 
in the Phase II extension study (VBP15-003) who had an incidental early morning 
cortisol drawn following an AE of presyncope had evidence of adrenal suppression.  In 
the VBP15-003 study, after 24 weeks of treatment, 0 of 8 tested participants (0.25 
mg/kg/day), 1 of 12 (8.3%) tested participants (0.75 mg/kg/day), 5 of 12 (41.7%) tested 
participants (2.0 mg/kg/day), and 8 of 9 (88.9%) tested participants (6.0 mg/kg/day) had a 
depressed morning cortisol (<3.6 μg/dL [100 nM]) consistent with chronic adrenal 
suppression.29  Thus, based on the available data in the Phase I and Phase II studies 
regarding the safety signal of suppression of the adrenal axis, the possibility of adrenal 
suppression is present in subjects at the 2.0 and 6.0 mg/kg/day dose levels.    
Section Changed: 
Section 7.1.1: Genetic Modifiers of DMD, paragraph #4 


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Original Text: 
none 
Revised Text: 
Results will be presented in an addendum report. 
Section Changed: 
Section 7.2.6: Pharmacodynamic Biomarker Panel, paragraphs #1 and #2 
Original Text: 
Blood samples will be collected to explore the effect of vamorolone on biomarkers 
associated with glucocorticoid safety concerns (secondary outcomes for adrenal 
suppression, insulin resistance, bone turnover and immune suppression), as listed in 
Table 19.   
Blood samples will be collected pre-dose at the Day 1 and Weeks 12, 24, 28, 40, and 48 
Visits, and at the final Week 52 Dose-tapering Period Visit for analysis of biomarkers for 
secondary outcome measures of adrenal suppression, bone turnover, and insulin 
resistance.  Approximately 2 mL of blood will be collected for the PD biomarker panel 
(osteocalcin, P1NP, and CTX bone turnover markers) at each scheduled collection time 
point; blood samples for analysis of morning cortisol levels (adrenal suppression 
biomarker) and fasting glucose and insulin (insulin resistance biomarkers) will be 
collected as part of the clinical laboratory tests and require no additional blood volume.  
All samples will be collected after the subject has fasted for ≥ 6 hours and prior to 
administration of the daily dose of study medication at dosing visits.  Blood samples for 
analysis of immune suppression (differential lymphocyte percentage) will be collected as 
part of the clinical laboratory tests (see Section 7.2.4).  Blood remaining from collected 
samples not needed for protocol-specified analyses at each of these time points may be 
stored for future exploratory biomarker studies for aspects of safety and efficacy.  These 
remaining blood samples may be released to scientists worldwide for research purposes, 
including research on biomarkers in DMD.  Any released samples will have no 
identifying subject information.   


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Revised Text: 
Blood samples will be collected to explore the effect of vamorolone on biomarkers 
associated with glucocorticoid safety concerns (secondary outcomes for adrenal 
suppression, insulin resistance, and bone turnover), as listed in Table 19.   
Blood samples will be collected pre-dose at the Day 1 and Weeks 12, 24, 28, 40, and 48 
Visits, and at the final Week 52 Dose-tapering Period Visit for analysis of biomarkers for 
secondary outcome measures of adrenal suppression, bone turnover, and insulin 
resistance.  Approximately 2 mL of blood will be collected for the PD biomarker panel 
(osteocalcin, P1NP, and CTX bone turnover markers) at each scheduled collection time 
point; blood samples for analysis of morning cortisol levels (adrenal suppression 
biomarker) and fasting glucose and insulin (insulin resistance biomarkers) will be 
collected as part of the clinical laboratory tests and require no additional blood volume.  
All samples will be collected after the subject has fasted for ≥ 6 hours and prior to 
administration of the daily dose of study medication at dosing visits.  Blood remaining 
from collected samples not needed for protocol-specified analyses at each of these time 
points may be stored for future exploratory biomarker studies for aspects of safety and 
efficacy.  These remaining blood samples may be released to scientists worldwide for 
research purposes, including research on biomarkers in DMD.  Any released samples will 
have no identifying subject information.   


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Section Changed: 
Section 7.2.6: Pharmacodynamic Biomarker Panel, Table 19 
Original Text: 
Table 21. Pharmacodynamic Biomarkers – Secondary Safety Outcomes 
Adrenal Suppression 
Cortisol - morning 
Insulin Resistance 
Glucose – fasting 
Insulin - fasting 
Bone Turnover 
Osteocalcin 
CTX1 
P1NP 
Immune Suppression 
 Differential lymphocyte percentage 
Revised Text: 
Table 22. Pharmacodynamic Biomarkers – Secondary Safety Outcomes 
Adrenal Suppression 
Cortisol - morning 
Insulin Resistance 
Glucose – fasting 
Insulin - fasting 
Bone Turnover 
Osteocalcin 
CTX1 
P1NP 
Section Changed: 
Section 7.2.13: Bone Health and DXA Scan (total body and spine), paragraph #2 
Original Text: 
Antero-posterior spine (L1-L4) and total body (without head) bone mineral density 
(BMD) by DXA scan will be collected.  DXA quality control will be performed as 
described in the Manual of Operations.  DXA scans will be analyzed centrally by a 
certified medical radiation technologist at Children’s Hospital of Ottawa in Ottawa, 
Canada, and then age-specific z-scores will be generated in order to chart the differences 
in the change in BMD z-scores among the different groups participating in this trial.  The 


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Screening result will represent a baseline assessment for long-term follow up.  Additional 
DXA scanning may be arranged if clinically indicated throughout the study.  
Revised Text: 
Antero-posterior spine (L1-L4) and total body (without head) bone mineral density 
(BMD) by DXA scan will be collected.  DXA quality control will be performed as 
described in the Manual of Operations.  DXA scans will be analyzed centrally by a 
certified medical radiation technologist at Children’s Hospital of Ottawa in Ottawa, 
Canada.  The Screening result will represent a baseline assessment for long-term follow 
up.  Additional DXA scanning may be arranged if clinically indicated throughout the 
study.  
Section Changed: 
Section 7.2.14: Spine X-rays, paragraph #2 
Original Text: 
none 
Revised Text: 
Spine x-ray data will be analyzed in an addendum report. 
Section Changed: 
Section 7.5.6: Serious Adverse Events, paragraph #9 
Original Text: 
none 
Revised Text: 
Hospital admissions scheduled prior to the study are not considered SAEs unless the 
hospitalization is prolonged due to an adverse event.  Planned admissions as part of the 
study, hospitalizations for scheduled treatment of a preexisting condition that has not 
worsened, and hospitalization for an elective procedure are not considered SAEs.  
Hospitalizations for fewer than 24 hours and emergency room/department visits are not 
considered SAEs. 


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Section Changed: 
Section 10.3: Analysis Populations 
Original Text: 
Three populations will be defined for data analysis: the Safety Population, the modified 
Intent-to-Treat Population, and the Pharmacokinetic Population.   
Revised Text: 
Four populations will be defined for data analysis: the Safety Population, the modified 
Intent-to-Treat Population, the Per Protocol Population (PPP), and the Pharmacokinetic 
Population.   
Section Changed: 
Section 10.3.3: Pharmacokinetic (PK) Population 
Original Text: 
10.3.3 Pharmacokinetic (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. 
Revised Text: 
10.3.3 Per Protocol Population 
The Per Protocol Population (PPP) will be those subjects in the mITT Population who 
had no major protocol deviations and will be the secondary analysis population for 
analysis of the efficacy data.  The PPP will also exclude some subjects because of missed 
assessments due to the COVID-19 pandemic.  Exclusion of subjects from the PPP will be 
made on a subject-by-subject basis prior to database hard lock 
10.3.4 Pharmacokinetic (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. 
Section Changed: 
Section 10.9.3: Subject Disposition, Demographics, and Baseline Characteristics, 
paragraph #2 


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Original Text: 
Subject demographics (e.g., age, race, and ethnicity) and baseline characteristics (e.g., 
height, weight, and months/years since DMD diagnosis) will be summarized 
descriptively by treatment group and overall, per analysis population.  In addition, tables 
will be presented according to age stratification.  Baseline characteristics between groups 
presented in these summary tables will be reviewed for any clinically relevant differences 
among the treatment groups or age stratification groups, and may be accounted for in the 
statistical models for the endpoints. 
Revised Text: 
Subject demographics (e.g., age, race, and ethnicity) and baseline characteristics (e.g., 
height, weight, and months/years since DMD diagnosis) will be summarized 
descriptively by treatment group and overall, per analysis population.  Baseline 
characteristics between groups presented in these summary tables will be reviewed for 
any clinically relevant differences among the treatment groups, and may be accounted for 
in the statistical models for the endpoints. 
Section Changed: 
Section 10.9.4: Efficacy Analyses 
Original Text: 
The evaluations of clinical efficacy will be performed using the mITT Population.  
Analyses will be done as per randomized treatment. 
All efficacy will be summarized and listed.  Where considered relevant, plots will be 
created. 
The primary efficacy outcome is the Time to Stand (TTSTAND) from supine (velocity).  
Secondary efficacy outcomes are the NSAA assessment, Time to Climb four stairs 
(TTCLIMB), Time to Run/Walk 10 meters (TTRW) the distance walked in 6 minutes 
(6MWT), hand-held myometry (elbow flexors and knee extensors), and ROM.  
TTSTAND, TTCLIMB, and TTRW will be analyzed using raw scores and velocity. 


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The primary efficacy outcome TTSTAND (velocity) change from baseline to Week 24 
will be compared between each of the two different vamorolone dose groups and the 
placebo group using a restricted maximum likelihood (REML)-based mixed model for 
repeated measures (MMRM).  This model includes fixed effects for treatment 
(vamorolone 2.0 mg/kg/day, vamorolone 6.0 mg/kg/day, prednisone 0.75 mg/kg/day, and 
placebo), week, baseline TTSTAND, age group (per stratification), and the treatment-by-
week interaction.  Study week will be included in the model as a categorical variable 
(Weeks 6, 12, and 24) along with the treatment-by-week interaction.  Within this model, 
pairwise comparisons (using least squares [LS] mean contrasts) will be made to compare 
TTSTAND at 24 weeks for each vamorolone dose level with placebo separately (primary 
efficacy outcome), for each vamorolone dose level with prednisone separately (secondary 
analysis), and for the high vamorolone dose level with the low vamorolone dose level 
(secondary analysis).  Treatments will also be compared at other weeks as secondary 
analyses.  An unstructured covariance matrix will be used, and underlying modelling 
assumptions will be checked.  If differences between baseline characteristics exist 
between the three treatment groups in this comparison, it will be investigated if 
adjustment for these characteristics is clinically relevant and necessary.  The secondary 
outcome measures will be compared using similar models.  Full details will be provided 
in the SAP. 
The following sensitivity or supportive analyses will be performed (see SAP for full 
details) for the primary efficacy and secondary efficacy endpoints: 
• Multiple imputations using MCMC methods for missing data; 
• Multiple imputations using a Control-based Pattern-Mixture Model for missing 
data. 
Subjects who are randomized to receive vamorolone 2.0 mg/kg/day or vamorolone 
6.0 mg/kg/day for both treatment periods will have TTSTAND velocity change from 
baseline data captured over 48 weeks compared with untreated DMD historical control 
data.  Full details will be provided in the SAP. 


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Revised Text: 
The evaluations of clinical efficacy will be performed using the mITT Population and 
PPP.  Analyses will be done as per randomized treatment. 
All efficacy will be summarized and listed.  Where considered relevant, plots will be 
created. 
The primary efficacy outcome is Time to Stand (TTSTAND) from supine (velocity), 
comparison of vamorolone 6.0 mg/kg/day vs. placebo.  Secondary and exploratory 
efficacy outcomes are TTSTAND (velocity), comparison of vamorolone 2.0 mg/kg/day 
vs. placebo; the NSAA assessment; Time to Climb four stairs (TTCLIMB) (velocity); 
Time to Run/Walk 10 meters (TTRW) (velocity); the distance walked in 6 minutes 
(6MWT); hand-held myometry (elbow flexors and knee extensors); and ROM.  
The primary efficacy outcome TTSTAND (velocity) change from baseline to Week 24 
will be compared between the 6.0 mg/kg/day vamorolone dose group and the placebo 
group using a restricted maximum likelihood (REML)-based mixed model for repeated 
measures (MMRM).  This model includes fixed effects for treatment (vamorolone 2.0 
mg/kg/day, vamorolone 6.0 mg/kg/day, prednisone 0.75 mg/kg/day, and placebo), week, 
baseline TTSTAND, age group (per stratification), and the treatment-by-week 
interaction.  Study week will be included in the model as a categorical variable (Weeks 6, 
12, and 24) along with the treatment-by-week interaction.  Within this model, pairwise 
comparisons (using least squares [LS] mean contrasts) will be made to compare 
TTSTAND velocity at 24 weeks for the vamorolone 6.0 mg/kg/day dose level with 
placebo (primary efficacy outcome).   
For secondary outcomes, the same models will be used as for the primary outcome 
(REML-based MMRM including fixed effects for treatment [vamorolone 2.0 mg/kg/day, 
vamorolone 6.0 mg/kg/day, prednisone 0.75 mg/kg/day, and placebo], age group [<6 
years; ≥ 6 years], week, baseline, and treatment-by-week interaction). 
An unstructured covariance matrix will be used, and underlying modelling assumptions 
will be checked.  If differences between baseline characteristics exist between the 
treatment groups, it will be investigated if adjustment for these characteristics is clinically 


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relevant and necessary.  The secondary outcome measures will be compared using similar 
models.  Full details will be provided in the SAP. 
The following sensitivity analyses will be performed (see SAP for full details) for the 
primary efficacy and secondary efficacy endpoints: 
• Multiple imputations using MCMC methods for missing data; 
• Multiple imputations using a Control-based Pattern-Mixture Model for missing 
data. 
Additional sensitivity analyses will be performed to assess the impact of COVID-19 on 
the primary endpoint.  Supportive analyses will also be performed on the primary 
endpoint.  Full details will be provided in the SAP. 
Subjects who are randomized to receive vamorolone 2.0 mg/kg/day or vamorolone 
6.0 mg/kg/day for both treatment periods will have TTSTAND velocity change from 
baseline data captured over 48 weeks compared with untreated DMD historical control 
data.  Full details will be provided in the SAP. 
Section Changed: 
Section 10.9.5: Safety Analyses, paragraphs #3-5 
Original Text: 
Safety data will include BMI, weight, vital signs, 2D-echocardiogram, DXA scan, spine 
X-ray, eye examination results, and ACTH Stimulation Test results, and ECG results, and 
these will be presented using descriptive statistics.  Safety laboratory data will be 
summarized using descriptive statistics, and out-of-range values will be listed.  For safety 
analyses, the vamorolone doses will be compared to prednisone.   
In Treatment Period #1, BMI z-score change from baseline data captured over 24 weeks 
will be compared for subjects who are randomized to receive vamorolone 2.0 mg/kg/day 
or vamorolone 6.0 mg/kg/day vs. subjects randomized to receive prednisone.  The same 
MMRM that is used for the primary efficacy analysis will be used for BMI z-score.  The 
test for statistical significance will be performed at the 0.05 level.  Subjects who are 
randomized to receive vamorolone 2.0 mg/kg/day or vamorolone 6.0 mg/kg/day for both 


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treatment periods will have their BMI z-score change from baseline data captured over 48 
weeks compared with prednisone-treated DMD historical control data.  Full details will 
be provided in the SAP. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 20.  The incidence of AEs will be summarized overall and by 
treatment group, SOC and preferred term; treatment group, SOC, preferred term, and 
intensity (CTCAE v 4.03 grade); and treatment group, SOC, preferred term, and 
relationship to study drug.  Additional AE analyses will be at the subject level: the 
number of subjects who had any AE, the distribution of number of AEs per subject within 
a treatment group, worst intensity in a subject within a treatment group, highest level of 
relationship to study treatment for each subject within a treatment group. 
Revised Text: 
Safety data will include BMI, weight, vital signs, 2D-echocardiogram, DXA scan, spine 
X-ray, eye examination results, and ACTH Stimulation Test results, and ECG results, and 
these will be presented using descriptive statistics.  Safety laboratory data will be 
summarized using descriptive statistics, and out-of-range values will be listed.  For safety 
analyses, the vamorolone doses during Treatment Period #1 will be compared to 
prednisone, as specified in the SAP.   
In Treatment Period #1, BMI z-score change from baseline results will be compared 
between treatment groups using an REML-based MMRM analysis with treatment group, 
week of the visit, and the treatment-by-week interaction as factors, and baseline BMI z-
score and age group as a covariate.  Week will be included in the model as a categorical 
variable (Week 12 and 24) along with the treatment-by-week interaction.  An 
unstructured within-subject covariance matrix will be used.  If this analysis fails to 
converge, Akaike’s information criterion will be used to select the best covariance 
structure from compound symmetry and autoregressive-1 (AR(1)).  The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. 
Change from baseline in all continuous clinical laboratory test results will be tested using 
one sample t-tests with p-values presented along with the descriptive statistics at each 


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assessment visit within each treatment group (note that pharmacodynamic biomarkers - 
CK for efficacy, fasting glucose and insulin for insulin resistance, and GLDH for safety - 
will be of special interest). 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 20.  The incidence of AEs will be summarized overall and by 
treatment group, SOC and preferred term; treatment group, SOC, preferred term, and 
intensity (CTCAE v 4.03 grade); and treatment group, SOC, preferred term, and 
relationship to study drug.  Additional AE analyses will be at the subject level: the 
number of subjects who had any AE, the distribution of number of AEs per subject within 
a treatment group, worst intensity in a subject within a treatment group, highest level of 
relationship to study treatment for each subject within a treatment group.  Adverse events 
associated with suicidality and abuse potential will be listed.  Full details will be provided 
in the SAP. 

