Clinical trial NCT01603407
Conditions: Duchenne Muscular Dystrophy
Keywords: prednisone deflazacort muscular dystrophy neuromuscular disease multi-center
Sponsor: University of Rochester
Start date: 2013-01-01; Completion date: 2019-11-01
Enrollment: 196 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The Finding the Optimum Regimen for Duchenne Muscular Dystrophy (FOR DMD) study will compare three ways of giving corticosteroids to boys with Duchenne muscular dystrophy (DMD) to determine which of the three ways increases muscle strength the most, and which causes the fewest side effects. Using the results of this study, the investigators aim to provide patients and families with clearer information about the best way to take these drugs.

Detailed description:
Boys with Duchenne muscular dystrophy experience progressive muscle weakness as they grow up. Corticosteroids are currently the only medicine that has been shown to increase muscle strength in boys with DMD. Benefits include an increase in the length of time that boys could continue to walk, reduction in the development of curvature of the spine, a longer time of adequate breathing, and possible protection against the development of heart problems.

Doctors have tried different ways of prescribing corticosteroids in order to decrease undesirable side effects of the drug. No controlled, long-term study has ever looked at the effects of different corticosteroids to see which one improves strength the most and which one causes the fewest side effects, over a period of time. Different doctors in different countries prescribe the drugs in different ways, and some do not prescribe corticosteroids at all.

The FOR DMD study will enroll boys with DMD ages 4-7. The study will look at three ways of taking the following corticosteroids by the mouth to determine which increases muscle strength the most, and which causes the fewest side effects:

1. Prednisone 0.75mg/kg/day
2. Prednisone 0.75mg/kg/day switching between 10 days on and 10 days off treatment
3. Deflazacort 0.9mg/kg/day.

The study will take place at 40 academic medical centers in the United States, Canada, United Kingdom, Germany and Italy.

Arms: arm 1: daily prednisone (0.75 mg/kg/day) arm 2: intermittent prednisone (0.75 mg/kg/day, 10 days on, 10 days off) arm 3: daily deflazacort (0.9 mg/kg/day
Interventions: intervention 1: Prednisone intervention 2: Prednisone intervention 3: Deflazacort
Intervention descriptions: intervention 1: daily prednisone (0.75 mg/kg/day) tablets for 36-60 months intervention 2: intermittent prednisone (0.75 mg/kg/day, 10 days on, 10 days off) tablets for 36 to 60 months intervention 3: daily deflazacort (0.9 mg/kg/day) tablets for 36-60 months

Protocol documents:
Prot_000.pdf: 
FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
1
FULL PROTOCOL TITLE 
 
Duchenne muscular dystrophy: double-blind randomized trial to find optimum steroid regimen 
 
(Short title: FOR-DMD) 
 
Study Chairs:  
Michela Guglieri, M.D. 
Senior Lecturer; Honorary Consultant in Human Genetics 
The John Walton Muscular Dystrophy Research Centre 
 
Newcastle upon Tyne, UK 
 
Robert C. Griggs, M.D. 
Professor of Neurology 
University of Rochester School of Medicine, Rochester, NY 
 
 
 
Supported by: 
The United States National Institutes of Health,  
The National Institute of Neurological  
Disorders and Stroke (NINDS) 
 
U01 NS061799 
U01 NS061795 
 
 
 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
2
 
Sponsor of IND:  
University of Rochester 
518 Hylan Building 
Rochester, New York 14627-0140 
TEL++585 275 3707 
FAX: ++ 585 276 2056 
Robert_griggs@urmc.rochester.edu 
Sponsor's Legal Representative in the EAA 
Mr. Sean Scott 
Regulatory Compliance Manager 
The Newcastle upon Tyne Hospitals NHS Foundation Trust 
Joint Research Office 
Level 1, Regent Point 
Regent Farm Road 
Gosforth 
Newcastle upon Tyne 
NE3 3HD 
TEL: +44 (0)191 282 4461 
sean.scott@nuth.nhs.uk 
 
Study EudraCT number: 2010-023744-33 
 
 
 
 
 
 
 
 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
3
Co-Principal Investigator and Chief Medical Coordinator: 
Michela Guglieri, M.D. 
The John Walton Muscular Dystrophy Research Centre 
Newcastle University 
Institute of Genetic Medicine 
Central Parkway 
NE1 3BZ, Newcastle upon Tyne 
 
Tel +44 191 2418649 
Fax: +44 191 2418770 
michela.guglieri@newcastle.ac.uk 
 
 
 
Co-Principal Investigator: 
Robert C. Griggs, M.D. 
Professor of Neurology 
University of Rochester School of Medicine 
601 Elmwood Avenue, Box 669 
Rochester, NY 14642 
 
TEL: 585 275 6072 
FAX: 585 276 2056 
Griggs_RobertResearch@urmc.rochester.edu 
 
 
 
Statistics and Data Management Co-PI: 
Michael McDermott, PhD 
Professor of Biostatistics and Neurology 
University of Rochester School of Medicine 
Department of Biostatistics and Computational Biology 
265 Crittenden Blvd, Box 630 
Rochester, NY 14642 
 
TEL: ++ 585 275-6685 
FAX: ++ 585 273 1031 
Michael_McDermott@urmc.rochester.edu 
 
 
 
 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
4
Statistics and Data Management Co-PI: 
Rabi Tawil, MD 
Professor of Neurology 
University of Rochester School of Medicine 
Department of Neurology 
601 Elmwood Avenue, Box 673 
Rochester, NY 14642 
 
TEL: ++ 585 275-6372 
FAX: ++ 585 273-1255 
Rabi_tawil@urmc.rochester.edu 
 
 
US Project Manager 
Kimberly A. Hart, MA 
Department of Neurology 
University of Rochester Medical Center 
601 Elmwood Avenue, Box 669 
Rochester, NY 14642 
 
TEL: 1-585-275-3767 
FAX: 585 276 2056 
E-mail: Kim_Hart@urmc.rochester.edu 
 
 
EU Project Manager 
Professor  Elaine McColl, BA, MSc, PhD 
Newcastle Clinical Trials Unit 
Institute of Health and Society 
Newcastle University 
4th Floor, William Leech Building 
The Medical School 
Framlington Place 
Newcastle upon Tyne 
NE2 4HH 
United Kingdom 
 
TEL: ++ 44 191 222 7260 
FAX: ++ 44 191 222 8901 
elaine.mccoll@newcastle.ac.uk  
 
 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
5
UK Project Manager 
 
Michelle Bardgett 
Newcastle Clinical Trials Unit 
Newcastle University 
1-4 Claremont Terrace 
Newcastle upon Tyne 
NE2 4AE 
United Kingdom 
 
Tel: +44 (0)191 208 2597 
Fax: +44 (0) 191 208 8901 
Michelle.Bardgett@newcastle.ac.uk 
 
 
UK Trial Manager 
 
Miss Gillian Watson 
Newcastle Clinical Trials Unit 
1-4 Claremont Terrace 
Newcastle upon Tyne 
NE2 4AE 
United Kingdom 
 
Tel: +44 (0)191 208 8813 
Fax: +44 (0)191 208 8901 
gillian.watson@newcastle.ac.uk 
 
  
 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
6
SYNOPSIS 
 
Study Title: 
Duchenne muscular dystrophy: double-blind randomized trial to find optimum steroid regimen  
 
Abbreviated title:  
FOR DMD 
 
EudraCT number: 2010-023744-33 
 
Objective: 
This is a multi-centre, double-blind, parallel group, 36-60 month study, comparing three 
corticosteroid regimens in wide use in DMD: 
• 
daily prednisone (0.75 mg/kg/day)  
• 
intermittent prednisone (0.75 mg/kg/day, 10 days on, 10 days off)  
• 
daily deflazacort (0.9 mg/kg/day).  
 
Primary study objective: The proposed randomized controlled trial will compare 3 
corticosteroid regimens to address the pragmatic hypothesis that daily corticosteroids 
(prednisone or deflazacort) will be of greater benefit in terms of function and subject/parent 
satisfaction than intermittent corticosteroids (prednisone). 
 
Secondary study objectives: A second hypothesis is that daily deflazacort will be associated 
with a better side effect profile than daily prednisone. The study protocol includes 
standardized regimens for prevention/ treatment of predictable side effects of corticosteroid 
medication, as well as standards of care for the general management of DMD. The trial 
directly addresses the current chaos in prescribed treatment schedules; its results will have 
direct impact on the current and future management of boys with DMD throughout the world 
by providing the evidence base for rational clinical practice.  
The results of the trial will allow the generation of clear and specific evidence-based 
guidelines for patient treatment. 
 
Design and Outcomes: 
The primary outcome variable will be a three-dimensional (multivariate) outcome consisting 
of the following three components (each averaged over all post-baseline follow-up visits 
through Month 36): (1) time to stand from lying (log-transformed), (2) forced vital capacity, 
and (3) subject/parent global satisfaction with treatment, as measured by the Treatment 
Satisfaction Questionnaire for Medication. 
Secondary outcome variables will include regimen tolerance, adverse event profile, 
secondary functional outcomes including the 6 minute walk test, quality of life, and cardiac 
function. 
The primary statistical analysis will consist of a global test of the null hypothesis that the 
corticosteroid regimens do not differ with regard to any of the three outcomes against the 
alternative that they differ (in the same direction) for all three outcome variables. The 
analyses will involve three separate pair-wise comparisons among the three treatment 
regimens using O’Brien’s OLS statistics, each performed using a Bonferroni-corrected two-
tailed significance level of 0.017. The analyses will be adjusted for covariates, namely 
country/region, baseline time to stand from lying, baseline FVC and initial weight band. A 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
7
sample size of 75 subjects per group (225 total) will provide adequate power to detect 
differences that are thought to be of minimal clinical significance between any two of the 
three treatment groups, assuming a 10% rate of subject withdrawal. 
 
Interventions and Duration: 
The trial will randomize 225 boys aged 4-7 years to 0.75 mg/kg/d prednisone; 0.75 mg/kg/d 
prednisone for 10 days alternating with 10 days off; or 0.9 mg/kg/d deflazacort. All boys will 
complete a minimum of 3 years (36 months) of treatment period with the option to remain on 
study drug (blinded) up to 60 months. Boys electing to continue in this trial beyond 36 
months will continue on blinded treatment but only primary outcome and safety variables will 
be collected at visits in Years 4 and 5.  Subjects choosing to participate for the full 60 months 
of the trial will be unblinded to treatment after completion of their 60-Month (5-Year) study 
visit. 
Commercial stock prednisone and deflazacort differ from one to another in appearance and 
their use would prevent blinding of subjects, parents and physicians to the allocated 
treatment. To achieve double-blinding, a clinical trials supplies company will manufacture 
identical tablets of prednisone and deflazacort, and matched placebo (to maintain blinding in 
the 10 days off period, for the intermittent prednisone regimen). This medication will be 
presented in form of tablets for oral administration.  This solution is preferred to over-
encapsulation of commercial stock tablets, as the resulting capsules would be quite large, 
presenting potential difficulties in swallowing for the younger children. 
Study drug will be presented in 20 day treatment wallets containing 2-6 tablets per day (i.e. a 
total of 40 to 120 tablets), depending on the weight band, in a blister pack. Dosage banding 
for different steroid regimens will be as follows: 
 
Band Weight 
range in kg 
Weight 
used for 
calculation 
of dose per 
kg 
Dose in mg 
based on 
0.75mg/kg 
Prednisone 
Number of 
tablets of 
Prednisone 
(5 mg) for 
this dose 
Dose in mg 
based on 
0.9mg/kg 
Deflazacort 
Number of 
tablets of 
Deflazacort 
(6 mg) for 
this dose 
A 
13-19.9 
13.33kg 
10mg 
2 
12mg 
2 
B 
20-25.9 
20.00kg 
15mg 
3 
18mg 
3 
C 
26-32.9 
26.67kg 
20mg 
4 
24mg 
4 
D 
33-39.9 
33.33kg 
25mg 
5 
30mg 
5 
E 
40+ 
40.00kg 
30mg 
6 
36mg 
6 
Bands represent weight ranges.  
 
Each wallet will be labelled with a multilingual booklet label and a single panel variable label.  
The wallets will be collated into kits containing either 7 wallets or 13 wallets.  Each kit will be 
labelled with a multilingual booklet and a single panel variable label. Six months after study 
enrollment ceases, only 13-wallet kits will be used for the remainder of the study. 
 
 
Sample Size and Population: 
Eligible boys will be those with confirmed DMD (defined as male with clinical signs 
compatible with DMD AND confirmed DMD mutation in the dystrophin gene 
[deletion/duplication of one or more exons, that are predicted as 'out-of-frame', or other 
mutations that are expected to preclude production of the dystrophin protein (i.e. nonsense 
mutation, deletion/duplication leading to a downstream stop codon)] ; age at least 4 years 
and under 8 years; ability to rise independently from floor; willingness and ability of parent or 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
8
legal guardian to give informed consent; willingness and ability to comply with scheduled 
visits, drug administration plan and study procedures; and ability to maintain reproducible 
FVC measurements.   
Exclusion criteria: history of major renal or hepatic impairment, immunosuppression or other 
contraindications to corticosteroid therapy; history of chronic systemic fungal or viral 
infections; diabetes mellitus; idiopathic hypercalciuria; lack of chicken pox immunity (as 
demonstrated by absence of antibodies via titer) and refusal to undergo no more than two 
separate immunizations (should initial immunization fail to produce antibodies); evidence of 
symptomatic cardiomyopathy; allergy/sensitivity to study drugs or their formulations; current 
or previous treatment with corticosteroids or other immunosuppressive treatments for DMD 
or other recurrent indications ; inability to take tablets; allergy/sensitivity to study drugs or 
their formulations; severe behavioral problems, including autism; previous or ongoing 
medical conditions, medical history, physical findings or laboratory abnormalities that could 
affect safety or impair the assessment of study results; weight of less than 13 kilograms; 
exposure to any investigational drug currently or within 3 months prior to start study 
treatment, unless exposure to investigational drug is a result of participation in a clinical trial 
that has a concurrent participation in FOR-DMD agreement in place. 
A sample size of 75 subjects per group (225 total) will provide adequate power to detect 
differences that are thought to be of minimal clinical significance between any two of the 
three treatment groups, assuming a 10% rate of subject withdrawal. 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
9
Protocol Signatures 
Authors 
 
Name: 
Professor R Griggs  
Role: Co-Principal Investigator 
 
Signature: 
 
 
 
 
Date: 
 
 
Name: 
Dr Michela Guglieri  
Role: Co-Principal Investigator &  
 
 
 
 
 
 
 
Chief Medical Coordinator 
Signature: 
 
 
 
 
Date:  
 
 
Name: 
Professor M McDermott 
Role: Statistics and Data 
Management Co-PI 
 
Signature: 
 
 
 
 
Date 
 
 
Name  
Professor Rabi Tawil 
Role: Statistics and Data 
Management Co-PI 
 
Signature: 
 
 
 
 
Date:  
 
 
Name: 
Kimberly Hart 
 
Role: Project Manager 
 
Signature: 
 
 
 
 
Date:  
 
 
Name: 
Professor Elaine McColl 
Role: Project Manager 
 
Signature: 
 
 
 
 
Date: 
 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
10
 
 
 
 
 
 
Principal Investigator 
 
Name: 
 
 
Site:   
(country-site code or institution name & location) 
 
Signature: 
 
 
 
 
Date:  


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
11
Abbreviations 
6MWT 6 minute walk test 
AAN American Academy of Neurology 
AE Adverse Event 
BMC Bone Mineral Content 
BMD Bone Mineral Density 
CIDD Clinical Investigations of Duchenne Dystrophy 
CRF Case Report Form 
DMD Duchenne Muscular Dystrophy 
DXA Dual Energy X-ray Absorptiometry 
ENMC European Neuromuscular Centre 
eCRFs Electronic Case Report Forms 
EK Egen Klassifikation scale   
FOR-DMD Finding the optimum regimen for DMD 
FVC Forced Vital Capacity 
GCP Good Clinical Practice 
ICH International Conference on Harmonization 
IRB Institutional Review Board 
MedDRA Medical Dictionary for Regulatory Activities 
MOO Manual of Operations 
NCTU Newcastle Clinical Trial Unit 
NIH National Institute of Health 
PedsQL Paediatric Quality of Life Inventory 
QoL Quality of Life 
REC Research Ethics Committee  
ROM Range Of Motion 
RRS Revised Rutter Scale 
SAE Serious Adverse Event 
SDQ Strengths and Difficulties Questionnaire 
SOP Standard Operating Procedure 
SSC Study Steering Committee 
SUSAR Suspected Unexpected Serious Adverse Reaction 
TSQM Treatment Satisfaction Questionnaire (Medication) 
VS Vital Signs 
 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
12
 
1 
STUDY OBJECTIVES ...................................................................................................16 
1.1 
PRIMARY OBJECTIVE ................................................................................................16 
1.2 
SECONDARY OBJECTIVES .........................................................................................16 
2 
BACKGROUND ............................................................................................................17 
2.1 
RATIONALE ..............................................................................................................17 
2.2 
SUPPORTING DATA ..................................................................................................18 
2.2.1 
Summary ..........................................................................................................18 
2.2.2 
Short-term effect of prednisone .........................................................................18 
2.2.2.1 
Muscle strength .........................................................................................18 
2.2.2.2 
Functional measures .................................................................................19 
2.2.2.3 
Forced vital capacity (FVC) .......................................................................19 
2.2.2.4 
Quality of Life ............................................................................................19 
2.2.2.5 
Side effects ...............................................................................................19 
2.2.2.6 
Comparisons with deflazacort ....................................................................19 
3 
STUDY DESIGN ...........................................................................................................20 
3.1 
OVERVIEW ............................................................................................................20 
3.2 
PRIMARY OUTCOME MEASURES .................................................................................20 
3.2.1 
Muscle function (time taken to rise from the floor, from supine to standing).......20 
3.2.2 
Respiratory function (Forced Vital Capacity – FVC) ..........................................21 
3.2.3 
Parent/subject satisfaction with treatment (global satisfaction rating from the 
Treatment Satisfaction Questionnaire for Medicine (TSQM)) .........................................21 
3.3 
SECONDARY OUTCOME MEASURES ...........................................................................21 
3.3.1 
Tolerability.........................................................................................................21 
3.3.2 
Adverse events .................................................................................................21 
3.3.3 
Secondary functional outcomes and disease milestones ...................................23 
3.3.3.1 
The North Star Ambulatory Assessment (NSAA) .......................................23 
3.3.3.2 
6MWT .......................................................................................................24 
3.3.3.3 
Range of motion (goniometry) ...................................................................24 
3.3.4 
Quality of Life ....................................................................................................24 
3.3.5 
Cardiac function ................................................................................................24 
3.4 
DEFINITION OF END OF STUDY ...................................................................................25 
4 
SELECTION AND ENROLLMENT OF SUBJECTS ......................................................26 
4.1 
INCLUSION CRITERIA.................................................................................................26 
4.2 
EXCLUSION CRITERIA ...............................................................................................26 
4.3 
STUDY ENROLMENT PROCEDURES ............................................................................27 
4.3.1 
Identification and recruitment methods ..............................................................27 
4.3.2 
Consent and assent procedures ........................................................................27 
4.3.3 
Documentation of outcomes of screening procedure .........................................28 
4.3.4 
Randomization procedures ...............................................................................28 
4.3.5 
Blinding .............................................................................................................29 
5 
STUDY INTERVENTIONS ............................................................................................31 
5.1 
STUDY MEDICATION .................................................................................................31 
5.1.1 
Study medication administration ........................................................................31 
5.1.2 
Supply, storage and return of study medication .................................................37 
5.1.3 
Adherence Assessment ....................................................................................38 
5.2 
HANDLING OF STUDY INTERVENTIONS .......................................................................39 
5.2.1 
Unblinding .........................................................................................................39 
5.3 
CONCOMITANT AND SUPPORTIVE CARE ......................................................................40 
5.3.1 
Concomitant and supportive care medications ..................................................40 
5.3.1.1 
Calcium and Vitamin D ..............................................................................40 
5.3.1.2 
Bisphosphonates .......................................................................................40 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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5.3.1.3 
Cardiac health ...........................................................................................40 
5.3.1.4 
Respiratory management ..........................................................................41 
5.3.1.5 
Infectious diseases ....................................................................................41 
5.3.1.6 
Trauma or surgical procedure ....................................................................41 
5.3.2 
Other supportive care interventions ...................................................................41 
5.3.2.1 
Protocol driven management .....................................................................41 
5.3.2.2 
Management of predictable adverse events ..............................................42 
5.3.2.2.1 Management of bone health..................................................................42 
5.3.2.2.2 Management of cataract development ..................................................42 
5.3.3 
Concomitant Interventions .................................................................................42 
5.3.3.1 
Prohibited Interventions .............................................................................42 
5.3.3.2 
Precautionary Interventions .......................................................................42 
5.3.3.2.1 Precautionary interventions in the event of behavior changes ...............43 
5.3.3.2.2 Precautionary interventions in the event of the development of 
Cushingoid appearance .........................................................................................43 
5.3.3.2.3 Precautionary interventions in the event of gastrointestinal symptoms 
(abdominal pain, heartburn, GI bleeding) ...............................................................43 
5.3.3.2.4 Precautionary interventions in the event of glycosuria ...........................44 
5.3.3.2.5 Precautionary interventions in the event of hypertension (blood pressure 
elevation compared to age norms) .........................................................................44 
5.3.3.2.6 Precautionary interventions in the event of immune/adrenal suppression
 
45 
5.3.3.2.7 Precautionary interventions in the event of skin changes ......................45 
5.3.3.2.8 Precautionary interventions in the event of slow growth (height 
restriction) 45 
5.3.3.2.9 Precautionary interventions in the event of (excessive) weight gain ......45 
5.3.3.2.10 Procedures in the event of the need to discontinue corticosteroids .....46 
6 
CLINICAL AND LABORATORY EVALUATIONS .........................................................47 
6.1 
SCHEDULE OF EVALUATIONS ....................................................................................47 
Table 6.1 b. Between-visit phone calls ........................................................................50 
6.2 
TIMING OF EVALUATIONS ..........................................................................................50 
6.2.1 
Pre-Randomization Evaluations ........................................................................50 
6.2.1.1 
Screening Period .......................................................................................50 
6.2.1.2 
Baseline / Study Entry ...............................................................................51 
6.2.2 
On-Study Evaluations .......................................................................................52 
6.2.2.1 
3-month follow-up visit ...............................................................................52 
6.2.2.2 
Evaluations to be carried out every 6 months ............................................53 
6.2.2.3 
Evaluations to be carried out annually .......................................................54 
6.2.2.4 
Evaluations to be carried out every two years, then annually .....................54 
6.2.2.5 
Evaluations to be carried out at 36 months ................................................55 
6.2.2.6 
Between-visit phone calls ..........................................................................55 
6.2.3 
Intervention Discontinuation Evaluations and Post-Intervention Evaluations .....55 
6.2.4 
Final Evaluations ...............................................................................................55 
6.3 
SPECIAL INSTRUCTIONS AND DEFINITIONS OF EVALUATIONS .......................................56 
6.3.1 
Informed Consent..............................................................................................56 
6.3.2 
Documentation of Duchenne Muscular Dystrophy (DMD) .................................56 
6.3.3 
Demographic Data ............................................................................................57 
6.3.4 
Medical History .................................................................................................57 
6.3.5 
Treatment History ..............................................................................................57 
6.3.6 
Concomitant Treatments ...................................................................................57 
6.3.7 
Study Intervention Modifications ........................................................................58 
6.3.8 
Clinical Assessments ........................................................................................58 
6.3.8.1 
Height, weight, BP and other vital signs.....................................................58 
6.3.8.2 
Physical examination .................................................................................58 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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6.3.8.3 
Skin examination .......................................................................................58 
6.3.8.4 
Eye examination ........................................................................................58 
6.3.8.5 
Cushingoid signs .......................................................................................59 
6.3.8.6 
Pulmonary function ....................................................................................59 
6.3.8.7 
Assessments of physical function ..............................................................59 
6.3.8.8 
DXA scans and lateral spine and wrist X-rays ...........................................59 
6.3.8.9 
Echocardiogram and ECG .........................................................................60 
6.3.9 
Laboratory Evaluations .....................................................................................60 
6.3.9.1 
Urinalysis ...................................................................................................60 
6.3.9.2 
Chicken pox and TB immunity ...................................................................61 
6.3.9.3 
Serum chemistry and hematology .............................................................61 
6.3.9.4 
Blood samples for 25-OH-D, serum calcium, phosphate, and alkaline 
phosphatase................................................................................................................61 
6.3.9.5 
Urinalysis for urinary calcium assessment .................................................62 
6.3.10 
Additional Evaluations ...................................................................................62 
6.3.10.1 
Dietary assessment and advice; behavioral assessment and advice; 
physiotherapy assessment and management ..............................................................62 
6.3.10.2 
Adverse events ..........................................................................................63 
6.3.11 
Questionnaires ..............................................................................................63 
6.3.11.1 
Treatment Satisfaction ...............................................................................63 
6.3.11.2 
Behavior ....................................................................................................63 
6.3.11.3 
Quality of Life (PedsQL) ............................................................................63 
6.3.12 
Adherence Assessments ...............................................................................64 
6.3.13 
Between visit phone calls ..............................................................................64 
6.4 
OFF-INTERVENTION REQUIREMENTS .........................................................................64 
6.5 
BIOBANKING ............................................................................................................64 
7 
MANAGEMENT OF ADVERSE EVENTS .....................................................................65 
7.1 
DEFINITION AND GRADING OF ADVERSE EVENTS .........................................................65 
7.1.1 
Defining ‘adverse event’ ....................................................................................65 
7.1.2 
Defining ‘serious adverse event’ ........................................................................66 
7.1.3 
Grading of severity of adverse events ...............................................................66 
7.1.4 
Relationship of an adverse event to study medication .......................................67 
7.2 
RECORDING AND REPORTING ADVERSE EVENTS .........................................................67 
7.2.1 
Adverse event recording ...................................................................................67 
7.2.2 
Adverse Event Reporting ..................................................................................68 
7.3 
EXPECTED ADVERSE EVENTS ....................................................................................70 
7.3.1 
Expected adverse events related to study medication .......................................70 
7.3.2 
Expected adverse events related to other study procedures .............................70 
7.4 
MANAGEMENT OF ADVERSE EVENTS ..........................................................................70 
7.4.1 
Behavioral problems .........................................................................................71 
7.4.2 
Bone health .......................................................................................................71 
7.4.3 
Weight gain .......................................................................................................71 
7.4.4 
Cataracts ..........................................................................................................71 
7.4.5 
Cushingoid appearance ....................................................................................71 
7.4.6 
Gastrointestinal symptoms (abdominal pain, heartburn, GI bleeding) ................72 
7.4.7 
Glycosuria .........................................................................................................72 
7.4.8 
Hypertension .....................................................................................................72 
7.4.9 
Immuno/adrenal suppression ............................................................................72 
7.4.10 
Skin changes .................................................................................................73 
7.4.11 
Slow growth...................................................................................................73 
7.5 
POSSIBLE BENEFITS .................................................................................................73 
8 
INTERVENTION DISCONTINUATION ..........................................................................74 
8.1 
CRITERIA FOR TREATMENT INTERRUPTION .................................................................74 
8.2 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ..............................................74 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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8.3 
PROCEDURES FOR MAINTAINING INVOLVEMENT OF SUBJECTSIN FOLLOW-UP ACTIVITIES 74 
9 
STATISTICAL CONSIDERATIONS ..............................................................................76 
9.1 
ANALYSIS OF THE PRIMARY OUTCOME VARIABLE FOR EFFICACY ..................................76 
9.1.1 
Primary statistical model ...................................................................................76 
9.1.2 
Adjustment for baseline characteristics .............................................................77 
9.1.3 
Model assumptions ...........................................................................................77 
9.1.4 
Treatment of missing data .................................................................................77 
9.2 
ANALYSIS OF THE SECONDARY OUTCOME VARIABLES FOR EFFICACY ...........................78 
9.2.1 
Analysis of continuous outcome variables .........................................................78 
9.2.2 
Analysis of times to disease milestones ............................................................79 
9.3 
ANALYSIS OF TOLERABILITY OUTCOMES .....................................................................80 
9.4 
ANALYSIS OF SAFETY OUTCOMES ..............................ERROR! BOOKMARK NOT DEFINED. 
9.5 
ANALYSIS OF MISCELLANEOUS OUTCOMES.................ERROR! BOOKMARK NOT DEFINED. 
9.6 
SAMPLE SIZE CONSIDERATIONS .................................................................................81 
9.7 
DATA AND SAFETY MONITORING ................................................................................85 
9.7.1 
General guidelines ............................................................................................85 
9.7.2 
Interim analyses for safety ................................................................................85 
9.7.3 
Interim analyses for efficacy and futility .............................................................85 
10 STUDY COMMITTEES..................................................................................................86 
10.1 STUDY STEERING COMMITTEE ..................................................................................86 
10.2 DATA SAFETY MONITORING BOARD ..........................................................................86 
11 DATA COLLECTION, STUDY RECORDS, SITE MONITORING, AND ADVERSE 
EXPERIENCE REPORTING ................................................................................................87 
11.1 STUDY RECORDS ................................................................................................87 
11.1.1 
RECORD TO BE KEPT .................................................................................87 
11.1.2 
Data to be collected for each subject .............................................................87 
11.1.3 
Site master file ..............................................................................................88 
11.2 MAINTAINING CONFIDENTIALITY OF MEDICAL RECORDS ...............................................88 
11.3 DATA MANAGEMENT AND QUALITY ASSURANCE ............................................90 
11.3.1 
Division of responsibilities .............................................................................90 
11.3.1.1 
Site responsibility ......................................................................................90 
11.3.1.2 
MSG-CC (Statistical Center) responsibilities .............................................90 
11.3.2 
Data flow and management ...........................................................................90 
11.3.3 
Quality control ...............................................................................................91 
11.3.4 
Staff Training .................................................................................................92 
11.3.5 
Quality assurance .........................................................................................92 
11.4 MONITORING ........................................................................................................92 
11.4.1 
Central monitoring .........................................................................................92 
11.4.2 
Site monitoring ..............................................................................................92 
12 HUMAN SUBJECTS .....................................................................................................93 
12.1 COMPLIANCE WITH ETHICAL AND REGULATORY GUIDELINES .......................................93 
12.2 INSTITUTIONAL REVIEW BOARD (IRB) REVIEW AND INFORMED CONSENT ....................93 
12.3 SUBJECT CONFIDENTIALITY ......................................................................................94 
12.4 STUDY MODIFICATION/DISCONTINUATION ..................................................................94 
13 PUBLICATION OF RESEARCH FINDINGS .................................................................95 
14 REFERENCES ..............................................................................................................96 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
16
 
1 
STUDY OBJECTIVES 
This investigator-initiated Phase III trial compares three steroid regimens for boys with 
Duchenne muscular dystrophy in regard to functional outcome and subject/parent 
satisfaction. The long-term objective of this trial is to identify the optimum steroid regimen for 
boys with Duchenne muscular dystrophy. 
1.1 Primary Objective 
The primary objective is to compare three most commonly in use corticosteroid regimens 
(0.75mg/kg/day prednisone; 0.75mg/kg/day prednisone 10 days on/10 days off; 
0.9mg/kg/day deflazacort) in regard to functional outcome and subject/parent satisfaction. 
The primary outcome variable is a multivariate (3-dimensional) measure, comprising two 
dimensions of function (time to rise from the floor, forced vital capacity) and one of 
satisfaction (global treatment satisfaction). The null hypothesis states that the three 
corticosteroid regimens do not differ from one to another with regard to any of the three 
dimensions of outcome while the alternative hypothesis states that they differ (in the same 
direction) with regard to at least one of the dimensions of outcome. 
1.2 Secondary Objectives 
The secondary objectives are to compare the three corticosteroid regimens with regard to: 
• Tolerability 
• Adverse events  
• Secondary functional outcomes and disease milestones 
• Quality of life 
• Cardiac function 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
17
2 
BACKGROUND 
2.1 Rationale 
The study population for this study is boys with confirmed Duchenne muscular dystrophy 
(DMD - defined as male with clinical signs compatible with DMD AND a confirmed DMD 
mutation in the dystrophin gene (out of frame deletion or duplication or point mutation); aged 
at least 4 years and under 8 years old at randomization and able to rise independently from 
the floor at that time (see Sections 4.1 and 4.2 for full inclusion and exclusion criteria). The 
age range reflects the population for which advice on corticosteroid treatment is of maximal 
clinical relevance. 
DMD is the most common childhood muscular dystrophy with a birth incidence worldwide of 
1 in 3,500 live male births. It is an X-linked recessive disorder, affecting almost exclusively 
boys. Mutations (mainly deletions) in the dystrophin gene are responsible for the disease. 
There is a high rate of new mutations in the dystrophin gene and in many cases there is no 
prior history of the disease in the family; prevention strategies are therefore not feasible on a 
large scale basis. The natural history of the disease is devastating and currently there is no 
curative treatment. Untreated, boys with DMD become progressively weak during childhood 
and are no longer ambulatory at a mean age of 9 years. Confinement to a wheelchair is 
followed by the development of spinal curvature, respiratory failure and cardiomyopathy. 
Without intervention, the mean age at death is 19 years (Brooke, Fenichel et al. 1983; 
Brooke, Fenichel et al. 1989).  
The progression and complications of DMD are remarkably predictable, with only minor 
variation from child to child. However, interventions designed to modify disease progression 
have slowly made an impact on survival and quality of life in DMD. With the provision of 
home nocturnal ventilation to ameliorate the impact of respiratory failure, survival is now 
common into the late twenties and thirties (Simonds, Muntoni et al. 1998; Eagle, Baudouin et 
al. 2002). Surveillance and early treatment of cardiomyopathy alters the natural history of this 
complication (Eagle, Baudouin et al. 2002; Bushby, Muntoni et al. 2003; Duboc, Meune et al. 
2005). Spinal surgery for scoliosis in addition to these other measures also improves 
survival. The perspective on DMD is therefore changing to recognize that it is a condition 
compatible with survival into adult life (Bushby, Finkel at al. 2010).  
This study will compare three corticosteroid regimens, taken orally in the morning in line with 
normal clinical practice for these drugs: (1) 0.75 mg/kg/day prednisone; (2) 0.75 mg/kg/day 
prednisone 10 days on / 10 days off; and (3) 0.9 mg/kg/day deflazacort. The study treatment 
will last for a minimum of 36 months for all subjects, and a maximum of 60 months for those 
recruited into the trial first and wishing to continue beyond 36 months. The longer duration of 
blinded intervention and follow-up for those subjects recruited early is in anticipation of the 
continued long-term unblinded follow-up of the full cohort of subjects at the end of this 3-5 
year study. 
Corticosteroids are the only pharmacological interventions currently available that increase 
muscle strength in DMD. The use of corticosteroids was first suggested in 1974. A recent 
Cochrane review, ENMC report, and AAN practice parameter identified six randomized 
controlled trials (RCTs) that provided reliable data on the benefit of daily corticosteroids in 
DMD over short periods, using change in muscle strength as the primary outcome measure 
(Bushby, Muntoni et al. 2004; Manzur, Kuntzer et al. 2008; Moxley, Ashwal et al. 2005). Both 
prednisone/prednisolone and deflazacort have been shown to increase muscle strength. 
Prednisone is the formulation of choice for this trial, since it was the more widely used 
formulation in previous trials. Two long-term cohort studies, reporting on the unblinded follow 
up of the children started on treatment in the original RCTs or subsequently, have shown 
substantial long-term functional benefits from the intervention: prolongation of ambulation 
into the mid-teens, reduction in the development of scoliosis, major preservation of 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
18
respiratory function and possible protection against the development of cardiomyopathy 
(Biggar, Gingras et al. 2001; Silversides, Webb et al. 2003; Biggar, Politano et al. 2004; 
Biggar, Harris et al. 2006). 
Since the initial publications on the use of corticosteroids in DMD, concerns about the side 
effects of daily regimens have led to the development of many alternative regimens designed 
either to give a lower dosage of corticosteroids or to allow “steroid holidays”, including, 
regimens that do not use corticosteroids every day. Only one of these latter regimens has 
been tested against placebo, while one other has been tested against daily corticosteroids; 
(Fenichel, Mendell et al. 1991; Sansome, Royston et al. 1993; Backman and Henriksson 
1995; Carter and McDonald 2000; Connolly, Schierbecker et al. 2002; Dubowitz and Kinali 
2002; Kinali, Mercuri et al. 2002; Merlini, Cicognani et al. 2003; Escolar, Hache et al. 2011). 
The long-term outcomes of these regimens are not clear; nevertheless, they are in regular 
and long-term use in clinics around the world. The lack of consistency in practice was 
documented by the ENMC survey of muscular dystrophy clinic physicians from the U.S., 
Canada, and Europe (Bushby, Muntoni et al. 2004): only 3 of 15 centers questioned use 
daily prednisone 0.75 mg/kg/day, 4 do not use corticosteroids at all, and 8 use lower dosage 
or intermittent prednisone or an alternative agent (deflazacort). Inconsistency of dosage was 
seen among and within different countries. It is therefore clear that there is equipoise 
concerning the optimum treatment regimen. If alternative regimens are not as effective as 
daily treatment, boys treated on these regimens may not be getting an adequate dosage. 
Patient and family questionnaires document high levels of frustration with the status quo and 
ask explicitly for more information to be generated to guide practice and inform families 
(Bushby, Muntoni et al. 2004). Despite the publication of consensus statements on this topic, 
patient experience continues to be that widely different corticosteroid regimens remain in use 
(source: PPMD conference July 2006; Griggs, Herr et al. 2013). 
2.2 Supporting Data 
2.2.1 Summary 
The current trial addresses questions that have arisen in the context of five previous 
controlled clinical trials of corticosteroids in DMD conducted by the Collaborative 
Investigation of Duchenne Dystrophy (CIDD) study group (Brooke, Fenichel et al. 1987; 
Fenichel, Florence et al. 1991; Fenichel, Mendell et al. 1991; Griggs, Moxley et al. 1991; 
Griggs, Moxley et al. 1993).  
2.2.2 Short-term effect of prednisone 
2.2.2.1 Muscle strength 
Average strength as ascertained by manual muscle testing was used as a primary outcome 
variable in all six (Beenaker et al. 2005) randomized controlled trials of 
prednisone/deflazacort in DMD. Each of 34 muscles was graded on a ten-point scale using a 
modification of the MRC grading system (Brooke, Fenichel et al. 1983). The scores were 
averaged across the 34 muscles to arrive at the average muscle strength score. This 
outcome variable was highly reproducible and was responsive to the treatment effects of 
prednisone in as little as 10 days (Griggs, Moxley et al. 1991). The relatively short duration of 
treatment in the CIDD studies made the use of functional outcomes, such as cessation of 
ambulation or decline in forced vital capacity, less practical as measures of efficacy, though 
improvement in these parameters was observed in secondary analyses. In the CIDD studies 
of prednisone, strength improvement reached a maximum by three months post intervention 
and was maintained (relative to placebo) at six months and 18 months. Comparison of the 
average muscle strength scores before and after six months of treatment showed a 4.8% 
decrease in the placebo group compared to a 6.7% increase in the 0.75 mg/kg/day 
prednisone group (p < 0.0001) (Fenichel, Mendell et al. 1991; Griggs, Moxley et al. 1991). 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
19
The results of the studies with daily prednisone (0.75 or 1.5 mg/kg/day) for six months 
indicated that treatment increased muscle strength and significantly slowed the progression 
of weakness. Alternate day prednisone was less effective than daily treatment (Fenichel, 
Mendell et al. 1991). A lower dosage of prednisone (0.30 mg/kg/day) was associated with 
significantly less improvement in strength but showed a lower frequency of side effects (e.g., 
weight gain) (Griggs, Moxley et al. 1991). 
2.2.2.2 Functional measures 
Short-term (6 months) CIDD group data included standardized timed function testing: time to 
arise from supine to standing, time to traverse 30 feet, time to climb 4 standard stairs. After 6 
months of treatment, there was a highly significant difference between prednisone and 
placebo for each measure of function. The average time to arise from the floor, from supine 
to standing for the placebo group was 6.17 vs. 4.17 seconds (p<0.0002) for the 
0.75mg/kg/day prednisone treatment group (Mendell, Moxley et al. 1989). Similar data were 
obtained in another trial (Griggs, Moxley et al. 1991). 
2.2.2.3 Forced vital capacity (FVC) 
Short-term (6 months) CIDD data on pulmonary function included standardized 
measurement of FVC. After 6 months of daily prednisone 0.75 mg/kg/day, FVC was 10.5% 
higher in the treated group than in the placebo group (p<0.0004) (Mendell, Moxley et al. 
1989) Nearly identical improvement was noted in another trial (Griggs, Moxley et al. 1991). 
2.2.2.4 Quality of Life 
Data on quality of life are available only from one short-term (six months) randomized 
placebo-controlled, crossover study using intermittent Prednisone 0.75 mg/kg/day for 10 
days per month. The QoL did not change significantly during the prednisone period. With 
every new measurement, however, subjects reported a slightly higher QoL, irrespective of 
given medication, resulting in an improvement in the emotional functioning and the total scale 
(Beenakker, Fock et al., 2005).   
2.2.2.5 Side effects 
Corticosteroids have a well documented range of side effects, not all of which have been 
reported in the DMD population. The most common side effects in the CIDD group 6-18 
month studies were weight gain and cushingoid change in facial appearance. Even with 18 
months of prednisone 0.75 mg/kg/day there was no significant increase in the number of 
subjects with hypertension, diabetes, gastro-intestinal (GI) bleeding, vertebral fractures, or 
cataracts. Behavioral change, acne, and GI complaints were of similar frequency in 
prednisone vs. placebo participants at both 6 and 18 months. Weight gain >20% occurred in 
75% of prednisone-treated boys after 18 months vs. only 43% of placebo-treated boys. 
Longer term, open follow-up (3 years) of CIDD subjects indicated that weight gain remained 
a problem. In addition, asymptomatic cataracts and glycosuria appeared in 11% of subjects 
treated for 3 years (Fenichel, Florence et al. 1991). 
2.2.2.6 Comparisons with deflazacort 
The CIDD group working as part of a U.S./Canadian MD collaborative group compared 
prednisone with deflazacort and placebo for 6 and 12 months of follow-up. Prednisone 0.75 
mg/kg/day and deflazacort 0.9 mg/kg/day had comparable effects on muscle strength, 
muscle function, and FVC. Side effects were less on deflazacort: weight gain (over baseline) 
on prednisone was 26.7% and on deflazacort 6.8 % (statistically significant, p < 0.01). Other 
studies of deflazacort showed similar results, but publication of randomized clinical trial data, 
especially over longer term treatment is lacking (Loftus, Allen et al. 1991; Angelini, Pegoraro 
et al. 1994; Bardare, Bianchi et al. 1994; Markham, Bryson et al. 1995; Reitter 1995; 
Lippuner, Casez et al. 1998; Biggar, Gingras et al. 2001). 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
20
3 
STUDY DESIGN 
3.1 OVERVIEW 
The study is an international, multicentre, randomized, double-blind controlled trial comparing 
three active corticosteroid regimens over three years of treatment: daily prednisone (0.75 
mg/kg/day) versus intermittent prednisone (0.75 mg/kg/day, 10 days on, 10 days off) versus 
daily deflazacort (0.9/mg/kg/day). All three regimens are in common use in boys with 
Duchenne muscular dystrophy. Prednisone is a corticosteroid licensed for use in a wide 
range of conditions. It has been shown to improve muscle function in boys with DMD. 
Prednisone, rather than prednisolone, is the formulation of choice for this trial for consistency 
and comparison with other trial data. Prednisone is not currently licensed for use in DMD and 
will therefore be considered an investigational medicinal product for the purposes of this trial. 
Deflazacort is a glucocorticoid derived from prednisolone, and is licensed in Europe for use 
in a wide range of conditions. Deflazacort is not currently licensed for the indication of 
muscular dystrophy and there has been less exposure of children to deflazacort compared to 
prednisone in clinical trials. Moreover, deflazacort is not approved for any indication in the 
U.S. Therefore for the purposes of this trial it will be considered an investigational medicinal 
product. 
It is anticipated that it will take 3.5 years to enroll all 225 subjects. Those recruited and 
therefore completing the three years of treatment first will have the option to continue study 
medications in a blinded fashion until they have completed 5 years of treatment. Therefore, 
all subjects will receive a minimum of 36 months of study medication and up to a maximum 
of 60 months treatment. This study will determine the relative efficacy and sustainability of 
these regimens over a longer time period than has previously been addressed. 
A unique feature of this trial, designed to make it truly relevant to clinical practice and 
standardized across such a large number of diverse sites, is the consideration given to 
standards of care, which might otherwise impinge on the outcomes of the trial, and the 
provision of clear guidelines to be applied across the trial population for the prophylaxis, 
monitoring and treatment of predictable corticosteroid related side effects / adverse events 
(Bushby K, Finkel R, 2010). 
 
