Conditions: Muscular Dystrophy, Duchenne
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
This is a randomized, open-label, pilot clinical trial of spironolactone suspension versus oral prednisolone for use in Duchenne muscular dystrophy. The goals are to determine the safety of 6 months of treatment with spironolactone treatment int he steroid-naive DMD population as well as to determine if either spironolactone or a standard clinical dose of corticosteroids results in equivalent improvement in time to complete the 100 meter timed test (100M).

Detailed description:
Until recently, the only treatment shown to improve strength and preserve ambulation in DMD patients was the use of glucocorticoids, which are accompanied by significant side effects including obesity, cushingoid features, osteoporosis, and behavioral disturbances. Spironolactone is an aldosterone antagonist primarily used as a potassium sparing diuretic that is widely used in the pediatric population, with limited side-effects including gynecomastia and hyperkalemia. Recent studies by Dr. Rafael-Fortney have evaluated the effect of spironolactone treatment in several different mouse models of DMD. Her results show that treatment of these mice demonstrates increased muscle membrane stabilization while reducing the negative side-effects typically associated with standard of care glucocorticoids. This pilot study is designed to determine whether this commonly used medication, spironolactone, may have similar beneficial effects with a lower side effect profile and be applicable to a wider population of DMD patients.

The hypothesis for this controlled pilot trial is that spironolactone and prednisolone are of equal efficacy in improving skeletal muscle function over a 6-month period, and that spironolactone will be well tolerated in this patient population.

One outcome is that both drugs demonstrate equal efficacy in motor function. This would then serve as pilot data for a longer term study.

Arms:
arm 1: An anticipated twelve subjects will be prescribed a standard clinical dose of spironolactone of 1 mg/kg/day. The spironolactone will be provided as suspension. arm 2: An anticipated twelve subjects will be prescribed a standard clinical dose of prednisolone of 0.75 mg/kg/day or weekend dosing per sites standard of care. The prednisolone will be provided will be provided as suspension.

Interventions: intervention 1: Spironolactone intervention 2: Prednisolone
Intervention descriptions: intervention 1: Spironolactone will be prescribed for 6 months, after which the family and primary care physician will determine to either remain on spironolactone or transfer to prednisolone. intervention 2: Prednisolone will be prescribed for 6 months as the clinical standard of care.

Protocol document:
Prot_SAP_000.pdf: 
Nationwide Children’s Hospital 
Clinical Protocol 
Spironolactone DMD 
 
 
CLINICAL PROTOCOL 
A randomized open label trial of spironolactone versus prednisolone in corticosteroid-naïve 
boys with DMD 
EXEMPT IND #: 136166 
PROTOCOL VERSION: 7.0 (08Mar2021) 
 
 
Sponsor-Principal Investigator: 
Kevin M. Flanigan, M.D., Nationwide Children’s Hospital 
Co-Investigators: 
Megan A. Waldrop, M.D., Nationwide Children’s Hospital 
Maryann Kaler, FNP, Nationwide Children’s Hospital 
Linda Cripe, M.D., Nationwide Children’s Hospital  
Jill Rafael-Fortney, Ph.D., The Ohio State University  
 
 
 
The Abigail Wexner Research Institute at Nationwide Children’s Hospital 
Center for Gene Therapy 


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1. 
TABLE OF CONTENTS 
1. 
Table of Contents..................................................................................................................... 1 
1.1 
List of Tables .................................................................................................................... 4 
2. 
Protocol Synopsis .................................................................................................................... 5 
3. 
List of Abbreviations and Definitions of Terms ...................................................................... 8 
4. 
Key Roles ................................................................................................................................ 9 
4.1 
Clinical Trial and Principal Investigator ........................................................................ 10 
5. 
Introduction: Background information and Scientific Rationale .......................................... 10 
5.1 
Background .................................................................................................................... 10 
5.2 
Rationale......................................................................................................................... 12 
6. 
Objectives and Purpose ......................................................................................................... 13 
6.1 
Primary Outcome ........................................................................................................... 13 
6.2 
Secondary Outcome ....................................................................................................... 13 
6.3 
Exploratory Outcome ..................................................................................................... 13 
7. 
Study Design and Endpoints .................................................................................................. 13 
7.1 
Overall Study Design ..................................................................................................... 13 
7.2 
Study Population ............................................................................................................ 14 
7.3 
Number of Subjects ........................................................................................................ 14 
7.4 
Dosing Plan .................................................................................................................... 14 
7.5 
Spironolactone Suspension ............................................................................................ 14 
7.6 
Prednisolone ................................................................................................................... 15 
7.7 
Establish Subject Identification Number........................................................................ 15 
8. 
Study Enrollment and Withdrawal ........................................................................................ 15 
8.1 
Subject Inclusion Criteria ............................................................................................... 15 
8.2 
Subject Exclusion Criteria .............................................................................................. 16 
8.3 
Randomization ............................................................................................................... 16 
8.4 
Baseline Assessment of Endpoints ................................................................................. 16 
8.5 
Subject Withdrawal Criteria ........................................................................................... 17 
9. 
Study Agent ........................................................................................................................... 18 
9.1 
Dispensing of Study Agent ............................................................................................ 18 
9.2 
Description of Study Drug ............................................................................................. 18 
9.3 
Potential Risks ................................................................................................................ 19 
9.3.1 
Risks Associated with Spironolactone .................................................................... 19 


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9.3.2 
Risks Associated with Corticosteroid Use .............................................................. 19 
10. Study Procedures and Schedule ............................................................................................. 19 
10.1 
Laboratory Procedures/Evaluations ............................................................................ 20 
10.1.1 Clinical Laboratory Evaluations ............................................................................. 20 
10.2 
Study Visits................................................................................................................. 20 
10.2.1 Timeline .................................................................................................................. 20 
10.3 
Day -14 to Day 0 (Screening Evaluations and First Dose)......................................... 22 
10.4 
Week 1 and Month 1 and 2 ......................................................................................... 22 
10.5 
Month 3....................................................................................................................... 22 
10.6 
Month 4 and 5 ............................................................................................................. 23 
10.7 
Month 6 (Final Visit) .................................................................................................. 23 
10.7.1 Long Term Monitoring ........................................................................................... 24 
10.8 
Concomitant Medications ........................................................................................... 24 
10.8.1 Prohibited Medications ........................................................................................... 24 
11. Assessment of Safety ............................................................................................................. 24 
11.1 
Adverse and Serious Adverse Events ......................................................................... 24 
11.1.1 Definition of Adverse Events.................................................................................. 24 
11.1.2 Unexpected Adverse Events (UAE) ....................................................................... 25 
11.1.3 Serious Adverse Event (SAE) ................................................................................. 25 
11.1.4 Life-threatening (21 CFR 312.32(a)) ...................................................................... 26 
11.2 
Relationship to Study Drug ........................................................................................ 26 
11.3 
Time Period and Frequency for Event Assessment and Follow-Up .......................... 26 
11.3.1 Obligations of the Principal Investigator ................................................................ 26 
11.3.2 Safety Reporting ..................................................................................................... 26 
11.3.3 Serious Adverse Event Reporting: Content and Format ......................................... 28 
11.3.4 Communication Plan with the Primary Care Physician .......................................... 28 
11.3.5 Follow-Up of Adverse Events ................................................................................ 29 
11.4 
Study Discontinuation Rules ...................................................................................... 29 
12. Clinical Monitoring ............................................................................................................... 29 
12.1 
Data Safety Monitoring Plan ...................................................................................... 29 
12.1.1 Safety Monitor Reporting ....................................................................................... 30 
12.2 
Institutional Review Board Monitoring & IRB Reliance ........................................... 30 
13. Statistical Considerations ...................................................................................................... 31 


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14. Source Documents and Access to Source Data/Documents .................................................. 31 
14.1 
Data Management and Study Forms .......................................................................... 31 
14.2 
Electronic Case Report Forms (eCRF) ....................................................................... 32 
14.3 
Inspection of Records ................................................................................................. 33 
15. Quality Assurance and Quality Control ................................................................................. 33 
15.1 
Study Monitoring ........................................................................................................ 33 
16. Ethics/Protection of Human Subjects .................................................................................... 34 
16.1 
Ethics Review ............................................................................................................. 34 
16.2 
Ethical Conduct of the Trial ....................................................................................... 34 
16.3 
Written Informed Consent .......................................................................................... 34 
17. Data Handling and Record Keeping ...................................................................................... 35 
17.1 
Retention of Records .................................................................................................. 35 
17.2 
Retention of Samples .................................................................................................. 36 
17.3 
Study Reports ............................................................................................................. 36 
17.3.1 Annual Study Reports ............................................................................................. 36 
17.3.2 Final Study Report .................................................................................................. 36 
18. Study Administration ............................................................................................................. 36 
18.1 
Coordinating Center ................................................................................................... 36 
18.2 
Overview of Principal Investigator Responsibilities .................................................. 36 
19. Conflict of Interest Policy...................................................................................................... 37 
20. References ............................................................................................................................. 38 
 


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1.1 
List of Tables 
Table 1 
Abbreviations and Specialist Terms ............................................................................. 8 
Table 2 
Investigational Product ............................................................................................... 18 
Table 3  
Schedule of Assessments ............................................................................................ 20 
 


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2. 
PROTOCOL SYNOPSIS 
Name of Sponsor: 
Kevin M. Flanigan, M.D. 
Name of Investigational Product: 
Spironolactone 
Name of Active Ingredient: 
Spironolactone 
Study Title: 
A randomized open label pilot trial of spironolactone versus 
prednisolone in corticosteroid-naïve boys with DMD 
Study Number: 
N=24 
Sponsor-Principal Investigator: 
Kevin M. Flanigan, M.D. 
Clinical Study Phase: 
Pilot Study 
Number of Centers: 
Four to seven centers 
Study Duration: 
6 months.  Subjects will undergo strength and functional testing at 
screening (Day -14 to 0) and monthly electrolyte testing.  Follow up 
strength and functional testing will occur on Days 90 and 180.  After 
6 months of treatment, all subjects will be offered standard 
glucocorticoid therapy based on their local clinic’s standard of care or 
continued dosing on the medication taken during the trial if there is 
clear established efficacy. 
Study Design: 
Randomized, open-label, pilot clinical trial of spironolactone 
suspension versus oral prednisolone 
Study Objectives: 
To determine if 6 months of treatment with either spironolactone or a 
standard clinical dose of corticosteroids results in equivalent 
improvement in time to complete the 100 meter timed test (100M). 
 