SAP_003.pdf: 
 
 
 
ReveraGen BioPharma, Inc. 
 
STATISTICAL ANALYSIS PLAN 
for Protocol VBP15-004 Treatment Period #1  
 
 
Protocol Title: 
A Phase IIb Randomized, Double-blind, Parallel Group, 
Placebo- and Active-controlled Study with Double-Blind 
Extension to Assess the Efficacy and Safety of Vamorolone in 
Ambulant Boys with Duchenne Muscular Dystrophy (DMD) 
Protocol Number 
VBP15-004 
Phase: 
Phase IIb 
Sponsor: 
ReveraGen BioPharma, Inc. 
155 Gibbs Street  
 
Suite 433 
Rockville, MD  20850 
 
Author: 
Summit Analytical, LLC 
8354 Northfield Blvd., Bldg. G Suite 3700 
Denver, CO 80238 
SAP Date: 
17 May 2021 
Status: 
Final Version 3.0 
 
 
 


ReveraGen BioPharma, Inc. 
 
Final Version 3.0 
Study VBP15-004 Statistical Analysis Plan 
 
17 May 2021 
IND#: 118,942
 
CONFIDENTIAL 
 
P a g e  | 2 
 
 
Statistical Analysis Plan Approval Form 
Sponsor: 
ReveraGen BioPharma, Inc. 
Protocol: 
VBP15-004 
Protocol Title: 
 
A Phase IIb Randomized, Double-blind, Parallel Group, Placebo- and Active-
controlled Study with Double-Blind Extension to Assess the Efficacy and 
Safety of Vamorolone in Ambulant Boys with Duchenne Muscular Dystrophy 
(DMD) 
SAP Version: 
Final v3.0 
SAP Date: 
17 May 2021 
 
The statistical analysis plan has been reviewed and approved. 
 
Sponsor: 
ReveraGen BioPharma, Inc. 
 
 
Eric Hoffman, PhD 
 
 
CEO 
 
 
 
 
 
 
 
 
Signature  
Date  
 
 
 
Author: 
Summit Analytical LLC 
 
 
Philip Shale, PhD 
 
 
Biostatistics 
 
 
 
 
 
 
 
 
Signature 
Date 
 
 
 
Reviewer:
Santhera Pharmaceuticals 
 
 
Mika Leinonen 
 
 
Head Biostatistics 
 
Signature
Date
Reviewer:
The Camden Group LLC 
 
 
Benjamin D. Schwartz, MD, PhD 
 
 
Consulting Medical Monitor 
 
 
 
 
 
 
 
 
Signature 
Date 


ReveraGen BioPharma, Inc. 
 
Final Version 3.0 
Study VBP15-004 Statistical Analysis Plan 
 
17 May 2021 
IND#: 118,942 
 
CONFIDENTIAL 
 
P a g e  | 3 
1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ............................................................................................................................... 3 
2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................... 6 
3. 
INTRODUCTION .......................................................................................................................................... 8 
3.1. 
Preface ............................................................................................................................................... 8 
3.2. 
Purpose of Analyses .......................................................................................................................... 8 
3.3. 
Summary of Statistical Analysis Changes to the Protocol ................................................................ 9 
4. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................... 11 
4.1. 
Study Objectives .............................................................................................................................. 11 
4.1.1. 
Primary Objectives ........................................................................................................ 11 
4.1.2. 
Secondary Objectives .................................................................................................... 11 
4.1.3. 
Exploratory Objectives .................................................................................................. 11 
4.2. 
Study Endpoints ............................................................................................................................... 12 
4.2.1. 
Safety Endpoints ............................................................................................................ 12 
4.2.2. 
Tolerability Endpoint ..................................................................................................... 13 
4.2.3. 
Efficacy Endpoints ........................................................................................................ 13 
4.2.4. 
Exploratory Patient-reported Outcomes Endpoints ....................................................... 14 
4.2.5. 
Pharmacodynamic Endpoints ........................................................................................ 15 
5. 
STUDY METHODS .................................................................................................................................... 16 
5.1. 
General Study Design and Plan ....................................................................................................... 16 
5.2. 
Inclusion – Exclusion Criteria and General Study Population ........................................................ 22 
5.3. 
Randomization and Blinding ........................................................................................................... 22 
5.4. 
Analysis Variables ........................................................................................................................... 22 
6. 
SAMPLE SIZE ............................................................................................................................................. 23 
7. 
GENERAL CONSIDERATIONS ................................................................................................................ 25 
7.1. 
Analysis Populations ....................................................................................................................... 25 
7.1.1. 
Safety Population ........................................................................................................... 25 
7.1.2. 
Modified Intent-to-Treat (mITT) Population ................................................................ 25 
7.1.3. 
Per Protocol Population ................................................................................................. 25 
7.2. 
Covariates and Subgroups ............................................................................................................... 26 
7.2.1. 
Planned Covariates ........................................................................................................ 26 
7.2.2. 
Subgroups ...................................................................................................................... 26 
7.3. 
Management of Analysis Data ........................................................................................................ 26 
7.3.1. 
Data Handling ................................................................................................................ 26 
7.3.2. 
Missing Data .................................................................................................................. 26 
7.3.3. 
Handling of Early Termination Visit Information ......................................................... 32 
7.3.4. 
Pooling of Investigational Sites ..................................................................................... 32 
7.3.5. 
Coding Conventions for Events and Medications ......................................................... 32 
7.3.6. 
Baseline Visits ............................................................................................................... 32 
7.3.7. 
Calculating Derived Variables ...................................................................................... 32 
7.3.8. 
Analysis Software .......................................................................................................... 37 
7.3.9. 
Study Data ..................................................................................................................... 37 
7.3.10. 
Period #1 Data Management Study Data Cutoff ........................................................... 38 
7.4. 
General Statistical Methodology ..................................................................................................... 39 
7.4.1. 
Statistical Summaries: Descriptive and Inferential ....................................................... 39 


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CONFIDENTIAL 
 
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7.4.2. 
Interim Analyses and Data Monitoring ......................................................................... 39 
7.4.3. 
Week 24 Analysis .......................................................................................................... 40 
7.4.4. 
Week 48 Analysis .......................................................................................................... 40 
7.4.5. 
Multiple Testing Procedures .......................................................................................... 40 
7.5. 
Summary of Study Data .................................................................................................................. 41 
7.5.1. 
Subject Summary Grouping .......................................................................................... 41 
7.5.2. 
Study Disposition .......................................................................................................... 41 
7.5.3. 
Protocol Deviations ....................................................................................................... 41 
7.5.4. 
Demographics and Baseline Characteristics ................................................................. 41 
7.5.5. 
Medical History ............................................................................................................. 42 
7.5.6. 
Prior and Concomitant Medications .............................................................................. 42 
7.5.7. 
Treatment Compliance and Study Drug Exposure ........................................................ 43 
7.6. 
Efficacy Analyses ............................................................................................................................ 43 
7.7. 
Safety Analyses ............................................................................................................................... 48 
7.7.1. 
Adverse Events .............................................................................................................. 48 
7.7.2. 
Vital Signs, 12-Lead ECG, and Laboratory Outcomes ................................................. 50 
7.7.3. 
Physical Examination .................................................................................................... 51 
7.7.4. 
Other Safety Measures .................................................................................................. 51 
7.8. 
Exploratory Analyses ...................................................................................................................... 52 
7.9. 
Pharmacodynamic (PD) Serum and Other Biomarkers ................................................................... 52 
8. 
REPORTING CONVENTIONS .................................................................................................................. 54 
8.1. 
General Reporting Conventions ...................................................................................................... 54 
8.2. 
Population Summary Conventions .................................................................................................. 55 
9. 
REFERENCES ............................................................................................................................................. 57 
10. APPENDICES .............................................................................................................................................. 59 
10.1. 
List of Tables, Listings, and Figures ............................................................................................... 59 
10.2. 
SAP Amendment Summary of Important Changes ......................................................................... 59 
 
 


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LIST OF TABLES 
 
Table 1 
Study Randomization Schedule ..................................................................................... 16 
Table 2 
Schedule of Study Activities ......................................................................................... 17 
 
 
LIST OF FIGURES 
 
Figure 1 
SDTM, ADaM, and TFL Development and Validation ................................................ 38 
 
 
 


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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 
ANCOVA 
analysis of covariance 
BL 
baseline 
BMC 
bone mineral content 
BMI 
body mass index 
CINRG 
Cooperative International Neuromuscular Research Group 
CK 
creatine kinase 
cm 
centimeter 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
carboxy-terminal telopeptide 
CV 
coefficient of variation 
dL 
deciliter 
DMD 
Duchenne muscular dystrophy 
DSMB 
data and safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
F/U 
follow-up 
g 
gram 
GLDH 
glutamate dehydrogenase 
HbA1c 
hemoglobin A1c 
HDL 
high density lipoprotein 
ICH 
International Conference on Harmonisation 
IND 
investigational new drug 
L 
Liter 
LLC 
limited liability company 
LDL 
low density lipoprotein 
LS 
least squares 
m 
meter 


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MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MI 
multiple imputation 
mL 
milliliter 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
No., n 
number 
NSAA 
North Star Ambulatory Assessment 
%CV 
percentage coefficient of variation 
PD 
pharmacodynamic(s) 
P1NP 
serum aminoterminal propeptide of type I collagen 
PK 
pharmacokinetic(s) 
PMM 
pattern mixture model 
PODCI 
Pediatric Outcomes Data Collection Instrument 
6MWT 
six-minute walk test 
REML 
restricted maximum likelihood 
ROM 
range of motion (test) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCR 
screening 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TSQM 
Treatment Satisfaction Questionnaire 
TTCLIMB 
time to climb (test) 
TTSTAND 
time to stand (test) 
TTRW 
time to run/walk (test) 
vs. 
versus 
WHO 
World Health Organization 
 


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3. 
INTRODUCTION 
3.1. 
Preface 
This document presents a statistical analysis plan (SAP) for Treatment Period #1 of 
ReveraGen BioPharma, Inc. Protocol VBP15-004, (A Phase IIb Randomized, Double-blind, 
Parallel Group, Placebo- and Active-controlled Study with Double-Blind Extension to Assess 
the Efficacy and Safety of Vamorolone in Ambulant Boys with Duchenne Muscular 
Dystrophy (DMD)). This SAP will provide the details and methods for analysis and reporting 
of the subject characteristics, safety, and efficacy information for data captured during 
Period #1 of this study, i.e. through the Week 24 Follow-up (F/U) Visit. A separate SAP will 
be developed for the data captured during the entire study (Period #1, Transition Period, and 
Period #2) (see Section 3.2 of this SAP). 
Reference materials for this SAP include the protocol VBP15-004 (Amendment #4 Dated: 28 
August 2020). 
The SAP described herein is an a priori plan. The SAP will be finalized and approved prior 
to database lock and unblinding. Statistical programming may occur as study data 
accumulate in order to have analysis programs ready at the time the study finishes.   
As divergent recommendations on the analysis plans for the VBP15-004 study were received 
by FDA and EMA, this version of the SAP is specifically designed for data analysis in line 
with FDA recommendation for analysis of Period #1 data. The separate SAP, as mentioned 
above, will be developed to accommodate recommendations specified by EMA, in addition 
to describing the data analysis of the entire study. 
For publication and other commercial purposes of the Period #1 VBP15-004 study data, the 
primary analysis as specified in this SAP will be considered the primary analysis of the 
study. 
3.2. 
Purpose of Analyses 
The purposes of the planned analyses described in this SAP are to assess the safety, 
tolerability, pharmacodynamics, and efficacy of two oral doses of vamorolone 
(2.0 mg/kg/day and 6.0 mg/kg/day) in ambulant boys ages 4-< 7 years with DMD. Safety and 
efficacy endpoints (clinical and biomarker) will be compared to a placebo group, and to a 
group treated with oral prednisone (0.75 mg/kg/day).  
The study has four periods: Treatment Period #1, a Transition Period, Treatment Period #2, 
and a Dose-tapering Period applicable to a subset of subjects.  
• Period #1 is a double-blind, placebo-controlled, prednisone-controlled 24-week 
treatment period; 


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• The Transition Period is a 4-week double-blind period during which all subjects taper 
off their placebo or prednisone tablets; and 
• Period #2 is a double-blind 20-week treatment period during which all subjects are 
treated with vamorolone 2.0 mg/kg/day or 6.0 mg/kg/day; and   
• The Dose-tapering Period is a 4-week double-blind period during which subjects who 
choose not to receive further vamorolone treatment by enrolling directly into a 
subsequent vamorolone general access program will have their dose of vamorolone 
suspension tapered and discontinued. 
This SAP is relevant to Period #1, the double-blind, placebo-controlled, prednisone-
controlled part of the study, with the clinical study report corresponding to the initial 
24-week Period #1. Results from the analyses completed will be included in the Period #1 
24-week clinical study report for VBP15-004, and may also be utilized for regulatory 
submissions, manuscripts, additional endpoint specific reports, or other clinical development 
activities.  
A separate SAP and clinical study report will be issued for the entire VBP15-004 study, 
including the initial 24-week Period #1, the Transition Period (Weeks 25-28), and the second 
20-week Period #2 (when all subjects are treated with vamorolone). The separate SAP for the 
entire VBP15-004 study will be finalized before unblinding of data from Period #1. 
Furthermore, the separate SAP defines the analyses as recommended by the EMA. The two 
SAPs of this study as consistent with each other regarding the analyses specific to Period #1, 
including the analysis of the primary and secondary efficacy endpoints (with the exception of 
which of the analyses is considered as primary by FDA and EMA, respectively).  
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. 
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 exception of those items noted in this section. 
Spine x-ray analysis is discussed in the protocol. It will be presented in a separate SAP and is 
not included in this SAP. 


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Analysis of DNA testing (genetic modifiers) is described as an additional exploratory 
endpoint in the protocol. However, the DNA samples will be stored for later testing after 
completion of the 48-week trial and are not analyzed in this SAP. 
Exploratory biomarkers mentioned in the protocol will be tested and described in a later 
report, with samples stored and studied later and are not included in this SAP. 
 