 
3.2 Primary outcome measures 
The primary outcome variable will be a three-dimensional outcome comprising muscle 
function, respiratory function and treatment satisfaction (see below). The average changes 
over all post-baseline assessments during the three year follow-up period will be of primary 
interest.  
3.2.1 Muscle function (time taken to rise from the floor, from supine to 
standing) 
A highly relevant functional endpoint in DMD is loss of independent ambulation, and altering 
the age at which this occurs is a major goal of corticosteroid therapy. However, within the 
Screening 
T-3 
T0 
T36 
T60 
Treatment Period 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
21
three-five year time span of this trial, this milestone will not be reached by most subjects, 
who will be enrolled at age 4-7 years. The time taken to rise from the floor progressively 
deteriorates over time and the ability to rise from the floor is lost before the loss of 
independent ambulation (McDonald, Henricson et al., 2010). The measure of choice is 
therefore a marker of decline in muscle function – the time taken for the subject to rise from 
the floor, from supine to standing, captured as part of the North Star Ambulatory 
Assessment.  
3.2.2 Respiratory function (Forced Vital Capacity – FVC) 
As respiratory failure is a major cause of death in DMD (Phillips, Quinlivan et al. 2001), 
improvement of the course of respiratory function, as measured by forced vital capacity, is a 
marker for potential increase in the time until nocturnal ventilation is required, and indeed of 
longevity and quality of life. Because of the young age of the subjects specific procedures 
have been developed to ensure reliability of measurements and to aid cooperation with the 
test.  Subjects may be sent home with practice aids to help reaching reliability and 
reproducibility of the FVC measures.  Re-test can be performed at any time within the 90-day 
Screening Period. 
3.2.3 Parent/subject satisfaction with treatment (global satisfaction 
rating from the Treatment Satisfaction Questionnaire for 
Medicine (TSQM)) 
Satisfaction with treatment is a patient-centered assessment of outcome, particularly relevant 
to a non-curative therapy applied in a chronic disease. The TSQM (Atkinson, Sinah et al. 
2004) has been validated in chronic disease groups and can determine the subject/parent 
perceived balance of benefit and side effects that may be a major determinant of 
corticosteroid success in DMD. The TSQM is a 14-item instrument, yielding four subscale 
scores: global satisfaction; effectiveness; side effects; and convenience. In this trial, because 
of the young age of the subjects, the parent(s) will complete the TSQM. Feasibility of this as 
a proxy measure has been demonstrated at the University of Rochester (Herr, Hart et al. 
2008).  
3.3 Secondary outcome measures 
The secondary outcome variables will include regimen tolerance, adverse event profile, 
secondary functional outcomes, quality of life, and cardiac function. 
3.3.1 Tolerability 
The key secondary outcome variable (“tolerability”) will be the ability to tolerate the starting 
regimen of corticosteroids, defined as completing 3-5 years of follow-up on study medication 
with no deviation from the initially prescribed dosage level (increases in dosage band to 
accommodate growth and weight gain are allowed).  
3.3.2 Adverse events 
A key factor to be taken into account in determining the most useful steroid regimen is the 
adverse event profile with the different regimens.  
The rates of occurrence and/or severity of the following predictable adverse events (i.e., 
known side effects of corticosteroids) will be recorded. 
 
Behavior problems 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
22
 
Bone fractures  
 
Cataracts  
 
Cushingoid features 
 
GI symptoms 
 
Hypertension 
 
Immune/adrenal suppression 
 
Slow growth (height restriction) 
 
Skin changes 
 
Weight gain 
 
Diabetes 
Areas where side effects prophylaxis and management have been closely prescribed include 
behavior changes, bone health, weight gain, and ocular changes.  
• 
Behavior changes  
A feared but to date poorly quantified side effect of corticosteroids in DMD is altered 
behavior. Behavioral problems are also reported in this group of patients without steroid 
treatment (Hinton, Nereo et al. 2006). Two particular aspects of behavior were identified as 
being particularly important for study in this trial: emotional well being and behaviors within 
the ADHD spectrum. The PARSIII, Iowa Conners scales and Strengths and Difficulties 
Questionnaire (SDQ) will be used to capture and document behavior changes, both negative 
and positive. Moreover, emotional distress will be assessed using the Revised Rutter Scale 
(RRS).  
• 
Bone health 
Long-term corticosteroid treatment has been proven to induce loss of bone mass and to 
increase the rate of fragility fractures even in young patients (Crabtree, Roper et al. 2010). 
Corticosteroids affect bone metabolism and calcium homeostasis, inhibiting of osteoblast 
activity and intestinal calcium absorption, hampering renal handling of calcium, and 
suppressing secretion of gonadal hormones and growth hormone. The net result is an 
increased bone resorption. Concerns about bone health with and without corticosteroid 
treatment in DMD have recently been the subject of three workshops (Biggar, Bachrach et al. 
2005; Quinlivan, Roper et al. 2005; Quinlivan, Shaw et al. 2010). To study the side effects of 
corticosteroid therapy on bone, the changes in bone density (as assessed by DXA scans), 
the frequency of fractures and the changes in bone turnover markers (in serum and urine) 
will be evaluated. For each fracture occurred during the study, the age, site, circumstances, 
treatment and outcome will be recorded.  DXA scans will not be performed at recruiting sites 
in Germany, per local regulations. 
All boys (with the exception of those in Germany) will have a lateral spine x-ray at their 36 
Month visit. An ancillary collaboration with Dr. Leanne Ward (Medical Director of the 
Children’s Hospital of Eastern Ontario - ‘CHEO’ - Bone Health Clinic) and Eric Hoffman, PhD 
(Vice President of Research, ReveraGen BioPharma) will allow for centralized reading of 
vertebral fractures in these de-identified spine images, once all FOR-DMD subject follow-up 
visits have been completed (i.e., upon FOR-DMD trial completion).  Images will be uploaded 
by the study sites into the Ottawa Bone Health Portal - a centralized, password-protected 
database (subjects/families will be asked to provide verbal consent for this via telephone 
conversation with their local FOR-DMD site PI/study staff).  The aim is to use the bone health 
data already collected in FOR-DMD (once published) to ultimately understand the relative 
impact of three difference conventional glucocorticosteroid prescriptions on bone health in 
boys with DMD compared to the novel dissociative steroid, vamorolone.  


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
23
• 
Weight gain 
The most common short and long-term side effect of corticosteroids is weight gain, especially 
in the age-range population recruited in this trial (Mendell, Moxley et al. 1989; Griggs, Moxley 
et al. 1991; Griggs, Moxley et al. 1993). Body weight will be strictly monitored in this trial and 
prophylactic measures have been planned with particular emphasis on advice on appetite 
control around the time that treatment is started. Advice on healthy eating will be reinforced 
at each follow up visit throughout the study.  
• 
Ocular changes 
Recent evidence indicates deflazacort may be more likely to cause cataracts and might also 
cause glaucoma in a larger population of patients.  As a safety measure, and because study 
treatment assignment is blinded such that boys taking deflazacort cannot be identified until 
the entire study has been completed, all boys participating in the FOR-DMD trial will be 
strongly encouraged to have a through eye examination by an ophthalmologist upon their 
completion or withdrawal from the study.  Recommended assessment includes visual acuity, 
intraocular pressure, slit-lamp lens exam and funduscopic exam (cup to disc ratio).   
3.3.3 Secondary functional outcomes and disease milestones  
3.3.3.1 The North Star Ambulatory Assessment (NSAA) 
The NSAA was developed specifically to address the need for a reliable evaluation of motor 
ability in ambulant children with DMD between the ages of 4-7. The starting point was the 
original Hammersmith Scale of Motor Ability (Main, Kairon et al., 2003). The NSAA 
addressed concerns about this scale relating primarily to ceiling effects, grading and lack of 
standardized instructions. In addition clinically meaningful items related to the construct of 
ambulation in DMD boys were selected by a group of expert physiotherapists in DMD taking 
into consideration the natural progression (or potential improvement) of the disease in 
ambulant boys (Scott and Mawson, 2006). The NSAA encompasses the important disease 
milestones such as ability to rise from the floor and ability to walk as well as skills that may 
be achieved or maintained following the use of steroids such as running, walking, hopping, 
jumping and lifting the head from supine. The scoring system reflects the disease specific 
characteristic patterns of movement seen in DMD. Each individual item is scored on an 
ordinal (three point) scale based on key functional activities that accurately reflect the course 
of the disease. Further validation of the scale has taken place in a multicenter study where 
the reliability between evaluators has been shown to be very good (Mazzone ES, Messina S 
et al., 2009). Furthermore recent psychometric evaluation (Rasch analysis) of the scale using 
assessments from 187 ambulant boys with DMD living in the UK has shown that the scale 
measures what it intends to, i.e. its construct validity is good (Mayhew, Cano et al. 2011).  
Rash analysis has shown that the item grades are clinically relevant as well as distinct and 
ordered correctly.  
The NSAA is also a secondary outcome in several international multi-center trials addressing 
the efficacy and safety of new therapeutic approaches (e.g. exon skipping).  
Application of the NSAA will provide the following secondary outcome measures in addition 
to the total score of functional ability: 
 Timed functional tests, comprising time to rise from the floor (a component of the 
primary outcome) and time to traverse (walk/run) 10 meters. Of primary interest will be 
the average value of these outcomes over all post-baseline visits over the three year 
follow-up period. 
 Timed Function Test Grading of the 10 meter walk/run and the timed rising from floor 
will be assessed on a 6 point scale to differentiate those subjects with similarly fast 
times who may achieve a ceiling time.  


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
24
 Documentation of additional motor skills that are not normally present in DMD - i.e., 
percentage of follow-up time over which the child is able to jump, run, hop, step up and 
down, and raise the head from supine. 
The use of the NSAA will also allow us to capture disease milestones 
 Time from randomization to loss of ambulation 
 Time from randomization to loss of the ability to stand from lying 
 Time from randomization to loss of the ability to rise from a chair 
 Time from randomization to loss of the ability to get up and down one step  
 
 
3.3.3.2 6MWT 
The 6 MWT has been specifically adapted for use in patients with DMD and was the primary 
outcome in the phase 2b trial of PTC 124 (McDonald CM, Henricson EK, et al., 2009). The 
6MWT will provide a measure of walking endurance compatible with daily life walking activity.  
 
3.3.3.3 Range of motion (goniometry) 
Many of the physiotherapeutic interventions relate to prevention of contractures particularly 
at the ankle joint. Documentation of range of motion at the ankle joint will ensure consistency 
of physiotherapy interventions in accordance with prescribed physiotherapy intervention and 
advice. Range of motion at the ankle joint will be measured with a standard goniometer. 
Training will be given and specific detailed instructions are included in the manual of 
operations. 
 
3.3.4 Quality of Life 
An additional domain of the secondary outcome measures for the trial will be quality of life. 
Most previous trials of corticosteroids in DMD have not included this element of treatment 
impact.  
The PedsQL (Varni, Seid et al. 1999; Varni, Seid et al. 2001; Varni, Seid et al. 2002) is a 
modular measure for which a neuromuscular disease-specific module has recently been 
developed. Both the generic core module of the PedsQL and the disease-specific fatigue 
module will be used. The generic core module comprises 23 questions and the NMD-specific 
module comprises an additional 25 questions.  
Quality of life will be measured both by child self-report (only in children aged 5 years and 
over, who have the required levels of literacy and intellectual capacity to respond) and by 
proxy (parent(s)/guardian(s)) report for all children. The average values of these outcomes 
over all post-baseline assessments during the three year follow-up period will be of primary 
interest. 
 
3.3.5 Cardiac function 
It has been established that even in this young age group of boys with DMD, there is a 
recognizable incidence of cardiomyopathy detectable on echocardiography and early 
treatment is indicated to slow its progression (Bushby, Muntoni et al. 2003; Duboc, Meune et 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
25
al. 2005). In this young population, earliest definite, echo detectable impairment of left 
ventricular function is defined as ejection fraction < 55% and/or fractional shortening < 28%. 
In the long term, the use of corticosteroid may have a cardio-protective effect (Silversides, 
Webb et al. 2003; Markham, Spicer et al. 2005). Cardiac status will be monitored by trans-
thoracic echocardiogram and 12-lead ECG at screening and every two years to the age of 10 
years, and annually thereafter, according to published guidelines (Bushby, Muntoni et al. 
2003); Bushby, Finkel et al. 2010) If echocardiogram shows any impaired left ventricular 
function and/or or evidence of regional motion abnormalities (posterior wall), the interval 
between evaluations will be reduced and adequate treatment will be initiated if indicated 
accordingly with guidelines/standards of care.  
 
3.4 Definition of end of study 
The end of the study will be 30 days after the point at which the last enrolled subject 
completes the 36 month treatment period.  


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
26
4 
SELECTION AND ENROLLMENT OF SUBJECTS 
4.1 Inclusion criteria 
1) Evidence of signed and dated informed consent form indicating that the subject and 
his parents or guardian (according to local legislation) have been informed about all 
pertinent aspects of the study. The child might be asked to give his assent, possibly 
in writing, if considered intellectually capable, in line with the legal requirements in the 
participating countries and with the permission of the parent(s)/guardian(s). 
2) Confirmed diagnosis of Duchenne muscular dystrophy defined as: Male with clinical 
signs compatible with DMD AND a confirmed DMD mutation in the dystrophin gene 
(deletion/duplication of one or more exons, that are predicted as 'out-of-frame', or 
other mutations that are expected to preclude production of the dystrophin protein 
(i.e. nonsense mutation, deletion/duplication leading to a downstream stop codon))    
3) Age ≥ 4 years and < 8 years at time of randomization. 
4) Ability to rise independently from floor, from supine to standing, as assessed at 
screening visit. 
5) Willingness and ability to comply with scheduled visits, drug administration plan and 
study procedures (including laboratory tests, NSAA, 6MWT, ECG, Echo, wrist X-Ray, 
DXA, PedsQL and TSQM questionnaires) as assessed by the site investigator at the 
end of the screening period.  
6) Ability to maintain reproducible FVC measurements. Boys must have reproducible 
measurements of FVC. The boy will be observed to insure complete understanding of 
the instructions and that he has given maximal effort. If the values continue to 
increase, the boy may be learning and testing will continue, if necessary, beyond the 
3 required trials until the boy reaches a plateau. To ensure the boy is capable of 
performing a reliable FVC, a SECOND FVC must be completed at the end of all other 
assessments at the Screening visit. To be eligible for randomization, there must be 
no more than a 20% difference between the best FVCs on the first and the second 
attempts. Additional FVC information is provided in the Clinical Evaluator Manual. 
 
4.2 Exclusion criteria 
1) History of major renal or hepatic impairment, immunosuppression or other 
contraindications to corticosteroid therapy. 
2) History of chronic systemic fungal or viral infections. Acute bacterial infection 
(including TB) would exclude from enrolment until the infection had been 
appropriately treated and resolved.  
3) Diabetes mellitus. 
4) Idiopathic hypercalcuria.  
5) Lack of chicken pox immunity (as demonstrated by absence of antibodies via titer) 
and refusal to undergo no more than two separate immunizations (should initial 
immunization fail to produce antibodies). 
6) Evidence of symptomatic cardiomyopathy at screening assessment. Asymptomatic 
cardiac abnormality on investigation would not be an exclusion. 
7) Current or previous treatment (greater than four consecutive weeks of oral therapy) 
with corticosteroids or other immunosuppressive treatments for DMD or other 
recurrent indications (e.g., asthma). 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
27
8) Inability to take tablets, as assessed by the site investigator by the end of the 
screening period. 
9) Allergy/sensitivity to study drugs or their formulations including lactose and/or sucrose 
intolerance. 
10) Severe behavioral problems, including severe autism. 
11) Previous or ongoing medical condition, medical history, physical findings or laboratory 
abnormalities that could affect safety, make it unlikely that treatment and follow up will 
be correctly completed or impair the assessment of study results, in the judgment of 
the site investigator.  
12) Weight of less than 13 kilograms. 
13) Exposure to any investigational drug currently or within 3 months prior to start of 
study treatment, unless exposure to investigational drug is a result of participation in 
a clinical trial that has a concurrent participation in FOR-DMD agreement in place. 
 
4.3 Study enrollment procedures 
4.3.1 Identification and recruitment methods 
All of the centers participating in the trial are referral centers for the diagnosis and 
management of DMD and other pediatric neuromuscular disorders and are responsible for 
the diagnosis of DMD within a specific geographical/population area. All subjects fulfilling the 
age and diagnostic criteria will be identified either at diagnosis or through investigators’ 
clinical databases, national and international registries or referrals, and potential eligibility for 
the study will be determined by reference to the inclusion and exclusion criteria (Sections 
4.1. and 4.2 above) in so far as these are documented in the child’s medical records. Those 
children appearing to meet study eligibility criteria based on the pre-screening review will be 
invited to attend for a screening visit. In advance of this visit, parents/guardians will be 
provided with written information about the trial in the local language (or a translation 
appropriate to their linguistic needs). This will be supported by information from local patient 
information groups who will be involved in publicizing the trial, where available. The trial 
information will be provided in a format for both parents (or guardians) and the boys 
themselves (at their parents’ or guardians’ discretion). This information will be supplied 
sufficiently far in advance of the screening visit, to allow parents/ guardians time to read and 
discuss the material with family members and health professionals, as desired. The 
opportunity to discuss the trial with a member of the study team will be also given (contact 
details will be provided with the study information sheets).  
4.3.2 Consent and assent procedures 
At the screening visit, the parent(s)/guardian(s) (with legal authority to consent on behalf of 
the child) and the child (at the discretion of the parents/guardians) will be given the 
opportunity to discuss the study with site personnel and to have any questions about the 
study answered. Only after their questions and concerns have been adequately addressed 
will their informed consent be sought. Consent and assent documents will be provided in the 
local language (or a translation appropriate to their linguistic needs). The procedure for 
obtaining informed consent and assent (e.g., whether one or both parents must provide 
consent) will be in line with the legal requirements in the participating countries; full details 
are given in the Manual of Operations. The consent form will be signed and dated by the 
parent(s)/guardian(s) and by the site Principal Investigator (or other member of the site 
investigation team who has been formally delegated this role – see the Manual of 
Operations). An original and two copies of the completed consent form will be made: one 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
28
copy to be given to the parent(s)/ guardian(s) along with a copy of the trial information sheet; 
the original will be filed in the Site Study File; one copy will be filed in the child’s general 
medical records.  
Where the child is intellectually capable of assenting (and in accordance with local 
regulations), and with the permission of the parent(s)/ guardian(s), the assent of the child 
himself will also be obtained, if possible in writing, copied and filed as for the consent form.  
 
4.3.3 Documentation of outcomes of screening procedure 
At the screening visit, subjects will be recruited following the provision of informed consent 
and assent (as described in Section 4.3.2). Since the assessment of eligibility may require 
the performance of procedures that are not part of normal clinical practice, informed consent 
will be sought prior to performing any study-related screening procedures. Eligibility of the 
child will then be re-assessed with reference to the inclusion and exclusion criteria (see 
Sections 4.1 and 4.2 above). For some of the criteria, a screening period of between 1 and 3 
months will be required (e.g., to assess bone and cardiac status, compliance with 
evaluations and trial medication, and screening for prior exposure to chicken pox or 
immunization). [For further details of screening visit assessments, see Section 6 below and 
the Manual of Operations.]  
Following consent procedures, the CRF 01 will begin to be completed by the site personnel, 
providing the following information: 
- 
Subject identification number 
- 
Subject initials 
- 
Subject date of birth 
- 
Date of screening (visit 1) 
The subject study ID number is 8 characters, 5 characters are given to the site number and 3 
characters for the subject number. The subject number at screening is preceded by S (6th 
character of full Study ID number) followed by 2 numbers (01-99) (e.g. DEU01S01 for the 
first subject screened at the first site in Germany). [If the subject is randomized the S will 
drop out and be replaced with an R and the 8 characters will be the unique subject 
identification number].  
Following screening procedure, a screening log (CRF00) will be completed by the site study 
coordinator as part of the screening CRFs and transmitted to the MSG Coordination and 
Biostatistics Centers (Rochester) via a web-based system with user name and password 
access to maintain a central screening monitor. Upon confirmation of all subject eligibility 
requirements the subject can be randomized and the baseline visit can be arranged. 
Randomization should be completed via the web-based system at least 10 days prior the 
baseline visit in order to allow study drug supply to be shipped to the site in time (see section 
4.3.4 below).  
Subjects deemed to be ineligible may be re-screened if there are any changes in their 
eligibility status.  Screening failures will be also recorded using the screening log, along with 
the reason for each invited child not participating (e.g., did not attend screening visit, 
ineligible due to concomitant illness, unwilling to consent due to preference for one drug 
regimen or other clinical trials or any other exclusion criteria).  
4.3.4 Randomization procedures 
Following consent and confirmation that the child is indeed eligible for the study, the child 
can be randomized into the study. Randomization should be performed at least 10 days prior 
the baseline visit (see Section 6 and the Manual of Operations) and will be achieved via a 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
29
web-based system with user name and password access. Randomization will be stratified by 
country. At the beginning of the trial, the clinical trials supply company will be provided with a 
list of allocations per country, corresponding to this randomization schedule. 
Randomization will require the site investigator, or designee, to verify that the child meets the 
inclusion/exclusion criteria of the study, and to verify that the child has not already been 
randomized. CRF01 (Screening and Randomization Form) must be completed via the web-
based system, so that the system can assign the subject to a treatment group.  
When the site investigator/designee completes the randomization procedures via the web-
based system, an e-mail report with the randomization number, the subject study ID number 
and the starting dose will be generated and sent to the site investigator, to the clinical trials 
supply company, the NCTU, the US Project Manager, and the MSG Coordination and 
Biostatistics Centers (Rochester) confirming enrollment into the trial. Following completion of 
randomization procedures, the subject study ID number will be 8 characters (5 characters 
given to the site number and 2 progressive numbering from 01 to 99 preceded by R which 
replaces the S given at screening) (e.g., DEU01R01). From the baseline visit, this number 
will be the unique subject identification number entered by the site on all subsequent 
worksheets and CRFs.  
The randomization number will be assigned by the web-based system and will be only used 
for study drug supply and shipment. Once the information (randomization number, subject 
identification number and subject weight) have been received and reconciled (by reference to 
the randomization number), the clinical trials supply company will prepare a subject-specific 
kit of medication and ship it to the site (see Section 5.1.2 below). 
Randomization procedures should be completed at least 10 days prior to the baseline visit in 
order to allow study drug supply to be shipped to the site in time to be provided to the subject 
by the site investigator at baseline visit.  
 
4.3.5 Blinding 
To achieve double-blinding, a clinical trials supplies company will manufacture identical 
tablets of prednisone and deflazacort, and matched placebo (to maintain blinding in the 10 
days off period, for the intermittent prednisone regimen). Subjects, parents/guardians, site 
investigators and all other site study staff will not know which steroid regimen has been 
assigned and will remain blinded to the identity of the treatment assignment until the subject 
has reached their 36-Month Visit. The only exception to this is if study drug becomes 
temporarily unavailable (expired, compromised, etc.) for a period of more than 21 days, such 
that a subject requires a prescription of prednisone/prednisolone to bridge the gap of study 
drug unavailability and knowledge of who is on the intermittent treatment regime is required 
to ensure the subject’s continued safety.  
After the 36-Month Visit, if the subject desires to transition to a different clinical trial that does 
not allow for concurrent participation in FOR-DMD and for which the subject’s treatment 
regimen must be known for inclusion, the FOR-DMD treatment blind will be broken.  
Furthermore if, after the 36-Month Visit, it is clinically warranted, the treatment blind will be 
broken.  If the blind is broken for either of the reasons previously stated, the treatment 
regimen will be shared on a “need-to-know” basis only.  The subject/family will be informed, 
and the site PI (if necessary), but the blind will be maintained for all other study staff.  
Additionally, the subject/family will be asked to not reveal their FOR-DMD treatment regimen 
with other members in the DMD community, either verbally or via social networking.  Prior to 
completion of the Month 36 visit, the FOR-DMD treatment regimen will not be revealed to 
subjects/families, site investigators, or study staff unless warranted in a medical emergency. 
Subjects who have their treatment blind broken at the 36-Month visit (or withdraw from taking 
study medication at any point in the trial), will be asked if they are willing to continue with 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
30
their FOR-DMD visits for follow-up, as per protocol. If they decide to continue receiving 
corticosteroids outside the FOR DMD trial, these can be prescribed by their local clinician as 
per local requirements.  
Subjects electing to remain on blinded treatment after their 36-Month visit and until their 
study completion will have their treatment regimen revealed upon occurrence of the 
following: 1) completion of their 60-Month visit or 2) after data from all subjects have been 
collected and the database has been locked. Once a subject has completed his 60-Month 
visit, the treatment blind will be broken on a “need-to-know” basis only, as described above.  
Families will be asked not to share the treatment regimen with the DMD community or via 
social networking, so as not to potential unblind those still participating in the trial.  Subjects 
or families who subvert the blind should be discontinued from the study. 
4.3.6 Blinding and concurrent participation in other trials 
Due to the longevity of follow-up in the FOR-DMD trial (up to 5 years), it is recognized that 
other trials for Duchenne muscular dystrophy (both investigator-led as well as industry-
sponsored) will likely be initiated during this time period and may vie for subject participation. 
Some of these trials may be particularly appealing should they offer new, investigative 
treatments beyond a corticosteroid regimen.  Nevertheless, for treatments currently under 
study/consideration, concomitant corticosteroid treatment is recommended.   
If a FOR-DMD subject expresses interest in participating in a separate DMD trial, the site 
PI/study staff should notify the FOR-DMD Chief Medical Coordinator (CMC) and the Project 
Manager of the trial/sponsor in question.  The CMC or Project Manager will contact the 
appropriate parties responsible for the other trial to determine if concurrent participation in 
two separate treatment trials would be feasible.  In most cases, the concurrent trial would 
require knowledge of the potential subject’s corticosteroid regimen as an inclusion criterion.  
The FOR-DMD Team will consider sharing a FOR-DMD subject’s treatment regimen (break 
the treatment blind) only if an agreement has been reached with the other trial/sponsor to 
ensure that the unblinded information will remain protected and will in no way be revealed to 
the subject/family or study staff (PI, coordinator, etc.). If an agreement between the FOR-
DMD Team and the specific trial/sponsor is not reached, and the subject chooses to enter 
the separate treatment trial, he will have the option to withdraw from the FOR-DMD study 
drug (following a medically-supervised study drug taper and arrangement for open-label 
treatment) and enter a different trial of his choosing, assuming he meets their eligibility 
requirements.  The FOR-DMD subject will not be unblinded to FOR-DMD treatment regimen 
in order to meet eligibility criteria for another clinical trial (i.e., knowledge of corticosteroid 
regimen) until he has completed his Month 36 visit (3 year).  After this milestone (36-Month 
visit), the subject’s treatment regimen may be revealed if the subject expresses interest in 
another trial and knowledge of current treatment regimen is expressly required for 
participation in the other trial.  In all cases, FOR-DMD subjects will be encouraged to 
continue their semi-annual FOR-DMD visits, if they are willing, regardless of whether they 
continue on FOR-DMD study drug or participate in another trial. 
If the FOR-DMD Team and responsible parties from another DMD treatment trial agree that 
concurrent participation in both trials is feasible, all parties will adhere to a Standard 
Operating Procedure (SOP) regarding the transmission of FOR-DMD subject data (treatment 
regimen, subject ID, mutation type, etc.) (Manual of Operations, Appendix 14).  
Representatives from both FOR-DMD and the other trial will sign off on the SOP.  
Additionally, the FOR-DMD subject/guardian/legal representative will be asked to provide 
separate informed consent, indicating their desire to participate in another trial while 
remaining in FOR-DMD.  The consent form will identify the FOR-DMD data that will be 
shared with the other trial.  A copy of the consent form will be stored in the subject’s FOR-
DMD study file, as well as in the other trial’s subject file. 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
31
5 
STUDY INTERVENTIONS 
5.1 Study Medication 
5.1.1 Study medication administration 
This study compares three active corticosteroid regimens over three years of treatment:  
• 
daily prednisone (0.75 mg/kg/day)  
• 
intermittent prednisone (0.75 mg/kg/day, 10 days on, 10 days off)  
• 
daily deflazacort (0.9 mg/kg/day).  
All regimens will be administered orally, in the morning at home, in line with normal clinical 
practice for the administration of corticosteroids for this indication.  
As indicated above, dosage is a function of the child’s weight. The initial dosage will be 
calculated from the child’s pre-entry weight (assessed at the last screening visit), as per the 
weight bands in Table 5.1. The initial dosage will be adjusted as necessary according to 
weight change at the three-month visit and at each subsequent 6-month follow-up visit. If 
adverse events are encountered, dosage adjustments will be made as per the schedules 
described in Section 5.3 below. Deviation from the expected dosage per weight will be 
recorded as a failure of the initial regimen (tolerability). 
Table 5.1 Weight bands of trial steroid regimens 
Study drug will be presented in 20 day treatment wallets containing 2-6 tablets per day (a 
total of 40 to 120 tablets per wallet) for all regimens depending on the weight band. Weight 
banding for different steroid regimens will be as follows: 
 
Band Weight 
range in kg 
Weight 
used for 
calculation 
of dose per 
kg 
Dose in mg 
based on 
0.75mg/kg 
Prednisone 
Number of 
tablets of 
Prednisone 
(5 mg) for 
this dose 
Dose in mg 
based on 
0.9mg/kg 
Deflazacort 
Number of 
tablets of 
Deflazacort 
(6 mg) for 
this dose 
A 
13-19.9 
13.33kg 
10mg 
2 
12mg 
2 
B 
20-25.9 
20.00kg 
15mg 
3 
18mg 
3 
C 
26-32.9 
26.67kg 
20mg 
4 
24mg 
4 
D 
33-39.9 
33.33kg 
25mg 
5 
30mg 
5 
E 
40+ 
40.00kg 
30mg 
6 
36mg 
6 
Bands represent weight ranges.  
 
Commercial stock prednisone and deflazacort differ from one another in appearance and 
their use would prevent blinding of patients, parents and physicians to the allocated 
treatment. To achieve double-blinding, a clinical trials supplies company will manufacture 
identical tablets of prednisone and deflazacort, and matched placebo (to maintain blinding in 
the 10 days off period, for the intermittent prednisone regimen). This medication will be 
presented in form of tablets for oral administration.  This solution is preferred to over-
encapsulation of commercial stock tablets, as the resulting capsules would be quite large, 
presenting potential difficulties in swallowing for the younger children 
 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
32
Each wallet will be labeled with a single panel variable label in the country specific language.  
Wallets will be packaged into 140-day (for first 2 x 3 months of study participation) or 260-
day supplies (for remainder of study) for shipment purposes, by collation into kits containing 
either 7 cards or 13 cards.  Each kit will be labeled with single panel variable label and an 
instruction sheet in the country specific language. 
It is anticipated that it will take 3.5 years to enroll all 225 subjects required for this trial. Those 
recruited and therefore completing the three years of treatment first will have the option to 
continue study medications in a blinded fashion until they complete their 5-year visit. 
Therefore all subjects will receive a minimum of 36 months of study medication and up to a 
maximum of 60 months blinded treatment, unless premature discontinuation or withdrawal 
occurs.  
Each enrolled subject will receive between 7 dispensing (subject recruited late in year 3) and 
11 dispensing (subjects recruited at the beginning of year 1). Subjects recruited in the 1st 
quarter of year 1 will receive 2 x 140 days’ supply (months 1-3 and 4-6) and 9 x 260 days 
supplies (months 7-12, 13-18, 19-24, 25-30, 31-36, 37-42, 43-48, 49-54, 55-60) and so on. 
At the end of the study (30 days after the last enrolled subject has completed the 36 months 
of treatment period), subjects and their families may be asked if they would be willing to 
provide new informed consent to participate in a 5 year follow up study.  
5.1.2 Interruption to study medication supply 
If FOR-DMD study drug becomes unavailable to subjects for any reason (expiration, lost or 
compromised in some way, etc.), safety procedures should be followed to ensure an 
uninterrupted supply of corticosteroid treatment for subjects until replacement FOR-DMD 
study drug is provided.  At no time should subjects take expired or compromised FOR-DMD 
study drug. 
Upon notification that a subject’s study drug is unavailable, the site investigator should 
prescribe (or arrange for provision of) daily prednisone or prednisolone (depending on the 
formulation available in their country) until the new study drug supply is provided to the 
subject.  Dosage for each subject will be equivalent to the dosage of FOR-DMD study drug 
the subject is currently taking (based on weight band).  This action should be documented in 
the subject study binder. 
To ensure subjects do not take expired/compromised FOR-DMD study drug, site study staff 
(PI, coordinator, study nurse, etc.) will telephone FOR-DMD families to ensure that the boys 
are taking the prescribed prednisone/prednisolone daily and will arrange for the prompt 
return of the expired/compromised study drug (this should be documented in the subject 
binder).  Expired/compromised drug should be returned to the study site for reconciliation 
and destruction.  Should a family not comply with timely (within 7 days of compromise) return 
of expired/compromised study drug, a registered letter should be sent to the family address 
on record, requesting return of the product. 
The choice of daily prednisone/prednisolone is based on two main factors: 
●It is available in all participating countries (unlike deflazacort) 
●Daily dosing is a safer choice for all subjects (as opposed to the intermittent, 10-day on/10-
day off regimen), as it does not put participants at an increased risk of adrenal suppression  
 
Safety Issues 
Children taking corticosteroids, whether daily or intermittently, for longer than six weeks will 
have adrenal suppression and be at risk of adrenal crisis.  This is an issue with all children, 
whether on the FOR-DMD protocol or undergoing usual clinical care. 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
33
For the 2/3 of FOR-DMD subjects randomly assigned to the (blinded) daily prednisone or 
daily deflazacort regime, there are no safety concerns associated with starting a daily 
prednisone/prednisolone regimen or with resuming FOR-DMD study drug, as appropriate 
doses of daily prednisone/prednisolone will be prescribed during the interval when FOR-
DMD study drug is unavailable.  When the new supply of FOR-DMD study drug is provided, 
subjects will switch back to their FOR-DMD drug wallets (Day 1) with no taper of the daily 
prescribed prednisone/prednisolone required. 
The remaining 1/3 of FOR-DMD subjects assigned to the intermittent dosing regimen will 
switch to daily prednisone/prednisolone while study drug is temporarily unavailable and then 
will need to switch back to the intermittent study drug regime after a period of daily 
administration.  This might put subjects at a potentially increased risk of adrenal crisis as 
they will have a period without corticosteroid treatment for 10 days at some point after 
resuming FOR-DMD study drug. 
Both clinical and biochemical evidence of adrenal suppression has been well described in 
children following discontinuation of therapeutic doses of systemic corticosteroids.1-4 Adrenal 
suppression has been demonstrated in children and adults exposed to courses as short as 5 
days, however resolution after short courses typically takes less than 2 weeks.5,6  
Biochemical evidence of adrenal suppression following acute lymphocytic leukaemia 
induction therapy has been demonstrated in the majority of children immediately following 
one month of supra-physiological corticosteroids with recovery by 2 weeks in many, and 
ongoing suppression for up to 34 weeks in a subset.7  A recent study of paediatric 
rheumatology patients who had received corticosteroids for a median duration of 40 weeks 
reported adrenal suppression in over 50% of patients, with time to recovery lasting beyond 7 
months in half and up to 1-2 years in some.8 Other studies have demonstrated duration of 
adrenal suppression beyond 18 months.9 Adrenal crisis and death in addition to milder signs 
and symptoms of adrenal insufficiency are well documented in individuals with adrenal 
suppression related to systemic glucocorticoid therapy.3,10-12  Risk factors for the 
development of symptomatic adrenal suppression in children receiving systemic 
corticosteroids remain unclear, however higher dose, longer duration and timing of 
administration of corticosteroids (evening >morning) are theoretical risks.13,14 
There is little evidence available in children who are on chronic high doses of systemic 
corticosteroids and tapering, although current guidance is that if the child has been on 
chronic high dosage steroids for more than 3 weeks then the dosage should be tapered. 
Corticosteroids should be tapered or discontinued at a rate dictated by the underlying 
condition in order to maintain disease remission.  In the case of DMD tapering and lowering 
the dosage below therapeutic levels could be detrimental to the participants in regards to 
motor function. 
The following procedures should be followed in situations where FOR-DMD study drug is 
temporarily unavailable.  In all scenarios below, all subjects will need close monitoring for 
any signs of adrenal suppression (with appropriate management, as noted below).  
 