To assess the safety of spironolactone treatment in the steroid naïve 
DMD population. 
Patient Population: 
Inclusion Criteria: 
• 
Duchenne muscular dystrophy (DMD) patients ≥4 to ≤7 years 
of age 
• 
Clinical features of DMD that include proximal predominant 
weakness and/or gait disturbance   
• 
Presence of a truncating mutation of the DMD gene in the 
patient or an affected male relative OR a muscle biopsy that 
demonstrates <5% dystrophin in the patient or an affected male 
relative 
• 
Normal left ventricular ejection fraction by screening 
echocardiogram 
• 
Ability to cooperate for testing 


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• 
No prior treatment with glucocorticoids or vamorolone 
• 
No concomitant experimental therapies 
Exclusion Criteria: 
• 
Subject amenable to or currently being treated with eteplirsen, 
golodirsen, casimersen, or viltolarsen 
• 
Hyperkalemia at screening 
• 
History of or ongoing renal failure (elevated creatinine, 
oliguria, anuria) 
• 
Hypersensitivity to spironolactone (rash, respiratory distress, 
arrhythmia, numbness or tingling of extremities) 
• 
Current treatment with an ACEi 
• 
Severe peptic ulcer disease or recent gastrointestinal 
perforations 
Study Procedures: 
Subjects will receive either prednisolone or spironolactone.  Strength 
and functional testing will occur at screening (Day -14 to 0) and at 90 
and 180 days after initiation.  
Study Outcomes: 
Primary:   
• 
Time to complete the 100 meter timed test (100M) 
Secondary:   
• 
Muscle strength as measured by dynamometry score, a 
composite score made up of values from maximum voluntary 
isometric contraction testing of the flexors and extensors of the 
elbows and knees, as measured in kilograms of force. 
• 
North Star Ambulatory Assessment (NSAA), a functional 
scale validated in the DMD population 
• 
4-stair climb 
• 
Time to arise from floor 
Exploratory: 
• 
Safety measures 
• 
Biomarker studies 
Sample Size: 
A total of 24 subjects are expected to be enrolled in this trial, with 12 
randomized to each treatment group. 
• 
Treatment Group 1:  Spironolactone 1 mg/kg/day (n=12 
subjects) 
• 
Treatment Group 2:  Prednisolone 0.75 mg/kg/day (n=12 
subjects) or weekend dosing per the sites standard of care 


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Statistical Analysis: 
Age-corrected 100M will be considered as the primary outcome, and 
will be evaluated using a two-one-sided t-test to test equivalency 
between treatment arms in the change from baseline to 6 months.  In 
addition, repeated measures ANOVA will be used to determine 
whether the trajectory across all three time points (baseline, 3mo, 
6mo) differs by treatment group.  Strength testing/dynamometry, 
NSAA, 4-stair climb, and time to arise from floor scores will be 
secondary outcomes, and will also be compared by treatment group 
using repeated measures ANOVA.  Biomarkers studies will be 
considered exploratory outcomes. 
Power: Prior studies evaluating the 100m walk test among patients 
with DMD have shown an average change over 6 months of  -2.9 
±7.8.  An effective sample size of 10 patients per group will provide 
80% power to declare equivalency with an equivalence margin of 
±10.6. 
Long-term follow-up: 
All adverse events will be followed until resolution or stabilization.  
 
 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
 
Table 1 
Abbreviations and Specialist Terms 
Abbreviation 
Definition 
ACEi 
Angiotensin Converting Enzyme Inhibitor 
DMD 
Duchenne muscular dystrophy 
MDA 
Muscular Dystrophy Association 
MR 
Mineralocorticoid Receptor 
NSAA 
North Start Ambulatory Assessment 
Sponsor-Investigator 
Nationwide Children’s Hospital Principal Investigator 
Principal Investigator 
Site Principal Investigators 
 
 
 


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4. 
KEY ROLES  
 
This clinical trial is a randomized, open-label, pilot study in which either spironolactone or 
prednisolone suspension will be delivered daily by mouth in steroid naïve DMD subjects.  
 
Kevin Flanigan, M.D. will serve as the Sponsor and Principal Investigator (Sponsor-Investigator) 
for this trial.  Dr. Flanigan received clinical fellowship training in Neuromuscular Disorders at 
the Johns Hopkins University, and post-doctoral training in Human Molecular Biology and 
Genetics at the University of Utah.  He is co-Director of the Nationwide Children’s Hospital 
Muscular Dystrophy Association (MDA) Clinic, and has extensive experience in translational 
research in DMD and related myopathic disorders.  He has participated as an investigator in 
multiple clinical trials in the muscular dystrophies, including trials of nonsense suppression,1, 2 
exon skipping,3, 4 and myostatin inhibition5.  He currently holds one active gene therapy IND: 
Phase I gene transfer clinical trial for Duchenne Muscular Dystrophy using 
rAAVrh74.MCK.GALGT2 (IND 16175).  He is the principal investigator and original IND 
initiating investigator of two ongoing trials: Phase I/II gene transfer clinical trial of 
scAAV9.U1a.SGSH for treatment of mucopolysaccharidosis type IIIA (Sanfilippo Syndrome 
type A) (IND 16850) and rAAV9.CMV.NAGLU for the treatment of mucopolysaccharidosis 
type IIIB (IND 16671).  
 
Megan Waldrop, M.D., an Assistant Professor at Nationwide Children’s Hospital/Ohio State 
University will serve as the lead Co-Investigator for this trial.  Dr. Waldrop is board-certified in 
Neurology with special qualifications in Pediatric Neurology and Neuromuscular Medicine.  She 
is currently a co-investigator on six active gene therapy trials at NCH, including a phase I gene 
transfer clinical trial for Duchenne Muscular Dystrophy using rAAVrh74.MCK.GALGT2 (IND 
16175), a phase I/II trial of rAAV9.CMV.NAGLU for the treatment of mucopolysaccharidosis 
type IIIB (Sanfilippo Syndrome type B) (IND 16671), a phase I/II gene transfer clinical trial of 
scAAV9.U1a.SGSH for the treatment of mucopolysaccharidosis type IIIA (Sanfilippo Syndrome 
type A) (IND 16850), and three clinical trials of AVXS-101 for the treatment of Spinal Muscular 
Atrophy (IND 15699). 
 
Jill Rafael-Fortney, PhD, will serve as Co-Investigator for this trial and may conduct the 
biomarker studies using the samples collected as part of this trial.  Dr. Rafael-Fortney has a B.A. 
from Cornell University in Genetics/Biology, a Ph.D. in Human Genetics from University of 
Michigan, and completed a postdoctoral fellowship at the University of Oxford.  She is a 
Professor of Physiology & Cell Biology at The Ohio State University and has vast expertise, 
starting during her Ph.D. studies, in the genetic, histological, cell biological, and biochemical 
characterization of skeletal and cardiac muscle pathologies related to Duchenne muscular 
dystrophy (DMD).  Her graduate work led to the dissection of the molecular structure-function 
relationships of the dystrophin protein that was used as a basis for dystrophin-based gene therapy 


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clinical trials and she developed the utrophin/dystrophin-deficient (dko) mouse model of DMD 
during her postdoctoral fellowship.  Most recently, her lab has carried out numerous preclinical 
and mechanistic studies demonstrating efficacy of mineralocorticoid receptor antagonists for 
cardiac and skeletal muscle pathologies in DMD mouse models.  She was part of the team that 
has published the translation of mineralocorticoid receptor antagonist efficacy for DMD 
cardiomyopathy (ClinicalTrials.gov identifier NCT01521546). 
 
Linda Cripe, M.D., a Professor of Pediatrics at Nationwide Children’s Hospital/The Ohio State 
University will serve as a Co-Investigator for this trial.  Dr. Cripe is a board-certified Pediatric 
Cardiologist with sub-specialty interest in the evaluation and treatment of the cardiomyopathy 
associated with neuromuscular disorders, specifically Duchenne muscular dystrophy.  She 
received a B.S. in biochemistry from The University of Iowa and a M.D. from The University of 
Iowa College of Medicine.  She completed a pediatric residency at the University of Iowa 
Hospitals and Clinics and a pediatric cardiology fellowship at The University of Iowa Hospitals 
and Clinics and Boston Children’s Hospital/Harvard Medical School.  Her work has focused on 
defining the natural history of the DMD associated cardiomyopathy by non-invasive imaging 
specifically by echocardiography and cardiac magnetic resonance imaging.  
 