 


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4. 
STUDY OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints defined in the protocol include safety, tolerability, 
pharmacokinetics, pharmacodynamics, and efficacy endpoints. Objectives and pre-specified 
endpoints for Treatment Period #1 are as follows: 
4.1. 
Study Objectives 
4.1.1. Primary Objectives 
The primary objectives of this study are: 
1. To compare the efficacy of vamorolone administered orally at daily doses of 
6.0 mg/kg over a 24-week treatment period vs. placebo in ambulant boys ages 4 to <7 
years with DMD; and  
2. To evaluate the safety and tolerability of vamorolone administered orally at daily 
doses of 2.0 mg/kg and 6.0 mg/kg in ambulant boys ages 4 to <7 years with DMD. 
4.1.2. Secondary Objectives 
The secondary objectives of this study are: 
1. To compare the efficacy of vamorolone administered orally at daily doses of 
2.0 mg/kg over a 24-week treatment period vs. placebo in ambulant boys ages 4 to <7 
years with DMD; 
2. To compare the safety of vamorolone administered orally at daily doses of 2.0 mg/kg 
and 6.0 mg/kg over a 24-week treatment period vs. daily prednisone 0.75 mg/kg in 
ambulant boys ages 4 to <7 years with DMD; and 
3. To compare the efficacy of vamorolone administered orally at daily doses of 
2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily prednisone 
0.75 mg/kg in ambulant boys ages 4 to <7 years with DMD. 
4.1.3. Exploratory Objectives 
The exploratory objectives of this study are:  
1. To evaluate the satisfaction with treatment of vamorolone administered orally at daily 
doses of 2.0 mg/kg and 6.0 mg/kg over a 24-week treatment period vs. daily 
prednisone 0.75 mg/kg in ambulant boys ages 4 to <7 years with DMD;  
2. To evaluate the effect of vamorolone administered orally at daily doses of 2.0 mg/kg 
and 6.0 mg/kg over a 24-week treatment period vs. daily prednisone 0.75 mg/kg on 
behaviour and neuropsychology;  
3. To evaluate the effect of vamorolone administered orally at daily doses of 2.0 mg/kg 
and 6.0 mg/kg over a 24-week treatment period vs. placebo on physical functioning. 
4. To assess the ease of administration of the study medication suspension to ambulant 
boys ages 4 to <7 years with DMD; 
5. To compare the effects of vamorolone administered orally at daily doses of 2.0 mg/kg 
and 6.0 mg/kg over a 24-week treatment period vs. placebo on potential serum 


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pharmacodynamics (PD) biomarkers of safety and efficacy in ambulant boys ages 4 
to <7 years with DMD;  
6. To compare the effects of vamorolone administered orally at daily doses of 2.0 mg/kg 
and 6.0 mg/kg over a 24-week treatment period vs. daily prednisone 0.75 mg/kg on 
potential serum PD biomarkers of safety and efficacy in ambulant boys ages 4 to 
<7 years with DMD; and 
7. To determine if candidate genetic modifiers of DMD (gene polymorphisms associated 
with disease severity, or response to glucocorticoid treatment) are similarly associated 
with vamorolone-treated DMD subjects (baseline disease severity, or response to 
vamorolone or prednisone treatment). 
4.2. 
Study Endpoints  
4.2.1. Safety Endpoints 
1. Linear growth velocity: Comparison of each vamorolone dose level group with the 
prednisone group in change in height percentile for age from baseline; 
2. Adrenal suppression: Comparison of each vamorolone dose level group with the 
prednisone group and of vamorolone 2.0 mg/kg/day vs. vamorolone 6.0 mg.kg/day in 
% of subjects with peak cortisol below 18 µg/dL (500 nM) in the ACTH stimulation 
test at Week 24 at 30 or 60 minutes after stimulation with Cosyntropin; 
3. Cushingoid features: Comparison of each vamorolone dose level group with the 
prednisone group in change from baseline to each of the scheduled on-treatment and 
post-treatment assessment time points (changes from baseline will be recorded as 
AEs);   
4. Dual-energy x-ray absorptiometry (DXA) scan: Comparison of both vamorolone dose 
level groups with the prednisone group: 
• 
Percent change from baseline to Week 24 in spine BMD (g/cm2) 
• 
Percent change from baseline to Week 24 in total body BMD (g/cm2) 
• 
Percent change from baseline to Week 24 spine and total body bone mass (bone 
mineral content, g) 
• 
Percent change from baseline to Week 24 in total body composition (lean mass 
(g), fat mass (g), fat-free mass (g), Lean Mass Index (kg/m2), and Fat Mass Index 
(kg/m2)); 
5. BMI Z-score: Comparison of each vamorolone dose level group with the prednisone 
group in change from baseline; 
6. Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) by 
system organ class (SOC): Overall by treatment, by treatment and relationship, and 
by treatment and intensity (see protocol Section Error! Reference source not 
found.);  
7. Vital signs (sitting blood pressure, heart rate, respiratory rate, and body temperature): 
Change from baseline to each of the scheduled on-treatment and post-treatment 
assessment time points; 


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8. Body weight, height, and BMI (kg/m2): Change from baseline to each of the 
scheduled on-treatment and post-treatment assessment time points; 
9. Clinical laboratory values: Change from baseline to each of the scheduled 
on-treatment and post-treatment assessment time points in: 
• 
Hematology and clinical chemistry 
• 
Lipid profile (triglycerides, total cholesterol, low density lipoprotein [LDL], high 
density lipoprotein [HDL]) 
• 
Vitamin D level 
• 
Urinalysis; 
10. 12-lead electrocardiogram (ECG): Change from baseline to each of the scheduled 
on-treatment and post-treatment assessment time points; 
11. 2D-echocardiogram: Change from baseline to Week 24; 
12. Eye examination for detection of clinically significant abnormalities (cataracts and/or 
glaucoma) at the Week 24 assessment compared to baseline. 
 
Data for the following additional safety outcomes will be listed only: 
1. Physical examination findings at each of the pretreatment, on-treatment, and 
post-treatment assessment time points; 
2. Fracture Questionnaire results at pretreatment and Week 24.  
4.2.2. Tolerability Endpoint 
1. Premature discontinuations of study treatment due to adverse events. 
4.2.3. Efficacy Endpoints 
4.2.3.1. Primary Efficacy Endpoint 
TTSTAND velocity (rise/second): Comparison of vamorolone 6.0 mg/kg/day dose level 
group versus the placebo group in change from baseline to the Week 24 assessment. The 
velocity will be calculated as defined in Section 7.3.7. 
4.2.3.2. Secondary Efficacy Endpoints (by fixed sequential testing following successful 
statistical testing of the primary efficacy endpoint) 
Change from baseline to Week 24 for the following comparisons: 
• TTSTAND velocity, vamorolone 2.0 mg/kg/day vs. placebo 
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 6.0 mg/kg/day vs. placebo 
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 2.0 mg/kg/day vs. placebo 
• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 6.0 mg/kg/day vs. 
placebo 
• Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 2.0 mg/kg/day vs. 
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• 6MWT meters walked, vamorolone 6.0 mg/kg/day vs. prednisone 
• 6MWT meters walked, vamorolone 2.0 mg/kg/day vs. prednisone 
 
4.2.3.3. Exploratory Efficacy Endpoints 
Change from baseline to each of the scheduled study assessment time points up to and 
including Week 24 for the following comparisons: 
• TTSTAND velocity, vamorolone 6.0 mg/kg/day vs. placebo (Week 6 and 12 only) 
• TTSTAND velocity, vamorolone 2.0 mg/kg/day vs. placebo (Week 6 and 12 only) 
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 6.0 mg/kg/day vs. placebo 
(Week 12 only) 
• 6 Minute Walk Test (6MWT) meters walked, vamorolone 2.0 mg/kg/day vs. placebo 
(Week 12 only) 
• TTRW 10 meters velocity, vamorolone 6.0 mg/kg/day vs. placebo (Week12 only) 
• TTRW 10 meters velocity, vamorolone 2.0 mg/kg/day vs. placebo (Week12 only) 
• 6MWT meters walked, vamorolone 6.0 mg/kg/day vs. prednisone (Week 12 only) 
• 6MWT meters walked, vamorolone 2.0 mg/kg/day vs. prednisone (Week 12 only) 
• NSAA total score, vamorolone 6.0 mg/kg/day vs. placebo 
• NSAA total score, vamorolone 2.0 mg/kg/day vs. placebo 
• Hand-held Myometry knee extensors, vamorolone 6.0 mg/kg/day vs. placebo 
• Hand-held Myometry knee extensors, vamorolone 2.0 mg/kg/day vs. placebo 
• Hand-held Myometry elbow flexors, vamorolone 6.0 mg/kg/day vs. placebo 
• Hand-held Myometry elbow flexors, vamorolone 2.0 mg/kg/day vs. placebo 
• Time to Climb (TTCLIMB) velocity, vamorolone 6.0 mg/kg/day vs. placebo 
• Time to Climb (TTCLIMB) velocity, vamorolone 2.0 mg/kg/day vs. placebo 
• Range of Motion (ROM) in the ankles, vamorolone 6.0 mg/kg/day vs. placebo 
• Range of Motion (ROM) in the ankles, vamorolone 2.0 mg/kg/day vs. placebo 
 
4.2.4. Exploratory Patient-reported Outcomes Endpoints 
1. Treatment satisfaction questionnaire (TSQM): Comparison of each vamorolone dose 
level group to the prednisone group at the Week 24 visit; 
2. Pediatric Outcomes Data Collection Instrument (PODCI): Comparison of each 
vamorolone dose level group to the placebo group for change from baseline to the 
Week 24 assessment; 
3. Behavioral changes (PARS III): Comparison of each vamorolone dose level group to 
the prednisone group and to the placebo group for change from baseline to each of the 
scheduled study assessment time points up to the Week 24 assessment for four PARS 
III subscores for peer relations, dependency, anxiety and depression, and withdrawal; 
4. Ease of study medication administration (Question 1 only; tablet vs. liquid) assessed 
at each of the scheduled study assessment time points; and  


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5. Blindedness Assessment at each of the scheduled study assessment time points.  
4.2.5. Pharmacodynamic Endpoints 
1. The following pharmacodynamic biomarkers are considered secondary outcome 
measures focusing on safety outcomes. In each case, the biomarkers studied reflect 
safety concerns of glucocorticoids: 
a. Adrenal suppression. First-in-morning serum cortisol levels (fasting and non-
fasting) will be measured. Cortisol measures falling below 3.6 µg/dL (or 
100 nM) will be considered to be indicative of the development of adrenal 
suppression. ACTH Stimulation Test will be performed at the Screening Visit 
and at the Week 24 Follow-up Visit (48 ± 3 hours after the final dose of 
Treatment Period #1 study medication): peak cortisol levels <18 µg/dL (or 
500 nM) 30 or 60 minutes after stimulation with Cosyntropin (250 µg) will be 
considered to be indicative of adrenal suppression, where peak is the higher of 
the 30- and 60-minute assessments.  
b. Bone turnover. Measures of serum osteocalcin are reflective of bone 
formation, and measures of serum CTX1 are reflective of bone resorption. 
Levels of osteocalcin and CTX1 predict later clinical safety concerns of 
osteopenia and bone fragility. 
c. Insulin resistance. Glucocorticoids cause both acute and chronic insulin 
resistance, with serum elevations of both insulin and glucose. Measures of 
hyperinsulinemia and hyperglycemia are accepted measures of insulin 
resistance. 
2. Exploratory biomarkers for aspects of safety and efficacy will be studied and reported 
at a later date. 


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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 Phase IIb study is a randomized, double-blind, parallel group, placebo- and active-
controlled study with double-blind extension to evaluate the long-term efficacy, safety, 
tolerability, PD, and population PK of vamorolone (the investigational medicine) compared 
to prednisone (active control) and placebo over a Treatment Period of 24 weeks in boys ages 
4 to <7 years with DMD (Period #1), and determine the persistence of effect over a total 
Treatment Period of 48 weeks. Six treatment groups will receive either vamorolone at one of 
two doses (2.0 mg/kg or 6.0 mg/kg), prednisone (0.75 mg/kg), or placebo once daily for 
24 weeks, and will receive vamorolone at one of two doses (2.0 mg/kg or 6.0 mg/kg) daily 
for an additional 20 weeks (Period #2). A total of approximately 120 subjects will be 
randomized into the study as shown in Table 11.  
Table 1 
Study Randomization Schedule 
Group 
Planned Number 
of Subjects 
Treatment Period #1 
(24 Weeks) 
Treatment Period #2 
(20 Weeks)  
1 
30 
Vamorolone, 2.0 mg/kg/day ® 
Vamorolone, 2.0 mg/kg/day 
2 
30 
Vamorolone, 6.0 mg/kg/day ® 
Vamorolone, 6.0 mg/kg/day 
3 
15 
Prednisone, 0.75 mg/kg/day ® 
Vamorolone, 2.0 mg/kg/day 
4 
15 
Prednisone, 0.75 mg/kg/day ® 
Vamorolone, 6.0 mg/kg/day 
5 
15 
Placebo ® 
Vamorolone, 2.0 mg/kg/day 
6 
15 
Placebo ® 
Vamorolone, 6.0 mg/kg/day 
 
 
Error! Reference source not found. presents the schedule of study procedures. 
 
 


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Table 2 
Schedule of Study Activities 
 
Pretreatment 
Period 
Treatment Period #1 
Transition 
Period 
Treatment Period #2 
Dose-tapering 
Period 
SCR 
BL 
Day 
Week 
Study Day or Week/Visit 
-33 
to -2a 
-1b 
1c 
2 
(±1d)d 
6 
(±3d)d 
12 
(±1w)d 
18 
(±1w)d 
24e 
(±1w)d 
24 
(F/U)e 
26 
28f 
(±1d)d 28+1d 
30 
(±1d)d 
34 
(±3d)d 
40 
(±1w)d 
48g 
(±1w)d 
48  
F/Ug 
50 
52h 
(±1d)d 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollmenti 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
 
X 
Cushingoid features 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
 
 
X 
Height 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Weight 
X 
X 
 
X 
X 
X 
Xl 
X 
 
 
X 
 
X 
X 
Xl 
X 
 
 
X 
Vital signsm 
X 
X 
Xn 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
X 
Blood for clinical labso 
X 
 
Xp 
Xp 
X 
Xp 
X 
Xp 
 
 
Xp 
 
Xp 
X 
Xp 
Xp 
 
 
Xp 
Blood for HbA1co 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Blood for vitamin Do 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Confirmation of varicella 
immunity 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisq 
X 
 
Xp 
Xp 
X 
Xp 
X 
Xp 
 
 
Xp 
 
Xp 
X 
Xp 
Xp 
 
 
Xp 
Blood for serum PD 
biomarker panelr,s 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
X 
Fasting blood for insulin, 
glucoses 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
X 
Blood for DNA Testing 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ACTH Stimulation Test 
X 
 
 
 
 
 
 
 
Xt 
 
 
 
 
 
 
 
Xt 
 
 
Blood for Plasma PK 
 
 
 
 
 
 
 
 
 
 
 
 
Xu 
 
 
 
 
 
 
12-lead ECGv 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
2D-echocardiogram 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 


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Pretreatment 
Period 
Treatment Period #1 
Transition 
Period 
Treatment Period #2 
Dose-tapering 
Period 
SCR 
BL 
Day 
Week 
Study Day or Week/Visit 
-33 
to -2a 
-1b 
1c 
2 
(±1d)d 
6 
(±3d)d 
12 
(±1w)d 
18 
(±1w)d 
24e 
(±1w)d 
24 
(F/U)e 
26 
28f 
(±1d)d 28+1d 
30 
(±1d)d 
34 
(±3d)d 
40 
(±1w)d 
48g 
(±1w)d 
48  
F/Ug 
50 
52h 
(±1d)d 
Eye examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
DXA scan 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Spine X-ray 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Fracture Questionnaire 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Dispense study medication 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
Return study medication/ 
compliance monitoring 
 
 
 
Xw 
X 
X 
X 
X 
 
 
X 
 
Xw 
X 
X 
X 
 
 
X 
Study medication dosingx 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Study medication dose 
tapering 
 
 
 
 
 
 
 
 
Xy 
 
X 
 
 
 
 
 
X 
 
X 
Telephone call to subjectz 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Time to Stand Test 
(TTSTAND) 
X 
X 
 
 
X 
X 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
 
Time to Climb Test 
(TTCLIMB) 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Time to Run/Walk Test 
(TTRW) 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
NSAAaa 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Myometry (elbow flexors, 
knee extensors) 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Six-minute Walk Test 
(6MWT) 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Range of Motion (ROM) – 
ankles 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 
Pediatric Outcomes Data 
Collection Instrument 
(PODCI) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Treatment Satisfaction 
Questionnaire (TSQM) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 