If FOR-DMD study drug will be resumed within 21 days 
●The subject should begin daily dosage (based on weight band) of prednisone/prednisolone 
the morning after the last dosage of FOR-DMD study drug was taken 
●When the new study drug supply is provided (no later than Day 21), subject should begin a 
new study drug wallet (beginning with “Day 1”) the morning after their last dosage of daily 
prednisone/prednisolone – this applies to ALL subjects, regardless of the FOR-DMD regime 
they are assigned (daily or intermittent) 
 
If FOR-DMD study drug will be resumed after 21 days 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
34
If there is cause to believe that the FOR-DMD study drug will not be made available to the 
subject within 21 days, unblinding to the FOR-DMD treatment regime for subjects assigned 
to the intermittent regime should take place early enough to allow families to receive 
appropriate bridging prescriptions until FOR-DMD study drug is again made available. 
●The subject should begin a daily dosage (based on weight) of prednisone/prednisolone the 
morning after the last dosage of FOR-DMD study drug was taken 
●On Day 22 (or as soon as the blinded regime is revealed) 
 
→If unblinding reveals that the subject was on a daily drug regime, the boy should 
 
continue daily prednisone/prednisolone prescription until FOR-DMD study drug 
 
becomes available. The subject should take FOR-DMD study drug (once available) 
 
beginning on “Day 1” of the wallet, the morning after the last dosage of daily 
 
prednisone/prednisolone was taken 
 
→If unblinding reveals that the subject was on an intermittent drug regime, the boy 
 
should be started on a prescribed intermittent regime of prednisone/prednisolone: 
 
 
○Initial dosing should be 10 days OFF, followed by 10 days of   
 
 
 
prednisone/prednisolone, continuing in this manner until FOR-DMD study drug 
 
 
becomes available (it is important to start with 10 days off to minimize risk of  
 
 
adrenal suppression) 
 
 
○”Day 1” of the FOR-DMD study drug wallet should be started ONLY after the 
 
 
subject has completed a full cycle of ’10 days off and 10 days on’ of   
 
 
prescribed prednisone/prednisolone. The study wallet “Day 1” would then be  
 
 
started after the 10 days of prednisone/prednisolone has finished 
 
Procedures to minimize risk 
●The “I am on Steroids” card should be updated with the current prednisone/prednisolone 
dosage and families provided with guidelines for emergency management of adrenal 
symptoms 
●Stress doses of steroids should be documented for each subject (i.e., “hydrocortisone 30 
mg/m2 in case of emergency”; see guidelines below) 
 
 
 
 
 
  
 
 
 
 
 
 
 
Symptoms of Possible Adrenal Suppression 
Poor linear growth 
Poor weight gain 
Anorexia 
Nausea/vomiting 
Malaise/dizziness 
Weakness/fatigue 
Headache 
Abdominal pain 
Myalgia/arthralgia 
Psychiatric symptoms 
Symptoms of Adrenal Crisis 
Hypotension (low blood pressure) hyponatraemia (low sodium levels), 
Hyperkalaemia (high potassium levels), Hypercalcaemia (high calcium 
levels), metabolic acidosis. 
Hypoglycemia (low blood sugar/seizure/coma) 
Signs and Symptoms Associated with AS 
Cushingoid features 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
35
 
Guidelines 
If a child is unwell, he will need to be reviewed for signs of adrenal suppression and given 
injectable steroids if appropriate. The child’s GP or the study PI involved in the child’s care 
should be contacted for advice. The child/subject may need to attend the Emergency Room 
to be assessed and given appropriate care. 
If a child lives in a remote area that is far away from a hospital, the child may be supplied 
with an injectable form of steroid to use in the event of a vomiting illness (i.e., hydrocortisone 
50-100mg per dose) or oral steroids to use as per the PI's discretion. This will enable families 
to treat potential steroid deficiency while on the way to the hospital or while waiting for help. 
Surgical procedures will require steroid cover –all doctors should be made aware of the fact 
that the child is on steroids. 
In Hospital 
Blood gas, glucose and electrolytes should be measured as a priority. Obtaining blood for 
measurement of cortisol and ACTH should be considered. This is guidance; individual 
hospitals should follow their own SOP for adrenal crisis treatment. 
If the child is hypotensive, 20ml/kg bolus of isotonic saline should be given to restore blood 
pressure. 
If the child is hypoglycaemic, 5ml/kg of 10% dextrose or equivalent should be given, followed 
by a saline/dextrose infusion to prevent recurrence. Fluid shoe administered cautiously 
because patients may be relatively fluid overloaded at presentation. 
Hydrocortisone should then be given in a dose of 50-100mg intravenously or intramuscularly 
(given it works more slowly) every 4 to 6 hours. In children <16kg, a smaller dose of 25mg 
every 4 to 6 hours can be given (or at a dose of 30mg/m2 in divided doses). 
The steroid regimen will need to be reviewed on regular basis although patients can usually 
return to oral medication when they are recovering. 
References 
1. 
Ahmet A, Brienza V, Tran A, et al. Frequency and Duration of Adrenal Suppression 
Following Glucocorticoid Therapy in Children with Rheumatic Diseases. Arthritis Care 
Res (Hoboken) 2016;[Epub ahead of print] Oct 9 2016:doi: 10.1002/acr.23123. 
2. 
Gordijn MS, Rensen N, Gemke RJ, van Dalen EC, Rotteveel J, Kaspers GJ. 
Hypothalamic-pituitary-adrenal 
(HPA) 
axis 
suppression 
after 
treatment 
with 
glucocorticoid therapy for childhood acute lymphoblastic leukaemia. Cochrane 
Database Syst Rev 2015:CD008727. 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
36
3. 
Einaudi S, Bertorello N, Masera N, et al. Adrenal axis function after high-dose steroid 
therapy for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 
2008;50:537-41. 
4. 
Goldbloom E, Ahmet A, Abish S, et al. Adrenal Suppression in the Pediatric Population 
in Canada.  2012 Results Canadian Pediatric Surveillance Program: Canadian 
Pediatric Surveillance Program; 2012:18-20. 
5. 
Zora JA, Zimmerman D, Carey TL, O'Connell EJ, Yunginger JW. Hypothalamic-
pituitary-adrenal axis suppression after short-term, high-dose glucocorticoid therapy 
in children with asthma. J Allergy Clin Immunol 1986;77:9-13. 
6. 
Henzen C, Suter A, Lerch E, Urbinelli R, Schorno XH, Briner VA. Suppression and 
recovery of adrenal response after short-term, high-dose glucocorticoid treatment. 
Lancet 2000;355:542-5. 
 7. 
Shulman DI, Palmert MR, Kemp SF. Adrenal insufficiency: still a cause of morbidity 
and death in childhood. Pediatrics 2007;119:e484-94. 
8. 
Gordijn MS, Rensen N, Gemke RJ, van Dalen EC, Rotteveel J, Kaspers GJ. 
Hypothalamic-pituitary-adrenal 
(HPA) 
axis 
suppression 
after 
treatment 
with 
glucocorticoid therapy for childhood acute lymphoblastic leukaemia. Cochrane 
Database Syst Rev 2015:CD008727. 
9. 
Ahmet A, Brienza V, Tran A, et al. Frequency and Duration of Adrenal Suppression 
Following Glucocorticoid Therapy in Children with Rheumatic Diseases. Arthritis Care 
Res (Hoboken) 2016;[Epub ahead of print] Oct 9 2016:doi: 10.1002/acr.23123 
10. 
Wildi-Runge S, Deladoey J, Belanger C, et al. A search for variables predicting cortisol 
response to low-dose corticotropin stimulation following supraphysiological doses of 
glucocorticoids. J Pediatr 2013;163:484-8. 
11. 
Dinsen S, Baslund B, Klose M, et al. Why glucocorticoid withdrawal may sometimes be 
as dangerous as the treatment itself. Eur J Intern Med 2013;24:714-20. 
12. 
Goldbloom EB, Mokashi A, Cummings EA, et al. Symptomatic adrenal suppression 
among children in Canada. Arch Dis Child 2017;102:338-9. 
13. 
Rix M, Birkebaek NH, Rosthoj S, Clausen N. Clinical impact of corticosteroid-induced 
adrenal suppression during treatment for acute lymphoblastic leukemia in children: a 
prospective observational study using the low-dose adrenocorticotropin test. J Pediatr 
2005;147:645-50. 
14. 
Hawcutt DB, Jorgensen AL, Wallin N, et al. Adrenal responses to a low-dose short 
synacthen test in children with asthma. Clin Endocrinol (Oxf)  2015;82:648-56. 
15. 
Adam HM. Fever and host responses. Pediatr Rev 1996;17:330-1. 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
37
5.1.3 Supply, storage and return of study medication 
At screening, a test packet containing placebo tablets will be provided by the site investigator 
to confirm the child’s ability to swallow tablets. The initial test of swallowing ability will take 
place in the screening clinic, but children will be allowed to take additional placebo tablets 
home to try in a more comfortable environment, if they struggle with the swallowing test in 
clinic.  At the beginning of the trial, the clinical trials supply company will provide each site 
with sufficient test packets for their anticipated recruitment numbers, with sufficient additional 
supplies to allow for a second test packet to be provided to each family if needed. These test 
packets will be stored in a locked cupboard, at normal room temperature. 
At the baseline visit the site investigator, or designee, will explain to parents the use, storage, 
re-supply and return of the study medication.  
Parents will be instructed to store study medication securely at room temperature. An “I am 
on steroids” card (in the local language) will be supplied and parents will be instructed that 
this should be carried at all times, and presented to their child’s health care providers in the 
case of routine treatment or medical emergencies.  The “I am on steroids” card must reflect 
the actual dose of study drug the subject is taking. Therefore, it needs to be updated when 
the subject moves to a different weight band (either up or down) during the study. This card 
should also be updated if study drug becomes temporarily unavailable such that a subject 
transitions to open label prednisone/prednisolone for a period of time. Site study staff will 
receive an electronic notification from the Data Management Team reminding them to update 
the subject’s “I am on Steroids” card when a change in the study drug dose is 
requested..Parents will also be instructed to retain empty study medication wallets and to 
return these, and any unused medication, to the site at each follow-up visit.  
When all entry criteria are met, and at least 10 days prior to the baseline visit subjects will be 
randomized via a web-based system (see Section 4.3.4). The clinical trials supply company 
will receive, by e-mail, notification of allocation, starting dose, country, study randomization 
number and subject identification number directly from the web-based system.  The clinical 
trials supply company will look up the appropriate country -specific list of allocations, to 
identify the regimen to which the child has been allocated. 
A subject-specific drug supply will be produced, labeled (with subject ID number and 
randomization number) and couriered to the pharmacy or clinic (according to local custom) at 
the recruiting site prior to the baseline visit for the subject. At baseline visit, the subject will be 
provided by the site staff with the first study drug supply (i.e. for months 1-3). Study 
medication will be initiated at home on the morning after the baseline visit. The initial drug 
supply will be sufficient (140 days) to allow for the 3-month visit to be carried out by the latest 
date permissible within the visit window (3 months ± 2 weeks from baseline). 
At subsequent follow-up visits (3 and 6 months post-baseline, and the 6-monthly intervals 
thereafter), the need for dosage adjustment will be reviewed by the site investigator, taking 
into account weight gain (which may mandate moving to the next weight band – see Table 
5.1 above) and side effects (which may mandate maintaining dose at the current level, or 
reducing to a lower weight band – see Section 5.3.3 below). The required dosage for the 
next treatment period (3 months for the 3-month visit, 6 months for all subsequent visits) will 
be communicated by the data system to the clinical trials supply company. The new subject-
specific drug supply will be packaged, labeled (as described above) and couriered to the site. 
The site personnel will record the date and number of wallets (7 or 13) received on the Study 
Drug Adherence Record Subjects and will then courier the drug supply to the subject’s home. 
Receipt of the shipment at the subject’s home needs to be confirmed to the site by a phone 
call. If a subject lives in close proximity to the study site and the family is agreeable, they 
may visit the study site to physically pick up the new drug supply.    
Study subjects will continue to take study medication from the previous dispensing until the 
new supplies arrive.  They will also be instructed to complete the wallet in current use at the 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
38
time of receipt of the new supplies, to avoid overdoses in the intermittent regime group. (see 
the Manual of Operation for details).  Subjects should only deviate from this schedule in the 
case of temporary unavailability of FOR-DMD study drug (See Section 5.1.2). 
To allow for slippage on study visit dates (within the permitted visit windows, see Section 
6.2), 140 days supply (i.e., 7 x 20-day wallets) will be provided for Months 1-3 and Months 4-
6. Similarly, for all subsequent 6-month periods, 260 days supply (i.e., 13 x 20-day wallets) 
will be provided. 
Used packaging and unused drug supply must be returned to the site at each visit, where it 
will be counted for adherence assessment. At each visit, the site investigator will provide the 
subject with study medications (from previous subject-specific supply brought to the visit) to 
be continued until the new supply is received at subject’s home. The site personnel will 
record the number of wallets given to the subject on the Study Drug Adherence Form and will 
collect them at the subject’s following visit.     
Study personnel must ensure that study drug supply (prior to handing to family or returned 
unused) is kept in a secure locked area with access limited to authorized personnel until it is 
destroyed. Destruction can be performed at site or can be arranged via the Clinical Trials 
Supplies Company  depending on local facilities.  
Prior to destruction of the study drug sites must ensure that all personal identifiers are 
removed from the wallets (i.e. no subject names should be readable). For GCP, sites will 
also need to provide the study Sponsor with a certificate of destruction from the people 
responsible for this (either the Clinical Trials Supplies Company or the site pharmacy). 
 Study Drug Adherence logs and tracking records will be maintained by each site and the 
clinical trials supply company to ensure accountability for trial supplies at all times. 
 
5.1.4 Adherence Assessment 
Parents/guardians will be required to return all empty and unused drug wallets to the study 
site at each visit. Study staff will assess compliance with trial medication by reviewing the 
wallets and counting the returned tablets. This information will be reported on the Study Drug 
Adherence Log (see the Manual of Operation for details).   
5.1.5 End of treatment period 
For a given subject, study drug will be discontinued after completion of his 60-Month visit or -
if the subject has not yet reached the 60-month visit - after the last enrolled subject 
completes the 36 month treatment period (see the Manual of Operation for details), unless 
the given subject chooses to withdraw from the trial prematurely. If a subject chooses to 
transition to another treatment trial after completion of his 36-month (3 year) FOR-DMD visit, 
the treatment blind may be broken and shared with the subject/family and PI.  The subject 
may then transition to open-label corticosteroids.  Additionally, if a subject has completed his 
36-month visit and the clinical opinion of the PI is that breaking the treatment blind would be 
clinically warranted, then the subject may transition to open-label corticosteroids, if indicated.  
Corticosteroids are available on prescription and therefore at the end of the study treatment 
period subjects can continue to receive corticosteroids as per care recommendation.   
 
 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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5.2 Handling of Study Interventions 
5.2.1 Unblinding 
Every attempt should be made to preserve the integrity of study drug blinding.  Prednisone 
and deflazacort are both corticosteroids with very similar side effect profiles, and therefore 
knowing which of these two drugs a child is receiving will not usually assist the decision 
making process for their management in the case of a medical emergency. All subjects will 
be provided with cards, to be carried at all times, stating “I am taking steroids” (in the local 
language) to be presented to medical staff in the event of routine treatment or a medical 
emergency. Moreover, the maximal dose of steroids that the subject might take according to 
his weight band will be recorded on the card by the site investigator or site staff to further 
reduce the need for unblinding. Information on the card will be reviewed at each study visit 
and updated each time a subject changes weight bands. There will, therefore, rarely be an 
indication for emergency unblinding. Experimental medications can usually be withdrawn 
without the need for unblinding in a subject experiencing an adverse event. Therefore in case 
of an adverse event which requires cessation of study treatment or medical interventions, the 
site investigator should provide adequate and necessary support to the subject without 
unblinding. However, an emergency unblinding procedure will be provided to allow site 
investigators to disclose a treatment assignment for an individual subject if clinical 
circumstances should require this. Each site will be provided with a patient-specific code-
break envelope at the time of patient randomization, to be held in a central and readily 
accessible location at site, and with local Standard Operating Procedures in place for 
accessing and opening these envelopes (see the Manual of Operation for details). We 
expect the need to emergency code-breaks to occur only very rarely; for example, when the 
subject needs emergency surgery and information about all treatment interventions is 
requested. In the exceptional circumstance that knowledge of the study drug assignment 
appears essential for providing appropriate medical management, the site investigator should 
make every effort to contact the chief medical coordinator to discuss the rational for breaking 
the blind. If the site investigator still believes that unblinding is needed, or the chief medical 
coordinator and the study PIs are uncontactable (see the Manual of Operation for details), 
the site investigator will follow the established local SOP for accessing and opening the 
code-break envelope for the subject in question. After breaking the blind, the site staff should 
record details regarding the reasons for breaking the blind and any adverse events leading to 
the unblinding in the subject’s notes, appropriate worksheets and CRF.  Once the blind is 
broken for a given subject, every attempt will be made to keep the subject in the study. If 
desired by the subject and his parents/ guardian(s) and clinically indicated, study medication 
might be continued. Even if the study medication is discontinued, for whatever reason, the 
child may continue to be followed-up in the study as per protocol, i.e., continue attending 6-
monthly visits for evaluations off trial medication. 
If a subject temporarily discontinues treatment due to an emergency but was not unblinded, 
study medication can be restarted (unless clinically contraindicated) and the subject can stay 
in the study.   
Once a subject has completed his 36-month visit (year 3), the treatment blind may be broken 
under the following circumstances: 1) the subject desires to transition to a different treatment 
trial that does not allow for concurrent participation in FOR-DMD and for which the subject’s 
treatment regimen must be known in order to participate in the other trial, OR 2) the FOR-
DMD PI believes knowledge of the FOR-DMD treatment regimen is clinically warranted (See 
Section 4.3.5 and Section 5.1.4, above). 
 
The FOR-DMD subject will not be unblinded to FOR-DMD treatment regimen in order to 
meet eligibility criteria for another clinical trial (i.e., knowledge of corticosteroid regimen) until 
he has completed his Month 36 visit (3 year) unless an agreement is in place to allow 
concurrent participation in both trials.  


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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5.3 Concomitant and supportive care  
5.3.1 Concomitant and supportive care medications 
Any treatment, including prescription and non-prescription drugs, herbal remedies and 
supplements that are taken by the subject during the study period, from screening to the end 
of the study, are considered concomitant medications and need to be collected and 
documented in the concomitant medication CRF page and in the subject’s file by the study 
staff (see the Manual of Operation for details).  
Concomitant treatment with Ataluren (Translarna) is allowed as it is not considered an 
investigational drug. Doses and start date of Ataluren/Translarna need to be recorded in the 
concomitant medication CFR page and in the subject’s file.  
The introduction of or dosage changes in any supportive care medication, and the reasons 
for its use in that subject, must be also reported. 
Use of drugs for concomitant indications should take into account possible interactions with 
corticosteroids (as reported on the Summary of Product Characteristics).  
Live vaccines should not be administered during corticosteroid treatment in accordance with 
the guidelines http://www.cdc.gov/nip/recs/contraindications_vacc.htm) and nonsteroidal anti-
inflammatories should be avoided.  
Use of dietary supplements and “health foods” (i.e. creatine, glutamine, coenzyme Q10) will 
be discouraged though not prohibited. For subjects who are on dietary supplements, a stable 
regimen should be maintained during the whole study. Details of all concomitant medications 
and any supplements in use will be recorded at each visit as concomitant medications. 
Subjects will be instructed about the importance of informing the clinical staff of the use of 
any drugs or remedies.  
5.3.1.1 Calcium and Vitamin D 
Adequate calcium and vitamin D intake is a first line prevention against the effects of long-
term corticosteroid therapy on bone metabolism. Dietary counseling will be provided to 
recommend a daily intake of 1000 mg of calcium with the diet and 400-1000 IU of vitamin D 
with adequate supplements (e.g. cholecalciferol)(Bianchi, Morandi et al. 2011) (See below, 
and the Manual of Operations for details of dietary and Vitamin D supplementation advice). 
Vitamin D deficiency and insufficiency will be treated with higher doses of oral Vitamin D 
supplementation (e.g. cholecalciferol) (See below, and the Manual of Operations for details 
of dietary advice). These recommendations, and the recommendations for bisphosphonate 
therapy in the case of vertebral fractures are in keeping with expert guidelines (Bianchi 2005; 
Quinlivan, Roper et al. 2005).Quinlivan, Shaw et al, 2010). Initiation of any supplement 
should be noted on the concomitant medication log. 
5.3.1.2 Bisphosphonates 
Osteoporosis and fractures, particularly vertebral fractures, are recognized side-effects of 
long-term treatment with corticosteroids. A protocol for the management of bone health is in 
place in this trial; see Section 5.3.2.2.1 below and the Manual of Operations for further 
details. In children in whom vertebral fractures are diagnosed, bisphosphonate therapy (i.e., 
pamidronate, 0.5-1 mg/kg intravenously, every 4 months) will be initiated in consultation with 
a bone specialist.  If bisphosphonate or other bone protection treatments are commenced, 
dose and starting date must be recorded as concomitant medication. 
5.3.1.3 Cardiac health 
A protocol for the management of cardiac health is in place in this trial in keeping with 
published expert guidelines (Bushby, Muntoni et al. 2003); Bushby, Finkel et al. 2010). Drug 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
41
interventions for cardiac events will be as follows, and should be initiated with consultation of 
a cardiologist.  
• 
If left ventricular ejection fraction falls below 55%  or fractional shortening below 28%, 
or regional motion abnormalities (posterior wall) are observed on echocardiogram, in 
the absence of symptoms, angiotensin converting-enzyme inhibitor [ACE] inhibitor 
therapy (e.g., perindopril 2 mg starting dosage) should be recommended. 
• 
If ACE-inhibitor therapy is not tolerated (e.g., because of cough), an angiotensin 
receptor blocker [ARB] (e.g., irbesartan 75 mg starting dosage) should be substituted. 
• 
If cardiac function continues to deteriorate asymptomatically despite the use of ACE 
inhibitor or ARB, the addition of a beta-blocking agent (i.e., bisoprolol 1.25 mg starting 
dosage; or metoprolol 25 mg 12-hourly starting dose; or carvedilol 3.125 mg hourly 
starting dosages; or similar agent) should be considered after optimum titration of ACE-
inhibitor or ARB therapy for the weight of the subject. 
• 
If any subject develops symptomatic left ventricular failure, diuretics (e.g., furosemide 
or bumetanide) and ACE-inhibitors or an ARB should be instituted, if the subject is not 
already taking them. Additional therapies should then be at the discretion of the 
physician in overall clinical charge of the subject. 
If cardiac medications are commenced, dose and starting date must be recorded as 
concomitant medication. 
 
5.3.1.4 Respiratory management 
Accordingly with standards of care, DMD boys should receive 23-valent pneumococcal 
polysaccharide vaccine and annual immunization with trivalent inactivated influenza vaccine. 
Other vaccines might be administered in accordance with country-specific guidelines but live-
vaccine should be avoided (see section 5.3.1 above). During an established infection, 
antibiotics are necessary, irrespective of oxygen saturation if positive evidence of an infection 
is established on culture and irrespective of culture results if pulse oximetry remains below 
95% in room air. Any vaccines administered after enrollment in the trial should be noted as 
concomitant medications.  
 
5.3.1.5 Infectious diseases  
Contact with people with potentially serious infectious diseases, such as measles, 
meningococcal meningitis, etc. should trigger appropriate prophylaxis which may be provided 
by a family physician in line with standard guidelines for children on long term treatment with 
corticosteroids. The site investigator should be notified of all instances of exposure to 
potentially serious infectious diseases. 
5.3.1.6 Trauma or surgical procedure 
Additional steroid cover should be provided following trauma or in the event of elective or 
emergency surgery (see Manual of Operations for details). 
 
5.3.2 Other supportive care interventions 
5.3.2.1 Protocol driven management 
Standard protocols (see the Manual of Operations for details) are in place in this trial for:  
• 
Dietary assessment and advice 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
42
• 
Behavioral assessment and advice 
• 
Physiotherapy assessment and management 
• 
Cardiac surveillance and management 
Interventions mandated by these protocols will be recorded; see the Manual of Operations 
for further details.  
5.3.2.2 Management of predictable adverse events 
Standard protocols (see Section 5.3.3.2 below and the Manual of Operations) are in place for 
the management of side effects of corticosteroid treatment. Specific interventions may be 
required and/or drug dosage may be adjusted, depending on the presence and severity of 
side effects. Details of dosage modifications, in the event of anticipated adverse events, are 
provided in Section 5.3.3.2 below.  
5.3.2.2.1 
Management of bone health  
Prophylactic measures for the management of bone health will include standardized dietary 
advice on calcium intake and adequate vitamin D supplementation (see Manual of 
Operations for details). Limb fractures will be treated with early mobilization. As vertebral 
fractures are often asymptomatic or mildly symptomatic in children with DMD, high suspicion 
should be considered especially following falls. Lateral spinal X-Ray should be performed in 
case of suspected vertebral fracture. Vertebral fractures will be treated with bisphosphonates 
intravenously (see section 5.3.1.2 above). No steroid dosage adjustment is mandated by the 
occurrence of fractures. 
5.3.2.2.2 
Management of cataract development  
The development of asymptomatic or symptomatic cataracts will trigger referral to an 
ophthalmologist for visual acuity measurement and subsequent follow up. No steroid dosage 
adjustment is mandated by the development of asymptomatic cataracts. Symptomatic 
cataracts will be treated as indicated in consultation with a specialist. 
 
5.3.3 Concomitant Interventions 
5.3.3.1 Prohibited Interventions 
During the study period, subjects will be asked not to enroll in other clinical trials without 
consulting the site investigator. The study group will assess other trials enrolling during the 
period of this study and determine on a case-by-case basis whether or not enrolment in a 
specific trial may compromise the scientific integrity of this corticosteroid trial (See Section 
4.3.6). However, subjects/parents will be at liberty to discontinue participation in this study if 
they so choose. 
The study protocol must be followed for management of adverse events, study drug dosage 
adjustment and precautionary interventions in order to maintain the integrity of the study and 
of study results (see Manual of Operations for details). Any deviation from the protocol must 
be reported and documented. 
5.3.3.2 Precautionary Interventions 
The default is that subjects will be managed on an increasing dosage of corticosteroids (i.e, 
adjusted upwards for growth) according to weight (see Table 5.1 above), as measured at 
each follow-up visit. In the case of the development of predictable corticosteroid related side 
effects, or if the child has not passed a weight band bounder, dosage can be first maintained 
(that is, not increased for the normal increase in weight). Secondly, the dosage can be 
reduced to the band or (sequentially) bands below the one predicted for weight. Finally, the 
dosage can be stopped altogether (see Manual of Operations for details). 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
43
Lack of acceptability of the study medication to the family for whatever reason (to be 
recorded) will be a further reason for dose alteration/stopping even if the medical indications 
are not met.  However, lack of acceptability of study medication to the family is typically not a 
medical emergency and should not warrant breaking the treatment blind. 
5.3.3.2.1 
Precautionary interventions in the event of behavior changes 
An assessment of behavior, including completion of the PARSIII, Iowa Conners – Parent, 
SDQ and RRS (allowing quantification of the severity of changes) will be made at baseline 
and at all follow-up visits through Month 36. As a prophylactic measure, standardized 
behavioral advice will be provided to all families at the screening visit, at baseline and will be 
reinforced at all follow-up visits (see the Manual of Operations for further details). In the case 
of behavior changes that are noted but are not disruptive to family/school life, behavior 
advice should be reinforced and referral to a child psychologist for support should be 
considered. Where behavior changes are disruptive to family/school life, referral to a child 
psychologist should be considered and the following dosage adjustments and other 
interventions will be implemented: 
• 
Steroid dosage not to be increased for weight if behavior changes persist despite 
behavioral advice.  
• 
Steroid dosage to be reduced to a lower band if there is no improvement or behavior 
changes are disruptive to school/family life, despite not increasing the dosage. 
• 
Steroid dosage to be stopped if there are severe behavior changes or they persist to be 
unacceptable disruption to school/family life. See Section 5.3.3.2.10 below for 
procedures for discontinuation of corticosteroids. 
5.3.3.2.2 
Precautionary interventions in the event of the development of Cushingoid 
appearance 
At each visit, the child will be assessed for the development of Cushingoid appearance (see 
Manual of Operations for details of assessment). If Cushingoid appearance, unacceptable to 
the child/family develops, dosage adjustment will be as follows: 
• 
Steroid dosage not to be increased for weight. 
• 
Steroid dosage to be reduced to a lower band if Cushingoid appearance, unacceptable 
to the child/family, persists despite not increasing the dosage. 
• 
Steroid dosage to be stopped if Cushingoid appearance, unacceptable to the 
child/family, persists on the lower dosage. See Section 5.3.3.2.10 below for procedures 
for discontinuation of corticosteroids. 
 
5.3.3.2.3 
Precautionary interventions in the event of gastrointestinal symptoms 
(abdominal pain, heartburn, GI bleeding) 
Prophylactic measures will include advice to avoid non-steroidal anti-inflammatory drugs. In 
the event of gastritis/gastroesophageal reflux (GERD) symptoms such as heartburn, 
treatment with Ranitidine (or Proton-pump inhibitors) and antacid should be initiated. If GI 
symptoms persist despite treatment with Ranitidine (or Proton-pump inhibitors) and antacid, 
screening investigations for peptic ulcer disease, including red blood count and faecal occult 
blood testing, should be arranged. Study treatment dosage adjustment will be as follows: 
• 
Steroid dosage not to be increased for weight and screening investigations for peptic 
ulcer disease should be initiated, if symptoms persist regardless treatment with 
Ranitidine (or Proton-pump inhibitors) and antacid. 
• 
Steroid dosage to be reduced to a lower band if screening investigations for peptic 
ulcer disease are negative but GI symptoms cannot be satisfactorily controlled on 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
44
Ranitidine (or Proton-pump inhibitors) and antacid and persist despite not the dosage 
and  
• 
Steroid dosage to be stopped if screening investigations for peptic ulcer disease are 
positive OR GI symptoms cannot be satisfactorily controlled on Ranitidine (or Proton-
pump inhibitors) and antacid and persist on the lower dosage. Referral to a specialist 
should also be arranged. See Section 5.3.3.2.10 below for procedures for 
discontinuation of corticosteroids. 
 
5.3.3.2.4 
Precautionary interventions in the event of glycosuria 
At each visit, a urinalysis will be performed to test for the presence of glycosuria. If glycosuria 
is detected (trace or greater), the urinalysis will be repeated within a week. If the second test 
confirms glycosuria, non-fasting (random) blood glucose should be checked within another 
week. If this too is abnormal, dietary advice should be reinforced and a fasting blood glucose 
test or 2-hour post-prandial test should be performed within 14 days. Further investigations 
(including HgbA1C) might be considered on individual subject based on the clinical judgment 
of the site investigator.  In the event of elevated fasting blood glucose, or elevated post-
prandial blood glucose, dosage modification will be as follows. 
• 
Steroid dosage to be reduced to a lower band in the event of fasting blood sugar > 110 
(6.1 mmol/L) and < 126 mg/dl (7 mmol/L), or blood glucose two hours after a meal > 
140 (7.7 mmol/L) and < 200 mg/dl (11.1 mmol/L) after dietary modification. 
• 
Steroid dosage to be stopped in the event of the development of diabetes mellitus as 
defined by fasting blood sugar > 126mg/dl (7mmol/L) or blood glucose 2 hours after a 
meal > 200mg/dl (11.1 mmol/L). See Section 5.3.3.2.10 below for procedures for 
discontinuation of corticosteroids. 
5.3.3.2.5 
Precautionary interventions in the event of hypertension (blood pressure 
elevation compared to age norms) 
Blood pressure will be assessed at each visit and compared to age norms. Prophylactic 
measures will include standardized advice about dietary sodium intake. In the event of high-
normal blood pressure (i.e., blood pressure in 90-99th centiles – see Manual of Operations for 
centile charts), the measurement will be repeated in a non-stress environment. Dietary 
recommendations (weight /sodium reduction) will be reinforced if high-normal blood pressure 
is persistent. In the event of confirmed hypertension (consistent and confirmed blood 
pressure equal to or above the 95th centile- see Manual of Operations for centile charts), 
repeat measurements will be made in a non-stress environment, on at least three separate 
visits, separated by 7 days apart or less if symptomatic. If there is continued evidence of 
significant hypertension on these repeat measurements, the child will be placed on a low 
sodium diet for 1 month (see MOO). Further investigations might be considered on individual 
subject based on the clinical judgment of the site investigator. If blood pressure is still 
elevated at repeat measurements after 1 month on low sodium diet, the following dosage 
adjustments will be made.  
• 
Steroid dosage to be reduced to a lower band in the event of a consistent increase in 
systolic blood pressure of 5 mmHg over the 99th percentile or in diastolic blood 
pressure of 10 mmHg over the 99th percentile for age after sodium restriction. A night-
time ACE-inhibitor should be added. If ACE-inhibitor therapy is not tolerated (e.g., 
because of cough), an angiotensin receptor blocker [ARB] (e.g., irbesartan 75 mg 
starting dosage) should be substituted. 
• 
Steroid dosage to be stopped in the event of confirmed hypertension, defined as an 
increase in systolic blood pressure of 5 mmHg over the 99th percentile or in diastolic 
blood pressure by 10mmHg over the 99th percentile for age despite treatment. See 
Section 5.3.3.2.10 below for procedures for discontinuation of corticosteroids. If 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
45
hypertension persists despite stopping steroid treatment, referral to a specialist should 
also be arranged to exclude other possible causes of hypertension.  
5.3.3.2.6 
Precautionary interventions in the event of immune/adrenal suppression 
Prophylactic measures against immune/adrenal suppression include: ensuring prior 
exposure to chicken pox/immunization (see Sections 4.2 and 6.2.1.1); tuberculosis 
prophylaxis according to local population guidelines in ‘at risk’ subjects; advice on promptly 
addressing minor infection; advice on corticosteroid cover in the case of illness, injury or 
surgery (see Section 5.3.1.6 above); guidelines regarding progressive reduction of steroids if 
discontinuation is required; disallowing live vaccines during treatment (see Section 5.3.3.1 
above).  
In the event of unusual infections or unusual responses to infection, initially there will be no 
steroid dosage modification. An unusually high frequency of infections/unusual organisms 
should prompt the seeking of advice from an immunology expert and steroid dosage 
adjustment as follows: 
• Steroid dosage not to be increased for weight. 
• Steroid dosage to be reduced to a lower band if an unusually high frequency of 
infections/unusual organisms persists despite not increasing the dosage. 
• Steroid dosage to be stopped if an unusually high frequency of infections/unusual 
organisms persists on the lower dosage. See Section 5.3.3.2.10 below for 
procedures for discontinuation of corticosteroids. 
5.3.3.2.7 
Precautionary interventions in the event of skin changes 
At each visit, an examination of the skin will be carried out. In the event of skin infections or 
acne, the condition will be treated as indicated, and there will normally be no steroid dosage 
modification. If skin changes (striae, acne, hypertrichosis) are unacceptable to the 
child/family dosage adjustment will be as follows: 
• 
Steroid dosage not to be increased for weight. 
• 
Steroid dosage to be reduced to a lower band if skin changes, unacceptable to the 
child/family persist despite not increasing the dosage. 
• 
Steroid dosage to be stopped if skin changes unacceptable to the child/family persist 
on the lower dosage. See Section 5.3.3.2.10 below for procedures for discontinuation 
of corticosteroids. 
5.3.3.2.8 
Precautionary interventions in the event of slow growth (height restriction) 
Height will be measured at each visit. If the change in height velocity consistent with 
predicted percentiles and pre-treatment height velocity, no steroid dosage modification will 
be required. If there is a failure to gain height, but this is not a cause of concern to 
child/family, no steroid dosage modification will be required. If a failure to gain height is 
observed and is unacceptable to child/family, dosage adjustment will be as follows: 
• 
Steroid dosage not to be increased for weight. 
• 
Steroid dosage to be reduced to a lower band if failure to gain height, unacceptable to 
the child/family, persists despite not increasing the dosage. 
• 
Steroid dosage to be stopped if failure to gain height unacceptable to the child/family 
persists on a lower dosage. See Section 5.3.3.2.10 below for procedures for 
discontinuation of corticosteroids. 
5.3.3.2.9 
Precautionary interventions in the event of (excessive) weight gain 
Weight will be measured at all visits and BMI (weight kg / height m2) calculated. Weight gain 
is a known side effect of corticosteroids. Prophylactic measures against undesirable weight 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
46
gain will include standardized dietary advice at screening, at the baseline visit and at all 
follow-up appointments (see Manual of Operations) with particular emphasis on advice on 
appetite control around the time that corticosteroids are started. Dosage adjustment will be 
as follows: 
• 
Steroid dosage not to be increased for weight in the event of annual weight gain > 1 
and < 4 BMI units for subjects younger than 10 years, and of annual weight gain > 2 
and < 4 BMI units for subjects older than 10 or if weight gain is unacceptable to the 
child/ family despite intervention. Dietetic advice will be reinforced. 
• 
Steroid dosage to be reduced to a lower band in the event of annual weight gain ≥ 4 
BMI units, despite dietary modifications or if weight gain is unacceptable to the child/ 
family despite intervention. 
• 
Steroid dosage to be stopped if weight gain continues despite dosage reduction and/or 
weight gain is unacceptable to the child/ family despite intervention. See Section 
5.3.3.2.10 below for procedures for discontinuation of corticosteroids. 
  