 
4.1 
Clinical Trial and Principal Investigator 
The trial will be carried out at the Abigail Wexner Research Institute at Nationwide Children’s 
Hospital.  Dr. Kevin Flanigan, Professor of Pediatrics and Neurology at the Ohio State 
University, and Center Director of the Center for Gene Therapy at the Abigail Wexner Research 
Institute at Nationwide Children’s Hospital, and Co-Director of the Muscular Dystrophy Clinic, 
will serve as the Sponsor-Principal Investigator.  All Co-Investigators and site investigators have 
extensive experience in the performance of clinical trials in the neuromuscular pediatric 
population. 
 
5. 
INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE 
 
5.1 
Background 
We propose a randomized open label pilot clinical trial of spironolactone versus prednisolone in 
corticosteroid-naïve boys ages 4-7 years old.  The glucocorticoids prednisolone and deflazacort 
have been shown to improve muscle strength and to prolong ambulation in boys with DMD8.  
The effects in mdx mice are controversial and neither has clearly been shown to reverse skeletal 
muscle pathology in human disease or in animal models.  The mechanism of action of 
corticosteroids is unclear, but several have been suggested, including stabilization of muscle 
membranes, diminishing the activation of calcium dependent proteases (and thus a decrease in 
subsequent myofiber degeneration), and decreasing intramuscular fibrosis.  Corticosteroids have 
a significant side effect profile that includes obesity, cushingoid features, osteoporosis, and 


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behavioral disturbances.  These side effects become pronounced after what may be a decade or 
more of treatment in boys with DMD, and often are the cause of cessation of therapy or 
subtherapeutic dosing in the shorter term.  
 
Spironolactone is an aldosterone antagonist primarily used as a potassium sparing diuretic.   
However, it also has anti-androgen effects, and is used to treat a variety of conditions, including 
hirsutism in women.  Its side effect profile is well known, and includes gynecomastia and 
hyperkalemia.  It is widely used, however, in the pediatric population, with limited side effects9.   
A recent study by Dr. Rafael-Fortney, a Co-Investigator, evaluated the effect of spironolactone 
treatment in the mdx mouse (the standard animal model of DMD) and mdx:utr+/- mouse also 
lacking 1 copy of utrophin since these mice demonstrate more severe histopathologic changes 
(including markedly increased fibrosis)10.  In several published studies, a combined treatment 
with the angiotensin converting enzyme (ACE) inhibitor lisinopril and mineralocorticoid 
receptor (MR) antagonist spironolactone reduces ongoing skeletal muscle damage and improves 
muscle function in DMD mouse models10-12.  These include improvements of cardiac, limb, and 
diaphragm function approaching 80% of normal following early treatment (at 4 weeks after 
birth), an extraordinary effect in comparison to many other preclinical studies of compounds that 
have been tested in humans – besting, for example, the protection provided by prednisone in the 
mdx mouse11.  These preclinical results have already been translated into a published double-
blind, placebo controlled clinical trial with the MR antagonist eplerenone showing efficacy in 
primary cardiac outcomes in DMD patients13.  Due to the inclusion criteria for this trial, many 
patients were already nonambulatory and skeletal muscle function was not assessed.  A second 
non-inferiority double-blind trial comparing specific and non-specific MR antagonists with 
primary cardiac outcomes is currently underway.  
 
Spironolactone and lisinopril target the mineralocorticoid receptor directly and indirectly, 
respectively, through the renin-angiotensin-aldosterone system.  Treatment with lisinopril alone 
improves histopathology, but cannot recapitulate improvements in skeletal muscle function of 
dystrophic mice after combined treatment with spironolactone14.  Dr. Rafael-Fortney has recently 
shown that the MR is present in both mouse and human skeletal muscle fibers15.  Treatment of 
normal human myotubes with aldosterone results in a large number of gene expression changes, 
supporting MR functions as a nuclear hormone receptor in skeletal muscles15.  Treatment of 
dystrophic mice also demonstrates increased muscle membrane stabilization as demonstrated by 
laser injury assays16.  
 
We have now also shown that infiltrating myeloid cells clustered in damaged areas of dystrophic 
mouse skeletal muscles have the capacity to produce the natural ligand of the MR, aldosterone16, 
which in excess is known to exacerbate tissue damage.  Aldosterone synthase protein levels are 
increased in leukocytes isolated from dystrophic mouse muscles compared with controls and 
local aldosterone levels in dystrophic skeletal muscles are increased, despite normal circulating 


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levels.  11β-HSD2, the enzyme that inactivates glucocorticoids to increase MR selectivity for 
aldosterone, is also increased in dystrophic mouse muscle tissues16.  These data suggest MR 
activation is in excess of physiological need, likely contributes to the pathology of muscular 
dystrophy, and explains the likely mechanism of preclinical efficacy of MR antagonists in 
skeletal muscles and heart.  Since DMD patients have even more muscle inflammation than 
dystrophic mice, this approach has the potential to be even more efficacious in patients. 
 
The pilot trial we propose will directly answer the question of whether spironolactone is as 
efficacious as prednisolone over 6 months of treatment in young patients (age ≥4 to ≤7 years) 
with DMD, as judged by the age-corrected 100 meter timed test and by dynamometry scores 
derived maximum voluntary isometric contraction testing of selected muscles and the time to 
climb 4 stairs.  For steroid-naïve patients, this could delay institution of prednisolone therapy – 
considered the standard of care – for up to 6 months.  However, it is important to recognize that 
not all DMD parents choose for their boys to go on steroids during this age window, and that 
there is no clear evidence based consensus of when treatment must be initiated.  Finally, we note 
that published data from Dr. Rafael-Fortney’s lab and others demonstrates that prednisolone 
results in increased cardiac deterioration in the mdx mice, suggesting cardio-toxic effects on 
dystrophic heart11, 17.  Therefore, we feel that delaying onset of steroid therapy is justified for this 
pilot trial in order to gain meaningful pilot data regarding spironolactone in DMD patients, and 
note that all subjects will be offered open label prednisolone therapy as a standard of care after 
completion of the trial.  If there is equal or greater efficacy with spironolactone, they may choose 
to continue on spironolactone. 
 
In this pilot trial we will use prednisolone since it is delivered as an oral suspension.  Since the 
standard of care regimen (daily versus weekend dosing of prednisolone) differs from site to site, 
each PI will have the discretion to assign subjects to their preferred regimen.  Equal efficacy has 
been shown between daily and weekend dosing regimens18. 
 
5.2 
Rationale 
DMD is a devastating disorder of childhood, leading to loss of ambulation by age 12 years, and 
typically to death between 20 and 30 years.  Until recently, the only treatment shown to improve 
strength and preserve ambulation in DMD patients was the use of glucocorticoids, which are 
accompanied by significant side effects.  Recent developments in gene corrective therapies (such 
as the exon-skipping oligomer eteplirsen or the nonsense-suppression compound ataluren) 
represent potential therapies only for those relatively small subsets of patients with mutations 
that are amenable to that specific corrective mechanism (around 13% and 15% of DMD patients, 
respectively)19.  We wish to determine whether another commonly used medication, 
spironolactone, may have similar beneficial effects with a lower side effect profile and be 
applicable to a wider population of DMD patients.  
 


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Our hypothesis for this controlled pilot trial is that spironolactone and prednisolone are of equal 
efficacy in improving skeletal muscle function over a 6-month period, and that spironolactone 
will be well tolerated in this patient population.   
 
One outcome is that both drugs demonstrate equal efficacy in motor function.  This would then 
serve as pilot data for a longer term study. 
 
6. 
OBJECTIVES AND PURPOSE 
 
6.1 
Primary Outcome 
The primary objective of this trial is to determine whether spironolactone has similar efficacy to 
glucocorticoids in improving muscle strength in steroid naïve DMD patients.  Glucocorticoids 
are the only medications that have been shown to change the clinical course of Duchenne 
muscular dystrophy, but have significant side effects (e.g., obesity, cushingoid features, 
osteoporosis, and behavioral disturbances).  Preclinical data suggests a significant protective 
effect from spironolactone in the mdx and mdx;utrn+/- animal models.  We propose a 
randomized, open-label pilot trial comparing spironolactone to prednisolone.  
 
The primary outcome measure will be the time to complete a 100 meter timed test (100M)20.  
 
6.2 
Secondary Outcome 
Secondary outcome measures will be Dynamometry score, which is a summation of maximum 
voluntary isometric contraction test values for knee flexion, knee extension, elbow flexion, and 
elbow extension; 4-stair climb; North Star Ambulatory Assessment (NSAA); and time to arise 
from the floor. 
 
6.3 
Exploratory Outcome 
An exploratory outcome is to assess the safety of delivering spironolactone to the steroid naïve 
DMD population.  Safety data will be monitored on a continual basis throughout the trial by the 
Principal Investigator and study staff.   
 
Additional exploratory outcomes include biomarker studies. 
 
7. 
STUDY DESIGN AND ENDPOINTS 
 
7.1 
Overall Study Design 
The proposed trial will involve 24 subjects with DMD.  Because DMD is an X-linked disorder, 
all subjects will be boys.  Subject selection will not exclude anyone on the basis of race or ethnic 
background.  
 


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12 subjects will be randomized to each treatment group as follows: 
• Treatment Group 1:  Spironolactone 1 mg/kg/day (n=12 subjects) 
• Treatment Group 2:  Prednisolone 0.75 mg/kg/day (n=12 subjects) or weekend dosing 
as per sites standard of care 
 
7.2 
Study Population 
DMD patients (n =24) will be enrolled in a randomized open label controlled trial of 
prednisolone (n= 10) versus spironolactone (n = 10) based on inclusion criteria as defined below.   
Four to seven collaborating centers will participate.  Up to 24 subjects (~ 3 at each site) can be 
enrolled to include a 10% drop-out rate. 
 