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Pretreatment 
Period 
Treatment Period #1 
Transition 
Period 
Treatment Period #2 
Dose-tapering 
Period 
SCR 
BL 
Day 
Week 
Study Day or Week/Visit 
-33 
to -2a 
-1b 
1c 
2 
(±1d)d 
6 
(±3d)d 
12 
(±1w)d 
18 
(±1w)d 
24e 
(±1w)d 
24 
(F/U)e 
26 
28f 
(±1d)d 28+1d 
30 
(±1d)d 
34 
(±3d)d 
40 
(±1w)d 
48g 
(±1w)d 
48  
F/Ug 
50 
52h 
(±1d)d 
PARS III 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Ease of Study Medication 
Administration 
Assessmentbb 
 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
 
Blindedness Assessment 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense subject diariescc 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
Return subject diaries 
 
 
 
X 
X 
X 
X 
X 
Xdd 
 
X 
 
X 
X 
X 
X 
Xee 
 
X 
AE/SAE recordingff 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xgg 
Concomitant medications 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Discharge from study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xhh 
 
Xii 
BL = Baseline; d = day(s); F/U = Follow-up; SCR = Screening; w = week.  
a. 
The Pretreatment Screening Period spans Day -33 through Day -2, but all screening procedures must be completed by Day -11. Subjects meeting all eligibility 
criteria will be randomized by Day -11, at least 10 days prior to the Baseline Day -1 Visit. 
b. 
Baseline Day -1, within 24 hours prior to administration of the first dose of study drug.  
c. 
Treatment Day 1 begins at the time of administration of the first dose of study medication in the clinic. 
d. 
Time windows around the Week 2, Week 6, Week 12, Week 18, and Week 24 Visits are allowances from date of Day 1 Visit. Time window around the Week 28 
Visit is allowance from date of Week 24 F/U Visit. Time windows around the Week 30, Week 34, Week 40, and Week 48 Visits are allowances from date of Week 
28+1d Visit. Time window around the Week 52 Visit is allowance from date of Week 48 F/U Visit. 
e. 
Subjects who prematurely discontinue from the study prior to Week 24 should complete the Week 24 assessments and the Week 24 Follow-up Visit ACTH 
Stimulation Test at the time of early withdrawal and undergo Early Discontinuation Dose-tapering, where possible (see protocol Section Error! Reference source 
not found. and Section Error! Reference source not found.). The Week 24 Follow-up Visit must occur to allow the ACTH Stimulation Test to be performed 
48 ± 3 hours after the final dose of Treatment Period #1 study medication.  
f. 
Subjects who prematurely discontinue from the study after Week 24 but prior to Week 28 should complete the Week 28 assessments, and undergo Early 
Discontinuation Dose-tapering, where possible (see protocol Section Error! Reference source not found.).  
g. 
Subjects who prematurely discontinue from the study after Week 28 but prior to Week 48 should complete the Week 48 assessments and the Week 48 Follow-up 
Visit ACTH Stimulation Test at the time of early withdrawal and undergo Dose-tapering, where possible (see protocol Section Error! Reference source not found. 
and Section Error! Reference source not found.). The Week 48 Follow-up Visit must occur to allow the ACTH Stimulation Test to be performed 48 ± 3 hours 
after the final dose of Treatment Period #2 study medication.  


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h. 
Subjects will have one study site visit during the Dose-tapering Period, at one week after the dose of liquid formulation has been discontinued (Week 52) (see 
protocol Section Error! Reference source not found.).  
i. 
Subjects are considered to be enrolled in the study at the time written informed consent is obtained. 
j. 
Study eligibility should be rechecked and confirmed at Baseline Day -1 Visit. 
k. 
Randomization occurs by Interactive Voice/Web Response System (IXRS) after subjects are confirmed to have met all study entry criteria, at least 10 days prior to 
the Baseline Day -1 Visit. 
l. 
Weight recorded at the Week 18 Visit and the Week 40 Visit will be used to calculate doses for study drug dispensed at the Week 24 Follow-up and Week 48 
Follow-up Visits, respectively. 
m. Sitting blood pressure, body temperature, respiratory rate, and heart rate. 
n. 
Vital signs recorded prior to administration of the first dose of study drug at the Day 1 Visit. 
o. 
Blood for hematology, chemistry, and lipids, including HbA1c and Vitamin D where applicable. 
p. 
Blood samples (collected after subjects have fasted for ≥ 6 hours) and urine collected at scheduled visit, and prior to dose of study drug where applicable.  
q. 
Urinalysis by dipstick and microscopic analysis. 
r. 
Blood collected for PD biomarkers includes secondary safety outcomes (morning cortisol, osteocalcin, CTX1, P1NP), and exploratory safety and efficacy PD biomarkers.  
s. 
Blood samples for PD biomarkers and fasting glucose and insulin determination will be collected after subjects have fasted for ≥ 6 hours, prior to the daily dose of study 
medication where applicable. 
t. 
Subjects will return to the study site for the Week 24 Follow-up Visit for an ACTH Stimulation Test 48 hours ± 3 hours after administration of the final dose of 
Treatment Period #1 study medication, and for the Week 48 Follow-up Visit for an ACTH Stimulation Test 48 hours ± 3 hours after administration of the final dose 
of Treatment Period #2 study medication (see protocol Section Error! Reference source not found.). 
u. 
Blood sample for population PK analysis will be collected 2 hours after administration of the daily dose of study medication. 
v. 
12-lead ECG recorded after subject has rested quietly in a supine position for at least 5 minutes. 
w. Study medication brought by subjects to the Week 2 Visit and Week 30 Visit for dosing and compliance assessment will be redispensed to subjects at the end of the 
visit. 
x. 
The dose of study medication on the days of the Day 1, Week 2, Week 12, Week 24, Week 28, Week 30, Week 40, and Week 48 Visits will be administered after 1) 
fasting blood draws; and 2) breakfast provided by the study site. All other doses will be taken at home. See protocol Section Error! Reference source not found. 
for other Day 1 pre-dose safety assessments. 
y. 
Doses of tablet study drug will be tapered and suspension study drug will be continued, during Weeks 24-28.  
z. 
Site study staff will contact the parent(s)/guardian(s) by telephone at Weeks 26 and 50 to ensure that the study drug tapering is proceeding according to protocol, to 
assess potential signs or symptoms indicative of adrenal suppression, and to address any questions the parent(s)/guardian(s) may have.  
aa. North Star Ambulatory Assessment; includes the Time to Stand Test (TTSTAND). 
bb. Ease of Study Medication Administration assessed at the Weeks 2, 12, and 24, 30, 40, and 48 Visits.  
cc. Subject diaries used to record any changes in concomitant medications taken, any AEs experienced during the study, and any incomplete or missed doses of study 
medication. 
dd. Subject diaries dispensed at the Week 24 Visit will be returned and redispensed at the Week 24 F/U Visit; final return will occur at the Week 28 Visit. 


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ee. Subject diaries dispensed at the Week 48 Visit will be returned at the Week 48 F/U Visit, and will be redispensed to subjects participating in the Dose-tapering Period for 
final return at the Week 52 Visit. 
ff. All AEs and SAEs must be recorded in the source documents and eCRF from the date of the subject’s written informed consent until the final Week 52 Visit or the 
subject’s participation in the study is completed (SAEs through 30 days after final study drug dose). Ongoing AEs will be followed to resolution, stabilization, or until 
such time the Investigator agrees follow-up is not necessary. 
gg. For subjects who do not continue to receive vamorolone through an additional vamorolone study or general access program, site staff will make a phone call to the home 
31-35 days after the final dose of study medication in VBP15-004 Dose-tapering Period to confirm the final SAE status of the subject. 
hh. Subjects who elect to continue vamorolone therapy by enrolling directly into an additional vamorolone study or general access program may be discharged from the 
study following completion of all final Week 48 assessments, including the Week 48 Follow-up Visit ACTH Stimulation Test. 
ii. 
Subjects who participate in the Dose-tapering Period may be discharged from the study following completion of all final Dose-Tapering Visit assessments (Week 52) 
(see protocol Section 6.3.7). 
 
 
 


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5.2. 
Inclusion – Exclusion Criteria and General Study Population 
Approximately 15 or 30 subjects with confirmed diagnosis of DMD (4-<7 years of age) will 
be randomized into each of the six groups (120 subjects total) (Table 1). 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 
Following consent and review of study entry criteria to confirm subject eligibility for the 
study, the subject can be randomized to treatment. Randomization should be performed at 
least 10 days prior to the baseline visit and will be achieved via the Interactive Voice/Web 
Response System (IXRS) system with username and password access. Randomization will be 
stratified by participant’s age at study entry (<6 vs. ≥ 6 years). Randomization will be 
stratified only by age; randomization will not be stratified by investigational site. 
Randomization will require the site investigator, or designee, to verify that the subject meets 
the inclusion/exclusion criteria of the study, and to verify that the child has not previously 
been randomized. Randomization for both Period #1 and Period #2 will be performed prior to 
study start. 
5.4. 
Analysis Variables 
Variables to be analyzed include demographics and baseline characteristics, safety variables, 
and efficacy variables. 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. 
 
 


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6. 
SAMPLE SIZE 
This is a randomized, double-blind, parallel group, placebo- and active-controlled study. 
Study medication is administered daily in this Phase IIb trial. Data for untreated subjects 
from the Cooperative International Neuromuscular Research Group (CINRG) Duchenne 
Natural History Study (Bellow et al., 2015; Spurney et al., 2014; McDonald et al., 2013; and 
Henricson et al., 2013) and data for prednisone treated subjects from the CINRG Prednisone 
study (Escolar et al., 2011) were used to help estimate sample sizes for this study.  
 
Note that subjects in the prednisone and placebo groups will actually be randomized into two 
groups each: 
 
• Prednisone 0.75 mg/kg/day ® Vamorolone 2.0 mg/kg/day (n=15);  
• Prednisone 0.75 mg/kg/day ® Vamorolone 6.0 mg/kg/day (n=15); 
• Placebo ® Vamorolone 2.0 mg/kg/day (n=15); or  
• Placebo ® Vamorolone 6.0 mg/kg/day (n=15). 
 
These groups will be pooled by initial treatment (prednisone or placebo) for the Treatment 
Period #1 analyses. 
 
If subjects withdraw early from the study in Period #1, additional subjects may be enrolled to 
achieve approximately 120 subjects completing the Week 24 Visit assessments. Subjects 
withdrawing during Period 2 will not be replaced. 
 
Analysis method: 
In the 24-week vamorolone dose-ranging study (VBP15-003) (Hoffman et al., 2019), doses 
of 0.25 and 0.75 mg/kg/day showed little evidence of clinical benefit, whereas doses of 2.0 
and 6.0 mg/kg/day both showed clear evidence of clinical benefit. The effect size of clinical 
efficacy depended on the motor outcomes measure (TTSTAND, TTRW, TTCLIMB, 6MWT 
and NSAA). 
 
More recently acquired data on 18-month treatment with vamorolone at 2.0 or 6.0 mg/kg/day 
(data from subjects who were in the 24-week VBP15-003 study and continued into VBP15-
LTE, with dose escalations to either 2.0 mg/kg/day or 6.0 mg/kg/day [dose escalation and de-
escalation were permitted in VBP15-LTE] and have a 12-month data assessment in VBP15-
LTE) have suggested that both the 2.0 and 6.0 mg/kg/day doses show long-term benefit that 
is comparable to that seen with glucocorticoids (prednisone and deflazacort) (Smith et al., 
2020). 
 
In consideration of having the primary efficacy endpoint be the comparison of 6.0 mg/kg/day 
vamorolone versus placebo in VBP15-004, sample size calculations were performed using 


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data from vamorolone-treated subjects from the VBP15-002/VBP15-003 24-week treatment 
period. The analysis compared TTSTAND velocity from the combined 2.0 and 6.0 
mg/kg/day groups (drug treated, Group A) to the combined 0.25 and 0.75 mg/kg/day 
(pseudo-placebo; Group B).   
 
LS means from the MMRM modeling of VBP15-002/VBP15-003 24-week data were used as 
parameter estimates of the population means in the sample size calculations for the 
comparison of the Treatment Group (2.0 + 6.0 mg/kg/day) vs. the Pseudo-Placebo Group 
(0.25 + 0.75 mg/kg/day) on the mean change from baseline at Week 24. For the estimates of 
standard deviations within each comparison group, simple descriptive statistics from the 
VBP15-002/VBP15-003 24-week data were used. We then estimated power using two-sided 
t-tests assuming unequal variance, with alpha =0.05.  
 
The following table shows the resultant estimated power for various sample sizes per 
comparison group for comparing the Treatment Group (2.0 + 6.0 mg/kg/day) vs. the Pseudo-
Placebo Group (0.25 + 0.75 mg/kg/day) on the mean change from baseline at Week 24 for 
the alternative hypothesis that H1: μ1 ≠ μ2 assuming an alpha level of 0.05 and parameter 
estimates from the analyses described above for TTSTAND velocity: 
 
Sample Size per 
Comparison Group 
μ1 
(Pseudo-
Placebo) 
μ2 
(Treatment 
Group) 
σ1 
(Pseudo-
Placebo) 
σ2 
(Treatment 
Group) 
Estimated Power 
25 
-0.0052 
0.0450 
0.0628 
0.0530 
84.89% 
28 
-0.0052 
0.0450 
0.0628 
0.0530 
88.76% 
30 
-0.0052 
0.0450 
0.0628 
0.0530 
90.81% 
 
The sample size of 25 per treatment group for 2.0 mg/kg/day, 6.0 mg/kg/day, prednisone, and 
placebo will result in a total enrollment of 100 subjects which will provide approximately 
85% power at alpha level 0.05 to detect a statistically significant difference between 6.0 
mg/kg/day and placebo on TTSTAND velocity at Week 24. Similarly, a total enrollment of 
120 subjects (30 per treatment group) will provide approximately 91% power at alpha level 
0.05 to detect a statistically significant difference between 6.0 mg/kg/day and placebo on 
TTSTAND velocity at Week 24. 
 
 
 


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7. 
GENERAL CONSIDERATIONS 
7.1. 
Analysis Populations 
Three populations will be defined for data analysis: the Safety Population, the modified 
Intent-to-Treat Population, and the Per Protocol Population.  
 
7.1.1. Safety Population 
All subjects who receive at least one dose of study medication will be included in the Safety 
Population. The Safety Population is the primary analysis population for safety and PD 
assessments. Results will be presented “as treated.” 
7.1.2. Modified Intent-to-Treat (mITT) Population  
All subjects who receive at least one dose of study medication and have at least one 
TTSTAND, TTRW, TTCLIMB, 6MWT, NSAA, myometry, or ROM post-baseline efficacy 
assessment will be included in the mITT Population. The mITT Population is the primary 
analysis population for clinical efficacy. Subjects who receive at least one dose but never 
have any of the aforementioned post-baseline efficacy assessments will be excluded. Results 
will be presented “as randomized.” 
7.1.3. Per Protocol Population 
The Per Protocol (PP) Population will be those subjects in the mITT Population who had no 
major protocol deviations and will be the secondary analysis population for analysis of the 
efficacy data. Exclusion of subjects from the PP Population will be made on a subject-by-
subject basis prior to database soft lock at the end of the 24-week treatment period. 
The patients with major violations impacting the evaluation of the primary endpoint 
(TTSTAND velocity) will be excluded from the PP Population. The major violations include 
the following: 
• Patient discontinues the study without completing the Week 24 assessment of TTSTAND 
velocity 
• Patient has missing TTSTAND velocity data at Week 24 due to the COVID-19 pandemic 
or due to other reasons. 
 


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7.2. 
Covariates and Subgroups 
7.2.1. Planned Covariates 
Covariates will include Baseline response and age group.  
7.2.2. Subgroups 
Descriptive summary statistics for TTSTAND velocity will be presented by 3 subgroups: 
baseline age <=5.0 years vs. >5.0 years; baseline age <=6.0 years vs. >6.0 years; and 
TTSTAND seconds at baseline <=5.0 seconds vs. >5.0 seconds.   
 