5.3.3.2.10 
Procedures in the event of the need to discontinue corticosteroids 
Study medication should not be stopped suddenly. A tapered reduction in dosage is required 
to avoid risks of adrenal failure. The blinded nature of this study precludes the identification 
of which of the daily doses of tablets are active drug and which are placebo in the intermittent 
regime. Therefore, tapering of drug dosage will be obtained using daily corticosteroids 
(prednisone) on prescription, starting to the equivalent dose of prednisone according to the 
weight band (e.g. band A: 10mg, band B: 15 mg; band C: 20 mg) and progressively reducing 
of 5 mg every 14 days until the dose of 5 mg/day, then 2.5mg/day for 14 days before 
discontinuing study drug (see Manual of Operation for details).  
Example: a boy on band C has to discontinue study drug due to a side effect which is 
unacceptable for the child and the family. Prednisone should be prescribed for the tapering 
and study drug discontinued. The initial dose of prednisone will be 15 mg/day for 14 days, 
followed by 10 mg/day for 14 days, than 5 mg/day for 14 days and then 2.5 mg/day for other 
14 days and then discontinued. 
Parents/guardians and the subject’s physician have to be informed that risk of adrenal failure 
persists for months following discontinuation of steroids. Particular attention has to be given 
to symptoms and signs of adrenal insufficiency, including vomiting, hypotension, 
hypoglycemia, dizziness and altered consciousness. Parents will be instructed to promptly 
contact the child’s physician or the local hospital if these symptoms should occur, for 
adequate advice and treatment.  
A telephone call to the parent(s)/guardian(s) will be made 30 days after the scheduled date 
of stopping study medication to check on any persisting adverse effects of study medication. 
All adverse events possibly due to study medication will be monitored until resolved. 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
47
 
6 
CLINICAL AND LABORATORY EVALUATIONS 
6.1 Schedule of Evaluations 
The schedule of evaluations is shown in Tables 6.1a and 6.1b  
Table 6.1a. Schedule of clinical and laboratory evaluations 
 
Visit  
Screening 
( T-3 to T-
10 Days) 
Baseline 
/ Entry 
(T0) 
Visit 
1 
(T3) 
Visit 
2 
 (T6) 
Visit 
3 
(T12)  
Visit 
4 
(T18) 
Visit 
5 
(T24)  
Visit 
6 
(T30) 
Visit 
7 
(T36)1  
Visit 
8 
(T42) 
Visit 
9 
(T48)  
Visit 
10 
(T54) 
Visit 
11 
(T60) 
Study month 
 
-3 to -10 
Days 
0 
3 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
Baseline data 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion 
criteria 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
Exclusion 
criteria 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TB immunity 
 X 
X2 
 
 
 
 
 
 
 
 
 
 
 
Chicken pox 
immunity 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
Ability to take 
tablets 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
Ability to 
comply with 
key study 
evaluations 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
Drug supply 
 
 
 
 
 
 
 
 
 
 
 
 
 
Establishment 
of starting drug 
dose 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 X3 
 
 
 
 
 
 
 
 
 
 
 
 
Order trial drug 
X3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review drug 
dosage 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence 
assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug 
Dispensing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinic based 
evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BP and other 
vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
48
Visit  
Screening 
( T-3 to T-
10 Days) 
Baseline 
/ Entry 
(T0) 
Visit 
1 
(T3) 
Visit 
2 
 (T6) 
Visit 
3 
(T12)  
Visit 
4 
(T18) 
Visit 
5 
(T24)  
Visit 
6 
(T30) 
Visit 
7 
(T36)1  
Visit 
8 
(T42) 
Visit 
9 
(T48)  
Visit 
10 
(T54) 
Visit 
11 
(T60) 
Study month 
 
-3 to -10 
Days 
0 
3 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
General 
physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis – 
glucose/  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis – 
urinary calcium 
assessment  
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Urine 
specimen 
collection for 
bone 
metabolites 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
Blood draw for 
hematology 
and chemistry  
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Blood draw for 
25-OH-D  
X 
 
X2 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood draw for 
serum calcium 
metabolites  
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Blood draw  
for bone 
metabolites 
 
X8 
 
 
X 
 
X 
 
X 
 
 
 
 
Blood draw for 
biobanking 
(optional – 
requires 
additional 
consent)  
 
X8 
 
 
X 
 
X 
 
X 
 
 
 
 
Skin 
examination 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eye 
examination4 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Cushingoid 
features 
assessment 
 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Details of 
concomitant 
meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Details of 
adverse 
events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessments 
and advice 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dietary 
assessment 
and advice 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Behavioral 
assessment 
and advice 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physiotherapy 
assessment 
and advice  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
49
Visit  
Screening 
( T-3 to T-
10 Days) 
Baseline 
/ Entry 
(T0) 
Visit 
1 
(T3) 
Visit 
2 
 (T6) 
Visit 
3 
(T12)  
Visit 
4 
(T18) 
Visit 
5 
(T24)  
Visit 
6 
(T30) 
Visit 
7 
(T36)1  
Visit 
8 
(T42) 
Visit 
9 
(T48)  
Visit 
10 
(T54) 
Visit 
11 
(T60) 
Study month 
 
-3 to -10 
Days 
0 
3 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
Functional 
assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
FVC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NSAA 
(includes 
timed rising 
from floor) 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6 MWT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
ROM at ankle 
joint 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Questionnaire 
assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Behavior 
scales (IOWA 
Connors & 
PARS III, 
SDQ, RRS) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
TSQM 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PEDSQoL – 
parent  
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
PEDSQoL – 
child 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Blindedness 
Assessment6 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Investigations  
 
 
 
 
 
 
 
 
 
 
 
 
 
DXA4 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Lateral spine 
X-ray4 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Wrist X-ray4 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Echo4,7 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
ECG4,7 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
1. T36 constitutes the “end of study” visit as it represents 36 months follow up which is the minimum envisaged. If 
a child withdraws from the study prematurely, every attempt should be made to complete the T36 assessments 
2. Repeat evaluation only if indicated from screening investigations 
3. Starting dose, randomization and trial drug ordering will be performed following screening procedures (and 
confirmation of subject’s eligibility) and at least 10 days prior the baseline visit 
4. These evaluations are likely to require a separate visit and may be performed within the allowed time scale so 
that individual appointments are less burdensome for families.  DXA will not be conducted at German sites. 
5. If a child losses the ability to walk independently during the study period, the Egen Klassifikation scale (EK) will 
replace the North Star Ambulatory Assessment 
6. If the subject withdraws from study medication before visit month 36 (T36), blindedness assessment should be 
performed at their first visit after study drug discontinuation  
7.  Echo and ECG at two-year intervals to age 10, then annually according to standard of care. So schedule of 
investigations needs to take into account the subject’s age. 
8.  Blood samples for bone metabolites and biobanking can be collected at baseline OR screening. If collected at 
screening with the other blood samples, the PI MUST ensure that the total dose of blood draw does not exceed 
the recommendation for research purposes (1-1.5ml/kg/day). 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
50
  Table 6.1 b. Between-visit phone calls 
 
Study month 
 
1 
2 
4 
5 
9 
15 
21 
27 
33 
37 
39 
45 
51 
57 
Call1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
The site doctor or the site coordinator will phone calls between visits to monitor adverse events, concomitant 
medications, adherence to regimen, and any subject and parent concerns monthly during the first 6 months 
following baseline visit, then every 3 months through Month 36 
 
6.2 Timing of Evaluations 
6.2.1 Pre-Randomization Evaluations 
6.2.1.1 Screening Period (T-3 to T-10 days) 
The screening visit to determine eligibility will take place a maximum of three months and a 
minimum of 10 days prior to baseline/entry visit. Evaluations should be completed within this 
time frame; according to local facilities, they need not necessarily all take place at one visit. 
The screening will assess: whether the subject meets inclusion criteria and is not ruled out by 
any exclusion criteria, as well as establishing pre-intervention status for comparisons over 
time. Screening procedures will be performed after signed consent/assent form has been 
obtained. 
The screening evaluations will record: 
• 
Demographic details 
• 
Medical history 
• 
Concomitant medications 
• 
Assessment of TB exposure / immunity (in ‘at risk’ children as identified through 
positive family history or at risk community, such as certain immigrant groups) 
• 
Assessment of chickenpox exposure / immunity 
• 
Ability and willingness to take tablets 
• 
Ability and willingness to comply with key study evaluations (FVC, NSAA).  
• 
Willingness and compliance to complete questionnaires (PedsQL and TSQM 
questionnaires). If the subject and or parents/guardians illiterate, outcome measures 
which require reading will be read by study staff to the subject and answers recorded (a 
note to file should be inserted in the subject chart if this is the case).  
• 
Height and weight 
• 
Blood pressure and other vital signs 
• 
General physical examination 
• 
Urinalysis for glycosuria. In the presence of glycosuria and an abnormal blood glucose 
test at the screening assessment, a fasting or 2 hours after a meal blood glucose 
should be obtained. Diabetes mellitus (fasting blood sugar > 126mg/dl or blood glucose 
2 hours after a meal > 200mg/dl) would exclude the child from the trial.  
• 
Urinalysis for urinary calcium assessment (urine calcium, urine creatinine, urine 
calcium/creatinine ratio). Hypercalcuria will be defined as a urine calcium (mg/dL)/ 
urine creatine (mg/dL) ratio >1.5. If hypercalciuria is detected, urinalysis will be 
repeated within a week for confirmation. Idiopathic hypercalcuria would exclude the 
child from the trial.  


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
51
• 
Blood specimen for random glucose, full blood count, urea, creatinine, electrolytes, 
creatine kinase, 25-OH-D, calcium metabolites, triglycerides, cholesterol, LDLs, HDLs, 
gamma-glytamyl transpeptidase (gamma-GT) and conjugated bilirubin. 
• 
Forced vital capacity (FVC) – 2 separate assessments (best of each assessment within 
20% of each other) 
• 
North Star Ambulatory Assessment 
• 
6MWT 
• 
ROM at ankle joint assessment 
• 
Physiotherapy assessment and advice   
• 
Eye examination 
• 
DXA scan (according to local custom and facilities, this may require a separate visit, 
but should be carried out prior to the child starting on study medication).  DXA scan will 
not be collected at German sites 
• 
Wrist X-ray (according to local facilities, this may require a separate visit, but should be 
carried out prior to the child starting on study medication) 
• 
12 lead ECG (according to local facilities, this may require a separate visit, but should 
be carried out prior to the child starting on study medication)  
• 
Echocardiograph (according to local facilities, this may require a separate visit, but 
should be carried out prior to the child starting on study medication) 
 
Once eligibility has been confirmed: 
 
• 
Randomization, establishment of starting drug dosage (number of tablets according for 
body weight) and ordering of trial supplies (to be completed at least 10 days before 
baseline visit) 
 
6.2.1.2 Baseline / Study Entry (T0) 
The baseline / study entry visit(s) will take place not more than three months and a minimum 
of 10 days after the screening/pre-entry visit. Evaluations should be completed within this 
time frame; according to local facilities, they need not necessarily all take place at one visit. 
The baseline / study entry evaluations will include:  
• 
Confirmation of eligibility criteria (review of inclusion and exclusion criteria) 
• 
Confirmation of ability and willingness to take tablets 
• 
Confirmation of ability and willingness to comply with key study evaluations (FVC, 
NSAA, questionnaires). If the subject and or parents /guardians illiterate, outcome 
measures which require reading, will be read by study staff to the subject and answers 
recorded (a note to file should be inserted in the subject chart if this is the case).  
• 
Recording of concomitant medications 
• 
Checking of chickenpox immunity (where immunity is unconfirmed at screening)  
• 
Checking of TB immunity(in ‘at risk’ children as identified through a positive family 
history or at risk community, where immunity is unconfirmed at screening) 
• 
Blood specimen for bone metabolites 
• 
Blood specimen for biobanking (optional – requires additional consent)  
• 
Urine specimen collection for bone metabolites 
• 
Height and weight 
• 
Blood pressure and other vital signs 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
52
• 
General physical examination 
• 
Skin examination 
• 
Examination of face and trunk for Cushingoid features 
• 
Urinalysis for glycosuria and presence of red blood cells. In the presence of glycosuria, 
a random blood glucose test should be performed. If this too is abnormal, a fasting 
blood glucose or 2 hours after a meal should be obtained before proceeding with 
randomization. Diabetes mellitus (fasting blood sugar > 126mg/dl or blood glucose 2 
hours after a meal > 200mg/dl) would exclude the child from the trial.   
• 
Forced vital capacity 
• 
North Star Ambulatory Assessment  
• 
6MWT 
• 
ROM at ankle joint assessment 
• 
Recording of adverse events 
• 
Administration (parental completion) of behavior scales (PARS III, Iowa Conners – 
Parent, SDQ-Parent, RRS)  
• 
Administration (parental and child completion) of PedsQL 
• 
Dietary assessment and advice  
• 
Behavioral assessment and advice  
• 
Physiotherapy assessment and advice 
• 
Drug dispensing and instruction for parents/guardians  
 
6.2.2 On-Study Evaluations 
The next 2 visits will take place 3 and 6 months post-baseline respectively, with a visit 
window of ± 14 days. Evaluation visits then continue at 6-monthly intervals, with a visit 
window of ± 30 days. Evaluations continue to a minimum of 36 months post-baseline, and up 
to a maximum of 60 months post-baseline, depending on how early in the study the subject 
was randomized and if they wish to continue in the trial beyond the 36-month visit. 
Evaluations need not necessarily all take place at one visit. 
 
6.2.2.1 3-month follow-up visit (Follow-up visit 1 - T3) 
The 3-month follow-up evaluations will comprise:-  
• 
Recording of concomitant medications 
• 
Height and weight  
• 
 
• 
Blood pressure and other vital signs 
• 
General physical examination 
• 
Examination of face and trunk for Cushingoid features  
• 
Blood draw for assessment of 25-OH-D (only in children found to be deficient at 
screening)  
• 
Urinalysis for glycosuria.  
• 
Assessment of forced vital capacity 
• 
North Star Ambulatory Assessment  
• 
6MWT  
• 
ROM at ankle joint assessment 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
53
• 
Administration (parental completion) of behavior scales (PARS III, Iowa Conners – 
Parent, SDQ-Parent, RRS) 
• 
Parental completion of Treatment Satisfaction Questionnaire with Medicine (TSQM) 
• 
Dietary assessment and advice  
• 
Behavioral assessment and advice  
• 
Physiotherapy assessment and advice  
• 
Recording of adverse events 
• 
Review drug dosage and order trial supplies  
• 
Adherence assessment  
• 
Drug dispensing 
 
 
6.2.2.2 Evaluations to be carried out every 6 months, through Month 36 
(Follow-up visits 2 to 7: T6, T12, T18, T24, T30, T36) 
The following evaluations will take place every 6 months up to, and including, Month 36.  
• 
Recording of concomitant medications 
• 
Height and weight 
• 
Blood pressure and other vital signs 
• 
General physical examination 
• 
Examination of face and trunk for Cushingoid features  
• 
Skin examination 
• 
Urinalysis for glycosuria 
• 
Forced vital capacity 
• 
North Star Ambulatory Assessment  
• 
6MWT 
• 
ROM at ankle joint assessment 
• 
Administration (parental completion) of behavior scales (PARS III, Iowa Conners – 
Parent, SDQ-Parent, RRS)  
• 
Parental completion of Treatment Satisfaction Questionnaire with Medicine (TSQM) 
• 
Dietary assessment and advice 
• 
Behavioral assessment and advice  
• 
Physiotherapy assessment and advice 
• 
Recording of adverse events  
• 
Review drug dosage and order trial supplies (not at ‘last visit’) 
• 
Adherence assessment 
• 
Drug dispensing (not at ‘last visit’) 
 
6.2.2.3 Evaluations to be carried out every 6 months, after Month 36 
(Follow-up visits 8 to 11: T42, T48, T54, T60) 
Following completion of the 36-Month visit, the following evaluations will take place every 6 
months for the remainder of the child’s participation in the study.  
• 
Recording of concomitant medications 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
54
• 
Height and weight 
• 
Blood pressure and other vital signs 
• 
General physical examination 
• 
Examination of face and trunk for Cushingoid features  
• 
Skin examination 
• 
Urinalysis for glycosuria 
• 
Forced vital capacity 
• 
North Star Ambulatory Assessment  
• 
Parental completion of Treatment Satisfaction Questionnaire with Medicine (TSQM) 
• 
Behavioral assessment and advice  
• 
Dietary assessment and advice 
• 
Physiotherapy assessment and advice 
• 
Recording of adverse events  
• 
Review drug dosage and order trial supplies (not at ‘last visit’) 
• 
Adherence assessment 
• 
Drug dispensing (not at ‘last visit’) 
 
 
6.2.2.4 Evaluations to be carried out annually (Follow-up visits 3, 5, 7, 9 
and 11: T12, T24, T36, T48, T60) 
In addition to the evaluations to be carried out every 6 months (Section 6.2.2.2, Section 
6.2.2.3 above), the following procedures will take place annually for the duration of the child’s 
participation in the study (procedures no longer completed after Month 36 are noted).  
• 
Eye examination (including a final, thorough exam by an ophthalmologist upon study 
completion or withdrawal) 
• 
*Parental and child completion of PedsQoL (only through Month 36) 
• 
Urinalysis for urinary calcium assessment (urine calcium, urine creatinine, urine 
calcium/creatinine ratio) 
• 
Blood specimen for 25-OH-D 
• 
Urine specimen collection for bone metabolites (only through Month 36) 
• 
Blood specimen for random glucose, full blood count, urea, creatinine, electrolytes, 
creatine kinase, calcium, phosphate, and alkaline phosphatase, triglycerides, 
cholesterol, LDLs, HDLs (only through Month 36) 
• 
Blood specimen for bone metabolites (only through Month 36) 
• 
Blood specimen for biobanking (optional – requires additional consent) 
• 
DXA 
 
6.2.2.5 Evaluations to be carried out every two years, then annually 
(Follow-up visits 5, 7, 9 and 11: T24, T36, T48 & T60) 
Echocardiograph and electrocardiography (12-lead ECG) should be conducted every two 
years until the child reaches the age of 10, annually thereafter, according to Standards of 
Care in DMD. More frequent visits can be arranged if clinically indicated.   
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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6.2.2.6 Evaluations to be carried out at 36 months (Visit 7: T36) 
In addition to the evaluations to be carried out every 6 months (Section 6.2.2.2, Section 
6.2.2.3 above) and annually (Section 6.2.2.3 above), the following evaluations will take place 
at the 36-month visit (Visit 7) in all subjects to yield a consistent post-intervention status for 
comparisons over time. 
• 
Blindedness Assessment  
• 
Lateral spine X-ray 
• 
Wrist X-ray 
• 
Blood specimen for gamma-glytamyl transpeptidase (gamma-GT) and total bilirubin. 
 
6.2.2.7 Between-visit phone calls 
The site coordinator will make phone calls between visits to monitor adverse events, 
concomitant medications, adherence to regimen, and any subject and parent concerns 
monthly (+/- 7 days) during the first 6 months following baseline visit, and every 3 months (+/- 
2 weeks) thereafter through Month 36. 
 
6.2.3 Intervention Discontinuation Evaluations and Post-
Intervention Evaluations 
The study design compares three active corticosteroid regimens over three years of 
treatment. It is anticipated that it will take 3.5 years to enroll all 225 subjects. Those recruited 
and therefore completing the treatment first will have the option to continue their study 
medications in a blinded fashion until they complete their 5-Year visit. Therefore all subjects 
will receive a minimum of 36 months of study medication and up to a maximum of 60 months 
treatment – in other words, the period of study intervention ranges from 36 to 60 months 
post-baseline.  
If trial medication is prematurely stopped at the instigation of the site investigator or family, 
for whatever reason, the child should continue to be followed-up in the study as per protocol, 
i.e., continue attending 6-monthly visits for evaluations off trial medication. The trial 
medication field of the worksheet/CRF should reflect the decision to discontinue trial 
medication. The date and reason for discontinuation should be recorded. Trial medication 
should not be stopped suddenly. A tapered reduction in dosage is required to avoid risks of 
adrenal failure. For details of how to taper dosage, see Section 5.3.3.2.10 above.  
If a child discontinues from both medication and follow-up, a full ‘final visit’ should be 
performed where possible. This will comprise the elements of Visit 7 (T36) and 
recommendation that the boy have a final, thorough eye examination. In the case of 
premature discontinuation from medication and follow-up, a telephone call to the parent(s)/ 
guardian(s) will be made 30 days after the last visit to check on any persisting adverse 
effects of study medication. 
 
6.2.4 Final Evaluations 
Because of the variable duration of participation in the study (36 to 60 months) any visit from 
Visit 7 (T36) to Visit 11 (T60) may represent the ‘final visit’ for a given subject. A thorough eye 
examination by an ophthalmologist will be strongly advised at this final visit for subjects who 
have already completed Visit 7 (T36) or whose designated final visit is Visit 7 (T36). As 
indicated in Section 6.2.3 above, in the case of premature discontinuation from both 
medication and follow-up, a full ‘final visit’ should be performed where possible, including the 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
56
elements of Visit 7 (T36), as described in Section 6.2.2.5 above, if the subject has not already 
had his visit 7.  
A telephone call to the parent(s)/guardian(s) will be made 30 days after the final visit to check 
on any persisting adverse effects of study medication. 
6.3 Special Instructions and Definitions of Evaluations 
 
6.3.1 Informed Consent 
Potentially eligible subjects and their parents or guardians (with legal authority to consent on 
behalf of the child as described in Section 4.3.2 above) will be invited by letter (and by phone 
if considered appropriate) to attend a screening visit. The invitation to attend will include a 
Subject Information Sheet (including a child-friendly version) and contact details of the 
investigator site.  
At the screening visit, the parent(s)/guardian(s) and the child (at the discretion of the 
parent(s)/guardian(s)), will be given the opportunity to discuss the study with site personnel 
and to have any questions about the study answered. Only once their questions and 
concerns have been adequately addressed will their informed consent be sought. The 
procedure for obtaining informed consent (e.g. whether one or both parents must provide 
consent) will be in line with the legal requirements in the participating countries; full details 
are given in the Manual of Operations.  
The consent form will be signed and dated by the parent(s)/ guardian(s) and the site 
Principal Investigator (or other member of the site investigation team who has been formally 
delegated this role – see the Manual of Operations). An original and two copies of the 
completed consent form will be made. One copy of the completed consent form will be given 
to the parent(s)/ guardian(s), along with a copy of the trial information sheet; the original will 
be filed in the subject’s Study File; one copy will be filed in the subject’s general medical 
records.  
Where the child is intellectually capable of assenting, and with the permission of the 
parent(s)/ guardian(s), the assent of the child himself will also be obtained, if possible in 
writing, copied and filed as for the consent.  
At the screening visit, subjects will be recruited following the provision of informed 
consent/assent (as described in Section 4.3.2 above). Since the assessment of eligibility may 
require the performance of procedures that are not part of normal clinical practice, informed 
consent will be sought prior to performing any study-related screening procedures. Eligibility 
of the child will then be re-assessed with reference to the inclusion and exclusion criteria 
(see Sections 4.1 and 4.2 above).  
If any modifications are made to the study that change the content of the information of the 
consent, then the subject and the parent(s)/ guardian(s) will be presented with the new 
information and asked to go through the written consent process again at the next visit. 
6.3.2 Documentation of Duchenne Muscular Dystrophy (DMD) 
All subjects recruited to this study will have a confirmed DMD (defined as male with clinical 
signs compatible with DMD AND confirmed DMD mutation in the dystrophin gene 
(deletion/duplication of one or more exons, that are predicted as 'out-of-frame', or other 
mutations that are expected to preclude production of the dystrophin protein (i.e. nonsense 
mutation, deletion/duplication leading to a downstream stop codon). A written copy of a 
genetic report of this information will be kept in the subject’s study file. 


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6.3.3 Demographic Data  
At the screening visit, basic demographic data will be recorded by reference to the medical 
records and questioning of parent(s)/guardian(s). See the Manual of Operations for details of 
the variables to be recorded. 
6.3.4 Medical History 
At the screening visit, a medical history will be recorded by reference to the medical records 
and questioning of parent(s)/guardian(s). Required details include: family history of DMD, 
diabetes and tuberculosis; birth history; medical history of the child, including any significant 
prior medical conditions and affected organs and systems; allergies and immunization 
history, with particular attention to TB immunity (if the subject has been exposed to risk), 
chicken pox immunity, allergies to corticosteroids and sucrose/lactose intolerance; 
achievement of developmental milestones; fracture history. Particular attention will be paid to 
those variables defining inclusion and exclusion criteria for the trial, and those indicative of 
contra-indications to or suggestive of the need for special precautions in the use of 
corticosteroids. See the Manual of Operations for details of the variables to be recorded.  
 
6.3.5 Treatment History 
At the screening visit, a history of medical and other treatments for DMD will be recorded, by 
reference to the medical records and questioning of parent(s)/guardian(s).  
Current or previous treatment (greater than four consecutive weeks of oral therapy) with 
corticosteroids or other immunosuppressive treatments for DMD (or for other recurrent 
indications, e.g., asthma) will be grounds for excluding the subject from the study. 
Particular attention will be paid on any anti-epileptic drugs as they might have an impact on 
bone mass.  
Details of previous medication for DMD or other medical conditions will be recorded as will 
details of any surgical interventions for DMD-related conditions (e.g. spinal surgery, tendon 
lengthening) and of physiotherapy interventions (e.g. use of splints). See the Manual of 
Operations for further details of the variables to be recorded. Such complications would not 
be expected in this population of 4-7 year old boys with DMD. 
6.3.6 Concomitant Treatments 
At the screening visit and all subsequent visits, details of concomitant medications (for DMD 
and for other conditions) will be recorded. Concomitant medications will include prescribed 
medication, over-the-counter purchases, vitamin supplements, herbal and homeopathic 
remedies. Details to be recorded will include: name of drug (generic name/active ingredients 
of drugs should be recorded, except in case of combination products); indication; start and (if 
applicable) stop dates; dose size; dose frequency. Parent(s)/guardian(s) will be asked to 
bring to the visit all medications in current use, in their packages, to facilitate accurate 
recording of the name and dosage of concomitant medications. See the Manual of 
Operations for further details of how to record this information. 
At the baseline visit and each follow-up visit, details of non-drug concomitant interventions for 
DMD will also be recorded. Standard protocols (see the Manual of Operations for details) are 
provided for dietary, behavioral and physiotherapy assessments and management, and for 
the management of: side effects of corticosteroid treatment, infectious diseases, trauma or 
surgical procedures, bone health, cardiac surveillance and management. Interventions 
mandated by these protocols will be recorded; see the Manual of Operations for further 
details. Orthopedic interventions for contracture management are infrequent in this age 
group. If an orthopedic procedure is performed for a child in the study the purpose and 
outcome will be carefully recorded. In accordance with the Standards of Care (Bushby, 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
58
Finkel et al. 2010) surgical interventions should be performed only after a multidisciplinary 
discussion. The Site Principal investigator should take part in the discussion to preserve the 
integrity of the study.  
Concomitant treatment with Ataluren (Traslarna) is allowed but must be recorded in the 
concomitant medication log with the specific dosage and start date.  
Concomitant participation in another study with investigational drugs might be possible, but it 
must be first discussed with the Chief Medical Coordinator and with the Project Manager. If a 
subject is enrolled in another clinical study, the investigational product should be recorded on 
the concomitant medication log with specification of the study protocol, starting dose and 
dosage.  This information should also be entered on CRF81. 
 
6.3.7 Study Intervention Modifications 
Drug dosage will be determined at least 10 days prior to the baseline/study entry visit, by 
reference to the subject’s weight (see Section 5.1.1 above) in order to allow study drug 
supply to be shipped to the site in time. Drug dosage will be reviewed and, if necessary, 
adjusted at each follow-up visit (Section 5.1.2). Dosage will normally be adjusted upwards for 
weight gain (see Table 5.1 above). The actual weight band and whether an increase has 
been made will be recorded at each follow-up visit. 
If adverse events are encountered, dosage adjustments will be made as per the schedule 
described in Section 5.3. Deviation from the expected dosage per weight will be recorded, 
with an indication of whether this involves holding dosage steady (i.e. not increasing in line 
with the expected dosage per weight) or reducing to a lower weight band.  
6.3.8 Clinical Assessments 
6.3.8.1 Height, weight, BP and other vital signs 
Height, weight, blood pressure and pulse rate will be recorded at screening and all 
subsequent visits. See the Manual of Operations for details of how to take and record these 
measurements. 
6.3.8.2 Physical examination 
A complete physical examination will be recorded at screening and at all subsequent visits. It 
will consist of a medical exam of organs and systems [head, eyes, ears, nose and throat 
(HEENT), lungs (auscultation), cardiovascular (heart auscultation and peripheral pulse), 
abdomen/GI, lymph nodes, musculoskeletal, neurological, spine, genitourinary/renal, skin/ 
mucosa, endocrine and extremities]. See the Manual of Operations for details of how to 
perform and record this examination.  
6.3.8.3 Skin examination 
Skin changes (striae, cutaneous/oral infection, acne, hypertrichosis) will be recorded by 
clinical observation at the baseline / study entry visit and at 6 monthly visits thereafter. See 
the Manual of Operations for details of how to perform and record this examination, and for 
how to manage cutaneous side-effects of corticosteroids. 
6.3.8.4 Eye examination 
An eye examination will be performed by a qualified eye care practitioner/optometrist at 
screening and annually thereafter to exclude cataracts and glaucoma (see the Manual of 
Operations for details of how to record this examination). Any suspicion of cataract will 
indicate referral for visual acuity assessment by an ophthalmologist. A thorough eye 
examination by an ophthalmologist will also be strongly recommended for each boy upon his 
study completion or withdrawal from the trial (see CRF 32). 


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6.3.8.5 Cushingoid signs 
An assessment of Cushingoid appearance (face and trunk) will be made by clinical 
observation at the baseline/study entry visit and at each follow up visit. See the Manual of 
Operations for details of how to perform and record this examination, and for how to manage 
the development of Cushingoid signs. 
6.3.8.6 Pulmonary function 
Forced vital capacity will be measured at the screening visit (to confirm ability to comply with 
this evaluation, as it comprises part of the primary outcome), at the baseline/study entry visit 
and at each follow up visit. At screening, to ensure the boy is capable of performing a reliable 
FVC, a SECOND FVC must be completed at the end of all other screening assessments. To 
be eligible for randomization, there must be no more than a 20% difference between the best 
FVCs on the first and the second attempts.  See the Manual of Operations for details of how 
to perform and record this evaluation. 
6.3.8.7 Assessments of physical function 
The assessment of motor skills (jumping, hopping, ability to lift the head from supine) and 
timed functional tests (time to stand from lying time to traverse 10 meters) will be assessed in 
the context of the North Star Ambulatory Assessment. This will be performed at screening to 
confirm eligibility to participate (by reference to the inclusion criterion of ability to rise 
independently from the floor) and ability to perform the assessment (since time to rise from 
the floor comprises part of the primary outcome).  
Timed Function Test Grading of the 10 meter walk/run and the timed rising from lying will be 
assessed on a 6 point scale to differentiate those subjects with similarly fast times who may 
achieve a ceiling time.  
The 6MWT will provide a measure of walking endurance compatible with daily life walking 
activity. ROM at the ankle joint will be also performed as part of the assessment of physical 
function to ensure consistency of physiotherapy interventions in accordance with prescribed 
physiotherapy intervention and advice. The North Star Ambulatory Assessment (NSAA), time 
functional tests, 6 MWT and ROM of ankle joints will be performed at screening, at the 
baseline/study entry visit and at each follow up visit up to and including Month 36. See the 
Manual of Operations for further details of how to perform and record these evaluations. If a 
subject losses the ability to walk independently during the study period, the Egen 
Klassifikation scale (EK) will replace the North Star Ambulatory Assessment (see the Manual 
of Operations for further details). 
 
The assessment of physical function (including the North Star Ambulatory Assessment, time 
functional tests and the 6MWT) will be video-recorded for quality-control purposes (See the 
Manual of Operation for further details). A separate consent will be obtained for this video-
recording. 
 
 
 
6.3.8.8 DXA scans and lateral spine and wrist X-rays 
Data on bone mass, density and body composition (fat and fat-free mass) will be collected by 
DXA in the screening period (depending on local facilities, this may require an additional visit 
but should be completed prior to starting study medication) and annually thereafter. For 
further details of how to perform and record these evaluations, and the management of bone 
health, please see the Manual of Operations. 
Copy of the DEXA scan should be sent to “Instituto Auxologico Italiano IRCCS, Milano” for 
quality control and future references (see the Manual of Operations for further details).  Site 
staff should provide copies of the DEXA scan to their site monitor during scheduled annual 


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60
visits.  The monitor will then gather the reports from all sites and forward them to the EU or 
North American Project Manager, as appropriate, who will in turn send the reports on to 
Istituto Auxologico Italiano (care Dr Maria Luisa Bianchi). 
Wrist x-rays will be performed in the screening period (depending on local facilities, this may 
require an additional visit but should be completed prior to starting study medication) and the 
36-month visit.  
Vertebral fractures will be recorded in medical history if detected during screening period and 
as adverse events if detected following baseline (see Section 7.1.1 below). A lateral spine X-
Ray will be performed at the 36-month visit to verify absence of asymptomatic vertebral 
fractures. Upon study completion, these spine images will be de-identified and uploaded by 
each site (with the exception of those in Germany) to a secure, password protected database 
for central analysis, provided verbal consent has been granted by the subject/family. 
6.3.8.9 Echocardiogram and ECG 
Cardiac status will be assessed in the screening period (depending on local customs and 
facilities, this may require an additional visit but should be completed prior to starting study 
medication) by standard trans-thoracic echocardiogram and 12-lead electrocardiograph 
(including rhythm strip). Repeat echocardiograms and ECGs will be required every two years 
until the child reaches the age of ten years and annually thereafter or at the onset of cardiac 
signs and symptoms if they occur earlier according with the standard recommendations in 
DMD. Increased cardiac surveillance should be arranged if clinically indicated and if 
abnormalities of left ventricular function are detected on Echocardiogram. These 
assessments will also be performed at the 36-month visit. The ECGs and the 
Echocardiograms must be manually reviewed and interpreted by medically qualified 
personnel. The findings will be categorized as: normal; abnormal but not clinically significant; 
abnormal and clinically significant.  An ECG or Echocardiogram result that is abnormal and 
clinically significant will be recorded in medical history if detected during screening period 
and will be considered as adverse events if detected following baseline (see Section 7.1.1 
below). Adequate management should be initiated if any abnormalities of clinical significance 
will be detected (see section 5.3.1.3). Site staff should provide copies of the ECG to their site 
monitor during scheduled annual visits.  The monitor will then gather the reports from all sites 
and forward them to the University of Rochester (see the Manual of Operations for further 
details) for future references. Echocardiograms on trial subjects must be retained for at least 
five years after study completion in a way that allows them to be readily available for 
independent re-evaluation by trial investigators. For further details of how to perform and 
record these evaluations, please see the Manual of Operations.  
 
6.3.9 Laboratory Evaluations 
6.3.9.1 Urinalysis  
A urine sample for urinalysis will be taken at the screening visit, at the baseline visit, and at 
all follow-up visits. Urinalysis will include analysis for glucose, blood and protein. Results will 
be recorded and categorized as: normal; abnormal but not clinically significant; abnormal and 
clinically significant. If glycosuria is detected (trace or greater) the urinalysis should be 
repeated within a week. If the second test confirms glycosuria, non-fasting (random) blood 
glucose should be checked within another week. If this too is abnormal, dietary advice should 
be reinforced and a fasting blood glucose test or 2-hour post-prandial test should be 
performed within 14 days. See the Manual of Operations for details of how to manage 
glycosuria finding. 
A urinalysis result that is abnormal and clinically significant will be considered as an adverse 
event, recorded as such and monitored until the event has resolved or stabilized at a level 
acceptable to the site Investigator. For further details of how to perform and record this 


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evaluation, and how to manage observed glycosuria or hematuria, please see the Manual of 
Operations.  
6.3.9.2 Chicken pox and TB immunity 
At screening, a blood sample will be taken for antibodies (IgG) to Varicella Zoster virus to 
confirm immunity.  If antibodies are not detected, immunization before starting the trial will be 
advised and the immunization status will be re-checked prior to randomization (see Manual 
of Operation for details). Lack of willingness to immunize a child who is not already immune 
to chicken pox will be a reason for exclusion of the child from the trial. If after two 
immunizations the child still does not show antibodies (IgG) to Varicella Zoster, the case 
should be discussed with the Chief Medical Coordinator. Assessment of TB exposure will be 
performed in order to identify “at risk” children (positive family history, at risk community such 
as certain immigrant group). In an “at risk” child, an immunization before starting the trial will 
be required and the immunization status will be re-checked prior to randomization (see 
Manual of Operation for details). Lack of willingness to immunize a child with a risk of TB 
who is not already immune to TB will comprise a reason for exclusion of the child from the 
trial.   
 
6.3.9.3 Serum chemistry and hematology  
Non-fasting blood samples for serum chemistry (including glucose, electrolytes, urea, 
creatinine, creatine kinase, triglycerides, cholesterol, LDLs, HDLs) and hematology (including 
white blood cell count with differential, hemoglobin, hematocrit, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, total red cell count and platelet 
count) will be collected and evaluated at the screening visit and annually thereafter, up to 
and including Month 36 (Visit 3, 5, 7). Gamma glytamyl transpeptidase and total bilirubin will 
be also performed on blood samples at screening and at end of study visit. All clinical 
laboratory test results will be entered into the data system directly from the printed lab 
reports, or first transcribed to the lab worksheet and then entered.  All results will be recorded 
and/or entered in standard units as displayed on the lab reports (the local laboratory range of 
each value will be held on file centrally). The actual result and units for each test will be 
captured, as well as indicator flags for out of normal range values and whether or not they 
are deemed by the site Principal Investigator to be clinically significant. All results will be 
interpreted and categorized using the following categories: normal; abnormal but not 
clinically significant; abnormal and clinically significant. Any laboratory test abnormality 
considered clinically significant will be confirmed by repeat testing. A laboratory test result 
that is abnormal and clinically significant on re-testing will be considered as an adverse 
event, recorded as such and monitored until the event has resolved or stabilized at a level 
acceptable to the site Principal Investigator. For further details of how to perform and record 
these evaluations, please see the Manual of Operations. 
 
6.3.9.4 Blood samples for 25-OH-D, serum calcium, phosphate, and 
alkaline phosphatase 
A blood sample for serum calcium, phosphate and alkaline phosphatase will be taken at the 
screening visit and annually thereafter, up to and including Month 36.  A blood sample for 25-
OH-D will be taken at the screening visit and annually thereafter throughout the subject’s 
participation in the trial. If deficiency or insufficiency is detected in 25-OH-D, it will be 
corrected by a vitamin D supplement (see the Manual of Operations) and noted as a 
concomitant medication. A blood test for 25-OH-D will be repeated at the 3 month visit in 
children shown to be deficient or insufficient at screening, and provided with Vitamin D 
supplementation, in order to verify normalization of the serum levels.  


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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For further details of how to perform the evaluations and on the management of bone health, 
please see the Manual of Operations. 
 
6.3.9.5 Urinalysis for urinary calcium assessment 
At the screening visit (i.e., before starting corticosteroid therapy, calcium or vitamin D) a urine 
sample will be collected and analyzed for urinary calcium, urine creatinine and urine calcium 
creatinine ratio to exclude the presence of hypercalciuria. Urinalysis for urinary calcium 
assessment will be repeated annually following the screening visit (visit 3, 5, 7, 9 and 11).  
Hypercalciuria in children is defined as urinary calcium excretion > 4 mg/kg/24 hours. Since 
collecting urine for 24 hours could be inconvenient and unsuitable for children, an 
approximate value will be obtained from an extemporaneous urine sample., Hypercalciuria is 
defined as a urine calcium (mg/dL)/urine creatine (mg/dL) ratio >1.5.  Detection of 
hypercalciuria will be confirmed by repeat testing. If the second test confirms hypercalciuria, 
urinalysis on 24 hours urine sample will be arranged. Diet and calcium supplement will be 
reviewed. Further investigations might be considered on individual subject based on 
presence of symptoms and clinical judgment of the site investigator. For further details of 
how to perform this evaluation and interpret and manage the findings, please see the Manual 
of Operations. 
 
6.3.9.6 Blood and urine samples for bone metabolites 
Non-fasting blood and urine samples will be collected at the baseline and annually thereafter, 
up through and including Month 36 (Visit 3, 5, 7) for the following markers of bone formation 
and resorption: 
- for bone formation: serum osteocalcin and bone specific alkaline phosphatase (BSAP) 
- for bone resorption: serum crosslinked C-telopeptide of Type I Collagen (CTx); urinary 
crosslinked C-telopeptide of Type I Collagen; crosslinked N-telopeptide of Type I Collagen 
(NTx); serum receptor activator of nuclear factor kappa-B ligand (RANKL) and serum 
osteoprotegerin (OPG). 
Samples will be sent to Dr ML Bianchi, “Instituto Auxologico Italiano IRCCS, Milano”, Italy for 
analysis. More details about sample collection, processing and shipment are provided in the 
Manual of Operations.  
 
 
6.3.10 Additional Evaluations 
6.3.10.1 
Dietary assessment and advice; behavioral assessment and 
advice; physiotherapy assessment and management 
Standard protocols for (a) dietary assessment and advice; (b) behavioral assessment 
(including parental completion of the PARSIII, Iowa Conners – Parent, SDQ and Rutters) and 
advice; (c) physiotherapy assessment and advice will be followed in this trial. An assessment 
of dietary status and of behavior will be made at the baseline/study entry and at all follow up 
visits. Behavioral management will be provided as indicated by the findings on assessment. 
Please see the Manual of Operations for further details. A standard of physiotherapy care for 
boys aged 4-12 with DMD will be instituted at all sites. Physiotherapy assessment and advice 
including ROM at ankle joint using a goniometry will be performed at screening, at the 
baseline/study entry visit and at all follow up visits (ROM and 6MWT will not be performed 
after Month 36). Compliance with the prescribed program will be assessed at each follow up 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
63
appointment. Further details of physiotherapy assessment and management are provided in 
the Manual of Operations.  
6.3.10.2 
Adverse events 
Adverse events must be assessed and documented at baseline and all subsequent visits. 
Participants will also be asked about any adverse events during the in between visit phone 
calls. A structured record of adverse events and reactions (see Section 7 for further details) 
will be made by reference to medical records and questioning of parent(s)/ guardian(s). See 
the Manual of Operations for further details. 
6.3.11 Questionnaires 
6.3.11.1 
Treatment Satisfaction 
Satisfaction with treatment will be measured at all post-baseline follow-up visits using the 
Treatment Satisfaction Questionnaire for Medication (TSQM) (Atkinson, Sinah et al. 2004). 
The TSQM consists of 14 Likert-scale items that yield four subscale scores: Effectiveness, 
Side Effects, Convenience, and Global Satisfaction (the latter being a component of the 
primary outcome variable for the proposed trial). There is not a child-report version of the 
TSQM available. Therefore, the parent(s)/guardian(s) will be asked to report from their 
perspective of the boy’s treatment. TSQM is available in all languages relevant for this study. 
See the Manual of Operations for further details of how to administer and score the TSQM. 
6.3.11.2 
Behavior 
Four instruments, for completion by the parent(s)/guardian(s) will be used for (1) behavior 
assessment screening and (2) evaluation of behavior change. These are (a) the Iowa-
Conners Parent Checklist , a scale focusing on ADHD symptomatology; (b) the PARS-III, a 
scale designed to measure psychosocial adjustment of children with chronic physical 
illnesses (Stein and Jessop 1990; Collett, Ohan et al. 2003; Collett, Ohan et al. 2003; Witt, 
Kasper et al. 2003); Hendriksen JG et al. 2009); (c) the Strengths and Difficulties 
Questionnaire, a scale focusing on inattention, peer relationships and pro-social behavior 
(Hysing M, et al. 2009; Read J, et al. 2010); (d) the Revised Rutter scale to assess emotional 
distress. Each instrument will be completed by the parent(s)/guardian(s) at the 
baseline/study entry visit and at each follow-up visit through Month 36. See the Manual of 
Operations for further details of how to administer and score these instruments. 
6.3.11.3 
Quality of Life (PedsQL) 
QoL will be measured at the baseline/study entry visit and annually thereafter through Month 
36. The QoL instrument to be used in this trial is the PedsQL (Varni, Seid et al. 1999; Varni, 
Seid et al. 2001; Varni, Seid et al. 2002), the generic core and the NMD-specific module. 
Versions of the PedsQL for completion by the subject (for children aged 5 and over) and for 
the parent(s)/guardian(s) acting as a proxy for the child are available. When the child is 
capable of self-completing an age-appropriate version he will do so. In all cases, regardless 
of the child’s capability to self-complete, the parent(s)/guardian(s) will complete the 
appropriate proxy version. If possible the same parent/caregiver should complete the 
questionnaires at all visits. See the Manual of Operations for further details of how to 
administer these instruments. 
6.3.12 Blindedness Assessment 
At Visit 7 (T36), parents/guardians will be asked to provide their opinion regarding which 
treatment and regimen (Prednisone versus Deflazacort; daily regimen versus intermittent 
regimen) their child has been taking during the study. The site Principal Investigator and 
Clinical Evaluator will be also asked to give their independent opinion. If a child prematurely 
discontinues from study medication (whether he continues follow up visits or is withdrawn 
from study medication and from the study), blindedness assessment should be performed at 
the time the medications are withdrawn.  