Power: Prior studies evaluating the 100m walk test among patients with DMD have shown an 
average change over 6 months of  -2.9 ±7.8.  An effective sample size of 10 patients per group 
will provide 80% power to declare equivalency with an equivalence margin of ±10.621. 
 
Siblings will be permitted to participate.  When sibling participation arises, the randomization 
will proceed as if they were unrelated. 
 
7.3 
Number of Subjects 
A total of 24 subjects will be enrolled. 
 
7.4 
Dosing Plan 
This is a randomized open label controlled pilot trial comparing spironolactone suspension and 
prednisolone.  Medications will be provided by each institutional pharmacy.  Each subject will 
be provided with a 90-day supply of medication.  Subjects will be enrolled for a period of 6 
months.  Specific criteria for administering the drugs are as follows: 
 
Patients fulfilling entry criteria will be enrolled in the trial and receive medication at designated 
dosing.  They will receive either prednisolone 0.75 mg/kg/day, or spironolactone 1 mg/kg/day.   
Weekend prednisolone dosing as per sites standard of care is an acceptable alternative.  
 
Subjects will be weighed at screening, Month 3, and Month 6.  Weight based dose adjustments to 
the study drug should be made by the Study Doctor.  
7.5 
Spironolactone Suspension  
Carospir® (spironolactone) 25 mg/5ml oral suspension is commercially available as a white to 
off-white, opaque, banana-flavored suspension and can be stored at room temperature.  The 
product is manufactured by CMP Pharma, Inc.  Study drug will be dosed daily at 1mg/kg. 
 


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Although spironolactone is commercially available in a suspension, it is NOT therapeutically 
equivalent to the tablets.  The suspension results in 15% to 37% higher serum concentration 
compared to the tablet.  Pediatric dosing is based on experience with tablets and 
extemporaneously compounded suspension. 
7.6 
Prednisolone 
The Study Doctor at each study site will prescribe their preferred regimen of prednisolone.  Daily 
dosing at 0.75 mg/kg/day or weekend dosing as per sites standard of care is acceptable.  Study 
drug will be provided by the pharmacy at each study site every 90 days.  The product is 
manufactured by Morton Grove Pharmaceuticals.  If at any point the drug becomes unavailable 
from this manufacturer, another manufacturer can be used to obtain the drug until available from 
Morton Grove Pharmaceuticals.  
 
Prednisolone is available commercially as a 15mg/5ml solution.  It can be stored at room 
temperature.  It is a clear solution with a grape odor and flavor.  It contains 1.8% alcohol. 
 
7.7 
Establish Subject Identification Number 
Research subjects will be assigned a randomization number (i.e., 1001, 1002, sequentially) prior 
to enrollment to facilitate randomization to one of two treatment groups, Spironolactone 
Treatment Group or Prednisolone Treatment Group.  Upon consent, every research subject will 
be assigned a Subject Identification code.  This will be done prior to any research procedures 
being scheduled, as they will require a Subject ID.  
 
The Subject Identification code is generated as follows:  
1) 3 letter site identifier 
2) 2 digit study number 
3) 3 digit sequential number of all candidates being screened  
 
Example: Subject ID: NCH-01-001 
  
8. 
STUDY ENROLLMENT AND WITHDRAWAL 
 
24 male DMD subjects, ages ≥4 to ≤7 years who are steroid naïve will be enrolled in this pilot 
clinical trial.  Subjects will be of any racial or ethnic background.  Enrollment will be ongoing.   
The assessment and full treatment plan will be used for all subjects. 
 
8.1 
Subject Inclusion Criteria 
Subjects must meet all of the following Inclusion Criteria: 
1. Duchenne muscular dystrophy (DMD) patients ≥4 to ≤7 years of age 
2. Clinical features of DMD that include proximal predominant weakness and/or gait 
disturbance   


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3. Presence of a truncating mutation of the DMD gene in the patient or an affected male 
relative OR a muscle biopsy that demonstrates <5% dystrophin in the patient or an 
affected male relative 
4. Normal left ventricular ejection fraction by screening echocardiogram 
5. Ability to cooperate for testing 
6. No prior treatment with glucocorticoids or vamorolone  
7. No concomitant experimental therapies 
 
8.2 
Subject Exclusion Criteria 
Subjects must not meet any of the following Exclusion Criteria: 
1. Subject amenable to or currently being treated with eteplirsen, golodirsen, casimersen, or 
viltolarsen 
2. Hyperkalemia at screening 
3. History of or ongoing renal failure (elevated creatinine, oliguria, anuria) 
4. Hypersensitivity to spironolactone (rash, respiratory distress, arrhythmia, numbness or 
tingling of extremities) 
5. Current treatment with an ACEi 
6. Severe peptic ulcer disease or recent gastrointestinal perforations 
 
8.3 
Randomization 
Nationwide Children’s Hospital pharmacy will serve as the lead pharmacy.  Randomization will 
be determined via the lead pharmacy.  Subjects at each site will be randomized 1:1 to receive 
treatment with either prednisolone at 0.75 mg/kg/day (or weekend dosing per sites standard of 
care) or spironolactone at 1mg/kg/day.  Subjects will be assigned treatment sequentially from the 
provided list.  Subjects will not be randomized until the echocardiogram and all lab results are 
finalized and reviewed by the Study Doctor. 
 
8.4 
Baseline Assessment of Endpoints 
After obtaining informed consent and completing the registration procedures, baseline subject 
history data will be collected, including records of all medications and supplements that the 
subject is taking.  The following assessments will be performed to confirm subject eligibility for 
this trial.  Screening tests must be completed prior to treatment administration as described in the 
study timeline.  Screening testing includes the following, which are discussed in detail below: 
• 100 meter timed test (100M) 
• Strength testing and dynamometry 
• North Star Ambulatory Assessment (NSAA) 
• 4-stair climb 
• Time to arise from floor 
• Echocardiogram 
• Baseline laboratory testing  


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The subject and his parents will be aware that his participation may be terminated after any of 
these screening procedures. 
 
There is no central laboratory for this trial.  Site-specific normal lab ranges will be documented 
in respective sites’ regulatory binders.  Lab ranges will be provided by each site’s laboratory.   
Laboratory tests with values within the clinically significant range will be repeated during the 
same visit whenever possible.  If the test result returns after the subject leaves the clinic, they 
will be immediately contacted.  Subjects will be asked to return to the outpatient clinic for a 
repeat test.  For non-local subjects, arrangements can be made to have the blood test redrawn in a 
laboratory close to home or by their primary care physician.  If still out of the range and 
clinically significant, the subject may be terminated from the study following discussion with the 
Clinical Safety Monitor. 
 
To avoid any confusion for the primary care physician, he or she will be informed (with 
permission from the subject) of their participation in the trial at the time of enrollment.  
 
8.5 
Subject Withdrawal Criteria 
Subjects meeting the following criteria will be withdrawn from the trial: 
 
1. Unable to tolerate study medication. 
2. Failure to keep an accurate medication log. 
3. Failure to keep study appointments. 
4. Missing more than 10% of prescribed doses of study medication.* 
 
*If a subject is missing more than 10% of prescribed doses, a discussion about the subject’s continuation in the trial 
will take place between the Principal Investigator and the Sponsor-Investigator. 
 
Corticosteroids are the standard of care for the treatment of Duchenne muscular dystrophy and 
have a well-known side effect profile (see section 9.3).  Subjects with any Grade 1 or higher 
(according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 
listed in section 11.1) adverse events that are anticipated and related to prednisolone use, will 
continue in the trial.  Subjects with any Grade 2 or higher adverse events that are anticipated and 
are possibly, probably or definitely related to spironolactone use will have the study drug held 
and will be re-challenged in 1 week.  If a subject experiences a recurrence of the adverse event, 
he may be withdrawn after discussion with the Clinical Safety Monitor.  Subjects with any Grade 
2 or higher adverse events that are unanticipated, may be withdrawn after discussion with the 
Clinical Safety Monitor.  The Principal Investigator will determine a clinically appropriate 
tapering regimen with respect to assigned study drug and length of time on drug. 
 


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Principal Investigators must report all participant withdrawals to the Sponsor-Investigator within 
48 hours of learning of the withdrawal.  The Sponsor-Investigator will then notify the Clinical 
Safety Monitor of the withdrawal within 3 business days of the Sponsor-Investigator learning of 
the withdrawal.  
 
9. 
STUDY AGENT 
 
Site pharmacies will dispense spironolactone and prednisolone per the site’s standard procedures.   
In the rare instance of a subject not being able to tolerate prednisolone, an equivalent dose of 
prednisone may be provided as crushed tablets after approval by the Sponsor-Investigator.  
 
9.1 
Dispensing of Study Agent 
Subjects will be provided a supply of study drug at Day 0 and Month 3 (Day 90).  A +/- 3 day 
window is acceptable for all visits after Day 0.  
 
9.2 
Description of Study Drug 
Table 2 
Investigational Product 
Product Name 
Spironolactone, USP 
Dosage Form 
25mg/5mL Oral Suspension 
Route of 
Administration 
Oral 
Physical Description 
Spironolactone, USP is practically insoluble in water, soluble in 
alcohol and freely soluble in benzene and in chloroform. 
 
