Clinical trial NCT01761292
Conditions: Duchenne Muscular Dystrophy (DMD)
Keywords: rare disease
Sponsor: Italfarmaco
Start date: 2013-04-01; Completion date: 2017-11-01
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of Parts 1 and 2 of the study were to establish the histologic effects of givinostat administered chronically at the selected daily dose.

The secondary objectives of Parts 1 and 2 of the study were as follows:

* To establish the effects of givinostat administered chronically at the selected daily dose on functional parameters, such as the 6-Minute Walk Test (6MWT), North Star Ambulatory Assessment (NSAA), and performance of upper limb (PUL)
* To establish the safety and tolerability of givinostat administered chronically at the selected daily dose in children with Duchenne muscular dystrophy (DMD)
* To explore the effects of givinostat administered chronically at the selected daily dose on parameters such as magnetic resonance imaging (MRI) and biomarkers
* To explore the acceptability/palatability of the oral suspension
* To explore whether the effects of givinostat on disease progression may be related to the type of DMD mutation.

The primary objective of the Extension of the study was to evaluate the safety and tolerability of long-term administration of givinostat administered chronically at the selected daily dose in children with DMD.

The secondary objectives of the Extensions were:

* To establish the effects of givinostat administered chronically at the selected daily dose on muscular functional parameters, such as the 6MWT, NSAA, and PUL (Extensions 1, 2, and 3)
* To explore the effects of givinostat administered chronically at the selected daily dose on parameters such as MRI (Extension 1)
* To collect information related to 2 biomarkers, latent Transforming growth factor β (TGFβ) binding protein 4 (LTBP4) and osteopontin genotype (at the beginning of Extension 2 only)
* To collect information related to time to wheelchair and how much time the children spend in wheelchair (Extension 3 - only for the children who were not able to complete the 6MWT)

Detailed description:
This is a 2-part, phase II study to assess the effects of Givinostat on muscle histologic parameters and on clinical parameters in ambulant children with DMD.

The safety, tolerability, and pharmacokinetics of Givinostat will also be assessed.

Approximately 20 children were to be enrolled in the study as follows: the first 4 children were to be treated at a low dose level of givinostat (25 mg twice daily \[BID\] in children who weighed 20 kg to 49 kg and 37.5 mg BID in children who weighed ≥ 50 kg).

If none of the stopping criteria were met after 2 weeks of treatment at the low dose, the review team was to determine the escalated dose level (ie, intermediate dose level) to be used for the treatment of an additional 8 children who were to be treated at the intermediate dose. The 4 children previously treated at the low dose level were also switched to the intermediate dose level.

If none of the stopping criteria were met after 2 weeks of treatment at the intermediate dose, the review team was to determine the subsequent escalated dose level to be used for the treatment of an additional 8 children who were to be treated at the high dose. All children treated at the intermediate dose level were to be switched to the high dose level.

Once all 20 children enrolled during Part 1 of the study had been treated for at least 2 weeks, the review team was to determine the recommended dose (RD) to be used in Part 2 based on the safety and tolerability profile observed and on the pharmacokinetic (PK) analyses. All the children enrolled were switched to the RD level (37.5 mg BID), which was administered for the subsequent 12 months of the study (Part 2).

At the end of Part 2 of the study, parents were asked to consent and patients to assent to continuing their participation in the Extension to receive the study treatment at least until the final analysis was performed (Part 3-Extensions; after 52 months of treatment). The patients received givinostat at the same ongoing dose, during the last visit planned at 12 months, and were treated for additional 40 months (Extensions 1, 2, and 3 up to month 52).

Arms: arm 1: Givinostat will be administered as 2 oral doses daily while the child is in fed state.
Interventions: intervention 1: Givinostat
Intervention descriptions: intervention 1: Givinostat, oral suspension 10 mg/mL or oral capsules 50 mg, administered orally under fed conditions at the dose of 25 mg BID, 37.5 mg BID, and 50 mg BID during Part 1 for two weeks, and 25 mg BID and 37.5 mg BID during Part 2 for 12 months. Givinostat, oral suspension 10 mg/mL, administered orally under fed conditions at the dose of 25 mg BID or 37.5 mg BID during Extension 1, and modified as per patient's weight during Extensions 2 and 3 (up to 52 months).

Protocol documents:
Prot_000.pdf: 
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Study Protocol 
A Two-Part Study to Assess the Safety and Tolerability, Pharmacokinetics, 
and Effects on Histology and Different Clinical Parameters of Givinostat in 
Ambulant Children with Duchenne Muscular Dystrophy 
Protocol Ref: DSC/11/2357/43 
Protocol Date: 01 August 2012 (final) 
NCT01761292


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16.
APPENDICES
16.1 
Study Information
16.1.1 
Protocol and Protocol Amendments


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Table of Contents 
16. APPENDICES ...........................................................................................................................1 
16.1 Study Information ....................................................................................................................1 
16.1.1 Protocol and Protocol Amendments .....................................................................................1 
Table of Contents .......................................................................................................................2 
STUDY PROTOCOL DSC/11/2357/43 - 01 August 2012 .......................................................4 
STUDY PROTOCOL DSC/11/2357/43, Amendment 1 - 05 December 2012 ........................77 
PROTOCOL DSC/11/2357/4, Amendment 1 Rationale, Summary of Changes - 05 
December 2012. ...............................................................................................................150 
STUDY PROTOCOL DSC/11/2357/43 - Amendment 7 - 11 April 2017 .............................153 
PROTOCOL DSC/11/2357/43, Amendment 7, Summary of Changes - 11 April 2017 ........244 


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Italfarmaco S.p.A. 
STUDY PROTOCOL 
Protocol Title: 
A Two-Part Study to Assess the Safety and 
Tolerability, Pharmacokinetics, and Effects 
on Histology and Different Clinical 
Parameters of Givinostat in Ambulant 
Children with Duchenne Muscular Dystrophy 
Protocol Number: 
DSC/11/2357/43 
Clinical Phase: 
2 
Protocol Date 
01 Aug 2012 (Final) 
EudraCT Number: 
2012-002566-12 
Sponsor 
Italfarmaco S.p.A. 
Via dei Lavoratori, 54 
20092 Cinisello Balsamo (MI) 
Italy 
Tel: +39 02 6443 2512 
Fax: +39 02 6443 3554 


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SYNOPSIS 
Title of Study: 
A Two-Part Study to Assess the Safety and Tolerability, 
Pharmacokinetics, and Effects on Histology and Different Clinical 
Parameters of Givinostat in Ambulant Children with Duchenne 
Muscular Dystrophy 
Protocol Number: 
DSC/11/2357/43 
Eudra CT Number 
2012-002566-12 
Investigators/ 
Study Centers: 
Children will be enrolled at approximately 5 study sites in Italy. 
Phase of Development: 
2 
Objectives: 
The primary objective of this study is as follows: 
    To establish the histologic effects of Givinostat administered 
chronically at the selected daily dose 
The secondary objectives of this study are as follows: 
    To establish the effects of Givinostat administered chronically 
at the selected daily dose on functional parameters, such as 
the 6-Minute Walk Test (6MWT), North Star Ambulatory 
Assessment (NSAA), and performance of upper limb (PUL) 
    To establish the safety and tolerability of Givinostat 
administered chronically at the selected daily dose in children 
with Duchenne muscular dystrophy (DMD) 
    To explore the effects of Givinostat administered chronically 
at the selected daily dose on parameters such as magnetic 
resonance imaging (MRI), biomarkers, and cytokines 
Design: 
This is a 2-part, phase 2 study to assess the effects of Givinostat on muscle 
histologic parameters and on clinical parameters in ambulant children with 
DMD. The safety, tolerability, and pharmacokinetics of Givinostat will 
also be assessed. 
Children who assent to participate in this study (if capable of doing so) and 
whose parent/guardian signs the informed consent to participate will 
undergo pre-study screening assessments up to 4 weeks (±2 weeks) before 
the first scheduled dose of study drug. 
Approximately 20 children will be enrolled in the study as follows: the 
first 4 children will be treated at a low dose level of Givinostat (25 mg BID 
in children who weigh 20–49 kg and 37.5 mg BID in children who weigh 


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≥50 kg). 
If none of the stopping criteria (see Section 3.3.5) are met after 2 weeks of 
treatment at the low dose, the review team will determine the escalated 
dose level (i.e., intermediate dose level) to be used for the treatment of an 
additional 8 children who will be treated at the intermediate dose. The 4 
children previously treated at the low dose level will also be switched to the 
intermediate dose level. 
If none of the stopping criteria are met after 2 weeks of treatment at the 
intermediate dose, the review team will determine the subsequent escalated 
dose level to be used for the treatment of an additional 8 children who will 
be treated at the high dose. All children treated at the intermediate dose 
level will be switched to the high dose level. 
Once all 20 children enrolled during the Part 1 of the study have been 
treated for at least 2 weeks, the review team will determine the 
recommended dose (RD) to be used in Part 2 based on the safety and 
tolerability profile observed and on the pharmacokinetic (PK) analyses. All 
the children enrolled will switch to the RD level, which will be 
administered for the subsequent 12 months of the study (Part 2). 
The additional children (if any) will be enrolled during Part 2 of the 
study and will receive the RD of Givinostat for 12 months. 
During Part 1 of the study, children will visit the center once each week. 
During Part 2 of the study, children will visit the study center per the 
schedule of assessments for a total of 11 visits, including follow up. 
Children may be evaluated more often if necessary for safety reasons. 
Children who discontinue the study drug early will be asked to come in for 
an end-of-study visit within 2 weeks after the last dose of study drug as 
well as the protocol-scheduled follow-up visit. Children who have ongoing 
adverse events at discontinuation will be followed until resolution or 
stabilization. 
Efficacy will be assessed through changes from baseline in biopsy at 1 year 
(Part 2) and changes from baseline in the 6MWT, PUL, and NSAA at 1 
year (Part 2). Exploratory efficacy parameters will include changes from 
baseline in MRI results, PK-pharmacodynamic correlations and measures 
of cytokines and micro ribonucleic acid (miRNA). Safety will be assessed 
by number of children experiencing adverse events (AEs); type, incidence, 
and severity of AEs correlated with dose; and measures of vital signs, 
clinical laboratory tests (blood chemistry, hematology, disease serologies, 
and urinalysis), echocardiographs, pulmonary function tests (PFTs; forced 
expiratory volume at 1 second [FEV1], forced vital capacity [FVC], and 
FEV1/FVC) and 12-lead ECGs. 
Plasma samples for PK measurements will be collected after 1 week of 
treatment with Givinostat, during Part 1 at pre-dose and 1, 2, 4, and 8 hours 


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post-dose. 
PK samples will also be collected during Part 2 of the study as follows: 
    At Visit 2, blood samples for PK analysis will be taken pre- 
dose and between 6 and 8 hours post-dose. 
    At Visit 3, blood samples for PK analysis will be collected 
pre-dose in the morning before study drug intake and between 
0 and 2 hours post-dose. 
    At Visit 4, blood samples for PK analysis will be taken 
pre-dose and between 2 and 4 hours post-dose. 
    At Visit 6, blood samples for PK analysis will be taken 
pre-dose and between 4 and 6 hours post-dose. 
Planned Sample Size: 
Approximately 20 children will be enrolled in Part 1 (dose-finding) of this 
study. 
Muscle fibers: a sample size of 20 children (from Part 1) completing the 
treatment period should provide 90% power (at a 2-sided alpha level of 
5%) to detect at least a 12.5% increase in muscle fiber area % (MFA%) 
between pre- and post-treatment (which corresponds approximately to a 
26% relative increase given the observed mean in the Desguerre 
publication of 48% [Desguerre I et al. 2009]), the ―worst case‖ standard 
deviation of 16%, which assumes that there is no correlation within a 
subject in the muscle area fiber percentage between pre- and post- 
treatment. This sample size is based on a paired t-test. In the event the 
data is not normally distributed, a Wilcoxon signed rank test will be used. 
After the first 20 baseline biopsies are collected, an interim analysis aimed 
at checking the real variability observed in the study will be implemented 
as follows: the within-subject standard deviation of MFA% will be 
calculated and the final sample size will be adjusted based on this observed 
standard deviation. A conservative approach will be adopted where the 
sample size may be increased but not decreased. 
Diagnosis and Key Subject 
Selection Criteria: 
Inclusion criteria: 
1.
Male children aged 7 to <11 years with an
immunohistochemical and molecular diagnosis of DMD.
2.
A parent/guardian and child can comply with all study
evaluations/procedures and return for all study activities.
3.
Able to complete the 2 screening 6MWTs with a minimal
distance of at least 250 m each. In addition, the results of
these tests must be within ±30 m of each other.


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4.
On a stable dose of systemic corticosteroids for at least
6 months.
5.
At least 6 months worth of data on the 6MWT (this will be
the ―historical‖ 6MWT).  From the moment of the historical
6MWT assessment(s), the child must not have received any
compound that could potentially affect the 6MWT, with the
exception of the stable steroid treatment.
6.
Parent/guardian has signed the informed consent form and
child has assented to be in the study (if applicable).
Exclusion criteria: 
1.
Initiation of systemic corticosteroid therapy within 6 months
prior to the start of study drug or change in systemic
corticosteroid therapy (e.g., initiation, change in type of drug,
dose modification not related to body weight change,
schedule modification, interruption, discontinuation, or
re-initiation) within 6 months prior to the start of study drug.
2.
Use of any pharmacologic treatment, other than
corticosteroids, that might have an effect on muscle strength
since the time of the historical 6MWT and in any case within
3 months prior to the start of study treatment (e.g., growth
hormone). Vitamin D, calcium, and integrators will be
allowed.
3.
Surgery that might have an effect on muscle strength or
function within 3 months before study entry or planned
surgery at any time during the study.
4.
Exposure to another investigational drug since the time of the
historical 6MWT and in any case within 3 months prior to the
start of study treatment.
5.
History of participation in gene therapy, cell-based therapy or
oligonucleotide therapy.
6.
Presence of other clinically significant disease that in the
opinion of the investigator places the child in unacceptable
risk for an adverse outcome or that could affect study results.
7.
Symptomatic cardiomyopathy or heart failure. If child has a
left ventricular ejection fraction <45% at screening, the
investigator should discuss inclusion of child in the study with
the medical monitor.
8.
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9.
Absolute neutrophil count: <1.5 x 109/L
10. Platelets: <100 x 109/L
11. Current or history of liver disease or impairment, including
but not limited to an elevated total bilirubin.
12. Inadequate renal function, as defined by serum creatinine >2 x
the upper limit of normal.
13. Positive test for hepatitis B surface antigen, hepatitis C
antibody, or human immunodeficiency virus at screening
14. A baseline QTc >450 msec, (as the mean of 3 consecutive
readings 5 minutes apart) or history of additional risk factors
for torsades de pointes (e.g., heart failure, hypokalemia,
family history of long QT syndrome).
15. Psychiatric illness/social situations rendering the potential
child unable to understand and comply with the study
protocol.
Treatments: 
The study drug (Givinostat) will be administered as 2 oral doses daily while 
the child is in the fed state. Children who enroll during Part 1 of the study 
will receive their assigned dose until the RD is determined. They will then 
receive up to 12 months of treatment with Givinostat at the RD. Additional 
children may be enrolled as needed during Part 2 to reach the sample size 
calculated after the interim analysis. Children who enroll during Part 2 will 
receive up to 12 months of treatment with Givinostat at the RD. The total 
duration of the study is anticipated to be 15 months. 
Main Parameters of 
Efficacy: 
The primary endpoint of this study is change in the value of MFA% 
comparing the histology biopsies before and after 12 months of treatment 
with Givinostat. 
The secondary efficacy endpoints of this study are as follows: 
    Change in additional histological endpoints (i.e., cross-sectional 
area, inflammation, necrosis, fibrosis, and muscle regeneration) 
after 12 months of treatment with Givinostat at the selected daily 
dose 
    Change in muscular function after 12 months of treatment with 
Givinostat at the selected daily dose based on the 6MWT 
    Change in muscular function after 12 months of treatment with 
Givinostat at the selected daily dose based on the NSAA 
 Change in muscular function after 12 months of treatment with 


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Givinostat at the selected daily dose based the PUL 
Main Parameters of Safety: 
    Number of children experiencing treatment-emergent AEs and 
serious adverse events (SAEs) 
    Type, incidence, and severity of treatment-emergent AEs and 
SAEs correlated with dose 
PK Parameters: 
Individual Givinostat concentrations tabulated by dose cohort 
along with descriptive statistics for Part 1 and tabulated along with 
descriptive statistic for Part 2. 
Exploratory Endpoints: 
Change in muscle, fat and fibrosis content after treatment with 
Givinostat as measured by MRI 
    Change in muscle biomarkers (e.g., miRNA) and cytokines 
following treatment with Givinostat 
    PK–PD correlations 
Key Statistical 
Considerations 
Efficacy analyses will be conducted on the ITT population, which is 
defined as all children who are enrolled in the Part 1 portion or entered the 
Part 2 portion of the study. 
All values will be expressed as means ± standard deviation or standard 
error of the mean. 
Each of all efficacy endpoints will be subject to normality test and formal 
statistical test performed will be based on whether it is normally 
distributed. If normal, statistical differences will be calculated using the 
paired t test; if not normal, Wilcoxon signed rank test will be used to assess 
the statistical significance of differences between groups. P<0.05 will be 
set as significant. 
General considerations: Data will be provided in data listings sorted by 
treatment group and child number. Tabular summaries will be presented by 
treatment group for Part 1. Categorical data will be summarized by the 
number and percentage of children in each category. Continuous variables 
will be summarized by descriptive statistics, including mean, standard 
deviation, median, minimum, and maximum. Confidence intervals (CIs) 
will be 2-sided, unless otherwise stated. Details of endpoint analyses will 
be described in the SAP. 
For analyses of change from baseline, baseline will generally be defined as 
the value collected before any Givinostat treatment is administered. If this 
value is missing, the last non-missing value prior to dosing will be used. 
Otherwise, missing observations will be treated as missing at random, and 
no data imputation will be performed. All data from the case report forms, 


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as well as any derived variables, will be presented in data listings. 
All hypothesis tests will be two-sided with a 5% significance level, and 
95% CIs will be used, unless stated otherwise. As this is a Phase 2 
exploratory study, no adjustments for multiplicity will made. 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................1 
SIGNATURE PAGE ...........................................................................................................2 
SYNOPSIS ...........................................................................................................................5 
TABLE OF CONTENTS ...................................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................16 
1 
Introduction ............................................................................................................18 
1.1 
Background on Duchenne Muscular Dystrophy .............................................................................18 
1.2 
Background on Givinostat ..............................................................................................................19 
1.3 
Rationale .........................................................................................................................................20 
1.3.1 
Study Rationale ...................................................................................................................20 
1.3.2 
Dose Rationale ....................................................................................................................21 
2 
Study Objectives ....................................................................................................25 
3 
Investigational Plan ................................................................................................26 
3.1 
Description of Overall Study Design and Plan ...............................................................................26 
3.2 
Selection of Study Population.........................................................................................................29 
3.2.1 
Inclusion Criteria ................................................................................................................29 
3.2.2 
Exclusion Criteria ...............................................................................................................30 
3.2.3 
Removal of Children from Therapy or Assessment............................................................31 
3.3 
Treatments ......................................................................................................................................32 
3.3.1 
Details of Study Treatment .................................................................................................32 
3.3.2 
Dosage Schedule .................................................................................................................32 
3.3.3 
Treatment Assignment ........................................................................................................33 
3.3.4 
Drug Packaging, Labeling, Storage, Dispensing, Investigational Medicinal Product 
Accountability, and Blinding............................................................................................................33 
3.3.5 
Dose Modifications .............................................................................................................34 


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3.3.6 
Treatment Compliance and IMP Accountability ................................................................ 37 
3.3.7 
Prior and Concomitant Illnesses and Treatments ............................................................... 37 
3.4 
Assessments .................................................................................................................................... 38 
3.4.1 
Schedule of Assessments .................................................................................................... 38 
3.4.2 
Study Procedures ................................................................................................................ 43 
3.4.3 
Assessments for End of Study (Visit 10 [Month 12]) ........................................................ 45 
3.4.4 
Early Termination Visit ...................................................................................................... 45 
3.4.5 
Follow-up Visit ................................................................................................................... 45 
3.4.6 
Description of Assessments ................................................................................................ 46 
3.4.7 
Appropriateness of Measurements...................................................................................... 50 
4 
Adverse Event Reporting .......................................................................................50 
4.1 
Definitions and Criteria .................................................................................................................. 50 
4.1.1 
Adverse Events ................................................................................................................... 50 
4.1.2 
Adverse Drug Reactions ..................................................................................................... 51 
4.1.3 
Unexpected Adverse Drug Reactions ................................................................................. 51 
4.1.4 
Serious Adverse Events ...................................................................................................... 51 
4.1.5 
Assessing Intensity and Relationship ................................................................................. 52 
4.2 
Reporting Procedures and Requirements ........................................................................................ 53 
4.2.1 
Adverse Events ................................................................................................................... 53 
4.2.2 
Serious Adverse Events ...................................................................................................... 54 
5 
Data Management and Statistical Analysis............................................................56 
5.1 
Data Management Considerations .................................................................................................. 56 
5.2 
Statistical Considerations................................................................................................................ 56 
5.2.1 
General Considerations ....................................................................................................... 57 
5.2.2 
Sample Size Justification .................................................................................................... 57 
5.2.3 
Analysis Populations .......................................................................................................... 58 
5.2.4 
Primary Endpoint ................................................................................................................ 58 


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5.2.5 
Secondary Efficacy Endpoints ............................................................................................ 58 
5.2.6 
Secondary Safety Endpoints ............................................................................................... 59 
5.2.7 
Secondary Pharmacokinetic Endpoints .............................................................................. 59 
5.2.8 
Exploratory Endpoints ........................................................................................................ 59 
5.2.9 
Efficacy Analyses ............................................................................................................... 60 
5.2.10 
Safety Analyses .............................................................................................................. 60 
5.2.11 
Pharmacokinetic Analyses .............................................................................................. 60 
5.2.12 
Interim Analyses ............................................................................................................. 60 
6 
Study Management ................................................................................................61 
6.1 
Approval and Consent .................................................................................................................... 61 
6.1.1 
Regulatory Guidelines ........................................................................................................ 61 
6.1.2 
Institutional Review Board/Independent Ethics Committees ............................................. 61 
6.1.3 
Informed Consent ............................................................................................................... 61 
6.2 
Discontinuation of the Study by the Sponsor ................................................................................. 62 
6.3 
Study Documentation ..................................................................................................................... 62 
6.4 
Study Monitoring and Auditing ...................................................................................................... 63 
6.5 
Retention of Records ...................................................................................................................... 63 
6.6 
Use of Study Findings ..................................................................................................................... 63 
6.7 
Publications..................................................................................................................................... 64 
7 
References ..............................................................................................................65 
8 
Appendices .............................................................................................................66 
Appendix 1: Drugs Known to Prolong the QTc Interval ...................................................67 
TABLES AND FIGURES 
Table 1 
Concentrations of Givinostat in Pediatric Studies to Date ............................... 22 
Table 2 
Expected Exposure by Weight ......................................................................... 23 


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Table 3 
Starting Dose (25 mg BID in Children Who Weigh 20–49 kg and  37.5 mg 
BID in Children Who Weigh ≥50 kg) ............................................................................... 24 
Table 4 
Second Dose (50 mg BID in Children Who Weigh 20–49 kg and 75 mg BID 
in Children Who Weigh ≥ 50kg)....................................................................................... 24 
Table 5 
Third Dose (75 mg BID in Children Who Weigh 20–49 kg and 100 mg BID 
in Children Who Weigh ≥50 kg)....................................................................................... 24 
Table 6 
Treatment Table ............................................................................................... 28 
Table 7 
Details of Study Treatment............................................................................... 32 
Figure 1  Cohort expansion, Cohort Abandoned and Dose Escalation Safety Rules for 
Part 1 .................................................................................................................................. 36 
Table 8 
Schedule of Assessments: Part 1 (Dose Escalation) ........................................ 39 
Table 9 
Schedule of Assessments: Part 2 (Proof of Mechanism) ................................. 41 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
6MWT 
6-Minute Walk Test
Ab 
Antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma–concentration time curve 
BID 
twice daily 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CL 
clearance 
CL/F 
volume of distribution 
cm 
Centimeter 
Cmax
maximum plasma concentration 
CMV 
Cytomegalovirus 
CPK 
creatine phosphokinase 
CrCl 
creatinine clearance 
CRP 
C-reactive protein
CSA 
cross-sectional area 
CSOM 
Clinical Study Operations Manual 
DMD 
Duchenne muscular dystrophy 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECHO 
Echocardiograph 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
FACS 
fluorescence-activated cell sorting 
FAP 
fibroadipongenic progenitors 
FEV1 
forced expiratory volume at 1 second 
FU 
follow up 
FVC 
forced vital capacity 
GI 
Gastrointestinal 
h 
hour 
H&E 
hematoxylin and eosin 
HbeAg 
hepatitis B e antigen 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HDAC 
histone deacetylase 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 


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IgM 
immunoglobulin M 
IL 
interleukin 
IMP 
investigational medicinal product 
ITT 
intent to treat 
JIA 
juvenile idiopathic arthritis 
KA 
absorption rate constant 
kg 
kilogram 
L 
liter 
LDH 
lactate dehydrogenase 
m 
Meter 
MFA% 
muscle fibers area % 
mg 
Milligram 
miRNA 
micro ribonucleic acid 
mL 
Milliliter 
MRI 
magnetic resonance imaging 
msec 
Millisecond 
MTD 
maximum-tolerated dose 
MuSC 
muscle satellite cells 
ng 
nanogram 
nmol 
nanomole 
NOAEL 
no observed adverse effect level 
NSAA 
North Star Ambulatory Assessment 
PD 
Pharmacodynamic 
PDGFR 
platelet-derived growth factor receptor 
PET 
polyethylene terephthalate 
PFT 
pulmonary function tests 
PK 
Pharmacokinetic 
PUL 
performance of upper limb 
QT 
QT interval 
QTc 
QT interval – corrected 
RBC 
red blood cells 
RD 
recommended dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOJIA 
systemic onset juvenile idiopathic arthritis 
SWI/SNF 
switch/sucrose non-fermentable 
TNF-α 
tumor necrosis factor-alpha 
V/F 
plasma volume 
V2/F 
peripheral volume 
WBC 
white blood cells 
WCT 
Worldwide Clinical Trials 


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1 Introduction 
1.1 Background on Duchenne Muscular Dystrophy 
Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular 
dystrophy, occurring in about 1 of every 3500 male newborns. The disease is inherited as 
an X-linked recessive disorder and is caused by mutation in the dystrophin gene on the 
X chromosome, resulting in dystrophin deficiency. The main function of dystrophin is to 
stabilize and link the muscle fiber cytoskeleton to the membrane. The lack of functional 
dystrophin results in the loss of dystrophin-glycoprotein complex, thereby rendering the 
muscle fibers less resistant to mechanical stress. 
Faulty muscle structure caused by the absence of extracellular or intracellular structural 
proteins results in cell membrane instability, initiating a cascade of deleterious events, 
such as uncontrolled calcium influx, apoptosis and necrosis, inflammation, and 
replacement of muscle with fibrotic tissue and fat (Consalvi S et al. 2011). The clinical 
effect of this deficiency can be dramatic and fatal. 
Patients begin to show symptoms of the disease between the ages of 3 to 5 years 
(Emery AEH 2002), which leads to severe muscle wasting and weakness. Patients with 
DMD usually stop walking by about 12 years of age and usually experience fatal 
respiratory failure in their early 20s (Eagle M et al. 2002). 
Treatment with steroids is currently used in a large portion of DMD patients, but it is 
palliative and complicated by serious side effects. No current treatment interrupts or 
halts the progression of DMD. 
By acting on muscle resident stem cells, histone deacetylase (HDAC) inhibitors increase 
skeletal myogenesis in vitro and in vivo (Iezzi S et al. 2002) and restore normal muscle 
morphology and increase the size and strength of myofibers in mdx mice a preclinical 
model of DMD (Minetti GC et al. 2006). 
The beneficial potential of the HDAC inhibitor Givinostat in the treatment of DMD has 
been studied in the mdx mouse disease model. In this model, long-term exposure to 
Givinostat effectively countered disease progression. In particular, Givinostat dose and 
concentration dependently increased the cross-sectional area of myofibers, decreased the 
cellular (inflammatory) infiltrate and prevented the formation of fibrotic scars. 
Pharmacokinetic (PK)–pharmacodynamic (PD) analysis suggests that exposures of 
Givinostat of 600 h*nmol/L are required to exert the beneficial effect. 


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1.2 Background on Givinostat 
Givinostat has been tested in long-term repeat-dose toxicology studies in rats, dogs, and 
monkeys. The main adverse effects (e.g., reduction in white blood cells [WBC], reduced 
thymus weight, bone marrow atrophy, and liver and possibly kidney function 
impairments) were observed only at high doses of drug. Most of these changes returned 
to baseline levels upon drug discontinuation or a trend toward resolution was seen at the 
end of the recovery period. 
In the rat, Givinostat was administered consecutively up to 26 weeks where the no 
observed adverse effect level (NOAEL) was 10 mg/kg/day. There were no side effects in 
dogs administered 12.5 mg/kg/day of Givinostat for 4 consecutive weeks. However, 
liquid feces were found in the animals receiving higher doses with consequent reduced 
absorption. For these reasons, the dog species was not further considered and general 
toxicology studies in non-rodents were continued in the monkey. In the monkey, 
Givinostat was well tolerated and similar toxicity profiles were seen in the 4-, 13-, and 
39-week studies, where the NOAELs were 10 mg/kg, 10 mg/kg, and 12 mg/kg,
respectively.
Givinostat had a favorable safety pharmacology profile. There was no observation of 
embryo-fetal toxicity in rats and in rabbits, or potential genotoxicity in mammalian cells 
in vitro and in vivo. The only sign of a possible adverse effect was seen at relatively high 
doses (>1  M) of Givinostat in vitro but not in vivo in cardiovascular safety 
pharmacology studies. 
Givinostat was given by oral gavage to juvenile rats starting at the age of weaning 
(25 days of age) at 4 different dosages: 0, 20, 60, or 180 mg/kg/day once-a day for 
4 weeks. Givinostat was well tolerated at the dosage up to 60 mg/kg/day. 
Treatment-related changes were detected at 180 mg/kg/day in the adrenals, bone marrow, 
liver, and spleen. The changes had resolved or showed partial recovery at the end of the 
study (mature animals). The NOAEL was set at 60 mg/kg/day. 
Givinostat has been tested in a number of clinical studies that enrolled for the following 
major indications: inflammation and oncology. In particular: 
 105 healthy volunteers have been enrolled in 3 phase 1 studies (single dose, 
repeat dose, and food interaction); 18 were treated with placebo. 
 422 patients have been enrolled in the phase 1–2 studies; 62 were treated with 
placebo. Of these, 33 were children with systemic onset juvenile idiopathic 
arthritis (SOJIA) or polyarticular juvenile idiopathic arthritis (JIA) treated 
with Givinostat at the following doses: 0.50 mg/kg twice daily (BID) and 
0.75 mg/kg BID for up to 3 months. 


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Givinostat has shown preliminary signs of clinical activity in subjects with SOJIA 
(study DSC/05/2357/19) as well as myeloproliferative disease (study DSC/07/2357/28). 
The maximum-administered dose was a single dose of 600 mg in healthy volunteers and 
up to 400 mg once per week in subjects with multiple myeloma. Doses up to 
approximately 100 mg BID were generally well tolerated. The most common adverse 
events (AEs) observed were thrombocytopenia as well as gastrointestinal (GI) toxicities. 
AEs were generally mild to moderate and reversible upon discontinuation of study drug. 
In particular, thrombocytopenia appeared in just a few days of treatment at 
thrombocytopenic doses and reverted to normal values within a few days/weeks after 
treatment discontinuation. Twenty-one AEs of QT interval – corrected (QTc) 
prolongations have been reported. In one case, the electrocardiogram (ECG) was 
manually read and the QTc value determined was normal, thus it was considered a 
spurious finding. Eight AEs of QTc prolongation were reported in subjects with chronic 
myeloproliferative diseases (study DSC/07/2357/28), 6 in subjects with Hodgkin‘s 
lymphoma (study DSC/07/2357/26), 2 in subjects with polycythemia vera (study 
DSC/08/2357/38), 2 in subjects with acute myeloid leukemia (study DSC/05/2357/15), 1 
in a subject with Crohn‘s disease (study DSC/06/2357/23), and 1 in a subject with SOJIA 
(study DSC/05/2357/19). No clear dose dependence was observed. In the 2 studies in 
healthy volunteers (DM/00/2357/01 and DM/00/2357/03) where ECG and QTc 
measurements were systematically assessed, no episode of QTc prolongation was 
observed. Details of each trial are included in the Investigator‘s Brochure (2012). 
1.3 Rationale 
1.3.1 
Study Rationale 
Different studies suggest that histone acetylation has a significant role in the pathogenesis 
of DMD and that inhibition of HDAC leads to a reduction in inflammation and fibrosis 
and an increase in muscle regeneration. In particular, two preclinical studies with 
Givinostat have shown that chronic treatment with this compound in a DMD mouse 
model (mdx mouse) determines a dose- and concentration-dependent reduction in 
inflammation and fibrosis and an increase in muscle regeneration, which in turn 
determines an improvement in muscular function. 
The primary objective of this study is to replicate these findings in humans. In particular, 
the primary objective of the study will be to demonstrate that Givinostat stimulates 
muscle regeneration by detecting an increase in the fraction of muscle biopsy occupied 
by muscle when comparing the muscle biopsy at study end versus the muscle biopsy at 
study start. Other objectives of the study will be to evaluate the effects of Givinostat on 
other histological parameters (inflammation, necrosis, fibrosis), on functional parameters 


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such as the 6-Minute Walk Test (6MWT), and on magnetic resonance imaging (MRI) and 
biomarkers. Finally, the safety and tolerability and pharmacokinetics of Givinostat will 
also be assessed. 
As the currently used dose of Givinostat is considered not sufficient to exert the expected 
positive effects (see dose rationale), the first part of the study will be used to escalate the 
dose to one yielding exposures expected to be efficacious and which are well tolerated. 
To ensure an adequate assessment of the safety, efficacy, and PK parameters in this 
study, and considering the expected mechanism of action of Givinostat in DMD, 
ambulant children aged 7 to <11 years, who have been on a stable steroid dose for at least 
the last 6 months and who have a 6MWT assessment performed at least 6 months before 
screening will be selected for participation in this study. 
1.3.2 
Dose Rationale 
Until now, Givinostat has been administered to 87 healthy volunteers and 360 patients 
enrolled in 17 phase 1–2 studies. Of the 360 patients, 33 were children/adolescents 
treated with either Givinostat 0.5 mg/kg BID or 0.75 mg/kg BID. The maximum dose 
was a single dose of 600 mg in healthy volunteers and up to 400 mg once per week in 
subjects with multiple myeloma. Subjects have been treated in clinical trials with daily 
doses of Givinostat for up to 6 months. Moreover, 31 patients with myeloproliferative 
diseases enrolled in a compassionate use program have been receiving givinostat at doses 
up to 50mg t.i.d for a period up to 4 years and 1 adolescent with JIA enrolled in the 
extension study has been receiving Givinostat 0.75 mg/kg since December 2011. 
Doses of Givinostat up to approximately 100 mg BID have generally been well tolerated. 
At higher doses of Givinostat, transient reductions hematological parameters (particularly 
platelets) and diarrhoea as well as nausea and vomiting were observed. AEs were 
generally mild to moderate and reversible upon discontinuation of study drug 
(Investigator‘s Brochure 2012). In particular, thrombocytopenia appeared in just a few 
days of treatment at thrombocytopenic doses and reverted to normal values within a few 
days/weeks after treatment discontinuation. Twenty AEs of QTc prolongation have been 
reported and confirmed in the clinical studies. Of these, only 1 episode of QTc 
prolongation was observed in a pediatric study. No episode of QTc prolongation was 
observed in the 2 studies of Givinostat in healthy volunteers where ECG and QTc 
measurements were systematically assessed. 
A population PK analysis was conducted using the PK data collected so far in all the 
clinical trials where PK samples were collected. In particular, PK data from 7 studies 
have been included (single- and repeat-dose studies in healthy volunteers, 2 studies in 


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Crohn‘s disease subjects, 1 study in subjects with SOJIA, 1 study in subjects with JIA, 
and 1 study in subjects with psoriasis) for a total of 226 subjects. Givinostat 
pharmacokinetics were described using a 2-compartment model with first order 
absorption showing clearance (CL/F)=118 L/h, plasma volume (V/F)=155 L, peripheral 
volume (V2/F)=514 L, and absorption rate constant (KA)=0.243 h-1. The covariate 
screening indicated weight and steroid co-administration as the most significant 
covariates on clearance (CL) parameters (no gender, formulation, age, or healthy 
volunteer vs. patient differences). However, the covariates effects were considered 
limited on pharmacokinetics (i.e., the presence of steroids was found to determine an 
increase of <30% in the population CL, and an increase of 10 kg was found to determine 
an increase of 10%–15% in CL). 
The mean exposure in healthy volunteers treated with Givinostat 100mg BID was 
1083 ng*h/mL (area under the plasma–concentration time curve from 0 to 12 hours 
[AUC0-12]) and 181.5 ng/mL (maximum plasma concentration [Cmax]). The estimated 
AUC0-12 and Cmax in children treated with Givinostat are reported in Table 1. 
Table 1 
Concentrations of Givinostat in Pediatric Studies to Date 
Disease State 
AUC0-12 (ng*h/mL) 
Cmax (ng/mL) 
SOJIA 
Median 
5th percentile 
95th percentile 
234.0 
126.4 
428.7 
31.5 
20.0 
55.3 
JIA 
Median 
5th percentile 
95th percentile 
206.4 
109.0 
492.7 
31.0 
14.9 
69.8 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; Cmax=maximum plasma 
concentration; SOJIA=systemic onset juvenile idiopathic arthritis; JIA=juvenile idiopathic arthritis. 
Preclinical studies in a mouse model of DMD (mdx mouse model) suggest that daily 
exposures (AUC0-24) of 600 nmol*h/L, i.e., approximately 300 ng*h/mL, are needed to 
exert beneficial histological and functional effects. As shown in Table 1, doses higher 
than those administered so far to children are needed to ensure that the majority of 
children are treated with doses that allow such exposures. Therefore, the first part of the 
study will escalate the dose to a maximum tolerated dose (MTD) that will then be 
recommended for the second part of the study. 
Because of the limited effect of weight on CL only 2 dose adjustments will be applied as 
follows: children who weigh 20–49 kg: Dose X; children who weigh ≥50 kg: Dose 
1.5X. 