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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6.3.13 Adherence Assessments 
At Visit 1 (T3) and at all subsequent follow-up visits, used, unused and empty trial drug 
(including the packaging) will be returned to the site investigator. The number of returned 
used packaging and unused tablets will be recorded. Instances of non-compliance (number 
of missed doses) will also be recorded. See the Manual of Operations for further details of 
this evaluation.  
6.3.14 Between visit phone calls 
The site coordinator will make phone calls between visits to monitor adverse events, 
concomitant medications, adherence to regimen, and any subject and parent concerns 
monthly (± 7 days) during the first 6 months following baseline visit, then every 3 months (± 
14 days) through Month 36. All adverse events and concomitant medications will be recorded 
on worksheets and subject’s study file.  
 
6.4 Off-Intervention Requirements 
A telephone call to the parent(s)/guardian(s) will be made 30 days after the scheduled date 
of stopping study medication, to check on any persisting adverse events. All adverse events 
possibly due to study medication will be monitored until resolved.  
 
6.5 Biobanking 
Samples should be collected for biobanking from as many subjects as possible at 
screening/baseline and annually thereafter. Standardized protocols for collecting, 
processing and storing the samples can be found for example at 
http://www.eurobiobank.org/en/documents/sops.htm. A separate consent will be required 
for collecting these samples, and the consent will be very broad so as not to restrict the use 
of the samples for future approved research projects. However, it will be explained to the 
subjects and their parents/guardians that the samples will be for research purposes, not for 
commercial use. Specimens will be stored in the biobanking facility in Newcastle upon 
Tyne, UK that is set up such as the EuroBioBank (cf. www.eurobiobank.org), with the 
stipulation that the samples be made available to all approved researchers. Possible future 
research includes proteomics and biomarker studies. 
Some blood samples will be processed by the centers locally to produce serum, but those 
blood samples from which DNA or RNA will be extracted, will only be collected by the 
centers but not be processed by them. The serum samples and the blood samples for later 
DNA or RNA extraction can be initially stored locally at the centers but will have to be 
shipped to the biobanking facility in Newcastle upon Tyne for processing. There are 
protocols available that are to be followed by the centers for these serum, plasma, DNA 
and RNA samples.  


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
65
 
7 
MANAGEMENT OF ADVERSE EVENTS  
7.1 Definition and grading of adverse events 
7.1.1 Defining ‘adverse event’ 
An adverse event (AE) is any untoward medical occurrence in a subject that occurs during 
the conduct of a clinical study of a pharmaceutical product, even if that event does not 
necessarily have a causal relationship to the study drug. This can, therefore, be any 
unfavourable and unintended physical sign, symptom, laboratory parameter, or disease 
entity that develops or worsens in severity during the course of the study, whether or not 
considered related to the study drug.  
Accordingly, an adverse event in the context of this study will include any of the following that 
occur after the consent has been signed:  
• 
Intercurrent illnesses  
• 
Physical injuries. Note: in case of injury, the outcome of the injury should be reported 
as AE (i.e. fracture following a fall). If a medical condition is known to have caused the 
injury or accident (i.e. dizziness causing a fall), this should also be reported as AE.  
• 
Adverse events that are suspected (possibly) to be related to study medications 
• 
Adverse events (possibly) related to concomitant medications  
• 
Significant worsening (change in nature, severity, or frequency) of the disease under 
study (DMD) or other pre-existing conditions  
• 
Drug interactions  
• 
Adverse events occurring during diagnostic procedures  
• 
Adverse events occurring during or as a result of study evaluative procedures 
• 
A laboratory or diagnostic test abnormality occurring after the start of the study (once 
confirmed by repeat testing) that results in the withdrawal of the subject from the study, 
requires medical treatment or further diagnostic work-up, or is considered by the site 
investigator to be clinically significant. Abnormal laboratory determinations at the 
screening visit that preclude a subject from entering the study or receiving study drug 
are not considered adverse events, but will be captured in order to monitor data from 
screen failures.  
• 
Abnormalities in physical examination or vital signs that require clinical interventions or 
further investigations (after repeated confirmatory test) or are considered by the site 
investigator to be clinically significant.  
• 
ECG and Echocardiogram abnormalities that require clinical intervention or further 
investigations unless they are associated with an already reported clinical event. 
• 
FVC abnormalities that require clinical interventions or further investigations unless 
they are associated with an already reported clinical event. 
Pre-existing conditions should be recorded at screening in the appropriate worksheets and 
CRF (medical history) but should not be reported as adverse events unless the condition 
worsens (increases in frequency and/or severity). Diagnostic and therapeutic invasive and 
non-invasive procedures (including surgeries) should not be reported as adverse events. 
However, the medical condition for which the procedure was performed should be recorded if 
it meets criteria for an adverse event. 


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7.1.2 Defining ‘serious adverse event’ 
Adverse events are classified as either serious or non-serious. A serious adverse event 
(SAE) is any adverse event occurring at any dose, which results in any of the following 
outcomes or actions:  
• 
Death  
• 
A life-threatening adverse event (i.e., the subject was at immediate risk of death from 
the event as it occurred); does not include an event that, had it occurred in a more 
severe form, might have caused death  
• 
In-patient hospitalization or prolongation of existing hospitalization (a hospitalization 
scheduled before enrolment for an elective procedure or treatment of a pre-existing 
condition, which has not worsened during participation in the study will not be 
considered a serious adverse event.). Treatments in the emergency room for 
procedures that do not require admission to the hospital and observational durations in 
the emergency room for less than 24 hours will be not considered serious.  
• 
A persistent or significant disability/incapacity (i.e., a substantial disruption of one’s 
ability to conduct normal life functions)  
• 
A congenital anomaly/birth defect  
• 
Any other important medical event that the site principal investigator or the sponsor 
judges to be serious or which is defined as serious by the regulatory agency in the local 
country. These events may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition  
An adverse event that does not meet any of the criteria for seriousness listed above should 
be regarded as a non-serious adverse event.  
7.1.3 Grading of severity of adverse events 
The severity of adverse events will be graded, whenever possible, according to the MedDRA.  
If a MedDRA criterion does not exist, the severity of each adverse event must be recorded 
using the following categories:  
• 
Mild (grade 1) 
 
No limitation of usual activities (no need of medical 
interventions) 
• 
Moderate (grade 2)  Some limitation of usual activities (medical intervention might 
be required) 
• 
Severe (grade 3)  
Inability to carry out usual activities (medical intervention and/or 
close follow-up likely needed)  
• 
Life-threatening (grade 4) Potential threat to life 
• 
Fatal (grade 5)  
 
Death 
Severity is not equivalent to seriousness. Severity is a measure of intensity; therefore a 
severe reaction may not be a serious reaction. A headache may be ‘severe’, i.e. may limit 
ability to carry out usual activities, but not constitute a ‘serious’ adverse event as defined in 
Section 7.1.2 above. Severity is judged by the parents/guardians according to impact of AE 
on the subject’s usual activities.  


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7.1.4 Relationship of an adverse event to study medication 
An adverse reaction (AR) is an untoward or unintended response to an investigational 
medicinal product (i.e. study medication or associated placebo) related to any dose 
administered. 
A suspected unexpected serious adverse reaction (SUSAR) is a serious (by SAE 
standards, as listed above) adverse reaction, the nature of which is not consistent with the 
applicable product information (see Section 5.3.3.2).  
For each adverse event, the site investigator (or another medically qualified individual at the 
site with delegated responsibility) must define and record the relationship to the study drug 
as one of the choices on the following scale:  
• 
DEFINITE: Causal relationship is certain (i.e., the temporal relationship between 
drug exposure and the adverse event onset/course is reasonable, other causes have 
been eliminated, and the event must be definitive pharmacologically or 
phenomenologically. 
• 
PROBABLE: High degree of certainty for causal relationship (i.e., the temporal 
relationship between drug exposure and the adverse event onset/course is reasonable, 
and other causes have been eliminated or are unlikely).  
• 
POSSIBLE : Causal relationship is uncertain (i.e., the temporal relationship between 
drug exposure and the adverse event onset/course is reasonable or unknown, and 
while other potential causes may or may not exist, a causal relationship to the study 
drug does not appear probable). 
• 
UNLIKELY: Not reasonably related, although a causal relationship cannot be 
ruled out (i.e., while the temporal relationship between drug exposure and the adverse 
event onset/course does not preclude causality, there is a clear alternate cause that is 
more likely to have caused the adverse event than the study drug)  
• 
NOT RELATED: No possible relationship (i.e., the temporal relationship between 
drug exposure and the adverse event onset/course is unreasonable or incompatible, or 
a causal relationship to study drug is implausible)  
7.2 Recording and reporting adverse events  
7.2.1 Adverse event recording 
For the purpose of adverse event recording, the study period is defined as that time period 
beginning with the day the informed consent is signed and end of the study for the subject 
concerned. 
The site investigator has to report all directly observed and all adverse events spontaneously 
reported by parents/caregivers. Moreover, at each visit after consenting and at each 
telephone contact with the parent/guardian, the site investigator must query for adverse 
events by asking an open-ended question such as “What unusual symptoms or medical 
problems has your child experienced since the last visit?” All reported or observed signs and 
symptoms will be recorded individually, except when considered multiple manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and laboratory test findings will 
be collectively recorded as a single diagnosis on the Adverse Events worksheet and CRF.  
The clinical course of each adverse event that is active at the final visit will be monitored at 
suitable intervals until resolution or stabilization, a determination of a cause unrelated to the 
study is made, or the subject is referred to the care of a local physician.  


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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The relationship to study drug, and seriousness of each adverse event as judged by the site 
investigator must be recorded on the adverse events worksheet. The severity, onset date, 
stop date, and outcome of each adverse event must be also recorded on the CRF, as must 
any action taken with the study drug in response to the adverse event.  
Classification of an adverse event as serious or non-serious determines the reporting 
procedures to be followed. Procedures for adverse event reporting are further described in 
Section 7.2.2 below and in the Manual of Operations. 
7.2.2  Adverse Event Reporting 
Anticipated adverse events are described in Section 7.3 and 7.4 below, including how these 
events should be classified and graded and further details on adverse events reporting are 
provided in the Manual of Operations. A Flowchart of the Process appears below. 
Classification 
Reporting time 
Reporting action 
 
 
 
Serious  
Within 24 hours 
Fax or email of the SAE form 
to the NCTU  
Complete CRF 30 & 
subject’s study file 
Non-serious 
Per CRF submission 
procedure 
Record and submit 
information on appropriate 
CRFs 
SAE forms should be sent preferably by fax to +44 (0) 191 222 8901 marked “For the 
attention of the FOR-DMD Trial Manager”. If no fax is available the SAE form can be sent 
electronically to for.dmd@ncl.ac.uk.  
 
More contact details for AE and SAE reporting are listed in the Manual of Operations.  
Adverse events will assessed by the site study staff at each visit by recording all voluntary 
complaints of subjects and by assessment of the clinical features. Adverse events will also 
be collected monthly during the first 6 months following baseline visit and every 3 months 
thereafter during “in between visit” phone calls. The NCTU will receive information about 
serious adverse events (SAEs), and will be responsible for disseminating information about 
SAEs to those concerned. An SAE is defined in Section 7.1.2 above.  
The study will comply with FDA and EU Clinical Trials Directive requirements and 
International Conference on Harmonization (ICH) GCP guidelines regarding reporting of AEs 
and SAEs to the appropriate regulatory and ethical authorities including definition of which 
SAEs require expedited reporting and the timelines and mechanisms for expedited reporting. 
Where the requirements vary between participating countries, the most stringent 
requirements will be followed.  
Upon occurrence of an SAE the site principal investigator or a person at site with delegated 
responsibility will be required to complete an SAE report form. They must also complete the 
adverse event CRF (CRF 30) and subject’s study file. The SAE report form should be signed 
by the site principal investigator; however if the site investigator is unable to sign at the time 
of the event, the clinical staff member reporting the SAE should sign the form. All SAE report 
forms must be faxed or emailed to the NCTU within 24 hours of the investigator learning of 
the event The NCTU will confirm notification of receipt of SAE with sites via email or phone 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
69
call. For any SAE report forms, the NCTU will liaise with the chief medical coordinator or the 
independent medical monitor.  
Parents/caregivers should be encouraged to promptly inform the site investigator about 
possible serious adverse events (e.g. hospitalization). However, in the event that the site 
investigator does not become aware of the occurrence of a serious adverse event 
immediately, the site investigator is to report the event within 24 hours after learning of it and 
to document his/her first awareness of the adverse event.   
Follow up information and outcome of the serious adverse event should be documented as 
“follow up” in the SAE report form and has to be sent to the NCTU by fax or e-mail.  Follow-
up information will be required if further information become available after completion of the 
initial SAE form. Ongoing SAE will be monitored by the site principal investigator until 
resolution. Follow –up SAE form should be sent to the NCTU every 15 days as update for 
ongoing SAEs until closed. The Chief Medical Coordinator in consultation with the site 
principal investigator will decide if and when and ongoing SAE should be closed if the event 
is not resolved.  
If available to the site at the time, supportive documents (i.e. discharge letter, laboratory and 
diagnostic test results) might be sent with follow up SAE forms. These supportive documents 
should be redacted in order to obscure subject’s identification details (e.g. name and 
surname, address). Only subject identification number and initials should be provided. The 
information in the Adverse Event page of the CRF and the SAE report form must match or be 
reconciled. 
See the Manual of Operations for contact details and further information regarding serious 
adverse event reporting. 
Each serious adverse event report received from the site principal investigator must be 
evaluated by the chief medical coordinator or the independent medical monitor. The chief 
medical coordinator will be responsible for confirming relatedness of the event to the study 
drug, in consultation with the independent medical monitor and the study principal 
investigators if required. The chief medical coordinator will also be responsible, after 
discussion with the independent medical monitor and the study principal investigators, to 
established expectedness of each SAE. If no agreement regarding expectedness will be 
reached, the DSMB will be provided with an unbiased written report of the event and queried 
to make final decision.  
If immediate reporting to the relevant IRB/REC is required by national legislation or custom, 
the appropriate IRB/REC will be notified by the site investigator in accordance with the 
relevant IRB/REC guidelines.  
Study principal investigators and the chief medical coordinator will determine reporting status 
of the SAE (e.g., whether expedited reporting is required). If the SAE requires expedited 
reporting, study principal investigator through the NCTU will contact the appropriate 
regulatory authority (FDA or equivalent) within 7 days of first knowledge of the SAE with a 
complete report to follow initial notification (an additional 8 days). For non-expedited 
reporting, the appropriate regulatory authority will be notified within 15 days. The study 
principal investigators will independently perform final adjudication with respect to the 
relationship of the SAE to study drug. The NCTU Trial Manager will ensure appropriate 
communication of the SAE and related correspondence from the regulatory authority to the 
Data and Safety Monitoring Board (DSMB) as well as to the site principal investigators to 
submit to their respective IRBs/RECs, if required, and will also ensure that those SAEs which 
require entry on to the Eudravigilance database are so entered. 
 
 
 


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The independent medical monitor (IMM) and the chief medical coordinator will be responsible 
for monitoring conditions and progress of enrolled subjects. The independent medical 
monitor and the Chief Medical Coordinator will receive 6- month cumulative reports of AEs 
from the MSG-CC. The IMM will communicate with the chief medical coordinator and the 
study principal investigators for any new safety concerns to be raised with the DSMB. 
The MSG-CC will be responsible for overseeing the preparation of (blinded) reports to the 
NINDS DSMB as well as interim communications through the principal investigators to 
program staff, should more frequent notification of safety issues be required. The IMM will be 
blinded as well, unless circumstances arise that the DSMB feel are necessary for unblinding. 
 
7.3 Expected adverse events 
7.3.1 Expected adverse events related to study medication 
Both prednisone and deflazacort are well established drugs and the side-effect profiles are 
well understood. Not all of these effects have been observed in children.  
There is extensive documentation of the side effects of short-term corticosteroids in boys 
with DMD. The effects of prednisone have been reported for 6 month and 18 month trials of 
daily prednisone as well as for longer term uncontrolled studies. There are also data for long-
term (up to 2 years) use of deflazacort in small numbers of boys. There is relatively little 
short-term or long-term data for the intermittent prednisone regimen. 
On the basis of these studies in DMD, mild side effects of corticosteroids are expected in a 
majority of subjects in both daily treatment groups and in some of the intermittent treatment 
groups. These include weight gain, cushingoid facial appearance, other manifestations of 
changes in fat distribution, excessive hair growth, and/or behavioral changes. Moderate side 
effects are expected (on the basis of these previous studies) to occur infrequently and 
include principally behavioral changes. Other mild side effects may be observed: acne, 
asymptomatic cataracts, glycosuria, loss of bone mineralization, abdominal striae, elevation 
of systolic or diastolic blood pressure. These side effects did not occur in a significant 
number of subjects treated with daily prednisone for up to 18 months and were infrequent in 
boys treated for 36 months. 
There were no significant serious side effects in boys treated for up to 18 months with daily 
prednisone. Longer duration treatment is associated with symptomatic cataract, symptomatic 
fractures, secondary loss of bone mineralization, risk of infection, diabetes, hypertension, 
pancreatitis, glaucoma, congestive heart failure. 
All adverse events will be monitored and recorded and may prompt dosage changes.  
7.3.2 Expected adverse events related to other study procedures 
During the collection of blood samples, boys may experience pain or bruising at the site. 
Localized clot formation and infections may occur, but this is rare. Fainting rarely occurs 
during or shortly after having blood drawn. 
DXA / X-ray involve minimal exposure to radiation. 
The other study procedures are not anticipated to cause adverse events. 
7.4 Management of adverse events 
A unique feature of this trial is the close attention paid by the planning groups to issues of 
baseline standards of care which might otherwise impinge on the outcomes of the trial as 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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well as clear guidelines to be applied across the trial population for the prophylaxis, 
monitoring and treatment of predictable corticosteroid-related side effects. Areas where side 
effect prophylaxis and management have been closely prescribed include behavior changes, 
bone health, and management of weight gain, due to their high occurrence in previous 
studies.  
7.4.1 Behavioral problems 
A feared but to date poorly quantified side effect of corticosteroids in DMD is altered 
behavior, in particular emotional lability and behaviors within the ADHD spectrum. Behavioral 
problems are also reported in this group of patients without steroid treatment (Hinton, Nereo 
et al. 2006). As a prophylactic measure, standardized behavioral advice will be provided to 
all families at the baseline visit and will be reinforced at all follow-up visits. In the case of 
behavior changes that are noted but are not disruptive to family/school life, consideration will 
be given to the provision of child psychology support. Where behavior changes are disruptive 
to family/school life, steroid dosage adjustments will be made as described in Section 
5.3.3.2.1 above.  
7.4.2 Bone health 
Bone thinning and subsequent fracture are recognized side effects of long-term 
corticosteroid use. Prophylactic measures to ameliorate the risk of these adverse events will 
include dietary counseling, including advice on a daily intake of 1000 mg of calcium with the 
diet and 400-1000 IU of vitamin D with adequate supplements (e.g. Cholecalciferol). Further 
vitamin D supplements will be recommended for subjects who show evidence of vitamin D 
deficiency or insufficiency until further monitoring (see Manual of Operation for details). 
Vertebral fractures will be treated with bisphosphonates intravenously (see 5.3.1.2 above). 
All supplements initiated should be noted on the concomitant medication log. 
7.4.3 Weight gain 
Weight gain is a common side effect of corticosteroids. Weight will be measured at all visits 
and BMI (weight kg / height m2) calculated. Prophylactic measures against undesirable 
weight gain will include standardized dietary advice (see Manual of Operations) with 
particular emphasis on advice on appetite control around the time that corticosteroids are 
started. In the event of annual weight gain > 1 and < 4 BMI units for subjects younger than 
10 years and > 2 and < 4 BMI units for subjects older than 10, dietetic advice will be 
reinforced, and there will be no steroid dosage modification. In the event of an annual 
increase in BMI of ≥ 4 units, despite dietary modifications, or if weight gain is unacceptable to 
the child/ family despite intervention, steroid dosage will be reduced to a lower band. In the 
event of continued weight gain despite dosage reduction and/or where weight gain is 
unacceptable to child/family despite intervention, steroid dosage will be stopped. See Section 
5.3.3.2.9 above. 
 
7.4.4 Cataracts 
There is an increased risk of cataracts in individuals on long-term corticosteroids which is 
often asymptomatic. The development of asymptomatic or symptomatic cataracts will trigger 
referral to ophthalmologist for visual acuity measurement and subsequent follow up.  
7.4.5 Cushingoid appearance 
The development of a Cushingoid appearance (Cushingoid facial appearance, other fat 
disposition) is a common side effect of corticosteroids. At each visit, the child will be 
assessed for the development of Cushingoid appearance (see Manual of Operations for 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
72
details of assessment). If Cushingoid appearance unacceptable to the child/family develops 
dosage adjustment will be as described in Section 5.3.3.2.2 above.  
7.4.6 Gastrointestinal symptoms (abdominal pain, heartburn, GI 
bleeding) 
Prophylactic measures against the anticipated side effect of gastrointestinal symptoms will 
include advice to avoid non steroidal anti-inflammatory drugs. In the event of 
gastritis/gastroesophageal reflux (GERD) symptoms, treatment with Ranitidine (or Proton-
pump inhibitors) and antacid should be initiated. If GI symptoms persist despite treatment 
with Ranitidine (or Proton-pump inhibitors) and antacid, dosage, adjustment will be as 
described in 5.3.3.2.3 above. 
7.4.7 Glycosuria 
There is an increased risk of glycosuria and diabetes mellitus in patients on long-term 
corticosteroid therapy. At each visit, a urinalysis test will be performed to test for the 
presence of glycosuria. If glycosuria is detected (trace or greater), the urinalysis will be 
repeated within a week. If the second test confirms glycosuria, non-fasting (random) blood 
glucose should be checked within another week. Dietary advice should be reinforced and a 
fasting blood glucose test or 2-hour post-prandial test should be performed. In the event of 
elevated fasting blood glucose, or elevated post-prandial blood glucose, dosage modification 
will be as described in Section 5.3.3.2.4 above. 
7.4.8 Hypertension  
Blood pressure will be assessed at each visit and compared to age norms. Prophylactic 
measures will include standardized advice about dietary sodium intake. In the event of high-
normal blood pressure (i.e., blood pressure in 90-99th centiles – see Manual of Operations for 
centile charts), the measurement will be repeated in a non-stress environment. Dietary 
recommendations (weight /sodium reduction) will be reinforced if high-normal blood pressure 
is persistent. In the event of confirmed hypertension (consistent and confirmed blood 
pressure equal or above 95th centile - see Manual of Operations for centile charts), repeat 
measurements will be made in a non-stress environment, on at least three separate visits, 
separated by 7 days apart. If there is continued evidence of significant hypertension on these 
repeat measurements, the child will be placed on a low sodium diet for 1 month (< 2.3 g 
sodium or 100 meq/day). If blood pressure is still elevated at repeat measurements after 1 
month on low sodium diet, drug dosage will be adjusted as described in Section 5.3.3.2.5 
above.  
7.4.9 Immuno/adrenal suppression 
The long-term use of corticosteroids can lead to immunosuppression. Contact with people 
with potentially serious infectious diseases, such as measles, meningococcal meningitis etc., 
should trigger appropriate prophylaxis (which may be provided by a family physician). 
Prophylactic measures against immune/adrenal suppression include: ensuring prior 
exposure to chicken pox/immunization; tuberculosis prophylaxis according to local population 
guidelines in ‘at risk’ children’; pneumococcal vaccination and annual flu vaccination; advice 
on corticosteroid cover in the case of illness, injury or surgery (see Section 5.3.1.6 above); 
disallowing live vaccines during treatment (see Section 5.3.1 above).  
In the event of unusual infections or unusual responses to infection, initially there will be no 
steroid dosage modification. An unusually high frequency of infections/unusual organisms 
should prompt the seeking of advice from an immunology expert and steroid dosage 
adjustment as described in Section 5.3.3.2.6 above. 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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7.4.10 Skin changes 
Skin changes, including acne, abdominal striae and hypertrichosis are recognized side 
effects of corticosteroids. At each visit, an examination of the skin will be carried out. In the 
event of skin infections or acne, the condition will be treated as indicated, and there will 
normally be no steroid dosage modification. If skin changes are unacceptable to the 
child/family dosage adjustment will be as described in 5.3.3.2.7 above.  
7.4.11 Slow growth 
Growth retardation is a recognized side effect of corticosteroids. If there is a failure to gain 
height, but this is not a cause of concern to child/family, no steroid dosage modification will 
be required. If a failure to gain height is observed and is unacceptable to child/family, dosage 
adjustment will be as described in 5.3.3.2.8 above.  
7.5 Possible benefits 
Subjects in the trial may benefit from frequent examinations by neuromuscular specialists, by 
application of standards of care for physiotherapy, cardiac follow up and respiratory care, 
from receiving (in all three arms of the trial) an active treatment for the management of DMD 
and from the application of explicit protocols for side effect prophylaxis and management.  
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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8 
 INTERVENTION DISCONTINUATION 
8.1 Criteria for treatment interruption  
The principal criteria for discontinuation of intervention (i.e. withdrawal from study 
medication) are the experience of significant and persistent adverse events, even following 
dose modification as described in Section 5.3.3 above.  
Study medication should not be stopped suddenly. A tapered reduction in dosage is required 
to avoid risks of adrenal failure. Procedures for achieving a tapered reduction are described 
in Section 5.3.3.2.10 above. 
After discontinuation of study medication due to adverse events, the subject will be asked to 
continue follow up visits until the end of the study. 
 
8.2 WITHDRAWAL OF SUBJECTS FROM THE STUDY 
All subjects who start the study should remain in the study whenever possible. However, 
reasons for withdrawal include: 
- 
Any subject or his parents/guardian have the right to withdraw from the study at any 
time without giving a reason 
- 
The site investigator, in consultation with the chief medical coordinator, may withdraw 
any subject from the study if in their opinion this is in the best interest of the subject 
- 
Any subject who becomes significantly non-compliant with study procedures, study 
follow-up and treatment should be withdrawn from the study if the circumstances 
increase risk to the subject.  
In case of withdrawal from the study, continued corticosteroids treatment (commercial 
prescription) is not forbidden; however, it would be important to reinforce risk of treatment 
without adequate follow-up. 
Study medication should not be stopped suddenly upon study withdrawal. A tapered 
reduction in dosage is required to avoid risks of adrenal failure. Procedures for achieving a 
tapered reduction are described in Section 5.3.3.2.10 above. 
8.3 
Procedures for maintaining involvement of subjects in follow-
up activities 
In the case of treatment discontinuation due to an adverse events or withdrawal of a subject 
from the study for whatever reason, a discontinuation worksheet should be completed by the 
site principal investigator and the chief medical coordinator should be informed (by email or 
phone call) within 5 working days. In addition, the site staff should record details regarding 
the reason of treatment interruption/withdrawal in the subject’s notes and in the appropriate 
case report form (CRF81). 
If study medication is prematurely discontinued at the instigation of the site investigator or 
family, for whatever reason (interruption or withdrawal), the child will be asked to continue to 
be followed-up in the study as per protocol, e.g., continue attending 6-monthly visits for 
evaluations off trial medication. The trial medication field of the worksheet should reflect the 
decision to discontinue trial medication. The date and reason for discontinuation should be 
recorded. If the subject is withdrawing from FOR-DMD study medication to participate in 
another clinical trial that does not allow for concurrent participation in FOR-DMD, the name of 
the trial should be noted in the “Notes” section of CRF81. Trial medication should not be 
stopped suddenly. A tapered reduction in dosage is required to avoid risks of adrenal failure. 
For details of how to taper dosage, see Section 5.3.3.2.10 above.  


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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If a child prematurely discontinues from both medication and follow-up, a full ‘final visit’ 
should be performed if possible. This will include the elements of Visit 7 (T36), as described in 
Section 6.2.2.5 above, as well as strong recommendation for the boy to have a thorough eye 
examination by an ophthalmologist. In the case of premature discontinuation from medication 
and follow-up, a telephone call to the parent(s)/guardian(s) will be made 30 days after the 
last visit to check on any persisting adverse events. Adverse events possibly due to study 
medication will be monitored until resolved. 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
76
9 
STATISTICAL CONSIDERATIONS 
9.1 Analysis of the primary outcome variable for efficacy 
9.1.1 Primary statistical model  
This trial is designed primarily to compare three corticosteroid regimens with regard to 
efficacy as measured by (1) time to stand from lying (log-transformed) averaged over all 
post-baseline visits during the three-year follow-up period (subjects no longer able to perform 
the task at a particular visit will be assigned the largest observed time in the sample), (2) 
forced vital capacity (FVC) averaged over all post-baseline visits during the three-year follow-
up period, and (3) subject/parent global satisfaction with treatment, as measured by the 
TSQM (completed by the parent), averaged over all post-baseline visits during the three-year 
follow-up period. These outcomes represent different but important aspects of the expected 
benefits of corticosteroid treatment. The primary statistical analysis will treat this as a 
multivariate (3-dimensional) outcome and will consist of global tests of the null hypothesis 
that the regimens do not differ with regard to any of the three outcomes against the 
alternative that they differ (in the same direction) for all three outcome variables, performed 
separately for each of the three pair-wise comparisons among the three corticosteroid 
regimens. 
The rationale for using a multivariate outcome is two-fold: the selection of a single primary 
outcome variable would be arbitrary, and the use of three outcome variables that are 
expected to similarly reflect differences between treatment regimens will be more powerful in 
detecting group differences than the use of a single outcome variable. A potential criticism of 
this approach is that the treatment groups may differ on some, but not all, outcomes in the 
same direction, in which case the power of the test may be compromised (see Section 9.6 
below). One treatment regimen would be preferred over another only if there is consistent 
and persuasive evidence of this across the three outcomes, so if this is not the case the 
compromise in power may be seen as an appealing characteristic of this approach. 
The test that will be used is based on the OLS (ordinary least-squares) statistic first proposed 
by O’Brien (O'Brien 1984). For a two-group comparison, this statistic is essentially an 
unweighted sum of the standardized two-sample statistics used for comparing the groups on 
each individual outcome. The analyses will involve three separate pair-wise comparisons 
among the three treatment regimens; each will be performed using a Bonferroni-corrected 
two-tailed significance level of 0.017 (this is two-tailed because it is not clear a priori which of 
the two regimens being compared will be superior, but it is expected that the superior 
regimen will be superior with respect to all three components of the outcome variable). The 
analyses will be adjusted for covariates, namely country, baseline time to stand from lying, 
baseline FVC, and initial weight band. This will be accomplished by using the adjusted 
treatment group means and corresponding estimated variance-covariance matrix from the 
appropriate multivariate analysis of covariance model in constructing the OLS statistic 
(Dallow et al., 2008). In order to ensure consistency of direction of the outcomes (i.e., higher 
values are “good” for all outcomes), the negative of time to stand from lying will be used for 
the formal statistical analyses. 
It should be emphasized that interpretation of these tests will be in terms of the global three-
dimensional outcome and that these tests do not identify the component on which the 
treatment groups differ. Follow-up analyses of the individual component outcomes, using a 
closed testing procedure, will also be performed in order to aid in the interpretation of the 
results of the global test for the multivariate outcome. This procedure will involve performing 
treatment group comparisons with regard to the three possible bivariate outcomes (time to 
stand from lying and FVC, FVC and TSQM, time to stand from lying and TSQM) as well as 
the individual outcomes. A treatment group comparison for an individual outcome will be 
considered to be statistically significant (at the 0.017 level) only if it is significant for the 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
77
trivariate outcome as well as for the bivariate outcomes of which the individual outcome is a 
component. It must be borne in mind, however, that the power to detect group differences for 
each of the individual outcomes will typically be lower than that for the multivariate outcome. 
9.1.2 Adjustment for baseline characteristics  
If clinically important differences are found among the three groups at baseline, particularly 
with regard to important variables such as age, the primary analyses will be repeated after 
statistically adjusting for these differences. These analyses, however, will be considered to 
be secondary. 
9.1.3 Model assumptions  
The underlying assumptions of the multivariate analysis of covariance model will be 
thoroughly checked (normality, linearity, etc.), and remedial measures (e.g., transformations) 
will be taken if serious violations of these assumptions are detected. Data from previous trials 
conducted by the CIDD group suggest that the model assumptions should be reasonable for 
the time to stand from lying and FVC components of the primary outcome variable (after 
transformation and averaging over time). The relatively large sample size (225 subjects) 
should also alleviate potential concerns about the multivariate normality assumption. 
9.1.4 Primary strategy for the treatment of missing data  
The primary analyses will be performed according to the intention-to-treat principle and will 
include all randomized subjects. Every effort will be made to retain subjects in this study and 
to collect all data at every visit. If a subject cannot tolerate or refuses to continue receiving 
the study intervention, the subject will continue to be followed and evaluated if willing, and 
any treatment received by the subject will be recorded. If a subject drops out, attempts will be 
made to bring the subject in for a final evaluation. Compliance with trial procedures, dosage 
modifications, dropouts, and reasons for dosage modification and subject withdrawal will be 
carefully tracked throughout the study. Multiple imputation will be used to accommodate 
missing data in the primary statistical analysis.  A key assumption underlying this analysis is 
that the missing data are “missing at random” (MAR), i.e., the probability that the responses 
are missing for a subject depends only on the set of observed data for that subject and not 
on the specific missing values that were not obtained (Little and Rubin, 2002). 
If a subject is missing a response at a particular visit, missing data will be imputed using a 
multivariate regression-based imputation model that is a natural extension of that often used 
in the univariate case (Little and Yau 1996). For subjects with complete data up to a 
particular visit, a multivariate multiple regression model will be fitted that includes the (3-
dimensional) outcome at that visit as the dependent variable and (3-dimensional) outcomes 
at previous visits, treatment group, and country as independent variables. Separate models 
will be similarly constructed for each visit. Using these regression models, a missing value for 
a subject at a particular visit will be imputed as a draw from the predictive distribution given 
the outcomes at previous visits (some possibly imputed), treatment group, and country; as in 
the univariate case, the imputed value will be the predicted value from the multivariate 
multiple regression model with an appropriate amount of “noise” added according to the 
residual covariance matrix of the imputation model (Little and Yau 1996). This will be done 
sequentially starting with the Month 3 visit. This process will be repeated 100 times, resulting 
in 100 complete analysis data sets. The analyses will be performed separately for each of 
the 100 complete analysis data sets and the results will be combined into one multiple 
imputation inference (estimated treatment effect and associated p-value) using established 
methods (Li et al., 1991; Schafer, 1997). This regression-based imputation strategy reflects 
the within-subject correlations for each outcome over time as well as the correlations among 
the three components of the outcome variable. 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
78
This approach to imputation should be superior to other strategies such as carrying forward 
the last available observation, which often yields unrealistic imputed values. The use of 
multiple imputation also avoids the problem of artificially increasing power through data 
imputation associated with single-imputation methods because it accounts for the uncertainty 
associated with the imputation (Schafer 1997; Little and Rubin 2002). Also, sensitivity 
analyses that make different assumptions (other than MAR) regarding the missing data 
mechanism can be accommodated using the multiple imputation approach (Carpenter et al., 
2013; O’Kelly and Ratitch, 2014). Such analyses will be performed, and it is hoped that the 
overall conclusions regarding the relative efficacy of the different regimens will not depend 
greatly on the imputation strategy used, particularly if subject dropout is minimized. 
9.2 Analysis of the secondary outcome variables for efficacy 
9.2.1 Analysis of continuous outcome variables 
Analyses of the secondary outcome variables for efficacy thought to be approximately 
normally distributed, such as time to go 10 meters (log-transformed), 6MWT (distance 
walked in 6 minutes), the North Star Ambulatory Assessment total score, TSQM subscales 
(effectiveness, side effects, convenience), fat-free mass (DXA), and quality of life (the 
generic PedsQL and its neuromuscular disease-specific module) will involve the use of a 
repeated-measures analysis of covariance model (i.e., the so-called “mixed model repeated-
measures”, or MMRM, analysis strategy (Molenberghs et al. 2004)) with treatment group as 
the factor of interest, country as a stratification factor, and the baseline value of the outcome 
variable and initial weight band as covariates. The model will also include terms for visit 
(categorical),  the interaction between treatment group and visit, and the interaction between 
the baseline value of the outcome variable and visit. The covariance matrix for the within-
subject observations will be modeled using an unstructured pattern.  This model will be used 
to determine 98.3% confidence intervals for the pair-wise group differences in adjusted mean 
response, averaged over all post-baseline visits. The confidence coefficient of 98.3% 
incorporates a Bonferroni adjustment for the three pair-wise comparisons among the three 
treatment groups. Confidence intervals for group differences in adjusted mean response at 
each visit can also be obtained using this model. Outcomes averaged over all post-baseline 
visits and at the final visit will be of primary interest. These analyses will also be performed 
for the individual components of the primary outcome variable (log-transformed time to stand 
from lying, FVC, and global satisfaction with treatment (TSQM)). 
 