Carospir Oral suspension contains 25 mg of the aldosterone 
antagonist spironolactone per 5 mL.  Inactive ingredients include 
sorbic acid, potassium sorbate, citric acid anhydrous, sodium citrate 
dehydrate, simethicone emulsion, saccharin sodium, xantham gum, 
Magnasweet 110, glycerin, banana flavor, and purified water. 
Manufacturer 
CMP Pharma, Inc. 
  
 
 Product Name 
Prednisolone Sodium Phosphate*, USP 
Dosage Form 
15 mg/5 mL Solution 
Route of 
Administration 
Oral 


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Physical Description 
Prednisolone Sodium Phosphate Oral Solution equivalent to 15 mg 
prednisolone per 5 mL contains the following inactive ingredients: 
alcohol 1.8%, dibasic sodium phosphate, glycerin, liquid sugar, 
monobasic sodium phosphate, natural and artificial grape flavor, 
purified water, sodium benzoate and sorbitol solution.  It may 
contain 10% dibasic sodium phosphate solution and/or 10% 
monobasic sodium phosphate solution to adjust pH between 6.0 and 
8.0.  Prednisolone sodium phosphate occurs as white or slightly 
yellow, friable granules or powder.  It is freely soluble in water; 
soluble in methanol; slightly soluble in alcohol and in chloroform; 
and very slightly soluble in acetone and in dioxane. 
Manufacturer 
Morton Grove Pharmaceuticals** 
*Contact the NCH study team if substituting with prednisone tablets. 
** If at any point the drug becomes unavailable from this manufacturer, another 
manufacturer can be used to obtain the drug until available from Morton Grove 
Pharmaceuticals. 
 
9.3 
Potential Risks  
Potential risks to study subjects include risks associated with administration of the study agent 
and with study procedures. 
9.3.1 Risks Associated with Spironolactone 
Common side effects associated with the use of spironolactone in this subject population may 
include: diarrhea, cramping, nausea, vomiting, somnolence, headache, ataxia, gynecomastia and 
urticaria.  
  
9.3.2 Risks Associated with Corticosteroid Use  
Common side effects associated with the use of prednisolone in this subject population may 
include: depression, euphoria, emotional instability, headache, seizures, vertigo, body fluid 
retention, hypernatremia, hypertension, acne, bruising, wound healing impairment, decreased 
body growth, increased risk of infection, diaphoresis, abdominal distention, pancreatitis, peptic 
ulcers, ulcerative esophagitis, hepatic impairment, steroid myopathy, and muscle weakness.  
Serious side effects may include: anaphylaxis, Cushing’s syndrome, hyperglycemia, and primary 
adrenocortical insufficiency. 
 
10. 
STUDY PROCEDURES AND SCHEDULE 
 
Subjects will complete study assessments monthly via online survey, phone, or at clinic visits for 
6 months. 


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10.1 
Laboratory Procedures/Evaluations 
Laboratory tests with values within the clinical significant range may be repeated during visits 
whenever possible.  If the test result returns after the subject leaves the clinic and the Study 
Doctor wants additional tests, they will be immediately contacted.  Subjects may be asked to 
return to the outpatient clinic for a repeat test.  For non-local subjects, arrangements can be made 
to have the blood test redrawn in a laboratory close to home or by their primary care physician. 
 
10.1.1 Clinical Laboratory Evaluations 
Functional Testing 
• 100 meter timed test (100M) 
• Strength testing and Dynamometry 
• North Star Ambulatory Assessment (NSAA) 
• 4-stair climb 
• Time to arise from floor 
 
Blood Chemistry 
Chemistry analysis will include the following at specified visits: 
• Creatine Kinase (Visits 1, 8) 
• Gamma Glutamyl Transferase (GGT) (Visits 1, 5, 8)  
• Creatinine (Visits 1, 5, 8) 
• Blood Urea Nitrogen (BUN) (Visits 1, 5, 8) 
• Glucose (Visits 1, 5, 8) 
• Cystatin C (Visits 1, 5, 8) 
• Electrolytes (Sodium, Potassium, Chloride, CO2) [All Visits] 
 
Cardiac 
Echocardiogram (Echo) will be conducted at the time points specified in Table 3. 
 
Research Blood Sample 
Blood samples will be collected for future research purposes, to examine/research potential 
disease modifiers and/or biomarkers.  Research blood samples may be distributed for future 
research to Jill Rafael-Fortney, PhD, at Ohio State University, a Co-Investigator on this study.  
 
10.2 
Study Visits 
10.2.1 Timeline 
Table 3  
Schedule of Assessments 
 


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Assessment 
Visit 1 
Study 
Drug 
Start1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Screening 
Week 
1 
Month 
1 
Month 
2 
Month 
3 
Month 
4 
Month 
5 
Month 
6 
Day  
-14 to 0 
Day 
0 
Day 
7 
Day 
30 
Day 
60 
Day 
90 
Day 
120 
Day 
150 
Day 
180 
Research Purposes Only 
Echocardiogram 
(Echo)2 
X 
 
 
 
 
 
 
 
X 
Biomarkers Blood 
Draw (plasma and 
white blood cells) 
X 
 
 
 
 
 
 
 
X 
Strength 
Testing/Dynamometry 
X 
 
 
 
 
X 
 
 
X 
Standard of Care 
Informed Consent 
X 
 
 
 
 
 
 
 
 
AE Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
X 
 
 
X 
Skin Exam 
X 
 
 
 
 
X 
 
 
X 
Cushingoid Exam 
X 
 
 
 
 
X 
 
 
X 
Medical History 
Review 
X 
 
 
 
 
X 
 
 
X 
100 Meter Timed Test 
X 
 
 
 
 
X 
 
 
X 
Parent Survey 
 
 
X 
X 
X 
 
X 
X 
 
4-Stair Climb 
X 
 
 
 
 
X 
 
 
X 
North Star Ambulatory 
Assessment (NSAA) 
X 
 
 
 
 
X 
 
 
X 
Time to Arise from 
Floor 
X 
 
 
 
 
X 
 
 
X 
Creatine Kinase 
X 
 
 
 
 
 
 
 
X 
Gamma Glutamyl 
Transferase (GGT) 
X 
 
 
 
 
X 
 
 
X 
Creatinine 
X 
 
 
 
 
X 
 
 
X 
Blood Urea Nitrogen 
(BUN) 
X 
 
 
 
 
X 
 
 
X 
Glucose 
X 
 
 
 
 
X 
 
 
X 
Cystatin C 
X 
 
 
 
 
X 
 
 
X 
Electrolytes3 
X 
 
X 
X 
X 
X 
X 
X 
X 
Medication Dispensing4 
 
X1 
 
 
 
X 
 
 
 
Vitals 
X 
 
 
 
 
X 
 
 
X 
1. Study drug will be dispensed and treatment initiated once eligibility is confirmed following receipt and review of results from 
screening visit procedures. The day study drug is started is considered Day 0. 


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2. A clinical echocardiogram within the previous 30 days prior to screening is acceptable for screening purposes. 
3. Includes: Sodium, Potassium, Chloride, CO2 
4. Medication dispensing will occur every 90 days, beginning at the time of randomization. 
 
10.3 
Day -14 to Day 0 (Screening Evaluations and First Dose) 
Informed consent will be obtained prior to the collection of any data and any study-related 
procedures.  Screening evaluations will be obtained.  Subjects will undergo a physical, skin, and 
cushingoid examination, vitals and a review of medical and concomitant medication histories.  
Echocardiogram, strength testing/dynamometry, and functional testing (100 meter timed test 
[100M], North Star Ambulatory Assessment [NSAA], 4-stair climb, and time to arise from floor 
test) will be conducted.  
 
Lab work will include the following: 
• Creatine Kinase 
• Gamma-glutamyl transferase (GGT) 
• Creatinine 
• Blood Urea Nitrogen (BUN) 
• Glucose 
• Serum Cystatin C 
• Electrolytes 
• Biomarkers blood draw (for plasma and white blood cells) 
 
Once eligibility has been confirmed (including lab results and echocardiogram review), the 
pharmacy will dispense a 90-day supply of study medication to the research team who will then 
provide the study medication to the subject’s parent/guardian.  If eligibility cannot be confirmed 
on the same day of screening, the study drug may be shipped to the subject and a pharmacist will 
counsel the parent or guardian via phone. The day study drug treatment is initiated is considered 
Day 0.  
 
10.4 
Week 1 and Month 1 and 2  
Subjects will be contacted by research staff via a REDCap survey to review concomitant 
medications and assess adverse events.  
 
Lab work will include the following: 
• Electrolytes 
 
10.5 
Month 3 
Subjects will return on Month 3 and undergo a physical, skin, and cushingoid examination, 
vitals.  Strength testing/dynamometry, and functional testing (to include 100 meter timed test, 
North Star Ambulatory Assessment [NSAA], 4-stair climb, and time to arise from floor test) will 


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be conducted.  Research staff will also review concomitant medications, updates to the medical 
history, and assess adverse events.  
 
Lab work will include the following: 
• Gamma-glutamyl transferase (GGT) 
• Creatinine 
• Blood Urea Nitrogen (BUN) 
• Glucose 
• Cystatin C 
• Electrolytes 
 
The pharmacy will dispense the supply of study medication to the research team who will then 
provide the study medication to the subject’s parent/guardian.  If lab results return after the 
subject leaves the clinic and the Study Doctor wants additional tests, they will be immediately 
contacted. 
 