7.3. 
Management of Analysis Data 
7.3.1. Data Handling 
For the summary of continuous values, and laboratory shift tables and ECG and 2D-echo 
interpretation and Eye examination, 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 or a test with abnormal results) will be used, unless on review, the medical monitor 
determines that the most conservative test result was spurious. Repeated tests will be 
included only if they reflect abnormal (low or high) results and the corresponding original 
results are normal.  
All laboratory values and ECG results, 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.  
The COVID-19 pandemic necessitated changes in the protocol to avoid unnecessary potential 
exposure of subjects to coronavirus and resulted in particular safety and efficacy assessments 
being made optional. As a result, there are multiple occurrences of missing data. The data 
that are missing due to COVID-19 will primarily be considered to be missing at random in 
the respective sensitivity analyses. Subjects that are determined to have an appreciable 
amount of missing data due to the COVID-19 pandemic may be excluded from the Per 
Protocol Population. See Section 7.3.2.3 for additional sensitivity analyses that will be 
performed for the primary efficacy endpoint. 
For subjects with missing or incomplete data, all available data will be included in statistical 
presentations. Unless otherwise specified (e.g., primary endpoint sensitivity analysis), 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 
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. 
 
7.3.2.2. 
Imputation Methods 
The primary analyses for the primary and secondary efficacy variables will be conducted on 
observed data only; the MMRMs will employ appropriate covariance structures to 
accommodate missing data as described in Section 7.6. Missing efficacy data will be imputed 
for sensitivity analyses on the primary and secondary efficacy endpoints using the following 
methods: 
• Multiple Imputations using Markov Chain Monte Carlo (MCMC); and 
• Multiple Imputations using a Control-based Pattern Mixture Model (PMM). 
The pattern and type of missing data will be summarized by visit. For each visit, the data will 
be classified as available, or missing. The missing data will be further classified as 
intermittent (missing value is followed by an observed value) or as measurement dropouts 
(all subsequent values after the missing value are missing). The intermittent missing data will 


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be further classified as missing due to COVID-19 or due to other reasons. The measurement 
dropouts will be further classified as inability of the subject to perform or complete the test 
due to disease-related disability, due to COVID-19, or due to other reasons. Once a subject is 
no longer able to perform or complete a test due to disability, all subsequent values to the 
missing values are missing. In conversion to velocity, all missing values due to inability to 
perform the test are imputed as “0” (this imputation is included in the endpoint analyses on 
TTSTAND velocity, TTRW velocity, and TTCLIMB velocity, and is carried out prior to the 
MCMC and PMM imputation for the sensitivity analyses of the primary endpoint TTSTAND 
and secondary endpoint TTRW velocity). The number and proportion of subjects in each 
category will be summarized by visit.  
 
MCMC (assuming data are missing at random- primary efficacy endpoint only, using all 
subjects):  
For multiple imputations (MI) using MCMC, 1000 “complete” (imputed) datasets will be 
produced and analyzed using all subjects (i.e., subjects without post-baseline assessments 
will be included in this MCMC imputation modeling). The MCMC imputation will be 
performed within treatment group and include variables for age at baseline, and response at 
baseline, Week 6, Week 12, and Week 24 (note that age is included as a surrogate for the 
randomization factor age group because the MCMC imputation in Proc MI assumes a 
multivariate normal distribution). After obtaining 1000 “complete” datasets of response 
values, change from baseline will be calculated, and each of these 1000 datasets will be 
analyzed using the MMRM described in Section 7.6 for the primary efficacy endpoint (i.e., 
the MMRM will be employed for each imputation separately on change from baseline). 
PROC MIANALYZE will then be used to combine the results across imputations. The SAS 
Proc MI code for performing this MCMC imputation is provided here: 
 
proc mi data=tadft out=tadftmcmc1 seed=5346434 minimum=0 nimpute=1000;  
 
by treatment; 
 
mcmc chain=multiple impute=full; 
 
var age baseline week_6 week_12 week_24; 
run; 
*********************************************** 
MINIMUM=0 sets a lower limit on imputed values. 
NIMPUTE specifies the number of fully imputed datasets to create. 
BY statement requires imputation to be done within treatment group. 
VAR statement lists variables in model, including response at each visit. 
 
Note: if any of the treatment levels has no missing data, the data from the treatment level in 
question will be excluded from the PROC MI procedure above (using WHERE statement). If 
this is done, the observed data from the treatment level in question (without any missing 
data) will be added to the output dataset produced above 1000 times, i.e. once for each round 
of imputation. 
Control-based PMM (assuming data are missing not at random- primary and secondary 
efficacy endpoints using mITT population): 


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The primary efficacy analysis model (MMRM) makes the assumption that missing data are 
“missing at random” (MAR). When data are MAR, the missingness of the data does not 
depend on the missing value after conditioning on the observed data (i.e., prior assessments 
and baseline covariates). Note that when the missingness of the data depends on the values of 
the missing variables after conditioning on the observed data, the data are called “missing not 
at random” (MNAR). In order to assess the MAR assumption, a control-based PMM will be 
utilized following the method discussed in Ratitch and O’Kelly (2011) for the primary 
efficacy endpoint. For this study, missing data due to COVID-19 is always assumed to be 
MAR. For the remaining missing data, assumption of MNAR will be used as shown below, 
using Copy-Reference imputation.  
The following provides an overview, followed by a detailed description, of the imputation 
and analysis steps. 
1. Imputation of all intermittent missing data with MI assuming MAR, in order to 
generate a dataset with monotone missing data structure. 
2. Based on dataset generated in Step 1: imputation of all monotone missing data 
with MI assuming MAR, in order to generate dataset with no missing data. 
3. Based on dataset generated in Step 2 (with no missing data): all visits that have 
monotone missing data that are not due to COVID-19 will be set back as missing. 
4. Based on dataset generated in Step 3: imputation of remaining monotone missing 
data (not related to COVID-19) with multiple imputation assuming MNAR 
(Copy-Reference imputation). 
5. Based on dataset generated in Step 4: analysis of imputed data with MMRMs. 
6. Combination of results from the MMRMs. 
Step 1: Imputation of intermittent missing data 
MI techniques will be applied in the mITT analysis set. For patients with intermittent missing 
values, a monotone missingness pattern will be generated. Intermittent missing values will be 
imputed using the MCMC methodology which assumes a multivariate normal distribution 
over all variables included in the imputation model. The MI procedure in SAS will be used 
for this purpose and this first MI step will be repeated 1000 times, generating 1000 different 
datasets with a monotone missing data structure. A random seed value will be used in the MI 
procedure and documented in this SAP, to allow replication of the analysis. Seed value of 
5346434 will be used. The imputation is based on the MAR assumption, i.e. the missing data 
are assumed to follow the same model as the other patients in their respective treatment arm. 
Age is included as a factor in the model because the randomization is stratified by age. 
The following SAS code will be used to generate the monotone missing data pattern: 
proc mi data=&data out=datamono nimpute=1000 seed=5346434 minimum=0; 
by trtp; 
var age base w6 w12 w24; 


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mcmc chain=multiple impute=monotone; 
run; 
Step 2: Imputation of all monotone missing data 
Using the dataset generated in Step 1, all remaining missing data will be imputed based on 
the assumption of MAR. The following SAS code will be used for the imputation assuming 
MAR. 
proc mi data=monotone out=imputed1 nimpute=1 seed=5346434 minimum=0; 
class trtp; 
by _imputation_; 
var age base w6 w12 w24; 
monotone regression; 
run; 
Step 3: Setting monotone missing data that are not due to COVID-19 back as missing 
After Step 2, information on reason for missing data (by patient and visit) will be merged to 
the dataset that contains no missing data. Within each patient, data from the visits that have 
monotone missing data with a reason for missing that are not due to COVID-19 will be set 
back as missing. 
 
The reason for missing data (by patient and visit) will be determined as follows: 
• According to the “VBP15-004 eCRF Guidelines Addendum for COVID-19 Protocol 
Clarification V.1.0”, sites were instructed to report the reason for not performing an 
assessment due to COVID-19 as “Other” and then provide a COVID-19 related 
reason as free text. If this free text field includes the string “COVID”, the reason will 
be classified as being due to COVID-19. If the free text does not include the string 
“COVID”, the reason will be classified as other. Before conducting this classification, 
the free text field will be checked for any possible spelling errors. 
 
Step 4: Imputation of remaining (non-COVID-19 related) missing data with assumption 
of MNAR 
The dataset generated in Step 3 (which contains monotone missing data) will be imputed 
based on the assumption of MNAR, using Copy-Reference imputation. The MNAR 
imputation will be based on trajectories in the placebo group, i.e. data from the placebo group 
only will be used to generate the imputations. For this, the MNAR statement will be used as 
described below.  
proc mi data=imputed2 out=imputed3 nimpute=1 seed=5346434 minimum=0; 
class trtp; 
by _imputation_; 
var age base w6 w12 w24; 
monotone regression; 
mnar model(w6 w12 w24 / modelobs=(trtp='Placebo')); 
run; 


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Step 5: Analysis of imputed data with MMRM 
After the missing data imputation is completed using the above steps, change from baseline 
values will be calculated in each of the imputed datasets at each visit. These 1000 datasets 
will be analyzed using the MMRM described in Section 7.6 for the primary efficacy 
endpoint. Treatment effects (difference in least squares [LS] means between treatments) from 
these 1000 analyses will then be combined using Rubin’s Method via the SAS PROC 
MIANALYZE procedure for each endpoint. 
7.3.2.3. 
Assessment of impact of COVID-19 on the primary endpoint 
The following COVID-19 related potential data issues will be addressed with additional 
sensitivity analyses: 
• Impact of assessments that are missing or delayed due to COVID-19 
• Impact of alternative assessment methods (motor assessment using video assessment 
method). 
In both these sensitivity analyses, the data that are missing (or set as missing) due to COVID-
19 are assumed to be missing at random (MAR), while the other missing data are assumed to 
be missing not at random (MNAR) (Meyer et al., 2020). 
Sensitivity analysis assessing the impact of assessments that are missing or delayed due 
to COVID-19 
In this sensitivity analysis, the assessments that were early or delayed by more than 21 days 
from the scheduled visit date due to COVID-19 will be set as missing. Scheduled visit date 
will be calculated from the first dose date. In case there is no documentation of whether the 
rescheduling by more than 21 days occurred is due to COVID-19 or due to other reasons, it 
will be classified as being due to COVID-19. After this step, all missing data will be 
categorized as being due to COVID-19 (either missing or set as missing due to delay) or 
being due to other causes. In this sensitivity analysis, the data assessed with alternative 
assessment methods will be treated as non-missing. The control-based PMM modelling 
approach defined in Section 7.3.2.2 will be used for this analysis. 
Sensitivity analysis assessing the impact of alternative assessment methods 
In this sensitivity analysis, the assessments that were performed using alternative methods 
(i.e., video assessments) due to COVID-19 will be set as missing. After this step, all missing 
data will be categorized as being missing due to COVID-19 (including alternative assessment 
methods) or being missing due to other causes (including the remaining missing data for any 
reason). Note that the data from visits that were delayed due to COVID-19 will be treated as 
non-missing. The control-based PMM modelling approach defined in Section 7.3.2.2 will be 
used for this analysis. 
 


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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 where the assessments are to be measured. If 
the closest scheduled visit has valid data, the early termination data will be assigned to the 
next available scheduled visit where the assessments are to be measured. 
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 20.0 or later) system for reporting (preferred term 
and body system). 
Prior and Concomitant medications will be coded using World Health Organization (WHO) 
Drug classification (Version 01 JUN 2017 or later). 
7.3.6. Baseline Visits  
Unless otherwise noted, Baseline will be the last response before first dose of study 
medication. For example, labs taken over multiple days for the Day 1 visit for a participant 
where there is not a complete Day 1 pre-dose lab panel completed at a single date will use 
individual labs taken closest to, but prior to, first dose as baseline.  
7.3.7. Calculating Derived Variables 
Age in years will be calculated as (informed consent date – birth date)/365.25. In case a 
patient has multiple informed consent dates, the date closest to and prior to baseline (i.e. the 
latest date) will be used. 
Efficacy Measures  
TTSTAND, TTRW, AND TTCLIMB in seconds, 6MWT in meters, NSAA subscores, hand-
held myometry, and ROM are captured directly via CRF. However, TTSTAND, TTCLIMB, 
and TTRW velocity results will be converted from seconds to velocities using the following 
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 


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Velocity will be set to 0 for responses determined to be missing due to disease progression 
(inability to do the test). Moreover, at the first visit a subject cannot perform the test due to 
disease progression, and at ALL subsequent visits, the raw score will be left as missing, and 
velocity will be imputed as 0. Note that a subject cannot have a missing response due to 
disease progression followed by visits with non-missing responses. In this scenario, the 
missing response will not be considered missing due to disease progression. Furthermore, the 
CRF captures missing due to disease progression in some cases explicitly as missing due to 
“Disease progression”. Also, subjects with TTSTAND graded as “Unable to stand from 
supine, even with use of chair” or “Assisted Gowers” will have that test and all later test 
velocities imputed as 0 due to disease progression. Similarly, subjects with TTRW graded as 
“Unable to walk independently” or “Unable to walk independently but can walk with knee-
ankle-foot or support from a person” will have that test and all later test velocities imputed as 
0 due to disease progression. And subjects with TTCLIMB graded as “Unable to climb 4 
standard stairs” will have that test and all later test velocities imputed as 0 due to disease 
progression. Note that for the primary and secondary analyses, velocity is imputed as 
described here only for unmissed subject visits. For example, if a subject discontinued the 
study at Week 12, and was unable to perform these tests at that visit due to disease 
progression, this subject would not have Week 24 velocity imputed.    
For elbow flexors and knee extensors, hand-held myometry measurements were collected 
unilaterally using the dominant side, if known. The best of 3 collected test results at each 
visit will be summarized. 
NSAA total score is calculated as the sum of all NSAA subscores only when none of the 
subscores are missing. 
 
Safety Measures 
For BMI Z-scores, the following computational example given age and sex for children aged 
2 to 20 years uses the 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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For height percentiles, the same computational formula for Z provided above in the BMI Z-
score example is used. However the reference table, given age and sex for children aged 2 to 
20 years, is the STATAGE.xls reference table (Stature-for-age charts, 2 to 20 years, LMS 
parameters and selected smoothed stature percentiles in centimeters, by sex and age at 
webpage “Percentile Data Files with LMS Values” 
https://www.cdc.gov/growthcharts/percentile_data_files.htm). Once the Z-score is calculated, 
the percentile is then derived from the standard normal cumulative distribution. 
 
For DXA scan data, 9 endpoints will be presented. Three of the 9 endpoints are derived 
endpoints, which use the following formulas: 
• Total body composition fat-free mass (g) = total body bone mineral content (BMC) 
(g) + total body lean mass (g) 
• Total body composition lean mass index (kg/m2) = (total body BMC + total body lean 
mass) / height2 (note that total body lean mass and total body BMC must be converted 
to kg, and height must be converted to m for this formula) 
• Total body composition fat mass index (kg/m2) = total body fat mass / height2 (note 
that total body fat mass must be converted to kg, and height must be converted to m 
for this formula) 
Exploratory Measures 
The TSQM Version II has 11 items, resulting in four specific domains of Effectiveness, Side 
Effects, Convenience, and Global Satisfaction. Scores for each domain are computed by 
adding the TSQM items in each domain and then transforming the composite score into a 
value ranging from 0 to 100. Of note, a score can be computed for a domain only if no more 
than one item is missing from that domain. The calculations specific to each domain are 
presented in detail below. 
• Global Satisfaction 
([Sum(Item 10 to Item 11) – 2] divided by 12) * 100  
If one item is missing  
([(Use the completed item)) – 1] divide by 6) * 100 
• Effectiveness 
([(Item 1 + Item 2) – 2] divide by 12) * 100  
If one item is missing  
([(Use the completed item)) – 1] divide by 6) * 100 
 
• Side Effects 
All ‘NA’ responses are coded as ‘5’ indicating ‘Not at all Dissatisfied’  
([Sum(Item 4 to Item 6) – 3] divide by 12) * 100  
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([(Sum(the two completed items)) – 2] divide by 8) * 100 
 
• Convenience 
([Sum(Item 7 to Item 9) – 3] divided by 18) * 100  
If one item is missing  
([(Sum(the two completed items)) – 2] divided by 12) * 100 
 
The PARS III (Stein R et al., 1990) is a brief parent-completed measure of psychosocial 
adjustment composed of 28 questions. The PARS III includes 6 psychosocial subscales (Peer 
Relations, Dependency, Hostility, Productivity, Anxiety/Depression, and Withdrawal) and a 
Total Score.  The 4 PARS III subscales for Peer Relations, Dependency, Anxiety and 
Depression, and Withdrawal will be calculated and analyzed in this SAP using the sum of the 
score of the questions for each subscale. All 28 questions use a 4-point interval rating scale, 
ranging from 1 = “never or rarely” to 4 = “always”. For calculating subscales, some 
questions are recoded so that higher scores always indicate better adjustment.  
Hostility and Productivity are not measured as they have not shown changes in DMD 
populations, and Total Score will not be analyzed. If a 4-item subscale is missing more than 
one item or a 6-item subscale is missing more than two items, it will not be scored. If less 
than one or two items, respectively, is missing, the subscale will be scored by replacing the 
missing item with the subject's mean of the non-missing items for that subscale.   
 