Other continuous outcome variables derived from the NSAA (percentage of follow-up time 
able to perform milestones such as hopping, jumping, and lifting the head from a supine 
position) will be similarly analyzed using an analysis of covariance model that includes 
treatment group, country, and initial weight band as independent variables. 
If clinically important differences are found among the three groups at baseline, particularly 
with regard to important variables such as age, the primary analyses will be repeated after 
statistically adjusting for these differences. These analyses, however, will be considered to 
be secondary. 
The interaction between treatment group and country will be investigated by including the 
appropriate interaction term in the repeated measures analysis of covariance model and 
testing for its significance. Also, interactions between treatment group and important baseline 
variables such as age, ethnicity, time to stand from lying (log-transformed), FVC and initial 
weight band will be examined separately in a similar fashion. Since the power to detect 
potentially meaningful interactions will be limited, the magnitudes of mean responses to 
treatment in the relevant subgroups will be examined. The observation of clinically important 
subgroup differences in mean treatment response (e.g., age 4-5 vs. age 6-7) will serve as 
hypothesis generation for possible future studies designed to specifically address the issue 
of differential therapeutic response. 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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9.2.2 Treatment of missing data for secondary outcome 
variables 
The principal analyses for the continuous secondary outcome variables for efficacy will be 
performed according to the intention-to-treat principle and will include all randomized 
subjects.  The repeated measures analysis of covariance model to be used for these 
analyses uses maximum likelihood to estimate the parameters of interest (treatment effects) 
using available data from all subjects and is a valid strategy under the MAR assumption 
(Molenberghs et al. 2004).  Analyses based on multiple imputation, similar to those described 
for the primary outcome variable (but without the multivariate adaptation), may also be 
performed. 
Because assumptions such as MAR are untestable with the observed data, sensitivity 
analyses will be performed that make various assumptions about the missing data 
mechanism.  Flexible multiple imputation strategies in the context of pattern-mixture models 
are well suited for this purpose (Carpenter et al., 2013; O’Kelly and Ratitch, 2014).  It is 
hoped that the overall conclusions regarding the relative efficacy of the regimens will not 
depend greatly on the analysis or imputation strategy used, particularly if subject dropout is 
minimized.  
9.2.3 Exploratory analyses accounting for protocol deviations 
and noncompliance 
Exploratory analyses will also be performed that, for example, may group subjects according 
to treatment actually received (whether or not this was the randomly assigned treatment). 
So-called “per-protocol” analyses will also be performed that include only subjects who 
complete the trial without any major protocol violations (e.g., < 80% compliance with study 
medication). The identification of subjects to be included in these analyses will be determined 
before the blind is broken (i.e., before data analysis). Of course, such analyses may lead to 
biased estimates of the actual treatment group differences, but they may provide an 
indication of the sensitivity of the analyses to treatment modification and noncompliance. 
Methods for bias reduction in this setting, such as those based on propensity score 
stratification (D’Agostino 1998) or inverse probability weighting (Lunceford and Davidian 
2004), can be employed. Other analyses may be performed that censor a subject’s data after 
the subject has withdrawn from study medication (if he agrees to continued follow-up) or who 
concurrently participate in clinical trials of other treatments. Other methods for causal 
inference that account for subjects switching treatment regimens can be explored (Xie and 
Heitjan 2004) should this occur with sufficiently high frequency. It should be realized, 
however, that this trial will only be able to purely address the issue of the comparison of the 
three different initial treatment strategies with respect to three-year outcome. In this sense it 
is a very pragmatic trial. 
9.2.4 Analysis of times to disease milestones 
Times from randomization to various disease milestones will be considered as secondary 
outcome variables for efficacy. These include time to loss of ambulation, time to loss of the 
ability to stand from lying, time to loss of the ability to rise from a chair, and time to loss of the 
ability to get up and down one step. Event times will be censored at the last follow-up time for 
subjects who do not reach the endpoint (milestone). These outcomes will be primarily 
analyzed using a Cox proportional hazards model that will include treatment group as the 
factor of interest, country as a stratification factor, and age and initial weight band as 
covariates. Confidence intervals for the adjusted hazard ratios representing pair-wise 
treatment group comparisons will be computed using this model. The underlying 
assumptions of this model will be checked using appropriate numerical and graphical 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
80
methods (Hosmer and Lemeshow 1999). Kaplan-Meier curves will be used to describe the 
cumulative probabilities of reaching the endpoint over time in the three treatment groups. 
Other aspects of the analysis of the primary outcome variable (e.g., further adjustment for 
baseline factors, examination of interactions) will be considered here as well. 
9.3 Analysis of tolerability and safety outcomes 
9.3.1 Tolerability outcomes 
Tolerability outcomes will include ability to complete the trial on the originally assigned 
dosage (for weight) of study medication (the most important secondary outcome variable), 
ability to complete the trial without switching drug regimens (i.e., discontinuing study 
medication), and ability to complete the trial. The proportions of subjects with these 
outcomes will be compared among the treatment groups in a pair-wise fashion using Fisher’s 
exact tests. Time until a dosage modification is required will also be compared among the 
treatment groups using the methods described above for analyzing times to disease 
milestones. The frequency of, and reasons for, dosage modifications, study drug 
discontinuations, and subject withdrawal will be thoroughly summarized by treatment group. 
9.3.2 Adverse events 
Adverse events will be tabulated by treatment group, severity, and perceived relationship to 
study drug. For each adverse event, pair-wise comparisons among the treatment groups will 
be performed regarding the occurrence of at least one event using Fisher's exact tests. The 
comparisons will be repeated excluding all mild adverse events. Similar analyses will be 
performed after grouping adverse events by body system using MedDRA coding. Individual 
adverse events will be listed. Particular attention will be paid in the analyses to significant 
behavioral changes, fractures, cataracts, Cushingoid appearance, GI symptoms, glycosuria, 
hypertension, immunosuppression, slow growth (height restriction), skin changes (e.g., 
excessive hair growth, acne, atrophy, easy bruising), (excessive) weight gain and abnormal 
echocardiography results, especially those requiring treatment. Adverse events that are 
classified as “serious” or lead to a dosage modification or withdrawal of study drug will also 
be carefully scrutinized. 
9.3.3 Continuous safety outcomes 
Continuous safety outcomes such as height, weight, body mass index, vital signs, DXA 
outcomes, bone age, vertebral height, markers of bone formation and resorption, 
echocardiography outcomes, behavioral ratings and laboratory test results will be analyzed 
descriptively. Results (actual values and changes from baseline) will be summarized by visit 
using descriptive statistics.  Formal analyses may be performed using methods similar to 
those described above for the secondary efficacy outcomes (repeated measures analysis of 
covariance). 
9.4 Miscellaneous analyses and outcomes 
9.4.1 Measures of compliance with study medication 
Compliance with study medication will be summarized by treatment group and visit.  It will be 
quantified as the percentage of doses of study medication that were apparently taken (based 
on the number of pills distributed compared to the number returned at each study visit) out of 
the number of doses expected.  Relevant circumstances such as dosage modifications will 
be taken into account in the calculation of the expected number of doses. 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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9.4.2 Blindedness Assessment 
The association between guessed treatment from the blindedness assessment and actual 
treatment will be assessed using a chi-square test. Results will also be summarized by 
confidence in the guess and primary/secondary reasons for the guess.  
9.4.3 Concomitant Medications 
A listing of concomitant medications will be provided for each subject.  Concomitant 
medication use will be summarized by treatment group according to the percentages of 
subjects using particular medications (or classes of medications). 
 
Exploratory analyses may be performed that tabulate certain adverse events (e.g., those that 
are unusual/unexpected or serious) by treatment group and use of particular concomitant 
medications. 
 
9.5 Sample size considerations 
As described in Section 9.1 above, the primary outcome variable will be three-dimensional 
and will consist of time to stand from lying (log-transformed) averaged over all post-baseline 
visits during the three-year follow-up period, forced vital capacity (FVC) averaged over all 
post-baseline visits, and (3) subject/parent global satisfaction with treatment, as measured by 
the TSQM, averaged over all post-baseline visits. The primary statistical analysis will be a 
global test of the null hypothesis that the corticosteroid regimens do not differ with regard to 
any of the three outcomes against the alternative that they differ (in the same direction) with 
regard to at least one of the outcomes. O’Brien’s OLS statistic will be used to carry out this 
test. The analyses will involve three separate pair-wise comparisons among the three 
treatment regimens; each will be performed using a Bonferroni-corrected two-tailed 
significance level of 0.017. 
Existing data from the trials comparing 0.75 mg/kg/day prednisone vs. placebo suggest that 
the effects of prednisone on the time to stand from lying and FVC outcomes are of a 
magnitude of one standard deviation unit (difference between the treatment group means 
divided by the standard deviation of the outcome, adjusted for baseline values) (Mendell, 
Moxley et al. 1989; Griggs, Moxley et al. 1991; Manzur, Kuntzer et al. 2004). A difference in 
mean response between two corticosteroid regimens of 0.50 standard deviation units (i.e., 
half of the effect of 0.75 mg/kg/day of prednisone vs. placebo) will be considered to be the 
group difference that is of minimal clinical significance on these two outcomes 
(corresponding to approximately 1 second on time to stand from lying and 0.08 liters on FVC 
for a single time point). For example, if the intermittent regimen provides at least 60% of the 
benefit of daily prednisone on these two outcomes, the difference between the regimens will 
not be judged to be clinically important.  
For global satisfaction with treatment on the TSQM, data on 378 subjects (mean age 50.5 
years, range 18 to 88 years) using oral medications for a variety of illnesses (migraine, 
arthritis, high blood pressure, high cholesterol, and depression) suggest that the group 
difference of minimal clinical significance may be slightly less than 0.50 standard deviation 
units (Atkinson, Sinah et al. 2004). Subjects who described the seriousness of their illness as 
“Moderate” and those who described it as “Severe” differed by approximately 0.40 standard 
deviation units on this scale. Also, subjects who appraised their health as “Excellent” or “Very 
Good” and those who appraised their health as “Good” or “Fair” differed by approximately 
0.50 standard deviation units on this scale. These data are limited in that they were not 
obtained in children or parents of children with Duchenne muscular dystrophy, but they do 
provide some idea of what group differences in mean response may be considered to be 
clinically important. 


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We performed a pilot study of the TSQM in 37 boys with Duchenne muscular dystrophy 
(DMD) between the ages of 4 and 12 years who were taking corticosteroids, 6 at the 
University of Rochester, 7 at the University of Kansas, 6 at Children’s Hospital of Western 
Ontario (Canada), and 18 at the University of Newcastle (UK) (Herr et al. 2008).  We 
collected data on the age and ambulatory status of the subjects, allowing us to examine the 
relationships between the TSQM subscale scores and these characteristics (Table 9.1).  
Although the small sample sizes limit our ability to detect significant differences among the 
groups determined by age or ambulatory status, the expected patterns of responses are 
apparent: lower mean Effectiveness and Global Satisfaction scores among those > 7 years 
old (p < 0.05) and among those unable to walk outside the home; lower Side Effects scores 
among those > 10 years old and among those unable to walk outside the home. 
 
 
 
 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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Table 9.1  Results of the TSQM Pilot Study in 37 Boys with DMD 
 
 
Age Group 
Ambulatory Status 
Scale 
4-6 
(n = 9) 
7-9 
(n = 11) 
10-12 
(n = 17) 
Able 
(n = 29) 
Home/Unable 
(n = 8) 
 
 
 
 
 
 
Effectiveness 
79.0 (16.1) 
58.6 (22.7) 
61.4 (26.2) 
68.8 (20.4) 
50.7 (31.5) 
Side Effects 
85.9 (18.2) 
83.5 (17.1) 
71.2 (29.3) 
82.6 (19.4) 
68.8 (31.9) 
Convenience 
88.9 (15.7) 
90.6 (11.4) 
88.0 (16.6) 
89.6 (13.9) 
87.3 (17.5) 
Global 
Satisfaction 
82.5 (18.2) 
67.1 (18.5) 
63.9 (26.7) 
73.2 (18.7) 
54.1 (35.2) 
 
Data from this study indicate that the mean global satisfaction with treatment differed by 
0.65-0.80 standard deviation units between boys age 4-6 and those age 7-12.  In this 
context, an effect size of 0.40 standard deviation units does not appear to be unacceptably 
large. 
The power of the test based on O’Brien’s OLS statistic also depends on the correlations 
among the three outcomes. Data on 51 subjects between the ages of 5 and 7 from the CIDD 
natural history cohort suggest that the correlation between the average time to stand from 
lying (log-transformed) and the average FVC over a three-year follow-up period is very small 
and possibly even slightly negative. Correlations between these outcomes and the TSQM 
global satisfaction rating, while expected to be mildly-to-moderately positive, were of 
unknown magnitude at the onset of the trial.  For this reason, an interim sample size re-
estimation was performed in July 2015 using all available longitudinal data, blind to treatment 
group assignment.  The results revealed that the three components of the primary outcome 
variable (log-transformed time to stand from lying, forced vital capacity, and subject/parent 
global satisfaction with treatment) were at best weakly correlated (0 < r < 0.25). 
Table 9.2 provides the power (estimated using Monte-Carlo simulation, with each estimate 
based on 50,000 replications) required to detect the specified treatment effects (differences 
between two groups, expressed in standard deviation units) under various assumptions 
regarding the correlations among the three outcomes, using O’Brien’s OLS test and a two-
tailed significance level of 0.017. A sample size of 67 subjects per group is assumed. This 
table indicates that a total sample size of 201 subjects (67 per group) will provide at least 
80% and often greater than 90% power to detect treatment effects of at least 0.45 standard 
deviation units on at least two of the three components and as little as 0.25 standard 
deviation units on the third component of the primary outcome variable.  The power becomes 
unacceptably low only in the case where there is no group difference in treatment 
satisfaction. To account for an anticipated 10% subject withdrawal rate, 225 subjects (75 per 
group) will be enrolled in the trial. 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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Table 9.2 Power calculations 
Effect Sizes 
Correlations 
 
∆T 
∆F 
∆S 
ρTF 
ρTS 
ρFS 
Power 
0.45 
0.45 
0 
0 
0 
0 
72% 
0.45 
0.45 
0 
0 
0.10 
0.10 
66% 
0.45 
0.45 
0 
0 
0.15 
0.15 
63% 
0.45 
0.45 
0 
0 
0.25 
0.25 
58% 
0.45 
0.45 
0.25 
0 
0 
0 
92% 
0.45 
0.45 
0.25 
0 
0.10 
0.10 
88% 
0.45 
0.45 
0.25 
0 
0.15 
0.15 
86% 
0.45 
0.45 
0.25 
0 
0.25 
0.25 
82% 
0.45 
0.45 
0.45 
0 
0 
0 
98% 
0.45 
0.45 
0.45 
0 
0.10 
0.10 
96% 
0.45 
0.45 
0.45 
0 
0.15 
0.15 
96% 
0.45 
0.45 
0.45 
0 
0.25 
0.25 
93% 
0.50 
0.50 
0 
0 
0 
0 
83% 
0.50 
0.50 
0 
0 
0.10 
0.10 
77% 
0.50 
0.50 
0 
0 
0.15 
0.15 
74% 
0.50 
0.50 
0 
0 
0.25 
0.25 
69% 
0.50 
0.50 
0.25 
0 
0 
0 
96% 
0.50 
0.50 
0.25 
0 
0.10 
0.10 
93% 
0.50 
0.50 
0.25 
0 
0.15 
0.15 
92% 
0.50 
0.50 
0.25 
0 
0.25 
0.25 
88% 
 
ΔT = Effect size for log(time to rise from the floor); ΔF = Effect size for FVC; ΔS = Effect size for global satisfaction 
with treatment. All values are expressed in standard deviation units. 
ρTF = Correlation between log(time to rise from the floor) and FVC; ρTS = Correlation between log(time to rise from 
the floor) and global satisfaction with treatment; ρTF = Correlation between FVC and global satisfaction with 
treatment. 
A secondary hypothesis concerns potential differences between daily deflazacort and daily 
prednisone with respect to adverse events, with intolerability (dosage reduction) and weight 
gain being the events of primary interest.  Data from the long-term trials of prednisone 
(Fenichel et al. 1991) suggest that nearly 50% of subjects may require a lower dosage of 
daily prednisone than 0.65 mg/kg during the three-year follow-up period.  The data from this 
study also indicate that subjects in the daily prednisone group will have an average weight 
gain of approximately 25% per year (standard deviation = 12%).  The sample size of 225 
subjects (75 per group) will provide 80% power to detect a group difference of 22% (50% in 
the daily prednisone group vs. 28% in the daily deflazacort group) regarding the percentage 
of subjects taking a reduced dosage at the end of the three-year follow-up period, using a 
chi-square test and a 5% significance level.  It will also provide > 80% power to detect a 
group difference of 6% (25% in the daily prednisone group vs. 19% in the daily deflazacort 
group) in mean annual weight gain during the three-year follow-up period, using a t-test and 
a 5% significance level (two-tailed). 
 
 


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9.6 Data and safety monitoring 
9.6.1 General guidelines 
The monitoring of data quality and subject safety in this trial will follow the NINDS Guidelines 
for Data and Safety Monitoring in Clinical Trials. The NINDS will appoint an independent 
Data and Safety Monitoring Board (DSMB) that will be responsible for periodic review of the 
data related to adverse events throughout the trial. The MSG-CC and the MSG Biostatistics 
Center will prepare data and make them available for review by the DSMB, including 
information on all serious adverse events, other adverse events, laboratory test results, 
recruitment and retention, data completeness and data quality. The DSMB will act 
independently to review the foregoing data. 
9.6.2 Interim analyses for safety 
Interim analyses of safety data will be performed periodically throughout the trial. While the 
safety of subjects will be the primary concern of the DSMB, it is difficult to formulate precise 
stopping guidelines that would cover all of the possible situations that might arise. Adverse 
events, particularly serious adverse events such as deaths and any that are unexpected will 
need to be carefully considered by the DSMB in terms of treatment group imbalances. The 
adverse events associated with daily corticosteroid use in DMD have been reasonably well 
characterized in previous studies and include behavioral changes, fractures, cataracts, 
Cushingoid appearance, GI symptoms, glycosuria, hypertension, immunosuppression (e.g., 
infections), slow growth (height restriction), skin changes (e.g., excessive hair growth, acne, 
atrophy, easy bruising), and abnormal weight gain. Detailed procedures are in place to 
clinically manage these anticipated adverse events (see Sections 5.3.2 and 7.4). The DSMB 
will be provided with estimated incidences of these adverse events based on data from 
previous clinical trials of daily prednisone to use as benchmarks at the outset of the trial 
since there will be no placebo group in this trial. 
9.6.3 Interim analyses for efficacy and futility 
This is a trial designed to compare three corticosteroid regimens commonly being used to 
treat boys with DMD throughout the world. One of the important issues that the proposed trial 
and its possible extension can eventually resolve is the long-term consequences of starting 
boys on a particular corticosteroid regimen relative to the competing regimens. Even if, say, 
daily corticosteroids were found to be superior to intermittent corticosteroids in terms of the 
primary outcome variable in an interim analysis, it would not be desirable to stop or modify 
the trial on the basis of this (relatively) short-term outcome. The rationale for intermittent 
corticosteroid regimens is that they are thought to reduce the side effect burden in the short-
term and, importantly, in the long-term. Therefore, it is important to maintain all subjects on 
their randomly assigned regimens for as long as possible in order to address issues related 
to the long-term consequences of treatment. We propose to conduct two interim analyses, 
after 33% and 66% of the subjects have completed 3 years of follow-up. The analysis of the 
primary outcome variable will be performed using an overall significance level of 0.001 
(instead of 0.05), a conservative Haybittle-Peto-type strategy.  We propose to have no 
interim analyses for the purpose of early identification of futility. 
The DSMB will periodically review data regarding the rate of subject accrual over time. If the 
NINDS, in consultation with the DSMB, determines that the accrual rate falls substantially 
below that which is necessary for the timely completion of the trial, the trial may be halted for 
futility. The trial may also be halted for futility if other indicators of trial performance (e.g., 
subject retention, data quality) suggest that this is appropriate. In particular, if a substantial 
number of subjects (> 20%) in a treatment group discontinue their assigned treatment 
regimen, it would be prudent for the DSMB to consider halting enrolment in that arm and 
modifying the trial to change the regimen of all subjects in that treatment group. 


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10 STUDY COMMITTEES 
10.1 Study Steering Committee 
A study steering committee (SSC – FOR-DMD) will be responsible for protocol development, 
review of any study amendment, and coordination of study conduct and interpretation of 
study results. The SSC comprises the principal investigators, the chief medical coordinator, 
the biostatistician, the project managers and several experts in DMD. Other specialists may 
be invited to participate as members of the SSC at any time if additional expertise is desired.  
10.2 Data and Safety Monitoring Board 
A data and safety monitoring board (DSMB), operating autonomously from the SSC and the 
site investigators, will be responsible for providing independent recommendations to the 
NINDS about risk-benefit of the study and any modification required during the course of the 
study. The DSMB will be appointed by the NIH and its members must not be actively 
involved in study design, conduct or daily management of this study and must not have 
financial, propriety, professional, or other interests that may affect impartial, independent 
decision-making.  
Specialists may be invited to participate as non-voting members at any time if additional 
expertise is desired. The DSMB will formally interact with the SSC through the sharing of 
minutes.  
The DSMB will be responsible for: 
 
 
Examining accumulated safety, efficacy, and other relevant data at pre-specified 
points during the course of the study in order to make recommendations concerning 
continuation, termination, or modification of the studies 
 
 
Reviewing major study design modifications proposed by the SSC prior to 
implementation of those modifications 
 
 
Reviewing the general progress of the studies as regards such issues as subject 
accrual, study conduct, and protocol violations 
 
 
Providing expert advice  to the SSC on an ad hoc basis regarding matters such as 
safety concerns or diagnostic evaluations in individual subjects 
 
Based on the results of its deliberations, the DSMB can recommend continuation of the 
studies unchanged, study interruption, study termination, modification of the studies, or 
alteration in the DSMB monitoring plan. 


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11 DATA COLLECTION, STUDY RECORDS, SITE 
MONITORING, AND ADVERSE EXPERIENCE 
REPORTING 
11.1 STUDY RECORDS 
11.1.1 RECORD TO BE KEPT 
This trial will use electronic remote data capture (eRDC). However, the impracticalities of 
real-time data entry in busy clinics are recognized. Therefore, data from evaluations (see 
Section 6 above) will be initially captured on paper work-sheets (essentially paper mock-ups 
of the electronic data capture screens) for subsequent entry to the eRDC system. 
Data capture, recording and entry will be the responsibility of site staff (site investigator, site 
coordinator, clinical evaluator); details of which members of site staff are responsible for 
specific activities will be recorded in the site delegation log. 
11.1.2 Data to be collected for each subject  
The following information will be collected and retained for each study subject. A study file 
will be created and maintained for each subject, will all relevant documentation filed in date 
order. 
• 
Documentary evidence of diagnosis of DMD. 
The original (top copy) of the signed informed consent form (and assent from child if 
appropriate), as well as originals of any subsequent re-consent forms that might be 
required. 
• 
Contact details form, to include name, address, shipping address and telephone 
number of child and parent(s)/guardian (if parents live separately, contact details for 
both parents to be sought), and name, address and telephone number of an alternative 
contact (e.g., grandparent) to be used in the event of apparent loss to follow-up. 
• 
Completed worksheets and questionnaires for all evaluations and all visits (see Section 
6 above and Manual of Operations). 
• 
Copies of laboratory reports, findings on DXA scans, spine and wrist X-rays, 
echocardiograph, ECG. 
• 
Copies of correspondence to and from other health professionals involved in the child’s 
care (e.g. family physician) where that correspondence has a possible bearing on the 
child’s participation in this trial (e.g. copy of letter to family physician indicating that the 
child is participating in this trial). 
• 
Copies of correspondence to and from the clinical trials supplies company (e.g., initial 
fax to confirm contact details for shipping of drug supply, subsequent faxes advising on 
drug dosage following review at follow-up visits). 
• 
Copies of correspondence (including notes of telephone calls) with the family in 
connection with the child’s participation in this trial. 
• 
Copies of correspondence (including notes of telephone calls) with the NCTU in 
connection with the child’s participation in this trial. 


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• 
Copies of correspondence (including notes of telephone calls) with the MSG-CC in 
connection with the child’s participation in this trial. 
A record of the fact that the child is participating in a clinical trial will be recorded in his 
general medical records, and a copy of the signed informed consent form will be provided to 
the appropriate clinic be kept in those records. 
 
11.1.3 Site master file 
In addition to the subject-specific Study Files, each site will also maintain a Site Master File, 
containing the following documents and materials. 
• 
Investigator site information (names and brief CVs for all personnel at site engaged in 
the trial, with indication of their role and evidence of their suitability by training and 
experience for that role, including training in Human Subject Research; delegation & 
authorized signature log). 
• 
Sub-contract with site and any relevant financial agreements 
• 
Site initiation letter 
• 
Copies of general communications with NCTU and MSG-CC (e.g., newsletters, records 
of PI meetings, records of general correspondence (including notes of telephone calls) 
regarding trial conduct).  
• 
Signed protocol and protocol amendments (if any) 
• 
Copy of Investigators Brochure / Summary of Product Characteristics 
• 
Central approvals (regulatory and central / national REC/IRB communications) where 
applicable, including progress & safety reporting to the appropriate bodies 
• 
Local approvals (local REC/IRB communications and any other locally required 
permissions, including progress & safety reporting to the appropriate bodies). 
• 
Master copy of subject information sheet(s) and consent form(s) (country- or site- 
specific translated and otherwise adapted versions). 
• 
A note stating the location of all source documents. 
• 
Laboratory documentation (e.g., local laboratory ranges, current 
accreditation/certification) 
• 
Insurance statement (where required) 
• 
Screening log 
• 
Reports of monitoring visits 
 
11.2 Maintaining confidentiality of medical records 
At randomization, unique non-informative identification numbers will be assigned by the site 
principal investigator to study subjects. The subject identification number will be the principal 
means of identifying study subjects. The subject identification number will be used on all 
documents relating to that subject, in eRDC and as the link between all study data files. 
Recording ‘strong’ identifiers (in particular, name and/or address) on study documents should 
be the exception rather than the norm. Such details will however be needed on informed 
consent forms, subject contact forms, correspondence with other health professionals and 
correspondence with the clinical trials supply company. Strong identifiers may also appear on 


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original laboratory reports and findings on DXA scans, spine and wrist X-rays, 
echocardiograph, ECG; such identifiers should be removed and replaced by the subject 
identification number on any copies of reports etc. submitted for central monitoring, review 
and/or analysis.  They will not, however, be entered into the central database. 
Source documents are the original documents where that source data was recorded; this 
could be the subjects’ medical file/records, laboratory reports, dispensing logs or the trial 
worksheets. Paper copies of all source documents should be stored under double lock 
(locked filing cabinet or cupboard, in a locked room) in individual subject Study Files at each 
site; only authorized study personnel (as indicated in the site delegation log) should have 
access to these records. Particular care should be exercised to ensure the confidentiality of 
any documents (e.g., consent forms, subject contact forms, correspondence with the clinical 
trials supply company) containing both identifying subject information (in particular, name 
and address) and the link to the subject identification number. Source documents shall be 
maintained at site as per local policy and/or national/local legislative requirement for data 
retention for clinical trials. 
In conformance with HIPAA regulations, no records or other documents containing ‘strong’ 
identifiers (e.g., name, address) should be released off-site unless it is so stated in the 
consent form. Records and forms (e.g. worksheets, questionnaire) that are pseudo-
anonymized (e.g., display subject identification number and initials, but not strong identifiers) 
may be released to authorized members of the NCTU and/or MSG-CC to facilitate central 
monitoring and data checks. The consent/subject information sheet will make it clear that this 
level of data release will be allowed. All staff at NCTU and MSG-CC who may see pseudo-
anonymized data or (in the case of the site monitor) fully identifiable data will be bound by 
explicit written codes of confidentiality. 
No names or other personal identifiers except for initials and date of death will be collected in 
the central database. Gender, date of birth, race and ethnicity will be collected solely for the 
purpose of mandated reporting and statistical analysis. 
All data files and other research documents (e.g., copies of pseudo-anonymized worksheets 
or correspondence with a site regarding a specific study subject) at the NCTU and at MSG-
CC will be kept under double lock and will be accessible only to authorized study personnel. 
Communication by fax will use a secure fax machine in a room not accessible to 
unauthorized individuals. No individual identifiers (other than subject identification number) 
will be displayed on data listings for internal use. All data listings will be shredded before 
recycling. No individual identifiers will ever be included in any published data listing, nor will 
any individual subject be identified in any publications from this study. 
Electronic data collected throughout the course of this study will be retained indefinitely. Data 
for an enrolled subject will be removed from the system and destroyed only at the written 
request of the subject (or his parent/guardian). Computerized data will be stored in Oracle 
databases residing on University of Rochester computer systems. Several layers of security 
will protect the database from unauthorized access. The University of Rochester’s 
Information Systems Department (ISD) and the Heart Research Follow up Program provide 
network level security, including password maintenance, firewall and antivirus protection, 
intruder tracking, regular backups, and disaster recovery. The MSG-CC employs additional 
password protection for access to folders containing confidential research data. User IDs and 
initial passwords will be assigned by the MSG-CC and transmitted to the users via secure 
email. NIH guidelines regarding the length, content, and frequency of changing of passwords 
will be followed.  
If a FOR-DMD subject elects to participate in another Duchenne MD clinical trial that allows 
for concurrent participation in FOR-DMD, some data, including (but not limited to) FOR-DMD 
subject ID, mutation information,  and FOR-DMD treatment regimen will need to be shared 
with staff/data managers affiliated with the other trial.  At no time prior to completion of the 
FOR-DMD Month 36 visit will the unblinded FOR-DMD treatment regimen be shared with the 


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subject/family or study personnel from either trial for the purpose of allowing concurrent 
participation in another trial.  Prior to completion of the Month 36 visit, a subject/family will be 
unblinded to FOR-DMD treatment regimen only in case of a medical emergency that 
warrants knowledge of the treatment regimen. If a subject elects to participate in both FOR-
DMD and another clinical trial, concurrently, the subject will be asked to sign a separate 
consent form for this purpose, giving permission for the FOR-DMD Team to share that 
subject’s data (i.e., treatment regimen) with the other trial. 
 
11.3 DATA MANAGEMENT AND QUALITY ASSURANCE 
11.3.1 Division of responsibilities 
11.3.1.1 
Site responsibility 
Site investigators, clinical evaluators and coordinators will be responsible for collecting data 
from the study subject, and from evaluations performed on the subject during the course of 
the trial. They will keep all source documents, worksheets and questionnaires related to each 
subject in a subject-specific Study File which will be kept in a secure area, accessible only to 
authorized study personnel. The study coordinators will be responsible for entering all data 
for a given subject visit into the online data management system within 5 working days of the 
conclusion of the visit. Where the online system indicates data entry problems the site 
coordinator will be responsible for investigating, and if necessary correcting, the flagged 
items. The site coordinator will also be responsible for resolving queries identified by the 
central data management group (MSG-CC) in a timely fashion (within one week of 
notification of the query). 
11.3.1.2 
MSG-CC (Statistical/Data Management Center) responsibilities  
Data Management staff at the MSG-CC will be responsible for data collection, processing, 
management and query processes, and the timely delivery of an accurate and complete 
database to the MSG Biostatistics Center. The study will use electronic web-based data 
entry using the clinical data-management system produced by eResearch Technologies 
(EXPeRT). The EXPeRT system is currently licensed to the Heart Research Follow-up 
Program. The MSG-CC will use the system deployed on Heart Research servers. MSG-CC 
will partner with Heart Research for actual system and database development. 
MSG-CC personnel will train site coordinators in the use of the system, provide user IDs and 
passwords to all authorized users, and monitor data security and integrity. The MSG-CC will 
also develop online data checking and validation tools to identify potential errors at the time 
of data entry, as well as batch programs for querying suspect data after data entry. They will 
provide a user guide (paper and online) to all users and will maintain a ‘help desk’ for 
answering questions and resolving user problems via phone and email. The MSG-CC will 
create programs to report on data completeness and quality, to meet DSMB requirements, 
and any other blinded reports deemed necessary for the successful implementation of the 
trial. At the conclusion of the study the MSG-CC will clean and lock all study databases, and 
provide a final copy of all data to the study biostatistician for analysis.  Unblinded data 
reports will be produced by the un-blinded biostatistics programmer. 
11.3.2 Data flow and management 
The EXPeRT system supports the collection and management of clinical data through 
several integrated subsystems that use a common relational database to consistently store 
the clinical data. A web-enabled portal provides access to the system services. The system 
is configured to have data entered electronically at the investigational sites, with at-source 
real-time data editing and correction. The underlying foundation of the system provides the 


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capability to define data editing rules for ensuring the quality and consistency of the clinical 
data, a query management process to track data discrepancies and their resolutions, and 
source monitoring and verification of the clinical data. 
The EXPeRT System provides audit trail, security mechanisms, and electronic signature 
capabilities that meet FDA 21 CFR Part 11 requirements regarding electronic records and 
electronic signatures. The Heart Research Follow-up Program’s use of this system meets 
FDA requirements for the validation of off-the-shelf software. An implemented quality system 
of documented policies and procedures governs the use of the EXPeRT System by the Heart 
Research Follow-up Program at the University of Rochester. The major components of the 
data management environment that will support the collection, processing, and reporting of 
data collected for this study are presented in Fig. 11. The diagram identifies the individual 
applications, databases storing the data, and points of user interface with the various 
applications. The Coordination Data Center (CDC) has a full complement of staff that 
effectively manages various clinical studies and clinical trials with this electronic data 
management system. This database permits data expansion, easy updating, and rapid 
retrieval; it has simplified report-generating routines and audit trail component.  
Figure 10.1 Major components of the EXPeRT-based electronic clinical data 
management system.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eDM is the electronic data management; eDE is the electronic data entry; and eRC is the 
electronic research community, the portal through which the eDE is accessed. 
11.3.3 Quality control  
All submitted data will be subject to an extensive computer edit-checking process for 
completeness, internal consistency, identification of numerical values outside specified 
rational limits, invalid codes, subject identification errors, and date errors. 
The CDC uses a tape backup routine consisting of full nightly, weekly, and monthly backups, 
with tapes moved to an off-site location on a quarterly basis to cover a physical disaster at 
the CDC. All servers and major computers are housed in a temperature-controlled room. The 
computers are provided with an uninterruptible conditioned power supply to maintain smooth 
current, with battery power to facilitate a safe shutdown in the event of a complete power 


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failure. All subject information stored on the computerized database will be identifiable only 
by a unique subject identification number. The computerized database will be provided with 
“password” security so that only authorized persons will have access to the information within 
the database. 
11.3.4 Staff Training 
Site staff will be trained on the data entry system at the beginning of the project. If turnover 
occurs at the site, new staff will be trained as needed. On-line user manuals and help 
screens are available at all times. Call in ‘help desk’ support will be available on a schedule 
that will allow all sites a minimum 3 hour a day call in window.  
11.3.5 Quality assurance 
To assure the quality of the trial conduct and data, the NCTU and MSG will monitor the 
progress of the study on a day to day basis and provide support to sites. Elements of 
progress assessment monitoring and quality assurance will include tracking recruitment 
rates, compliance with visit schedules, timeliness and completeness of electronic data entry, 
compliance with adverse event reporting etc. The large number and geographical dispersion 
of sites in this trial necessitate a mixture of central and site monitoring to check for regulatory 
compliance and data entry accuracy. All monitoring findings will be reported and followed up 
with the appropriate persons in a timely manner. 
 
11.4 MONITORING 
11.4.1 Central monitoring  
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) will be reviewed and stored at the University of 
Rochester prior to site authorization/initiation. (For less experienced sites, a site initiation visit 
may be conducted by the Site Monitor) 
11.4.2 Site monitoring  
In compliance with GCP guidelines and sound clinical research principles, a monitoring plan 
will be developed. The monitor will visit each site when the first subject has been on study 
drug for 3 months, annually thereafter and at close out. While at the site, the monitor will: 
• 
Review 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;  
• 
Review site REC/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; 


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• 
Ensure that laboratory results conform to study standards and that investigations 
required to be transmitted centrally are compatible;  
• 
Collect copies of de-identified DXA scans (N/A in Germany) and EKG/Echo reports to 
transport to the Project Manager (either in UK or in Rochester, as appropriate).  
 
Reports of these visits will be provided to the NCTU (charged with seeing protocol 
compliance) and the University of Rochester (study sponsor). Each site will receive a report 
on the visits to that site, with indications of required actions (if any).  The Project Managers in 
will periodically review the site monitoring reports for their area of oversight (EU or US/CAN) 
with the lead project investigators (Dr. Bushby or Dr. Griggs) or the Chief Medical 
Coordinator.. 
 
 
12 HUMAN SUBJECTS 
12.1 Compliance with Ethical and Regulatory Guidelines 
 
The site investigator will be responsible for assuring that the clinical study is performed in 
accordance with GCP guidance documents and all other regulations and guidance pertaining 
to the conduct of clinical trials in the participating countries (US: GCP guidance; all EU 
countries: EU Clinical Trials Directive (2004) and its enactment into legislation in each 
participating EU country, and the Declaration of Helsinki (revised version of Edinburgh, 
Scotland, 2000); UK: Research Governance Framework for Health and Social Care (2nd 
edition)); Canada GCP guidance;  Italy:  Decreto legislativo 24 giugno 2003, n. 211 
http://oss-sper-clin.agenziafarmaco.it/normativa/dlgs_211_24-6-03_Dir_UE_sper.pdf; 
Germany:   In accordance with the provisions of the AMG and the GCP regulations, the 
Federal Data Protection Act or the applicable /Land/ Data Protection Act, the requirements of 
Good Clinical Practice (GCP) and in compliance with the Declaration of Helsinki, as 
amended. 
 
12.2 Institutional Review Board (IRB) Review and Informed 
Consent 
Informed consent will be obtained from the parents/guardians (with legal authority to consent 
on behalf of the child) of the boys and an assent process appropriate to the age of each boy 
will be carried out. The consent and assent will be obtained by the research coordinator and 
site investigator prior to initiation of any evaluations. 
As part of the assent process, the boy will be told that when he comes for his regular doctor’s 
visit that the doctor would like to write some of the information down to use in a big science 
project to see which way of taking his medicine helps the most and causes the least amount 
of gaining weight, feeling upset, or having weaker bones. He will be asked if he has any 
questions and if he would like to be part of the study. 
The site investigator will explain the nature of the study and the risks of participation in the 
study to each parent and subject at an initial office visit in an unhurried discussion. A copy of 
the informed consent form and assent form will be given to the parents and subject to read. 
The site investigator will again explain thoroughly the experimental nature of the study and 
the risks of participation in the study to each family, prior to the boy entering the study and 
beginning the screening evaluations. If the subject and parents/guardians still wish to 


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participate in the study, the parent/guardian will sign and date the informed consent form 
along with the site investigator. The child will sign the assent form or give verbal assent. The 
original copy of the signed and dated consent and assent forms will be retained by the site 
investigator and one copy will be provided to the family.  
The protocol and model informed consent and assent documents will be reviewed by the 
NCTU’s and the University of Rochester’s Ethics Committee/IRB prior to distribution to each 
investigative site for IRB submission. Copies of the written approval and approved informed 
consent document will be provided to the NCTU and University of Rochester prior to 
enrolment of subjects. 
 
12.3 Subject Confidentiality 
 
The measurements and observations that will be recorded will take place during the routine 
out-patient visits that boys with DMD receive as standard of care. The data will be recorded 
in the patient medical chart but will then also be captured on the research forms. The 
information will be kept confidential and entered in the secure electronic database. All 
medical records and study data will be kept confidential. A confidential and unique subject 
identification number will be used to identify each subject’s research case report forms and 
all communications, in accordance with the Health Insurance Portability and Accountability 
Act. No names or other personal identifiers except for initials and date of death will be 
collected in the central database. Gender, date of birth, race and ethnicity will be collected 
solely for the purpose of mandated reporting and statistical analysis. Only site personnel and 
the clinical trials supplies company will have access to subject identities. The site monitor will 
see this information during site visits. All records will be kept in locked drawers. Information 
will not be released without written permission of the subject, except as necessary for 
monitoring by IRB, the FDA, the NINDS, the OHRP, and similar European regulatory bodies.  
 
Medical information to be obtained from the subjects will include demographics, medical 
history, the results of physical examination, and concomitant medication usage. Subjects will 
provide blood and urine specimens; they will have wrist and lateral spine x-rays, DXA’s, 
EEG’s, and ECHO cardiograms; they will have tests of forced vital capacity and muscle 
function. Each boy and a parent/guardian will be asked to fill out questionnaires about 
Quality of Life. The parent/guardian will fill out a questionnaire about satisfaction with the 
treatment and the PARSIII, Iowa Connors – Parent, SDQ and Revised Rutter scales to 
assess the boy’s behavioral changes. 
 
All study records will be maintained for 10 years after the end on the study or 2 years post 
marketing or 2 years after shipment and delivery of the drug for investigational use is 
discontinued and FDA has been so notified, whichever is longer.  
 
12.4 Study Modification/Discontinuation 
 
The study may be modified or discontinued at any time by the IRB, the NINDS, the OHRP, 
the FDA, or other government agencies as part of their duties to ensure that research 
subjects are protected.


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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13 PUBLICATION OF RESEARCH FINDINGS 
 
The members of the FOR-DMD SSC will be responsible for ensuring that this protocol is 
listed at the clinicaltrials.gov website and that information at the website relating to study 
design and conduct is appropriately updated during the course of the study. 
 
Results from the trial, whether positive or negative, will be submitted for publication.  
 
All articles utilizing data on subjects recruited in the study must acknowledge support from 
the NIH. 
 
The FOR DMD Steering Committee will serve as the Publication Committee for review of the 
proposed content and authorship of all papers based on study data. This review should occur 
before data are released for preparation of abstracts or papers. A Publication Policy 
Committee has been established to develop a policy on the authorship of papers reporting 
study data. 
 


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muscular dystrophy and myotonic dystrophy.  Proceedings of 107th ENMC 
Workshop. " Neuromuscular Disorders 13: 166-172. 


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Bushby K, Finkel R, et al. (2010) "Diagnosis and management of Duchenne muscular 
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Lancet Neurol.;9(1):77-93. Review. 
Bushby K, Finkel R,et al. (2010). " Diagnosis and management of Duchenne muscular 
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Carpenter JR, Roger JH, Kenward MG (2013).  "Analysis of longitudinal trials with protocol 
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multiple imputation."  J Biopharm Statist 23:1352-1371. 
Carter, G. T. and C. M. McDonald (2000). "Preserving function in Duchenne dystrophy with 
long-term pulse prednisone therapy." American Journal of Phys Med Rehabilitation 
79: 455-458. 
Collett, B. R., J. L. Ohan, et al. (2003). "Ten-year review of rating scales. V: scales assessing 
attention-deficit/hyperactivity disorder." J Am Acad Child Adolesc Psychiatry 42(9): 
1015-1037. 
Collett, B. R., J. L. Ohan, et al. (2003). "Ten-year review of rating scales. VI: scales 
assessing externalizing behaviors." J Am Acad Child Adolesc Psychiatry 42(10): 
1143-1170. 
Connolly, A., J. Schierbecker, et al. (2002). "High dose weekly oral prednisone improves 
strength in boys with Duchenne Dystrophy.   ." Neuromuscul Disorders 12: 917-925. 
Crabtree NJ, Roper H, et al. (2010). " Regional changes in bone area and bone mineral 
content in boys with duchenne muscular dystrophy receiving corticosteroid therapy." J 
Pediatr. 156(3):450-5.  
D'Agostino RB (1998). " Propensity score methods for bias reduction in the comparison of a 
treatment to a non-randomized control group. Stat Med. 1998 Oct 15;17(19):2265-81 
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left ventricular disfunction in Duchenne muscular dystrophy." Journal of American 
College of Cardiology 45: 855-857. 
Dubowitz, V. and M. e. a. Kinali (2002). "Remission of clinical signs in early Duchenne 
Dystrophy on intermittent low-dosage prednisolone therapy." European Journal of 
Paediatric Neurology 6: 153-159. 
Eagle, M., S. V. Baudouin, et al. (2002). "Survival in Duchenne muscular dystrophy: 
improvements in life expectancy since 1967 and the impact of home nocturnal 
ventilation." Neuromuscular Disorders 12(10): 926-929. 
Escolar DM, Hache LP et al (2011). " Randomized, blinded trial of weekend vs daily 
prednisone in Duchenne muscular dystrophy." Neurology 77(5):444-52. 
Fenichel, G. M., J. M. Florence, et al. (1991). "Long-term benefit from prednisone therapy in 
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Fenichel, G. M., J. R. Mendell, et al. (1991). "A comparison of daily and alternate-day 
prednisone therapy in the treatment of Duchenne muscular dystrophy." Archives of 
Neurology 48(6): 575-579. 
Griggs RC, Herr BE et al. (2013) "Corticosteroids in Duchenne muscular dystrophy: major 
variations in practice." Muscle Nerve 48(1): 27-31. 
Griggs, R. C., R. T. Moxley, 3rd, et al. (1993). "Duchenne dystrophy: randomized, controlled 
trial of prednisone (18 months) and azathioprine (12 months)[see comment]." 
Neurology 43(3 Pt 1): 520-527. 