10.6 
Month 4 and 5 
Subjects will be contacted by research staff via a REDCap survey to review concomitant 
medications and assess adverse events.  
 
Lab work will include the following: 
• Electrolytes 
 
10.7 
Month 6 (Final Visit) 
Subjects will undergo a physical, skin, and cushingoid examination, vitals and a review of 
medical and concomitant medication histories.  Echocardiogram, strength testing/dynamometry, 
and functional testing (to include 100 meter timed test [100M], North Star Ambulatory 
Assessment [NSAA], 4-stair climb and time to arise from floor test) will be conducted. 
 
Lab work will include the following: 
• Creatine Kinase 
• Gamma-glutamyl transferase (GGT) 
• Creatinine 
• Blood Urea Nitrogen (BUN) 
• Glucose 
• Cystatin C 
• Electrolytes 
• Biomarkers blood draw (for plasma and white blood cells) 
 


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Research staff will review concomitant medications, updates to the medical history, and assess 
adverse events. 
 
10.7.1 Long Term Monitoring 
All adverse events occurring throughout the subject’s participation in the trial through 30 days 
after the subject’s final study visit will be documented and followed until resolution or 
stabilization.  Research staff will contact subjects 30 days after the subject’s final study visit to 
check for any new AEs and to obtain any new information regarding ongoing AEs.  
 
10.8 
Concomitant Medications 
Prescribed and over the counter medications used in the 2 weeks prior to trial initiation will be 
recorded at the screening visit and changes in these medications will be recorded during each 
subsequent medical history review.  The Principal Investigator will encourage subjects to 
maintain the medication and supplements they are on at enrollment through the course of the 
trial.  
 
10.8.1 Prohibited Medications 
Concomitant use of any of the following medications is prohibited: 
•  ACEi 
• Potassium supplementation 
 
11. 
ASSESSMENT OF SAFETY 
 
One of the primary objectives for this pilot clinical trial is safety.  Withdrawal criteria are based 
on the development of unacceptable toxicity, as described in section 8.5. 
 
11.1 
Adverse and Serious Adverse Events 
11.1.1 Definition of Adverse Events 
All Adverse Events (AE) will be reported to the Reviewing IRB at annual continuing reviews.   
 
AEs will be collected throughout the trial from informed consent to 30 days after the subject’s 
final study visit.  All AEs that occur after any subject has been enrolled, before treatment, during 
treatment, or within 30 days after the last study visit, whether or not they are related to the study, 
must be recorded in the eCRF. 
 
Adverse Event:  Adverse event means any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. 
 
Adverse events will be graded by the investigator and as used in the CTCAE v.4.03 accordingly:  
 


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1. Mild 
2. Moderate 
3. Severe 
4. Life threatening or debilitating 
5. Fatal.  
 
Adverse Reaction: An adverse reaction means any adverse event caused by a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude that 
the drug caused the event. 
 
Suspected Adverse Reaction (21 CFR 312.32(a)): A suspected adverse reaction means any 
adverse event for which there is a reasonable possibility that the drug caused the adverse event.   
‘Reasonable possibility’ means there is evidence to suggest a causal relationship between the 
drug and the adverse event.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug.   
Suspected adverse events will be reported to the Reviewing IRB at study closeout. 
 
11.1.2 Unexpected Adverse Events (UAE) 
Unexpected adverse events are those which are not previously reported with the subject's 
underlying disease or with the procedures to be used in this trial, or are related to a known 
toxicity but differ because of greater severity or specificity.  
 
11.1.3 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the Sponsor-Investigator or Principal Investigator, it results in any of the following outcomes: 
death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect.  Important medical events 
that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  A serious 
adverse events refers to a grade of 3, 4, or 5. 
 
All SAEs that occur after any subject has signed informed consent, before treatment, during 
treatment or within 30 days following the last study visit, whether or not they are related to the 
trial must be recorded. 
 


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11.1.4 Life-threatening (21 CFR 312.32(a))  
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Sponsor-Investigator or Principal Investigator, its occurrence places the subject at 
immediate risk of death.  It does not include an adverse event or suspected adverse reaction that, 
had it occurred in a more severe form, might have caused death. 
 
11.2 
Relationship to Study Drug 
Association or relatedness to the study agent, study procedures and the subject's pre-existing 
disease will be graded as follows:  
 
1. Definitely related 
2. Probably related 
3. Possibly related 
4. Unlikely related 
5. Unrelated 
 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable”, the event will be considered to be related to the investigational product 
for the purposes of expedited regulatory reporting. 
 
11.3 
Time Period and Frequency for Event Assessment and Follow-Up 
11.3.1 Obligations of the Principal Investigator  
All serious adverse events should be reported to the Sponsor-Investigator regardless of severity, 
relatedness, or expectedness.  The Principal Investigator will provide an electronic report to the 
Sponsor-Investigator who will report to the Reviewing IRB on any serious adverse event that is 
both unexpected and related to the use of the corticosteroid product (i.e. there is reasonable 
possibility that the event may have been caused by the use of the product; the Principal 
Investigator will not await definitive proof of association before reporting such events). 
  
The Principal Investigator will adhere to any other serious adverse event reporting requirements 
in accordance with federal regulations, state laws, and the local institutional policies and 
procedures, as applicable. 
  
The Principal Investigator will be responsible for ensuring that the reporting requirements are 
fulfilled and will be held accountable for any reporting lapses. 
 
11.3.2 Safety Reporting  
All serious adverse events that are unexpected and possibly, probably, or definitely related to 
the use of either study drug should be reported to the Sponsor-Investigator within 48 hours of 
the Principal Investigator’s initial receipt of the information.  All other serious adverse events 


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should be reported to the Sponsor-Investigator within 7 days of the Principal Investigator’s 
initial receipt of the information. 
 
The Sponsor-Investigator will report serious adverse events that are unexpected and possibly, 
probably, or definitely related to the use of either study drug to the Reviewing IRB according to 
regulatory requirements described as follows: 
 
Any serious adverse event that is fatal or life-threatening, that is unexpected and related to the 
use of either study drug will be reported to the Reviewing IRB as soon as possible, but not later 
than 3 business days after the Sponsor-Investigator’s initial receipt of the information.  
 
Serious adverse events that are unexpected and related to the use of either study drug, but are not 
fatal or life-threatening, will be reported to the Reviewing IRB as soon as possible, but not later 
than 3 business days after the Sponsor-Investigator’s initial receipt of the information.   
 
If, after further evaluation, an unexpected serious adverse event initially considered not to be 
related to the use of either study drug is subsequently determined to be related, then the event 
will be reported to the Sponsor-Investigator within 48 hours of the determination.  The Sponsor-
Investigator will report to the Reviewing IRB within 3 business days of the Sponsor-Investigator 
learning of the determination. 
 
Relevant additional clinical and laboratory data will become available following the initial 
serious adverse event report.  Principal Investigators must report follow-up information to the 
Sponsor-Investigator within 48 hours of initial receipt of the information.  All follow-up 
information relevant to a serious adverse event that is unexpected and related to the use of either 
study drug will be reported to the Reviewing IRB within 3 business days of the Sponsor-
Investigator’s initial receipt of the information.  
 
If a serious adverse event occurs within 30 days after a subject’s final study visit and is 
determined to be unexpected and related to the use of either study drug, that event will be 
reported to the Reviewing IRB within 3 business days of the Sponsor-Investigator learning of 
the determination. 
 
Should a serious adverse event deemed possibly, probably or definitely related to the study agent 
occur during administration, the study agent will be discontinued, appropriate treatment will be 
given under medical supervision and the subject will be examined as frequently as necessary 
thereafter until symptoms cease or stabilize. 
 
All new information and significant noncompliance indicating a new or increased risk or new 
safety issue as defined in the Reviewing IRB policies will be reported to the Sponsor-


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Investigator within 48 hours of the Principal Investigator learning of the information.  The 
Sponsor-Investigator will report to the Reviewing IRB within 3 business days of the Sponsor-
Investigator’s initial receipt of the information.  This includes deviations from the protocol that 
harmed subjects or others or that indicates subjects or others might be at an increased risk of 
harm. 
 
The Sponsor-Investigator will inform the Clinical Safety Monitor of all serious adverse events 
regardless of severity, relatedness, or expectedness and of all instances of significant non-
compliance impacting patient safety within 48 hours of the Sponsor-Investigator’s initial receipt 
of the information. 
 
11.3.3 Serious Adverse Event Reporting: Content and Format  
The serious adverse event report will include, but need not be limited to: (1) the date of the 
event; (2) designation of the report as an initial report or a follow-up report, identification of all 
safety reports previously filed for the clinical protocol concerning a similar adverse event, and an 
analysis of the significance of the adverse event in light of previous similar reports; (3) clinical 
site; (4) the Principal Investigator; (5) study drug; (6) route of administration e.g. intravenous or 
oral; (7) dosing schedule; (8) a complete description of the event; (9) relevant clinical 
observations; (10) relevant clinical history; (11) relevant tests that were or are planned to be 
conducted; (12) date of any treatment of the event; and (13) the suspected cause of the event.   
These items will be reported electronically to the Sponsor-Investigator who will then report to 
the Reviewing IRB as appropriate. 
 
11.3.4 Communication Plan with the Primary Care Physician 
Close communication should be established with the primary care physician of all study subjects 
and will be maintained throughout the trial if necessary.  The important hallmarks of the trial will 
be explained.  We may request laboratory reports, hospitalizations, clinical notes and any other 
relevant medical records pertaining to intercurrent events taking place during this 6-month study.  
The Principal Investigator will initiate an investigation to determine the possibility of an adverse 
event related to this trial and will adhere to the adverse event reporting requirements in 
accordance with federal regulations, state laws, and the local institutional policies and 
procedures, as applicable. 
 