The questions summed for each subscale presented in this SAP are as follows: 
Peer Relations 
• Spent time with friends? 
• Made friends without difficulty? 
• Joined others of own accord? 
• Had many different friends? 
 
Dependency 
• Wanted help in things he could have done on own? 
• Been unable to decide things for self? 
• Asked for help when could have figured things out? 
• Asked unnecessary questions instead of working on own? 
 
Anxiety and Depression 
• Complained about problems? 
• Seemed restless, tense? 
• Said people didn’t care about him? 
• Seemed sad? 
• Said he couldn’t do things right? 
• Acted afraid or apprehensive? 
 
Withdrawal 


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• Sat and stared without doing anything? 
• Appeared listless and apathetic? 
• Seemed unaware of things going on around? 
• Shown little interest in things, had to be pushed into activity? 
 
For PODCI subscale Upper Extremity and Physical Function, the following 8 questions will 
be summed to provide a raw score where a minimum of 4 question responses must be non-
missing and valid: 
• Lift heavy books? 
• Pour a half gallon of milk? 
• Open a jar that has been opened before? 
• Use a fork and spoon? 
• Comb his hair? 
• Button buttons? 
• Write with a pencil? 
• Turn doorknobs? 
The standardized Upper Extremity and Physical Function score is calculated as [(4 - mean of 
non-missing questions used to calculate the raw score) / 3] * 100. Note that response scores 
of 5 indicate that the subject was too young for the activity and are set to missing by Data 
Management when calculating the subscale score (see POSNA (PODCI) Child Proxy 
Scoring Outcomes Instrument).  
 
For PODCI subscale Transfers and Basic Mobility, the following 11 questions will be 
summed to provide a raw score where a minimum of 7 question responses must be non-
missing and valid:  
• Put on his coat? 
• Climb one flight of stairs? 
• Walk one block? 
• Get on and off a bus? 
• Stand while washing his hands and face at a sink? 
• Sit in a regular chair without holding on? 
• Get on and off a toilet or chair? 
• Get in and out of bed? 
• Bend over from a standing position and pick up something off the floor? 
• How often does your child need help from another person for sitting and standing? 
• How often does your child use assistive devices (such as braces, crutches, or 
wheelchair) for sitting and standing? 
 
The standardized Transfers and Basic Mobility score is calculated as [(4 - mean of non-
missing questions used to calculate the raw score) / 3] * 100. Note that the responses to the 
last 2 questions are rescaled if used in calculating the sum and standardize score as follows:  
rescaled = [(response - 1) * 3/4] + 1. Note that response scores of 5 indicate that the subject 


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was too young for the activity and are set to missing by Data Management when calculating 
the subscale score (see POSNA (PODCI) Child Proxy Scoring Outcomes Instrument). 
 
7.3.8. Analysis Software 
Data manipulation, tabulation of descriptive statistics, and graphical representations will be 
performed primarily using SAS (release 9.4 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. 
7.3.9. Study Data 
Study data identified in the schedule for time and events (Table 2 Schedule of Study 
Activities) are collected, and source verified, on the electronic data capture tool: 
OpenClinica. 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 (note that any hardcoding of data will be captured in notes-to-file 
requiring Sponsor approval and detailed in the relevant reviewer guide). 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 in this SAP are 
described in Figure 1. Note that the methods described here for Period #1 may need to be 
modified in order to incorporate the 2 periods of the study in the whole Study SAP. 


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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. 
 
7.3.10. Period #1 Data Management Study Data Cutoff  
As detailed in the Data Management Plan v2.0, raw datasets will be separated by Data 
Management into data captured on CRFs up to Week 24, which will include Week 24 F/U 
data, and data captured on CRFs after Week 24. Only the “up to Week 24” datasets will be 
transferred to Summit Analytical for analysis in this SAP.  
Data from “up to Week 24 visit” events will be selected from non-visit eCRFs (informed 
consent, adverse events, concomitant medications, and concomitant non-drug treatment 
form) using the study event variable, including only visits labeled “up to Week 24”. The 
Unscheduled Visit and End of Study event (Discharge from Study CRF) data will be 
separated using the event date of the Unscheduled Visit and the Last Date of Study 


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Participation, respectively, and the first date of dose tapering from the Study Drug Return 
eCRF at the Week 28 visit for each participant during the transition period to Treatment 
Period #2. For participants lost to follow up, screen failures, and participants lost to follow up 
during Treatment Period #1, all data is included. The other event data will be separated using 
the study event variable, including only visits up to and including Week 24.   
7.4. 
General Statistical Methodology 
7.4.1. Statistical Summaries: Descriptive and Inferential 
Unless otherwise specified, 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. See Section 7.4.5 for 
more details on the handling of multiple comparisons for the efficacy analyses. 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.  
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 
safety data. The DSMB will meet at regular intervals to review all pertinent safety data. 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. 


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7.4.3. Week 24 Analysis 
The primary analyses described in this SAP are the analyses which will be performed after 
all subjects complete the Week 24 F/U Visit (or complete the Week 24 Visit for subjects who 
were unable to complete the Week 24 F/U Visit) (end of Treatment Period #1). The results 
from these analyses will be provided to regulatory authorities. Investigators, study subjects, 
study staff, and monitors will remain blinded throughout the duration of the 52-week study. 
The Sponsor, including data management and statistical personnel, will be unblinded after all 
subjects have completed the Week 24 F/U Visit to provide analysis of Period #1.  
7.4.4. Week 48 Analysis 
The Week 48 analyses will be performed after all subjects complete Week 48 of Treatment 
Period #2 and the subsequent 4-week double-blind Dose-tapering Period, if applicable, and 
will be the subject of a second SAP. The results from these analyses will be provided to 
regulatory authorities. All study staff may be unblinded after database lock of data from the 
entire study.  
7.4.5. Multiple Testing Procedures 
The primary efficacy endpoint tests vamorolone 6.0 mg/kg/day dose group vs. placebo using 
TTSTAND velocity at Week 24 and occurs during Treatment Period #1 of the study. The 
primary efficacy endpoint supports the primary objective of this study. The study is thus 
powered for the efficacy comparison as described in Section 6 using an alpha level of 0.05 
for success.  
 
The secondary efficacy endpoints will be tested at Week 24 along with the primary efficacy 
endpoint using a fixed sequential testing process where the fixed sequence of testing will be 
done in the following order: 
 
1. TTSTAND velocity, vamorolone 2.0 mg/kg/day vs placebo 
2. 6 Minute Walk Test (6MWT) meters walked, vamorolone 6.0 mg/kg/day vs. placebo 
3. 6 Minute Walk Test (6MWT) meters walked, vamorolone 2.0 mg/kg/day vs. placebo 
4. Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 6.0 mg/kg/day vs. 
placebo 
5. Time to Run/Walk (TTRW) 10 meters velocity, vamorolone 2.0 mg/kg/day vs. 
placebo 
6. 6MWT meters walked, vamorolone 6.0 mg/kg/day vs. prednisone 
7. 6MWT meters walked, vamorolone 2.0 mg/kg/day vs. prednisone 
 
Each test in the sequence will be carried out using a two-sided alpha level of 0.05. Statistical 
testing of the primary/secondary efficacy endpoints will stop if a p-value >0.05 occurs or if a 
p-value ≤0.05 occurs in the wrong direction. In case the fixed sequential testing process 
stops, the results of the subsequent tests will be reported with nominal p-values, but p-values 


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≤0.05 in the right direction will not be considered proof of statistical testing success in these 
subsequent tests. 
 
All other analyses will not be corrected for multiple comparisons (tests will be performed at a 
nominal alpha level of 0.05), as they will be viewed and handled in the perspective of not 
testing a formal hypothesis. 
 
7.5. 
Summary of Study Data 
7.5.1. Subject Summary Grouping 
In general, and unless otherwise noted, data summaries will be presented by treatment group. 
7.5.2. Study Disposition 
Subject counts will be summarized by analysis population.  
 
The number of subjects enrolled (i.e., signed informed consent form), screened following 
enrollment, randomized following screening, completing Week 24 and Week 24 F/U, 
discontinuing early, and the reason for discontinuation from the study will be summarized.  
 
The number of subjects randomized by country and site will be tabulated in a summary table 
by analysis population. 
 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented. In addition, the reasons for failing 
screening will be listed. Also, the duration of treatment (time from first dose to last dose 
during Period #1) will be presented in the listing. 
 
7.5.3. Protocol Deviations 
All protocol deviations will be presented in a by-subject data listing. Deviations will be 
presented by subject and site. Deviations incurred due to COVID-19 pandemic study 
modifications will be noted. Important deviations will be classified.  
Protocol deviations will be summarized descriptively, categorically, by treatment group for 
all analysis populations. 
7.5.4. Demographics and Baseline Characteristics 
Subject demographics (age, race, and ethnicity), baseline characteristics (height, height 
percentile, weight, body mass index [BMI], BMI Z-score, and months since first DMD 
symptoms noticed), and baseline efficacy data for TTSTAND in seconds, 6MWT, and 
NSAA total score will be summarized descriptively, either continuously or categorically by 
treatment group for all analysis populations.  


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Subjects that indicate more than 1 race will be counted under “Multiple” in the race 
tabulation. 
All demographic and baseline information, including DMD mutation type, will be presented 
in by-subject listings (note that date of birth will be excluded from the listings). 
7.5.5. Medical History 
Subject medical and surgical history will be collected during the screening period 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 
MedDRA (version 20.0 or later). The number and percentage of subjects with any medical 
history events will be summarized by system organ class and preferred term by treatment 
group (and overall) for the Safety Population. At each level of tabulation subjects will be 
counted once if they had 1 or more of each such event.  
Subject medical history data will be presented in a by-subject listing. 
7.5.6. Prior and Concomitant Medications 
A categorical summary of prior and all concomitant medications and non-pharmacological 
treatments taken prior to and during the course of the study will be presented in tabular form 
summarizing the number and percentage of subjects by anatomical therapeutic chemical 
classification level and preferred name by treatment group (and overall) using the World 
Health Organization (WHO) Drug classification (Version 01 JUN 2017 or later) for the 
Safety Population. At each level of tabulation subjects will be counted once if they had 1 or 
more of instance of medication usage.   
A concomitant medication is defined as any medication taken on or after the day of first 
exposure to study drug up until the Week 52 Visit. Concomitant medications taken on or 
after the first exposure to study drug until the end of the Week 24 F/U Visit will be 
summarized in the Period #1 analyses. 
Prior medications are defined as any medications that are taken prior to the day of first 
exposure to study drug, collected from up to 3 months prior to Screening. 
Medications missing year from date information will be considered concomitant medications 
unless other date information shows clearly that the medication was not concomitant. 
All prior medications, concomitant medications, and non-pharmacological treatments will be 
presented in by-subject listings. 


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7.5.7. Treatment Compliance and Study Drug Exposure 
Study drug administration and treatment compliance, and study drug exposure will be 
summarized descriptively for suspension and tablets separately for the Safety Population and 
the mITT Population.  
 
Suspension administration and compliance will be calculated based on the weight of 
suspension in grams. For each subject, the total suspension administered will be estimated 
from the total weight of the suspension bottles dispensed and returned (amount dispensed g – 
amount returned g), as collected on the CRF. Further, the amount of suspension prescribed is 
captured on the CRF in mL. This data will be used to calculate the total suspension 
prescribed for each subject and converted to grams (1 mL suspension = 1 g suspension). 
Compliance percentage will then be calculated as the total suspension administered g / total 
suspension prescribed g x 100%. These endpoints will be summarized for all treatment 
groups and overall. 
 
Tablet administration and compliance will calculated be based on the count of tablets 
dispensed and returned, and the count of tablets prescribed. The count of tablets dispensed 
and returned is captured on the CRF and will be used to calculate the total tablets 
administered for each subject. Further, for each subject, the prescribed tablet dosing is 
captured on the CRF in mg, which will be converted to a count of tablets (1 tablet = 5 mg). 
Compliance percentage will then be calculated as the total tablets administered count / total 
tablets prescribed count x 100%. These endpoints will be summarized for all treatment 
groups and overall. 
 
For vamorolone, exposure will be presented only for the vamorolone treatment groups. For 
the 6.0 mg/kg/day treatment group, vamorolone exposure will be calculated as the total 
suspension administered g x 40 mg/g (there are 40 mg vamorolone per g of 6 mg 
suspension). Similarly for the 2.0 mg/kg/day treatment group, vamorolone exposure will be 
calculated as the total suspension administered g x 13.3 mg/g (there are 13.3 mg vamorolone 
per g of 2 mg suspension).   
 
For prednisone, exposure will be presented only for the prednisone treatment group. 
Prednisone exposure will be calculated as the total tablets administered x 5 mg.   
 
Treatment administration, compliance, and exposure data will be presented in by-subject 
listings. 
 
7.6. 
Efficacy Analyses 
The evaluations of clinical efficacy will be performed using the mITT Population and Per 
Protocol Population, unless otherwise noted. Analyses will be done as per randomized 
treatment. Only data captured during Treatment Period #1 (Screening to Week 24) will be 
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All efficacy data will be summarized descriptively for observed and change from baseline by 
treatment group and visit, and will be presented in by-subject listings. Where considered 
relevant, plots will be created. 
 
The primary efficacy outcome, TTSTAND (velocity) change from baseline to Week 24, will 
be compared between the 6.0 mg/kg/day vamorolone group and the placebo group using a 
restricted maximum likelihood (REML)-based MMRM. This model includes fixed effects for 
treatment (vamorolone 2.0 mg/kg/day, vamorolone 6.0 mg/kg/day, prednisone 0.75 
mg/kg/day, and placebo), age group (<6 years; ≥6 years), week, baseline TTSTAND 
velocity, and the treatment-by-week interaction. Study week will be included in the model as 
a categorical variable (Weeks 6, 12, and 24) along with the treatment-by-week interaction. 
Within this model, pairwise comparisons (using LS mean contrasts) will be made to compare 
TTSTAND velocity at 24 weeks for vamorolone 6.0 mg/kg/day dose level with placebo 
(primary efficacy outcome).  
 
For secondary and exploratory efficacy outcomes, as detailed in Sections 4.2.3.2 and 4.2.3.3, 
the same models will be used as for primary outcome (REML-based MMRM including fixed 
effects for treatment [vamorolone 2.0 mg/kg/day, vamorolone 6.0 mg/kg/day, prednisone 
0.75 mg/kg/day, and placebo], age group [<6 years; ≥6 years], week, response variable 
baseline, and the treatment-by-week interaction).  
 
Additional tests are done in exploratory analyses. See Section 7.4.5 for more details on the 
handling of multiple comparisons of secondary analyses.  
 
An unstructured covariance matrix will be used, and underlying modelling assumptions will 
be checked. If this analysis fails to converge, Akaike’s information criterion will be used to 
select the best covariance structure from compound symmetry and autoregressive-1 (AR(1)). 
The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. If differences between baseline characteristics exist between the treatment groups, 
it will be investigated if adjustment for these characteristics is clinically relevant and 
necessary. The secondary outcome measures will be compared using similar models.  
 