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Griggs, R. C., R. T. Moxley, 3rd, et al. (1991). "Prednisone in Duchenne dystrophy. A 
randomized, controlled trial defining the time course and dose response. Clinical 
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Herr BE, Hart KA, et al. (2008). Surrogate completion of the Treatment Satisfaction 
Questionnaire for Medication for a trial of corticosteroids in Duchenne muscular 
dystrophy.  Neurother; 5:490. 
Hinton, V. J., N. E. Nereo, et al. (2006). "Social behavior problems in boys with Duchenne 
muscular dystrophy." J Dev Behav Pediatr 27(6): 470-476. 
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& Sons. 
Kinali, M., E. Mercuri, et al. (2002). "An effective, low-dosage, intermittent schedule of 
prednisolone in the long-term treatment of early cases of Duchenne dystrophy." 
Neuromuscular Disorders 12 Suppl 1: S169-174. 
Lippuner, K., J. P. Casez, et al. (1998). "Effects of deflazacort versus prednisone on bone 
mass, body composition, and lipid profile: a randomized, double blind study in kidney 
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Wiley & Sons. 
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prednisone in juvenile chronic (or rheumatoid) arthritis: a relatively bone-sparing 
effect of deflazacort." Pediatrics 88(3): 428-436. 
Lunceford, J. K. and M. Davidian (2004). "Stratification and weighting via the propensity 
score in estimation of causal treatment effects: a comparative study." Stat Med 
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Main M, Kairon H, et al. (2003)."The Hammersmith functional motor scale for children with 
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Mayhew A, Cano S,et al. (2011). Moving towards meaningful measurement: Rasch analysis 
of the North Star Ambulatory Assessment in Duchenne muscular dystrophy. Dev Med 
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prognostic marker in patients with Duchenne muscular dystrophy." Am J Respir Crit 
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prevalence, treatment and prevention [Report of a muscular dystrophy campaign 
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Quinlivan R, Shaw N, Bushby K. (2010). " 170th ENMC International Workshop: bone 
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APPENDIX A. DECLARATION OF HELSINKI 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th World Medical Association General Assembly Helsinki, Finland, June 
1964 and amended by the 29th World Medical Association General Assembly, Tokyo, Japan, 
October 1975 35th World Medical Association General Assembly, Venice, Italy, October 
1983 41st World Medical Association General Assembly, Hong Kong, September 1989 48th 
World Medical Association General Assembly, Somerset West, Republic of South Africa, 
October 1996 and the 52nd World Medical Association General Assembly, Edinburgh, 
Scotland, October 2000 
 
A. Introduction 
1. The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other subjects in medical research 
involving human subjects. Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people. The 
physician's knowledge and conscience are dedicated to the fulfilment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my patient will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act only in the patient's interest when 
providing medical care which might have the effect of weakening the physical and mental 
condition of the patient." 
4. Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
5. In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology 
and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic 
methods must continuously be challenged through research for their effectiveness, 
efficiency, accessibility and quality. 
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human beings 
and protect their health and rights. Some research populations are vulnerable and need 
special protection. The particular needs of the economically and medically disadvantaged 
must be recognized. Special attention is also required for those who cannot give or refuse 
consent for themselves, for those who may be subject to giving consent under duress, for 
those who will not benefit personally from the research and for those for whom the research 
is combined with care. 


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9. Research investigators should be aware of the ethical, legal and regulatory requirements 
for research on human subjects in their own countries as well as applicable international 
requirements. No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration. 
 
B. Basic Principles for All Medical Research 
1. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
2. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation. 
3. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
4. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol. This protocol should be submitted 
for consideration, comment, guidance, and where appropriate, approval to a specially 
appointed ethical review committee, which must be independent of the investigator, or any 
other kind of undue influence. This independent committee should be in conformity with the 
laws and regulations of the country in which the research experiment is performed. The 
committee has the right to monitor ongoing trials. The researcher has the obligation to 
provide monitoring information to the committee, especially any serious adverse events. The 
researcher should also submit to the committee, for review, information regarding funding, 
sponsors, institutional affiliations, other potential conflicts of interest and incentives for 
subjects. 
5. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in this 
Declaration. 
6. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. The 
responsibility for the human subject must always rest with a medically qualified person and 
never rest on the subject of the research, even though the subject has given consent.  
7. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others. This does not preclude the participation of healthy volunteers in medical 
research. The design of all studies should be publicly available. 
8. Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians should cease any investigation if the risks are found to 
outweigh the potential benefits or if there is conclusive proof of positive and beneficial 
results. 
9. Medical research involving human subjects should only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the subject. This is especially 
important when the human subjects are healthy volunteers. 
10. Medical research is only justified if there is a reasonable likelihood that the populations in 
which the research is carried out stand to benefit from the results of the research. 
11. The subjects must be volunteers and informed subjects in the research project. 


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12. The right of research subjects to safeguard their integrity must always be respected. 
Every precaution should be taken to respect the privacy of the subject, the confidentiality of 
the patient's information and to minimize the impact of the study on the subject's physical 
and mental integrity and on the personality of the subject. 
13. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and the 
discomfort it may entail. The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without reprisal. 
After ensuring that the subject has understood the information, the physician should then 
obtain the subject's freely-given informed consent, preferably in writing. If the consent cannot 
be obtained in writing, the non-written consent must be formally documented and witnessed. 
14. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or may 
consent under duress. In that case the informed consent should be obtained by a well-
informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
15. For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the site investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law. These 
groups should not be included in research unless the research is necessary to promote the 
health of the population represented and this research cannot instead be performed on 
legally competent persons. 
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent 
to decisions about participation in research, the site investigator must obtain that assent in 
addition to the consent of the legally authorized representative. 
17. Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population. The 
specific reasons for involving research subjects with a condition that renders them unable to 
give informed consent should be stated in the experimental protocol for consideration and 
approval of the review committee. The protocol should state that consent to remain in the 
research should be obtained as soon as possible from the individual or a legally authorized 
surrogate. 
18. Both authors and publishers have ethical obligations. In publication of the results of 
research, the site investigators are obliged to preserve the accuracy of the results. Negative 
as well as positive results should be published or otherwise publicly available. Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared in 
the publication. Reports of experimentation not in accordance with the principles laid down in 
this Declaration should not be accepted for publication. 
 
C. Additional Principles for Medical Research Combined with Medical Care 
19. The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value. When 
medical research is combined with medical care, additional standards apply to protect the 
patients who are research subjects. 
20. The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods. This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists. 


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21. At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by the 
study. 
22. The physician should fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship. 
23. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from the 
patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic 
measures, if in the physician's judgment it offers hope of saving life, re-establishing health or 
alleviating suffering. Where possible, these measures should be made the object of 
research, designed to evaluate their safety and efficacy. In all cases, new information should 
be recorded and, where appropriate, published. The other relevant guidelines of this 
Declaration should be followed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL ADDENDUM  
 
FOR-DMD Flow Sheet for Data 
 
Subject data collected at site where subject was recruited/randomized 
 
(Data is raw at this point and the FOR-DMD staff performing the procedure are entering 
the raw data onto a data collection form as it is gathered) 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
↓ 
Data entered into EXPeRT (online data management system) by site where subject had 
visit 
 
(DATA MAY BE SEEN BY STUDY COORDINATOR, PI, PHYSICAL THERAPIST, 
DATA ENTRY PERSON – ESSENTIALLY ALL OF FOR-DMD STAFF AT THE SITE – MAY 
ALSO BE REVIEWED (IF REQUESTED) BY  SITE’S LOCAL ETHICS OR R&D 
COMMITTEE; ALSO WILL BE SEEN BY SITE MONITOR FOR GIVEN COUNTRY 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
↓ 
All data entered in EXPeRT has only a SUBJECT ID attached, however one form also 
shows date of birth (SUBJECT ID is a combination of country letters and number, and 
sequential numbers – i.e., USA01R02, where USA is country, 01 is Rochester site, R means 
subjects was randomized, and 02 is the sequential order of subjects randomized at site) – 
this (and Date of Birth) is the only identifier entered in the online data system at this stage 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
↓ 
Data entered in EXPeRT (only has subject ID/DOB) may be reviewed by the following: 
 
 
University of Rochester FOR-DMD Data Management Team  
 
 
University of Rochester Biostatistician(s)  
 
 
University of Rochester Project Manager and Lead Principal Investigator 
University of Newcastle FOR-DMD Management Team, including Project 
Manager and PI 
 
 
NIH/NINDS staff associated with FOR-DMD review/approval 
 
 
Data Safety Monitoring Board (assigned by NIH/NINDS) 
 
 
Medical Monitor for FOR-DMD trial 
 
 
FDA (for IND) 
Competent authorities in other countries (MHRA in UK, BfARm in Germany, 
Health Canada, AIFA in Italy) 
 
 
 
To meet regulations or for reasons related to this research, the study investigator may share 
a copy of the consent form and records that identify the subject with the following people:   
• 
The University of Rochester  
• 
The Institute for Human Genetics in the United Kingdom 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
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• 
The study sponsor: National Institutes of Health, which is a part of the Department of 
Health and Human Services (a federal government department) 
• 
The Newcastle upon Tyne Hospital’s NHS Foundation Trust (the institution that 
contracts with the drug supply company) 
• 
Food and Drug Administration (FDA) (the governmental agency that oversees research 
of investigational agents in the United States) 
• 
The regulatory agencies that are similar to FDA in the other countries participating in 
this study 
• 
The Institutional Review Board (IRB) or Research Ethics Committee (IEC) [INSERT 
APPROPRIATE NAME] (an institutional committee that makes certain that your child’s rights 
are protected) 
• 
The Newcastle Clinical Trials Unit, Institute of Health and Society, Newcastle University 
(the center that manages the clinical aspects of this study) 
• 
The Muscle Study Group Coordination Center at the University of Rochester (the 
center that manages the information (data) from the study) 
• 
The Department of Biostatistics at the University of Rochester (the center that will be 
analyzing the data and will prepare tables, graphs and figures for publication purposes) 
• 
Catalent (the company that is supplying the study drugs) 
• 
“Instituto Auxologico Italiano IRCCS, in Milan Italy (the center that will be analyzing the 
DEXA scans and bone measurements using blood and urine samples) 
• 
MRC Neuromuscular Center BioBank in Newcastle upon Tyne, UK for use in future 
approved research projects (Optional)  
• 
Data Safety Monitoring Board (DSMB) (the committee that follows the study data 
several times during any given year for any safety concerns as well as how quickly the study 
is enrolling) 
• 
Medical Monitor (the doctor who monitors the day to day safety of people who are in 
the study) 
• 
The research investigators at the OTHER clinical centers that are participating in the 
study. 
 
 
Data flow and management 
The EXPeRT system supports the collection and management of clinical data through 
several integrated subsystems that use a common relational database to consistently store 
the clinical data. A web-enabled portal provides access to the system services. The system 
is configured to have data entered electronically at the investigational sites, with at-source 
real-time data editing and correction. The underlying foundation of the system provides the 
capability to define data editing rules for ensuring the quality and consistency of the clinical 
data, a query management process to track data discrepancies and their resolutions, and 
source monitoring and verification of the clinical data. 
The EXPeRT System provides audit trail, security mechanisms, and electronic signature 
capabilities that meet FDA 21 CFR Part 11 requirements regarding electronic records and 
electronic signatures. The Heart Research Follow-up Program’s use of this system meets 
FDA requirements for the validation of off-the-shelf software. An implemented quality system 
of documented policies and procedures governs the use of the EXPeRT System by the Heart 
Research Follow-up Program at the University of Rochester. The major components of the 
data management environment that will support the collection, processing, and reporting of 
data collected for this study are presented in Fig. 11. The diagram identifies the individual 


FOR DMD study.  Study protocol v 3.2, 18 Dec 2019 
106
applications, databases storing the data, and points of user interface with the various 
applications. The Coordination Data Center (CDC) has a full complement of staff that 
effectively manages various clinical studies and clinical trials with this electronic data 
management system. This database permits data expansion, easy updating, and rapid 
retrieval; it has simplified report-generating routines and audit trail component.  
Major components of the EXPeRT-based electronic clinical data management system.  
 
 
 
 
 
 
 
 
 
 
 
 
 
eDM is the electronic data management; eDE is the electronic data entry; and eRC is the 
electronic research community, the portal through which the eDE is accessed. 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
DUCHENNE MUSCULAR DYSTROPHY: DOUBLE-BLIND RANDOMIZED 
TRIAL TO FIND OPTIMUM STEROID REGIMEN 
Study Acronym:  FOR-DMD 
Protocol Version:  3.2 
Clinical Phase:  Phase IV 
IND #:  109849 
Principal Investigators, Clinical Center 
Robert C. Griggs, M.D. 
Michela Guglieri, M.D. 
Principal Investigators, Biostatistics and Coordination Center 
Michael P. McDermott, Ph.D. 
Rabi Tawil, M.D. 
Version 1.0: February 10, 2012 
Version 2.0: February 16, 2021 
Supported by Grants U01 NS061799 (University of Rochester) and U01 NS061795 
(University of Rochester) from the National Institute of Neurological Disorders and 
Stroke (NINDS) 


SIGNATURES 
 
 
Michael P. McDermott, Ph.D. 
Date 
Co-Principal Investigator 
Director, MSG Biostatistics Center 
 
 
Rabi Tawil, M.D. 
Date 
Co-Principal Investigator 
Director, MSG Coordination Center 
 
 
Robert C. Griggs, M.D. 
Date 
Co-Principal Investigator 
Study Co-Chair 
18 Feb 2021          
Date 
2162021
 
Michela Guglieri, M.D. 
Co-Principal Investigator 
Study Co-Chair and Chief Medical Director 


TABLE OF CONTENTS 
Page 
1. STUDY OB ECTIVES 
............................................................................................... 1 
1.1. Primary Obective 
............................................................................................... 1 
1.2. Secondary Obective 
........................................................................................... 1 
2. STUDY DESIGN 
......................................................................................................... 1 
3. RANDOMIZATION AND BLINDING 
.................................................................... 2 
4. OUTCOME VARIABLES 
......................................................................................... 3 
4.1. Primary Outcome Variable 
................................................................................ 3 
4.2. Secondary Outcome Variables for Efficacy 
...................................................... 3 
4.3. Outcome Variables for Safety and Tolerability ............................................... 4 
4.4. Scoring Considerations 
....................................................................................... 5 
4.4.1. Timed Functional Tests 
............................................................................ 5 
4.4.2. Forced Vital Capacity (FVC) 
................................................................... 5 
4.4.3. Height and eight 
.................................................................................... 5 
4.4.4. Treatment Satisfaction uestionnaire for Medication (TS M) 
.......... 5 
4.4.5. Peds L Generic Core .............................................................................. 6 
4.4.6. Peds L Neuromuscular Module 
............................................................. 6 
4.4.7. Iowa Conners AS Parent Scale 
............................................................. 7 
4.4.8. PARS-III Scale 
.......................................................................................... 7 
4.4.9. Strength and Difficulties uestionnaire (SD) 
..................................... 7 
4.4.10. 
Revised Rutter Scale 
................................................................................. 8 
5. SAMPLE SIZE DETERMINATION 
........................................................................ 8 
5.1. Supporting Data and ustification for the Chosen Effect Sie 
........................ 8 
5.2. Sample Sie Determination for the Primary Outcome Variable 
.................. 10 
5.3. Sample Sie Considerations for Safety Outcomes 
.......................................... 11 
6. GENERAL DATA HANDLING AND STATISTICAL CONSIDERATIONS 
... 11
6.1. Analysis Cohorts ............................................................................................... 11 
6.2. General Considerations 
.................................................................................... 12 
6.3. Interim Analyses ............................................................................................... 13 
7. STATISTICAL ANALYSIS .................................................................................... 13 
7.1. Baseline Characteristics ................................................................................... 13 
7.2. Participant Disposition 
..................................................................................... 14 
7.3. Eposure to Study Medication 
......................................................................... 14 
7.4. Analysis of the Primary Outcome Variable 
.................................................... 15 
7.4.1. General Approach .................................................................................. 15 
7.4.2. Adustment for Baseline Characteristics 
.............................................. 16 
7.4.3. Verification of Model Assumptions 
....................................................... 16 
7.4.4. Primary Strategy for the Treatment of Missing Data 
......................... 16 
7.5. Analysis of the Secondary Outcome Variables for Efficacy 
.......................... 16 
7.5.1. Analysis of Continuous Outcome Variables Obtained at Each 
   Follow-up Visit........................................................................................ 
16 
7.5.2. Analysis of Continuous Outcome Variables Obtained at Annual 


   Visits 
................................
................................
........................................ 18 
7.5.3. Eamination of Treatment-by-Covariate Interactions ....................... 18 
7.5.4. Treatment of Missing Data for Secondary Outcome Variables 
......... 19 
7.5.5. Analyses of Individual NSAA Items 
...................................................... 19 
7.6. Analysis of Tolerability and Safety Outcomes 
................................................ 20 
7.6.1. Tolerability Outcomes 
................................
............................................ 20 
7.6.2. Adverse Events 
....................................................................................... 20 
7.6.3. Additional Safety Outcomes 
................................
.................................. 21 
7.7. Miscellaneous Analyses and Outcomes 
........................................................... 21 
7.7.1. Concomitant Medications 
................................
...................................... 21 
7.7.2. Blindedness Assessment 
................................
......................................... 22 
7.7.3. Protocol Deviations 
................................................................................ 22 
 
8. CHANGES FROM THE STUDY PROTOCOL 
.................................................... 22 
 
9. REFERENCES 
........................................................................................................ 23 
 
APPENDI: DATABASE MODIFICATIONS FOR ANALYSIS 
............................. 25 


 
1 
1.   STUDY OB ECTIVES
1.1.  Primary Obective 
The primary obective of this study is to compare the three most commonly used 
corticosteroid regimens (0.75mgkgday prednisone 0.75mgkgday prednisone 10 days 
on10 days off 0.9mgkgday deflaacort) with regard to functional outcome and 
participantparent satisfaction with treatment in boys with Duchenne muscular dystrophy 
(DMD) previously untreated with corticosteroid therapy.  The trial will address the 
pragmatic hypothesis that both daily prednisone and daily deflaacort will be of greater 
benefit in terms of function and participantparent satisfaction with treatment than 
intermittent prednisone given over a 36-month period. 
1.2.  Secondary Obective 
The secondary obectives are to compare the three corticosteroid regimens over a period 
of 36 months with regard to tolerability, adverse events, secondary functional outcomes 
and disease milestones, uality of life, and cardiac function. 
2.   STUDY DESIGN
FOR-DMD is an international multicenter, randomied, double-blind, controlled trial in 
which approimately 225 boys with proven DMD between the ages of 4 and 7 will be 
randomied at 32 sites in 5 countries to receive either daily prednisone (0.75 mgkg), 
daily deflaacort (0.90 mgkg), or intermittent (10 days on, 10 days off) prednisone (0.75 
mgkg) and followed for a minimum of 36 months.  Eligible boys will be those with 
confirmed DMD, age at least 4 years and under 8 years ability to rise independently 
from the floor and ability to maintain reproducible forced vital capacity (FVC) 
measurements.  Detailed eligibility criteria are provided in Sections 4.1 and 4.2 of the 
Study Protocol. 
Following provision of informed consent and screening and baseline visits to determine 
eligibility, randomiation to the study interventions will occur.  The boys will be 
followed prospectively and systematically for 36-60 months of double-blind observation.  
As described in the Study Protocol (Section 5.3), there is careful monitoring for 
participant safety and the design includes standardied management protocols for 
prophylais and treatment of adverse events, particularly those that are anticipated to 
occur with chronic corticosteroid treatment over the course of the trial. 
The Schedule of Activities is described in detail in Sections 6.1-6.3 of the Study Protocol.  
Assessments of the primary and secondary outcomes will be conducted at up to 12 in-
person visits (baseline, Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60).  Telephone 
contacts half-way between each visit will be made to inuire about adverse events and 
medication compliance and to aid in study retention.  The primary outcome variable will 
be based on data obtained through Month 36, but all participants will be followed for up 


 
 
2 
to 60 months until the last participant has completed the 36-month visit.  The core 
evaluations during each in-person visit are described in detail in the Study Protocol.  The 
dosage of study medication will be adusted as appropriate according to weight and, if 
necessary, adverse events.  Provisions for switching to daily prednisone in case of 
temporary interruption of study medication supply (e.g., due to epiration or loss) are 
provided in Section 5.1.2 of the Study Protocol.  Participants who withdraw from study 
medication will continue to be followed in the trial, if willing, even if they are 
participating in a clinical trial of an investigational treatment and the protocol for that 
trial allows concurrent participation in the FOR-DMD trial. 
 
 
3.   RANDOMIZATION AND BLINDING 
 
The randomiation process is described in Section 4.3.4 of the Study Protocol.  A 
programmer in the Muscle Study Group (MSG) Biostatistics Center will generate the 
randomiation plan using a SAS program, in accordance with the MSG Biostatistics 
Center SOPs.  The randomiation will be stratified by country and will include blocking 
to ensure balance among the treatment groups after a certain number of participants have 
been enrolled in each country. 
 
Assignment lists for each country will be generated for use in the enrollment module and 
a separate fill list will be generated for the clinical trials supply company prior to the start 
of the trial.  Randomiation will be initiated by the site investigatordesignee via a secure 
web-based system with username and password access.  After appropriate information 
verifying the participants eligibility and weight, the participant ID number, 
randomiation ID number, and starting dosage will be generated and sent to the clinical 
trials supply company.  Randomiation procedures should be completed at least 10 days 
prior to the baseline visit in order to allow the study medication to be shipped to the site 
in time to be provided to the participant by the site investigator at baseline visit. 
 
As described in Section 4.3.5 of the Study Protocol, the double-blind is facilitated by the 
preparation and packaging of study medication.  All study personnel, with the eception 
of a designated unblinded programmer and unblinded statistician in the MSG 
Biostatistics Center, will have access to the treatment assignments.  The chief roles of the 
unblinded programmer and statistician will involve preparing unblinded reports for 
closed sessions of meetings of the Data and Safety Monitoring Board (DSMB) they will 
not communicate with any other involved staff regarding study-related matters. 
 
The unblinded programmer in the MSG Biostatistics Center will prepare sealed 
emergency drug disclosure envelopes with individual treatment assignments for 
distribution to the sites as participants are enrolled.  Potential reasons for unblinding the 
treatment assignment for an individual participant include the following: 
 
 Occurrence of a medical emergency such that knowledge of treatment assignment 
is necessary for providing appropriate medical management. 


 
 
3 
 Desire of the participant to enroll in a clinical trial of an investigational treatment 
for which knowledge of the participants treatment assignment is reuired for 
eligibility (allowed only for participants who have completed the Month 36 visit). 
 udgment on the part of the site investigator that revelation of the participants 
treatment assignment is clinically warranted (only allowed for participants who 
have completed the Month 36 visit). 
 Temporary interruption of study medication supply that persists beyond 21 days, 
in which case knowledge of whether the participant has been assigned to a daily 
vs. intermittent corticosteroid regimen is reuired for participant safety (see 
Section 5.1.2 of the Study Protocol). 
 
In each case, unblinding will be restricted to those who have a need to know the identity 
of the treatment assignment, as outlined in Section 4.3.5 of the Study Protocol. 
 
 
4.   OUTCOME VARIABLES 
 
4.1.  Primary Outcome Variable 
 
The primary outcome variable is a three-dimensional (multivariate) outcome consisting 
of the following three components (each averaged over all post-baseline follow-up visits 
through Month 36): (1) rise from the floor velocity (2) forced vital capacity and (3) 
participantparent global satisfaction with treatment, as measured by the Treatment 
Satisfaction uestionnaire for Medication (TS M).  These components represent 
different but important aspects of the epected benefits of corticosteroid treatment. 
 
Two components of the primary outcome variable (rise from the floor velocity and FVC) 
were selected because of obvious clinical relevance.  They also relate to longer term 
outcomes (loss of ambulation and respiratory failure) that are impossible to capture in a 
study with 36-60 months of participant follow-up.  The third component of the primary 
outcome variable, global satisfaction with treatment, is essential for measuring the 
benefitside effect balance that is crucial to consider for a non-curative treatment in a 
chronic disease.  Importantly, all three components of the primary outcome variable are 
relatively straightforward and easy to measure. 
 
4.2.  Secondary Outcome Variables for Efficacy 
 
The secondary outcome variables for efficacy include the following (each averaged over 
all post-baseline follow-up visits): 
 
 Ten-meter walkrun velocity 
 Distance walked in 6 minutes (6M T) 
 North Star Ambulatory Assessment (NSAA) total score 
 TS M subscale scores (Effectiveness, Side Effects, Convenience) 
 Lean mass (raw value and percentage of total mass) (D A) 
 Range of motion at ankle dorsifleion (left and right sides) 


 
 
4 
 uality of life (Generic Peds L: Physical Functioning, Emotional Functioning, 
Social Functioning, School Functioning, Psychosocial Health, and total scores 
Neuromuscular disease-specific module: About My Neuromuscular Disease, 
Communication, About Our Family Resources, and total scores) 
 
Other secondary outcome variables, based on the NSAA, will include times from the 
baseline evaluation to loss of independent ambulation and time to loss of the ability to 
rise from the floor.  The time at loss of ambulation will be defined in two ways: (1) the 
post-baseline time when the participant was first classified as Unable on NSAA Item 2 
( alk 10 Meters) and (2) the first post-baseline time at which the participant was unable 
to perform the timed task of alkRun 10 Meters.  The time at loss of the ability to rise 
from the floor will be defined as the first post-baseline time at which the participant was 
unable to perform the timed task of Rise from the Floor. 
 
Transitions over time in other individual NSAA item scores will also be analyed. 
 
4.3.  Outcome Variables for Safety and Tolerability 
 
Measures of safety include the following: 
 
 Corticosteroid dosage 
 Adverse events (AEs) 
 Serious adverse events (SAEs) 
 Height, weight, body mass inde (BMI) 
 Vital signs (systolicdiastolic blood pressure, pulse) 
 D A bone outcomes (bone area, bone mineral content BMC, bone mineral 
density BMD, and Z-score in the lumbar spine bone area, BMC, BMD, and Z-
score in total body) 
 D A fat mass (raw value and percentage of total mass) and total mass 
 rist radiography outcomes (bone age, difference between chronological age and 
bone age) 
 Echocardiography and ECG outcomes (eection fraction, fractional shortening, PR 
interval, heart rate) 
 Iowa Conners AS
Parent scale scores (InattentiveOveractive IO, 
OppositionalDefiant OD, and total scores, IO score  10, OD score  9) 
 PARS-III scores (Peer Relations, Dependency, Hostility, Productivity, 
AnietyDepression, ithdrawal, and total scores, total score  72) 
 Strengths and Difficulties uestionnaire (SD) scores (Emotional Problems, 
Conduct Problems, Hyperactivity, Peer Problems, Prosocial, Eternaliing, 
Internaliing, Total Difficulties, and Impact scores) 
 Revised Rutter scale total score 
 Laboratory test results (urinalysis, serum chemistry, and hematology) 
 
Measures of tolerability include the following: 
 


 
 
5 
 Ability to complete the trial on the originally assigned dosage (for weight) of 
study medication 
 Ability to complete the trial without switching medication regimens (i.e., 
discontinuing study medication) 
 Ability to complete the trial 
 
4.4.  Scoring Considerations 
 
4.4.1. Timed Functional Tests 
 
For the time to rise from the floor and time to walkrun 10 meters measures, the value 
becomes infinite when the participant is not able to perform the task.  In the database, the 
values for these outcomes will be entered as 999.  These outcomes will be transformed 
using reciprocals for purposes of analysis, with those unable to perform the task being 
assigned a transformed value of ero.  This strategy, the use of a velocity-type measure 
rather than a time, has the following advantages: (1) the transformed values are 
approimately normally distributed and (2) like the other two components of the primary 
outcome variable, higher values of the outcome variable represent better performance.  It 
is becoming standard in the analysis of data from DMD clinical trials. 
 
4.4.2. Forced Vital Capacity (FVC) 
 
The summary measure of FVC will be taken as the maimum value (in liters) over the 
three trials performed. 
 
4.4.3. Height and eight 
 
Besides direct measures of height and weight, Z-scores and percentiles will be computed 
using CDC growth charts (https: www.cdc.govgrowthchartspercentiledatafiles.htm).  
Heights that were estimated using ulna length will not be included in the analyses. 
 
4.4.4. Treatment Satisfaction uestionnaire for Medication (TS M) 
 
 Effectiveness score  (Sum of Items 1-3  3)  100  18.  If one item is missing, 
then this is computed as (Sum of completed items  2)  100  12.  If more than 
one item is missing, then the score is missing. 
 Side Effects score  100 if Item 4  No otherwise, Side Effects score  (Sum of 
Items 5-8  4)  100  16.  If one item is missing, then this is computed as (Sum 
of completed items  3)  100  12.  If more than one item is missing, then the 
score is missing. 
 Convenience score  (Sum of Items 9-11  3)  100  18.  If one item is missing, 
then this is computed as (Sum of completed items  2)  100  12.  If more than 
one item is missing, then the score is missing. 
 Global Satisfaction score  (Sum of Items 12-14  3)  100  14.  If either Item 12 
or Item 13 is missing and Item 14 is non-missing, then this is computed as (Sum 
of completed items  2)  100  10.  If Item 14 is missing and Items 12 and 13 are 


 
 
6 
non-missing, then this is computed as (Sum of completed items  2)  100  8.  If 
more than one item is missing, then the score is missing. 
 
4.4.5. Peds L Generic Core 
 
Prior to computing scores, all items are reverse scored and linearly transformed to a 0-
100 scale: 0  100 1  75, 2  50, 3  25, 4  0. 
 
 Physical Functioning score  Mean of Items 1-8.  If 50 or fewer of the items are 
missing, then the mean is taken over the completed items.  If  50 of the items 
are missing, then the score is missing. 
 Emotional Functioning score  Mean of Items 1-5.  If 50 or fewer of the items 
are missing, then the mean is taken over the completed items.  If  50 of the 
items are missing, then the score is missing. 
 Social Functioning score  Mean of Items 1-5.  If 50 or fewer of the items are 
missing, then the mean is taken over the completed items.  If  50 of the items 
are missing, then the score is missing. 
 School Functioning score  Mean of Items 1-5.  If 50 or fewer of the items are 
missing, then the mean is taken over the completed items.  If  50 of the items 
are missing, then the score is missing. 
 Psychosocial Health score  Mean of all items included in the Emotional 
Functioning, Social Functioning, and School Functioning subscales.  If 50 or 
fewer of the items are missing, then the mean is taken over the completed items.  
If  50 of the items are missing, then the score is missing. 
 Total score  Mean of all items included in the instrument.  If 50 or fewer of the 
items are missing, then the mean is taken over the completed items.  If  50 of 
the items are missing, then the score is missing. 
 
4.4.6. Peds L Neuromuscular Module 
 
Prior to computing scores, all items are reverse scored and linearly transformed to a 0-
100 scale: 0  100 1  75, 2  50, 3  25, 4  0. 
 
 About My Neuromuscular Disease score  Mean of Items 1-17.  If 50 or fewer 
of the items are missing, then the mean is taken over the completed items.  If  
50 of the items are missing, then the score is missing. 
 Communication score  Mean of Items 1-3.  If 50 or fewer of the items are 
missing, then the mean is taken over the completed items.  If  50 of the items 
are missing, then the score is missing. 
 About Our Family Resources score  Mean of Items 1-5.  If 50 or fewer of the 
items are missing, then the mean is taken over the completed items.  If  50 of 
the items are missing, then the score is missing. 
 Total score  Mean of all items included in the instrument.  If 50 or fewer of the 
items are missing, then the mean is taken over the completed items.  If  50 of 
the items are missing, then the score is missing. 
 


 
 
7 
4.4.7. Iowa Conners AS -Parent Scale 
 
 InattentiveOveractive (IO) score  Sum of Items 1-5 
 OppositionalDefiant (OD) score  Sum of Items 6-10 
 Total score  Sum of Items 1-10 
 
4.4.8. PARS-III Scale 
 
For Items 1-4 and 15-18, scoring should be as follows: 
 
Never or Rarely  1, Sometimes  2, Often  3, Always  4 
 
For Items 5-14 and 19-28, scoring should be as follows: 
 
Never or Rarely  4, Sometimes  3, Often  2, Always  1 
 
 Peer Relations score  Sum of Items 1-4 
 Dependency score  Sum of Items 5-8 
 Hostility score  Sum of Items 9-14 
 Productivity score  Sum of Items 15-18 
 AnietyDepression score  Sum of Items 19-24 
 ithdrawal score  Sum of Items 25-28 
 Total score  Sum of Items 1-28 
 
If a 4-item subscale is missing more than 1 item or if a 6-item subscale is missing more 
than 2 items, then the score is missing.  Otherwise, the score is computed as the mean of 
the completed items  the total number of items on the scale (4 or 6). 
 
4.4.9. Strength and Difficulties uestionnaire (SD) 
 
Most items are scored as Not True  0, Somewhat True  1, and Certainly True  2.  The 
eceptions are for Items 7, 11, 14, 21, and 25 which are scored as Not True  2, 
Somewhat True  1, and Certainly True  0. 
 
 Emotional Problems score  Sum of Items 3, 8, 13, 16, and 24 
 Conduct Problems score  Sum of Items 5, 7, 12, 18, and 22 
 Hyperactivity score  Sum of Items 2, 10, 15, 21, and 25 
 Peer Problems score  Sum of Items 6, 11, 14, 19, and 23 
 Prosocial score  Sum of Items 1, 4, 9, 17, and 20 
 
If a subscale is missing more than 2 items, then the score is missing.  Otherwise, the score 
is computed as the mean of the completed items  5. 
 
 Eternaliing score  Sum of Conduct Problems and Hyperactivity scores 
 Internaliing score  Sum of Emotional Problems and Peer Problems scores 


 
 
8 
 Total Difficulties score  Sum of Emotional Problems, Conduct Problems, 
Hyperactivity, and Peer Problems scores 
 Impact score  0 if the child reports no difficulties.  Otherwise, this is computed 
as the sum of the UpsetDistress, Home Life, Friendships, Classroom Learning, 
and Leisure Activities items, each scored as Not at All  0, Only a Little  0, 
uite a Lot  1, and A Great Deal  2. 
 
4.4.10. Revised Rutter Scale 
 
The total score is the sum of Items 1-8. 
 
 
5.   SAMPLE SIZE DETERMINATION 
 
As originally planned, the primary outcome variable for the trial was to be three-
dimensional consisting of time to rise from the floor (log-transformed) averaged over all 
post-baseline visits during the 36-month follow-up period, forced vital capacity (FVC) 
averaged over all post-baseline visits, and (3) participantparent global satisfaction with 
treatment, as measured by the TS M, averaged over all post-baseline visits.  The primary 
statistical analysis was planned as a global test of the null hypothesis that the 
corticosteroid regimens do not differ with regard to any of the three outcomes against the 
alternative that they differ (in the same direction) with regard to at least one of the 
outcomes.  The sample sie was determined assuming that OBriens ordinary least-
suares (OLS) statistic OBrien, 1984 would be used to carry out this test.  The analyses 
will involve three separate pair-wise comparisons among the three treatment regimens 
each will be performed using a Bonferroni-corrected two-tailed significance level of 
0.017. 
 
5.1.  Supporting Data and ustification for the Chosen Effect Sie 
 
Eisting data from the trials comparing 0.75 mgkgday prednisone vs. placebo suggest 
that the effects of prednisone on the time to rise from the floor (log-transformed) and 
FVC outcomes are of a magnitude of one standard deviation unit (difference between the 
treatment group means divided by the standard deviation of the outcome, adusted for 
baseline values) Mendell et al., 1989 Griggs et al., 1991 Manur et al., 2004.  A 
difference in mean response between two corticosteroid regimens of 0.50 standard 
deviation units (i.e., half of the effect of 0.75 mgkgday of prednisone vs. placebo) was 
considered to be the group difference that is of minimal clinical significance on these two 
outcomes. 
 
For global satisfaction with treatment on the TS M, data on 378 subects (mean age 50.5 
years, range 18 to 88 years) using oral medications for a variety of illnesses (migraine, 
arthritis, high blood pressure, high cholesterol, and depression) suggest that the group 
difference of minimal clinical significance may be slightly less than 0.50 standard 
deviation units Atkinson et al., 2004.  Subects who described the seriousness of their 
illness as Moderate and those who described it as Severe differed by approimately 


 
 
9 
0.40 standard deviation units on this scale.  Also, subects who appraised their health as 
Ecellent or Very Good and those who appraised their health as Good or Fair 
differed by approimately 0.50 standard deviation units on this scale.  These data are 
limited in that they were not obtained in children or parents of children with Duchenne 
muscular dystrophy, but they do provide some idea of what group differences in mean 
response might be considered to be clinically important. 
 
e performed a pilot study of the TS M in 37 boys with Duchenne muscular dystrophy 
(DMD) between the ages of 4 and 12 years who were taking corticosteroids, 6 at the 
University of Rochester, 7 at the University of ansas, 6 at Childrens Hospital of 
estern Ontario (Canada), and 18 at the University of Newcastle (U) Herr et al., 2008.  
e collected data on the age and ambulatory status of the participants, allowing us to 
eamine the relationships between the TS M subscale scores and these characteristics 
(Table 1).  Although the small sample sies limit our ability to detect significant 
differences among the groups determined by age or ambulatory status, the epected 
patterns of responses are apparent: lower mean Effectiveness and Global Satisfaction 
scores among those  7 years old (p  0.05) and among those unable to walk outside the 
home lower Side Effects scores among those  10 years old and among those unable to 
walk outside the home. 
 
Table 1.  Results of the TS M Pilot Study in 37 Boys with DMD 
 
 
Age Group 
Ambulatory Status 
Scale 
4-6 
(n  9) 
7-9 
(n  11) 
10-12 
(n  17) 
Able 
(n  29) 
HomeUnable 
(n  8) 
 
    
    
    
 
 
Effectiveness  79.0 (16.1)  58.6 (22.7)  61.4 (26.2)  68.8 (20.4)   50.7 (31.5) 
Side Effects   85.9 (18.2)  83.5 (17.1)  71.2 (29.3)  82.6 (19.4)   68.8 (31.9) 
Convenience  88.9 (15.7)  90.6 (11.4)  88.0 (16.6)  89.6 (13.9)   87.3 (17.5) 
Global 
Satisfaction 
82.5 (18.2)   67.1 (18.5)   63.9 (26.7)   73.2 (18.7)   54.1 (35.2) 
 
Data from this study indicate that the mean global satisfaction with treatment differed by 
0.65-0.80 standard deviation units between boys age 4-6 and those age 7-12.  In this 
contet, an effect sie of 0.40 standard deviation units does not appear to be unacceptably 
large. 
 
The power of the test based on OBriens OLS statistic also depends on the correlations 
among the three outcomes.  Data on 51 participants between the ages of 5 and 7 from the 
Clinical Investigation of Duchenne Dystrophy (CIDD) natural history cohort suggest that 
the correlation between the average time to rise from the floor (log-transformed) and the 
average FVC over a 36-month follow-up period is very small and possibly even slightly 
negative.  Correlations between these outcomes and the TS M global satisfaction rating, 
while epected to be mildly-to-moderately positive, were of unknown magnitude at the 
onset of the trial.  For this reason, an interim sample sie re-estimation was performed in 
uly 2015 using all available longitudinal data, blind to treatment group assignment.  The 


 
 
10 
results revealed that the three components of the primary outcome variable (log-
transformed time to rise from the floor, forced vital capacity, and participantparent 
global satisfaction with treatment) were at best weakly correlated (0  r  0.25). 
 