During the consent process, the Principal Investigator or designated Co-Investigator will 
emphasize the importance of subject communication with our study team.  Any routine or non-
routine doctor’s visits or medical care received during the 6 months of this trial should be 
reported to the study team.  The Study Doctor will explain to the subject that copies of any 
relevant medical records of those visits will be requested from their medical care provider. 
 


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11.3.5 Follow-Up of Adverse Events 
All adverse events will be followed until resolution or stabilization. 
 
11.4 
Study Discontinuation Rules 
An independent Clinical Safety Monitor will monitor safety data on a continual basis throughout 
the trial.  The Clinical Safety Monitor can recommend early termination of the trial for reasons 
of safety.  Study enrollment will be halted by the Principal Investigators when any subject 
experiences a Grade 3 or higher adverse event toxicity that is unanticipated and possibly, 
probably, or definitely related to the study drug that presents with clinical symptoms and requires 
medical treatment.  This will include any subject death, hospitalization, or important clinical 
laboratory finding.  If after review by the Clinical Safety Monitor and the Reviewing IRB, the 
decision is made to continue, the trial will proceed according to Section 10 of this protocol. 
 
Anticipated adverse events related to progression of Duchenne muscular dystrophy may include 
muscle weakness, elevated creatine kinase levels, loss of ambulation, scoliosis, short stature, and 
intellectual disability.  
 
Anticipated adverse events related to prednisolone treatment, which is the standard of care, may 
include weight gain, cushingnoid features, long bone fractures, acne, behavioral disturbance, and 
short stature (see section 9.3.2 for additional potential side effects). 
 
Anticipated adverse events related to spironolactone treatment may include increased potassium 
levels, increased breast tissue mass, diarrhea, cramping, nausea, vomiting, headache, sleepiness, 
unsteadiness, and urticaria (see section 9.3.1 for additional potential side effects).  
 
12. 
CLINICAL MONITORING 
 
12.1 
Data Safety Monitoring Plan 
Dr. Richard Shell will serve as Clinical Safety Monitor for this trial.  Dr. Shell is a pediatric 
pulmonologist and critical care specialist at NCH, and an Associate Professor of Pediatrics at the 
Ohio State University.  Dr. Shell will be asked to review all subjects’ laboratory results monthly.  
He will be apprised of all adverse events, as per the Reviewing IRB policy.  He will prepare 
interim safety reports 3 months and 6 months after the first subject is dosed and a final safety 
report after all subjects complete 6 months of dosing. The Clinical Safety Monitor can 
recommend early termination of the trial for reasons of safety. 
 
The Clinical Safety Monitor’s responsibilities are to: 
• review the plans for data and safety monitoring; 


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• consider factors external to the study when relevant information becomes available, such 
as scientific or therapeutic developments that may have an impact on participant safety or 
the ethics of the trial; 
• review study performance, make recommendations and assist in the resolution of 
problems reported by the Principal Investigators; 
• review monthly safety data to determine safety signals or trends; 
• ensure the confidentiality of the trial data; and, 
• assist by commenting on any problems with study conduct, enrollment, and sample size 
and/or data collection. 
 
12.1.1 Safety Monitor Reporting 
Reports describing the status of the study will be prepared by the Sponsor-Investigator and 
associated staff and sent to the Clinical Safety Monitor the end of each month, or at the Clinical 
Safety Monitor’s request.  
 
Reports will include the following: 
• A brief narrative of the trial status, including the target enrollment, current and projected 
time to completing enrollment.  Any significant events and/or difficulties should be 
briefly described in this narrative; 
• A brief narrative for each subject describing age, race and ethnicity and other relevant 
demographic characteristics.  The narrative for each subject should briefly describe his 
study status (i.e., dose level, visit number, adverse event information); 
• A timeline outlining the trial progress relative to visit number for each subject, as well as 
time points for each SAE.  A total for Adverse Events (AEs) for each subject should be 
included; 
• A summary of AEs by classification; 
• A listing of AE details grouped by subject; 
• A listing of SAE details grouped by subject; 
• A listing of deaths; 
• A summary of clinically significant laboratory test results; 
 
12.2 
Institutional Review Board Monitoring & IRB Reliance 
The Principal Investigators will obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the Reviewing IRB for this trial, including the subject’s consent 
forms and recruitment materials, must be maintained by the Principal Investigators and made 
available for inspection. 
 
The NCH IRB has offered to serve as the Reviewing IRB for all institutions via SMART IRB.   
Participating sites of this protocol are encouraged to utilize this infrastructure to expedite the 
review process.  Participating sites will need to be existing members of the SMART IRB Master 


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Common Reciprocal Institutional Review Board Authorization Agreement to utilize the NCH 
IRB as their IRB of record.  Sites that use the single IRB will rely on the NCH IRB approval in 
order for all study sites to have the same IRB determination, consent template(s), and expiration 
date. 
 
Sites that choose not to use the NCH IRB as IRB of record must provide the Coordinating Center 
with a copy of the initial IRB protocol approval and the yearly IRB continuing reviews. 
 
Modifications will be submitted to the NCH IRB for their review and approval prior to 
implementation.  When a modification to a protocol substantially alters the study design or 
increases potential risk to the study subject, the informed consent form will be revised and if 
applicable, subject's consent to continue participation will again be obtained. 
 
13. 
STATISTICAL CONSIDERATIONS 
 
Age-corrected 100M will be considered as the primary outcome, and will be evaluated using a 
two-one-sided t-test to test equivalency between treatment arms in the change from baseline to 6 
months.  In addition, repeated measures ANOVA will be used to determine whether the 
trajectory across all three time points (baseline, 3mo, 6mo) differs by treatment group.  Strength 
testing/dynamometry, NSAA, 4-stair climb, and time to arise from floor scores will be secondary 
outcomes, and will also be compared by treatment group using repeated measures ANOVA.   
Biomarkers studies will be considered exploratory outcomes. 
 
Power: Prior studies evaluating the 100m walk test among patients with DMD have shown an 
average change over 6 months of  -2.9 ±7.8.  An effective sample size of 10 patients per group 
will provide 80% power to declare equivalency with an equivalence margin of ±10.621. 
 
14. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
 
14.1 
Data Management and Study Forms 
Research material obtained from identifiable living human subjects includes reports of: history 
and physical assessments, blood, strength testing/dynamometry testing, NSAA, 4-stair climb, 
time to arise from floor, clinical assessments, adverse events, and autopsies.  Copies of case 
report forms, original test results, subject medical records, signed subject informed consents, 
correspondence, and any other documents of the subjects, relevant to the conduct of the trial will 
be kept on file by the Principal Investigator.  All material or data collected as part of the trial will 
be obtained specifically for research purposes. 
 


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In collaboration with the study team, the Research Informatics Core designed a data collection 
system (Open Clinica) for managing the clinical trial.  A web-based database was created and it 
will be managed by authorized users.  CRFs will be transcribed to this web-based database via 
eCRFs.  Data will be extracted from source documents (lab reports, echo reports, etc.) and 
transferred to the database as well.  All source documents will be kept in the subject research 
binder.  The secured portal will feature view and edit capability with field validations for quality 
controls, change history attribute, and reporting.  
 
An additional data collection system (REDCap) has been developed to help assess adverse 
events and concomitant medications remotely.  REDCap surveys will be sent by each site to 
subjects’ parent(s)/guardian at week 1 and months 1, 2, 4 and 5.  These timepoints require blood 
testing for electrolytes which can be done offsite, without a visit with the study team.  Responses 
to the surveys will be reviewed to ensure all adverse events and concomitant medications are 
recorded.  Follow-up phone calls will be done when necessary. 
 
14.2 
Electronic Case Report Forms (eCRF) 
Adequate and accurate case records will be maintained and all relevant observations and data 
related to the trial will be recorded.  This will include medical history/physical examination, 
hematology, clinical chemistry and serology results, etc. as specified in this protocol.  All data 
and observations will be documented on electronic Case Report Forms (eCRF) by source 
documentation using the Open Clinica Electronic Data Capture designed for the trial. 
 
A study monitor from NCH will have access to the data to monitor adherence to the protocol and 
to applicable FDA regulations, and the maintenance of adequate and accurate clinical records.   
An electronic Case Report Form (eCRF) will be completed for every subject that was registered 
for participation in the trial.  The eCRFs will be completed as information becomes available. 
 
Completed eCRFs will be reviewed by the study monitor in detail on a regular basis against the 
source documentation for accuracy and completeness.  The monitor will make a decision as to 
the data acceptability.  If errors or omissions are found in the course of a data audit, or if 
clarification of data is required, the eCRF(s) in question will be corrected by the PI or the PI’s 
designee.  Data resolution may be generated on omissions or clarifications, to be completed, 
electronically signed and dated, and maintained as a part of the eCRF.   
 
The Principal Investigator or the designated Co-Investigator will sign and accept the indicated 
eCRF.  This signature will indicate that thorough inspection of the data therein has been made 
and will thereby certify the contents of the form.   After the completion of the trial, completed 
eCRFs will be retained in the archives. 
 


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14.3 
Inspection of Records 
The Principal Investigator agrees to allow the study monitor to inspect the drug storage area, 
study drug stocks, drug accountability records, subject charts, study source documents, and other 
records relative to study conduct. 
 