The following sensitivity analyses will be performed using the MMRM analysis described 
above for the primary outcome (TTSTAND velocity vamorolone 6.0 mg/kg/day dose group 
versus placebo and presented for Week 24), and the secondary outcomes, presented for Week 
24, (TTSTAND velocity vamorolone 2.0 mg/kg/day vs placebo; 6MWT meters walked 
vamorolone 6.0 mg/kg/day vs. placebo; 6MWT meters walked vamorolone 2.0 mg/kg/day 
vs. placebo; TTRW 10 meters velocity vamorolone 6.0 mg/kg/day vs. placebo; TTRW 10 
meters velocity vamorolone 2.0 mg/kg/day vs. placebo; 6MWT meters walked vamorolone 
6.0 mg/kg/day vs. prednisone; and 6MWT meters walked vamorolone 2.0 mg/kg/day vs. 
prednisone) (see Section 7.3.2.2  for more details): 


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• Multiple imputation using MCMC methods for missing data on TTSTAND velocity 
and 6MWT, using the mITT population; 
• Multiple imputation using MCMC methods for missing data on TTSTAND velocity 
and 6MWT, using all subjects, including those with no baseline or post-baseline 
assessment; 
• Multiple imputation using MCMC methods for missing data on TTSTAND velocity 
and 6MWT, using randomized subjects who have non-missing baseline data; 
• No imputation on TTSTAND velocity and 6MWT, using randomized subjects with no 
missing assessments; 
• Multiple imputation using a Control-based Pattern-Mixture Model for missing data on 
the primary and secondary efficacy endpoints, using the mITT population. 
The following COVID-19 sensitivity analyses will be performed using the MMRM analysis 
described above for the primary outcome (TTSTAND velocity vamorolone 6.0 mg/kg/day 
dose group versus placebo and presented for Week 24 using the mITT population) (see 
Section 7.3.2.3 for more details): 
• Impact of assessments that are missing or delayed due to COVID-19 
• Impact of alternative assessment methods (motor assessment using video assessment 
method) 
The following sensitivity analysis assessing the impact of the most influential TTSTAND 
observations will be performed using the MMRM analysis described above for the primary 
outcome TTSTAND velocity vamorolone 6.0 mg/kg/day dose group versus placebo and 
presented for Week 24 using the mITT population: All TTSTAND values that are <2.5 
seconds (0.4 rises per second) will be imputed as 2.5 seconds. After this imputation, the data 
will be analyzed similarly as for the primary analysis. The rationale of this sensitivity 
analysis is provided below. 
• The time to rise testing protocol caps the time allowed to rise at 30 seconds (0.033 
rises per second). The velocity transformation diminishes the impact of large 
fluctuations in timed performance at the more impaired end of the spectrum. When a 
patient cannot perform the test anymore, a standardized value is assigned 
(velocity=0).  In this case, e.g. a 45 second actual performance is imputed as unable 
to perform the test (velocity=0).  
• A challenge of the velocity transformation in the less impaired spectrum of DMD is 
that variability in reaction time of the subject or the variability in initiating the 
stopwatch by the clinical evaluator (typically about 0.5 seconds) can impact the 
velocity substantially even though a small change in time to rise at the less impaired 
end of the scale is not clinically meaningful in terms of disease progression or 
improvement.  For example, a deterioration from 2.0 seconds to 2.5 seconds in rise 
time would translate to a deterioration of 0.1 rises per second in velocity which is 
twice the pre-specified effect size of this study.  
• The lower limit of normal for time to rise from the floor for 4 to 6 year old or older 
healthy typically developing patients (defined as 5th percentile or better) from a 
natural history cohort from Belgium (Hoskens, et al. 2019) was found to be 2.5 


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seconds. Therefore, incremental small changes in rise times below 2.5 seconds would 
be deemed to be not clinically meaningful and are observed in virtually all healthy 
typically developing children with normal phenotype.  There is likelihood that the 
signal to noise ratio below 2.5 seconds would be suboptimal as large changes in 
velocity would be calculated with small changes in absolute times.   
• Therefore, to mitigate the effect of reaction time on the calculated velocity at the less 
impaired end of the scale and to diminish the likelihood that a 0.2 to 0.5 second 
change in rise from floor time occurring in the normal range of functioning would 
result in a large change in velocity, a sensitivity analysis will be performed that 
transforms all values below 2.5 seconds to a value of 2.5 seconds.  For example, a 0.5 
second change in the normal end of the spectrum from 2.5 to 2.0 seconds or from 2 to 
2.5 seconds, which would result in a calculated change in velocity of 0.1 rises per 
second will be treated as a change of 0 (2.5 seconds on both measures), for the 
purposes of this sensitivity analysis. 
 
The following sensitivity analysis due to missing 6MWT data, which pools other motor 
function tests, will be presented: 
• As reported by McDonald et al. (2013), the motor function tests TTSTAND, TTRW, 
TTCLIMB, and 6MWT are correlated in patients with DMD as they all measure 
timed motor function. In order to evaluate the impact of vamorolone treatment on 
timed motor function using as complete dataset as possible, an additional sensitivity 
analysis will be conducted by pooling the data from all the motor function tests 
except TTSTAND (i.e., TTRW velocity, TTCLIMB velocity, and 6MWT). The 
rationale for this sensitivity analysis is to use as much data as possible to estimate the 
impact of missing data. Due to the correlation both between the parameters and 
within the repeated longitudinal assessments, this analysis is expected to provide 
further information on the consistency of the effects. The concept of pooling data 
from multiple motor function endpoints in DMD has been introduced by Li et al. 
(2020). The analysis defined below uses similar concept of pooling data from the 
timed tests used in DMD, using these data in a sensitivity analysis based on a 
multivariate repeated measures model.  
o First, the test data will be standardized by using the percentage change from 
baseline as the endpoint. The percentage change will be calculated as (value at 
visit – baseline value) / baseline value x 100%, calculated from the endpoints 
as used in the original statistical analysis, i.e. from velocities or distances. All 
the percentual change values from the three tests, TTRW, TTCLIMB, and 
6MWT, will be entered to a single statistical model.  
o A model similar to the MMRM model presented in this SAP will be used, but 
in addition to the fixed factors included in the MMRM detailed above, the 
parameter (TTRW velocity, TTCLIMB velocity, or 6MWT) and all 2- and 3-
level interaction terms between treatment group, visit and parameter will be 
added. The model will use the Kronecker product covariance structure, as 
proposed by Galecki (1994). Accordingly, the covariance structure will be set 


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as type=un@ar(1) in the REPEATED statement of the MIXED procedure. 
The SAS code for implementing this kind of model with the MIXED 
procedure is provided by Gao et al. (2006) and outlined below. 
proc mixed; 
class usubjid age paramcd trtp avisit; 
model chg=age paramcd trtp avisit paramcd*trtp paramcd*avisit trtp*avisit 
      paramcd*trtp*avisit / ddfm=kr; 
repeated paramcd avisit / subject=usubjid type=un@ar(1); 
run; 
 
As support for the primary and secondary efficacy endpoint analyses, the pattern and type of 
missing data will be summarized for the primary and secondary efficacy endpoints by visit. 
For each visit, the data will be classified as available, or missing. The missing data will be 
further classified as intermittent (missing value is followed by an observed value) or as 
measurement dropouts (all subsequent values after the missing value are missing). The 
intermittent missing data will be further classified as missing due to COVID-19 or due to 
other reasons. The measurement dropouts will be further classified as inability of the subject 
to perform the test due to disease-related disability, due to COVID-19, or due to other 
reasons. 
 
Furthermore, a supportive responder analysis of the TTSTAND velocity primary and 
secondary efficacy endpoints (comparison of vamorolone 6.0 mg/kg/day dose group versus 
the placebo group and 2.0 mg/kg/day dose group versus the placebo group at Week 24 
assessment) will be conducted by classifying the endpoint data as improvements (better 
velocity compared to baseline) versus non-improvements (same or worse velocity compared 
to baseline). The responder endpoints will be tabulated at Week 24 by treatment group, and 
the percentage of responders will be compared between vamorolone 6.0 mg/kg/day dose 
group versus placebo group and 2.0 mg/kg/day dose group versus placebo group using 
descriptive statistics and Fisher’s exact test. This analysis will be performed on the mITT 
population. Further, this analysis will be done 2 ways, first on observed cases only, and then 
again assuming subjects with a missing Week 24 assessment will be considered non-
improvers. 
 
In addition to the summary tables described above, TTSTAND velocity at Week 24 will be 
presented in 3 summary tables of continuous descriptive statistics on observed response and 
change from baseline by treatment group and time point using the mITT population by 3 
subgroups: baseline age <=5.0 years vs. >5.0 years; baseline age <=6.0 years vs. >6.0 years; 
and TTSTAND seconds at baseline <=5.0 seconds vs. >5.0 seconds. 
 
TTSTAND in seconds will be presented in a summary table of continuous descriptive 
statistics on observed response and change from baseline by treatment group and time point 
using the mITT population. 
 


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TTSTAND in seconds will be presented in a shift table for Week 24 shift from baseline for 
categories of <5 seconds, 5 to 10 seconds, and >10 seconds. Subject counts and percentages 
will be tabulated by treatment group for the mITT population. Percentages will be based on 
the number of subjects with a baseline and Week 24 assessment. 
  
Additional supportive analyses for the primary efficacy endpoint may be performed.  They 
include excluding subjects with large differences between the screening and baseline value 
TTSTAND velocity scores (larger than 2 standard deviations) and excluding subjects who 
had their TTSTAND times measured at a visit using live video remote streaming, instead of 
recorded and times measured from the live recording. 
 
7.7. 
Safety Analyses 
Safety analyses will be performed using the Safety Population and will be completed using 
the actual treatment a subject received. All safety data will be presented in by-subject listings 
as well as in tables and figures as described below. In general, descriptive statistics for each 
safety endpoint will be presented by time point and treatment group. Where considered 
relevant, plots will be created. 
 
Safety data from Treatment Period #1 will be summarized together by treatment group. 
7.7.1. Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 20.0. 
 
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). AEs with missing year from the start date will be considered treatment-
emergent unless it is clear from non-missing date information that the AE started prior to first 
dose of study drug. For the Period #1 analyses described herein, AEs and TEAEs which 
occur through the subject’s Week 24 F/U Visit are included. Serious AEs 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, with the cut-off for the Period #1 analyses at the 
Week 24 F/U Visit (or Week 24 Visit for subjects who did not have a Week 24 F/U Visit). If 
the onset of an AE is on Day 1 and its relationship to time of study drug administration is 
unknown, then the AE will be counted as treatment-emergent. If the onset of the AE is on 
Day 1 but is known to have onset prior to the time of the first administration of study drug, 
the AE will not be considered treatment emergent. 
 
The number and percent of subjects with any TEAEs will be summarized by system organ 
class and preferred term by treatment group (and overall). At each level of tabulation (e.g., 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. (Note that the ADaM ADAE dataset will 


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include the coded terms for SOC, PT, Highest Level Term, Highest Level Group Term, and 
Lowest Level Term.) 
 
Level of intensity will be assessed using the CTCAE grading (CTCAE v 4.03 grade). 
The following summary tables and subject level listings will be presented for TEAE data: 
• Overall summary of TEAEs 
• Summary table of incidence of TEAEs by descending incidence by PT 
• Summary table of incidence of TEAEs by SOC and PT (will include counts of 
subjects and events) 
• Summary table of incidence of serious TEAEs by SOC and PT (will include counts of 
subjects and events) 
• Summary table of incidence of TEAEs by maximum relatedness to treatment by SOC 
and PT 
• Summary table of incidence of TEAEs by maximum intensity by SOC and PT 
• Summary table of incidence of TEAEs leading to study drug discontinuation by SOC 
and PT 
• Summary table of incidence 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 
A listing will present all AEs associated with suicidality (Maund et al., 2014), where adverse 
event listing preferred term and verbatim term data will be searched and reported for terms: 
• “suic”, “overdos, “attempt”, “cut”, “gas”, “hang”, “hung”, “jump”, “mutilate”, 
“overdos”, “self damage”, “self harm”, “self inflict”, “self injur”, “shoot”, and “slash” 
• “poi”, “emot”, “labi”, “hos”, “vio”, “agg”, “thought”, and “think”. 
 
A listing will present all AEs associated with abuse potential (Bossard et al., 2016), where 
adverse event listing preferred term and verbatim term data will be searched and reported for 
terms: 
• “drug”, “chemical”, “abuse”, “dependence”, “disuse”, “diversion”, “withdrawal”, 
“mood”, “substance”, “unapproved”, “polysubstance”, “euphoric”, “addict”, 
“dysthymic” 
Obvious false positives (e.g., “gas” in “gastrointestinal, “cut” in “acute,” and “vio” in 
“behavior”) will be excluded as per FDA (Posner et al., 2007). 


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7.7.2. Vital Signs, 12-Lead ECG, and Laboratory Outcomes 
Vital signs, including height and height percentile, weight, and BMI and BMI Z-score, 
clinical laboratory test results, and other laboratory test results not detailed elsewhere in this 
SAP will be summarized at each assessment time point by treatment group 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. 
 
Height percentile change from baseline and BMI Z-score change from baseline results will 
be compared between treatment groups using an REML-based MMRM analysis with 
treatment group, week of the visit, and the treatment-by-week interaction as factors, and 
baseline response (height percentile or BMI Z-score) and age group as a covariate. Week will 
be included in the model as a categorical variable (Week 12 and 24) along with the 
treatment-by-week interaction. An unstructured within-subject covariance matrix will be 
used. If this analysis fails to converge, Akaike’s information criterion will be used to select 
the best covariance structure from compound symmetry and autoregressive-1 (AR(1)). The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
 
Overall ECG interpretation will be summarized categorically by assessment response and via 
shift table presenting Normal/Abnormal Not Clinically Significant/Abnormal Clinically 
Significant and will also be presented in by-subject listings. 
 
Clinical laboratory summary tables for continuous descriptive statistics will include only 
central lab data. Change from baseline in all continuous clinical laboratory test results will be 
tested using one sample t-tests with p-values presented along with the descriptive statistics at 
each assessment visit within each treatment group (note that pharmacodynamic biomarkers- 
creatine kinase [CK] for efficacy, fasting glucose and insulin for insulin resistance, and 
glutamate dehydrogenase [GLDH] for safety- will be of special interest).  
Clinical laboratory test results will also be presented in shift tables for all laboratory 
parameters where low/normal/high or normal/abnormal status can be ascertained. These shift 
tables will include central and local lab data. Abnormal clinical lab test results will be 
presented in a table listing where low/normal/high or abnormal/normal status can be 
ascertained. 
 
 
Low/normal/high or normal/abnormal flags will be imputed on local lab data only if the 
normal flag is missing and a lower and/or upper normal range are provided in the raw data 
for the observation so that the lab response can be assessed as low/normal/high or 
normal/abnormal depending on the normal range data provided. Note that this same 
imputation will also be carried out on vitamin D data from the central lab when possible. 
 
For by-subject listings, clinically significant response (yes/no) will be presented as collected 
for local labs. 


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Lab results that are below the lower limit of quantification will be divided by 2 for analysis 
(ex., a lab response of “<0.1” will be analyzed as 0.05). Lab results that are above the upper 
level of quantification will be analyzed using the upper level of quantification (ex., a lab 
response of “>1500” will be analyzed as 1500).  
 
Central lab results will be presented using both U.S. conventional units and SI units. Local 
lab results will be presented using the units as collected. 
 
Except for lab results and follow-up eye and ECG examinations, 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.  
 
7.7.3. Physical Examination 
Physical examination results will be presented in by-subject listings. 
7.7.4. Other Safety Measures 
Cushingoid features will be summarized by presenting the number and percentage of subjects 
by treatment group that develop them as adverse events. 
 
2D-echocardiogram results will be summarized by treatment group at Baseline and Week 24. 
The number and percent of subjects who have normal, abnormal not clinically significant, or 
abnormal clinically significant findings will be summarized by treatment group using shift 
tables. 
 
Eye examination results will be summarized at Baseline and Week 24. The number and 
percent of subjects who have a cataract present (yes/no) will be summarized by treatment 
group for left eye and right eye separately. The same summary will be performed for the 
presence of glaucoma (yes/no), though not broken out by left and right eye. Intraocular 
pressure readings will be presented in by-subject listings. Note that the window for the Week 
24 eye exam data to be included in summary tables is the Week 24 scheduled visit date +-6 
weeks. 
 