5.2.  Sample Sie Determination for the Primary Outcome Variable 
 
Table 2 provides the power (estimated using Monte-Carlo simulation, with each estimate 
based on 50,000 replications) reuired to detect the specified treatment effects 
(differences between two groups, epressed in standard deviation units) under various 
assumptions regarding the correlations among the three outcomes, using OBriens OLS 
test and a two-tailed significance level of 0.017.  A sample sie of 67 participants per 
group is assumed.  This table indicates that a total sample sie of 201 participants (67 per 
group) will provide at least 80 and often greater than 90 power to detect treatment 
effects of at least 0.45 standard deviation units on at least two of the three components 
and as little as 0.25 standard deviation units on the third component of the primary 
outcome variable.  The power becomes unacceptably low only in the case where there is 
no group difference in treatment satisfaction.  To account for an anticipated 10 
participant withdrawal rate, 225 participants (75 per group) were to be enrolled in the 
trial. 
 
Table 2.  Power Calculations for the Primary Outcome Variable 
 
Effect Sies 
Correlations 
 
T 
F 
S 
TF    
TS    
FS    
Power 
0.45    
0.45    
0 
0 
0 
0 
72 
0.45    
0.45    
0 
0 
0.10    
0.10    
66 
0.45    
0.45    
0 
0 
0.15    
0.15    
63 
0.45    
0.45    
0 
0 
0.25    
0.25    
58 
0.45    
0.45    
0.25    
0 
0 
0 
92 
0.45    
0.45    
0.25    
0 
0.10    
0.10    
88 
0.45    
0.45    
0.25    
0 
0.15    
0.15    
86 
0.45    
0.45    
0.25    
0 
0.25    
0.25    
82 
0.45    
0.45    
0.45    
0 
0 
0 
98 
0.45    
0.45    
0.45    
0 
0.10    
0.10    
96 
0.45    
0.45    
0.45    
0 
0.15    
0.15    
96 
0.45    
0.45    
0.45    
0 
0.25    
0.25    
93 
0.50    
0.50    
0 
0 
0 
0 
83 
0.50    
0.50    
0 
0 
0.10    
0.10    
77 
0.50    
0.50    
0 
0 
0.15    
0.15    
74 
0.50    
0.50    
0 
0 
0.25    
0.25    
69 
0.50    
0.50    
0.25    
0 
0 
0 
96 
0.50    
0.50    
0.25    
0 
0.10    
0.10    
93 


 
 
11 
0.50    
0.50    
0.25    
0 
0.15    
0.15    
92 
0.50    
0.50    
0.25    
0 
0.25    
0.25    
88 
 
T  Effect sie for log(time to rise from the floor) F  Effect sie for FVC S  Effect sie for global satisfaction 
with treatment.  All values are epressed in standard deviation units. 
 
TF  Correlation between log(time to rise from the floor) and FVC TS  Correlation between log(time to rise from the 
floor) and global satisfaction with treatment TF  Correlation between FVC and global satisfaction with treatment. 
 
5.3.  Sample Sie Considerations for Safety Outcomes 
 
A secondary hypothesis concerns potential differences between daily deflaacort and 
daily prednisone with respect to adverse events, with intolerability (dosage reduction) and 
weight gain being the events of primary interest.  Data from the long-term trials of 
prednisone Fenichel et al., 1991 suggest that nearly 50 of participants may reuire a 
lower dosage of daily prednisone than 0.65 mgkg during the 36-month follow-up period.  
The data from this study also indicate that participants in the daily prednisone group will 
have an average weight gain of approimately 25 per year (standard deviation  12 ).  
The sample sie of 225 participants (75 per group) will provide 80 power to detect a 
group difference of 22 (50 in the daily prednisone group vs. 28 in the daily 
deflaacort group) regarding the percentage of participants taking a reduced dosage at the 
end of the 36-month follow-up period, using a chi-suare test and a 5 significance level.  
It will also provide  80 power to detect a group difference of 6 (25 in the daily 
prednisone group vs. 19 in the daily deflaacort group) in mean annual weight gain 
during the 36-month follow-up period, using a t-test and a 5 significance level (two-
tailed). 
 
Due to difficulties in recruitment, the FOR-DMD trial ultimately randomied 196 
participants. 
 
 
6.   GENERAL DATA HANDLING AND STATISTICAL CONSIDERATIONS 
 
6.1.  Analysis Cohorts 
 
Given the highly pragmatic nature of the FOR-DMD trial, the primary statistical analyses 
will be performed according to the treatment to which the participants were randomly 
assigned and with minimal eclusion of data collected during the trial.  All analyses will 
be based on data collected up to and including the Month 36 visit. 
 
Primary Analysis Cohort: The primary analyses of all efficacy and safety data (other than 
adverse event data and tolerability outcomes) will be performed using all available data 
from all randomied participants who contribute at least one post-baseline value of the 
outcome of interest, with the eception of data obtained after enrollment of the 
participant in another trial of an investigational treatment.  In particular, the following 
data will be included: 
 


 
 
12 
 Data from participants obtained after they discontinued study medication but 
remained in follow-up on a corticosteroid regimen of their familys choice 
 Data from participants obtained after unblinding of the identity of the 
participants assigned corticosteroid regimen 
 Data from participants obtained during temporary interruption of study 
medication causing them to switch to open-label prednisone 
 
The analysis of adverse event data and tolerability outcomes will be performed using data 
from all randomied participants, i.e., the denominators in the calculation of percentages 
of participants eperiencing adverse events or intolerability will be the numbers of 
randomied participants in the treatment groups. 
 
Sensitivity Analysis Cohort: Analyses of the efficacy and safety data will be repeated 
after ecluding data from the three categories listed above (after discontinuation of study 
medication, after unblinding, during temporary interruption of study medication). 
 
6.2.  General Considerations 
 
All analyses described in this document were pre-specified and defined prior to breaking 
the study blind.  All other analyses performed subseuently will be considered post hoc 
and eploratory. 
 
Unless otherwise specified, all significance testing will be performed using a two-tailed 
5 level.  Likewise, confidence intervals will be computed using a 95 confidence 
coefficient. 
 
For purposes of statistical analysis, baseline values will be considered to be those that are 
the last measurements obtained at or before the Month 0 visit and prior to the first dose of 
study medication.  If a value was scheduled to be obtained at the Month 0 visit but is 
missing, the value at the screening visit may be used instead. 
 
Due to a variety of factors, most notably scheduling difficulties, several visits may be 
performed out-of-window as defined by the Study Protocol.  The statistical analyses of 
longitudinal data will use the visit label assigned to each assessment regardless of 
whether the visit was technically performed out-of-window.  This convention will 
minimie the amount of missing data.  Data from unscheduled visits (including early 
withdrawal visits) will be assigned to the closest scheduled post-baseline visit that 
includes the assessment(s) of interest.  For efficacy assessments, if there is more than one 
value recorded at a particular visit, the value from the unscheduled visit will not be used.  
For safety assessments, if there is more than one value recorded at a particular visit, the 
worst value will be used for analysis. 
 
Considerations for dealing with other specific data anomalies are provided in the 
Appendi. 
 
 


 
 
13 
6.3.  Interim Analyses 
 
Interim analyses of safety data will be performed periodically (approimately every 6 
months) throughout the trial.  A Data and Safety Monitoring Board (DSMB) appointed 
by the trial sponsor (NINDS) will review reports of participant safety, data uality, and 
other indicators of study performance, including accrual.  The adverse events associated 
with daily corticosteroid use in DMD have been reasonably well characteried in 
previous studies and include behavioral changes, fractures, cataracts, Cushingoid 
appearance, GI symptoms, glycosuria, hypertension, immunosuppression (e.g., 
infections), slow growth (height restriction), skin changes (e.g., ecessive hair growth, 
acne, atrophy, easy bruising), and abnormal weight gain.  Detailed procedures are in 
place to clinically manage these anticipated adverse events (see Sections 5.3 and 7.4 of 
the Study Protocol). 
 
Due to concerns regarding slow enrollment in the trial, a blinded interim analysis was 
performed after 90 participants had completed 12 months of follow-up (uly 2015) in 
order to determine whether the sample sie could be reduced from the originally planned 
300 to a number that was feasible given the study timeline.  This determination was made 
based on the correlations among the three components of the primary outcome variable 
(averaged over available time points), which were completely unknown for those 
involving the TS M Global Satisfaction score.  The results revealed that the three 
components of the primary outcome variable were at best weakly correlated (0  r  
0.25), allowing the target sample sie to be reduced to 225 (see Sections 5.1 and 5.2 
above).  The DSMB agreed with this proposal. 
 
A single interim analysis for efficacy was performed after 95 participants had completed 
(or were scheduled to have completed) 36 months of follow-up (une 2017).  The 
analysis of the primary outcome variable was performed using an overall significance 
level of 0.001 (instead of 0.05), a conservative Haybittle-Peto-type strategy.  Upon 
reviewing the results of this analysis, the DSMB recommended continuation of the trial.  
No interim analyses were performed for the purpose of early identification of futility. 
 
 
7.   STATISTICAL ANALYSIS 
 
7.1.  Baseline Characteristics 
 
Baseline characteristics of participants, including demographic information, family 
history, medical history, and efficacy and safety outcomes will be presented overall and 
by treatment group for all randomied participants.  uantitative variables will be 
summaried with sample sie, mean, standard deviation, median, 1
st and 3
rd uartiles, 
minimum, and maimum.  Categorical variables will be summaried using freuencies 
and percentages. 
 
 
 


 
 
14 
7.2.  Participant Disposition 
 
A complete accounting of participant disposition will be summaried overall and by 
treatment group, including a tabulation of participants in the following categories: 
completion of follow-up on study medication, completion of follow-up after permanent 
discontinuation of study medication, withdrawal while on study medication, and 
withdrawal after permanent discontinuation of study medication.   
 
Other tabulations will include those of temporary interruption of study medication 
causing a switch to open-label prednisone, unblinding of the identity of the participants 
assigned corticosteroid regimen, and enrollment in another trial of an investigational 
treatment. 
 
Listings of the reasons for withdrawal, permanent discontinuation of study medication, 
and unblinding of the identity of the participants assigned corticosteroid regimen will be 
produced, along with the timing of these events. 
 
7.3.  Eposure to study medication 
 
Each participants eposure to study medication will be summaried separately for each 
treatment group by the total number of days on study medication and the average dosage 
(epressed in mgkg of body weight) over all days of eposure.  Periods of time when the 
participant had a temporary interruption of study medication causing a switch to open-
label prednisone will not be counted in these summaries.  These summaries will be 
calculated based on the dosage of study medication prescribed by the investigator (i.e., 
not taking compliance into account). 
 
A plot of average dosage prescribed by the investigator over time (averaged for each 3-
month or 6-month visit interval beginning with the day of the first dose) will be provided 
for each treatment group.  For each individual participant, the average dosage between 
two time intervals will be computed as the cumulative dosage during that interval divided 
by the number of days in the interval. 
 
Deviations from the planned study medication dosage based on weight band will be listed 
and summaried by treatment group, including reasons for the deviation. 
 
Descriptive statistics for the time that participants were eposed to open-label prednisone 
due to a temporary interruption of study medication will be provided by treatment group. 
 
Compliance with study medication will be summaried by treatment group.  Compliance 
will be uantified as the percentage of doses of study medication that were apparently 
taken (based on the number of pills dispensed compared to the number returned at each 
study visit) out of the number of doses epected to have been taken.  Relevant 
circumstances such as dosage modifications will be taken into account in the calculation 
of the epected number of doses. 
 


 
 
15 
7.4.  Analysis of the Primary Outcome Variable 
 
7.4.1. General Approach 
 
This trial is designed primarily to compare three corticosteroid regimens with regard to 
efficacy, as measured by a three-dimensional (multivariate) outcome consisting of the 
following three components (each averaged over all post-baseline follow-up visits 
through Month 36): (1) rise from the floor velocity (2) forced vital capacity and (3) 
participantparent global satisfaction with treatment, as measured by the Treatment 
Satisfaction uestionnaire for Medication (TS M).  The primary statistical analysis will 
consist of global tests of the null hypothesis that the regimens do not differ with regard to 
any of the three outcomes against the alternative that they differ (in the same direction) 
for all three outcome variables, performed separately for each of the three pair-wise 
comparisons among the three corticosteroid regimens using a Bonferroni-corrected two-
tailed significance level of 0.017. 
 
For each pairwise comparison among the treatment groups, the overall strategy for the 
analysis of the multivariate outcome will be to analye each of the outcomes separately, 
and then combine the p-values associated with the three outcomes using a two-sided 
version of the inverse normal combination statistic Stouffer et al., 1949.  The null 
distribution of the statistic has a simple form when the p-values are independent, but in 
this case independence among the three outcomes (and, hence, the three p-values) cannot 
be assumed.  Therefore, a re-randomiation test will be used to compute the overall p-
value Rosenberger and Lachin, 2016.  This strategy will properly account for the 
dependence among the three p-values. 
 
The p-values for the treatment group comparisons for two of the individual components 
of the primary outcome variable (rise from the floor velocity and FVC) will be derived 
from separate repeated measures analysis of covariance models (i.e., the mied model 
repeated measures, or MMRM, analysis strategy) Mallinckrodt, 2008, with terms for 
treatment group (three levels), country, baseline weight band (A vs. BC), the baseline 
value of the outcome variable, time (treated as a categorical variable), and interaction 
terms for the baseline value of the outcome variable and time, and for treatment group 
and time.  The p-values for the treatment group comparisons for the third component of 
the primary outcome variable, global satisfaction with treatment, will be derived from a 
similar model, but since this outcome variable is not measured at baseline, the model will 
instead include baseline values for rise from the floor velocity and FVC (with no 
interactions between these baseline variables and time).  The covariance matri for the 
within-participant observations will be modeled using an unstructured pattern.  If the 
unstructured covariance matri results in a lack of convergence, the following covariance 
structures will be used in seuence: heterogeneous Toeplit, heterogeneous 
autoregressive, and heterogeneous compound symmetry.  The enward-Roger 
approimation enward and Roger, 2009 will be used to estimate the denominator 
degrees of freedom.  The pair-wise treatment group differences will be estimated using 
appropriate contrasts that uantify the comparisons regarding the average value of the 
outcome variable over all post-baseline visits. 


 
 
16 
 
The overall test statistic will be the inverse normal combination statistic: 
 
 
(    )
3
1
1
1   ,
N
i
i
p
    
  
 
where 1   2     
3
, 
  , 
 and 
p p    p are the upper one-tailed p-values for the three outcome variables 
and 
( )
1
   is the inverse normal cumulative distribution function.  This statistic is very 
similar to OBriens OLS statistic, i.e., the unweighted sum of the individual standardied 
test statistics for the three outcome variables.  To see this, note that in the contet of 
multivariate normal outcomes, asymptotically, OBriens OLS statistic is the sum of the 
Z-statistics for the three outcomes, reecting the overall null hypothesis for either large 
positive values or large negative values of this statistic.  Let 
 
 
(    )    ( )
0
1    ,   1
, 2, 3,
i     H   i   i
i
p  P  Z     
 i
    
    
    
 
 
where i is the observed value of .
i
Z   Then 
 
 
(    )
3   
3
1
1   
1
1
i
i
i   
i
p
    
    
  
 
 
and the null hypothesis would be reected for either large positive values or large negative 
values of this statistic. 
 
The overall two-tailed p-value for comparing two treatment groups using the inverse 
normal combination statistic will be determined based on its re-randomiation 
distribution.  This will be estimated using a random sample of 15,000 repetitions of the 
randomiation, each performed in eactly the same way as the original randomiation 
was performed (permuted blocks, stratified by country). 
 
It should be emphasied that interpretation of these tests will be in terms of the global 
three-dimensional outcome and that these tests do not identify the component on which 
the treatment groups differ.  Follow-up analyses of the individual component outcomes, 
using a closed testing procedure Marcus et al., 1976, will also be performed in order to 
aid in the interpretation of the results of the global test for the multivariate outcome.  This 
procedure will involve performing treatment group comparisons with regard to the three 
possible bivariate outcomes (rise from the floor velocity and FVC, FVC and TS M, rise 
from the floor velocity and TS M) as well as the individual outcomes.  A treatment 
group comparison for an individual outcome will be considered to be statistically 
significant (at the 0.017 level) only if it is also significant for the trivariate outcome as 
well as for the bivariate outcomes of which the individual outcome is a component. 
 
Pair-wise treatment group differences in adusted mean response, averaged over all post-
baseline visits, will be summaried for the rise from the floor velocity, FVC, and global 


 
 
17 
satisfaction with treatment outcomes using 98.3 confidence intervals.  The confidence 
coefficient of 98.3 incorporates a Bonferroni adustment for the three pair-wise 
comparisons among the three treatment groups. 
 
7.4.2. Adustment for Baseline Characteristics 
 
If clinically important differences are found among the three groups at baseline, 
particularly with regard to important variables such as age, the primary analyses may be 
repeated after statistically adusting for these differences.  These analyses, however, will 
be considered to be secondary. 
 
7.4.3. Verification of Model Assumptions 
 
The underlying assumptions of the repeated measures analysis of covariance models for 
the individual outcomes (normality, linearity) will be thoroughly checked.  Secondary 
analyses that incorporate remedial measures (e.g., variable transformation) may be 
performed if warranted.  The relatively large sample sie (196 participants) should 
alleviate potential concerns about the normality assumption. 
 
7.4.4. Primary Strategy for the Treatment of Missing Data 
 
The primary analyses for the rise from the floor velocity, FVC, and global satisfaction 
with treatment outcomes will be performed using MMRM hence, missing data will be 
appropriately accommodated under the missing at random assumption using direct 
likelihood Mallinckrodt, 2008. 
 
7.5. Analysis of the Secondary Outcome Variables for Efficacy 
 
7.5.1. Analysis of Continuous Outcome Variables Obtained at Each Follow-up Visit 
 
The secondary outcome variables for efficacy that were obtained at each follow-up visit 
and thought to be approimately normally distributed include 10-meter walkrun velocity, 
distance walked in 6 minutes (6M T), NSAA total score, TS M subscales 
(effectiveness, side effects, convenience), and range of motion at ankle dorsifleion (left 
and right sides). 
 
These outcome variables will be analyed using repeated measures analysis of covariance 
models (i.e., the MMRM analysis strategy) with terms for treatment group (three levels), 
country, baseline weight band (A vs. BC), the baseline value of the outcome variable, 
time (treated as a categorical variable), and interaction terms for the baseline value of the 
outcome variable and time, and for treatment group and time.  Again, since the TS M 
was not administered at baseline, the models for the TS M subscales will include 
baseline values for rise from the floor velocity and FVC (with no interactions between 
these baseline variables and time) instead of the baseline value of the outcome variable.  
The covariance matri for the within-participant observations will be modeled using an 
unstructured pattern.  The pair-wise treatment group differences will be estimated using 


 
 
18 
appropriate contrasts that uantify the comparisons regarding the average value of the 
outcome variable over all post-baseline visits.  Confidence intervals for pair-wise group 
differences in adusted mean response at each visit will also be obtained using this model, 
but these will be of secondary interest. 
 
7.5.2. Analysis of Continuous Outcome Variables Obtained at Annual Visits 
 
The secondary outcome variables for efficacy that were measured at annual visits include 
lean mass (D A) and uality of life scores (generic Peds L and its neuromuscular 
disease-specific module).  These will be analyed using an analysis of covariance model 
with terms for treatment group (three levels), country, baseline weight band (A vs. BC) 
(for the uality of life scores only), and the baseline value of the outcome variable.  Due 
to several participants having no follow-up data for these outcome variables, the models 
will include further adustment for baseline age and baseline NSAA total score.  Separate 
analyses will be performed for outcomes at each annual visit.  For each uality of life 
score, analysis of the average score across the annual visits will also be performed.  
Confidence intervals for pair-wise group differences in adusted mean response will be 
obtained using these model. 
 
Due to the relatively large percentage of participants with missing baseline data for these 
outcome variables, multiple imputation will be used to accommodate missing data.  First, 
the monotone data augmentation method using Markov Chain Monte Carlo Li, 1988 
Liu, 1993 will be used to impute the small amount of missing data that are reuired to 
make the missing data pattern monotone.  Net, for participants with complete data up to 
a particular visit, a multiple regression model will be fit that includes the outcome at that 
visit as the dependent variable and outcomes at previous visits, treatment group, country, 
baseline weight band (for the uality of life scores only), baseline age, and baseline 
NSAA total score as independent variables.  Separate models will be similarly 
constructed for each visit.  Using these regression models, a missing value for a 
participant at a particular visit will be imputed as a draw from the predictive distribution 
given the outcomes at previous visits (some possibly imputed), treatment group, and 
country.  This will be done seuentially starting with the Month 12 visit.  This process 
will be repeated 100 times, resulting in 100 complete analysis data sets.  The analyses 
will be performed separately for each of the 100 complete analysis data sets and the 
results will be combined into one multiple imputation inference (estimated adusted 
treatment group differences and p-values) using established methods Schafer, 1997. 
 
7.5.3. Eamination of Treatment-by-Covariate Interactions 
 
Analyses will be performed to eplore potential interactions between treatment group and 
covariates with respect to selected outcome variables (averaged over all post-baseline 
visits).  These outcome variables will include rise from the floor velocity, FVC, TS M 
global satisfaction with treatment, 10-meter walkrun velocity, distance walked in 6 
minutes (6M T), and NSAA total score. 
 


 
 
19 
The interaction between treatment group and countryregion will be investigated by 
including the appropriate interaction term in the analysis of covariance model and testing 
for its significance.  Interactions between treatment group and the following baseline 
variables will also be eplored: age group ( 6,  6 years), ethnicity (hispanic, non-
hispanic), time to rise from the floor ( 5, 5-8,  8 seconds), NSAA total score ( 20, 20-
25,  25), and initial weight band (A, BC) will be eamined separately in a similar 
fashion.   
 
Since the power to detect potentially meaningful interactions will be limited, the 
magnitudes of mean responses to treatment in the relevant subgroups will be eamined.  
The observation of clinically important subgroup differences in mean treatment response 
(e.g., age  6 vs. age  6) will serve as hypothesis generation for possible future studies 
designed to specifically address the issue of differential therapeutic response. 
 
7.5.4. Treatment of Missing Data for Secondary Outcome Variables 
 
As noted in Section 7.4.4 above, for the secondary outcomes obtained at each follow-up 
visit, missing data will be appropriately accommodated under the missing at random 
assumption using direct likelihood Mallinckrodt, 2008.  Multiple imputation will be 
used instead, as noted in Section 7.5.2 above, for the secondary outcome variables 
obtained at annual visits due to the elevated freuency of missing baseline values. 
 
7.5.5. Analyses of Individual NSAA Items 
 
The individual items on the NSAA are generally scored as 0  Unable to achieve 
independently, 1  Able to achieve independently with a modified method, and 2  Able 
to achieve normally.  Although DMD is a progressive disease, most of these item scores 
can transition in either direction (i.e., improvement or decline) in the contet of 
corticosteroid treatment.  Therefore, multi-state models for panel data albfleisch and 
Lawless, 1985 ackson, 2011 will be used to compare the treatment groups with respect 
to the patterns of transition between the different states (i.e., NSAA scores of 0, 1, or 
2). 
 
Multi-state models assume that the transitions between the different states occur in 
continuous time, even though the data are observed only at discrete visits.  In these 
models, therefore, it will be assumed that one can only transition between adacent states.  
For eample, one cannot transition directly from a state (score) of 2 to a state of 0 
without having transitioned through a state of 1.  The models also employ a Markov 
assumption, i.e., that the probability of transitioning to a particular state at any time 
depends only on the current state and not on the observation process leading up to that 
state.  It will also be assumed that the transition probabilities remain constant over time 
(time-homogeneous model), though this assumption can be relaed if needed. 
 
The models will include treatment group, country, age, and initial weight band (A, BC) 
as independent variables.  The transition intensity matrices for each treatment group (for 
selected values of country, age, and initial weight band) will be presented, and treatment 


 
 
20 
group differences regarding the transition between different states will be summaried 
with haard ratios and their associated 98.3 confidence intervals under a proportional 
intensity assumption.  The models will also allow estimation of the mean total time in 
each state (out of 36 months) for each treatment group, with bootstrap confidence 
intervals, for selected values of country, age, and initial weight band. 
 
NSAA items that are assumed to only progress and not improve include rising from the 
floor and walking.  Times from the baseline visit to loss of the ability to rise from the 
floor and to loss of independent ambulation will be primarily analyed using a Co 
proportional haards model that will include treatment group as the factor of interest and 
age and initial weight band as covariates.  Confidence intervals (98.3 ) for the adusted 
haard ratios representing pair-wise treatment group comparisons will be computed using 
this model. 
 
Event times will be censored at the last follow-up time for participants who do not reach 
the endpoint (milestone).  aplan-Meier curves will be used to describe the cumulative 
probabilities of reaching the endpoint over time in the three treatment groups. 
 
7.6. Analysis of Tolerability and Safety Outcomes 
 
7.6.1. Tolerability Outcomes 
 
Tolerability outcomes will include ability to complete the trial on the originally assigned 
dosage (for weight) of study medication, ability to complete the trial without switching 
drug regimens (i.e., discontinuing study medication), and ability to complete the trial.  
The proportions of participants with these outcomes will be compared among the 
treatment groups using Fishers eact tests. 
 
7.6.2. Adverse Events 
 
A treatment-emergent adverse event is defined as an adverse event with an onset date on 
or after the start of dosing of study medication.  Analyses of adverse events will only be 
performed for treatment-emergent adverse events.  Adverse events that occurred prior to 
the start of dosing of study medication will only be included in the listings specified 
below. 
 
The freuencies of individual adverse events will be tabulated by treatment group, body 
system, and preferred term.  For each preferred term, the number ( ) of participants 
eperiencing the event and the total number of events will be presented.  For each 
adverse event, pair-wise comparisons among the treatment groups will be performed 
regarding the occurrence of at least one event using Fishers eact tests.  The 
comparisons will be repeated ecluding all mild events if a participant had repeat 
occurrences of the same event, the event with the highest severity will be considered for 
these comparisons.  Similar analyses will be performed at the level of body system rather 
than preferred term. 
 


 
 
21 
Listings of individual adverse events will be produced, including treatment group, 
participant ID number, site, preferred term, days after randomiation, event duration 
(days), perceived relationship to study medication, action taken, epected (yesno), 
severity, serious (yesno), and outcome.  Similar listings of individual serious adverse 
events and adverse events leading to a modification in dosage will also be produced. 
 
7.6.3. Additional Safety Outcomes 
 
Continuous measures of safety including height, weight, BMI, vital signs, D A 
outcomes, bone age, difference between chronological age and bone age, 
echocardiography outcomes, and behavioral scale scores will be analyed using the 
methods described in Section 7.5.1 or Section 7.5.2 above, depending on the 
completeness of the baseline information for each outcome variable.  Dichotomous Iowa 
Conners outcomes (IO score  10, OD score  9) and PARS-III total score  72 will be 
tabulated by treatment group and visit. 
 
The freuencies of individual laboratory abnormalities (high and low separately) will be 
tabulated by treatment group.  For each laboratory test, the number ( ) of participants 
eperiencing the abnormality and the total number of abnormal tests will be presented.  
For each laboratory test, pair-wise comparisons among the treatment groups will be 
performed regarding the occurrence of at least one abnormality using Fishers eact tests.  
The comparisons will be repeated ecluding all abnormalities that are not deemed 
clinically significant if a participant had repeat occurrences of the same abnormality, the 
abnormality with the highest level of clinical significance will be considered for these 
comparisons. 
 
Results of laboratory tests (actual values and changes from baseline) will be summaried 
by treatment group and visit using descriptive statistics. 
 
Listings of individual laboratory abnormalities will be produced, including treatment 
group, participant ID number, site, laboratory test, days after randomiation, value, and 
clinical significance. 
 
Echocardiography and ECG abnormalities will be summaried in a similar manner as the 
laboratory tests. 
 
7.7. Miscellaneous Analyses and Outcomes 
 
7.7.1. Concomitant Medications 
 
Concomitant medication use will be summaried by treatment group according to the 
percentages of participants using particular medications (or classes of medications) at or 
after the start of dosing of study medication. 
 


 
 
22 
A listing of concomitant medications will be provided, including participant ID number, 
site, treatment group, medication, dosage, freuency, form, indication, start date, and stop 
date. 
 
7.7.2. Blindedness Assessment 
 
Guessed treatment assignment from the Blindedness Assessment will be tabulated by 
actual treatment assignment separately for the parentsguardians, site investigators, and 
site clinical evaluatorscoordinators.  Chi-suare tests will be used to determine whether 
or not the distributions of the guessed treatments of the parentsguardians (or site 
investigators, or site clinical evaluatorscoordinators) differ among the actual treatment 
groups.  The certainty of the guesses and the primary and secondary reasons for the 
guesses will also be summaried by guessed treatmentactual treatment combination. 
 
7.7.3. Protocol Deviations 
 
A listing of protocol deviations will be provided, including participant ID number, site, 
treatment group, month, date of the deviation, nature of the deviation, reason for the 
deviation, and comments. 
 
 
8.   CHANGES FROM THE STUDY PROTOCOL 
 
The following modifications were made to the plans for statistical analysis specified in 
the protocol (all modifications were made prior to unblinding): 
 
 The analysis plan for the primary outcome variable was modified due to a greater 
number of participants than epected who lost the ability to rise from the floor 
during the trial.  The protocol states that participants who do not have the ability 
to rise from the floor at a particular visit will be assigned the largest observed 
time in the sample for purposes of analysis.  Apart from the arbitrary nature of the 
assignment of the largest observed time in the sample to these incompletely 
ascertained outcomes, this strategy also renders the multivariate normality 
assumption somewhat uestionable, both for the statistical model and for the 
multiple imputation strategy that was proposed to accommodate missing data. 
 
The analysis plan contains two substantial modifications: (1) use of the reciprocal 
transformation of the time to rise from the floor, epressing the outcome as the 
rise from the floor velocity, and (2) analying each of the components of the 
three-dimensional outcome variable separately and then combining the resulting 
p-values rather than using OBriens OLS test.  The latter modification yields a 
test based on re-randomiation that is similar to OBriens OLS test but does not 
rely on the assumption of multivariate normality (though it does assume normality 
for the individual outcome variables). 
 


 
 
23 
 The analysis cohorts for the primary and secondary outcome variables were 
specified in greater detail, with the principal changes due to (1) a small number of 
participants who contributed no post-baseline data for the primary outcome 
variable and (2) the focus on the trial having pragmatic aims.  ith respect to the 
latter point, the per-protocol analyses mentioned in the protocol have been 
eliminated. 
 
 The analysis of the time to walkrun 10 meters was modified to use the reciprocal 
transformation (10-meter walkrun velocity) to accommodate the loss of the 
ability of some participants to perform this task. 
 
 The analysis plan was modified for the secondary efficacy outcome variables 
collected at annual visits due to (1) the number of participants who had missing 
data at baseline (necessitating the use of multiple imputation) and (2) the number 
of participants who had no post-baseline data (necessitating the adustment for 
additional covariates). 
 
 The analysis plan for the individual NSAA items was modified in recognition of 
the fact that the scores on these items could either improve or worsen in the 
contet of corticosteroid treatment and disease progression.  The analyses of times 
to disease milestones were restricted to time to loss of independent ambulation 
and time to loss of the ability to rise from the floor with very rare eception, 
these abilities were not regained once lost.  Due to the relatively low incidence of 
these milestone events, the plan to stratify by country in the analyses was 
eliminated. 
 
 
9.   REFERENCES 
 
Atkinson M, Sinha A, Hass SL, Colman SS, umar RN, Brod M, Rowland CR.  
Validation of a general measure of treatment satisfaction, the Treatment Satisfaction 
uestionnaire for Medication (TS M), using a national panel study of chronic disease.  
Health ual Life Outcomes 2004 2:12. 
 
Fenichel GM, Florence M, Pestronk A, Mendell R, Moley RT III, Griggs RC, Brooke 
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completion of the Treatment Satisfaction uestionnaire for Medication for a trial of 
corticosteroids in Duchenne muscular dystrophy.  Neurother 2008 5:490. 


 
 
24 
 
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25 
APPENDI: DATABASE MODIFICATIONS FOR ANALYSIS 
 
 
Imputation of Missing Scale Items 
 
Missing total scores on the NSAA, Iowa Conners, and Revised Rutter scales due to a 
small number of missing items were imputed as follows: 
 
1. Imputing the missing item scores by carrying forward the item scores from the 
previous visit or, if the item scores were missing at the screeningbaseline visit, by 
carrying backwards the item scores from the subseuent visit.  For the NSAA, 
item imputation was also based on the ambulatory status of the participant in 
some cases. 
 
2. Recomputing the total score using the observed and imputed item scores. 
 
NSAA Scale 
 
Participant ID  Month Change 
CAN04R01    
36   Item 5: Changed to 1  Item 11 Changed to 0 
GBR01R02    
6   Item 17: Changed to 1 
GBR02R09    
36   Item 5: Changed to 1 
GBR07R19    
24   Item 11: Changed to 0 
GBR09R01    
SC   Item 13: Changed to 1 
GBR09R01    
0   Items 8 and 9: Changed to 2 
USA01R11    
3   Items 11 and 17: Changed to 1 
USA01R12    
24   Item 11: Changed to 1 
USA03R02    
18   Items 11 and 17: Changed to 0 
USA03R02    
24   Items 11 and 17: Changed to 0 
USA03R02    
30   Items 11 and 17: Changed to 0 
USA03R02    
36   All items ecept for Item 10: Changed to 0 
USA05R13    
30   Items 10 and 14: Changed to 2 
USA05R13    
36   Item 3: Changed to 1 
USA07R01    
SC   Item 10: Changed to 1 
USA07R05    
24   Item 17: Changed to 1 
USA09R03    
30   Item 13: Changed to 0 
USA10R10    
3   Item 12: Changed to 1 
 
 
Iowa Conners Scale 
 
Participant ID  Month Change 
CAN01R03    
12   Item 9: Changed to 0 
CAN01R03    
36   Item 6: Changed to 0 
DEU04R03    
12   Item 4: Changed to 0 
GBR03R18    
6   Item 10: Changed to 1 


 
 
26 
GBR03R18    
24   Item 3: Changed to 1 Item 10: Changed to 0 
ITA04R06    
0   Item 5: Changed to 0 
ITA04R06    
36   Item 5: Changed to 0 
ITA06R09    
18   Item 7: Changed to 0 
USA01R01    
0   Item 2: Changed to 1 
USA01R04    
36   Item 3: Changed to 2 
USA01R06    
3   Item 8: Changed to 0 
USA01R06    
12   Item 1: Changed to 2 Item 3: Changed to 0 
USA01R06    
30   Item 1: Changed to 1 
USA01R10    
3   Item 7: Changed to 0 
USA02R07    
0   Item 2: Changed to 1 
USA03R02    
30   Item 1: Changed to 1 
USA10R01    
36   Item 7: Changed to 0 
USA10R06    
0   Item 7: Changed to 2 
USA10R06    
24   Item 7: Changed to 2 
USA10R07    
0   Item 7: Changed to 1 
USA11R03    
3   Item 10: Changed to 1 
 
 
Revised Rutter Scale 
 
Participant ID  Month Change 
CAN01R01    
36   Item 4: Changed to 0 
DEU01R08    
6   Item 7: Changed to 1 
DEU03R05    
0   Item 1: Changed to 0 
GBR06R09    
18   Item 4: Changed to 0 
GBR09R04    
24   Item 6: Changed to 1 
USA01R06    
30   Item 1: Changed to 0 
USA02R02    
0   Item 5: Changed to 1 
USA05R09    
6   Item 4: Changed to 1 
USA06R01    
36   Item 7: Changed to 0 
USA07R03    
6   Item 8: Changed to 1 
USA10R06    
12   Item 6: Changed to 0 
USA14R11    
0   Item 4: Changed to 0 
 
 
Use of Efficacy Outcome Data from Unscheduled or Shifted Visits 
 
Participant ID  Month Change 
DEU06R01    
36   Use ECHOECG data from Month 30 visit 
GBR06R01    
24 
Use 10-meter walkrun time and si -minute walk test data 
from unscheduled visit on 120115 
GBR06R06    
3 
Use NSAA, range of motion at ankle dorsifleion, and si -
minute walk test data from unscheduled visit on 110414 
GBR06R06    
12   Use data from unscheduled visit on 041715 


 
 
27 
 
 
Imputation of Missing NSAA and Si-Minute alk Test Data Due to Loss of Ability 
to Perform the Task 
 
For the NSAA timed tasks (rise from the floor and walkrun 10 meters), a time of 999 
is recorded in the database if the corresponding NSAA item (11 or 17) is scored as 0 
and the time was entered as either missing or 0.  There were several instances where 
there were missing NSAA total scores and times as well as si -minute walk test distances, 
but it was clear from the comments recorded on the corresponding case report forms that 
the participant no longer had the ability to perform the tasks. 
 
Participant ID  Months Change 
CAN01R03    
24   Si-minute walk test distance set to 0 
CAN01R03    
30, 36 All NSAA items set to 0 NSAA timed tasks set to 999 
si-minute walk test distance set to 0  
CAN02R05    
30 
All NSAA items set to 0 NSAA timed tasks set to 999 
si-minute walk test distance set to 0  
CAN02R05    24, 36  Si-minute walk test distance set to 0  
DEU06R06    
36   Si-minute walk test distance set to 0  
GBR03R09    
36   Si-minute walk test distance set to 0  
GBR07R19    
24   Time to rise from the floor set to 999 
ITA03R02    
30   Si-minute walk test distance set to 0 
ITA03R02    
36 
All NSAA items set to 0 NSAA timed tasks set to 999 
si-minute walk test distance set to 0  
USA02R05    
18   Si-minute walk test distance set to 0  
USA02R05 
24, 30, 
36 
All NSAA items set to 0 NSAA timed tasks set to 999 
si-minute walk test distance set to 0  
USA03R02 
18, 24, 
30, 36 
NSAA timed tasks set to 999 si -minute walk test 
distance set to 0 
USA06R01    
36   Si-minute walk test distance set to 0  
USA09R04 
24, 30, 
36 
All NSAA items set to 0 NSAA timed tasks set to 999 
si-minute walk test distance set to 0  
USA10R07    24, 30  Si-minute walk test distance set to 0  
USA10R07    
36 
All NSAA items set to 0 NSAA timed tasks set to 999 
si-minute walk test distance set to 0  
USA10R08    
36   Si-minute walk test distance set to 0  
USA10R10    
36   Si-minute walk test distance set to 0  
USA11R01    
36 
All NSAA items set to 0 NSAA timed tasks set to 999 
si-minute walk test distance set to 0  
USA15R01    
24   Si-minute walk test distance set to 0  
USA15R01    
36 
All NSAA items set to 0 NSAA timed tasks set to 999 
si-minute walk test distance set to 0  
 
 
 


 
 
28 
Si-minute alk Test Results Deemed Invalid 
 
The following si-minute walk test distances were set to missing due to the evaluator 
deeming the results invalid on the case report form. 
 
Participant ID  Months Participant ID  Months Participant ID  Months 
CAN01R04    
6   GBR07R11    
30   USA09R05    
3 
CAN02R06    
0    GBR07R15    
6    USA10R01 
SC, 0, 
6, 12, 
18, 24, 
30, 36 
CAN02R11    
0   USA01R04    
12   USA10R03    
6 
CAN04R01    
0, 6, 18  USA01R07    
3    USA10R04 
SC, 0, 
3, 12, 
30 
GBR01R10    
SC   USA02R09    
24   USA10R05    
0 
GBR02R11    
24   USA07R01    3, 6, 12 USA11R02    
18 
GBR03R03    
36   USA07R02    
SC   USA14R11    
12 
GBR03R16    
36   USA07R04    
0   USA15R09    
3 
GBR07R01    
3   USA07R05    
24   USA18R01    
0, 6 
GBR07R04    
SC   USA09R01 
SC, 0, 
6, 18, 
30, 36 
 
 
 
 
Imputation of Missing Baseline NSAA Timed Tasks 
 
One four year-old participant (USA18R01) did not have the NSAA timed tasks 
performed at either the Screening visit or the Baseline visit due to issues with cooperation.  
These values were singly imputed using a regression model for the relationship between 
the baseline value (Y) and the Month 3 value () for participants with data at both time 
points. 
 
 
Values Deemed Implausible 
 
The following values were deemed implausible and set to missing. 
 
Participant ID   Month Change 
GBR06R05    
36   Si-minute walk test distance set to missing 
GBR06R09    
18   Ten-meter walkrun time set to missing 
USA11R03    
30   Forced vital capacity set to missing 
 
 
 
 


 
 
29 
Missing Medication Start Dates 
 
Participant ID   Change 
GBR06R06 
Missing medication start date imputed as one day after the 
medication ship date 
GBR06R09 
Missing medication start date imputed as one day after the 
medication ship date 
GBR06R10 
Missing medication start date imputed as one day after the 
medication ship date 
 
 
Height Values Estimated from Ulna Length 
 
Participant heights at the following visits were estimated from ulna length therefore, 
height, height percentile, height Z-score, and body mass inde were set to missing. 
 
Participant ID    
Months 
CAN01R03 
30 
USA01R08 
30, 36 
USA02R05 
36 
USA03R02 
18, 24, 30 
USA09R03 
SC 
USA09R04    
18, 24, 30, 36 
USA10R07 
30