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The starting dose will be 25 mg BID in children who weigh 20–49 kg and 37.5 mg BID 
in children who weigh ≥50 kg. Table 2 reports the expected median, 5th, and 95th 
percentile exposures in children weighing 20, 30, 40, 50, and 60kg. 
Table 2 
Expected Exposure by Weight 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
263 
223 
203 
283 
257 
5th percentile 
127 
107 
97 
132 
123 
95th percentile 
564 
466 
426 
603 
542 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours 
Expected exposures fall within the range of exposures safely tested in children with 
SOJIA and JIA and well within the exposures in adults treated with 100 mg BID. 
If safety and tolerability of the starting dose is confirmed in the first group of children 
treated, the dose will be escalated in the second group of children enrolled. The children 
treated at the lower dose will also be switched to the escalated dose level. Similarly, if 
the safety and tolerability of the second dose level is confirmed, the dose will be further 
escalated in the third group of children enrolled, and the children treated at the second 
dose level will be switched to the higher dose level. 
Dose escalation will be decided based on the safety and tolerability profile observed, and 
on the PK analyses in the children treated until a dose-escalation decision is made.  In 
any case each dose escalation should not yield more than a doubling of the expected 
exposure. An example of dose escalation based on the data available so far is provided in 
Table 3, Table 4, and Table 5 show the starting, second, and third dose, respectively. 


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Table 3 
Starting Dose (25 mg BID in Children Who Weigh 20–49 kg and 
37.5 mg BID in Children Who Weigh ≥50 kg) 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
263 
223 
203 
283 
257 
5th percentile 
127 
107 
97 
132 
123 
95th percentile 
564 
466 
426 
603 
542 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; BID=twice daily. 
Table 4 
Second Dose (50 mg BID in Children Who Weigh 20–49 kg and 75 mg 
BID in Children Who Weigh ≥ 50kg) 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
527 
445 
407 
566 
515 
5th percentile 
253 
215 
194 
263 
246 
95th percentile 
1129 
932 
852 
1205 
1084 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; BID=twice daily. 
Table 5 
Third Dose (75 mg BID in Children Who Weigh 20–49 kg and 100 mg 
BID in Children Who Weigh ≥50 kg) 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
790 
668 
610 
755 
686 
5th percentile 
381 
322 
290 
351 
329 
95th percentile 
1693 
1398 
1278 
1607 
1446 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; BID=twice daily. 
Once all 20 children enrolled in Part 1 of the study have been treated for at least 2 weeks, 
the review team will decide the recommended dose (RD) to be used in Part 2 based on 
the safety and tolerability profile observed and on the PK analyses. 
All children will then switch to the RD, which will be administered for the subsequent 
12 months of the study (Part 2). 


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This clinical study has been designed to comply with the Good Clinical Practice 
guidelines. 
2 Study Objectives 
Primary Objective 
The primary objective of this study is as follows: 
 To establish the histologic effects of Givinostat administered chronically at 
the selected daily dose 
Secondary Objectives 
The secondary objectives of this study are as follows: 
 To establish the effects of Givinostat administered chronically at the selected 
daily dose on functional parameters, such as the 6MWT, North Star 
Ambulatory Assessment (NSAA), and performance of upper limb (PUL) 
 To establish the safety and tolerability of Givinostat administered chronically 
at the selected daily dose in children with DMD 
 To explore the effects of Givinostat administered chronically at the selected 
daily dose on parameters such as MRI, biomarkers, and cytokines 
Primary Endpoint 
The primary endpoint of this study is as follows: 
 Change in the value of muscle fiber area % (MFA%) comparing the histology 
biopsies before and after 12 months of treatment with Givinostat 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study are as follows: 
 Change in additional histological endpoints (i.e., cross-sectional area, 
inflammation, necrosis, fibrosis, and muscle regeneration) after 12 months of 
treatment with Givinostat at the selected daily dose 
 Change in muscular function after 12 months of treatment with Givinostat at 
the selected daily dose based on the 6MWT 
 Change in muscular function after 12 months of treatment with Givinostat at 
the selected daily dose based on the NSAA 


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 Change in muscular function after 12 months of treatment with Givinostat at 
the selected daily dose based the PUL 
Safety Endpoints 
The safety endpoints of this study are as follows: 
 Number of children experiencing treatment-emergent AEs and serious AEs 
(SAEs) 
 Type, incidence, and severity of treatment-related AEs and SAEs 
 Measures of vital signs, clinical laboratory tests (blood chemistry, 
hematology, disease serologies), echocardiographs (ECHOs), pulmonary 
function tests (PFTs; forced expiratory volume at 1 second [FEV1], forced 
vital capacity [FVC], and FEV1/FVC), and 12-lead ECGs. 
Pharmacokinetic Endpoints 
The PK endpoints of this study are as follows: 
 Individual Givinostat concentrations tabulated by dose cohort along with 
descriptive statistics for Part 1 and tabulated along with descriptive statistic 
for Part 2. 
Exploratory Endpoints 
The exploratory endpoints of this study are as follows: 
 Change in muscle, fat and fibrosis content after treatment with Givinostat as 
measured by MRI 
 Change in muscle biomarkers (e.g., miRNA) and cytokines following 
treatment with Givinostat 
 PK–PD correlations 
3 Investigational Plan 
3.1 Description of Overall Study Design and Plan 
This is a 2-part, phase 2 study to assess the effects of Givinostat on muscle histologic 
parameters and on clinical parameters in ambulant children with DMD. The safety, 
tolerability, and pharmacokinetics of Givinostat will also be assessed. 


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Children who assent to participate in this study (if capable of doing so) and whose 
parent/guardian signs the informed consent to participate will undergo pre-study 
screening assessments up to 4 weeks (±2 weeks) before the first scheduled dose of study 
drug. 
Approximately 20 children will be enrolled in the study as follows: the first 4 children 
will be treated at a low dose level of Givinostat (25 mg BID in children who weigh 
20-49 kg and 37.5 mg BID in children who weigh ≥50 kg).
If none of the stopping criteria (see Section 3.3.5 for stopping criteria) are met after 
2 weeks of treatment at the low dose, the review team will determine the escalated dose 
level (i.e., intermediate dose level) to be used for the treatment of an additional 8 children 
who will be treated at the intermediate dose. The 4 children previously treated at the low 
dose level will also be switched to the intermediate dose level. 
If none of the stopping criteria are met after 2 weeks of treatment at the intermediate 
dose, the review team will determine the subsequent escalated dose level to be used for 
the treatment of an additional 8 children who will be treated at the high dose. All 
children treated at the intermediate dose level will be switched to the high dose level. 
Once all 20 children enrolled during the Part 1 of the study have been treated for at least 
2 weeks, the review team will determine the RD to be used in Part 2 based on the safety 
and tolerability profile observed and on the PK analyses. All the children enrolled will 
switch to the RD level, which will be administered for the subsequent 12 months of the 
study (Part 2). 
After the 20 baseline biopsies are collected, an interim analysis aimed at checking the 
real variability of MFA% observed in the study will be implemented, the within-subject 
standard deviation of MFA% will be calculated, and the final sample size will be adjusted 
based on this interim analysis and in particular on the observed standard deviation. A 
conservative approach will be adopted, where the sample size may be increased but not 
decreased. 
The additional children (if any) will be enrolled during Part 2 of the study and will 
receive the RD of Givinostat for 12 months. 
A treatment table for the study is presented in Table 6. 


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Table 6 
Treatment Table 
PART 1 
PART 2 
Treatment Visitc 
Treatment Visitc 
Subject 
1 
2a
3 
4a
5 
6 
a 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10b 
1–4 
5–12 
13–20 
Additional 
children 
(if any) 
a At the end of Week 2 (Visit 2) at every dose level, a safety check is foreseen. 
b At the end of Month 12, an efficacy analysis on biopsy results and functional tests is foreseen. 
c The visits during Part 1 will be performed every 7 days (±1 day); the visits during Part 2 will be 
performed periodically every 1 – 1.5 months (± 7 days). 
Legend: 
25 – 37.5 mg BID – low dose level 
Intermediate dose level 
High dose level 
Recommended dose level 
During Part 1 of the study, children will visit the center once a week.  During Part 2 of 
the study, children will visit the study center per the schedule of assessments for a total of 
10 visits, not including follow up. Children may be evaluated more often if necessary for 
safety reasons. Children who discontinue the study drug early will be asked to come in 
for an end-of-study visit within 1 week after the last dose of study drug. Children who 
have ongoing AEs at discontinuation will be followed until resolution or stabilization. 
Efficacy will be assessed through changes from baseline in biopsy at 1 year (Part 2) and 
changes from baseline in the 6MWT, PUL, and NSAA at 1 year (Part 2). Exploratory 
efficacy parameters will include changes from baseline in MRI results, PK/PD 
correlations, and measures of cytokines and miRNA. Safety will be assessed by number 
of children experiencing treatment-emergent AEs and SAEs; type, incidence, and severity 
of treatment-emergent AEs and SAEs; and measures of vital signs, clinical laboratory 
tests (blood chemistry, hematology, disease serologies), ECHOs, PFTs (FEV1, FVC, and 
FEV1/FVC), and 12-lead ECGs. 


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Plasma samples for PK measurements will be collected after 1 week of treatment with 
givinostat, during Part 1: at pre-dose and 1, 2, 4, and 8 hours post-dose. 
PK samples will also be collected during Part 2 of the study. At Visit 2, blood samples 
for PK analysis should be taken pre-dose and between 6 and 8 hours post-dose. At 
Visit 3, blood samples for PK analysis should be collected pre-dose in the morning before 
drug intake and between 0 and 2 hours post-dose. At Visit 4, blood samples for PK 
analysis should be taken pre-dose and between 2 and 4 hours post-dose. At Visit 6, blood 
samples for PK analysis should be taken pre-dose and between 4 and 6 hours post-dose. 
3.2 Selection of Study Population 
This study will enroll approximately 20 ambulatory male children with an established 
diagnosis of DMD who are at least 7 years of age but <11 years of age. Additional 
children could be enrolled in the second part of the study, after the interim evaluation of 
baseline biopsies if the observed variability is higher than the one used for the current 
sample size estimate. Children will be enrolled at approximately 5 study sites in Italy. 
Specific entry criteria are detailed in Section 3.2.1 and Section 3.2.2. 
3.2.1 
Inclusion Criteria 
Children meeting all of the following inclusion criteria are eligible for inclusion in the 
study: 
1.
Male children aged 7 to <11 years with an immunohistochemical and
molecular diagnosis of DMD.
2.
Parent/guardian has signed the informed consent form and child has assented
to be in the study (if applicable).
3.
Able to complete t he 2 screening 6MWTs with a minimal distance of at least
250 m each. In addition, the results of theses 2 tests must be within ±30 m of
each other.
4.
On a stable dose of systemic corticosteroids for at least 6 months.
5.
At least 6 months worth of data on the 6MWT (this will be the ―historical‖
6MWT). From the moment of the historical 6MWT assessment(s), the child
must not have received any compound that could potentially affect the
6MWT, with the exception of the stable steroid treatment.
6.
A parent/guardian and child can comply with all study evaluations/procedures
and return for all study activities.


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3.2.2 
Exclusion Criteria 
Children meeting any of the following exclusion criteria will not be enrolled in the study. 
1.
Initiation of systemic corticosteroid therapy within 6 months prior to the start
of study drug or change in systemic corticosteroid therapy (e.g., initiation,
change in type of drug, dose modification not related to body weight change,
schedule modification, interruption, discontinuation, or re-initiation) within
6 months prior to the start of study drug.
2.
Use of any pharmacologic treatment, other than corticosteroids, that might
have an effect on muscle strength since the time of the historical 6MWT and
in any case within 3 months prior to the start of study treatment (e.g., growth
hormone). Vitamin D, calcium, and integrators will be allowed.
3.
Surgery that might have an effect on muscle strength or function within 3
months before study entry or planned surgery at any time during the study.
4.
Exposure to another investigational drug since the time of the historical
6MWT and in any case within 3 months prior to the start of study treatment.
5.
History of participation in gene therapy, cell-based therapy or oligonucleotide
therapy.
6.
Presence of other clinically significant disease that in the opinion of the
investigator places the child in unacceptable risk for an adverse outcome or
that could affect study results.
7.
Symptomatic cardiomyopathy or heart failure. If child has a left ventricular
ejection fraction <45% at screening, the investigator should discuss inclusion
of child in the study with the medical monitor.
8.
Inadequate hematological function
9.
Absolute neutrophil count: <1.5 x 109/L
10. Platelets: <100 x 109/L
11. Current or history of liver disease or impairment, including but not limited to
an elevated total bilirubin.
12. Inadequate renal function, as defined by serum creatinine >2 x the upper limit
of normal.


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13. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human
immunodeficiency virus at screening
14. A baseline QTc >450 msec, (as the mean of 3 consecutive readings 5 minutes
apart) or history of additional risk factors for torsades de pointes (e.g., heart
failure, hypokalemia, family history of long QT syndrome).
15. Psychiatric illness/social situations rendering the potential child unable to
understand and comply with the study protocol.
3.2.3 
Removal of Children from Therapy or Assessment 
A child will be considered to have completed the study when he completes the 
12-month/end-of-study visit (Visit 10) in Part 2. If a child is discontinued at any time
after entering the study, the investigator will make every effort to see the child and
complete the early termination and follow-up assessments as shown in Section 3.4.5. All
adverse events should be followed until the child recovers or his condition stabilizes.
A termination electronic case report form (eCRF) should be completed for every child 
who receives study drug, whether or not the child completes the study. The reason for any 
early discontinuation should be indicated on this form. The primary reason for a child 
withdrawing prematurely should be selected from the following standard categories of 
early termination: 
 Adverse Event (Adverse Reaction): Clinical or laboratory events occurred 
that, in the medical judgment of the investigator for the best interest of the 
child, are grounds for discontinuation. This includes serious adverse events 
(SAEs) and non-serious AEs, regardless of relation to study drug. 
Death: The child died. 
Withdrawal of Consent: The child or his parent/guardian desired to withdraw 
from further participation in the study in the absence of an 
investigator-determined medical need to withdraw. If the child or 
parent/guardian gave a reason for withdrawing, it should be recorded in the 
eCRF. 
 Protocol Violation: The child‘s findings or conduct failed to meet the 
protocol entry criteria or failed to adhere to the protocol requirements (e.g., 
drug noncompliance, failure to return for defined number of visits). The 
violation necessitated premature termination from the study. 
 Lost to Follow-Up: The child stopped coming for visits, and study personnel 
were unable to contact the child. 


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 Other: The child was terminated for a reason other than those listed above, 
such as theft or loss of study drugs or termination of study by sponsor. 
3.3 Treatments 
3.3.1 
Details of Study Treatment 
Details about study drug are provided in Table 7. 
Table 7 
Details of Study Treatment 
Givinostat^ 
Drug name 
Givinostat 
Manufacturer 
Italfarmaco S.p.A. 
Dose(s) 
1st dose level: 
25 mg (children 20–49 kg) 
37.5 mg (children ≥50 kg) 
2nd dose level: 
50 mg (children 20–49 kg) 
75 mg (children ≥ 50 kg)* 
3rd dose level: 
75 mg (children 20–49 kg) 
100 mg (children ≥ 50 kg)* 
Dose frequency 
BID 
Route 
Oral under fed conditions 
Formulation 
Oral suspension and/or capsules 
^Givinostat is used to indicate the whole study drug name Givinostat hydrochloride monohydrate. The 
dosages / concentrations of the study drug are expressed as Givinostat hydrochloride monohydrate. 
* Estimated doses based on current knowledge.
BID=twice daily
3.3.2 
Dosage Schedule 
Study drug will be administered as 2 oral doses daily while the child is in the fed state. 
Children who enroll during Part 1 of the study will receive their assigned dose until the 
RD is determined. They will then receive up to 12 months of treatment with Givinostat 


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at the RD. Additional children may be enrolled as needed during Part 2 to reach the 
sample size calculated after the interim analysis. Children who enroll during Part 2 will 
receive up to 12 months of treatment with Givinostat at the RD. 
3.3.3 
Treatment Assignment 
All children will receive study drug. Children enrolled in Part 1 of the study will start to 
take either the low, intermediate, or high dose, depending on the needs of the study at the 
time of enrollment and they will switch to the RD when the review team decide that this 
dose is safe (see Table 6). 
When the safety review team has determined the RD, all children currently on study drug 
will be switched to that dose (the RD), and Part 2 of the study will commence. All 
children who enroll during Part 2 (if applicable) of the study will be given the RD of 
Givinostat. 
3.3.4 
Drug Packaging, Labeling, Storage, Dispensing, Investigational Medicinal Product 
Accountability, and Blinding 
Drug Packaging - Oral Suspension 
The primary packaging will consist of an amber plastic bottle containing the suspension. 
The secondary packaging will be a carton box containing 1 amber bottle and a syringe 
dosing system for dispensing the suspension. 
All the bottles will contain 120 mL of suspension. 
Drug Packaging - Capsules 
Capsules will be supplied as 50 mg hard gelatin capsules for oral administration in white 
plastic bottles containing 30 capsules each. 
Labeling 
The primary and secondary labels will show all the information requested according to 
the Annex 13 of the Good Manufacturing Practice. Bottles containing Givinostat will be 
labeled in local language (i.e., Italian). 
Storage 
The investigational medicinal product (IMP; Givinostat) will be stored at Italfarmaco until 
distribution to the investigational sites. The investigational site will store the IMP under 
the conditions specified in the label (i.e., 5 ±3°C for the oral suspension and <30°C for 
the capsules), ensuring that it is not accessible to unauthorized persons until it is 
dispensed to the child‘s parents/legal guardians. 


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Dispensing 
The investigational site will be supplied initially with a congruous number of suspension 
bottles and capsule bottles, in order to have sufficient supply of study drug to treat the 
children who are enrolled in the study. 
All IMP supplies are to be used only for this protocol and for no other purpose. 
The investigator will be responsible for the delivery of IMP to the child‘s parents/legal 
guardians according to the protocol. 
Children will be administered the IMP on an outpatient basis. 
At each scheduled visit, the investigator will supply the children with the appropriate 
number of suspension bottles and/or capsules bottles, sufficient to cover the treatment 
until the following visit (i.e., 1 week of treatment during Part 1 of the study and 1 to 1.5 
months, during Part 2 of the study). 
Italfarmaco will provide to the investigator a table with volume of suspension and/or 
number of capsules to be administered according to body weight and dose level. 
The investigator will provide to the child‘s parent/legal guardian written instruction on 
the dosage and corresponding volume in milliliters of suspension and/or number of 
capsules to be taken at each administration. Refer to the relevant Clinical Study 
Operations Manual (CSOM) for more detailed information. 
Blinding 
Not applicable. This is an open-label study. 
Emergency Procedure for Unblinding 
Not applicable. This is an open-label study. 
3.3.5 
Dose Modifications 
3.3.5.1 Child Stopping and Dose Reduction Safety Rules 
Permanent Stopping Rule 
Study drug should be permanently stopped if any of the following occur: 
Severe diarrhea (i.e., increase of ≥7 stools per day) 
Any drug-related SAE 
QTc >500 msec 
Platelets ≤50 x 109/L 


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Temporary Stopping and Dose Reduction Safety Rule 
Study drug should be temporarily stopped if any of the following occur: 
Platelets ≤75 x 109/L but >50 x 109/L 
Moderate diarrhea (i.e., increase of 4 to 6 stools per day) 
Study drug may be resumed at a reduced dose level once the event resolves. Such a dose 
reduction can happen only once per child. The treatment can be temporarily interrupted 
for a maximum of 4 weeks. If the child has not recovered from the AE after this period, 
the treatment should be permanently discontinued. 
If a child has a medical event not necessarily drug related that requires interruption of 
study drug dosing for >4 weeks, the review team will determine if the child may resume 
study drug treatment. 
Cohort Expansion Safety Rules 
The review team can decide to expand the first cohort of children and enroll additional 4 
children (for a total of 8 children treated at the first dose level), on the basis of safety, 
tolerability, and PK results in the children treated in that cohort, according but not limited 
to the following rules: 
 If 1 child experiences any type of stopping criterion (as defined in the permanent 
and temporary stopping rules), or 
 If 2 children experience different types of stopping criterion (e.g., 1 child 
experiences hematological toxicity and another child experiences GI toxicity). 
3.3.5.2 Cohort Abandoned Safety Rules 
The review team can also decide to abandon a given dose level on the basis of safety, 
tolerability and PK results in the children treated at that dose level, according to but not 
limited to the following rules: 
If >2 children experience any type of stopping criterion, or 
If ≥2 or more children experience the same type of stopping criterion 
3.3.5.3 Cohort Dose Escalation Safety Rules 
During Part 1 of the study, each child will receive study drug at a specific dose level. 
Once the first 4 children have been treated for at least 2 weeks, the review team will 
examine safety and tolerability data and PK results and decide if the children can be 
switched to the escalated dose level and if the second group of children can start the 
treatment at the escalated dose level. 


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After a further 2 weeks, the review team will decide if the already treated children at the 
lower and intermediate dose levels can switch to the highest dose and if the third and last 
group of children can start the treatment at the highest dose level. 
The children should be switched to the escalated dose level (i.e., intermediate or high 
dose level) only if no or only 1 stopping criterion per dose level occurred. 
For more details, see Figure 1. 
3.3.5.4 Study Stopping Safety Rules 
If 2 or more stopping criteria occur in the lower dose, the study will be temporarily 
stopped to allow a reassessment of the risks and benefits of the compound. 
Figure 1 
Cohort expansion, Cohort Abandoned and Dose Escalation Safety 
Rules for Part 1 
SC=stopping criterion, as defined under permanent and temporary stopping rules. 
The review team will include: the Principal Investigators, the Study Chair, the Medical 
Monitor and other Italfarmaco representatives. 
0 SC 
YES 
GO to the escalated dose level 
3 or more 
SC 
YES 
CLOSE the dose level 
NO 
NO  
NO 
YES, 2 SC of a different type 
EXPAND the dose level to 8 
children (if applicable, i.e., low 
dose level) or ESCALATE to 
next dose level 
2 SC 
YES, 2 SC of the same type 
CLOSE the dose level 
YES 
1 SC 
EXPAND the dose level to 8 
children (if applicable, i.e., low 
dose level) or ESCALATE to 
next dose level 


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3.3.6 
Treatment Compliance and IMP Accountability 
At each visit, the child‘s parents/legal guardians will bring back to the study site all the 
bottles previously received (used, partially used, and unused) and receive a new supply of 
the IMP. 
All unused IMP will be not re-dispensed by the investigator to another child. 
The investigator will maintain accurate records of the disposition of all IMP received, 
distributed to children (including date and time), and accidentally lost or destroyed. 
When dispensing the bottles to the children, the investigator will attach the relevant 
tear-off label to the relevant form. 
Oral Suspension Accountability 
The residual volume of suspension in the bottles will be measured by the investigator by 
means of a calibrated glass cylinder supplied by Italfarmaco and reported in the Drug 
Accountability Form and in the eCRF. 
Capsule Accountability 
The investigator will count the capsules unused for each bottle and insert the number in 
the Drug Accountability Form and in the eCRF. 
Periodically throughout and at the conclusion of the study, a representative of Italfarmaco 
S.p.A. or its delegate will conduct an inventory of all study drug supplies and the bottles
of oral suspension and/or capsules used, partially used, and unused will be destroyed at
the site, if possible, or sent back to Italfarmaco.
Missed doses are not to be recovered and they should be recorded in the eCRF and in the 
Drug Accountability Form, specifying the reason for any missed dose. 
For more detailed procedures, please refer to the relevant CSOM. 
3.3.7 
Prior and Concomitant Illnesses and Treatments 
Prior and Concomitant Illnesses 
Investigators should document all significant illnesses that the child has experienced 
within 6 months of screening. Additional illnesses present at the time informed consent 
is given are to be regarded as concomitant illnesses. Illnesses first occurring or detected 
during the study and/or worsening of a concomitant illness during the study are to be 
documented as AEs in the eCRF. 


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Prior and Concomitant Treatments 
Prior treatments, defined as those taken within 6 months prior to screening, should be 
recorded in the eCRF as prior medications. 
Concomitant treatments are defined as treatments taken after study drug administration. 
Children should be on stable systemic corticosteroid therapy for at least 6 months prior to 
initiation of study drug. That is, there have been no changes in systemic corticosteroid 
therapy (e.g., initiation, change in type of drug, dose modification not related to body 
weight change, schedule modification, interruption, discontinuation, or re-initiation) 
during the previous 6 months. 
Supportive treatments, such as anti-emetics, anti-diarrheals, anti-pyretics, anti-allergics, 
analgesics, and antibiotics are allowed. 
Use of Vitamin D, calcium and integrators if clinically indicated before enrolment and for 
duration of the trial are allowed. 
The following medications are prohibited prior to (as noted below) and during study 
treatment: 
 Other investigational agents within 3 months of start of study drug, since time 
historical 6MWT data was obtained, or while on study 
 Prior gene therapy or cell-based therapy or oligonucleotide therapy prior to study 
treatment or while on study 
 Any pharmacologic treatments (other than stable doses of corticosteroids) that 
might have an effect on muscle strength since the time of the historical 6MWT 
and in any case within 3 months prior to the start of study treatment (e.g., growth 
hormone). or while on study 
 Drugs that prolong the QTc interval (see Appendix 1: Drugs Known to Prolong 
the QTc Interval) 
3.4 Assessments 
3.4.1 
Schedule of Assessments 
The procedures to be performed during the study are outlined in the Schedule of 
Assessments (Table 8 and Table 9). A detailed description of each assessment may be 
found in Section 3.4.2. 


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Table 8 
Schedule of Assessments: Part 1 (Dose Escalation) 
Assessment 
Screen/ 
Pre-Studya 
Part 1 (Approximately 20 Children) 
Week 
-4 (±2 weeks)
0 
1 
2 
3 
4 
5 
Visit (1-day window) 
0 
1 
2 
3 
4 
5 
6 
Informed consent and 
assent 
X 
Medical history/ 
eligibility 
X 
Concomitant 
medications 
Xb
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
12-lead ECGc
X 
X 
X 
X 
X 
X 
X 
ECHOc 
X 
PFTs (FEV1, FVC, 
FEV1/FVC)c 
X 
Clinical laboratory 
testsc,d 
X 
X 
X 
X 
X 
X 
X 
Urinalysisb,c 
X 
X 
X 
X 
X 
X 
X 
Cytokine 
X 
miRNA 
X 
Serologye 
X 
Quality of Life test 
X 
Muscle evaluations 
(6MWTf, NSAAg, 
PULg) 
X 
Muscle biopsy 
X 
MRI 
X 
PK assessmenth 
Xi 
Xi 
Xi 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Study drug 
administration 
X 
X 
X 
X 
X 
X 
6MWT=6-Minute Walk Test; CMV=cytomegalovirus; EBV=Epstein Barr virus; ECG=electrocardiogram; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; MRI=magnetic resonance imaging; 
NSAA=North Star Ambulatory assessment; PFTs=pulmonary function tests; PK=pharmacokinetic. 
a During the pre-study visit, historical function data (from 6 months before the pre-study visit) will be 
collected. 
b Obtain prior medications at screening as well. 
c To be performed more frequently, if clinically indicated. 
d The following laboratory parameters will be assessed: hematology: RBC, hemoglobin, hematocrit, WBC 
with differential, platelets, ANC, and abnormal cells; blood chemistry: total bilirubin, alkaline 
phosphatase, amylase, ALT, AST, LDH, CRP, creatine kinase, total protein, albumin, uric acid, sodium, 


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potassium, chloride, calcium, glucose, creatinine, BUN, and CPK (CrCl will be calculated by the Cockcroft 
and Gault formula); urinalysis: pH, specific gravity, protein, glucose, ketones, cytology, and myoglobin. 
e The following serology tests will be conducted: ELISA for HIV-Ab, HCV-Ab, HbsAg, HbeAg, 
anti-EBV, and anti-CMV IgM. 
f During the pre-study visit, the historical function data relevant to 6MWTs will be collected: (1) result 
from 6MWT performed at least 6 months before the pre-study visit, and (2) result from 2 6MWT 
performed within 4 weeks prior to treatment start will be necessary and inserted into the eCRF. 
g During the pre-study visit, the functional data relevant to the NSAA and PUL will be collected: results 
performed within 4 weeks prior to treatment start will be necessary and inserted into the eCRF. 
h At Visit 2, 4, and 6, blood samples for PK analysis should be collected pre-dose in the morning before 
drug intake and at 1, 2, 4, and 8 hours post-dose. It is important to record the time of PK assessments and 
the time of the last drug intake in the evening before the PK assessment. 
i At Visit 2, the first 4 patients will have PK assessments performed; at Visit 4, the next 8 patients will have 
PK assessments performed; at Visit 6, the next set of 8 patients will have PK assessments performed. 


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Table 9 
Schedule of Assessments: Part 2 (Proof of Mechanism) 
Assessment 
Part 2 (All Children)j 
12/ 
EOS 
Visiti 
FU 
Visit 
Month of Study: 
0 
1 
2 
3 
4.5 
6 
7.5 
9 
10.5 
12 
-- 
Visit (1 week 
window) 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGc
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECHOc 
X 
PFTs (FEV1, 
FVC, 
FEV1/FVC)c 
X 
Clinical 
laboratory 
testsc,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisc,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serologye 
Quality of life 
test 
X 
Muscle 
evaluations 
(6MWTf, 
NSAAg, PULg) 
X 
X 
X 
X 
Muscle biopsy 
X 
MRI 
X 
Cytokine 
X 
X 
X 
X 
miRNA 
X 
X 
X 
X 
PK assessmenth 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6MWT=6-Minute Walk Test; CMV=cytomegalovirus; EBV=Epstein Barr virus; ECG=electrocardiogram; 
EOS=end of study; FU=follow up; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
MRI=magnetic resonance imaging; NSAA=North Star Ambulatory assessment; PK=pharmacokinetic. 
a The screening visit is only for children newly enrolled in Part 2. Children who were enrolled in Part 1 do 
not need to repeat the screening visit. For the relevant assessment, see Table 3 (screen/Pre study visit). 
b Obtain prior medications at screening as well. 
c To be performed more frequently, if clinically indicated. 


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d The following laboratory parameters will be assessed: Hematology: RBC, hemoglobin, hematocrit, WBC 
with differential, platelets, ANC, and abnormal cells; Blood chemistry: total bilirubin, alkaline 
phosphatase, amylase, ALT, AST, LDH, CRP, troponin 1, creatine kinase, total protein, albumin, uric acid, 
sodium, potassium, chloride, calcium, glucose, creatinine, BUN, and CPK (CrCl will be calculated by the 
Cockcroft and Gault formula); Urinalysis: pH, specific gravity, protein, glucose, ketones, cytology, and 
myoglobin. 
e The following serology tests will be conducted: ELISA for HIV-Ab, HCV-Ab, HbsAg, HbeAg, 
anti-EBV, and anti-CMV IgM. 
f During the pre-study visit, the historical function data relevant to 3 6MWTs will be collected: (1) result 
from 6MWT performed at least 6 months before the pre-study visit, and (2) result from 6MWT performed 
within 4 ±2 weeks prior to treatment start will be necessary and inserted into the eCRF. 
g During the pre-study visit, the functional data relevant to the NSAA and PUL will be collected: results 
performed within 4±2 weeks prior to treatment start will be necessary and inserted into the eCRF. 
h At Visit 2, blood samples for PK analysis should be taken pre-dose and between 6 and 8 hours post-dose. 
At Visit 3, blood samples for PK analysis should be collected pre-dose in the morning before drug intake 
and between 0 and 2 hours post-dose. At Visit 4, blood samples for PK analysis should be taken pre-dose 
and between 2 and 4 hours post-dose. At Visit 6, blood samples for PK analysis should be taken pre-dose 
and between 4 and 6 hours post-dose. It is important to record the time of PK assessments. 
i Children who discontinue participation prior to completion the study should perform the Early 
Termination Visit within 2 weeks after the last drug intake. For the assessments to be performed, see 
―12/EOS visit.‖ 
j Once all 20 children enrolled during the Part 1 of the study have been treated for at least 2 weeks, the 
review team will determine the RD to be used in Part 2 based on the safety and tolerability profile observed 
and on the PK analyses. All the children enrolled will switch to the RD level, which will be administered 
for the subsequent 12 months of the study (Part 2). 


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3.4.2 
Study Procedures 
3.4.2.1 Pre-Study (Screening)—(Day -28 [±2 Weeks]) 
The assessments during the pre-study phase will determine the child’s eligibility for the 
study and also their ability to comply with protocol requirements by completing all 
screening assessments. All children will undergo all screening assessments, regardless 
of whether they are enrolled during Part 1 or Part 2 of the study. 
The following procedures will be performed and recorded during the screening period: 
 Obtain written informed consent from the child‘s parent/legal guardian and assent 
from the child, if applicable. 
Collect medical history. 
Review inclusion and exclusion criteria. 
Obtain and record current and prior medications (taken in the past 6 months). 
Perform a physical examination. 
Measure vital signs: blood pressure, pulse rate, body temperature. 
Measure height and weight. 
Obtain a 12-lead ECG in triplicate. 
Obtain an ECHO. 
Obtain PFT measurements: FEV1, FVC, FEV1/FVC. 
Obtain blood samples for hematology, blood chemistry, and disease serology 
tests. 
Obtain a urine sample for urinalysis. 
Obtain blood samples for cytokine measurements and miRNA. 
Perform a quality of life test 
Perform the muscle evaluations: 
o
6MWT (collect historical data on tests performed at least 6 months prior to
the pre-study visit and within 4 ± 2 weeks of pre-study visit).
o
NSAA and PUL (collect results from within 4 ± 2 weeks prior to treatment
start).
 Obtain a muscle biopsy (brachial biceps; please refer to Section 3.4.6 for 
instructions; obtained within 4 ± 2 weeks prior to the start of treatment). 
 Obtain an MRI of dystrophic muscle (quadriceps femoris; does not need to be 
repeated if obtained within 4 ± 2 weeks prior to the start of treatment). 
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3.4.2.2 Weekly Visits (Part 1; Weeks 0 to 6) 
Children will visit the study center weekly during Part 1 of the study. Children will 
continue to come in weekly (i.e., every 7 ± 1 days) until they are switched to Part 2 of the 
study when the RD is selected. At each visit (unless otherwise indicated), the following 
assessments will be performed and recorded: 
Obtain and record concomitant medications. 
Perform a physical examination. 
Measure vital signs: blood pressure, pulse rate, body temperature. 
Measure weight. 
Obtain a 12-lead ECG in triplicate. 
Obtain blood samples for hematology and blood chemistry. 
Obtain a urine sample for urinalysis. 
Obtain blood for PK assessments at Visit 2 only as noted in the schedule of 
assessments. 
Dispense IMP and perform accountability. 
Assess AEs. 
3.4.2.3 Part 2 Visits (Months 1 to 10.5) 
Children will visit the study center as noted in the schedule of assessments during Part 2 
of the study (i.e., every 1 to 1.5 months ± 1 week). At each visit (unless otherwise 
indicated), the following assessments will be performed and recorded: 
Obtain and record concomitant medications. 
Perform a physical examination. 
Measure vital signs: blood pressure, pulse rate, body temperature. 
Measure height and weight. 
Obtain a 12-lead ECG in triplicate. 
Obtain blood sample for hematology and blood chemistry. 
Obtain blood samples for cytokine and miRNA (Visits 4 and 6 only). 
Obtain a urine sample for urinalysis. 
Obtain blood for a PK assessments at Visits 2, 3, 4, and 6 only as noted in the 
schedule of assessments. 
Obtain muscle evaluations (6MTW, NSAA, and PUL; Visits 4 and 6 only). 
Dispense IMP and perform accountability. 
Assess AEs. 


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3.4.3 
Assessments for End of Study (Visit 10 [Month 12]) 
Children who remain in the study will continue to take study drug through Visit 10. The 
end-of-study visit overlaps with the 12-month visit, if the child completes treatment. 
The following assessments will be performed and recorded: 
Obtain and record concomitant medications. 
Perform a physical examination. 
Measure vital signs: blood pressure, pulse rate, body temperature. 
Measure height and weight. 
Obtain a 12-lead ECG in triplicate. 
Obtain an ECHO. 
Obtain PFT measurements: FEV1, FVC, FEV1/FVC. 
Obtain blood samples for hematology and blood chemistry. 
Obtain a urine sample for urinalysis. 
Perform a quality of life test. 
Obtain muscle evaluations (6MWT, NSAA, PUL). 
Perform a muscle biopsy (please refer to Section 3.4.6 for instructions). 
Obtain an MRI of dystrophic muscle. 
Obtain blood samples for cytokines and miRNA. 
Perform accountability. 
Assess AEs. 
3.4.4 
Early Termination Visit 
Children who discontinue participation prior to completion of all study drug 
administration (i.e., 12 months of treatment) will be asked to return to the hospital within 
2 weeks after the last dose of study drug for completion of the same assessments given at 
the End of Study visit (for details, see Section 3.4.3). 
3.4.5 
Follow-up Visit 
All children, regardless of whether they complete the study or terminate early in Part 1 or 
Part 2 should return to the study center within 4 weeks of the last dose of study drug for 
the follow-up visit. 
The following assessments will be performed and recorded: 
Obtain and record concomitant medications. 
Perform a physical examination. 
Measure vital signs: blood pressure, pulse rate, body temperature. 