15. 
QUALITY ASSURANCE AND QUALITY CONTROL 
 
15.1 
Study Monitoring 
NCH will act as the central monitor for the study.  The trial will be monitored in compliance 
with the relevant parts of 21 CFR and according to the ICH GCP Guidelines.  During the trial, 
the study monitor will have regular contact with the investigational site to provide information 
and support to the Principal Investigator(s) and to confirm that the investigational team is 
adhering to the protocol and ICH/GCP guidelines.   
 
No deviations from the protocol shall be made except in emergency situations where alternative 
treatment is necessary for the protection, proper care and well-being of subjects.  Protocol 
deviations will be monitored throughout the study.  
 
The procedures outlined in the protocol and case report forms will be carefully reviewed by the 
PI and staff prior to study initiation to ensure appropriate interpretation and implementation.   
Copies of all documentation essential for site initiation (e.g., notification of national/local 
regulatory and ethical approval and any other permissions required, copies of CVs for all site 
staff, completed delegation and signature log, etc.) will be reviewed by the study monitor prior to 
site authorization/initiation.   
 
The study monitor will review new and/or updated site study data (as available) and call each site 
monthly, beginning 30 days after enrollment of the first subject, and at close out.  Monthly calls 
can be forgone if no subject visits have occurred in the previous month.  The study monitor will 
be available between visits if the Principal Investigator(s) or other staff needs information or 
advice. 
 
The study monitor will perform the following monthly as appropriate and available: 
• Review available on-site resources (personnel, space, equipment, milieu); 
• Discuss the study protocol and visit schedule with staff to ensure familiarity; 
• Review maintenance of study records; 
• Review the informed consent forms executed by participating research subjects, and the 
process by which consent was obtained; 
• Review submitted study data to ensure consistency with source documentation, and to 
ensure study data have been collected in an accurate, complete and timely manner, 
consistent with the protocol and GCP’s;  


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• Review REDCap responses for subjects enrolled at the site and compare the responses to 
study data to ensure adequate reporting of adverse events and recording of concomitant 
medications; 
• Review site IRB approvals and regulatory documentation (e.g. Clinical Trial 
Authorizations) to ensure all such regulatory and ethical documents are correct and up to 
date;  
• Assist the sites with resolution of electronic data clarifications (queries); 
• Ensure that all serious adverse events have been properly and promptly reported; 
• Ensure that laboratory results conform to study standards  
 
16. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
16.1 
Ethics Review 
The final study protocol, including the final version of the informed consent forms, must be 
approved or given a favorable opinion in writing by the Reviewing IRB.  The Sponsor-
Investigator is responsible for informing the Reviewing IRB of any amendment to the protocol in 
accordance with the Reviewing IRB’s requirements.  The protocol must be re-approved by the 
Reviewing IRB upon receipt of amendments and annually, as required by Nationwide Children’s 
Hospital. 
 
16.2 
Ethical Conduct of the Trial 
The trial will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements. 
 
16.3 
Written Informed Consent 
Legally effective and properly executed written informed consent, in compliance with 21 CFR 
50 and the International Conference on Harmonization (ICH) guidelines, will be obtained from 
each subject before the subject is entered into the trial or before any unusual or non-routine 
procedure is performed that involves risk to the subject.  At subject enrollment, the Principal 
Investigator or designated Co-Investigator will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the trial.   
Subjects must also be notified that they are free to discontinue from the trial at any time.  The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
 
Attention will be directed to the basic elements that are required for incorporation into the 
informed consent under US Federal Regulations for Protection of Human Subjects [21CFR 
50.25(a)].  If new information related to the trial arises, subjects may be asked to sign a revised 
document depending on the changes.  Initial consent will be obtained only by the Principal 


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Investigator or a designated Co-Investigator delegated the task of initial consenting.  For any 
changes requiring re-consent of the subject, re-consent can be performed according to the 
procedures defined in this section of the protocol by a study team member delegated the task of 
re-consenting by the Principal Investigator.  Signed consent forms will remain in each subject's 
research chart and be available for the verification by study monitors at any time.  The Principal 
Investigator must maintain the original, signed ICF.  Subjects will be given a signed, dated copy 
of their consent form documents. 
 
Signatures are required from both parent(s)/legal guardian(s) of the subject in order to consent 
for the subject’s participation in the study due to the risk level of the study as determined by the 
NCH IRB.  All parent(s)/guardian(s) must be present to consent in person for initial consent.  
Prior approval from the Reviewing IRB must be obtained if extreme circumstances will only 
allow for one parent/guardian to be present in person and the other present by telephone for 
initial consent. For changes requiring re-consent, re-consent from both parent(s)/guardian(s) can 
be obtained at the subject’s next in-person visit unless the changes warrant immediate re-consent 
between visits.  No prior approval from the Revieweing IRB is necessary to obtain re-consent 
from one or both parent(s)/guardian(s) via phone unless otherwise required by local site policies.  
 
17. 
DATA HANDLING AND RECORD KEEPING 
 
17.1 
Retention of Records 
All primary data that are a result of the original observations and activities of the trial and that 
are necessary for the reconstruction and evaluation of any study report will be retained in a 
secure archive at the study site for a period of at least 2 years after the formal closure of the 
study.  These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirement(s) or if needed by the Sponsor.  The Sponsor should inform 
the investigator(s)/institution(s) in writing of the need for record retention and should notify the 
investigator(s)/institution(s) in writing when the trial-related records are no longer needed. 
 
If the investigator is no longer able to fulfill their record retention obligations (for example if 
they leave to work at another institution, or retires), they should make arrangements of who will 
ensure that the documents are retained securely while maintaining subject confidentiality. 
 
The site will maintain a research regulatory binder.  In this binder, there will be tabbed sections 
for study documents including, but not limited to, the following: study personnel identification 
and signature list, subject screening records, subject roster (names omitted), protocol and 
amendments or administrative changes, FDA Form 1572 (if required), study staff Curricula 
Vitae, Reviewing IRB documentation, an approved sample ICF, drug accountability records, 
correspondence, site monitoring reports, and lab accreditations and normal values.  The site must 


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keep this binder current and available for review by the Sponsor, Reviewing IRB, FDA, and 
other similar regulatory bodies. 
 
17.2 
Retention of Samples 
The identified storage laboratory will be responsible for arranging storage of any remaining or 
unused biological samples as well as properly documenting the storage procedures, once all 
study-required analyses are complete, as per sample processing requirements until such time that 
the Sponsor-Investigator provides external storage vendor transfer or destruction instructions. 
 
17.3 
Study Reports  
17.3.1 Annual Study Reports 
Annual continuing reviews will be submitted to the Reviewing IRB, including information about 
current study status, study amendments, changes in study risk and adverse event reporting, 
targeted and completed study enrollment, subject withdrawal, summary of study findings, or 
publication information. 
 
17.3.2 Final Study Report 
The final study report will include data through the final study visit. 
 
18. 
STUDY ADMINISTRATION 
18.1 
Coordinating Center 
The Nationwide Children's Center for Gene Therapy at the Abigail Wexner Research Institute is 
the Coordinating Center for the entire trial.   
 
The Coordinating Center is responsible for the following: 
• Development and maintenance of the Manual of Operating Procedures 
• Training and reliability testing of additional sites 
• Enrollment of subjects at NCH 
• Curating data in the database 
• Obtaining informed consent from subjects at NCH  
• Adverse event monitoring and reporting 
 
18.2 
Overview of Principal Investigator Responsibilities 
In conducting the clinical trial, each site’s Principal Investigator is responsible: 
• For ensuring that a clinical investigation is conducted according to applicable regulations; 
• For protecting the rights, safety, and welfare of subjects under the investigator's care;  
• For the control of the study drug under investigation;  


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• To conduct the trial in accordance with the relevant, current protocol(s) and to only make 
changes in the protocol after notifying the Sponsor-Investigator, except when necessary 
to protect the safety, rights, or welfare of subjects; 
• To personally conduct or supervise the research study; 
• To inform the subjects, that the drugs are being used for investigational purposes and to 
ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 
and institutional review board (IRB) review and approval in 21 CFR Part 56 are met; 
• To report to the Sponsor-Investigator adverse experiences that occur in the course of the 
investigations(s) in accordance with 21 CFR 3 12.64; 
• To ensure that all associates, colleagues, and employees assisting in the conduct of the 
trial are informed about their obligations in meeting the above commitments; 
• To maintain adequate and accurate records and to make those records available to the 
FDA and other similar regulatory bodies for inspection in accordance with 21 CFR 3 
12.68; 
• That Reviewing IRB will be responsible for the initial and continuing review and 
approval of the clinical investigation; 
• To promptly report directly to the Sponsor-Investigator for appropriate reporting to the 
Reviewing IRB all changes in the research activity and all unanticipated problems 
involving risks to human subjects or others; 
• To not make any changes in the research without the Reviewing IRB approval, except 
where necessary to eliminate apparent immediate hazards to human subjects; 
• To comply with all other requirements regarding the obligations of Principal 
Investigators and all other pertinent requirements in 2 1 CFR 3 12. 
 
19. 
CONFLICT OF INTEREST POLICY 
 
The Principal Investigators and Co-Investigators will have no financial, scientific or other 
conflicts of interest with the trial.  Conflicts of interest can include professional, proprietary, and 
miscellaneous interests as described in the NIH Grant Policy Statement and 45 CFR Part 94. 
 
 
 
 
 
 
 
 
 
 
 


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20. 
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