ACTH Stimulation Test results will be summarized by treatment group at Baseline and Week 
24 Follow-up. The peak cortisol measurement from the 30-minute and 60-minute tests will 
be used in the analysis. The number and percent of subjects who have peak cortisol levels 
<18 µg/dL (<500 nM) or ≥ 18 µg/dL (≥ 500 nM) will be summarized by treatment group. 
Pearson Chi-square or Fisher’s exact tests will be used to compare each vamorolone dose 
with prednisone, and the two vamorolone doses with each other. Note that the analysis 
windows for the 30-minute and 60-minute tests are 30 minutes +-15 minutes and 60 minutes 
+-15 minutes, respectively. Assessments outside these windows will not be included in the 
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DXA scan data will be summarized by treatment group at Baseline and Week 24. Descriptive 
continuous statistics will be presented for observed response, change from baseline, and 
percent change from baseline. Further, each vamorolone dose group will be compared with 
prednisone on the percent change from baseline utilizing LS means from an ANCOVA 
model with treatment group (all treatment groups included) as a main effect and age group at 
study entry and baseline result as covariates. 
 
Fracture questionnaire results will be presented in by-subject listings. 
 
7.8. 
Exploratory Analyses 
Patient Reported Outcomes including the TSQM, PARS III, and Ease of Study Medication 
Administration Assessment will be listed and presented using descriptive statistics by 
treatment and time point using the Safety Population. PODCI data will be presented similarly 
using the mITT Population. The Blindedness Assessment will be listed and presented using 
descriptive statistics by treatment at Week 24 using the Safety Population. 
 
Each vamorolone dose group will be compared with prednisone on TSQM response at Week 
24 utilizing LS means from an ANCOVA model with treatment group (all treatment groups 
included) as a main effect and age group at study entry as a covariate. 
 
Each vamorolone dose group will be compared with prednisone and placebo on the change 
from baseline in PARS III utilizing a REML-based MMRM with treatment group (all 
treatment groups included), week of the visit, and the treatment-by-week interaction as 
factors, and age group at study entry and baseline result as covariates for PARS III subscores 
for peer relations, dependency, anxiety and depression, and withdrawal. 
 
Physical functioning will be assessed by completion of the PODCI. Two subscales (Upper 
Extremity and Physical Function, and Transfers and Basic Mobility) will be summarized 
descriptively as a continuous endpoint by treatment group at each time point collected. 
Observed scores and change from baseline will be presented. Standardized scores will be 
used for the analyses. All PODCI data will be presented in a by-subject listing. Each 
vamorolone dose group will be compared with placebo on the change from baseline utilizing 
an ANCOVA model with treatment group (all treatment groups included) as a main effect 
and age group at study entry and baseline result as covariates. 
 
7.9. 
Pharmacodynamic (PD) Serum and Other Biomarkers 
The evaluations of PD will be performed using the Safety Population. Analyses will be done 
as per actually received treatment. 
     
Serum PD biomarkers of adrenal axis suppression, insulin resistance, and bone turnover will 
be assessed at Baseline, Week 12, and Week 24. Additional exploratory PD biomarkers of 


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both safety and efficacy may be assessed. Vamorolone-treated groups will be compared to 
both prednisone-treated and placebo groups. 
 
The descriptive summaries will include continuous descriptive statistics on observed and 
change from baseline at each week by treatment group. Continuous descriptive statistics will 
be provided along with interquartile range. One sample t-tests will be provided to test if the 
change from baseline mean values are different from zero within each treatment group. 
 
PD biomarker change from baseline results will be compared between treatment groups using 
REML-based MMRM analyses with treatment group, week of the visit, and the treatment-by-
week interaction as factors, and age group at study entry and baseline result as a covariate. 
Week will be included in the model as a categorical variable (Week 12 and 24) along with 
the treatment-by-week interaction. An unstructured within-subject covariance matrix will be 
used. If this analysis fails to converge, Akaike’s information criterion will be used to select 
the best covariance structure from compound symmetry and autoregressive-1 (AR(1)). The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
(Note that HbA1c is collected only once following baseline. It will be analyzed using an 
ANCOVA model in a similar manner as described here for the MMRM analyses. The 
ANCOVA model will include treatment group as a main effect, and age group at study entry 
and baseline result as covariates.) 
 
For first-in-morning serum cortisol levels, along with the statistics described above, the 
number and percent of subjects who have cortisol levels <3.6 µg/dL (<100 nM) or ≥ 3.6 
µg/dL (≥ 100 nM) will be summarized by treatment group. Pearson Chi-square or Fisher’s 
exact tests will be used to compare each vamorolone dose with prednisone, and the two 
vamorolone doses with each other, similarly to how ACTH simulated cortisol levels are to be 
tested. 
 
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. 
 
 
 


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8. 
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 
8.1. 
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. 
• 
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,a,b). 
• 
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 


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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).  
8.2. 
Population Summary Conventions 
• 
Population(s) represented on the tables or data listings will be clearly 
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, coefficient of variation [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 (ie., SAS® Software version 9.4 or 


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Final Version 3.0 
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IND#: 118,942 
 
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later) may be reported at the default level of precision. P-values <0.0001 
should be reported as <0.0001 not 0.0000. 
 
 


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9. 
REFERENCES 
Bello L, Kesari A, Gordish-Dressman H, et al. Genetic modifiers of ambulation in the 
Cooperative International Neuromuscular Research Group Duchenne natural history study. 
Ann Neurol. 2015; 77(4):684-696. 
 
Bossard JB, Ponté C, Dupouy J, Lapeyre-Mestre M, Jouanjus E. Disproportionality Analysis 
for the Assessment of Abuse and Dependence Potential of Pregabalin in the French 
Pharmacovigilance Database. Clin Drug Investig. 2016;36(9):735‐742. 
 
Escolar DM, Hache LP, Clemens PR, et al. Randomized, blinded trial of weekend vs. daily 
prednisone in Duchenne muscular dystrophy. Neurology. 2011; 77(5):444-452. 
 
Galecki AT. General class of covariance structures for two or more repeated factors in 
longitudinal data analysis. Communications in Statistics - Theory and Methods, 23:11, 3105-
3119 (1994). 
 
Henricson EK, Abresch RT, Cnaan A, et al. The Cooperative International Neuromuscular 
Research Group Duchenne natural history study: glucocorticoid treatment preserves 
clinically meaningful function milestones and reduces rate of disease progression as 
measured by manual muscle testing and other commonly used clinical trial outcome 
measures. Muscle Nerve. 2013; 48(1):55-67. 
 
ICH E9 Expert Working Group. Statistical Principles for Clinical Trials: ICH Harmonized 
Tripartite Guideline, September 1998. 
 
Li D, McDonald CM, Elfring GL, Souza M, McIntosh J, Kim DH, Wei LJ. Assessment of 
Treatment Effect With Multiple Outcomes in 2 Clinical Trials of Patients With Duchenne 
Muscular Dystrophy. JAMA Netw Open. 2020 Feb 5;3(2). 
 
Maund E, Tendal B, Hróbjartsson A, Lundh A, Gøtzsche PC. Coding of adverse events of 
suicidality in clinical study reports of duloxetine for the treatment of major depressive 
disorder: descriptive study. BMJ. 2014;348:g3555. 
 
McDonald CM, Henricson EK, Abresch RT, Duong T, Joyce NC, Hu F, Clemens PR, 
Hoffman EP, Cnaan A, Gordish-Dressman H; CINRG Investigators. Long-term effects of 
glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular 
dystrophy: a prospective cohort study. Lancet. 2018 Feb 3;391(10119):451-461. doi: 
10.1016/S0140-6736(17)32160-8.  
 
McDonald CM, Henricson EK, Abresch RT, et al. The Cooperative International 
Neuromuscular Research Group Duchenne natural history study – a longitudinal 


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investigation in the era of glucocorticoid therapy: design of protocol and the methods used. 
Muscle Nerve. 2013; 48(1):32-54. 
 
Meyer RD, Ratitch B, Wolbers M, Marchenko O, Quan H, Li D, Fletcher C, Li X, Wright D, 
Shentu Y, Englert S, Shen W, Dey J, Liu T, Zhou M, Bohidar N, Zhao PL & Hale M. 
Statistical Issues and Recommendations for Clinical Trials Conducted During the COVID-19 
Pandemic, Statistics in Biopharmaceutical Research, 2020; 12 (4): 399-411. DOI: 
10.1080/19466315.2020.1779122. 
 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007 Jul;164(7):1035-43. doi: 
10.1176/ajp.2007.164.7.1035. PMID: 17606655; PMCID: PMC3804920. 
 
Ratitch B, O’Kelly M. Imputation of Pattern-Mixture Models Using Standard SAS/STAT 
Procedures, PharmaSUG 2011 - Paper SP04. 
 
Smith EC, Conklin LS, Hoffman EP, Clemens PR, Mah JK, Finkel RS, Guglieri M, Tulinius 
M, Nevo Y, Ryan MM, Webster R, Castro D, Kuntz NL, Kerchner L, Morgenroth LP, 
Arrieta A, Shimony M, Jaros M, Shale P, Gordish-Dressman H, Hagerty L, Dang UJ, 
Damsker JM, Schwartz BD, Mengle-Gaw LJ, McDonald CM; CINRG VBP15 and DNHS 
Investigators. Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-
month interim analysis of a non-randomized open-label extension study. PLoS Med. 2020 
Sep 21;17(9):e1003222. doi:10.1371/journal.pmed.1003222. PMID: 32956407; PMCID: 
PMC7505441. 
 
Spurney C, Shimizu R, Morgenroth LP, et al. Cooperative International Neuromuscular 
Research Group Duchenne Natural History Study demonstrates insufficient diagnosis and 
treatment of cardiomyopathy in Duchenne muscular dystrophy. Muscle Nerve. 2014; Aug; 
50(2):250-256. 
 
Stein R, Jessop D. Manual for Personal Adjustment and Role Skills Scale, Albert Einstein 
College of Medicine of Yeshiva University. 1990. 
  
 
 


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Final Version 3.0 
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10. 
APPENDICES 
10.1. 
List of Tables, Listings, and Figures 
A table of contents (TOC) of all SAP tables, listings, and figures will be provided in an 
external programming shell document. 
10.2. 
SAP Amendment Summary of Important Changes 
SAP 
Version  Section 
Description of Change 
Final 
v2.0 
7.7.1 Adverse 
Events 
The following clarification was added to the 
description of listings for AEs associated with 
suicidality and abuse potential:  
 
Obvious false positives (e.g., “gas” in “gastrointestinal, 
“cut” in “acute,” and “vio” in “behavior”) will be 
excluded as per FDA (Posner et al., 2007). 
Final 
v3.0 
3.1 Preface 
Clarified language to indicate a separate analysis plan 
will be developed to accommodate recommendations 
specified by EMA.  
 
Updated language to indicate that for publication and 
other commercial purposes of the Period #1 VBP15-
004 study data, this FDA-specific SAP will be applied. 
Final 
v3.0 
3.3 Summary 
of Statistical 
Analysis 
Changes to the 
Protocol 
Clarified that spine x-ray analysis is discussed in the 
protocol. However, it will be presented in a separate 
SAP and is not included in this SAP. 
 
Noted that analysis of DNA testing (Week 24) is 
mentioned as an additional exploratory endpoint in the 
protocol but will not be analyzed in this SAP. 
 
Noted that exploratory biomarkers mentioned in the 
protocol will be stored and studied later and are not 
included in this SAP. 
Final 
v3.0 
4.2.1 Safety 
Endpoints 
Clarified language to indicate that the peak cortisol 
level after ATCH stimulation will be used to assess 
adrenal suppression. 
 
Clarified language by adding BMI (kg/m2) as a safety 
endpoint to the list of safety endpoints. 


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SAP 
Version  Section 
Description of Change 
Final 
v3.0 
4.2.5 
Pharmacodyna
mic Endpoints 
Clarified language to indicate first-in-morning serum 
cortisol levels can include fasting and non-fasting data. 
 
Clarified language to indicate that the peak cortisol 
level 30 or 60 minutes after ATCH stimulation will be 
used to assess adrenal suppression. 
Final 
v3.0 
7.1.2 Modified 
Intent-to-Treat 
(mITT) 
Population 
Clarified language defining the mITT population. 
Final 
v3.0 
7.1.3 Per 
Protocol 
Population 
Clarified language defining the Per Protocol 
population. 
Final 
v3.0 
7.2.2 
Subgroups 
Added subgroup analyses to the TTSTAND velocity 
summary statististics. 
Final 
v3.0 
7.3.1 Data 
Handling 
Added 2D-echo interpretation and eye examination 
data to rules on handling unscheduled data. 
Final 
v3.0 
7.3.2 Missing 
Data 
Added clarification regarding classification of data 
missing due to COVID-19. 
Final 
v3.0 
7.3.2.1 
Handling of 
Missing Date 
Values 
Removed imputation rules for missing AE times 
because time is not collected for AEs. 
Final 
v3.0 
7.3.2.2 
Imputation 
Methods 
Added details to describe the MCMC and PMM 
multiple imputation analyses. 
Final 
v3.0 
7.3.2.3 
Assessment of 
impact of 
COVID-19 on 
the primary 
endpoint 
Added details to describe the multiple imputation 
analyses. 
Final 
v3.0 
7.3.7 
Calculating 
Derived 
Variables 
Clarified the calculation of age for the study. 
 
Added language to clarify that the best of 3 collected 
results for elbow flexors and knee extensors will be 
analyzed. 
 
Added details for BMI Z-score and height percentile 
calculation. 
 


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SAP 
Version  Section 
Description of Change 
Added details for DXA endpoint calculations. 
 
Added details for PARS III and PODCI questionnaires. 
Final 
v3.0 
7.3.10 Period 
#1 Data 
Management 
Study Data 
Cutoff 
Added language detailing the data cutoff performed by 
Data Management. 
Final 
v3.0 
7.5.2 Study 
Disposition 
Additional details added to clarify tabulations. 
Final 
v3.0 
7.5.4 
Demographics 
and Baseline 
Characteristics 
Additional details added to clarify tabulations. 
Final 
v3.0 
7.5.5 Medical 
History 
Additional details added to clarify tabulations. 
Final 
v3.0 
7.5.6 Prior and 
Concomitant 
Medications 
Additional details added to clarify tabulations. 
Final 
v3.0 
7.5.7 
Treatment 
Compliance 
and Study 
Drug Exposure 
Added description of administration, exposure, and 
compliance calculations. 
Final 
v3.0 
7.6 Efficacy 
Analyses 
Added details on numerous sensitivity analyses for 
handling missing responses. 
 
Added clarification on the TTSTAND velocity 
responder analysis. 
 
Added detail on TTSTAND velocity subgroup 
summary tables. 
 
Add summary tables for TTSTAND seconds. 
Final 
v3.0 
7.7.1 Adverse 
Events 
Clarified that AEs with missing year from the start date 
will be considered treatment-emergent unless it is clear 
from non-missing date information that the AE started 
prior to first dose of study drug. 
Final 
v3.0 
7.7.2 Vital 
Signs, 12-Lead 
ECG, and 
Added language to clarify that height percentile will be 
analyzed using MMRM similar to BMI Z-score. 
 


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SAP 
Version  Section 
Description of Change 
Laboratory 
Outcomes 
Clarified that only central lab data will be included in 
summary tables of continuous descriptive statistics. 
 
Clarified that laboratory shift tables will include central 
and local lab data. 
 
Added language to clarify imputation of 
low/normal/high range flags and normal/abnormal 
range flags. 
 
Clarified how lab results that are below or above limit 
of quantification will be handled. 
Final 
v3.0 
7.7.4 Other 
Safety 
Measures 
Added detail for ACTH stimulation test windowing. 
 
Added language to describe how DXA scan data will 
be analyzed. 
Final 
v3.0 
7.8 
Exploratory 
Analyses  
Added language to clarify the statistical analyses being 
performed to compare vamorolone treatment groups to 
prednisone and placebo on TSQM, PARS III, and 
PODCI. 
 
Added clarification on the presentation of blindedness 
assessment data. 
Final 
v3.0 
7.9 
Pharmacodyna
mic (PD) 
Serum and 
Other 
Biomarkers 
Added details on HbA1c analysis. 
 
Added language to clarify the statistical analysis for 
assessing adrenal suppression being performed on first-
in-morning cortisol. 
Final 
v3.0 
9 References 
Additional references added.