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Obtain a 12-lead ECG in triplicate. 
Obtain blood samples for hematology and blood chemistry. 
Obtain a urine sample for urinalysis. 
Assess AEs. 
3.4.6 
Description of Assessments 
Unless otherwise indicated, all assessments will be performed by the investigator or other 
regular study personnel. Assessments are to be performed according to the schedule 
shown in Section 3.4.1. The assessments at the end-of-study and follow-up visits should 
also be performed if the child terminates the study early. 
Efficacy Assessments 
Muscle Biopsies: A first brachial biceps biopsy (baseline) will be taken prior to the first 
dose of study drug. A second brachial biceps biopsy will be taken at the end of study 
from the opposite arm. 
The muscle biopsy samples from the biceps muscle will be collected by open biopsy 
according to standard hospital procedures for obtaining muscle biopsies from children. 
The minimum amount of muscle tissue required is a small piece of muscle of at least 
0.5 x 0.5 x 0.5 cm. The muscle sample, embedded with tragacanth gum on a piece of 
cork, must be frozen in liquid nitrogen-cooled 2-methylbutane and stored at -80°C or 
-70ºC until shipment.
The collection, processing, and shipment of these muscle biopsy samples to the Ospedale 
Pediatrico Bambino Gesù laboratory will be described in detail in the study-specific 
laboratory manual. 
6- Minute Walk Test: A modified version of the 6MWT recommended by American
Thoracic Society (2002) for use in adults will be performed.
North Star Ambulatory Assessment: The NSAA will be graded using the standard 
scorecard with each assessment rated as 0 – unable to achieve independently, 1 – 
modified method but achieves goal independent of physical assistance from another, or 2 
– normal with no obvious modification of activity.
Performance of Upper Limb: The PUL was devised to assess motor performance in the 
upper limb for patients with Becker and Duchenne muscular dystrophy.  The purpose is 
to assess change that occurs in motor performance of the upper limb over time from when 
a child is still ambulant until he loses all arm function when non-ambulant. The PUL will 


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be administered according to the guidelines developed by the Physiotherapy Working 
Group (Mayhew A et al. 2012, Mercuri E et al. 2012). 
MRIs: MRIs will be taken at quadriceps femoris and evaluated per the specifications in 
the Clinical Study Operation Manual (CSOM). 
Cytokines and miRNA: The following cytokines may be evaluated: tumor-necrosis 
factor-alpha (TNF-α), interleukin (IL)-1, and IL-6. In addition, miR-1, miR-133, and 
miR-206 may be evaluated. Additional cytokines and miRNA parameters may be 
evaluated if warranted. Evaluation of cytokines and miRNA will be documented in a 
separate report. 
Other efficacy assessments – exploratory analysis of muscle biopsies: Muscle biopsies 
will be analyzed in 2 distinct steps, by using different complementary approaches 
(fluorescence-activated cell sorting [FACS]-mediated isolation of cells and functional 
characterization ex vivo and staining of frozen sections) that are finalized to the 
identification and functional/molecular characterization of specific cell types that 
contribute to the regeneration or fibro-adipogenic degeneration of dystrophic muscles. 
These cells include muscle satellite cells (MuSCs) and a heterogeneous population that is 
referred to as ―fibro-adipogenic progenitors‖ (FAPs). These cell types can be isolated by 
FACS in mouse and human muscle samples as distinct populations, based on specific 
combination of surface antigens. 
In the mouse system, MuSCs can be isolated from skeletal muscles by FACS, as 
CD34pos/α7-integrinpos/Sca1neg cells (Sacco A et al. 2008), while FAPs are isolated either 
as CD34pos/α7integrinneg/Sca1pos cells or platelet-derived growth factor receptor (PDGFR) 
PDGFR- α pos cells (Joe AW et al. 2010; Uezumi A et al. 2010). In muscle biopsies of 
human patients or normal individuals, MuSCs are isolated as PDGFR- α neg/α7- 
integrinpos/N-CAM pos cells, while FAPs can be isolated as PDGFR- α neg/α7- 
integrinpos/N-CAM pos cells. 
Pre-clinical studies have demonstrated that functional interactions between these cell 
types contributes to the disease progression in mouse models of DMD (mdx mice) and 
that HDAC inhibitors promote the FAP property of stimulating muscle regeneration at 
the expense of fibro-adipogenic degeneration. The sponsor has identified a novel nuclear 
network that regulates FAP lineage identity and ability to support regeneration or 
fibro-adipogenic degeneration in dystrophic muscles. This network consists of an 
HDAC-repressed miRNA (the myomiRs 1.2, 133a and 206) that target 2 specific 
sub-units (BAF60a and b) of the switch/sucrose non-fermentable (SWI/SNF) chromatin 
remodeling complex, which promotes the expression of fibro-adipogenic genes. Upon 
treatment with HDAC inhibitors, de-repression of myomiRs 1.2, 133a and 206 causes the 


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down regulation of BAF60a and b, and the simultaneous activation of BAF60c, leading 
to the formation of BAF60c-based SWI/SNF complex that promotes skeletal myogenesis 
in FAPs. The sponsor has found that mdx mice that respond to HDAC inhibitors, such as 
Givinostat, show increased levels of BAF60c and myomiRs 1.2, 133a and 206. 
1.
FACS-sorting of MuSCs and FAPs from biopsies of children before and at the
end of the treatment will be used to measure: a) the relative amount of these cell
populations; b) their ability to differentiate in culture, in myogenic and adipogenic
media, and their functional interactions by co-culture experiments; c) gene and
miRNA expression analysis by quantitative polymerase chain reaction.
It should be emphasized that in vitro exposure to Givinostat of MuSCs and FAPs
from biopsies of children before the treatment might provide a useful measure
predictive of child response that can be used to better select children in a
follow-up trial.
2.
Histologic analysis of muscle sections from biopsies of children before and at the
end of the treatment will be used to measure: a) the expression levels of BAF60
a, b, and c variants, and myomiRs 1.2, 133a and 206 in MuSCs and FAPs, which
will be identified as Pax7pos or PDGFR- α pos, respectively.
Safety Assessments 
Physical Examination: Physical examination will include examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, heart, lungs, 
abdomen, lymph nodes, extremities, and nervous system. An AE form must be 
completed for all changes identified as clinically noteworthy. Height without shoes and 
weight will be recorded as noted in the schedule of assessments. 
Vital Signs: Vital signs will include body temperature (ºC), pulse rate, and blood 
pressure. 
Electrocardiogram: Standard 12-lead ECGs will be conducted in triplicate per the 
schedule of assessments and more often if clinically indicated. ECG will be acquired at 
the sites, then ECG data will be transmitted and a central reading will be performed. For 
details, see the relevant CSOM. 
ECHOs: Standard ECHOs will be conducted as per the schedule of assessments and 
more often if clinically indicated. 
Pulmonary function tests: FEV1, FVC, and FEV1/FVC, will be collected per the site‘s 
standard process as noted in the schedule of assessments and more often if clinically 
indicated. 


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Laboratory Parameters: The following laboratory tests are to be performed as indicated 
in the schedule of assessments and more often if clinically indicated: 
 Hematology: red blood cell (RBC) count, hemoglobin, hematocrit, WBC count 
with differential, platelets, ANC, and abnormal cells 
 Blood chemistry: total bilirubin, alkaline phosphatase, amylase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase 
(LDH), C-reactive protein (CRP), creatine kinase, total protein, albumin, uric 
acid, sodium, potassium, chloride, calcium, glucose, creatinine, blood urea 
nitrogen (BUN), and creatine phosphokinase (CPK) (creatinine clearance [CrCl] 
will be calculated by the Cockcroft and Gault formula.) 
 Urinalysis: pH of freshly voided specimen, specific gravity, protein, glucose, 
ketones, cytology, and myoglobin 
 Other: enzyme-linked immunosorbent assay (ELISA) for HIV- Ab, HCV-Ab, 
HbsAg, hepatitis B e antigen (HbeAg), anti-EBV, and anti-cytomegalovirus 
(CMV) immunoglobulin M (IgM).
Lab tests will be performed and analyzed by a local laboratory to ensure consistent 
interpretation of results. In the event of an unexplained clinically noteworthy abnormal 
laboratory test value, the test should be repeated immediately and followed up until it has 
returned to the normal range and/or an adequate explanation of the abnormality is found. 
Adverse Events:  An AE is any is ―any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment (International Conference on 
Harmonisation [ICH] E2A).‖ All medical and psychiatric conditions (except those 
related to the indication under study) present at screening will be documented on the 
Prior Illnesses eCRF. Changes in these conditions and new symptoms, physical signs, 
syndromes, or diseases should be noted on the AE eCRF during the rest of the study. 
Laboratory abnormalities should be recorded as AEs only if they meet the criteria for an 
SAE, result in discontinuation of the study drug, require medical intervention, or are 
judged by the investigator to be clinically significant changes from baseline values. See 
Section 4, for additional information. 
Pharmacokinetic Assessments 
Blood samples for PK assessments will be collected as indicated in the schedule of 
assessments. Additional information about the PK time points will be provided in the 
relevant CSOM. 


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Quality of Life Assessment 
The PedsQL Test will be performed before treatment start and at the end of the study. 
3.4.7 
Appropriateness of Measurements 
All assessments to be used in this study are commonly used, standard measurements 
frequently seen in DMD studies. 
4 Adverse Event Reporting 
Throughout the course of the study, all AEs will be monitored and reported in the AE 
eCRF, including the event‘s seriousness, severity, action taken, and relationship to the 
IMP. If AEs occur, the first concern will be the safety of the children. All AEs will be 
followed until resolved or stable and the outcome documented on the appropriate eCRF. 
In order to avoid vague, ambiguous, or colloquial expressions, all AEs should be 
recorded in standard medical terminology rather than the child‘s or parent‘s/legal 
guardian‘s own words. 
4.1 Definitions and Criteria 
4.1.1 
Adverse Events 
An AE is ―any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment (ICH E2A)‖. 
AEs include: 
Onset of any clinical sign or symptom 
Worsening (change in nature, severity or frequency) of conditions present at the 
start of the trial 
Subject deterioration due to the primary illness 
Intercurrent illness(es) 
Drug interactions 
Events related or possibly related to concomitant medications 
Abnormal laboratory values, as well as significant shifts from baseline within the 
range of normal that the investigator considers to be clinically significant 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 


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4.1.2 
Adverse Drug Reactions 
In the pre-approval clinical experience with a new medicinal product: ―all noxious and 
unintended responses to a medicinal product related to any dose should be considered 
Adverse Drug Reaction. 
4.1.3 
Unexpected Adverse Drug Reactions 
An unexpected adverse drug reaction is an event in which the nature or severity is not 
consistent with the applicable product information (e.g., Investigator‘s Brochure for an 
unapproved IMP). 
4.1.4 
Serious Adverse Events 
An SAE (experience) or reaction is any untoward medical occurrence that at any dose: 
Is fatal (results in the outcome death) 
Is life-threatening* 
Requires inpatient hospitalization or prolongs existing hospitalization 
Results in persistent or significant disability/incapacity 
Is a congenital anomaly/birth defect 
Is medically significant or requires intervention to prevent one or other of the 
outcomes listed above 
*The term life-threatening refers to an event in which the subject was at risk of death at the time of the
event; it does not refer to an event which hypothetically might have caused death if it were more severe.
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the child or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
An SAE is not necessarily severe; e.g., an overnight hospitalization for a diagnostic 
procedure must be reported as an SAE even though the occurrence is not medically 
serious. By the same token, a severe AE is not necessarily serious: nausea of several 
hours‘ duration may be rated as severe but may not be considered serious. 


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4.1.5 
Assessing Intensity and Relationship 
All AEs will be assessed on 2 descriptive parameters: intensity and relationship to study 
drug: 
Intensity refers to the ―severity‖ of an event and references impact on a child‘s 
functioning. 
Relationship refers to the likelihood that the event being assessed was caused by the 
study drug. 
Intensity 
Each AE will be classified according to the following criteria: 
Mild: 
The AE does not interfere in a significant manner with the 
child‘s normal functioning level. 
Moderate: 
The AE produces some impairment of functioning, but is 
not hazardous to health. 
Severe: 
The AE produces significant impairment of functioning or 
incapacitation and is a definite hazard to the child‘s health. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the experience should be noted. If the intensity category changes 
over a number of days, those changes should be recorded separately (with distinct onset 
dates). 
Relationship 
Each AE will be assessed as to its relationship to study drug based on the following 
criteria. Although investigator attribution will be collected for reported events, for 
analytic purposes a temporal association with the use of study drug will be assumed 
sufficient for at least plausible association. 
Not 
related: 
No causal relationship exists between the investigational 
product and the AE, but an obvious alternative cause 
exists, e.g., the child‘s underlying medical condition or 
concomitant therapy. 
Related: 
There is a reasonable/plausible possibility that the AE may 
have been caused by the investigational product. 


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When assessing the relationship to study drug, the follow criteria will be considered: 
Positive rechallenge 
Positive dechallenge (resolution upon stopping suspect product, in absence of 
other intervention or treatment) 
Known class effect 
Biological plausibility 
Lack of alternative explanation—concomitant drug or disease 
Factors to be considered in assessing the relationship of the AE to study drug include: 
The temporal sequence from IMP administration 
The recovery on discontinuation and recurrence on reintroduction 
The concomitant diseases 
The evolution of the treated disease 
The concomitant medication(s) 
The pharmacology and pharmacokinetics of the IMP 
4.2 Reporting Procedures and Requirements 
4.2.1 
Adverse Events 
The investigator or his/her designees are requested to collect and assess any spontaneous 
AE reported by the child and to question the child about AEs and intercurrent illnesses at 
each visit during the treatment period and follow-up. The questioning of children 
regarding AEs is generalized such as ―How have you been feeling since your last visit?‖ 
Any AE occurring after the informed consent form/assent has been signed and up to the 
follow-up study visit, whether volunteered by the child; discovered during general 
questioning by the investigators; or detected through physical examination, laboratory 
test, or other means will be recorded on the specific section of the eCRF. Each AE will 
be described by: 
Seriousness 
Duration (start and end dates) 
Severity 
Relationship to the IMP 
Action taken 
Outcome 
The severity of AE should be assessed and graded according to the most recently 
published National Cancer Institute Common Terminology Criteria for AEs (v. 4.0). 


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The relationship to the investigational drug should be assessed as: 
Related to IMP 
Not related to IMP 
Unknown 
The assessment of the relationship of an AE to the administration of IMP is a clinical 
decision based on all available information at the time of the completion of the eCRF. 
An assessment of ‗not related‘ would include the existence of a clear alternative 
explanation, or non-plausibility. 
An assessment of ‗related‘ indicates that there is a reasonable suspicion that the AE is 
associated with the use of the IMP. 
4.2.1.1 Abnormal Laboratory Findings and Other Objective Measurements 
Abnormal laboratory findings and other objective measurements should not be routinely 
captured and reported as AEs in the eCRF as they will be collected and analyzed 
separately. However, abnormal laboratory findings and other objective measurements 
that meet the criteria for an SAE, result in discontinuation of the IMP, require medical 
intervention, or are judged by the investigator to be clinically significant changes from 
baseline values should be captured and reported as AEs in the eCRF. 
When reporting an abnormal laboratory finding as an AE in the eCRF, a clinical 
diagnosis should be recorded in addition to the abnormal value itself, if this is available 
(for example ―anemia‖ in addition to ―hemoglobin = 10.5 g/dL‖). 
4.2.1.2 Baseline Medical Conditions 
Medical conditions present at the screening visit that do not worsen in severity or 
frequency during the study are defined as baseline medical conditions and are not AEs. 
These medical conditions should be adequately documented on the appropriate page of 
the eCRF (i.e., the medical history page). However, medical conditions present at the 
initial study visit that worsen in severity or frequency during the study should be recorded 
and reported as AEs. 
4.2.2 
Serious Adverse Events 
Any SAE, including death from any cause that occurs after a child has signed the 
informed consent /assent and up to the final follow-up visit (regardless of relationship to 
study drug) must be reported by the investigators to the sponsor within 24 hours of 
learning of its occurrence. 


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Related SAEs MUST be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed. 
The investigators are required to complete the SAE form provided by the sponsor. 
Sufficient details must be provided to allow for a complete medical assessment of the AE 
and independent determination of possible causality. The investigators are obliged to 
pursue and provide additional information as requested by the sponsor‘s drug safety 
manager, or study director, or designee. 
The investigator must send notification of the SAE to the sponsor‘s Drug Safety Unit by 
faxing the SAE form, within 24 hours of a SAE, at the number specified below; then, the 
investigator must confirm any SAE notifications by mailing to the mail address or 
phoning to the phone number specified below: 
Aurelio Scotti 
Drug Safety Unit, Chemi S.p.A. 
Via dei Lavoratori 
54 20092 Cinisello Balsamo (MI), Italy 
Fax: 02 6610 6538 
phone: +39 02 6443 2510, mobile +39 333 9262611 
e-mail: drug-safety@italfarmaco.com
a. scotti@italfarmaco.com
The same procedure must be applied to the SAE follow-up information. 
The sponsor‘s drug safety manager will report all serious and unexpected AE that are 
related to the use of the study drug to the competent authority within the required time 
and following procedures required by applicable laws. It is imperative that the sponsor 
be informed as soon as possible, so that reporting can be done within the required time 
frame. 
The SAEs will also be recorded in the AE section of the eCRF. 
Overdose and Other Situations Putting the Child at Risk of an Adverse Reaction 
Any instance of overdose (suspected or confirmed) must be reported to the sponsor 
within 24 hours and be fully documented as a SAE. Details of any signs or symptoms 
and their management should be recorded including details of any antidote(s) or 
systematic treatment administered. Any signs or symptoms of overdose will be treated 
symptomatically. 


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Any other situations putting the child at risk of adverse reaction, such as misuse and 
abuse, medication errors, suspicion of transmission of infective agents must be reported 
to the sponsor within 24 hours and be fully documented as a SAE. 
5 Data Management and Statistical Analysis 
5.1 Data Management Considerations 
Electronic CRFs will be employed for this study. Completed eCRFs for this study will be 
forwarded to the sponsor or its representative where editing and construction of a 
quality-assured database will occur. The statistical analysis of these data will be 
performed by the sponsor or its representative. 
Data Analysis of the Biopsies 
All images will be digitally captured, using both light microscopy (hematoxylin and eosin 
[H&E] and Gomori trichrome stain) and fluorescence microscopy coupled to the 
Olympus Fluoview FV1000 confocal microscope. Fields for fluorescent imaging will be 
randomly selected while viewing the laminin-dystrophin signal. 
In the only step involving operator discretion, all image parameters including pinhole 
size, detector gain, amplifier offset, amplifier gain, and laser intensity will be first set for 
the dystrophin and laminin channels using normal control tissue, and the same setting 
used for all samples imaged on a given day. Frame size, scan speed, and averaging will 
be the same for all images. For each sample 4 non-overlapping images for each channel 
will be acquired and stored as 12-bit fluorescent images (.TIFF) for analysis. A single 
technician will perform all sectioning, staining, and morphometry steps, while another 
operator will execute the confocal imaging. 
Image processing and quantitative analyses will be done using Metamorph (Molecular 
Devices, Inc.) software program using a custom script. Additional details are provided in 
the relevant CSOM. 
5.2 Statistical Considerations 
The statistical analysis will be undertaken by the contract research organization 
Worldwide Clinical Trials (WCT) in collaboration with the sponsor. 
Any deviations from the analyses described below will be included in the Statistical 
Analysis Plan (SAP). 


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5.2.1 
General Considerations 
Data will be provided in data listings sorted by treatment group and child number. 
Tabular summaries will be presented by treatment group for Part 1. Categorical data will 
be summarized by the number and percentage of children in each category. Continuous 
variables will be summarized by descriptive statistics, including mean, standard 
deviation, median, minimum, and maximum. Confidence intervals (CIs) will be 2-sided, 
unless otherwise stated. Details of endpoint analyses will be described in the SAP. 
For analyses of change from baseline, baseline will generally be defined as the value 
collected before any Givinostat treatment is administered. If this value is unavailable, the 
last non-missing value prior to dosing will be used. Otherwise, missing observations will 
be treated as missing at random, and no data imputation will be performed. All data from 
the CRFs, as well as any derived variables, will be presented in data listings. 
All hypothesis tests will be two-sided with a 5% significance level, and 95% CIs will be 
used, unless stated otherwise. As this is a Phase 2 exploratory study, no adjustments for 
multiplicity will made. 
5.2.2 
Sample Size Justification 
A minimum of 20 evaluable children will be enrolled in this study. 
5.2.2.1 Part 1 
Approximately 20 children will be enrolled in Part 1 (dose-finding) of this study. 
5.2.2.2 Part 2 
Muscle fibers: a sample size of 20 children from part 1 completing the treatment period 
of part 2 should provide 90% power (at a 2-sided alpha level of 5%) to detect at least a 
12.5% increase in MFA% between pre- and post-treatment (which corresponds 
approximately to a 26% relative increase given the observed mean in the Desguerre 
publication of 48% [Desguerre I et al. 2009]), the ―worst case‖ standard deviation of 
16%, which assumes that there is no correlation within a subject in the muscle area fiber 
percentage between pre- and post-treatment. This sample size is based on a paired t-test 
and the assumption of normal distribution of MFA%. 
After the first 20 baseline biopsies are collected, an interim analysis aimed at checking 
the real variability observed in the study will be implemented: the within-subject 
standard deviation of MFA% will be calculated, the actual distribution of MFA% will be 
checked and the final sample size will be adjusted based on the observed standard 
deviation and actual distribution of MFA%. Results by Al-Sunduqchi and Guenther 
(1990) indicate that power calculations for the Wilcoxon test may be made using the 


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standard t-test formulations with a simple adjustment to the sample size. The size of the 
adjustment depends upon the actual distribution of the data. They give sample size 
adjustment factors for four distributions. These are 1 for the uniform distribution, 2/3 for 
the double exponential distribution, 9/π2 for the logistic distribution, and π/3 for the 
normal distribution. So depending on the actual distribution of MFA%, sample size 
re-calculation will be based on a Wilcoxon Signed Rank test with the corresponding 
adjustment if the observed distribution of MFA% is not normal. 
5.2.3 
Analysis Populations 
The intent-to-treat (ITT) population includes all children who are enrolled in the Part 1 
portion or entered the Part 2 portion of the study. The efficacy analysis will be conducted 
based on the ITT population. 
The evaluable population will include all children who are in the Part 2 of the study, 
receive Givinostat of at least 80% dose, have at least one baseline and one post-baseline 
assessment of biopsies, and have no major protocol violations. The evaluable population 
will be identified prior to database lock. A sensitivity analysis may be conducted based 
on the evaluable population. 
The safety population will include all children who receive any investigational product. 
The safety analysis will be conducted based on the safety population. 
The PK population will include all children with at least one quantifiable post-dose 
concentration datum available. All statistical analyses of PK data will be performed 
using the PK population. 
5.2.4 
Primary Endpoint 
The primary endpoint of this study is change in the value of MFA% comparing the 
histology biopsies before and after 12 months of treatment with Givinostat. 
5.2.5 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following: 
 Change in additional histological endpoints (i.e., cross-sectional area, 
inflammation, necrosis, fibrosis, and muscle regeneration) after 12 months of 
treatment with Givinostat at the selected daily dose 
 Change in muscular function after 12 months of treatment with Givinostat at the 
selected daily dose based on the 6MWT 
 Change in muscular function after 12 months of treatment with Givinostat at the 
selected daily dose based on the NSAA 


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 Change in muscular function after 12 months of treatment with Givinostat at the 
selected daily dose based the PUL 
Additional details on secondary efficacy endpoints will be provided in the SAP. 
5.2.6 
Secondary Safety Endpoints 
The secondary safety endpoints will include the following: 
The number of children experiencing AEs 
The type, incidence, and severity of AEs correlated with dose 
ECG, ECHO, vital sign, physical examination, PFTs, and clinical laboratory 
parameter findings 
5.2.7 
Secondary Pharmacokinetic Endpoints 
Individual Givinostat concentrations will be tabulated by dose cohort along with 
descriptive statistics for Part 1 and tabulated along with descriptive statistic for Part 2. 
Noncompartmental PK data analysis will be performed for data obtained from each dose 
cohort with scheduled PK sample collection. If data allows, descriptive statistics of 
noncompartmental PK parameters (area under the plasma–concentration time curve, 
maximum plasma concentration, clearance, terminal elimination half-life) will be 
provided. 
5.2.8 
Exploratory Endpoints 
The exploratory endpoints will include the following: 
 Changes in muscle, fat, and fibrosis content after treatment with Givinostat as 
measured by MRI 
 Change biomarkers (e.g., miRNA) and cytokine following treatment with 
Givinostat 
 PK–PD correlations 
5.2.8.1 Magnetic Resonance Imaging 
MRI will be collected via T1w imaging and quantitative Dixon imaging (the fat content of 
the image as a percentage of the total signal per voxel). Additional details will be provided 
in the SAP. 
5.2.8.2 miRNA and Cytokine Parameters 
miR-1, miR-133, and miR-206 as well as TNF-α, IL-1, and IL-6 will be evaluated. Other 
miRNA and cytokine parameters may be evaluated as appropriate.  Additional details 
will be provided in the SAP. 


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5.2.9 
Efficacy Analyses 
Efficacy analyses will be conducted on the evaluable population. 
All values will be expressed as means ± standard deviation or standard error of the mean. 
Each of all efficacy endpoints will be subject to normality test and formal statistical test 
performed will be based on whether it is normally distributed. If normal, statistical 
differences will be calculated using the paired t test; if not normal, Wilcoxon signed rank 
test will be used to assess the statistical significance of differences between groups. 
P<0.05 will be set as significant. 
5.2.10 Safety Analyses 
Safety analyses will be conducted on the safety population. 
The safety of Givinostat will be assessed primarily by summarizing treatment-emergent 
AEs and SAEs. Other safety data (e.g., laboratory, ECG, PFTs, physical examination, 
and vital sign findings) will be summarized. Treatment-emergent AEs and SAEs that 
occur after administration of Givinostat will be summarized by system organ class and 
preferred terms, by severity, and by relationship to investigational product. Change from 
baseline in laboratory values, ECG findings, PFTs, physical examination findings, and 
vital signs measurements will be summarized. 
5.2.11 Pharmacokinetic Analyses 
The PK analysis will be conducted on the PK population. 
Plasma concentrations from Part 1 will be listed and tabulated by dose and time point for 
all children and time points with at least 1 PK assessment. Plasma concentrations from 
Part 2 will be listed and tabulated by time point for all children and time points with at 
least 1 PK assessment. 
Descriptive statistics for all PK parameters for Part 1 will be calculated by treatment. 
Descriptive statistics for all PK parameters for Part 2 will also be calculated. These 
tables will include number of observations, mean, standard deviation, median, minimum 
and maximum and additionally the geometric mean and coefficient of variation (not for 
time to maximum plasma concentration). 
5.2.12 Interim Analyses 
The following interim analyses will be conducted: 


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 After the first 20 baseline biopsies are collected, the between-subject standard 
deviation of MFA% fraction will be calculated, the actual distribution of MFA% 
will be checked. The within-subject standard deviation will be estimated by 
between-subject standard deviation under the ―worst case‖ scenario, which 
assumes that there is no correlation within a subject in the muscle area fiber 
percentage between pre- and post-treatment. 
 Based on the standard deviation obtained above, the final sample size will be 
adjusted. A conservative approach will be adopted, where the sample size may be 
increased but not decreased. 
6 Study Management 
6.1 Approval and Consent 
6.1.1 
Regulatory Guidelines 
The study will be performed in accordance with local national laws (as applicable), the 
guidelines of the ICH, and the guidelines of the Declaration of Helsinki adopted by the 
18th World Medical Assembly in Helsinki, Finland in 1964 and amended by subsequent 
assemblies in Tokyo, Japan in 1975; Venice, Italy in 1983; Hong Kong in 1989; Somerset 
West, South Africa in 1996, and in Edinburgh, Scotland in October 2000. These 
guidelines are on file at WCT. 
This clinical study has been designed to comply with the Good Clinical Practice 
guidelines. 
6.1.2 
Institutional Review Board/Independent Ethics Committees 
This study will be undertaken only after approval of the protocol has been obtained from 
the appropriate Independent Ethics Committee (IEC), and a copy of the approval has 
been received by Italfarmaco S.p.A. 
The IEC must be informed of all subsequent protocol amendments and should be asked 
whether a re-evaluation of the ethical aspects of the study is necessary. 
If applicable, interim reports on the study and reviews of its progress will be submitted to 
the IEC by the investigator at intervals stipulated in their guidelines. 
6.1.3 
Informed Consent 
For each trial subject, written informed consent from the legally accepted representative 
will be obtained prior to any protocol-related activities. Informed assent may be obtained 
from children who are capable of providing assent. As part of this procedure, the 


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principal investigator or a designated representative must explain orally and in writing the 
nature, duration, and purpose of the study, and the action of the drug in such a manner 
that the child and (if applicable) appointed guardian are aware of the potential risks, 
inconveniences, or adverse effects that may occur. Children and their legally accepted 
representatives should be given ample time and opportunity to inquire about the details of 
the study prior to deciding whether to participate in the study. It is the responsibility of 
the investigator to ensure that all questions about the study are answered to the 
satisfaction of the children and their legally accepted representatives. 
Children and their legally accepted representatives should be informed that children may 
withdraw from the study at any time. They will receive all information that is required 
by local regulations and ICH guidelines. The principal investigator or a designated 
representative will provide the sponsor or its representative with a copy of the 
IEC-approved informed consent form prior to the start of the study. 
The informed consent form should be signed and dated by the child‘s legally accepted 
representative and the investigator on the same day. If the child and/or legally accepted 
representative are not able to read, an impartial witness should be present during the 
informed consent discussion, and the witness must co-sign and date the informed consent 
form. The child‘s legally accepted representative and/or impartial witness should receive 
a copy of the signed documents. 
For details of the information provided, refer to the informed consent form. 
6.2 Discontinuation of the Study by the Sponsor 
The sponsor reserves the right to discontinue the study at this site or at multiple sites for 
safety or administrative reasons at any time. In particular, a site that does not recruit at a 
reasonable rate may be discontinued. Should the study be terminated and/or the site 
closed for whatever reason, all documentation and study medication pertaining to the 
study must be returned to the sponsor or its representative. 
6.3 Study Documentation 
The investigator will supply the sponsor with: 
Curricula vitae for all investigators 
Signed protocol signature page 
List of IEC members and their occupations/affiliations or multiple assurance 
number 
Letter indicating IEC approval to conduct the protocol 
Copy of IEC-approved informed consent form 
Laboratory certification records and reference ranges 


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The main documents that will be supplied by the Sponsor to investigator are: 
Clinical study protocol 
Investigational drug brochure 
Sample informed consent form 
eCRFs/instruction manual 
Insurance letter 
6.4 Study Monitoring and Auditing 
This study will be monitored at all stages of its development by the clinical research 
personnel employed by the sponsor or its representative. Monitoring will include 
personal visits and telephone communication to assure that the investigation is conducted 
according to protocol and in order to comply with guidelines of Good Clinical Practice. 
On-site review of eCRFs will include a review of forms for completeness and clarity, and 
consistency with source documents available for each child. Note that a variety of 
original documents, data, and records will be considered as source documents in this trial. 
The eCRF itself is not to be used as a source document under any circumstances. 
Medical advisors and clinical research associates or assistants may request to witness 
child evaluations occurring as part of this protocol. The investigator and appropriate 
personnel will be periodically requested to attend meetings/workshops organized by the 
sponsor to assure acceptable protocol execution. The study may be subject to audit by 
the sponsor or by regulatory authorities. If such an audit occurs, the investigator must 
agree to allow access to required child records. By signing this protocol, the investigator 
grants permission to personnel from the sponsor, its representatives, and appropriate 
regulatory authorities for on-site monitoring of all appropriate study documentation, as 
well as on-site review of the procedures employed in eCRF generation, where clinically 
appropriate. 
6.5 Retention of Records 
The investigator must arrange for retention of study records at the site. The nature of the 
records and the duration of the retention period must meet the requirements of the 
relevant regulatory authority. In addition, because this is an international study, the 
retention period must meet the requirements of the most stringent authority. The 
investigator should take measures to prevent accidental or premature destruction of these 
documents. 
6.6 Use of Study Findings 
By signing the study protocol, the investigator agrees to the use of results of the study for 
the purposes of national and international registration. If necessary, the authorities will 


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be notified of the investigator‘s name, address, qualifications, and extent of involvement. 
Reports covering clinical and biometric aspects of the study will be prepared by the 
sponsor or its representative. 
6.7 Publications 
The sponsor assures that the key design elements of this protocol will be posted in a 
publicly accessible database, such as clinicaltrials.gov. In addition, upon study 
completion and finalization of the study report the results of this study will be either 
submitted for publication and/or posted in a publicly accessible database of clinical study 
results. 


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7 References 
Al-Sunduqchi MS. 1990. Determining the Appropriate Sample Size for Inferences Based on the 
Wilcoxon Statistics. Ph.D. dissertation under the direction of William C. Guenther, Dept. of 
Statistics, University of Wyoming, Laramie, Wyoming. 
American Thoracic Society. ATS Statement: Guidelines for the 6-Minute Walk Test. Am J Respir 
Crit Care Med 2002;166:111-117. 
Consalvi S, Saccone V, Giordani L, Minetti G, Mozzetta C, Puri PL. Histone deacetylase 
inhibitors in the treatment of muscular dystrophies: epigenetic drugs for genetic diseases. Mol 
Med. 2011 May-Jun;17(5-6):457-65. 
Desguerre I, Mayer M, Leturcq F, Barbet JP, Gherardi RK, Christov C. Endomysial fibrosis in 
Duchenne muscular dystrophy: a marker of poor outcome associated with macrophage alternative 
activation. J Neuropathol Exp Neurol 2009;68:762–773. 
Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne 
muscular dystrophy: improvements in life expectancy since 1967 and the impact of home 
nocturnal ventilation. Neuromuscul Disord. 2002;12(10):926-9. 
Emery AE. The muscular dystrophies. Lancet. 2002;359(9307):687-95. 
Iezzi S, Cossu G, Nervi C, Sartorelli V, Puri PL. Stage-specific modulation of skeletal 
myogenesis by inhibitors of nuclear deacetylases. Proc Natl Acad Sci U S A. 2002 May 
28;99(11):7757-62. 
ITF2357 Investigator‘s Brochure. Edition No. 11.0. Release Date January 2012. 
Joe AW, Yi L, Natarajan A, Le Grand F, So L, et al. Muscle injury activates resident 
fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol 2010;12:153-63. 
Mayhew A, Eagle M, Mazzone E, et al. Performance of Upper Limb Module for DMD (PUL for 
DMD). Draft 1. March 31, 2012. 
Mercuri E, McDonald C, Mayhew A, et al. International workshop on assessment of upper limb 
function in Duchenne Muscular Dystrophy: Rome, 15-16 February 2012. Neuromuscul Disord 
2012 Jul 12. [Epub ahead of print] 
Minetti GC, Colussi C, Adami R, et al. Functional and morphological recovery of dystrophic 
muscles in mice treated with deacetylase inhibitors. Nat Med. 2006 Oct;12(10):1147-50. 
Sacco A, Doyonnas R, Kraft P, Vitorovic S, Blau HM. Self-renewal and expansion of single 
transplanted muscle stem cells. Nature. 2008 Nov 27;456(7221):502-6. 
Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct 
from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol 
2010;12:143-52. 


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8 Appendices 


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Appendix 1: Drugs Known to Prolong the QTc Interval 
Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Albuterol 
(Proventil®;Ventolin®) 
ß2-receptor agonist/Asthma 
Congenital 
QT Avoid 
Alfuzosin (Uroxatral®) 
Alpha1-blocker/Benign prostatic 
hyperplasia 
Possible 
Risk of 
TdP 
Amantadine (Symmetrel®) 
Dopaminergic/Anti-viral/Anti- 
infective/ Parkinson's Disease 
Possible 
Risk of 
TdP 
Amiodarone (Cordarone®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males,TdP risk 
regarded as low 
Risk of 
TdP 
Amiodarone (Pacerone®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males,TdP risk 
regarded as low 
Risk of 
TdP 
Amitriptyline (Elavil®) 
Tricyclic 
Antidepressant/depression 
Risk of TdP with overdosage 
Conditional 
TdP Risk 
Amphetamine (Dexedrine®) 
CNS stimulant/ADHD 
This includes 
dextroamphetamine and 
amphetamine / 
dextroamphetamine 
combinations. 
Congenital 
QT Avoid 
Amphetamine (Adderall® ) 
CNS stimulant/ADHD 
This includes 
dextroamphetamine and 
amphetamine / 
dextroamphetamine 
combinations. 
Congenital 
QT Avoid 
Arsenic trioxide (Trisenox®) 
Anti-cancer/Leukemia 
Risk of 
TdP 
Astemizole (Hismanal®) 
Antihistamine/Allergic rhinitis 
No Longer available in U.S. 
Risk of 
TdP 
Atazanavir (Reyataz® ) 
Protease inhibitor/HIV 
Possible 
Risk of 
TdP 
Atomoxetine (Strattera®) 
norepinephrine reuptake inhibitor 
/ADHD 
Congenital 
QT Avoid 
Azithromycin (Zithromax®) 
Antibiotic/bacterial infection 
Risk of 
TdP 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Bepridil (Vascor®) 
Anti-anginal/heart pain 
Females>Males 
Risk of 
TdP 
Chloral hydrate (Noctec®) 
Sedative/sedation/ insomnia 
Possible 
Risk of 
TdP 
Chloroquine (Aralen®) 
Anti-malarial/malaria infection 
Risk of 
TdP 
Chlorpromazine 
(Thorazine®) 
Anti-psychotic/ Anti- 
emetic/schizophrenia/ nausea 
Risk of 
TdP 
Ciprofloxacin (Cipro®) 
Antibiotic/bacterial infection 
Drug metabolism inhibitor- 
Risk for drug interactions 
Conditional 
TdP Risk 
Cisapride (Propulsid®) 
GI stimulant/heartburn 
No longer available in the 
U.S.; available in Mexico
Risk of 
TdP 
Citalopram (Celexa®) 
Anti-depressant/depression 
Risk of 
TdP 
Clarithromycin (Biaxin®) 
Antibiotic/bacterial infection 
Risk of 
TdP 
Clomipramine (Anafranil®) 
Tricyclic 
Antidepressant/depression 
Conditional 
TdP Risk 
Clozapine (Clozaril®) 
Anti-psychotic/schizophrenia 
Possible 
Risk of 
TdP 
Cocaine (Cocaine) 
Local anesthetic/ 
Cardiac stimulant 
Congenital 
QT Avoid 
Desipramine (Pertofrane®) 
Tricyclic 
Antidepressant/depression 
Risk of TdP with overdosage 
Conditional 
TdP Risk 
Dexmethylphenidate 
(Focalin®) 
CNS stimulant/ADHD 
Congenital 
QT Avoid 
Diphenhydramine 
(Benadryl®) 
Antihistamine/Allergic rhinitis, 
insomnia 
Risk of QT increase/TdP in 
overdosages 
Conditional 
TdP Risk 
Diphenhydramine (Nytol®) 
Antihistamine/Allergic rhinitis, 
insomnia 
Risk of QT increase/TdP in 
overdosages 
Conditional 
TdP Risk 
Disopyramide (Norpace®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males 
Risk of 
TdP 
Dobutamine (Dobutrex®) 
Catecholamine/heart failure and 
Congenital 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
shock 
QT Avoid 
Dofetilide (Tikosyn®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Risk of 
TdP 
Dolasetron (Anzemet®) 
Anti-nausea/nausea, vomiting 
Possible 
Risk of 
TdP 
Domperidone (Motilium®) 
Anti-nausea/nausea 
Not available in the U.S. 
Risk of 
TdP 
Dopamine (Intropine®) 
Inotropic agent/heart failure; 
hypotension; shock 
Congenital 
QT Avoid 
Doxepin (Sinequan®) 
Tricyclic 
Antidepressant/depression 
Conditional 
TdP Risk 
Dronedarone (Multaq®) 
Anti-arrhythmic/Atrial Fibrillation 
Possible 
Risk of 
TdP 
Droperidol (Inapsine®) 
Sedative;Anti-nausea/anesthesia 
adjunct, nausea 
Risk of 
TdP 
Ephedrine (Broncholate®) 
Bronchodilator, 
decongestant/Allergies, sinusitis, 
asthma 
Congenital 
QT Avoid 
Ephedrine (Rynatuss®) 
Bronchodilator, 
decongestant/Allergies, sinusitis, 
asthma 
Congenital 
QT Avoid 
Epinephrine (Primatene®) 
catecholamine, 
vasoconstrictor/anaphylaxis, 
allergic reactions 
Cardiac stimulant 
Congenital 
QT Avoid 
Epinephrine (Bronkaid®) 
catecholamine, 
vasoconstrictor/anaphylaxis, 
allergic reactions 
Cardiac stimulant 
Congenital 
QT Avoid 
Eribulin (Halaven® ) 
Anti-cancer/metastatic breast 
neoplasias 
Possible 
Risk of 
TdP 
Erythromycin (E.E.S.® ) 
Antibiotic;GI stimulant/bacterial 
infection; increase GI motility 
Females>Males 
Risk of 
TdP 
Erythromycin (Erythrocin®) 
Antibiotic;GI stimulant/bacterial 
infection; increase GI motility 
Females>Males 
Risk of 
TdP 
Escitalopram (Cipralex®) 
Anti-depressant/Major depression/ 
Possible 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Anxiety disorders 
Risk of 
TdP 
Escitalopram (Lexapro®) 
Anti-depressant/Major depression/ 
Anxiety disorders 
Possible 
Risk of 
TdP 
Famotidine (Pepcid®) 
H2-receptor antagonist/Peptic 
ulcer/ GERD 
Possible 
Risk of 
TdP 
Felbamate (Felbatrol®) 
Anti-convulsant/seizure 
Possible 
Risk of 
TdP 
Fenfluramine (Pondimin®) 
Appetite suppressant/dieting, 
weight loss 
Congenital 
QT Avoid 
Fingolimod (Gilenya®) 
Immunosuppressant/Multiple 
Sclerosis 
Possible 
Risk of 
TdP 
Flecainide (Tambocor®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Risk of 
TdP 
Fluconazole (Diflucan®) 
Anti-fungal/fungal infection 
Drug metabolism inhibitor- 
Risk for drug interactions 
Conditional 
TdP Risk 
Fluoxetine (Prozac®) 
Anti-depressant/depression 
Conditional 
TdP Risk 
Fluoxetine (Sarafem®) 
Anti-depressant/depression 
Conditional 
TdP Risk 
Foscarnet (Foscavir®) 
Anti-viral/HIV infection 
Possible 
Risk of 
TdP 
Fosphenytoin (Cerebyx®) 
Anti-convulsant/seizure 
Possible 
Risk of 
TdP 
Galantamine (Reminyl®) 
Cholinesterase inhibitor/ 
Dementia, Alzheimer's 
Conditional 
TdP Risk 
Gatifloxacin (Tequin®) 
Antibiotic/bacterial infection 
Possible 
Risk of 
TdP 
Gemifloxacin (Factive®) 
Antibiotic/bacterial infection 
Possible 
Risk of 
TdP 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Granisetron (Kytril®) 
Anti-nausea/nausea and vomiting 
Possible 
Risk of 
TdP 
Halofantrine (Halfan®) 
Anti-malarial/malaria infection 
Females>Males 
Risk of 
TdP 
Haloperidol (Haldol®) 
Anti-psychotic/schizophrenia, 
agitation 
When given intravenously or 
at higher-than- recommended 
doses, risk of sudden death, 
QT prolongation and torsades 
increases. 
Risk of 
TdP 
Ibutilide (Corvert®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males 
Risk of 
TdP 
Iloperidone (Fanapt®) 
Antipsychotic, 
atypical/Schizophrenia 
Possible 
Risk of 
TdP 
Imipramine (Norfranil®) 
Tricyclic 
Antidepressant/depression 
Risk of TdP in overdosage 
Conditional 
TdP Risk 
Indapamide (Lozol®) 
Diuretic/stimulate urine & salt loss 
Possible 
Risk of 
TdP 
Isoproterenol (Isupres®) 
Catecholamine/allergic reaction 
Congenital 
QT Avoid 
Isoproterenol (Medihaler- 
Iso®) 
Catecholamine/allergic reaction 
Congenital 
QT Avoid 
Isradipine (Dynacirc®) 
Anti-hypertensive/high blood 
pressure 
Possible 
Risk of 
TdP 
Itraconazole (Sporanox®) 
Anti-fungal/fungal infection 
Drug metabolism inhibitor- 
Risk for drug interactions 
Conditional 
TdP Risk 
Ketoconazole (Nizoral®) 
Anti-fungal/fungal infection 
Drug metabolism inhibitor 
Conditional 
TdP Risk 
Lapatinib (Tykerb®) 
Anti-cancer/breast cancer, 
metastatic 
Possible 
Risk of 
TdP 
Lapatinib (Tyverb®) 
Anti-cancer/breast cancer, 
metastatic 
Possible 
Risk of 
TdP 
Levalbuterol (Xopenex® ) 
Bronchodilator/asthma 
Congenital 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
QT Avoid 
Levofloxacin (Levaquin®) 
Antibiotic/bacterial infection 
Possible 
Risk of 
TdP 
Levomethadyl (Orlaam®) 
Opiate agonist/pain control, 
narcotic dependence 
Not available in the U.S. 
Risk of 
TdP 
Lisdexamfetamine 
(Vyvanse® ) 
CNS stimulant/ADHD 
Congenital 
QT Avoid 
Lithium (Eskalith®) 
Anti-mania/bipolar disorder 
Possible 
Risk of 
TdP 
Lithium (Lithobid®) 
Anti-mania/bipolar disorder 
Possible 
Risk of 
TdP 
Mesoridazine (Serentil®) 
Anti-psychotic/schizophrenia 
Risk of 
TdP 
Metaproterenol (Alupent®) 
Bronchodilator/asthma 
Congenital 
QT Avoid 
Metaproterenol (Metaprel®) 
Bronchodilator/asthma 
Congenital 
QT Avoid 
Methadone (Dolophine®) 
Opiate agonist/pain control, 
narcotic dependence 
Females>Males 
Risk of 
TdP 
Methadone (Methadose®) 
Opiate agonist/pain control, 
narcotic dependence 
Females>Males 
Risk of 
TdP 
Methylphenidate (Ritalin®) 
CNS stimulant/ADHD 
Congenital 
QT Avoid 
Methylphenidate (Concerta® 
) 
CNS stimulant/ADHD 
Congenital 
QT Avoid 
Midodrine (ProAmatine®) 
Vasoconstrictor/low blood 
pressure, fainting 
Congenital 
QT Avoid 
Moexipril/HCTZ (Uniretic®) Anti-hypertensive/high blood 
pressure 
Possible 
Risk of 
TdP 
Moxifloxacin (Avelox®) 
Antibiotic/bacterial infection 
Risk of 
TdP 
Nicardipine (Cardene®) 
Anti-hypertensive/high blood 
Possible 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
pressure 
Risk of 
TdP 
Nilotinib (Tasigna® ) 
Anti-cancer/Leukemia 
Possible 
Risk of 
TdP 
Norepinephrine 
(Levophed®) 
Vasconstrictor, Inotrope/shock, 
low blood pressure 
Congenital 
QT Avoid 
Nortriptyline (Pamelor®) 
Tricyclic 
Antidepressant/depression 
Conditional 
TdP Risk 
Octreotide (Sandostatin®) 
Endocrine/acromegaly, carcinoid 
diarrhea 
Possible 
Risk of 
TdP 
Ofloxacin (Floxin®) 
Antibiotic/bacterial infection 
Possible 
Risk of 
TdP 
Ondansetron (Zofran®) 
Anti-emetic/nausea and vomiting 
Possible 
Risk of 
TdP 
Oxytocin (Pitocin®) 
Oxytocic/Labor stimulation 
Possible 
Risk of 
TdP 
Paliperidone (Invega®) 
Antipsychotic, 
atypical/Schizophrenia 
Possible 
Risk of 
TdP 
Paroxetine (Paxil®) 
Anti-depressant/depression 
Conditional 
TdP Risk 
Pentamidine (NebuPent®) 
Anti-infective/pneumocystis 
pneumonia 
Females>Males 
Risk of 
TdP 
Pentamidine (Pentam®) 
Anti-infective/pneumocystis 
pneumonia 
Females>Males 
Risk of 
TdP 
Perflutren lipid microspheres 
(Definity® ) 
Imaging contrast 
agent/Echocardiography 
Possible 
Risk of 
TdP 
Phentermine (Fastin®) 
Appetite suppressant/dieting, 
weight loss 
Congenital 
QT Avoid 
Phentermine (Adipex®) 
Appetite suppressant/dieting, 
weight loss 
Congenital 
QT Avoid 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Phenylephrine 
(Neosynephrine®) 
Vasoconstrictor, decongestant/low 
blood pressure, allergies, sinusitis, 
asthma 
Congenital 
QT Avoid 
Phenylpropanolamine 
(Acutrim®) 
Decongestant/allergies, sinusitis, 
asthma 
No longer available in the 
U.S. 
Congenital 
QT Avoid 
Phenylpropanolamine 
(Dexatrim®) 
Decongestant/allergies, sinusitis, 
asthma 
No longer available in the 
U.S. 
Congenital 
QT Avoid 
Pimozide (Orap® ) 
Anti-psychotic/Tourette's tics 
Females>Males 
Risk of 
TdP 
Probucol (Lorelco®) 
Antilipemic/Hypercholesterolemia 
No longer available in U.S. 
Risk of 
TdP 
Procainamide (Pronestyl®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Risk of 
TdP 
Procainamide (Procan® ) 
Anti-arrhythmic/abnormal heart 
rhythm 
Risk of 
TdP 
Protriptyline (Vivactil®) 
Tricyclic 
Antidepressant/depression 
Conditional 
TdP Risk 
Pseudoephedrine 
(PediaCare®) 
Decongestant/allergies, sinusitis, 
asthma 
Congenital 
QT Avoid 
Pseudoephedrine (Sudafed®) 
Decongestant/allergies, sinusitis, 
asthma 
Congenital 
QT Avoid 
Quetiapine (Seroquel® ) 
Anti-psychotic/schizophrenia 
Possible 
Risk of 
TdP 
Quinidine (Quinaglute®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males 
Risk of 
TdP 
Quinidine (Cardioquin® ) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males 
Risk of 
TdP 
Ranolazine (Ranexa® ) 
Anti-anginal/chronic angina 
Possible 
Risk of 
TdP 
Risperidone (Risperdal® ) 
Anti-psychotic/schizophrenia 
Possible 
Risk of 
TdP 
Ritodrine (Yutopar®) 
Uterine relaxant/prevent premature 
labor 
Congenital 
QT Avoid 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Ritonavir (Norvir®) 
Protease inhibitor/HIV 
Conditional 
TdP Risk 
Roxithromycin* (Rulide®) 
Antibiotic/bacterial infection 
*not available in the United
States
Possible 
Risk of 
TdP 
Salmeterol (Serevent® ) 
Sympathomimetic/asthma, COPD 
Congenital 
QT Avoid 
Sertindole (Serdolect®) 
Antipsychotic, atypical/Anxiety, 
Schizophrenia 
Possible 
Risk of 
TdP 
Sertindole (Serlect®) 
Antipsychotic, atypical/Anxiety, 
Schizophrenia 
Possible 
Risk of 
TdP 
Sertraline (Zoloft®) 
Anti-depressant/depression 
Conditional 
TdP Risk 
Sibutramine (Meridia®) 
Appetitie suppressant/dieting, 
weight loss 
Congenital 
QT Avoid 
Solifenacin (VESIcare®) 
muscarinic receptor 
anatagonist/treatment of overactive 
bladder 
Conditional 
TdP Risk 
Sotalol (Betapace® ) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males 
Risk of 
TdP 
Sparfloxacin (Zagam® ) 
Antibiotic/bacterial infection 
Risk of 
TdP 
Sunitinib (Sutent®) 
Anti-cancer/RCC, GIST 
Possible 
Risk of 
TdP 
Tacrolimus (Prograf®) 
Immunosuppressant/Immune 
suppression 
Possible 
Risk of 
TdP 
Tamoxifen (Nolvadex® ) 
Anti-cancer/breast cancer 
Possible 
Risk of 
TdP 
Telithromycin (Ketek®) 
Antibiotic/bacterial infection 
Possible 
Risk of 
TdP 
Terbutaline (Brethine®) 
Bronchodilator/asthma 
Congenital 
QT Avoid 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Terfenadine (Seldane®) 
Antihistamine/Allergic rhinitis 
No longer available in U.S. 
Risk of 
TdP 
Thioridazine (Mellaril® ) 
Anti-psychotic/schizophrenia 
Risk of 
TdP 
Tizanidine (Zanaflex® ) 
Muscle relaxant/ 
Possible 
Risk of 
TdP 
Tolterodine (Detrol®) 
Bladder Antispasmodic/ 
Congenital 
QT Avoid 
Tolterodine (Detrol LA®) 
Bladder Antispasmodic/ 
Congenital 
QT Avoid 
Trazodone (Desyrel®) 
Anti-depressant/Depression, 
insomnia 
Conditional 
TdP Risk 
Trimethoprim-Sulfa 
(Bactrim®) 
Antibiotic/bacterial infection 
Conditional 
TdP Risk 
Trimethoprim-Sulfa (Sulfa®) Antibiotic/bacterial infection 
Conditional 
TdP Risk 
Trimipramine (Surmontil®) 
Tricyclic 
Antidepressant/depression 
Conditional 
TdP Risk 
Vandetanib (Caprelsa®) 
Anti-cancer/Thyroid cancer 
Risk of 
TdP 
Vardenafil (Levitra® ) 
phosphodiesterase 
inhibitor/vasodilator 
Possible 
Risk of 
TdP 
Venlafaxine (Effexor® ) 
Anti-depressant/depression 
Possible 
Risk of 
TdP 
Voriconazole (VFend® ) 
Anti-fungal/anti-fungal 
Possible 
Risk of 
TdP 
Ziprasidone (Geodon® ) 
Anti-psychotic/schizophrenia 
Possible 
Risk of 
TdP 
Source: Arizona Center for Education and Research on Therapeutics. Updated 17 May 
2012. http://www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm. Accessed 
15 June 2012. 


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Italfarmaco S.p.A. 
STUDY PROTOCOL 
Protocol Title: 
A Two-Part Study to Assess the Safety and 
Tolerability, Pharmacokinetics, and Effects 
on Histology and Different Clinical 
Parameters of Givinostat in Ambulant 
Children with Duchenne Muscular Dystrophy 
Protocol Number: 
DSC/11/2357/43 
Clinical Phase: 
2 
Protocol Date 
Amendment 1 
01 Aug 2012 
05 Dec 2012 
EudraCT Number: 
2012-002566-12 
Sponsor 
Italfarmaco S.p.A. 
Via dei Lavoratori, 54 
20092 Cinisello Balsamo (MI) 
Italy 
Tel: +39 02 6443 2512 
Fax: +39 02 6443 3554 


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SYNOPSIS 
Title of Study: 
A Two-Part Study to Assess the Safety and Tolerability, 
Pharmacokinetics, and Effects on Histology and Different Clinical 
Parameters of Givinostat in Ambulant Children with Duchenne 
Muscular Dystrophy 
Protocol Number: 
DSC/11/2357/43 
Eudra CT Number 
2012-002566-12 
Investigators/ 
Study Centers: 
Children will be enrolled at approximately 5 study sites in Italy. 
Phase of Development: 
2 
Objectives: 
The primary objective of this study is as follows: 
    To establish the histologic effects of Givinostat administered 
chronically at the selected daily dose 
The secondary objectives of this study are as follows: 
    To establish the effects of Givinostat administered chronically 
at the selected daily dose on functional parameters, such as 
the 6-Minute Walk Test (6MWT), North Star Ambulatory 
Assessment (NSAA), and performance of upper limb (PUL) 
    To establish the safety and tolerability of Givinostat 
administered chronically at the selected daily dose in children 
with Duchenne muscular dystrophy (DMD) 
    To explore the effects of Givinostat administered chronically 
at the selected daily dose on parameters such as magnetic 
resonance imaging (MRI), biomarkers, and cytokines 
Design: 
This is a 2-part, phase 2 study to assess the effects of Givinostat on muscle 
histologic parameters and on clinical parameters in ambulant children with 
DMD. The safety, tolerability, and pharmacokinetics of Givinostat will 
also be assessed. 
Children who assent to participate in this study (if capable of doing so) and 
whose parent/guardian signs the informed consent to participate will 
undergo pre-study screening assessments up to 4 weeks (±2 weeks) before 
the first scheduled dose of study drug. 
Approximately 20 children will be enrolled in the study as follows: the 
first 4 children will be treated at a low dose level of Givinostat (25 mg 
twice daily [BID] in children who weigh 20–49 kg and 37.5 mg BID in 


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children who weigh ≥50 kg). 
If none of the stopping criteria (see Section 3.3.5) are met after 2 weeks of 
treatment at the low dose, the review team will determine the escalated 
dose level (i.e., intermediate dose level) to be used for the treatment of an 
additional 8 children who will be treated at the intermediate dose. The 4 
children previously treated at the low dose level will also be switched to the 
intermediate dose level. 
If none of the stopping criteria are met after 2 weeks of treatment at the 
intermediate dose, the review team will determine the subsequent escalated 
dose level to be used for the treatment of an additional 8 children who will 
be treated at the high dose. All children treated at the intermediate dose 
level will be switched to the high dose level. 
Once all 20 children enrolled during the Part 1 of the study have been 
treated for at least 2 weeks, the review team will determine the 
recommended dose (RD) to be used in Part 2 based on the safety and 
tolerability profile observed and on the pharmacokinetic (PK) analyses. All 
the children enrolled will switch to the RD level, which will be 
administered for the subsequent 12 months of the study (Part 2). 
The additional children (if any) will be enrolled during Part 2 of the study 
and will receive the RD of Givinostat for 12 months. 
During Part 1 of the study, children will visit the center once each week. 
During Part 2 of the study, children will visit the study center per the 
schedule of assessments for a total of 11 visits, including follow up. 
Children may be evaluated more often if necessary for safety reasons. 
Children who discontinue the study drug early will be asked to come in for 
an end-of-study visit within 2 weeks after the last dose of study drug as 
well as the protocol-scheduled follow-up visit. Children who have ongoing 
adverse events (AEs) at discontinuation will be followed until resolution or 
stabilization. 
Efficacy will be assessed through changes from baseline in biopsy at 1 year 
(Part 2) and changes from baseline in the 6MWT, PUL, and NSAA at 
1 year (Part 2). Exploratory efficacy parameters will include changes from 
baseline in MRI results, PK-pharmacodynamic correlations and measures 
of cytokines and micro ribonucleic acid (miRNA). Safety will be assessed 
by number of children experiencing AEs; type, incidence, and severity of 
AEs correlated with dose; and measures of vital signs, clinical laboratory 
tests (blood chemistry, hematology, disease serologies, and urinalysis), 
echocardiographs, pulmonary function tests (PFTs; forced expiratory 
volume at 1 second [FEV1], forced vital capacity [FVC], and FEV1/FVC) 
and 12-lead electrocardiograms. 
Plasma samples for PK measurements will be collected after 1 week of 
treatment with Givinostat, during Part 1 at pre-dose in the morning before 


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drug intake and at 1, 2, 4, and 8 hours post-dose. 
PK samples will also be collected during Part 2 of the study as follows: 
    At Visit 2, blood samples for PK analysis will be taken pre- 
dose and between 6 and 8 hours post-dose. 
    At Visit 3, blood samples for PK analysis will be collected 
pre-dose in the morning before study drug intake and between 
0 and 2 hours post-dose. 
    At Visit 4, blood samples for PK analysis will be taken 
pre-dose and between 2 and 4 hours post-dose. 
    At Visit 6, blood samples for PK analysis will be taken 
pre-dose and between 4 and 6 hours post-dose. 
Planned Sample Size: 
Approximately 20 children will be enrolled in Part 1 (dose-finding) of this 
study. 
Muscle fibers: a sample size of 20 children (from Part 1) completing the 
treatment period should provide 90% power (at a 2-sided alpha level of 
5%) to detect at least a 12.5% increase in muscle fiber area % (MFA%) 
between pre- and post-treatment (which corresponds approximately to a 
26% relative increase given the observed mean in the Desguerre 
publication of 48% [Desguerre I et al. 2009]), the ―worst case‖ standard 
deviation of 16%, which assumes that there is no correlation within a 
subject in the muscle area fiber percentage between pre- and post- 
treatment. This sample size is based on a paired t-test. In the event the 
data is not normally distributed, a Wilcoxon signed rank test will be used. 
After the first 20 baseline biopsies are collected, an interim analysis aimed 
at checking the real variability observed in the study will be implemented 
as follows: the within-subject standard deviation of MFA% will be 
calculated and the final sample size will be adjusted based on this observed 
standard deviation. A conservative approach will be adopted where the 
sample size may be increased but not decreased. 
Diagnosis and Key Subject 
Selection Criteria: 
Inclusion criteria: 
1.
Male children aged 7 to <11 years with an
immunohistochemical and molecular diagnosis of DMD.
2.
A parent/guardian and child can comply with all study
evaluations/procedures and return for all study activities.
3.
Able to complete the 2 screening 6MWTs with a minimal
distance of at least 250 m each. In addition, the results of
these tests must be within ±30 m of each other.


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4.
On a stable dose of systemic corticosteroids for at least
6 months.
5.
At least 6 months worth of data on the 6MWT (this will be
the ―historical‖ 6MWT).  From the moment of the historical
6MWT assessment(s), the child must not have received any
compound that could potentially affect the 6MWT, with the
exception of the stable steroid treatment.
6.
Parent/guardian has signed the informed consent form and
child has assented to be in the study (if applicable).
Exclusion criteria: 
1.
Initiation of systemic corticosteroid therapy within 6 months
prior to the start of study drug or change in systemic
corticosteroid therapy (e.g., initiation, change in type of drug,
dose modification not related to body weight change,
schedule modification, interruption, discontinuation, or
re-initiation) within 6 months prior to the start of study drug.
2.
Use of any pharmacologic treatment, other than
corticosteroids, that might have an effect on muscle strength
since the time of the historical 6MWT and in any case within
3 months prior to the start of study treatment (e.g., growth
hormone). Vitamin D, calcium, and integrators will be
allowed.
3.
Surgery that might have an effect on muscle strength or
function within 3 months before study entry or planned
surgery at any time during the study.
4.
Exposure to another investigational drug since the time of the
historical 6MWT and in any case within 3 months prior to the
start of study treatment.
5.
History of participation in gene therapy, cell-based therapy, or
oligonucleotide therapy.
6.
Presence of other clinically significant disease that in the
opinion of the investigator places the child in unacceptable
risk for an adverse outcome or that could affect study results.
7.
Symptomatic cardiomyopathy or heart failure. If child has a
left ventricular ejection fraction <45% at screening, the
investigator should discuss inclusion of child in the study with
the medical monitor.
8.
Inadequate hematological function


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9.
Absolute neutrophil count: <1.5 x 109/L
10. Platelets: <100 x 109/L
11. Current or history of liver disease or impairment, including
but not limited to an elevated total bilirubin.
12. Inadequate renal function, as defined by serum creatinine >2 x
the upper limit of normal.
13. Positive test for hepatitis B surface antigen, hepatitis C
antibody, or human immunodeficiency virus at screening
14. A baseline QTc >450 msec, (as the mean of 3 consecutive
readings 5 minutes apart) or history of additional risk factors
for torsades de pointes (e.g., heart failure, hypokalemia,
family history of long QT syndrome).
15. Psychiatric illness/social situations rendering the potential
child unable to understand and comply with the study
protocol.
Treatments: 
The study drug (Givinostat) will be administered as 2 oral doses daily while 
the child is in the fed state. Children who enroll during Part 1 of the study 
will receive their assigned dose until the RD is determined. They will then 
receive up to 12 months of treatment with Givinostat at the RD. Additional 
children may be enrolled as needed during Part 2 to reach the sample size 
calculated after the interim analysis. Children who enroll during Part 2 will 
receive up to 12 months of treatment with Givinostat at the RD. The total 
duration of the study is anticipated to be 15 months. 
Main Parameters of 
Efficacy: 
The primary endpoint of this study is change in the value of MFA% 
comparing the histology biopsies before and after 12 months of treatment 
with Givinostat. 
The secondary efficacy endpoints of this study are as follows: 
    Change in additional histological endpoints (i.e., cross-sectional 
area, inflammation, necrosis, fibrosis, and muscle regeneration) 
after 12 months of treatment with Givinostat at the selected daily 
dose 
    Change in muscular function after 12 months of treatment with 
Givinostat at the selected daily dose based on the 6MWT 
    Change in muscular function after 12 months of treatment with 
Givinostat at the selected daily dose based on the NSAA 
 Change in muscular function after 12 months of treatment with 


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Givinostat at the selected daily dose based the PUL 
Main Parameters of Safety: 
    Number of children experiencing treatment-emergent AEs and 
serious adverse events (SAEs) 
    Type, incidence, and severity of treatment-emergent AEs and 
SAEs correlated with dose 
PK Parameters: 
Individual Givinostat concentrations tabulated by dose cohort 
along with descriptive statistics for Part 1 and tabulated along with 
descriptive statistic for Part 2. 
Exploratory Endpoints: 
Change in muscle, fat and fibrosis content after treatment with 
Givinostat as measured by MRI 
    Change in muscle biomarkers (e.g., miRNA) and cytokines 
following treatment with Givinostat 
    PK–PD correlations 
Key Statistical 
Considerations 
Efficacy analyses will be conducted on the intent-to-treat (ITT) population, 
which is defined as all children who are enrolled in the Part 1 portion or 
entered the Part 2 portion of the study. 
All values will be expressed as means ± standard deviation or standard 
error of the mean. 
Each of all efficacy endpoints will be subject to normality test and formal 
statistical test performed will be based on whether it is normally 
distributed. If normal, statistical differences will be calculated using the 
paired t test; if not normal, Wilcoxon signed rank test will be used to assess 
the statistical significance of differences between groups. P<0.05 will be 
set as significant. 
General considerations: Data will be provided in data listings sorted by 
treatment group and child number. Tabular summaries will be presented by 
treatment group for Part 1. Categorical data will be summarized by the 
number and percentage of children in each category. Continuous variables 
will be summarized by descriptive statistics, including mean, standard 
deviation, median, minimum, and maximum. Confidence intervals (CIs) 
will be 2-sided, unless otherwise stated. Details of endpoint analyses will 
be described in the Statistical Analysis Plan. 
For analyses of change from baseline, baseline will generally be defined as 
the value collected before any Givinostat treatment is administered. If this 
value is missing, the last non-missing value prior to dosing will be used. 
Otherwise, missing observations will be treated as missing at random, and 
no data imputation will be performed. All data from the case report forms, 


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as well as any derived variables, will be presented in data listings. 
All hypothesis tests will be two-sided with a 5% significance level, and 
95% CIs will be used, unless stated otherwise. As this is a Phase 2 
exploratory study, no adjustments for multiplicity will made. 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................77 
SYNOPSIS ...........................................................................................................................78 
TABLE OF CONTENTS ...................................................................................................84 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................89 
1 Introduction ..................................................................................................................91 
1.1 
Background on Duchenne Muscular Dystrophy .............................................................................91 
1.2 
Background on Givinostat ...............................................................................................................92 
1.3 
Rationale..........................................................................................................................................93 
1.3.1 
Study Rationale....................................................................................................................93 
1.3.2 
Dose Rationale .....................................................................................................................94 
2 Study Objectives ..........................................................................................................98 
3 Investigational Plan ......................................................................................................99 
3.1 
Description of Overall Study Design and Plan................................................................................102 
3.2 
Selection of Study Population .........................................................................................................102 
3.2.1 
Inclusion Criteria .................................................................................................................102 
3.2.2 
Exclusion Criteria ................................................................................................................103 
3.2.3 
Removal of Children from Therapy or Assessment ............................................................104 
3.3 
Treatments .......................................................................................................................................105 
3.3.1 
Details of Study Treatment ..................................................................................................105 
3.3.2 
Dosage Schedule..................................................................................................................105 
3.3.3 
Treatment Assignment .........................................................................................................106 
3.3.4 
Drug Packaging, Labeling, Storage, Dispensing, Investigational Medicinal Product 
Accountability, and Blinding
106 
3.3.5 
Dose Modifications..............................................................................................................107 


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3.3.6 
Treatment Compliance and IMP Accountability ............................................................... 110 
3.3.7 
Prior and Concomitant Illnesses and Treatments .............................................................. 110 
3.4 
Assessments .................................................................................................................................. 111 
3.4.1 
Schedule of Assessments ................................................................................................... 111 
3.4.2 
Study Procedures ............................................................................................................... 116 
3.4.3 
Assessments for End of Study (Visit 10 [Month 12]) ....................................................... 118 
3.4.4 
Early Termination Visit ..................................................................................................... 118 
3.4.5 
Follow-up Visit .................................................................................................................. 118 
3.4.6 
Description of Assessments ............................................................................................... 119 
3.4.7 
Appropriateness of Measurements .................................................................................... 123 
4 Adverse Event Reporting ...........................................................................................123 
4.1 
Definitions and Criteria ................................................................................................................. 123 
4.1.1 
Adverse Events .................................................................................................................. 123 
4.1.2 
Adverse Drug Reactions .................................................................................................... 124 
4.1.3 
Unexpected Adverse Drug Reactions ................................................................................ 124 
4.1.4 
Serious Adverse Events ..................................................................................................... 124 
4.1.5 
Assessing Intensity and Relationship ................................................................................ 125 
4.2 
Reporting Procedures and Requirements ...................................................................................... 126 
4.2.1 
Adverse Events .................................................................................................................. 126 
4.2.2 
Serious Adverse Events ..................................................................................................... 128 
5 Data Management and Statistical Analysis................................................................129 
5.1 
Data Management Considerations ................................................................................................ 129 
5.2 
Statistical Considerations .............................................................................................................. 129 
5.2.1 
General Considerations...................................................................................................... 130 
5.2.2 
Sample Size Justification ................................................................................................... 130 
5.2.3 
Analysis Populations ......................................................................................................... 131 
5.2.4 
Primary Endpoint ............................................................................................................... 131 


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5.2.5 
Secondary Efficacy Endpoints ........................................................................................... 131 
5.2.6 
Secondary Safety Endpoints .............................................................................................. 132 
5.2.7 
Secondary Pharmacokinetic Endpoints ............................................................................. 132 
5.2.8 
Exploratory Endpoints ....................................................................................................... 132 
5.2.9 
Efficacy Analyses .............................................................................................................. 133 
5.2.10 
Safety Analyses ............................................................................................................... 133 
5.2.11 
Pharmacokinetic Analyses............................................................................................... 133 
5.2.12 
Interim Analyses .............................................................................................................. 134 
6 Study Management ....................................................................................................134 
6.1 
Approval and Consent ................................................................................................................... 134 
6.1.1 
Regulatory Guidelines ....................................................................................................... 134 
6.1.2 
Institutional Review Board/Independent Ethics Committees ............................................ 134 
6.1.3 
Informed Consent .............................................................................................................. 135 
6.2 
Discontinuation of the Study by the Sponsor ................................................................................ 135 
6.3 
Study Documentation .................................................................................................................... 135 
6.4 
Study Monitoring and Auditing .................................................................................................... 136 
6.5 
Retention of Records ..................................................................................................................... 136 
6.6 
Use of Study Findings ................................................................................................................... 137 
6.7 
Publications ................................................................................................................................... 137 
7 References ..................................................................................................................138 
8 Appendices .................................................................................................................139 
Appendix 1: Drugs Known to Prolong the QTc Interval .................................................140 
TABLES AND FIGURES 
Table 1 
Concentrations of Givinostat in Pediatric Studies to Date ............................... 95 
Table 2 
Expected Exposure by Weight ......................................................................... 96 


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Table 3 
Starting Dose (25 mg BID in Children Who Weigh 20–49 kg and  37.5 mg 
BID in Children Who Weigh ≥50 kg) ............................................................................... 97 
Table 4 
Second Dose (50 mg BID in Children Who Weigh 20–49 kg and 75 mg BID 
in Children Who Weigh ≥ 50kg)....................................................................................... 97 
Table 5 
Third Dose (75 mg BID in Children Who Weigh 20–49 kg and 100 mg BID 
in Children Who Weigh ≥50 kg)....................................................................................... 97 
Table 6 
Treatment Table ............................................................................................... 101 
Table 7 
Details of Study Treatment............................................................................... 105 
Figure 1  Cohort expansion, Cohort Abandoned and Dose Escalation Safety Rules for 
Part 1……………………………………………………………………………………109 
Table 8 
Schedule of Assessments: Part 1 (Dose Escalation) ........................................ 112 
Table 9 
Schedule of Assessments: Part 2 (Proof of Mechanism) ................................. 114 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
6MWT 
6-Minute Walk Test
Ab 
Antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma–concentration time curve 
BID 
twice daily 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CL 
clearance 
CL/F 
volume of distribution 
cm 
Centimeter 
Cmax
maximum plasma concentration 
CMV 
Cytomegalovirus 
CPK 
creatine phosphokinase 
CrCl 
creatinine clearance 
CRP 
C-reactive protein
CSA 
cross-sectional area 
CSOM 
Clinical Study Operations Manual 
DMD 
Duchenne muscular dystrophy 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECHO 
Echocardiograph 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
FACS 
fluorescence-activated cell sorting 
FAP 
fibroadipongenic progenitors 
FEV1 
forced expiratory volume at 1 second 
FU 
follow up 
FVC 
forced vital capacity 
GI 
Gastrointestinal 
h 
hour 
H&E 
hematoxylin and eosin 
HbeAg 
hepatitis B e antigen 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HDAC 
histone deacetylase 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 


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IgM 
immunoglobulin M 
IL 
interleukin 
IMP 
investigational medicinal product 
ITT 
intent to treat 
JIA 
juvenile idiopathic arthritis 
KA 
absorption rate constant 
kg 
kilogram 
L 
liter 
LDH 
lactate dehydrogenase 
m 
Meter 
MFA% 
muscle fibers area % 
mg 
Milligram 
miRNA 
micro ribonucleic acid 
mL 
Milliliter 
MRI 
magnetic resonance imaging 
msec 
Millisecond 
MTD 
maximum-tolerated dose 
MuSC 
muscle satellite cells 
ng 
nanogram 
nmol 
nanomole 
NOAEL 
no observed adverse effect level 
NSAA 
North Star Ambulatory Assessment 
PD 
Pharmacodynamic 
PDGFR 
platelet-derived growth factor receptor 
PET 
polyethylene terephthalate 
PFT 
pulmonary function tests 
PK 
Pharmacokinetic 
PUL 
performance of upper limb 
QT 
QT interval 
QTc 
QT interval – corrected 
RBC 
red blood cells 
RD 
recommended dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOJIA 
systemic onset juvenile idiopathic arthritis 
SWI/SNF 
switch/sucrose non-fermentable 
TNF-α 
tumor necrosis factor-alpha 
V/F 
plasma volume 
V2/F 
peripheral volume 
WBC 
white blood cells 
WCT 
Worldwide Clinical Trials 


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1 Introduction 
1.1 Background on Duchenne Muscular Dystrophy 
Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular 
dystrophy, occurring in about 1 of every 3500 male newborns. The disease is inherited as 
an X-linked recessive disorder and is caused by mutation in the dystrophin gene on the 
X chromosome, resulting in dystrophin deficiency. The main function of dystrophin is to 
stabilize and link the muscle fiber cytoskeleton to the membrane. The lack of functional 
dystrophin results in the loss of dystrophin-glycoprotein complex, thereby rendering the 
muscle fibers less resistant to mechanical stress. 
Faulty muscle structure caused by the absence of extracellular or intracellular structural 
proteins results in cell membrane instability, initiating a cascade of deleterious events, 
such as uncontrolled calcium influx, apoptosis and necrosis, inflammation, and 
replacement of muscle with fibrotic tissue and fat (Consalvi S et al. 2011). The clinical 
effect of this deficiency can be dramatic and fatal. 
Patients begin to show symptoms of the disease between the ages of 3 to 5 years 
(Emery AEH 2002), which leads to severe muscle wasting and weakness. Patients with 
DMD usually stop walking by about 12 years of age and usually experience fatal 
respiratory failure in their early 20s (Eagle M et al. 2002). 
Treatment with steroids is currently used in a large portion of DMD patients, but it is 
palliative and complicated by serious side effects. No current treatment interrupts or 
halts the progression of DMD. 
By acting on muscle resident stem cells, histone deacetylase (HDAC) inhibitors increase 
skeletal myogenesis in vitro and in vivo (Iezzi S et al. 2002) and restore normal muscle 
morphology and increase the size and strength of myofibers in mdx mice a preclinical 
model of DMD (Minetti GC et al. 2006). 
The beneficial potential of the HDAC inhibitor Givinostat in the treatment of DMD has 
been studied in the mdx mouse disease model. In this model, long-term exposure to 
Givinostat effectively countered disease progression. In particular, Givinostat dose and 
concentration dependently increased the cross-sectional area of myofibers, decreased the 
cellular (inflammatory) infiltrate and prevented the formation of fibrotic scars. 
Pharmacokinetic (PK)–pharmacodynamic (PD) analysis suggests that exposures of 
Givinostat of 600 h*nmol/L are required to exert the beneficial effect. 


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1.2 Background on Givinostat 
Givinostat has been tested in long-term repeat-dose toxicology studies in rats, dogs, and 
monkeys. The main adverse effects (e.g., reduction in white blood cells [WBC], reduced 
thymus weight, bone marrow atrophy, and liver and possibly kidney function 
impairments) were observed only at high doses of drug. Most of these changes returned 
to baseline levels upon drug discontinuation or a trend toward resolution was seen at the 
end of the recovery period. 
In the rat, Givinostat was administered consecutively up to 26 weeks where the no 
observed adverse effect level (NOAEL) was 10 mg/kg/day. There were no side effects in 
dogs administered 12.5 mg/kg/day of Givinostat for 4 consecutive weeks. However, 
liquid feces were found in the animals receiving higher doses with consequent reduced 
absorption. For these reasons, the dog species was not further considered and general 
toxicology studies in non-rodents were continued in the monkey. In the monkey, 
Givinostat was well tolerated and similar toxicity profiles were seen in the 4-, 13-, and 
39-week studies, where the NOAELs were 10 mg/kg, 10 mg/kg, and 12 mg/kg,
respectively.
Givinostat had a favorable safety pharmacology profile. There was no observation of 
embryo-fetal toxicity in rats and in rabbits, or potential genotoxicity in mammalian cells 
in vitro and in vivo. The only sign of a possible adverse effect was seen at relatively high 
doses (>1  M) of Givinostat in vitro but not in vivo in cardiovascular safety 
pharmacology studies. 
Givinostat was given by oral gavage to juvenile rats starting at the age of weaning 
(25 days of age) at 4 different dosages: 0, 20, 60, or 180 mg/kg/day once-a day for 
4 weeks. Givinostat was well tolerated at the dosage up to 60 mg/kg/day. 
Treatment-related changes were detected at 180 mg/kg/day in the adrenals, bone marrow, 
liver, and spleen. The changes had resolved or showed partial recovery at the end of the 
study (mature animals). The NOAEL was set at 60 mg/kg/day. 
Givinostat has been tested in a number of clinical studies that enrolled for the following 
major indications: inflammation and oncology. In particular: 
 105 healthy volunteers have been enrolled in 3 phase 1 studies (single dose, 
repeat dose, and food interaction); 18 were treated with placebo. 
 422 patients have been enrolled in the phase 1–2 studies; 62 were treated with 
placebo. Of these, 33 were children with systemic onset juvenile idiopathic 
arthritis (SOJIA) or polyarticular juvenile idiopathic arthritis (JIA) treated 
with Givinostat at the following doses: 0.50 mg/kg twice daily (BID) and 
0.75 mg/kg BID for up to 3 months. 


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Givinostat has shown preliminary signs of clinical activity in subjects with SOJIA 
(study DSC/05/2357/19) as well as myeloproliferative disease (study DSC/07/2357/28). 
The maximum-administered dose was a single dose of 600 mg in healthy volunteers and 
up to 400 mg once per week in subjects with multiple myeloma. Doses up to 
approximately 100 mg BID were generally well tolerated. The most common adverse 
events (AEs) observed were thrombocytopenia as well as gastrointestinal (GI) toxicities. 
AEs were generally mild to moderate and reversible upon discontinuation of study drug. 
In particular, thrombocytopenia appeared in just a few days of treatment at 
thrombocytopenic doses and reverted to normal values within a few days/weeks after 
treatment discontinuation. Twenty-one AEs of QT interval – corrected (QTc) 
prolongations have been reported. In one case, the electrocardiogram (ECG) was 
manually read and the QTc value determined was normal, thus it was considered a 
spurious finding. Eight AEs of QTc prolongation were reported in subjects with chronic 
myeloproliferative diseases (study DSC/07/2357/28), 6 in subjects with Hodgkin‘s 
lymphoma (study DSC/07/2357/26), 2 in subjects with polycythemia vera (study 
DSC/08/2357/38), 2 in subjects with acute myeloid leukemia (study DSC/05/2357/15), 1 
in a subject with Crohn‘s disease (study DSC/06/2357/23), and 1 in a subject with SOJIA 
(study DSC/05/2357/19). No clear dose dependence was observed. In the 2 studies in 
healthy volunteers (DM/00/2357/01 and DM/00/2357/03) where ECG and QTc 
measurements were systematically assessed, no episode of QTc prolongation was 
observed. Details of each trial are included in the Investigator‘s Brochure (2012). 
1.3 Rationale 
1.3.1 
Study Rationale 
Different studies suggest that histone acetylation has a significant role in the pathogenesis 
of DMD and that inhibition of HDAC leads to a reduction in inflammation and fibrosis 
and an increase in muscle regeneration. In particular, two preclinical studies with 
Givinostat have shown that chronic treatment with this compound in a DMD mouse 
model (mdx mouse) determines a dose- and concentration-dependent reduction in 
inflammation and fibrosis and an increase in muscle regeneration, which in turn 
determines an improvement in muscular function. 
The primary objective of this study is to replicate these findings in humans. In particular, 
the primary objective of the study will be to demonstrate that Givinostat stimulates 
muscle regeneration by detecting an increase in the fraction of muscle biopsy occupied 
by muscle when comparing the muscle biopsy at study end versus the muscle biopsy at 
study start. Other objectives of the study will be to evaluate the effects of Givinostat on 
other histological parameters (inflammation, necrosis, fibrosis), on functional parameters 


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such as the 6-Minute Walk Test (6MWT), and on magnetic resonance imaging (MRI) and 
biomarkers. Finally, the safety and tolerability and pharmacokinetics of Givinostat will 
also be assessed. 
As the currently used dose of Givinostat is considered not sufficient to exert the expected 
positive effects (see dose rationale), the first part of the study will be used to escalate the 
dose to one yielding exposures expected to be efficacious and which are well tolerated. 
To ensure an adequate assessment of the safety, efficacy, and PK parameters in this 
study, and considering the expected mechanism of action of Givinostat in DMD, 
ambulant children aged 7 to <11 years, who have been on a stable steroid dose for at least 
the last 6 months and who have a 6MWT assessment performed at least 6 months before 
screening will be selected for participation in this study. 
1.3.2 
Dose Rationale 
Until now, Givinostat has been administered to 87 healthy volunteers and 360 patients 
enrolled in 17 phase 1–2 studies. Of the 360 patients, 33 were children/adolescents 
treated with either Givinostat 0.5 mg/kg BID or 0.75 mg/kg BID. The maximum dose 
was a single dose of 600 mg in healthy volunteers and up to 400 mg once per week in 
subjects with multiple myeloma. Subjects have been treated in clinical trials with daily 
doses of Givinostat for up to 6 months. Moreover, 31 patients with myeloproliferative 
diseases enrolled in a compassionate use program have been receiving givinostat at doses 
up to 50 mg 3 times daily for a period up to 4 years and 1 adolescent with JIA enrolled in 
the extension study has been receiving Givinostat 0.75 mg/kg since December 2011. 
Doses of Givinostat up to approximately 100 mg BID have generally been well tolerated. 
At higher doses of Givinostat, transient reductions hematological parameters (particularly 
platelets) and diarrhoea as well as nausea and vomiting were observed. AEs were 
generally mild to moderate and reversible upon discontinuation of study drug 
(Investigator‘s Brochure 2012). In particular, thrombocytopenia appeared in just a few 
days of treatment at thrombocytopenic doses and reverted to normal values within a few 
days/weeks after treatment discontinuation. Twenty AEs of QTc prolongation have been 
reported and confirmed in the clinical studies. Of these, only 1 episode of QTc 
prolongation was observed in a pediatric study. No episode of QTc prolongation was 
observed in the 2 studies of Givinostat in healthy volunteers where ECG and QTc 
measurements were systematically assessed. 
A population PK analysis was conducted using the PK data collected so far in all the 
clinical trials where PK samples were collected. In particular, PK data from 7 studies 
have been included (single- and repeat-dose studies in healthy volunteers, 2 studies in 


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Crohn‘s disease subjects, 1 study in subjects with SOJIA, 1 study in subjects with JIA, 
and 1 study in subjects with psoriasis) for a total of 226 subjects. Givinostat 
pharmacokinetics were described using a 2-compartment model with first order 
absorption showing clearance (CL/F)=118 L/h, plasma volume (V/F)=155 L, peripheral 
volume (V2/F)=514 L, and absorption rate constant (KA)=0.243 h-1. The covariate 
screening indicated weight and steroid co-administration as the most significant 
covariates on clearance (CL) parameters (no gender, formulation, age, or healthy 
volunteer vs. patient differences). However, the covariates effects were considered 
limited on pharmacokinetics (i.e., the presence of steroids was found to determine an 
increase of <30% in the population CL, and an increase of 10 kg was found to determine 
an increase of 10%–15% in CL). 
The mean exposure in healthy volunteers treated with Givinostat 100 mg BID was 
1083 ng*h/mL (area under the plasma–concentration time curve from 0 to 12 hours 
[AUC0-12]) and 181.5 ng/mL (maximum plasma concentration [Cmax]). The estimated 
AUC0-12 and Cmax in children treated with Givinostat are reported in Table 1. 
Table 1 
Concentrations of Givinostat in Pediatric Studies to Date 
Disease State 
AUC0-12 (ng*h/mL) 
Cmax (ng/mL) 
SOJIA 
Median 
5th percentile 
95th percentile 
234.0 
126.4 
428.7 
31.5 
20.0 
55.3 
JIA 
Median 
5th percentile 
95th percentile 
206.4 
109.0 
492.7 
31.0 
14.9 
69.8 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; Cmax=maximum plasma 
concentration; SOJIA=systemic onset juvenile idiopathic arthritis; JIA=juvenile idiopathic arthritis. 
Preclinical studies in a mouse model of DMD (mdx mouse model) suggest that daily 
exposures (AUC0-24) of 600 nmol*h/L, i.e., approximately 300 ng*h/mL, are needed to 
exert beneficial histological and functional effects. As shown in Table 1, doses higher 
than those administered so far to children are needed to ensure that the majority of 
children are treated with doses that allow such exposures. Therefore, the first part of the 
study will escalate the dose to a maximum tolerated dose (MTD) that will then be 
recommended for the second part of the study. 
Because of the limited effect of weight on CL only 2 dose adjustments will be applied as 
follows: children who weigh 20–49 kg: Dose X; children who weigh ≥50 kg: 
Dose 1.5X. 


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The starting dose will be 25 mg BID in children who weigh 20–49 kg and 37.5 mg BID 
in children who weigh ≥50 kg. Table 2 reports the expected median, 5th, and 95th 
percentile exposures in children weighing 20, 30, 40, 50, and 60 kg. 
Table 2 
Expected Exposure by Weight 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
263 
223 
203 
283 
257 
5th percentile 
127 
107 
97 
132 
123 
95th percentile 
564 
466 
426 
603 
542 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours 
Expected exposures fall within the range of exposures safely tested in children with 
SOJIA and JIA and well within the exposures in adults treated with 100 mg BID. 
If safety and tolerability of the starting dose is confirmed in the first group of children 
treated, the dose will be escalated in the second group of children enrolled. The children 
treated at the lower dose will also be switched to the escalated dose level. Similarly, if 
the safety and tolerability of the second dose level is confirmed, the dose will be further 
escalated in the third group of children enrolled, and the children treated at the second 
dose level will be switched to the higher dose level. 
Dose escalation will be decided based on the safety and tolerability profile observed, and 
on the PK analyses in the children treated until a dose-escalation decision is made.  In 
any case each dose escalation should not yield more than a doubling of the expected 
exposure. An example of dose escalation based on the data available so far is provided in 
Table 3, Table 4, and Table 5 show the starting, second, and third dose, respectively. 


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Table 3 
Starting Dose (25 mg BID in Children Who Weigh 20–49 kg and 
37.5 mg BID in Children Who Weigh ≥50 kg) 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
263 
223 
203 
283 
257 
5th percentile 
127 
107 
97 
132 
123 
95th percentile 
564 
466 
426 
603 
542 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; BID=twice daily. 
Table 4 
Second Dose (50 mg BID in Children Who Weigh 20–49 kg and 75 mg 
BID in Children Who Weigh ≥ 50kg) 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
527 
445 
407 
566 
515 
5th percentile 
254 
215 
194 
263 
246 
95th percentile 
1129 
932 
852 
1205 
1084 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; BID=twice daily. 
Table 5 
Third Dose (75 mg BID in Children Who Weigh 20–49 kg and 100 mg 
BID in Children Who Weigh ≥50 kg) 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
790 
668 
610 
755 
686 
5th percentile 
381 
322 
290 
351 
329 
95th percentile 
1693 
1398 
1278 
1607 
1446 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; BID=twice daily. 
Once all 20 children enrolled in Part 1 of the study have been treated for at least 2 weeks, 
the review team will decide the recommended dose (RD) to be used in Part 2 based on 
the safety and tolerability profile observed and on the PK analyses. 
All children will then switch to the RD, which will be administered for the subsequent 
12 months of the study (Part 2). 


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This clinical study has been designed to comply with the Good Clinical Practice 
guidelines. 
2 Study Objectives 
Primary Objective 
The primary objective of this study is as follows: 
 To establish the histologic effects of Givinostat administered chronically at 
the selected daily dose 
Secondary Objectives 
The secondary objectives of this study are as follows: 
 To establish the effects of Givinostat administered chronically at the selected 
daily dose on functional parameters, such as the 6MWT, North Star 
Ambulatory Assessment (NSAA), and performance of upper limb (PUL) 
 To establish the safety and tolerability of Givinostat administered chronically 
at the selected daily dose in children with DMD 
 To explore the effects of Givinostat administered chronically at the selected 
daily dose on parameters such as MRI, biomarkers, and cytokines 
Primary Endpoint 
The primary endpoint of this study is as follows: 
 Change in the value of muscle fiber area % (MFA%) comparing the histology 
biopsies before and after 12 months of treatment with Givinostat 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study are as follows: 
 Change in additional histological endpoints (i.e., cross-sectional area, 
inflammation, necrosis, fibrosis, and muscle regeneration) after 12 months of 
treatment with Givinostat at the selected daily dose 
 Change in muscular function after 12 months of treatment with Givinostat at 
the selected daily dose based on the 6MWT 
 Change in muscular function after 12 months of treatment with Givinostat at 
the selected daily dose based on the NSAA 


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 Change in muscular function after 12 months of treatment with Givinostat at 
the selected daily dose based the PUL 
Safety Endpoints 
The safety endpoints of this study are as follows: 
 Number of children experiencing treatment-emergent AEs and serious AEs 
(SAEs) 
 Type, incidence, and severity of treatment-related AEs and SAEs 
 Measures of vital signs, clinical laboratory tests (blood chemistry, 
hematology, disease serologies), echocardiographs (ECHOs), pulmonary 
function tests (PFTs; forced expiratory volume at 1 second [FEV1], forced 
vital capacity [FVC], and FEV1/FVC), and 12-lead ECGs. 
Pharmacokinetic Endpoints 
The PK endpoints of this study are as follows: 
 Individual Givinostat concentrations tabulated by dose cohort along with 
descriptive statistics for Part 1 and tabulated along with descriptive statistic 
for Part 2. 
Exploratory Endpoints 
The exploratory endpoints of this study are as follows: 
 Change in muscle, fat, and fibrosis content after treatment with Givinostat as 
measured by MRI 
 Change in muscle biomarkers (e.g., miRNA) and cytokines following 
treatment with Givinostat 
 PK–PD correlations 
3 Investigational Plan 
3.1 Description of Overall Study Design and Plan 
This is a 2-part, phase 2 study to assess the effects of Givinostat on muscle histologic 
parameters and on clinical parameters in ambulant children with DMD. The safety, 
tolerability, and pharmacokinetics of Givinostat will also be assessed. 


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Children who assent to participate in this study (if capable of doing so) and whose 
parent/guardian signs the informed consent to participate will undergo pre-study 
screening assessments up to 4 weeks (±2 weeks) before the first scheduled dose of study 
drug. 
Approximately 20 children will be enrolled in the study as follows: the first 4 children 
will be treated at a low dose level of Givinostat (25 mg BID in children who weigh 
20-49 kg and 37.5 mg BID in children who weigh ≥50 kg).
If none of the stopping criteria (see Section 3.3.5 for stopping criteria) are met after 
2 weeks of treatment at the low dose, the review team will determine the escalated dose 
level (i.e., intermediate dose level) to be used for the treatment of an additional 8 children 
who will be treated at the intermediate dose. The 4 children previously treated at the low 
dose level will also be switched to the intermediate dose level. 
If none of the stopping criteria are met after 2 weeks of treatment at the intermediate 
dose, the review team will determine the subsequent escalated dose level to be used for 
the treatment of an additional 8 children who will be treated at the high dose. All 
children treated at the intermediate dose level will be switched to the high dose level. 
Once all 20 children enrolled during the Part 1 of the study have been treated for at least 
2 weeks, the review team will determine the RD to be used in Part 2 based on the safety 
and tolerability profile observed and on the PK analyses. All the children enrolled will 
switch to the RD level, which will be administered for the subsequent 12 months of the 
study (Part 2). 
After the 20 baseline biopsies are collected, an interim analysis aimed at checking the 
real variability of MFA% observed in the study will be implemented, the within-subject 
standard deviation of MFA% will be calculated, and the final sample size will be adjusted 
based on this interim analysis and in particular on the observed standard deviation. A 
conservative approach will be adopted, where the sample size may be increased but not 
decreased. 
The additional children (if any) will be enrolled during Part 2 of the study and will 
receive the RD of Givinostat for 12 months. 
A treatment table for the study is presented in Table 6. 


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Table 6 
Treatment Table 
PART 1 
PART 2 
Treatment Visitc 
Treatment Visitc 
Subject 
1 
2a
3 
4a
5 
6a
1 
2 
3 
4 
5 
6 
7 
8 
9 
10b 
1–4 
5–12 
13–20 
Additional 
children 
(if any) 
a At the end of Week 2 (Visit 2) at every dose level, a safety check is foreseen. 
b At the end of Month 12, an efficacy analysis on biopsy results and functional tests is foreseen. 
c The visits during Part 1 will be performed every 7 days (±1 day); the visits during Part 2 will be 
performed periodically every 1 – 1.5 months (± 7 days). 
Legend: 
25 – 37.5 mg BID – low dose level 
Intermediate dose level 
High dose level 
Recommended dose level 
During Part 1 of the study, children will visit the center once a week.  During Part 2 of 
the study, children will visit the study center per the schedule of assessments for a total of 
10 visits, not including follow up. Children may be evaluated more often if necessary for 
safety reasons. Children who discontinue the study drug early will be asked to come in 
for an end-of-study visit within 1 week after the last dose of study drug. Children who 
have ongoing AEs at discontinuation will be followed until resolution or stabilization. 
Efficacy will be assessed through changes from baseline in biopsy at 1 year (Part 2) and 
changes from baseline in the 6MWT, PUL, and NSAA at 1 year (Part 2). Exploratory 
efficacy parameters will include changes from baseline in MRI results, PK–PD 
correlations, and measures of cytokines and miRNA. Safety will be assessed by number 
of children experiencing treatment-emergent AEs and SAEs; type, incidence, and severity 
of treatment-emergent AEs and SAEs; and measures of vital signs, clinical laboratory 
tests (blood chemistry, hematology, disease serologies), ECHOs, PFTs (FEV1, FVC, and 
FEV1/FVC), and 12-lead ECGs. 


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After 1 week of treatment, blood samples for PK measurements will be collected 
pre-dose in the morning before drug intake and at 1, 2, 4, and 8 hours post-dose. 
PK samples will also be collected during Part 2 of the study. At Visit 2, blood samples 
for PK analysis should be taken pre-dose and between 6 and 8 hours post-dose. At 
Visit 3, blood samples for PK analysis should be collected pre-dose in the morning before 
drug intake and between 0 and 2 hours post-dose. At Visit 4, blood samples for PK 
analysis should be taken pre-dose and between 2 and 4 hours post-dose. At Visit 6, blood 
samples for PK analysis should be taken pre-dose and between 4 and 6 hours post-dose. 
3.2 Selection of Study Population 
This study will enroll approximately 20 ambulatory male children with an established 
diagnosis of DMD who are at least 7 years of age but <11 years of age. Additional 
children could be enrolled in the second part of the study, after the interim evaluation of 
baseline biopsies if the observed variability is higher than the one used for the current 
sample size estimate. Children will be enrolled at approximately 5 study sites in Italy. 
Specific entry criteria are detailed in Section 3.2.1 and Section 3.2.2. 
3.2.1 
Inclusion Criteria 
Children meeting all of the following inclusion criteria are eligible for inclusion in the 
study: 
1.
Male children aged 7 to <11 years with an immunohistochemical and
molecular diagnosis of DMD.
2.
Parent/guardian has signed the informed consent form and child has assented
to be in the study (if applicable).
3.
Able to complete t he 2 screening 6MWTs with a minimal distance of at least
250 m each. In addition, the results of theses 2 tests must be within ±30 m of
each other.
4.
On a stable dose of systemic corticosteroids for at least 6 months.
5.
At least 6 months worth of data on the 6MWT (this will be the ―historical‖
6MWT). From the moment of the historical 6MWT assessment(s), the child
must not have received any compound that could potentially affect the
6MWT, with the exception of the stable steroid treatment.
6.
A parent/guardian and child can comply with all study evaluations/procedures
and return for all study activities.


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3.2.2 
Exclusion Criteria 
Children meeting any of the following exclusion criteria will not be enrolled in the study. 
1.
Initiation of systemic corticosteroid therapy within 6 months prior to the start
of study drug or change in systemic corticosteroid therapy (e.g., initiation,
change in type of drug, dose modification not related to body weight change,
schedule modification, interruption, discontinuation, or re-initiation) within
6 months prior to the start of study drug.
2.
Use of any pharmacologic treatment, other than corticosteroids, that might
have an effect on muscle strength since the time of the historical 6MWT and
in any case within 3 months prior to the start of study treatment (e.g., growth
hormone). Vitamin D, calcium, and integrators will be allowed.
3.
Surgery that might have an effect on muscle strength or function within 3
months before study entry or planned surgery at any time during the study.
4.
Exposure to another investigational drug since the time of the historical
6MWT and in any case within 3 months prior to the start of study treatment.
5.
History of participation in gene therapy, cell-based therapy or oligonucleotide
therapy.
6.
Presence of other clinically significant disease that in the opinion of the
investigator places the child in unacceptable risk for an adverse outcome or
that could affect study results.
7.
Symptomatic cardiomyopathy or heart failure. If child has a left ventricular
ejection fraction <45% at screening, the investigator should discuss inclusion
of child in the study with the medical monitor.
8.
Inadequate hematological function
9.
Absolute neutrophil count: <1.5 x 109/L
10. Platelets: <100 x 109/L
11. Current or history of liver disease or impairment, including but not limited to
an elevated total bilirubin.
12. Inadequate renal function, as defined by serum creatinine >2 x the upper limit
of normal.


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13. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human
immunodeficiency virus at screening
14. A baseline QTc >450 msec, (as the mean of 3 consecutive readings 5 minutes
apart) or history of additional risk factors for torsades de pointes (e.g., heart
failure, hypokalemia, family history of long QT syndrome).
15. Psychiatric illness/social situations rendering the potential child unable to
understand and comply with the study protocol.
3.2.3 
Removal of Children from Therapy or Assessment 
A child will be considered to have completed the study when he completes the 
12-month/end-of-study visit (Visit 10) in Part 2. If a child is discontinued at any time
after entering the study, the investigator will make every effort to see the child and
complete the early termination and follow-up assessments as shown in Section 3.4.5. All
AEs should be followed until the child recovers or his condition stabilizes.
A termination electronic case report form (eCRF) should be completed for every child 
who receives study drug, whether or not the child completes the study. The reason for any 
early discontinuation should be indicated on this form. The primary reason for a child 
withdrawing prematurely should be selected from the following standard categories of 
early termination: 
 Adverse Event (Adverse Reaction): Clinical or laboratory events occurred 
that, in the medical judgment of the investigator for the best interest of the 
child, are grounds for discontinuation. This includes serious adverse events 
(SAEs) and non-serious AEs, regardless of relation to study drug. 
Death: The child died. 
Withdrawal of Consent: The child or his parent/guardian desired to withdraw 
from further participation in the study in the absence of an 
investigator-determined medical need to withdraw. If the child or 
parent/guardian gave a reason for withdrawing, it should be recorded in the 
eCRF. 
 Protocol Violation: The child‘s findings or conduct failed to meet the 
protocol entry criteria or failed to adhere to the protocol requirements (e.g., 
drug noncompliance, failure to return for defined number of visits). The 
violation necessitated premature termination from the study. 
 Lost to Follow-Up: The child stopped coming for visits, and study personnel 
were unable to contact the child. 


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 Other: The child was terminated for a reason other than those listed above, 
such as theft or loss of study drugs or termination of study by sponsor. 
3.3 Treatments 
3.3.1 
Details of Study Treatment 
Details about study drug are provided in Table 7. 
Table 7 
Details of Study Treatment 
Givinostat^ 
Drug name 
Givinostat 
Manufacturer 
Italfarmaco S.p.A. 
Dose(s) 
1st dose level: 
25 mg (children 20–49 kg) 
37.5 mg (children ≥50 kg) 
2nd dose level: 
50 mg (children 20–49 kg) 
75 mg (children ≥ 50 kg)* 
3rd dose level: 
75 mg (children 20–49 kg) 
100 mg (children ≥ 50 kg)* 
Dose frequency 
BID 
Route 
Oral under fed conditions 
Formulation 
Oral suspension and/or capsules 
^Givinostat is used to indicate the whole study drug name Givinostat hydrochloride monohydrate. The 
dosages / concentrations of the study drug are expressed as Givinostat hydrochloride monohydrate. 
* Estimated doses based on current knowledge.
BID=twice daily
3.3.2 
Dosage Schedule 
Study drug will be administered as 2 oral doses daily while the child is in the fed state. 
Children who enroll during Part 1 of the study will receive their assigned dose until the 
RD is determined. They will then receive up to 12 months of treatment with Givinostat 


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at the RD. Additional children may be enrolled as needed during Part 2 to reach the 
sample size calculated after the interim analysis. Children who enroll during Part 2 will 
receive up to 12 months of treatment with Givinostat at the RD. 
3.3.3 
Treatment Assignment 
All children will receive study drug. Children enrolled in Part 1 of the study will start to 
take either the low, intermediate, or high dose, depending on the needs of the study at the 
time of enrollment and they will switch to the RD when the review team decide that this 
dose is safe (see Table 6). 
When the safety review team has determined the RD, all children currently on study drug 
will be switched to that dose (the RD), and Part 2 of the study will commence. All 
children who enroll during Part 2 (if applicable) of the study will be given the RD of 
Givinostat. 
3.3.4 
Drug Packaging, Labeling, Storage, Dispensing, Investigational Medicinal Product 
Accountability, and Blinding 
Drug Packaging - Oral Suspension 
The primary packaging will consist of an amber plastic bottle containing the suspension. 
The secondary packaging will be a carton box containing 1 amber bottle and a syringe 
dosing system for dispensing the suspension. 
All the bottles will contain 120 mL of suspension. 
Drug Packaging - Capsules 
Capsules will be supplied as 50 mg hard gelatin capsules for oral administration in white 
plastic bottles containing 30 capsules each. 
Labeling 
The primary and secondary labels will show all the information requested according to 
the Annex 13 of the Good Manufacturing Practice. Bottles containing Givinostat will be 
labeled in local language (i.e., Italian). 
Storage 
The investigational medicinal product (IMP; Givinostat) will be stored at Italfarmaco until 
distribution to the investigational sites. The investigational site will store the IMP under 
the conditions specified in the label (i.e., 5 ±3°C for the oral suspension and <30°C for 
the capsules), ensuring that it is not accessible to unauthorized persons until it is 
dispensed to the child‘s parents/legal guardians. 


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Dispensing 
The investigational site will be supplied initially with a congruous number of suspension 
bottles and capsule bottles, in order to have sufficient supply of study drug to treat the 
children who are enrolled in the study. 
All IMP supplies are to be used only for this protocol and for no other purpose. 
The investigator will be responsible for the delivery of IMP to the child‘s parents/legal 
guardians according to the protocol. 
Children will be administered the IMP on an outpatient basis. 
At each scheduled visit, the investigator will supply the children with the appropriate 
number of suspension bottles and/or capsules bottles, sufficient to cover the treatment 
until the following visit (i.e., 1 week of treatment during Part 1 of the study and 1 to 
1.5 months, during Part 2 of the study). 
Italfarmaco will provide to the investigator a table with volume of suspension and/or 
number of capsules to be administered according to body weight and dose level. 
The investigator will provide to the child‘s parent/legal guardian written instruction on 
the dosage and corresponding volume in milliliters of suspension and/or number of 
capsules to be taken at each administration. Refer to the relevant Clinical Study 
Operations Manual (CSOM) for more detailed information. 
Blinding 
Not applicable. This is an open-label study. 
Emergency Procedure for Unblinding 
Not applicable. This is an open-label study. 
3.3.5 
Dose Modifications 
3.3.5.1 Child Stopping and Dose Reduction Safety Rules 
Permanent Stopping Rule 
Study drug should be permanently stopped if any of the following occur: 
Severe diarrhea (i.e., increase of ≥7 stools per day) 
Any drug-related SAE 
QTc >500 msec 
Platelets ≤50 x 109/L 


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Temporary Stopping and Dose Reduction Safety Rule 
Study drug should be temporarily stopped if any of the following occur: 
Platelets ≤75 x 109/L but >50 x 109/L 
Moderate diarrhea (i.e., increase of 4 to 6 stools per day) 
Study drug may be resumed at a reduced dose level once the event resolves. Such a dose 
reduction can happen only once per child. The treatment can be temporarily interrupted 
for a maximum of 4 weeks. If the child has not recovered from the AE after this period, 
the treatment should be permanently discontinued. 
If a child has a medical event not necessarily drug related that requires interruption of 
study drug dosing for >4 weeks, the review team will determine if the child may resume 
study drug treatment. 
Cohort Expansion Safety Rules 
The review team can decide to expand the first cohort of children and enroll additional 4 
children (for a total of 8 children treated at the first dose level), on the basis of safety, 
tolerability, and PK results in the children treated in that cohort, according but not limited 
to the following rules: 
 If 1 child experiences any type of stopping criterion (as defined in the permanent 
and temporary stopping rules), or 
 If 2 children experience different types of stopping criterion (e.g., 1 child 
experiences hematological toxicity and another child experiences GI toxicity). 
3.3.5.2 Cohort Abandoned Safety Rules 
The review team can also decide to abandon a given dose level on the basis of safety, 
tolerability and PK results in the children treated at that dose level, according to but not 
limited to the following rules: 
If >2 children experience any type of stopping criterion, or 
If ≥2 or more children experience the same type of stopping criterion 
3.3.5.3 Cohort Dose Escalation Safety Rules 
During Part 1 of the study, each child will receive study drug at a specific dose level. 
Once the first 4 children have been treated for at least 2 weeks, the review team will 
examine safety and tolerability data and PK results and decide if the children can be 
switched to the escalated dose level and if the second group of children can start the 
treatment at the escalated dose level. 


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After a further 2 weeks, the review team will decide if the already treated children at the 
lower and intermediate dose levels can switch to the highest dose and if the third and last 
group of children can start the treatment at the highest dose level. 
The children should be switched to the escalated dose level (i.e., intermediate or high 
dose level) only if no or only 1 stopping criterion per dose level occurred. 
For more details, see Figure 1. 
3.3.5.4 Study Stopping Safety Rules 
If 2 or more stopping criteria occur in the lower dose, the study will be temporarily 
stopped to allow a reassessment of the risks and benefits of the compound. 
Figure 1 
Cohort expansion, Cohort Abandoned and Dose Escalation Safety 
Rules for Part 1 
SC=stopping criterion, as defined under permanent and temporary stopping rules. 
The review team will include: the Principal Investigators, the Study Chair, the Medical 
Monitor and other Italfarmaco representatives. 
0 SC 
YES 
GO to the escalated dose level 
3 or more 
SC 
YES 
CLOSE the dose level 
NO 
NO  
NO 
YES, 2 SC of a different type 
EXPAND the dose level to 8 
children (if applicable, i.e., low 
dose level) or ESCALATE to 
next dose level 
2 SC 
YES, 2 SC of the same type 
CLOSE the dose level 
YES 
1 SC 
EXPAND the dose level to 8 
children (if applicable, i.e., low 
dose level) or ESCALATE to 
next dose level 


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3.3.6 
Treatment Compliance and IMP Accountability 
At each visit, the child‘s parents/legal guardians will bring back to the study site all the 
bottles previously received (used, partially used, and unused) and receive a new supply of 
the IMP. 
All unused IMP will be not re-dispensed by the investigator to another child. 
The investigator will maintain accurate records of the disposition of all IMP received, 
distributed to children (including date and time), and accidentally lost or destroyed. 
When dispensing the bottles to the children, the investigator will attach the relevant 
tear-off label to the relevant form. 
Oral Suspension Accountability 
The residual volume of suspension in the bottles will be measured by the investigator by 
means of a calibrated glass cylinder supplied by Italfarmaco and reported in the Drug 
Accountability Form and in the eCRF. 
Capsule Accountability 
The investigator will count the capsules unused for each bottle and insert the number in 
the Drug Accountability Form and in the eCRF. 
Periodically throughout and at the conclusion of the study, a representative of Italfarmaco 
S.p.A. or its delegate will conduct an inventory of all study drug supplies and the bottles
of oral suspension and/or capsules used, partially used, and unused will be destroyed at
the site, if possible, or sent back to Italfarmaco.
Missed doses are not to be recovered and they should be recorded in the eCRF and in the 
Drug Accountability Form, specifying the reason for any missed dose. 
For more detailed procedures, please refer to the relevant CSOM. 
3.3.7 
Prior and Concomitant Illnesses and Treatments 
Prior and Concomitant Illnesses 
Investigators should document all significant illnesses that the child has experienced 
within 6 months of screening. Additional illnesses present at the time informed consent 
is given are to be regarded as concomitant illnesses. Illnesses first occurring or detected 
during the study and/or worsening of a concomitant illness during the study are to be 
documented as AEs in the eCRF. 


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Prior and Concomitant Treatments 
Prior treatments, defined as those taken within 6 months prior to screening, should be 
recorded in the eCRF as prior medications. 
Concomitant treatments are defined as treatments taken after study drug administration. 
Children should be on stable systemic corticosteroid therapy for at least 6 months prior to 
initiation of study drug. That is, there have been no changes in systemic corticosteroid 
therapy (e.g., initiation, change in type of drug, dose modification not related to body 
weight change, schedule modification, interruption, discontinuation, or re-initiation) 
during the previous 6 months. 
Supportive treatments, such as anti-emetics, anti-diarrheals, anti-pyretics, anti-allergics, 
analgesics, and antibiotics are allowed. 
Use of Vitamin D, calcium and integrators if clinically indicated before enrolment and for 
duration of the trial are allowed. 
The following medications are prohibited prior to (as noted below) and during study 
treatment: 
 Other investigational agents within 3 months of start of study drug, since time 
historical 6MWT data was obtained, or while on study 
 Prior gene therapy or cell-based therapy or oligonucleotide therapy prior to study 
treatment or while on study 
 Any pharmacologic treatments (other than stable doses of corticosteroids) that 
might have an effect on muscle strength since the time of the historical 6MWT 
and in any case within 3 months prior to the start of study treatment (e.g., growth 
hormone) or while on study 
 Drugs that prolong the QTc interval (see Appendix 1: Drugs Known to Prolong 
the QTc Interval) 
3.4 Assessments 
3.4.1 
Schedule of Assessments 
The procedures to be performed during the study are outlined in the Schedule of 
Assessments (Table 8 and Table 9). A detailed description of each assessment may be 
found in Section 3.4.2. 


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Table 8 
Schedule of Assessments: Part 1 (Dose Escalation) 
Assessment 
Screen/ 
Pre-Studya 
Part 1 (Approximately 20 Children) 
Week 
-4 (±2 weeks)
0 
1 
2 
3 
4 
5 
Visit (1-day window) 
0 
1 
2 
3 
4 
5 
6 
Informed consent and 
assent 
X 
Medical history/ 
eligibility 
X 
Concomitant 
medications 
Xb
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
12-lead ECGc
X 
X 
X 
X 
X 
X 
X 
ECHOc 
X 
PFTs (FEV1, FVC, 
FEV1/FVC)c 
X 
Clinical laboratory 
testsc,d 
X 
X 
X 
X 
X 
X 
X 
Urinalysisb,c 
X 
X 
X 
X 
X 
X 
X 
Cytokine 
X 
miRNA 
X 
Serologye 
X 
Quality of Life test 
X 
Muscle evaluations 
(6MWTf, NSAAg, 
PULg) 
X 
Muscle biopsy 
X 
MRI 
Xi 
PK assessmenth 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Study drug 
administration 
X 
X 
X 
X 
X 
X 
6MWT=6-Minute Walk Test; CMV=cytomegalovirus; EBV=Epstein Barr virus; ECG=electrocardiogram; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; MRI=magnetic resonance imaging; 
NSAA=North Star Ambulatory assessment; PFTs=pulmonary function tests; PK=pharmacokinetic. 
a During the pre-study visit, historical function data (from 6 months before the pre-study visit) will be 
collected. 
b Obtain prior medications at screening as well. 
c To be performed more frequently, if clinically indicated. 
d The following laboratory parameters will be assessed: hematology: RBC, hemoglobin, hematocrit, WBC 
with differential, platelets, and abnormal cells; blood chemistry: total bilirubin, alkaline phosphatase, 
amylase, ALT, AST, LDH, CRP, creatine kinase, total protein, albumin, uric acid, sodium, potassium, 


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chloride, calcium, glucose, creatinine, BUN, and CPK (CrCl will be calculated by the Cockcroft and Gault 
formula); urinalysis: pH, specific gravity, protein, glucose, ketones, cytology, and myoglobin. 
e The following serology tests will be conducted: ELISA for HIV-Ab, HCV-Ab, HbsAg, HbeAg, 
anti-EBV, and anti-CMV IgM. 
f During the pre-study visit, the historical function data relevant to 6MWTs will be collected: (1) result 
from 6MWT performed at least 6 months before the pre-study visit, and (2) result from 2 6MWT 
performed within 4 weeks prior to treatment start will be necessary and inserted into the eCRF. 
g During the pre-study visit, the functional data relevant to the NSAA and PUL will be collected: results 
performed within 4 weeks prior to treatment start will be necessary and inserted into the eCRF. 
h After 1 week of treatment, blood samples for PK analysis should be collected pre-dose in the morning 
before drug intake and at 1, 2, 4, and 8 hours post-dose. It is important to record the time of PK 
assessments and the time of the last drug intake in the evening before the PK assessment. 
i Obtain an MRI of muscle (initially on the muscles of the lower limb and, if possible, on the muscles of the 
upper limb). MRI does not need to be repeated if obtained within 4 ± 2 weeks prior to the start of 
treatment. 


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Table 9 
Schedule of Assessments: Part 2 (Proof of Mechanism) 
Assessment 
Part 2 (All Children)j 
12/ 
EOS 
Visiti 
FU 
Visit 
Month of Study: 
0 
1 
2 
3 
4.5 
6 
7.5 
9 
10.5 
12 
-- 
Visit (1 week 
window) 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGc
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECHOc 
X 
PFTs (FEV1, 
FVC, 
FEV1/FVC)c 
X 
Clinical 
laboratory 
testsc,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisc,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serologye 
Quality of life 
test 
X 
Muscle 
evaluations 
(6MWTf, 
NSAAg, PULg) 
X 
X 
X 
X 
Muscle biopsy 
X 
MRI 
X 
Cytokine 
X 
X 
X 
X 
miRNA 
X 
X 
X 
X 
PK assessmenth 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6MWT=6-Minute Walk Test; CMV=cytomegalovirus; EBV=Epstein Barr virus; ECG=electrocardiogram; 
EOS=end of study; FU=follow up; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
MRI=magnetic resonance imaging; NSAA=North Star Ambulatory assessment; PK=pharmacokinetic. 
a The screening visit is only for children newly enrolled in Part 2. Children who were enrolled in Part 1 do 
not need to repeat the screening visit. For the relevant assessment, see Table 3 (screen/Pre study visit). 
b Obtain prior medications at screening as well. 
c To be performed more frequently, if clinically indicated. 


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d The following laboratory parameters will be assessed: Hematology: RBC, hemoglobin, hematocrit, WBC 
with differential, platelets, ANC, and abnormal cells; Blood chemistry: total bilirubin, alkaline 
phosphatase, amylase, ALT, AST, LDH, CRP, creatine kinase, total protein, albumin, uric acid, sodium, 
potassium, chloride, calcium, glucose, creatinine, BUN, and CPK (CrCl will be calculated by the Cockcroft 
and Gault formula); Urinalysis: pH, specific gravity, protein, glucose, ketones, cytology, and myoglobin. 
e The following serology tests will be conducted: ELISA for HIV-Ab, HCV-Ab, HbsAg, HbeAg, 
anti-EBV, and anti-CMV IgM. 
f During the pre-study visit, the historical function data relevant to 3 6MWTs will be collected: (1) result 
from 6MWT performed at least 6 months before the pre-study visit, and (2) result from 6MWT performed 
within 4 ±2 weeks prior to treatment start will be necessary and inserted into the eCRF. 
g During the pre-study visit, the functional data relevant to the NSAA and PUL will be collected: results 
performed within 4±2 weeks prior to treatment start will be necessary and inserted into the eCRF. 
h At Visit 2, blood samples for PK analysis should be taken pre-dose and between 6 and 8 hours post-dose. 
At Visit 3, blood samples for PK analysis should be collected pre-dose in the morning before drug intake 
and between 0 and 2 hours post-dose. At Visit 4, blood samples for PK analysis should be taken pre-dose 
and between 2 and 4 hours post-dose. At Visit 6, blood samples for PK analysis should be taken pre-dose 
and between 4 and 6 hours post-dose. It is important to record the time of PK assessments. 
i Children who discontinue participation prior to completion the study should perform the Early 
Termination Visit within 2 weeks after the last drug intake. For the assessments to be performed, see 
―12/EOS visit.‖ 
j Once all 20 children enrolled during the Part 1 of the study have been treated for at least 2 weeks, the 
review team will determine the RD to be used in Part 2 based on the safety and tolerability profile observed 
and on the PK analyses. All the children enrolled will switch to the RD level, which will be administered 
for the subsequent 12 months of the study (Part 2). 


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3.4.2 
Study Procedures 
3.4.2.1 Pre-Study (Screening)—(Day -28 [±2 Weeks]) 
The assessments during the pre-study phase will determine the child’s eligibility for the 
study and also their ability to comply with protocol requirements by completing all 
screening assessments. All children will undergo all screening assessments, regardless 
of whether they are enrolled during Part 1 or Part 2 of the study. 
The following procedures will be performed and recorded during the screening period: 
 Obtain written informed consent from the child‘s parent/legal guardian and assent 
from the child, if applicable. 
Collect medical history. 
Review inclusion and exclusion criteria. 
Obtain and record current and prior medications (taken in the past 6 months). 
Perform a physical examination. 
Measure vital signs: blood pressure, pulse rate, body temperature. 
Measure height and weight. 
Obtain a 12-lead ECG in triplicate. 
Obtain an ECHO. 
Obtain PFT measurements: FEV1, FVC, FEV1/FVC. 
Obtain blood samples for hematology, blood chemistry, and disease serology 
tests. 
Obtain a urine sample for urinalysis. 
Obtain blood samples for cytokine measurements and miRNA. 
Perform a quality of life test 
Perform the muscle evaluations: 
o
6MWT (collect historical data on tests performed at least 6 months prior to
the pre-study visit and within 4 ± 2 weeks of pre-study visit).
o
NSAA and PUL (collect results from within 4 ± 2 weeks prior to treatment
start).
 Obtain a muscle biopsy (brachial biceps; please refer to Section 3.4.6 for 
instructions; obtained within 4 ± 2 weeks prior to the start of treatment). 
 Obtain an MRI of muscle (initially on the muscles of the lower limb and, if 
possible, on the muscles of the upper limb; MRI does not need to be repeated if 
obtained within 4 ± 2 weeks prior to the start of treatment). 
Assess AEs 


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3.4.2.2 Weekly Visits (Part 1; Weeks 0 to 6) 
Children will visit the study center weekly during Part 1 of the study. Children will 
continue to come in weekly (i.e., every 7 ± 1 days) until they are switched to Part 2 of the 
study when the RD is selected. At each visit (unless otherwise indicated), the following 
assessments will be performed and recorded: 
Obtain and record concomitant medications. 
Perform a physical examination. 
Measure vital signs: blood pressure, pulse rate, body temperature. 
Measure weight. 
Obtain a 12-lead ECG in triplicate. 
Obtain blood samples for hematology and blood chemistry. 
Obtain a urine sample for urinalysis. 
Obtain blood for PK assessments at Visit 2 only as noted in the schedule of 
assessments. 
Dispense IMP and perform accountability. 
Assess AEs. 
3.4.2.3 Part 2 Visits (Months 1 to 10.5) 
Children will visit the study center as noted in the schedule of assessments during Part 2 
of the study (i.e., every 1 to 1.5 months ± 1 week). At each visit (unless otherwise 
indicated), the following assessments will be performed and recorded: 
Obtain and record concomitant medications. 
Perform a physical examination. 
Measure vital signs: blood pressure, pulse rate, body temperature. 
Measure height and weight. 
Obtain a 12-lead ECG in triplicate. 
Obtain blood sample for hematology and blood chemistry. 
Obtain blood samples for cytokine and miRNA (Visits 4 and 6 only). 
Obtain a urine sample for urinalysis. 
Obtain blood for a PK assessments at Visits 2, 3, 4, and 6 only as noted in the 
schedule of assessments. 
Obtain muscle evaluations (6MTW, NSAA, and PUL; Visits 4 and 6 only). 
Dispense IMP and perform accountability. 
Assess AEs. 


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3.4.3 
Assessments for End of Study (Visit 10 [Month 12]) 
Children who remain in the study will continue to take study drug through Visit 10. The 
end-of-study visit overlaps with the 12-month visit, if the child completes treatment. 
The following assessments will be performed and recorded: 
Obtain and record concomitant medications. 
Perform a physical examination. 
Measure vital signs: blood pressure, pulse rate, body temperature. 
Measure height and weight. 
Obtain a 12-lead ECG in triplicate. 
Obtain an ECHO. 
Obtain PFT measurements: FEV1, FVC, FEV1/FVC. 
Obtain blood samples for hematology and blood chemistry. 
Obtain a urine sample for urinalysis. 
Perform a quality of life test. 
Obtain muscle evaluations (6MWT, NSAA, PUL). 
Perform a muscle biopsy (please refer to Section 3.4.6 for instructions). 
Obtain an MRI of dystrophic muscle. 
Obtain blood samples for cytokines and miRNA. 
Perform accountability. 
Assess AEs. 
3.4.4 
Early Termination Visit 
Children who discontinue participation prior to completion of all study drug 
administration (i.e., 12 months of treatment) will be asked to return to the hospital within 
2 weeks after the last dose of study drug for completion of the same assessments given at 
the End of Study visit (for details, see Section 3.4.3). 
3.4.5 
Follow-up Visit 
All children, regardless of whether they complete the study or terminate early in Part 1 or 
Part 2 should return to the study center within 4 weeks of the last dose of study drug for 
the follow-up visit. 
The following assessments will be performed and recorded: 
Obtain and record concomitant medications. 
Perform a physical examination. 
Measure vital signs: blood pressure, pulse rate, body temperature. 


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Obtain a 12-lead ECG in triplicate. 
Obtain blood samples for hematology and blood chemistry. 
Obtain a urine sample for urinalysis. 
Assess AEs. 
3.4.6 
Description of Assessments 
Unless otherwise indicated, all assessments will be performed by the investigator or other 
regular study personnel. Assessments are to be performed according to the schedule 
shown in Section 3.4.1. The assessments at the end-of-study and follow-up visits should 
also be performed if the child terminates the study early. 
Efficacy Assessments 
Muscle Biopsies: A first brachial biceps biopsy (baseline) will be taken prior to the first 
dose of study drug. A second brachial biceps biopsy will be taken at the end of study 
from the opposite arm. 
The muscle biopsy samples from the biceps muscle will be collected by open biopsy 
according to standard hospital procedures for obtaining muscle biopsies from children. 
The minimum amount of muscle tissue required is a small piece of muscle of at least 
0.5 x 0.5 x 0.5 cm. The muscle sample, embedded with tragacanth gum on a piece of 
cork, must be frozen in liquid nitrogen-cooled 2-methylbutane and stored at -80°C or 
-70ºC until shipment.
The collection, processing, and shipment of these muscle biopsy samples to the Ospedale 
Pediatrico Bambino Gesù laboratory will be described in detail in the study-specific 
laboratory manual. 
6- Minute Walk Test: A modified version of the 6MWT recommended by American
Thoracic Society (2002) for use in adults will be performed.
North Star Ambulatory Assessment: The NSAA will be graded using the standard 
scorecard with each assessment rated as 0 – unable to achieve independently, 1 – 
modified method but achieves goal independent of physical assistance from another, or 2 
– normal with no obvious modification of activity.
Performance of Upper Limb: The PUL was devised to assess motor performance in the 
upper limb for patients with Becker and Duchenne muscular dystrophy.  The purpose is 
to assess change that occurs in motor performance of the upper limb over time from when 
a child is still ambulant until he loses all arm function when non-ambulant. The PUL will 


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be administered according to the guidelines developed by the Physiotherapy Working 
Group (Mayhew A et al. 2012, Mercuri E et al. 2012). 
MRIs: MRIs will be taken of muscle (initially on the muscles of the lower limb and, if 
possible, on the muscles of the upper limb) and evaluated per the specifications in the 
CSOM. 
Cytokines and miRNA: The following cytokines may be evaluated: tumor-necrosis 
factor-alpha (TNF-α), interleukin (IL)-1, and IL-6. In addition, miR-1, miR-133, and 
miR-206 may be evaluated. Additional cytokines and miRNA parameters may be 
evaluated if warranted. Evaluation of cytokines and miRNA will be documented in a 
separate report. 
Other efficacy assessments – exploratory analysis of muscle biopsies: Muscle biopsies 
will be analyzed in 2 distinct steps, by using different complementary approaches 
(fluorescence-activated cell sorting [FACS]-mediated isolation of cells and functional 
characterization ex vivo and staining of frozen sections) that are finalized to the 
identification and functional/molecular characterization of specific cell types that 
contribute to the regeneration or fibro-adipogenic degeneration of dystrophic muscles. 
These cells include muscle satellite cells (MuSCs) and a heterogeneous population that is 
referred to as ―fibro-adipogenic progenitors‖ (FAPs). These cell types can be isolated by 
FACS in mouse and human muscle samples as distinct populations, based on specific 
combination of surface antigens. 
In the mouse system, MuSCs can be isolated from skeletal muscles by FACS, as 
CD34pos/α7-integrinpos/Sca1neg cells (Sacco A et al. 2008), while FAPs are isolated either 
as CD34pos/α7integrinneg/Sca1pos cells or platelet-derived growth factor receptor (PDGFR) 
PDGFR- α pos cells (Joe AW et al. 2010; Uezumi A et al. 2010). In muscle biopsies of 
human patients or normal individuals, MuSCs are isolated as PDGFR- α neg/α7- 
integrinpos/N-CAM pos cells, while FAPs can be isolated as PDGFR- α neg/α7- 
integrinpos/N-CAM pos cells. 
Pre-clinical studies have demonstrated that functional interactions between these cell 
types contributes to the disease progression in mouse models of DMD (mdx mice) and 
that HDAC inhibitors promote the FAP property of stimulating muscle regeneration at 
the expense of fibro-adipogenic degeneration. The sponsor has identified a novel nuclear 
network that regulates FAP lineage identity and ability to support regeneration or 
fibro-adipogenic degeneration in dystrophic muscles. This network consists of an 
HDAC-repressed miRNA (the myomiRs 1.2, 133a and 206) that target 2 specific 
sub-units (BAF60a and b) of the switch/sucrose non-fermentable (SWI/SNF) chromatin 
remodeling complex, which promotes the expression of fibro-adipogenic genes. Upon 


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treatment with HDAC inhibitors, de-repression of myomiRs 1.2, 133a and 206 causes the 
down regulation of BAF60a and b, and the simultaneous activation of BAF60c, leading 
to the formation of BAF60c-based SWI/SNF complex that promotes skeletal myogenesis 
in FAPs. The sponsor has found that mdx mice that respond to HDAC inhibitors, such as 
Givinostat, show increased levels of BAF60c and myomiRs 1.2, 133a and 206. 
1.
FACS-sorting of MuSCs and FAPs from biopsies of children before and at the
end of the treatment will be used to measure: a) the relative amount of these cell
populations; b) their ability to differentiate in culture, in myogenic and adipogenic
media, and their functional interactions by co-culture experiments; c) gene and
miRNA expression analysis by quantitative polymerase chain reaction.
It should be emphasized that in vitro exposure to Givinostat of MuSCs and FAPs
from biopsies of children before the treatment might provide a useful measure
predictive of child response that can be used to better select children in a
follow-up trial.
2.
Histologic analysis of muscle sections from biopsies of children before and at the
end of the treatment will be used to measure: a) the expression levels of BAF60
a, b, and c variants, and myomiRs 1.2, 133a and 206 in MuSCs and FAPs, which
will be identified as Pax7pos or PDGFR- α pos, respectively.
Safety Assessments 
Physical Examination: Physical examination will include examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, heart, lungs, 
abdomen, lymph nodes, extremities, and nervous system. An AE form must be 
completed for all changes identified as clinically noteworthy. Height without shoes and 
weight will be recorded as noted in the schedule of assessments. 
Vital Signs: Vital signs will include body temperature (ºC), pulse rate, and blood 
pressure. 
Electrocardiogram: Standard 12-lead ECGs will be conducted in triplicate per the 
schedule of assessments and more often if clinically indicated. ECG will be acquired at 
the sites, then ECG data will be transmitted and a central reading will be performed. For 
details, see the relevant CSOM. 
ECHOs: Standard ECHOs will be conducted as per the schedule of assessments and 
more often if clinically indicated. 


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Pulmonary function tests: FEV1, FVC, and FEV1/FVC, will be collected per the site‘s 
standard process as noted in the schedule of assessments and more often if clinically 
indicated. 
Laboratory Parameters: The following laboratory tests are to be performed as indicated 
in the schedule of assessments and more often if clinically indicated: 
 Hematology: red blood cell (RBC) count, hemoglobin, hematocrit, WBC count 
with differential, platelets, ANC, and abnormal cells 
 Blood chemistry: total bilirubin, alkaline phosphatase, amylase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase 
(LDH), C-reactive protein (CRP), creatine kinase, total protein, albumin, uric 
acid, sodium, potassium, chloride, calcium, glucose, creatinine, blood urea 
nitrogen (BUN), and creatine phosphokinase (CPK) (creatinine clearance [CrCl] 
will be calculated by the Cockcroft and Gault formula.) 
 Urinalysis: pH of freshly voided specimen, specific gravity, protein, glucose, 
ketones, cytology, and myoglobin 
 Other: enzyme-linked immunosorbent assay (ELISA) for HIV- Ab, HCV-Ab, 
HbsAg, hepatitis B e antigen (HbeAg), anti-EBV, and anti-cytomegalovirus 
(CMV) immunoglobulin M (IgM).
Lab tests will be performed and analyzed by a local laboratory to ensure consistent 
interpretation of results. In the event of an unexplained clinically noteworthy abnormal 
laboratory test value, the test should be repeated immediately and followed up until it has 
returned to the normal range and/or an adequate explanation of the abnormality is found. 
Adverse Events:  An AE is any is ―any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment (International Conference on 
Harmonisation [ICH] E2A).‖ All medical and psychiatric conditions (except those 
related to the indication under study) present at screening will be documented on the 
Prior Illnesses eCRF. Changes in these conditions and new symptoms, physical signs, 
syndromes, or diseases should be noted on the AE eCRF during the rest of the study. 
Laboratory abnormalities should be recorded as AEs only if they meet the criteria for an 
SAE, result in discontinuation of the study drug, require medical intervention, or are 
judged by the investigator to be clinically significant changes from baseline values. See 
Section 4, for additional information. 


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Pharmacokinetic Assessments 
Blood samples for PK assessments will be collected as indicated in the schedule of 
assessments. Additional information about the PK time points will be provided in the 
relevant CSOM. 
Quality of Life Assessment 
The PedsQL Test will be performed before treatment start and at the end of the study. 
3.4.7 
Appropriateness of Measurements 
All assessments to be used in this study are commonly used, standard measurements 
frequently seen in DMD studies. 
4 Adverse Event Reporting 
Throughout the course of the study, all AEs will be monitored and reported in the AE 
eCRF, including the event‘s seriousness, severity, action taken, and relationship to the 
IMP. If AEs occur, the first concern will be the safety of the children. All AEs will be 
followed until resolved or stable and the outcome documented on the appropriate eCRF. 
In order to avoid vague, ambiguous, or colloquial expressions, all AEs should be 
recorded in standard medical terminology rather than the child‘s or parent‘s/legal 
guardian‘s own words. 
4.1 Definitions and Criteria 
4.1.1 
Adverse Events 
An AE is ―any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment (ICH E2A)‖. 
AEs include: 
Onset of any clinical sign or symptom 
Worsening (change in nature, severity or frequency) of conditions present at the 
start of the trial 
Subject deterioration due to the primary illness 
Intercurrent illness(es) 
Drug interactions 
Events related or possibly related to concomitant medications 


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 Abnormal laboratory values, as well as significant shifts from baseline within the 
range of normal that the investigator considers to be clinically significant 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
4.1.2 
Adverse Drug Reactions 
In the pre-approval clinical experience with a new medicinal product: ―all noxious and 
unintended responses to a medicinal product related to any dose should be considered 
Adverse Drug Reaction.‖ 
4.1.3 
Unexpected Adverse Drug Reactions 
An unexpected adverse drug reaction is an event in which the nature or severity is not 
consistent with the applicable product information (e.g., Investigator‘s Brochure for an 
unapproved IMP). 
4.1.4 
Serious Adverse Events 
An SAE (experience) or reaction is any untoward medical occurrence that at any dose: 
Is fatal (results in the outcome death) 
Is life-threatening* 
Requires inpatient hospitalization or prolongs existing hospitalization 
Results in persistent or significant disability/incapacity 
Is a congenital anomaly/birth defect 
Is medically significant or requires intervention to prevent one or other of the 
outcomes listed above 
*The term life-threatening refers to an event in which the subject was at risk of death at the time of the
event; it does not refer to an event which hypothetically might have caused death if it were more severe.
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the child or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 


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Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
An SAE is not necessarily severe; e.g., an overnight hospitalization for a diagnostic 
procedure must be reported as an SAE even though the occurrence is not medically 
serious. By the same token, a severe AE is not necessarily serious: nausea of several 
hours‘ duration may be rated as severe but may not be considered serious. 
4.1.5 
Assessing Intensity and Relationship 
All AEs will be assessed on 2 descriptive parameters: intensity and relationship to study 
drug: 
Intensity refers to the ―severity‖ of an event and references impact on a child‘s 
functioning. 
Relationship refers to the likelihood that the event being assessed was caused by the 
study drug. 
Intensity 
Each AE will be classified according to the following criteria: 
Mild: 
The AE does not interfere in a significant manner with the 
child‘s normal functioning level. 
Moderate: 
The AE produces some impairment of functioning, but is 
not hazardous to health. 
Severe: 
The AE produces significant impairment of functioning or 
incapacitation and is a definite hazard to the child‘s health. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the experience should be noted. If the intensity category changes 
over a number of days, those changes should be recorded separately (with distinct onset 
dates). 
Relationship 
Each AE will be assessed as to its relationship to study drug based on the following 
criteria. Although investigator attribution will be collected for reported events, for 
analytic purposes a temporal association with the use of study drug will be assumed 
sufficient for at least plausible association. 
Not 
No causal relationship exists between the investigational 
product and the AE, but an obvious alternative cause 


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related: 
exists, e.g., the child‘s underlying medical condition or 
concomitant therapy. 
Related: 
There is a reasonable/plausible possibility that the AE may 
have been caused by the investigational product. 
When assessing the relationship to study drug, the follow criteria will be considered: 
Positive rechallenge 
Positive dechallenge (resolution upon stopping suspect product, in absence of 
other intervention or treatment) 
Known class effect 
Biological plausibility 
Lack of alternative explanation—concomitant drug or disease 
Factors to be considered in assessing the relationship of the AE to study drug include: 
The temporal sequence from IMP administration 
The recovery on discontinuation and recurrence on reintroduction 
The concomitant diseases 
The evolution of the treated disease 
The concomitant medication(s) 
The pharmacology and pharmacokinetics of the IMP 
4.2 Reporting Procedures and Requirements 
4.2.1 
Adverse Events 
The investigator or his/her designees are requested to collect and assess any spontaneous 
AE reported by the child and to question the child about AEs and intercurrent illnesses at 
each visit during the treatment period and follow-up. The questioning of children 
regarding AEs is generalized such as ―How have you been feeling since your last visit?‖ 
Any AE occurring after the informed consent form/assent has been signed and up to the 
follow-up study visit, whether volunteered by the child; discovered during general 
questioning by the investigators; or detected through physical examination, laboratory 
test, or other means will be recorded on the specific section of the eCRF. Each AE will 
be described by: 
Seriousness 
Duration (start and end dates) 
Severity 
Relationship to the IMP 


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Action taken 
Outcome 
The severity of AE should be assessed and graded according to the most recently 
published National Cancer Institute Common Terminology Criteria for AEs (v. 4.0). 
The relationship to the investigational drug should be assessed as: 
Related to IMP 
Not related to IMP 
Unknown 
The assessment of the relationship of an AE to the administration of IMP is a clinical 
decision based on all available information at the time of the completion of the eCRF. 
An assessment of ‗not related‘ would include the existence of a clear alternative 
explanation, or non-plausibility. 
An assessment of ‗related‘ indicates that there is a reasonable suspicion that the AE is 
associated with the use of the IMP. 
4.2.1.1 Abnormal Laboratory Findings and Other Objective Measurements 
Abnormal laboratory findings and other objective measurements should not be routinely 
captured and reported as AEs in the eCRF as they will be collected and analyzed 
separately. However, abnormal laboratory findings and other objective measurements 
that meet the criteria for an SAE, result in discontinuation of the IMP, require medical 
intervention, or are judged by the investigator to be clinically significant changes from 
baseline values should be captured and reported as AEs in the eCRF. 
When reporting an abnormal laboratory finding as an AE in the eCRF, a clinical 
diagnosis should be recorded in addition to the abnormal value itself, if this is available 
(for example ―anemia‖ in addition to ―hemoglobin = 10.5 g/dL‖). 
4.2.1.2 Baseline Medical Conditions 
Medical conditions present at the screening visit that do not worsen in severity or 
frequency during the study are defined as baseline medical conditions and are not AEs. 
These medical conditions should be adequately documented on the appropriate page of 
the eCRF (i.e., the medical history page). However, medical conditions present at the 
initial study visit that worsen in severity or frequency during the study should be recorded 
and reported as AEs. 


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4.2.2 
Serious Adverse Events 
Any SAE, including death from any cause that occurs after a child has signed the 
informed consent /assent and up to the final follow-up visit (regardless of relationship to 
study drug) must be reported by the investigators to the sponsor within 24 hours of 
learning of its occurrence. 
Related SAEs MUST be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed. 
The investigators are required to complete the SAE form provided by the sponsor. 
Sufficient details must be provided to allow for a complete medical assessment of the AE 
and independent determination of possible causality. The investigators are obliged to 
pursue and provide additional information as requested by the sponsor‘s drug safety 
manager, or study director, or designee. 
The investigator must send notification of the SAE to the sponsor‘s Drug Safety Unit by 
faxing the SAE form, within 24 hours of a SAE, at the number specified below; then, the 
investigator must confirm any SAE notifications by mailing to the mail address or 
phoning to the phone number specified below: 
Aurelio Scotti 
Drug Safety Unit, Chemi S.p.A. 
Via dei Lavoratori 
54 20092 Cinisello Balsamo (MI), Italy 
Fax: 02 6610 6538 
phone: +39 02 6443 2510, mobile +39 333 9262611 
e-mail: drug-safety@italfarmaco.com
a. scotti@italfarmaco.com
The same procedure must be applied to the SAE follow-up information. 
The sponsor‘s drug safety manager will report all serious and unexpected AE that are 
related to the use of the study drug to the competent authority within the required time 
and following procedures required by applicable laws. It is imperative that the sponsor 
be informed as soon as possible, so that reporting can be done within the required time 
frame. 
The SAEs will also be recorded in the AE section of the eCRF. 
Overdose and Other Situations Putting the Child at Risk of an Adverse Reaction 


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Any instance of overdose (suspected or confirmed) must be reported to the sponsor 
within 24 hours and be fully documented as a SAE. Details of any signs or symptoms 
and their management should be recorded including details of any antidote(s) or 
systematic treatment administered. Any signs or symptoms of overdose will be treated 
symptomatically. 
Any other situations putting the child at risk of adverse reaction, such as misuse and 
abuse, medication errors, suspicion of transmission of infective agents must be reported 
to the sponsor within 24 hours and be fully documented as a SAE. 
5 Data Management and Statistical Analysis 
5.1 Data Management Considerations 
Electronic CRFs will be employed for this study. Completed eCRFs for this study will be 
forwarded to the sponsor or its representative where editing and construction of a 
quality-assured database will occur. The statistical analysis of these data will be 
performed by the sponsor or its representative. 
Data Analysis of the Biopsies 
All images will be digitally captured, using both light microscopy (hematoxylin and eosin 
[H&E] and Gomori trichrome stain) and fluorescence microscopy coupled to the 
Olympus Fluoview FV1000 confocal microscope. Fields for fluorescent imaging will be 
randomly selected while viewing the laminin-dystrophin signal. 
In the only step involving operator discretion, all image parameters including pinhole 
size, detector gain, amplifier offset, amplifier gain, and laser intensity will be first set for 
the dystrophin and laminin channels using normal control tissue, and the same setting 
used for all samples imaged on a given day. Frame size, scan speed, and averaging will 
be the same for all images. For each sample 4 non-overlapping images for each channel 
will be acquired and stored as 12-bit fluorescent images (.TIFF) for analysis. A single 
technician will perform all sectioning, staining, and morphometry steps, while another 
operator will execute the confocal imaging. 
Image processing and quantitative analyses will be done using Metamorph (Molecular 
Devices, Inc.) software program using a custom script. Additional details are provided in 
the relevant CSOM. 
5.2 Statistical Considerations 
The statistical analysis will be undertaken by the contract research organization 
Worldwide Clinical Trials (WCT) in collaboration with the sponsor. 


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Any deviations from the analyses described below will be included in the Statistical 
Analysis Plan (SAP). 
5.2.1 
General Considerations 
Data will be provided in data listings sorted by treatment group and child number. 
Tabular summaries will be presented by treatment group for Part 1. Categorical data will 
be summarized by the number and percentage of children in each category. Continuous 
variables will be summarized by descriptive statistics, including mean, standard 
deviation, median, minimum, and maximum. Confidence intervals (CIs) will be 2-sided, 
unless otherwise stated. Details of endpoint analyses will be described in the SAP. 
For analyses of change from baseline, baseline will generally be defined as the value 
collected before any Givinostat treatment is administered. If this value is unavailable, the 
last non-missing value prior to dosing will be used. Otherwise, missing observations will 
be treated as missing at random, and no data imputation will be performed. All data from 
the CRFs, as well as any derived variables, will be presented in data listings. 
All hypothesis tests will be two-sided with a 5% significance level, and 95% CIs will be 
used, unless stated otherwise. As this is a Phase 2 exploratory study, no adjustments for 
multiplicity will made. 
5.2.2 
Sample Size Justification 
A minimum of 20 evaluable children will be enrolled in this study. 
5.2.2.1 Part 1 
Approximately 20 children will be enrolled in Part 1 (dose-finding) of this study. 
5.2.2.2 Part 2 
Muscle fibers: a sample size of 20 children from part 1 completing the treatment period 
of part 2 should provide 90% power (at a 2-sided alpha level of 5%) to detect at least a 
12.5% increase in MFA% between pre- and post-treatment (which corresponds 
approximately to a 26% relative increase given the observed mean in the Desguerre 
publication of 48% [Desguerre I et al. 2009]), the ―worst case‖ standard deviation of 
16%, which assumes that there is no correlation within a subject in the muscle area fiber 
percentage between pre- and post-treatment. This sample size is based on a paired t-test 
and the assumption of normal distribution of MFA%. 
After the first 20 baseline biopsies are collected, an interim analysis aimed at checking 
the real variability observed in the study will be implemented: the within-subject 
standard deviation of MFA% will be calculated, the actual distribution of MFA% will be 
checked and the final sample size will be adjusted based on the observed standard 


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deviation and actual distribution of MFA%. Results by Al-Sunduqchi and Guenther 
(1990) indicate that power calculations for the Wilcoxon test may be made using the 
standard t-test formulations with a simple adjustment to the sample size. The size of the 
adjustment depends upon the actual distribution of the data. They give sample size 
adjustment factors for four distributions. These are 1 for the uniform distribution, 2/3 for 
the double exponential distribution, 9/π2 for the logistic distribution, and π/3 for the 
normal distribution. So depending on the actual distribution of MFA%, sample size 
re-calculation will be based on a Wilcoxon Signed Rank test with the corresponding 
adjustment if the observed distribution of MFA% is not normal. 
5.2.3 
Analysis Populations 
The intent-to-treat (ITT) population includes all children who are enrolled in the Part 1 
portion or entered the Part 2 portion of the study. The efficacy analysis will be conducted 
based on the ITT population. 
The evaluable population will include all children who are in the Part 2 of the study, 
receive Givinostat of at least 80% dose, have at least one baseline and one post-baseline 
assessment of biopsies, and have no major protocol violations. The evaluable population 
will be identified prior to database lock. A sensitivity analysis may be conducted based 
on the evaluable population. 
The safety population will include all children who receive any investigational product. 
The safety analysis will be conducted based on the safety population. 
The PK population will include all children with at least one quantifiable post-dose 
concentration datum available. All statistical analyses of PK data will be performed 
using the PK population. 
5.2.4 
Primary Endpoint 
The primary endpoint of this study is change in the value of MFA% comparing the 
histology biopsies before and after 12 months of treatment with Givinostat. 
5.2.5 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following: 
 Change in additional histological endpoints (i.e., cross-sectional area, 
inflammation, necrosis, fibrosis, and muscle regeneration) after 12 months of 
treatment with Givinostat at the selected daily dose 
 Change in muscular function after 12 months of treatment with Givinostat at the 
selected daily dose based on the 6MWT 


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 Change in muscular function after 12 months of treatment with Givinostat at the 
selected daily dose based on the NSAA 
 Change in muscular function after 12 months of treatment with Givinostat at the 
selected daily dose based the PUL 
Additional details on secondary efficacy endpoints will be provided in the SAP. 
5.2.6 
Secondary Safety Endpoints 
The secondary safety endpoints will include the following: 
The number of children experiencing AEs 
The type, incidence, and severity of AEs correlated with dose 
ECG, ECHO, vital sign, physical examination, PFTs, and clinical laboratory 
parameter findings 
5.2.7 
Secondary Pharmacokinetic Endpoints 
Individual Givinostat concentrations will be tabulated by dose cohort along with 
descriptive statistics for Part 1 and tabulated along with descriptive statistic for Part 2. 
Noncompartmental PK data analysis will be performed for data obtained from each dose 
cohort with scheduled PK sample collection. If data allows, descriptive statistics of 
noncompartmental PK parameters (area under the plasma–concentration time curve, 
maximum plasma concentration, clearance, terminal elimination half-life) will be 
provided. 
5.2.8 
Exploratory Endpoints 
The exploratory endpoints will include the following: 
 Changes in muscle, fat, and fibrosis content after treatment with Givinostat as 
measured by MRI 
 Change biomarkers (e.g., miRNA) and cytokine following treatment with 
Givinostat 
 PK–PD correlations 
5.2.8.1 Magnetic Resonance Imaging 
MRI will be collected via T1w imaging and quantitative Dixon imaging (the fat content 
of the image as a percentage of the total signal per voxel). Additional details will be 
provided in the SAP. 


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5.2.8.2 miRNA and Cytokine Parameters 
miR-1, miR-133, and miR-206 as well as TNF-α, IL-1, and IL-6 will be evaluated. Other 
miRNA and cytokine parameters may be evaluated as appropriate.  Additional details 
will be provided in the SAP. 
5.2.9 
Efficacy Analyses 
Efficacy analyses will be conducted on the evaluable population. 
All values will be expressed as means ± standard deviation or standard error of the mean. 
Each of all efficacy endpoints will be subject to normality test and formal statistical test 
performed will be based on whether it is normally distributed. If normal, statistical 
differences will be calculated using the paired t test; if not normal, Wilcoxon signed rank 
test will be used to assess the statistical significance of differences between groups. 
P<0.05 will be set as significant. 
5.2.10 Safety Analyses 
Safety analyses will be conducted on the safety population. 
The safety of Givinostat will be assessed primarily by summarizing treatment-emergent 
AEs and SAEs. Other safety data (e.g., laboratory, ECG, PFTs, physical examination, 
and vital sign findings) will be summarized. Treatment-emergent AEs and SAEs that 
occur after administration of Givinostat will be summarized by system organ class and 
preferred terms, by severity, and by relationship to investigational product. Change from 
baseline in laboratory values, ECG findings, PFTs, physical examination findings, and 
vital signs measurements will be summarized. 
5.2.11 Pharmacokinetic Analyses 
The PK analysis will be conducted on the PK population. 
Plasma concentrations from Part 1 will be listed and tabulated by dose and time point for 
all children and time points with at least 1 PK assessment. Plasma concentrations from 
Part 2 will be listed and tabulated by time point for all children and time points with at 
least 1 PK assessment. 
Descriptive statistics for all PK parameters for Part 1 will be calculated by treatment. 
Descriptive statistics for all PK parameters for Part 2 will also be calculated. These 
tables will include number of observations, mean, standard deviation, median, minimum 
and maximum and additionally the geometric mean and coefficient of variation (not for 
time to maximum plasma concentration). 


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5.2.12 Interim Analyses 
The following interim analyses will be conducted: 
 After the first 20 baseline biopsies are collected, the between-subject standard 
deviation of MFA% fraction will be calculated, the actual distribution of MFA% 
will be checked. The within-subject standard deviation will be estimated by 
between-subject standard deviation under the ―worst case‖ scenario, which 
assumes that there is no correlation within a subject in the muscle area fiber 
percentage between pre- and post-treatment. 
 Based on the standard deviation obtained above, the final sample size will be 
adjusted. A conservative approach will be adopted, where the sample size may be 
increased but not decreased. 
6 Study Management 
6.1 Approval and Consent 
6.1.1 
Regulatory Guidelines 
The study will be performed in accordance with local national laws (as applicable), the 
guidelines of the ICH, and the guidelines of the Declaration of Helsinki adopted by the 
18th World Medical Assembly in Helsinki, Finland in 1964 and amended by subsequent 
assemblies in Tokyo, Japan in 1975; Venice, Italy in 1983; Hong Kong in 1989; Somerset 
West, South Africa in 1996, and in Edinburgh, Scotland in October 2000. These 
guidelines are on file at WCT. 
This clinical study has been designed to comply with the Good Clinical Practice 
guidelines. 
6.1.2 
Institutional Review Board/Independent Ethics Committees 
This study will be undertaken only after approval of the protocol has been obtained from 
the appropriate Independent Ethics Committee (IEC), and a copy of the approval has 
been received by Italfarmaco S.p.A. 
The IEC must be informed of all subsequent protocol amendments and should be asked 
whether a re-evaluation of the ethical aspects of the study is necessary. 
If applicable, interim reports on the study and reviews of its progress will be submitted to 
the IEC by the investigator at intervals stipulated in their guidelines. 


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6.1.3 
Informed Consent 
For each trial subject, written informed consent from the legally accepted representative 
will be obtained prior to any protocol-related activities. Informed assent may be obtained 
from children who are capable of providing assent. As part of this procedure, the 
principal investigator or a designated representative must explain orally and in writing the 
nature, duration, and purpose of the study, and the action of the drug in such a manner 
that the child and (if applicable) appointed guardian are aware of the potential risks, 
inconveniences, or adverse effects that may occur. Children and their legally accepted 
representatives should be given ample time and opportunity to inquire about the details of 
the study prior to deciding whether to participate in the study. It is the responsibility of 
the investigator to ensure that all questions about the study are answered to the 
satisfaction of the children and their legally accepted representatives. 
Children and their legally accepted representatives should be informed that children may 
withdraw from the study at any time. They will receive all information that is required 
by local regulations and ICH guidelines. The principal investigator or a designated 
representative will provide the sponsor or its representative with a copy of the 
IEC-approved informed consent form prior to the start of the study. 
The informed consent form should be signed and dated by the child‘s legally accepted 
representative and the investigator on the same day. If the child and/or legally accepted 
representative are not able to read, an impartial witness should be present during the 
informed consent discussion, and the witness must co-sign and date the informed consent 
form. The child‘s legally accepted representative and/or impartial witness should receive 
a copy of the signed documents. 
For details of the information provided, refer to the informed consent form. 
6.2 Discontinuation of the Study by the Sponsor 
The sponsor reserves the right to discontinue the study at this site or at multiple sites for 
safety or administrative reasons at any time. In particular, a site that does not recruit at a 
reasonable rate may be discontinued. Should the study be terminated and/or the site 
closed for whatever reason, all documentation and study medication pertaining to the 
study must be returned to the sponsor or its representative. 
6.3 Study Documentation 
The investigator will supply the sponsor with: 
Curricula vitae for all investigators 
Signed protocol signature page 


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 List of IEC members and their occupations/affiliations or multiple assurance 
number 
Letter indicating IEC approval to conduct the protocol 
Copy of IEC-approved informed consent form 
Laboratory certification records and reference ranges 
The main documents that will be supplied by the Sponsor to investigator are: 
Clinical study protocol 
Investigational drug brochure 
Sample informed consent form 
eCRFs/instruction manual 
Insurance letter 
6.4 Study Monitoring and Auditing 
This study will be monitored at all stages of its development by the clinical research 
personnel employed by the sponsor or its representative. Monitoring will include 
personal visits and telephone communication to assure that the investigation is conducted 
according to protocol and in order to comply with guidelines of Good Clinical Practice. 
On-site review of eCRFs will include a review of forms for completeness and clarity, and 
consistency with source documents available for each child. Note that a variety of 
original documents, data, and records will be considered as source documents in this trial. 
The eCRF itself is not to be used as a source document under any circumstances. 
Medical advisors and clinical research associates or assistants may request to witness 
child evaluations occurring as part of this protocol. The investigator and appropriate 
personnel will be periodically requested to attend meetings/workshops organized by the 
sponsor to assure acceptable protocol execution. The study may be subject to audit by 
the sponsor or by regulatory authorities. If such an audit occurs, the investigator must 
agree to allow access to required child records. By signing this protocol, the investigator 
grants permission to personnel from the sponsor, its representatives, and appropriate 
regulatory authorities for on-site monitoring of all appropriate study documentation, as 
well as on-site review of the procedures employed in eCRF generation, where clinically 
appropriate. 
6.5 Retention of Records 
The investigator must arrange for retention of study records at the site. The nature of the 
records and the duration of the retention period must meet the requirements of the 
relevant regulatory authority. In addition, because this is an international study, the 
retention period must meet the requirements of the most stringent authority. The 


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investigator should take measures to prevent accidental or premature destruction of these 
documents. 
6.6 Use of Study Findings 
By signing the study protocol, the investigator agrees to the use of results of the study for 
the purposes of national and international registration. If necessary, the authorities will 
be notified of the investigator‘s name, address, qualifications, and extent of involvement. 
Reports covering clinical and biometric aspects of the study will be prepared by the 
sponsor or its representative. 
6.7 Publications 
The sponsor assures that the key design elements of this protocol will be posted in a 
publicly accessible database, such as clinicaltrials.gov. In addition, upon study 
completion and finalization of the study report the results of this study will be either 
submitted for publication and/or posted in a publicly accessible database of clinical study 
results. 


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7 References 
Al-Sunduqchi MS. 1990. Determining the Appropriate Sample Size for Inferences Based on the 
Wilcoxon Statistics. Ph.D. dissertation under the direction of William C. Guenther, Dept. of 
Statistics, University of Wyoming, Laramie, Wyoming. 
American Thoracic Society. ATS Statement: Guidelines for the 6-Minute Walk Test. Am J Respir 
Crit Care Med 2002;166:111-117. 
Consalvi S, Saccone V, Giordani L, Minetti G, Mozzetta C, Puri PL. Histone deacetylase 
inhibitors in the treatment of muscular dystrophies: epigenetic drugs for genetic diseases. Mol 
Med. 2011 May-Jun;17(5-6):457-65. 
Desguerre I, Mayer M, Leturcq F, Barbet JP, Gherardi RK, Christov C. Endomysial fibrosis in 
Duchenne muscular dystrophy: a marker of poor outcome associated with macrophage alternative 
activation. J Neuropathol Exp Neurol 2009;68:762–773. 
Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne 
muscular dystrophy: improvements in life expectancy since 1967 and the impact of home 
nocturnal ventilation. Neuromuscul Disord. 2002;12(10):926-9. 
Emery AE. The muscular dystrophies. Lancet. 2002;359(9307):687-95. 
Iezzi S, Cossu G, Nervi C, Sartorelli V, Puri PL. Stage-specific modulation of skeletal 
myogenesis by inhibitors of nuclear deacetylases. Proc Natl Acad Sci U S A. 2002 May 
28;99(11):7757-62. 
ITF2357 Investigator‘s Brochure. Edition No. 11.0. Release Date January 2012. 
Joe AW, Yi L, Natarajan A, Le Grand F, So L, et al. Muscle injury activates resident 
fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol 2010;12:153-63. 
Mayhew A, Eagle M, Mazzone E, et al. Performance of Upper Limb Module for DMD (PUL for 
DMD). Draft 1. March 31, 2012. 
Mercuri E, McDonald C, Mayhew A, et al. International workshop on assessment of upper limb 
function in Duchenne Muscular Dystrophy: Rome, 15-16 February 2012. Neuromuscul Disord 
2012 Jul 12. [Epub ahead of print] 
Minetti GC, Colussi C, Adami R, et al. Functional and morphological recovery of dystrophic 
muscles in mice treated with deacetylase inhibitors. Nat Med. 2006 Oct;12(10):1147-50. 
Sacco A, Doyonnas R, Kraft P, Vitorovic S, Blau HM. Self-renewal and expansion of single 
transplanted muscle stem cells. Nature. 2008 Nov 27;456(7221):502-6. 
Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct 
from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol 
2010;12:143-52. 


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8 Appendices 


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Appendix 1: Drugs Known to Prolong the QTc Interval 
Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Albuterol 
(Proventil®;Ventolin®) 
ß2-receptor agonist/Asthma 
Congenital 
QT Avoid 
Alfuzosin (Uroxatral®) 
Alpha1-blocker/Benign prostatic 
hyperplasia 
Possible 
Risk of 
TdP 
Amantadine (Symmetrel®) 
Dopaminergic/Anti-viral/Anti- 
infective/ Parkinson's Disease 
Possible 
Risk of 
TdP 
Amiodarone (Cordarone®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males,TdP risk 
regarded as low 
Risk of 
TdP 
Amiodarone (Pacerone®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males,TdP risk 
regarded as low 
Risk of 
TdP 
Amitriptyline (Elavil®) 
Tricyclic 
Antidepressant/depression 
Risk of TdP with overdosage 
Conditional 
TdP Risk 
Amphetamine (Dexedrine®) 
CNS stimulant/ADHD 
This includes 
dextroamphetamine and 
amphetamine / 
dextroamphetamine 
combinations. 
Congenital 
QT Avoid 
Amphetamine (Adderall® ) 
CNS stimulant/ADHD 
This includes 
dextroamphetamine and 
amphetamine / 
dextroamphetamine 
combinations. 
Congenital 
QT Avoid 
Arsenic trioxide (Trisenox®) 
Anti-cancer/Leukemia 
Risk of 
TdP 
Astemizole (Hismanal®) 
Antihistamine/Allergic rhinitis 
No Longer available in U.S. 
Risk of 
TdP 
Atazanavir (Reyataz® ) 
Protease inhibitor/HIV 
Possible 
Risk of 
TdP 
Atomoxetine (Strattera®) 
norepinephrine reuptake inhibitor 
/ADHD 
Congenital 
QT Avoid 
Azithromycin (Zithromax®) 
Antibiotic/bacterial infection 
Risk of 
TdP 


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Version 1.0 16 Sep 2019 
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Amendment 1, 05 Dec 2012 
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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Bepridil (Vascor®) 
Anti-anginal/heart pain 
Females>Males 
Risk of 
TdP 
Chloral hydrate (Noctec®) 
Sedative/sedation/ insomnia 
Possible 
Risk of 
TdP 
Chloroquine (Aralen®) 
Anti-malarial/malaria infection 
Risk of 
TdP 
Chlorpromazine 
(Thorazine®) 
Anti-psychotic/ Anti- 
emetic/schizophrenia/ nausea 
Risk of 
TdP 
Ciprofloxacin (Cipro®) 
Antibiotic/bacterial infection 
Drug metabolism inhibitor- 
Risk for drug interactions 
Conditional 
TdP Risk 
Cisapride (Propulsid®) 
GI stimulant/heartburn 
No longer available in the 
U.S.; available in Mexico
Risk of 
TdP 
Citalopram (Celexa®) 
Anti-depressant/depression 
Risk of 
TdP 
Clarithromycin (Biaxin®) 
Antibiotic/bacterial infection 
Risk of 
TdP 
Clomipramine (Anafranil®) 
Tricyclic 
Antidepressant/depression 
Conditional 
TdP Risk 
Clozapine (Clozaril®) 
Anti-psychotic/schizophrenia 
Possible 
Risk of 
TdP 
Cocaine (Cocaine) 
Local anesthetic/ 
Cardiac stimulant 
Congenital 
QT Avoid 
Desipramine (Pertofrane®) 
Tricyclic 
Antidepressant/depression 
Risk of TdP with overdosage 
Conditional 
TdP Risk 
Dexmethylphenidate 
(Focalin®) 
CNS stimulant/ADHD 
Congenital 
QT Avoid 
Diphenhydramine 
(Benadryl®) 
Antihistamine/Allergic rhinitis, 
insomnia 
Risk of QT increase/TdP in 
overdosages 
Conditional 
TdP Risk 
Diphenhydramine (Nytol®) 
Antihistamine/Allergic rhinitis, 
insomnia 
Risk of QT increase/TdP in 
overdosages 
Conditional 
TdP Risk 
Disopyramide (Norpace®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males 
Risk of 
TdP 
Dobutamine (Dobutrex®) 
Catecholamine/heart failure and 
Congenital 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
shock 
QT Avoid 
Dofetilide (Tikosyn®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Risk of 
TdP 
Dolasetron (Anzemet®) 
Anti-nausea/nausea, vomiting 
Possible 
Risk of 
TdP 
Domperidone (Motilium®) 
Anti-nausea/nausea 
Not available in the U.S. 
Risk of 
TdP 
Dopamine (Intropine®) 
Inotropic agent/heart failure; 
hypotension; shock 
Congenital 
QT Avoid 
Doxepin (Sinequan®) 
Tricyclic 
Antidepressant/depression 
Conditional 
TdP Risk 
Dronedarone (Multaq®) 
Anti-arrhythmic/Atrial Fibrillation 
Possible 
Risk of 
TdP 
Droperidol (Inapsine®) 
Sedative;Anti-nausea/anesthesia 
adjunct, nausea 
Risk of 
TdP 
Ephedrine (Broncholate®) 
Bronchodilator, 
decongestant/Allergies, sinusitis, 
asthma 
Congenital 
QT Avoid 
Ephedrine (Rynatuss®) 
Bronchodilator, 
decongestant/Allergies, sinusitis, 
asthma 
Congenital 
QT Avoid 
Epinephrine (Primatene®) 
catecholamine, 
vasoconstrictor/anaphylaxis, 
allergic reactions 
Cardiac stimulant 
Congenital 
QT Avoid 
Epinephrine (Bronkaid®) 
catecholamine, 
vasoconstrictor/anaphylaxis, 
allergic reactions 
Cardiac stimulant 
Congenital 
QT Avoid 
Eribulin (Halaven® ) 
Anti-cancer/metastatic breast 
neoplasias 
Possible 
Risk of 
TdP 
Erythromycin (E.E.S.® ) 
Antibiotic;GI stimulant/bacterial 
infection; increase GI motility 
Females>Males 
Risk of 
TdP 
Erythromycin (Erythrocin®) 
Antibiotic;GI stimulant/bacterial 
infection; increase GI motility 
Females>Males 
Risk of 
TdP 
Escitalopram (Cipralex®) 
Anti-depressant/Major depression/ 
Possible 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Anxiety disorders 
Risk of 
TdP 
Escitalopram (Lexapro®) 
Anti-depressant/Major depression/ 
Anxiety disorders 
Possible 
Risk of 
TdP 
Famotidine (Pepcid®) 
H2-receptor antagonist/Peptic 
ulcer/ GERD 
Possible 
Risk of 
TdP 
Felbamate (Felbatrol®) 
Anti-convulsant/seizure 
Possible 
Risk of 
TdP 
Fenfluramine (Pondimin®) 
Appetite suppressant/dieting, 
weight loss 
Congenital 
QT Avoid 
Fingolimod (Gilenya®) 
Immunosuppressant/Multiple 
Sclerosis 
Possible 
Risk of 
TdP 
Flecainide (Tambocor®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Risk of 
TdP 
Fluconazole (Diflucan®) 
Anti-fungal/fungal infection 
Drug metabolism inhibitor- 
Risk for drug interactions 
Conditional 
TdP Risk 
Fluoxetine (Prozac®) 
Anti-depressant/depression 
Conditional 
TdP Risk 
Fluoxetine (Sarafem®) 
Anti-depressant/depression 
Conditional 
TdP Risk 
Foscarnet (Foscavir®) 
Anti-viral/HIV infection 
Possible 
Risk of 
TdP 
Fosphenytoin (Cerebyx®) 
Anti-convulsant/seizure 
Possible 
Risk of 
TdP 
Galantamine (Reminyl®) 
Cholinesterase inhibitor/ 
Dementia, Alzheimer's 
Conditional 
TdP Risk 
Gatifloxacin (Tequin®) 
Antibiotic/bacterial infection 
Possible 
Risk of 
TdP 
Gemifloxacin (Factive®) 
Antibiotic/bacterial infection 
Possible 
Risk of 
TdP 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Granisetron (Kytril®) 
Anti-nausea/nausea and vomiting 
Possible 
Risk of 
TdP 
Halofantrine (Halfan®) 
Anti-malarial/malaria infection 
Females>Males 
Risk of 
TdP 
Haloperidol (Haldol®) 
Anti-psychotic/schizophrenia, 
agitation 
When given intravenously or 
at higher-than- recommended 
doses, risk of sudden death, 
QT prolongation and torsades 
increases. 
Risk of 
TdP 
Ibutilide (Corvert®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males 
Risk of 
TdP 
Iloperidone (Fanapt®) 
Antipsychotic, 
atypical/Schizophrenia 
Possible 
Risk of 
TdP 
Imipramine (Norfranil®) 
Tricyclic 
Antidepressant/depression 
Risk of TdP in overdosage 
Conditional 
TdP Risk 
Indapamide (Lozol®) 
Diuretic/stimulate urine & salt loss 
Possible 
Risk of 
TdP 
Isoproterenol (Isupres®) 
Catecholamine/allergic reaction 
Congenital 
QT Avoid 
Isoproterenol (Medihaler- 
Iso®) 
Catecholamine/allergic reaction 
Congenital 
QT Avoid 
Isradipine (Dynacirc®) 
Anti-hypertensive/high blood 
pressure 
Possible 
Risk of 
TdP 
Itraconazole (Sporanox®) 
Anti-fungal/fungal infection 
Drug metabolism inhibitor- 
Risk for drug interactions 
Conditional 
TdP Risk 
Ketoconazole (Nizoral®) 
Anti-fungal/fungal infection 
Drug metabolism inhibitor 
Conditional 
TdP Risk 
Lapatinib (Tykerb®) 
Anti-cancer/breast cancer, 
metastatic 
Possible 
Risk of 
TdP 
Lapatinib (Tyverb®) 
Anti-cancer/breast cancer, 
metastatic 
Possible 
Risk of 
TdP 
Levalbuterol (Xopenex® ) 
Bronchodilator/asthma 
Congenital 


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Amendment 1, 05 Dec 2012 
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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
QT Avoid 
Levofloxacin (Levaquin®) 
Antibiotic/bacterial infection 
Possible 
Risk of 
TdP 
Levomethadyl (Orlaam®) 
Opiate agonist/pain control, 
narcotic dependence 
Not available in the U.S. 
Risk of 
TdP 
Lisdexamfetamine 
(Vyvanse® ) 
CNS stimulant/ADHD 
Congenital 
QT Avoid 
Lithium (Eskalith®) 
Anti-mania/bipolar disorder 
Possible 
Risk of 
TdP 
Lithium (Lithobid®) 
Anti-mania/bipolar disorder 
Possible 
Risk of 
TdP 
Mesoridazine (Serentil®) 
Anti-psychotic/schizophrenia 
Risk of 
TdP 
Metaproterenol (Alupent®) 
Bronchodilator/asthma 
Congenital 
QT Avoid 
Metaproterenol (Metaprel®) 
Bronchodilator/asthma 
Congenital 
QT Avoid 
Methadone (Dolophine®) 
Opiate agonist/pain control, 
narcotic dependence 
Females>Males 
Risk of 
TdP 
Methadone (Methadose®) 
Opiate agonist/pain control, 
narcotic dependence 
Females>Males 
Risk of 
TdP 
Methylphenidate (Ritalin®) 
CNS stimulant/ADHD 
Congenital 
QT Avoid 
Methylphenidate (Concerta® 
) 
CNS stimulant/ADHD 
Congenital 
QT Avoid 
Midodrine (ProAmatine®) 
Vasoconstrictor/low blood 
pressure, fainting 
Congenital 
QT Avoid 
Moexipril/HCTZ (Uniretic®) Anti-hypertensive/high blood 
pressure 
Possible 
Risk of 
TdP 
Moxifloxacin (Avelox®) 
Antibiotic/bacterial infection 
Risk of 
TdP 
Nicardipine (Cardene®) 
Anti-hypertensive/high blood 
Possible 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
pressure 
Risk of 
TdP 
Nilotinib (Tasigna® ) 
Anti-cancer/Leukemia 
Possible 
Risk of 
TdP 
Norepinephrine 
(Levophed®) 
Vasconstrictor, Inotrope/shock, 
low blood pressure 
Congenital 
QT Avoid 
Nortriptyline (Pamelor®) 
Tricyclic 
Antidepressant/depression 
Conditional 
TdP Risk 
Octreotide (Sandostatin®) 
Endocrine/acromegaly, carcinoid 
diarrhea 
Possible 
Risk of 
TdP 
Ofloxacin (Floxin®) 
Antibiotic/bacterial infection 
Possible 
Risk of 
TdP 
Ondansetron (Zofran®) 
Anti-emetic/nausea and vomiting 
Possible 
Risk of 
TdP 
Oxytocin (Pitocin®) 
Oxytocic/Labor stimulation 
Possible 
Risk of 
TdP 
Paliperidone (Invega®) 
Antipsychotic, 
atypical/Schizophrenia 
Possible 
Risk of 
TdP 
Paroxetine (Paxil®) 
Anti-depressant/depression 
Conditional 
TdP Risk 
Pentamidine (NebuPent®) 
Anti-infective/pneumocystis 
pneumonia 
Females>Males 
Risk of 
TdP 
Pentamidine (Pentam®) 
Anti-infective/pneumocystis 
pneumonia 
Females>Males 
Risk of 
TdP 
Perflutren lipid microspheres 
(Definity® ) 
Imaging contrast 
agent/Echocardiography 
Possible 
Risk of 
TdP 
Phentermine (Fastin®) 
Appetite suppressant/dieting, 
weight loss 
Congenital 
QT Avoid 
Phentermine (Adipex®) 
Appetite suppressant/dieting, 
weight loss 
Congenital 
QT Avoid 


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Amendment 1, 05 Dec 2012 
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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Phenylephrine 
(Neosynephrine®) 
Vasoconstrictor, decongestant/low 
blood pressure, allergies, sinusitis, 
asthma 
Congenital 
QT Avoid 
Phenylpropanolamine 
(Acutrim®) 
Decongestant/allergies, sinusitis, 
asthma 
No longer available in the 
U.S. 
Congenital 
QT Avoid 
Phenylpropanolamine 
(Dexatrim®) 
Decongestant/allergies, sinusitis, 
asthma 
No longer available in the 
U.S. 
Congenital 
QT Avoid 
Pimozide (Orap® ) 
Anti-psychotic/Tourette's tics 
Females>Males 
Risk of 
TdP 
Probucol (Lorelco®) 
Antilipemic/Hypercholesterolemia 
No longer available in U.S. 
Risk of 
TdP 
Procainamide (Pronestyl®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Risk of 
TdP 
Procainamide (Procan® ) 
Anti-arrhythmic/abnormal heart 
rhythm 
Risk of 
TdP 
Protriptyline (Vivactil®) 
Tricyclic 
Antidepressant/depression 
Conditional 
TdP Risk 
Pseudoephedrine 
(PediaCare®) 
Decongestant/allergies, sinusitis, 
asthma 
Congenital 
QT Avoid 
Pseudoephedrine (Sudafed®) 
Decongestant/allergies, sinusitis, 
asthma 
Congenital 
QT Avoid 
Quetiapine (Seroquel® ) 
Anti-psychotic/schizophrenia 
Possible 
Risk of 
TdP 
Quinidine (Quinaglute®) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males 
Risk of 
TdP 
Quinidine (Cardioquin® ) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males 
Risk of 
TdP 
Ranolazine (Ranexa® ) 
Anti-anginal/chronic angina 
Possible 
Risk of 
TdP 
Risperidone (Risperdal® ) 
Anti-psychotic/schizophrenia 
Possible 
Risk of 
TdP 
Ritodrine (Yutopar®) 
Uterine relaxant/prevent premature 
labor 
Congenital 
QT Avoid 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Ritonavir (Norvir®) 
Protease inhibitor/HIV 
Conditional 
TdP Risk 
Roxithromycin* (Rulide®) 
Antibiotic/bacterial infection 
*not available in the United
States
Possible 
Risk of 
TdP 
Salmeterol (Serevent® ) 
Sympathomimetic/asthma, COPD 
Congenital 
QT Avoid 
Sertindole (Serdolect®) 
Antipsychotic, atypical/Anxiety, 
Schizophrenia 
Possible 
Risk of 
TdP 
Sertindole (Serlect®) 
Antipsychotic, atypical/Anxiety, 
Schizophrenia 
Possible 
Risk of 
TdP 
Sertraline (Zoloft®) 
Anti-depressant/depression 
Conditional 
TdP Risk 
Sibutramine (Meridia®) 
Appetitie suppressant/dieting, 
weight loss 
Congenital 
QT Avoid 
Solifenacin (VESIcare®) 
muscarinic receptor 
anatagonist/treatment of overactive 
bladder 
Conditional 
TdP Risk 
Sotalol (Betapace® ) 
Anti-arrhythmic/abnormal heart 
rhythm 
Females>Males 
Risk of 
TdP 
Sparfloxacin (Zagam® ) 
Antibiotic/bacterial infection 
Risk of 
TdP 
Sunitinib (Sutent®) 
Anti-cancer/RCC, GIST 
Possible 
Risk of 
TdP 
Tacrolimus (Prograf®) 
Immunosuppressant/Immune 
suppression 
Possible 
Risk of 
TdP 
Tamoxifen (Nolvadex® ) 
Anti-cancer/breast cancer 
Possible 
Risk of 
TdP 
Telithromycin (Ketek®) 
Antibiotic/bacterial infection 
Possible 
Risk of 
TdP 
Terbutaline (Brethine®) 
Bronchodilator/asthma 
Congenital 
QT Avoid 


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Generic Name 
(Brand Name) 
Drug Class / Clinical Usage 
Comments 
Risk List 
Terfenadine (Seldane®) 
Antihistamine/Allergic rhinitis 
No longer available in U.S. 
Risk of 
TdP 
Thioridazine (Mellaril® ) 
Anti-psychotic/schizophrenia 
Risk of 
TdP 
Tizanidine (Zanaflex® ) 
Muscle relaxant/ 
Possible 
Risk of 
TdP 
Tolterodine (Detrol®) 
Bladder Antispasmodic/ 
Congenital 
QT Avoid 
Tolterodine (Detrol LA®) 
Bladder Antispasmodic/ 
Congenital 
QT Avoid 
Trazodone (Desyrel®) 
Anti-depressant/Depression, 
insomnia 
Conditional 
TdP Risk 
Trimethoprim-Sulfa 
(Bactrim®) 
Antibiotic/bacterial infection 
Conditional 
TdP Risk 
Trimethoprim-Sulfa (Sulfa®) Antibiotic/bacterial infection 
Conditional 
TdP Risk 
Trimipramine (Surmontil®) 
Tricyclic 
Antidepressant/depression 
Conditional 
TdP Risk 
Vandetanib (Caprelsa®) 
Anti-cancer/Thyroid cancer 
Risk of 
TdP 
Vardenafil (Levitra® ) 
phosphodiesterase 
inhibitor/vasodilator 
Possible 
Risk of 
TdP 
Venlafaxine (Effexor® ) 
Anti-depressant/depression 
Possible 
Risk of 
TdP 
Voriconazole (VFend® ) 
Anti-fungal/anti-fungal 
Possible 
Risk of 
TdP 
Ziprasidone (Geodon® ) 
Anti-psychotic/schizophrenia 
Possible 
Risk of 
TdP 
Source: Arizona Center for Education and Research on Therapeutics. Updated 17 May 
2012. http://www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm. Accessed 
15 June 2012. 


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AMENDMENT 1 RATIONALE 
Protocol DSC/11/2357/4 has been amended for the following reasons: 
 To add the magnetic resonance imaging (MRI) of muscle on the upper limb, if it is 
possible and if the child is compliant. 
 To better describe the muscles to be observed during the MRI, inserting “muscle of lower 
limb” instead of “quadriceps femoris” and “muscle of upper limb” instead of “brachial 
biceps. 
   To clarify the timing around the collection of pharmacokinetic (PK) blood samples. 
The following is the rationale for the amendment: 
 During the study, the children will perform functional test to evaluate the muscular 
strength of the upper limb (i.e., performance of upper limb [PUL]). It is advisable to 
also collect the data from the MRI on upper limbs to compare the functional and 
radiological results. 
 The acquisition of MRI imaging is relevant not only to a single muscle (e.g., quadriceps 
or biceps) but a number of muscles should be observed and analysed. It is preferable to 
insert in the protocol the generic definition of “upper limb muscles” and “lower limb 
muscles.” 
The changes relevant to “muscle of lower limbs” instead of “quadriceps femoris” and “muscle of 
the upper limbs” instead of “brachial biceps” do not modify the MRI duration and acquisition 
time and, consequently, do not modify the impact the study will have on the children who 
participate. 
In addition, minor typographical and formatting corrections have been made, as appropriate. 
AMENDMENT 1 SUMMARY OF CHANGES 
Substantive additions to the protocol are denoted in bold. Substantive deletions are in 
strikethrough. 
Section 3.1 Description of Overall Study Design and Plan 
Plasma After 1 week of treatment, blood samples for PK measurements will be collected after 
1 week of treatment with givinostat during Part 1: at pre-dose in the morning before drug 
intake and at 1, 2, 4, and 8 hours post-dose. 
Section 3.4.1 Schedule of 
Assessments 
Table 8 Schedule of 
Assessments: Part 1 
(Dose Escalation) 
“ANC” has been 
removed from 
footnote of the table. 


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Footnote h has 
been modified for 
clarity and 
consistency: “At 
Visit 2, 4, and 6 
After 1 week of 
treatment, blood 
samples for PK 
analysis should be 
collected pre-dose 
in the morning 
before drug intake 
and at 1, 2, 4, and 
8 hours post-dose. 
It is important to 
record the time of 
PK assessments 
and the time of the 
last drug intake in 
the evening before 
the PK 
assessment.” 
The original footnote i has 
been removed from the 
table. 
 
Footnote i text has 
been added replaced 
with: “Obtain an 
MRI of muscle 
(initially on the 
muscles of the lower 
limb and, if possible, 
on the muscles of the 
upper limb). MRI 
does not need 
to be repeated 
if obtained 
within 4 ± 2 
weeks prior to 
the start of 
treatment.” 
Table 9 Schedule of 
Assessments: Part 2 
(Proof of Mechanism) 
 
“Troponin 1” has 
been removed from 
footnote d. 
 
Section 3.4.2.1 Pre-
Study (Screening)—
(Day -28 [±2 Weeks]) 
   Obtain an MRI of 
dystrophic muscle 
(quadriceps 
femoris initially 
on the muscles of 
the lower limb, 
and, if possible, 
on the muscles of 
the upper limb; 
MRI does not 
need to be 
repeated if 
obtained within 4 
± 2 weeks prior to 
the start of 
treatment). 
Section 3.4.6 
Description of 
Assessments 
 
MRIs: MRIs will 
be taken at of 
muscle (initially 
on the quadriceps 
femoris muscles 
of the lower limb 
and, if possible, 
on the 
muscles of 
the upper 
limb) and 
evaluated per 
the 
specifications 
in the 
CSOM. 


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Italfarmaco S.p.A. 
STUDY PROTOCOL 
Protocol Title: 
A Two-Part Study to Assess the Safety 
and Tolerability, Pharmacokinetics, and 
Effects on Histology and Different 
Clinical Parameters of Givinostat in 
Ambulant Children with Duchenne 
Muscular Dystrophy 
Protocol Number: 
DSC/11/2357/43 
Clinical Phase: 
2 
Original Protocol Date 
Amendment 1 
Amendment 2 
Amendment 3 
Amendment 4 
Amendment 5 
Amendment 6 
Amendment 7 
01 Aug 2012 
05 Dec 2012 
25 Mar 2013 
23 Oct 2013 
17 Apr 2014 
16 Mar 2015 
06 Jan 2016 
11 Apr 2017 


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EudraCT Number: 
2012-002566-12 
Sponsor 
Italfarmaco S.p.A. 
Via dei Lavoratori, 54 
20092 Cinisello Balsamo (MI) 
Italy 
Tel: +39 02 6443 2512 
Fax: +39 02 6443 3554 
SYNOPSIS 
Title of Study: 
A Two-Part Study to Assess the Safety and Tolerability, 
Pharmacokinetics, and Effects on Histology and Different Clinical 
Parameters of Givinostat in Ambulant Children with Duchenne 
Muscular Dystrophy 
Protocol Number: 
DSC/11/2357/43 
Eudra CT Number 
2012-002566-12 
Investigators/ 
Study Centers: 
Children will be enrolled at approximately 5 study sites in Italy. 
Phase of Development: 
2 


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Objectives: 
The primary objective of this study is as follows: 
•
To establish the histologic effects of Givinostat administered
chronically at the selected daily dose
The secondary objectives of this study are as follows: 
•
To establish the effects of Givinostat administered chronically
at the selected daily dose on functional parameters, such as
the 6-Minute Walk Test (6MWT), North Star Ambulatory
Assessment (NSAA), and performance of upper limb (PUL)
•
To establish the safety and tolerability of Givinostat
administered chronically at the selected daily dose in children
with Duchenne muscular dystrophy (DMD)
•
To explore the effects of Givinostat administered chronically
at the selected daily dose on parameters such as magnetic
resonance imaging (MRI) and biomarkers
•
To explore the acceptability/palatability of the oral suspension
•
To explore whether the effects of Givinostat on disease
progression may be related to the type of DMD mutation
Extension Phases: 
The primary objective is to evaluate the safety and tolerability of long-term 
administration of Givinostat administered chronically at the selected daily 
dose in children with DMD. 
The secondary objectives are: 
•
To establish the effects of Givinostat administered chronically
at the selected daily dose on other functional parameters, such
as the 6MWT, NSAA, and PUL (Extension 1, 2, 3)
•
To explore the effects of Givinostat administered chronically
at the selected daily dose on parameters such as MRI
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•
To collect information related to 2 biomarkers, LTBP4 and
osteopontin genotype (at the beginning of Extension 2 only)
•
To collect information related to time to wheelchair and how
much time the children spend in wheelchair (Extension 3 –
only for the children that are not able to complete the 6MWT)
Design: 
This is a 2-part, phase 2 study to assess the effects of Givinostat on muscle 
histologic parameters and on clinical parameters in ambulant children with 
DMD. The safety, tolerability, and pharmacokinetics of Givinostat will 
also be assessed. 
Children who assent to participate in this study (if capable of doing so) and 
whose parent/guardian signs the informed consent to participate will 
undergo pre-study screening assessments up to 4 weeks (±2 weeks) before 
the first scheduled dose of study drug. In addition, patients will be asked to 
share information concerning the type of mutation they carry in relation to 
DMD. 
PART 1: 
Approximately 20 children will be enrolled in the study as follows: the 
first 4 children will be treated at a low dose level of Givinostat (25 mg 
twice daily [BID] in children who weigh 20–49 kg and 37.5 mg BID in 
children who weigh ≥50 kg). 
If none of the stopping criteria (see Section 3.3.5) are met after 2 weeks of 
treatment at the low dose, the review team will determine the escalated 
dose level (i.e., intermediate dose level) to be used for the treatment of an 
additional 8 children who will be treated at the intermediate dose. The 
4 children previously treated at the low dose level will also be switched to 
the intermediate dose level. 
If none of the stopping criteria are met after 2 weeks of treatment at the 
intermediate dose, the review team will determine the subsequent escalated 
dose level to be used for the treatment of an additional 8 children who will 
be treated at the high dose. All children treated at the intermediate dose 
level will be switched to the high dose level. 
PART 2: 
Once all 20 children enrolled during the Part 1 of the study have been 
treated for at least 2 weeks, the review team will determine the 
recommended dose (RD) to be used in Part 2 based on the safety and 
tolerability profile observed and on the pharmacokinetic (PK) analyses. All 
the children enrolled will switch to the RD level, which will be 
administered for the subsequent 12 months of the study (Part 2). 
As of July 2013, the safety and tolerability assessments of Givinostat from 
Part 1 of the study were completed and the Safety Review Team 
determined the RD to be 37.5 mg, BID. The Safety Review Team also 


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recommended performing additional platelet count assessments every 
week, to maintain a stricter control and to monitor this parameter for safety 
reasons. 
In addition, as of September 2013, after assessing approximately 2 months 
of data on the platelet counts, the Safety Review Team decided to reduce 
the RD in subjects with platelet count ≤150 x 109/L to 25-mg BID 
Givinostat. Subjects with platelet count >150 x 109/L will continue on 
37.5-mg Givinostat. 
EXTENSION 1 
A first extension phase study treatment is foreseen in order to allow the 
patients to continue study treatment at least until the final analysis is 
performed (Part 2; after 12 months of treatment). Part 2 was originally 
planned with a 12-month study drug treatment. At 12 months, an efficacy 
and safety analysis will be conducted. If the results show a positive effect 
on patients, and no safety concern is raised, then patients will continue 
study treatment for up to another 12 months to evaluate the safety and 
tolerability of long-term administration of Givinostat and to evaluate the 
effect of treatment on muscle function. 
EXTENSION 2 
Since the histology results of the first 12 months of treatment are positive, a 
second extension phase is foreseen in order to allow the patients to continue 
a study treatment that supports a beneficial effect of Givinostat in DMD. 
The children on treatment in the Extension 1 will be asked to continue in 
the Extension 2 and will receive Givinostat at the same ongoing dose for a 
maximum of an additional 12 months. During Extension 2, the dose will be 
adjusted based on the weight of the children. 
During Part 1 of the study, children will visit the center once each week. 
During Part 2 of the study, children will visit the study center per the 
schedule of assessments for a total of 11 visits, or 17 visits if they will 
continue treatment in Extension 1 of the study, and 23 visits if they 
continue treatment in Extension 2 of the study, including follow up. 
Children may be evaluated more often if necessary for safety reasons. 
Children who discontinue the study drug early will be asked to come in for 
an end-of-study visit within 2 weeks after the last dose of study drug as 
well as the protocol-scheduled follow-up visit. Children who have ongoing 
adverse events (AEs) at discontinuation will be followed until resolution or 
stabilization. 
Efficacy will be assessed through changes from baseline in biopsy at 1 year 
(Part 2) and changes from baseline in the 6MWT, PUL, and NSAA at 
1 year (Part 2), at 2 years (Extension 1), and at 3 years (Extension 2). 
Exploratory efficacy parameters will include changes from baseline in MRI 
results, PK-pharmacodynamic correlations, and measures of micro 
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performed to investigate whether the effects of Givinostat on disease 
progression may be related to the type of DMD mutation. Safety will be 
assessed by number of children experiencing treatment-emergent AEs and 
serious adverse events (SAEs); type, incidence, and severity of treatment- 
emergent AEs and SAEs; and measures of vital signs, clinical laboratory 
tests (blood chemistry, hematology, disease serologies, and urinalysis), 
echocardiographs, pulmonary function tests (PFTs; forced expiratory 
volume at 1 second [FEV1], forced vital capacity [FVC], FEV1/FVC, and 
peak expiratory flow [PEF]) and 12-lead electrocardiograms (ECG). In 
Part 2 and during the extension phases, additional safety evaluations (i.e, 
laboratory re-testing, AE assessments), or additional medical evaluations 
may be performed at unscheduled visit(s) at the discretion of the 
Investigator. 
Plasma samples for PK measurements will be collected after 1 week of 
treatment with Givinostat, during Part 1 at pre-dose in the morning before 
drug intake and at 1, 2, 4, and 8 hours post-dose. 
PK samples will also be collected during Part 2 of the study as follows: 
•
At Visit 2, blood samples for PK analysis will be taken pre- 
dose and between 6 and 8 hours post-dose.
•
At Visit 3, blood samples for PK analysis will be collected
pre-dose in the morning before study drug intake and between
0 and 2 hours post-dose.
•
At Visit 4, blood samples for PK analysis will be taken
pre-dose and between 2 and 4 hours post-dose.
•
At Visit 6, blood samples for PK analysis will be taken
pre-dose and between 4 and 6 hours post-dose.
•
At Visit 10, blood samples for PK analysis will be taken at
pre-dose and at 1, 2, 4, and 8 hours post-dose.
EXTENSION 3 
A third extension phase is foreseen in order to allow the patients to 
continue a study treatment that supports a beneficial effect of Givinostat in 
DMD. The children on treatment in the Extension 2 will be asked to 
continue in the Extension 3 and will receive Givinostat at the same ongoing 
dose for a maximum of an additional 12 months. During Extension 3, the 
dose will be adjusted based on the weight of the children. 
This part of the study will be additionally extended until the activation of 
the Long Term Safety Study (Study NDSC/14/2357/51 - EUDRACT: 
2017-000397-10). During Part 1 of the study, children will visit the center 
once each week. During Part 2 of the study, children will visit the study 
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they continue treatment in Extension 1 of the study, 23 visits if they 
continue treatment in Extension 2 of the study and 27 visits if they continue 
treatment in Extension 3, including follow up. Children may be evaluated 
more often if necessary for safety reasons. Children who discontinue the 
study drug early will be asked to come in for an end-of-study visit within 2 
weeks after the last dose of study drug as well as the protocol-scheduled 
follow-up visit. Children who have ongoing adverse events (AEs) at 
discontinuation will be followed until resolution or stabilization. 
Efficacy will be assessed through changes from baseline in biopsy at 1 year 
(Part 2) and changes from baseline in the 6MWT, PUL, and NSAA at 
1 year (Part 2), at 2 years (Extension 1), at 3 years (Extension 2) and at 
4 years (Extension 3). Exploratory efficacy parameters will include 
changes from baseline in MRI results, and measures of miRNA. In 
addition, exploratory analysis will be performed to investigate whether the 
effects of Givinostat on disease progression may be related to the type of 
DMD mutation. Safety will be assessed by number of children 
experiencing treatment-emergent AEs and SAEs; type, incidence, and 
severity of treatment-emergent AEs and SAEs; and measures of vital signs, 
clinical laboratory tests (blood chemistry, hematology, disease serologies, 
and urinalysis), echocardiographs, pulmonary function tests (PFTs; FEV1, 
FVC, FEV1/FVC, and PEF) and 12-lead ECGs. In Part 2 and during the 
extension phases, additional safety evaluations (i.e., laboratory re-testing, 
AE assessments), or additional medical evaluations may be performed at 
unscheduled visit(s) at the discretion of the Investigator. 
Planned Sample Size: 
Approximately 20 children will be enrolled in Part 1 (dose-finding) of this 
study. 
Muscle fibers: a sample size of 20 children (from Part 1) completing the 
treatment period should provide 90% power (at a 2-sided alpha level of 
5%) to detect at least a 12.5% increase in muscle fiber area % (MFA%) 
between pre- and post-treatment (which corresponds approximately to a 
26% relative increase given the observed mean in the Desguerre 
publication of 48% [Desguerre I et al. 2009]), the “worst case” standard 
deviation of 16%, which assumes that there is no correlation within a 
subject in the muscle area fiber percentage between pre- and 
post-treatment. This sample size is based on a paired t-test. In the event 
the data is not normally distributed, a Wilcoxon signed rank test will be 
used. 
After the first 20 baseline biopsies are collected, an interim analysis aimed 
at checking the real variability observed in the study will be implemented 
as follows: the within-subject standard deviation of MFA% will be 
calculated and the final sample size will be adjusted based on this observed 
standard deviation. A conservative approach will be adopted where the 
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Diagnosis and Key Subject 
Selection Criteria: 
Inclusion criteria: 
1.
Male children aged 7 to <11 years with an
immunohistochemical and molecular diagnosis of DMD.
2.
A parent/guardian and child can comply with all study
evaluations/procedures and return for all study activities.
3.
Able to complete the 2 screening 6MWTs with a minimal
distance of at least 250 m each. In addition, the results of
these tests must be within ±30 m of each other.
4.
On a stable dose of systemic corticosteroids for at least
6 months.
5.
At least 6 months worth of data on the 6MWT (this will be
the “historical” 6MWT). From the moment of the historical
6MWT assessment(s), the child must not have received any
compound that could potentially affect the 6MWT, with the
exception of the stable steroid treatment.
6.
Parent/guardian has signed the informed consent form and
child has assented to be in the study (if applicable).
Exclusion criteria: 
1.
Initiation of systemic corticosteroid therapy within 6 months
prior to the start of study drug or change in systemic
corticosteroid therapy (e.g., initiation, change in type of drug,
dose modification not related to body weight change,
schedule modification, interruption, discontinuation, or
re-initiation) within 6 months prior to the start of study drug.
2.
Use of any pharmacologic treatment, other than
corticosteroids, that might have an effect on muscle strength
since the time of the historical 6MWT and in any case within
3 months prior to the start of study treatment (e.g., growth
hormone). Vitamin D, calcium, and integrators will be
allowed.
3.
Surgery that might have an effect on muscle strength or
function within 3 months before study entry or planned
surgery at any time during the study.
4.
Exposure to another investigational drug since the time of the
historical 6MWT and in any case within 3 months prior to the
start of study treatment.
5.
History of participation in gene therapy, cell-based therapy, or
oligonucleotide therapy.
6.
Presence of other clinically significant disease that in the
opinion of the investigator places the child in unacceptable
risk for an adverse outcome or that could affect study results.
7.
Symptomatic cardiomyopathy or heart failure. If child has a
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investigator should discuss inclusion of child in the study with 
the medical monitor. 
8.
Inadequate hematological function
9.
Absolute neutrophil count: <1.5 x 109/L
10. Platelets: <100 x 109/L
11. Current or history of liver disease or impairment, including
but not limited to an elevated total bilirubin.
12. Inadequate renal function, as defined by serum creatinine >2 x
the upper limit of normal.
13. Positive test for hepatitis B surface antigen, hepatitis C
antibody, or human immunodeficiency virus at screening
14. A baseline QTc >450 msec, (as the mean of 3 consecutive
readings 5 minutes apart) or history of additional risk factors
for torsades de pointes (e.g., heart failure, hypokalemia,
family history of long QT syndrome).
15. Psychiatric illness/social situations rendering the potential
child unable to understand and comply with the study
protocol.
Treatments: 
The study drug (Givinostat) will be administered as 2 oral doses daily while 
the child is in the fed state. Children who enroll during Part 1 of the study 
will receive their assigned dose until the RD is determined. They will then 
receive up to 12 months of treatment with Givinostat at the RD. 
Moreover, children who will be enrolled in the extension phases will 
receive Givinostat at the same ongoing dose (during the last visit planned at 
12 months of treatment) for a maximum of an additional 40 months 
(12 months for Extension 1, 12 months for Extension 2, and 16 months for 
Extension 3). 
Additional children may be enrolled as needed during Part 2 to reach the 
sample size calculated after the interim analysis. Children who enroll 
during Part 2 will receive up to 12 or 48 months (if they will be enrolled in 
the extension phases) of treatment with Givinostat at the RD. During 
Extensions 2 and 3, the dose will be adjusted based on the weight of the 
children. The total duration of the study is anticipated to be 15 months, and 
an additional 40 months for Extension 1 (12 months), Extension 2 
(12 months), and Extension 3 (16 months). 
Main Parameters of 
Efficacy: 
The primary endpoint of this study is change in the value of MFA% 
comparing the histology biopsies before and after 12 months of treatment 
with Givinostat. 
The secondary efficacy endpoints of this study are as follows: 
•
Change in additional histological endpoints (i.e., cross- 
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regeneration) after 12 months of treatment with Givinostat at 
the selected daily dose 
•
Change in muscular function after 12 months of treatment
with Givinostat at the selected daily dose based on the 6MWT
•
Change in muscular function after 12 months of treatment
with Givinostat at the selected daily dose based on the NSAA
•
Change in muscular function after 12 months of treatment
with Givinostat at the selected daily dose based the PUL
Extension Phases: 
The primary endpoints for the extension phases are the following: 
•
Number of children experiencing treatment-emergent AEs
and SAEs
•
Type, incidence, and severity of treatment-emergent AEs and
SAEs correlated with dose
As secondary endpoints, the change in muscular function after 24 months, 
36 months, and 52 months (Extension 1, Extension 2, and Extension 3, 
respectively) of treatment with Givinostat as assessed by 6MWT, NSAA, 
and PUL will be investigated. For the children that are not able to complete 
the 6MWT, the time to wheelchair and how much time the children spend 
in wheelchair were assessed. 
Main Parameters of Safety: 
•
Number of children experiencing treatment-emergent AEs and
SAEs
•
Type, incidence, and severity of treatment-emergent AEs and
SAEs correlated with dose
PK Parameters: 
•
Individual Givinostat concentrations tabulated by dose cohort
along with descriptive statistics for Part 1 and tabulated along with
descriptive statistics for Part 2.
Exploratory Endpoints: 
•
Change in muscle, fat and fibrosis content after treatment with
Givinostat as measured by MRI (also evaluated during
Extension 1)
•
Change in muscle biomarkers (e.g., miRNA) following treatment
with Givinostat
•
PK–PD correlations
•
Evaluation of acceptability/palatability of the oral suspension
•
Evaluation of any correlation between the effects of Givinostat on
disease progression and the type of DMD mutation patients may
have in relation to their disease
Key Statistical 
Considerations 
Efficacy analyses will be conducted on the intent-to-treat (ITT) population, 
which is defined as all children who are enrolled in the Part 1 portion or 
entered the Part 2 portion of the study. 


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All values will be expressed as means ± standard deviation or standard 
error of the mean. 
Each of all efficacy endpoints will be subject to normality test and formal 
statistical test performed will be based on whether it is normally 
distributed. If normal, statistical differences will be calculated using the 
paired t test; if not normal, Wilcoxon signed rank test will be used to assess 
the statistical significance of differences between groups. P<0.05 will be 
set as significant. 
General considerations: Data will be provided in data listings sorted by 
treatment group and child number. Tabular summaries will be presented by 
treatment group for Part 1. Categorical data will be summarized by the 
number and percentage of children in each category. Continuous variables 
will be summarized by descriptive statistics, including mean, standard 
deviation, median, minimum, and maximum. Confidence intervals (CIs) 
will be 2-sided, unless otherwise stated. Details of endpoint analyses will 
be described in the Statistical Analysis Plan. 
For analyses of change from baseline, baseline will generally be defined as 
the value collected before any Givinostat treatment is administered. If this 
value is missing, the last non-missing value prior to dosing will be used. 
Otherwise, missing observations will be treated as missing at random, and 
no data imputation will be performed. All data from the case report forms, 
as well as any derived variables, will be presented in data listings. 
All hypothesis tests will be two-sided with a 5% significance level, and 
95% Cis will be used, unless stated otherwise. As this is a Phase 2 
exploratory study, no adjustments for multiplicity will be made. 


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TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................154 
SYNOPSIS ...........................................................................................................................156 
TABLE OF CONTENTS ...................................................................................................165 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................170 
1 
Introduction ..................................................................................................172 
1.1 
Background on Duchenne Muscular Dystrophy ...................................................................172 
1.2 
Background on Givinostat ....................................................................................................172 
1.3 
Rationale ...............................................................................................................................174 
1.3.1 Study Rationale .....................................................................................................................174 
1.3.2 Dose Rationale – Part 1 and Part 2 .......................................................................................175 
1.3.3 Dose Rationale - Extension Phases .......................................................................................179 
2 
Study Objectives ...........................................................................................181 
3 
Investigational Plan ......................................................................................184 
3.1 
Description of Overall Study Design and Plan .....................................................................184 
3.1.1 Extension Phases ...................................................................................................................187 
3.2 
Selection of Study Population ...............................................................................................188 
3.2.1 Inclusion Criteria ..................................................................................................................189 
3.2.2 Exclusion Criteria .................................................................................................................189 
3.2.3 Removal of Children from Therapy or Assessment ..............................................................190 
3.3 
Treatments ............................................................................................................................191 
3.3.1 Details of Study Treatment ...................................................................................................191 
3.3.2 Dosage Schedule ...................................................................................................................192 
3.3.3 Treatment Assignment ..........................................................................................................193 
3.3.4 Drug Packaging, Labeling, Storage, Dispensing, Investigational Medicinal Product 
Accountability, and Blinding……………………………………………………………...193 


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3.3.5 Dose Modifications .............................................................................................................195 
3.3.6 Treatment Compliance and IMP Accountability ................................................................198 
3.3.7 Prior and Concomitant Illnesses and Treatments ...............................................................199 
3.4 
Assessments ........................................................................................................................200 
3.4.1 Schedule of Assessments ....................................................................................................200 
3.4.2 Study Procedures ................................................................................................................207 
3.4.3 Unscheduled Visits .............................................................................................................209 
3.4.4 Assessments for End of Study Part 2 (Visit 10 [Month 12])/Beginning of Extension 
Phase 1 ................................................................................................................................209 
3.4.5 Extension Phase 1 Visits (Months 12 to 22) .......................................................................210 
3.4.6 Assessments for End of Extension Phase 1 (Visit 16 [Month 24])/Beginning of 
Extension Phase 2 ...............................................................................................................210 
3.4.7 Extension Phase 2 Visits (Months 24 to 34) .......................................................................211 
3.4.8 Assessments for End of Extension Phase 2 (Visit 22 [Month 36]/Beginning of 
Extension Phase 3) ..............................................................................................................211 
3.4.9 Extension Phase 3 Visits (Months 40 to 48) .......................................................................212 
3.4.10 Assessments for End of Extension Phase 3 (Visit 26 [Month 52]) ....................................212 
3.4.11 Early Termination Visit ......................................................................................................213 
3.4.12 Follow-up Visit ...................................................................................................................213 
3.4.13 Description of Assessments ................................................................................................213 
3.4.14 Appropriateness of Measurements ......................................................................................218 
4 
Adverse Event Reporting ...........................................................................219 
4.1 
Definitions and Criteria ......................................................................................................219 
4.1.1 Adverse Events ...................................................................................................................219 
4.1.2 Adverse Drug Reactions .....................................................................................................219 
4.1.3 Unexpected Adverse Drug Reactions .................................................................................220 
4.1.4 Serious Adverse Events ......................................................................................................220 
4.1.5 Assessing Intensity and Relationship .................................................................................220 
4.2 
Reporting Procedures and Requirements ............................................................................222 


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4.2.1 Adverse Events ...................................................................................................................222 
4.2.2 Serious Adverse Events ......................................................................................................223 
5 
Data Management and Statistical Analysis ................................................224 
5.1 
Data Management Considerations ......................................................................................224 
5.2 
Statistical Considerations ....................................................................................................225 
5.2.1 General Considerations .......................................................................................................225 
5.2.2 Sample Size Justification ....................................................................................................226 
5.2.3 Analysis Populations...........................................................................................................227 
5.2.4 Primary Endpoint ................................................................................................................227 
5.2.5 Secondary Efficacy Endpoints ............................................................................................227 
5.2.6 Safety Endpoints .................................................................................................................228 
5.2.7 Secondary Pharmacokinetic Endpoints...............................................................................228 
5.2.8 Exploratory Endpoints ........................................................................................................228 
5.2.9 Efficacy Analyses ...............................................................................................................229 
5.2.10 Safety Analyses...................................................................................................................229 
5.2.11 Pharmacokinetic Analyses ..................................................................................................230 
5.2.12 Interim Analyses .................................................................................................................230 
5.2.13 Analysis at Month 12 ..........................................................................................................230 
6 
Study Management .....................................................................................231 
6.1 
Approval and Consent ........................................................................................................231 
6.1.1 Regulatory Guidelines ........................................................................................................231 
6.1.2 Institutional Review Board/Independent Ethics Committees .............................................231 
6.1.3 Informed Consent ...............................................................................................................231 
6.2 
Discontinuation of the Study by the Sponsor .....................................................................232 
6.3 
Study Documentation .........................................................................................................232 
6.4 
Study Monitoring and Auditing ..........................................................................................233 
6.5 
Retention of Records ..........................................................................................................233 
6.6 
Use of Study Findings .........................................................................................................233 


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6.7 
Publications .........................................................................................................................233 
7 
References ..................................................................................................235 
8 
Appendices .................................................................................................237 
Appendix 1: Drugs Known to Prolong the QTc Interval .................................................238 


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TABLES AND FIGURES 
Table 1 
Concentrations of Givinostat in Pediatric Studies to Date..............................176 
Table 2 
Expected Exposure by Weight ........................................................................177 
Table 3 
Starting Dose (25 mg BID in Children Who Weigh 20–49 kg and 37.5 mg 
BID in Children Who Weigh ≥50 kg)……………………………………177 
Table 4 
Second Dose (50 mg BID in Children Who Weigh 20–49 kg and 75 mg 
BID in Children Who Weigh ≥ 50kg).............................................................178 
Table 5 
Third Dose (75 mg BID in Children Who Weigh 20–49 kg and 100 mg 
BID in Children Who Weigh ≥50 kg).............................................................178 
Table 6 
Simulation Cmax (ng/mL) After Different Oral Doses of Givinostat to 
Patients Weighing 10-70 kg (1200 Simulations for Each Patient Weight).....180 
Table 7 
Simulation AUC0-12 (ng h/mL) after Different Oral Doses of Givinostat to 
Patients Weighing 10-70 kg (1200 Simulations for Each Patient Weight)...181 
Table 8 
Treatment Table – Part 1 and Part 2 ...............................................................186 
Table 9 
Details of Study Treatment .............................................................................192 
Figure 1 
Cohort expansion, Cohort Abandoned and Dose Escalation Safety Rules 
for Part 1 .........................................................................................................197 
Table 10 
Starting Dose:  37.5 mg BID ..........................................................................198 
Table 11 
Starting Dose:  25 mg BID .............................................................................198 
Table 12 
Schedule of Assessments:  Part 1 (Dose Escalation) ......................................201 
Table 13 
Schedule of Assessments:  Part 2 (Proof of Mechanism) ...............................203 
Table 14 
Schedule of Assessments: Extension Phases .................................................205 
Figure 2 
Five-Point Hedonic Scale – Face Depictions..................................................218 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
6MWT 
6-Minute Walk Test
6MWD 
6-Minute Walk Distance
Ab 
Antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma–concentration time curve 
BID 
twice daily 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CL 
clearance 
CL/F 
volume of distribution 
cm 
Centimeter 
Cmax
maximum plasma concentration 
CMV 
Cytomegalovirus 
CPK 
creatine phosphokinase 
CrCl 
creatinine clearance 
CRP 
C-reactive protein
CSA 
cross-sectional area 
CSOM 
Clinical Study Operations Manual 
DMD 
Duchenne muscular dystrophy 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECHO 
Echocardiograph 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
FACS 
fluorescence-activated cell sorting 
FAP 
fibroadipongenic progenitors 
FEV1
forced expiratory volume at 1 second 
FU 
follow up 
FVC 
forced vital capacity 
GI 
Gastrointestinal 
h 
hour 
H&E 
hematoxylin and eosin 
HbeAg 
hepatitis B e antigen 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HDAC 
histone deacetylase 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 


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IgM 
immunoglobulin M 
IL 
interleukin 
IMP 
investigational medicinal product 
ITT 
intent to treat 
JIA 
juvenile idiopathic arthritis 
KA 
absorption rate constant 
kg 
kilogram 
L 
liter 
LDH 
lactate dehydrogenase 
LTBP4 
latent TGFβ binding protein 4 
m 
Meter 
MFA% 
muscle fibers area % 
mg 
Milligram 
miRNA 
micro ribonucleic acid 
mL 
Milliliter 
MRI 
magnetic resonance imaging 
msec 
Millisecond 
MTD 
maximum-tolerated dose 
MuSC 
muscle satellite cells 
ng 
nanogram 
nmol 
nanomole 
NOAEL 
no observed adverse effect level 
NSAA 
North Star Ambulatory Assessment 
PD 
Pharmacodynamic 
PDGFR 
platelet-derived growth factor receptor 
PEF 
peak expiratory flow 
PET 
polyethylene terephthalate 
PFT 
pulmonary function tests 
PK 
Pharmacokinetic 
PUL 
performance of upper limb 
QT 
QT interval 
QTc 
QT interval – corrected 
RBC 
red blood cells 
RD 
recommended dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOJIA 
systemic onset juvenile idiopathic arthritis 
SWI/SNF 
switch/sucrose non-fermentable 
TNF-α 
tumor necrosis factor-alpha 
V/F 
plasma volume 
V2/F 
peripheral volume 
WBC 
white blood cells 
WCT 
Worldwide Clinical Trials 


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1 Introduction 
1.1 Background on Duchenne Muscular Dystrophy 
Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular 
dystrophy, occurring in about 1 of every 3500 male newborns. The disease is inherited as 
an X-linked recessive disorder and is caused by mutation in the dystrophin gene on the 
X chromosome, resulting in dystrophin deficiency. The main function of dystrophin is to 
stabilize and link the muscle fiber cytoskeleton to the membrane. The lack of functional 
dystrophin results in the loss of dystrophin-glycoprotein complex, thereby rendering the 
muscle fibers less resistant to mechanical stress. 
Faulty muscle structure caused by the absence of extracellular or intracellular structural 
proteins results in cell membrane instability, initiating a cascade of deleterious events, 
such as uncontrolled calcium influx, apoptosis and necrosis, inflammation, and 
replacement of muscle with fibrotic tissue and fat (Consalvi S et al. 2011). The clinical 
effect of this deficiency can be dramatic and fatal. 
Patients begin to show symptoms of the disease between the ages of 3 to 5 years 
(Emery AE 2002), which leads to severe muscle wasting and weakness. Patients with 
DMD usually stop walking by about 12 years of age and usually experience fatal 
respiratory failure in their early 20s (Eagle M et al. 2002). 
Treatment with steroids is currently used in a large portion of DMD patients, but it is 
palliative and complicated by serious side effects. No current treatment interrupts or 
halts the progression of DMD. 
By acting on muscle resident stem cells, histone deacetylase (HDAC) inhibitors increase 
skeletal myogenesis in vitro and in vivo (Iezzi S et al. 2002) and restore normal muscle 
morphology and increase the size and strength of myofibers in mdx mice a preclinical 
model of DMD (Minetti GC et al. 2006). 
The beneficial potential of the HDAC inhibitor Givinostat in the treatment of DMD has 
been studied in the mdx mouse disease model. In this model, long-term exposure to 
Givinostat effectively countered disease progression. In particular, Givinostat dose and 
concentration dependently increased the cross-sectional area of myofibers, decreased the 
cellular (inflammatory) infiltrate and prevented the formation of fibrotic scars. 
Pharmacokinetic (PK)–pharmacodynamic (PD) analysis suggests that exposures of 
Givinostat of 600 h*nmol/L are required to exert the beneficial effect. 
1.2 Background on Givinostat 
Givinostat has been tested in long-term repeat-dose toxicology studies in rats, dogs, and 
monkeys. The main adverse effects (e.g., reduction in white blood cells [WBC], reduced 


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thymus weight, bone marrow atrophy, and liver and possibly kidney function 
impairments) were observed only at high doses of drug. Most of these changes returned 
to baseline levels upon drug discontinuation or a trend toward resolution was seen at the 
end of the recovery period. 
In the rat, Givinostat was administered consecutively up to 26 weeks where the no 
observed adverse effect level (NOAEL) was 10 mg/kg/day. There were no side effects in 
dogs administered 12.5 mg/kg/day of Givinostat for 4 consecutive weeks. However, 
liquid feces were found in the animals receiving higher doses with consequent reduced 
absorption. For these reasons, the dog species was not further considered and general 
toxicology studies in non-rodents were continued in the monkey. In the monkey, 
Givinostat was well tolerated and similar toxicity profiles were seen in the 4-, 13-, and 
39- week studies, where the NOAELs were 10 mg/kg, 10 mg/kg, and 12 mg/kg,
respectively.
Givinostat had a favorable safety pharmacology profile. There was no observation of 
embryo-fetal toxicity in rats and in rabbits, or potential genotoxicity in mammalian cells 
in vitro and in vivo. The only sign of a possible adverse effect was seen at relatively high 
doses (>1µM) of Givinostat in vitro but not in vivo in cardiovascular safety 
pharmacology studies. 
Givinostat was given by oral gavage to juvenile rats starting at the age of weaning 
(25 days of age) at 4 different dosages: 0, 20, 60, or 180 mg/kg/day once-a day for 
4 weeks. Givinostat was well tolerated at the dosage up to 60 mg/kg/day. 
Treatment-related changes were detected at 180 mg/kg/day in the adrenals, bone marrow, 
liver, and spleen. The changes had resolved or showed partial recovery at the end of the 
study (mature animals). The NOAEL was set at 60 mg/kg/day. 
Givinostat has been tested in a number of clinical studies that enrolled for the following 
major indications: inflammation and oncology. In particular: 
•
105 healthy volunteers have been enrolled in 3 phase 1 studies (single dose,
repeat dose, and food interaction); 18 were treated with placebo.
•
422 patients have been enrolled in the phase 1–2 studies; 62 were treated with
placebo. Of these, 33 were children with systemic onset juvenile idiopathic
arthritis (SOJIA) or polyarticular juvenile idiopathic arthritis (JIA) treated
with Givinostat at the following doses: 0.50 mg/kg twice daily (BID) and
0.75 mg/kg BID for up to 3 months.
Givinostat has shown preliminary signs of clinical activity in subjects with SOJIA 
(study DSC/05/2357/19) as well as myeloproliferative disease (study DSC/07/2357/28). 


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The maximum-administered dose was a single dose of 600 mg in healthy volunteers and 
up to 400 mg once per week in subjects with multiple myeloma. Doses up to 
approximately 100 mg BID were generally well tolerated. The most common adverse 
events (AEs) observed were thrombocytopenia as well as gastrointestinal (GI) toxicities. 
AEs were generally mild to moderate and reversible upon discontinuation of study drug. 
In particular, thrombocytopenia appeared in just a few days of treatment at 
thrombocytopenic doses and reverted to normal values within a few days/weeks after 
treatment discontinuation. Twenty-one AEs of QT interval – corrected (QTc) 
prolongations have been reported. In one case, the electrocardiogram (ECG) was 
manually read and the QTc value determined was normal, thus it was considered a 
spurious finding. Eight AEs of QTc prolongation were reported in subjects with chronic 
myeloproliferative diseases (study DSC/07/2357/28), 6 in subjects with Hodgkin’s 
lymphoma (study DSC/07/2357/26), 2 in subjects with polycythemia vera (study 
DSC/08/2357/38), 2 in subjects with acute myeloid leukemia (study DSC/05/2357/15), 
1 in a subject with Crohn’s disease (study DSC/06/2357/23), and 1 in a subject with 
SOJIA (study DSC/05/2357/19). No clear dose dependence was observed. In the 
2 studies in healthy volunteers (DM/00/2357/01 and DM/00/2357/03) where ECG and 
QTc measurements were systematically assessed, no episode of QTc prolongation was 
observed. Details of each trial are included in the Investigator’s Brochure (2012). 
1.3 Rationale 
1.3.1 
Study Rationale 
Different studies suggest that histone acetylation has a significant role in the pathogenesis 
of DMD and that inhibition of HDAC leads to a reduction in inflammation and fibrosis 
and an increase in muscle regeneration. In particular, two preclinical studies with 
Givinostat have shown that chronic treatment with this compound in a DMD mouse 
model (mdx mouse) determines a dose- and concentration-dependent reduction in 
inflammation and fibrosis and an increase in muscle regeneration, which in turn 
determines an improvement in muscular function. 
The primary objective of this study is to replicate these findings in humans. In particular, 
the primary objective of the study will be to demonstrate that Givinostat stimulates 
muscle regeneration by detecting an increase in the fraction of muscle biopsy occupied 
by muscle when comparing the muscle biopsy at study end versus the muscle biopsy at 
study start. Other objectives of the study will be to evaluate the effects of Givinostat on 
other histological parameters (inflammation, necrosis, fibrosis), on functional parameters 
such as the 6-Minute Walk Test (6MWT), and on magnetic resonance imaging (MRI) and 
biomarkers. Finally, the safety and tolerability and pharmacokinetics of Givinostat will 
also be assessed. 


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As the currently used dose of Givinostat is considered not sufficient to exert the expected 
positive effects (see dose rationale), the first part of the study will be used to escalate the 
dose to one yielding exposures expected to be efficacious and which are well tolerated. 
To ensure an adequate assessment of the safety, efficacy, and PK parameters in this 
study, and considering the expected mechanism of action of Givinostat in DMD, 
ambulant children aged 7 to <11 years, who have been on a stable steroid dose for at least 
the last 6 months and who have a 6MWT assessment performed at least 6 months before 
screening will be selected for participation in this study. 
1.3.2 
Dose Rationale – Part 1 and Part 2 
Until now, Givinostat has been administered to 87 healthy volunteers and 360 patients 
enrolled in 17 phase 1–2 studies. Of the 360 patients, 33 were children/adolescents 
treated with either Givinostat 0.5 mg/kg BID or 0.75 mg/kg BID. The maximum dose 
was a single dose of 600 mg in healthy volunteers and up to 400 mg once per week in 
subjects with multiple myeloma. Subjects have been treated in clinical trials with daily 
doses of Givinostat for up to 6 months. Moreover, 31 patients with myeloproliferative 
diseases enrolled in a compassionate use program have been receiving Givinostat at doses 
up to 50 mg 3 x daily for a period up to 4 years and 1 adolescent with JIA enrolled in the 
extension study has been receiving Givinostat 0.75 mg/kg since December 2011. 
Doses of Givinostat up to approximately 100 mg BID have generally been well tolerated. 
At higher doses of Givinostat, transient reductions hematological parameters (particularly 
platelets) and diarrhoea as well as nausea and vomiting were observed. AEs were 
generally mild to moderate and reversible upon discontinuation of study drug 
(Investigator’s Brochure 2012). In particular, thrombocytopenia appeared in just a few 
days of treatment at thrombocytopenic doses and reverted to normal values within a few 
days/weeks after treatment discontinuation. Twenty AEs of QTc prolongation have been 
reported and confirmed in the clinical studies. Of these, only 1 episode of QTc 
prolongation was observed in a pediatric study. No episode of QTc prolongation was 
observed in the 2 studies of Givinostat in healthy volunteers where ECG and QTc 
measurements were systematically assessed. 
A population PK analysis was conducted using the PK data collected so far in all the 
clinical trials where PK samples were collected. In particular, PK data from 7 studies 
have been included (single- and repeat-dose studies in healthy volunteers, 2 studies in 
Crohn’s disease subjects, 1 study in subjects with SOJIA, 1 study in subjects with JIA, 
and 1 study in subjects with psoriasis) for a total of 226 subjects. Givinostat 
pharmacokinetics were described using a 2-compartment model with first order 
absorption showing clearance (CL/F)=118 L/h, plasma volume (V/F)=155 L, peripheral 
volume (V2/F)=514 L, and absorption rate constant (KA)=0.243 h-1. The covariate 


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screening indicated weight and steroid co-administration as the most significant 
covariates on clearance (CL) parameters (no gender, formulation, age, or healthy 
volunteer vs. patient differences). However, the covariates effects were considered 
limited on pharmacokinetics (i.e., the presence of steroids was found to determine an 
increase of <30% in the population CL, and an increase of 10 kg was found to determine 
an increase of 10%–15% in CL). 
The mean exposure in healthy volunteers treated with Givinostat 100 mg BID was 
1083 ng*h/mL (area under the plasma–concentration time curve from 0 to 12 hours 
[AUC0-12]) and 181.5 ng/mL (maximum plasma concentration [Cmax]). The estimated 
AUC0-12 and Cmax in children treated with Givinostat are reported in Table 1. 
Table 1 
Concentrations of Givinostat in Pediatric Studies to Date 
Disease State 
AUC0-12 (ng*h/mL) 
Cmax (ng/mL) 
SOJIA 
Median 
5th percentile 
95th percentile 
234.0 
126.4 
428.7 
31.5 
20.0 
55.3 
JIA 
Median 
5th percentile 
95th percentile 
206.4 
109.0 
492.7 
31.0 
14.9 
69.8 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; Cmax=maximum plasma 
concentration; SOJIA=systemic onset juvenile idiopathic arthritis; JIA=juvenile idiopathic arthritis. 
Preclinical studies in a mouse model of DMD (mdx mouse model) suggest that daily 
exposures (AUC0-24) of 600 nmol*h/L, i.e., approximately 300 ng*h/mL, are needed to 
exert beneficial histological and functional effects. As shown in Table 1, doses higher 
than those administered so far to children are needed to ensure that the majority of 
children are treated with doses that allow such exposures. Therefore, the first part of the 
study will escalate the dose to a maximum tolerated dose (MTD) that will then be 
recommended for the second part of the study. 
Because of the limited effect of weight on CL, only 2 dose adjustments will be applied as 
follows: children who weigh 20–49 kg: 25 mg BID; children who weigh ≥50 kg: 
37.5 mg BID. 
The starting dose will be 25 mg BID in children who weigh 20–49 kg and 37.5 mg BID 
in children who weigh ≥50 kg. Table 2 reports the expected median, 5th, and 95th 
percentile exposures in children weighing 20, 30, 40, 50, and 60 kg. 


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Table 2 
Expected Exposure by Weight 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
263 
223 
203 
283 
257 
5th percentile 
127 
107 
97 
132 
123 
95th percentile 
564 
466 
426 
603 
542 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours 
Expected exposures fall within the range of exposures safely tested in children with 
SOJIA and JIA and well within the exposures in adults treated with 100 mg BID. 
If safety and tolerability of the starting dose is confirmed in the first group of children 
treated, the dose will be escalated in the second group of children enrolled. The children 
treated at the lower dose will also be switched to the escalated dose level. Similarly, if 
the safety and tolerability of the second dose level is confirmed, the dose will be further 
escalated in the third group of children enrolled, and the children treated at the second 
dose level will be switched to the higher dose level. 
Dose escalation will be decided based on the safety and tolerability profile observed, and 
on the PK analyses in the children treated until a dose-escalation decision is made.  In 
any case, each dose escalation should not yield more than a doubling of the expected 
exposure. An example of dose escalation based on the data available so far is provided in 
Table 3, Table 4, and Table 5, which show the starting, second, and third dose, 
respectively. 
Table 3 
Starting Dose (25 mg BID in Children Who Weigh 20–49 kg and 
37.5 mg BID in Children Who Weigh ≥50 kg) 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
263 
223 
203 
283 
257 
5th percentile 
127 
107 
97 
132 
123 
95th percentile 
564 
466 
426 
603 
542 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; BID=twice daily. 


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Table 4 
Second Dose (50 mg BID in Children Who Weigh 20–49 kg and 75 mg 
BID in Children Who Weigh ≥ 50kg) 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
527 
445 
407 
566 
515 
5th percentile 
254 
215 
194 
263 
246 
95th percentile 
1129 
932 
852 
1205 
1084 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; BID=twice daily. 
Table 5 
Third Dose (75 mg BID in Children Who Weigh 20–49 kg and 100 mg 
BID in Children Who Weigh ≥50 kg) 
Weight (kg) 
20 
30 
40 
50 
60 
AUC0-12 (ng h/mL) 
Median 
790 
668 
610 
755 
686 
5th percentile 
381 
322 
290 
351 
329 
95th percentile 
1693 
1398 
1278 
1607 
1446 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; BID=twice daily. 
Once all 20 children enrolled in Part 1 of the study have been treated for at least 2 weeks, 
the review team will decide the recommended dose (RD) to be used in Part 2 based on 
the safety and tolerability profile observed and on the PK analyses. 
All children will then switch to the RD, which will be administered for the subsequent 
12 months of the study (Part 2). 
As of July 2013, the safety and tolerability assessments of Givinostat from Part 1 of the 
study were completed and the Safety Review Team determined the RD to be 37.5 mg 
BID. The Safety Review Team also recommended performing additional platelet count 
assessments every week to maintain a stricter control and to monitor this parameter for 
safety reasons. 
In addition, as of September 2013, after assessing approximately 2 months of data on the 
platelet counts, the Safety Review Team decided to reduce the RD in subjects with 
platelet count ≤150 x 109/L to 25-mg BID Givinostat. Subjects with platelet count 
>150 x 109/L will continue on 37.5-mg Givinostat.


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This clinical study has been designed to comply with the Good Clinical Practice 
guidelines. 
1.3.3 
Dose Rationale - Extension Phases 
Extension 1: An extension study phase is foreseen in order to allow the patients to 
continue study treatment at least until the final analysis is performed (Part 2; after 
12 months of treatment). 
All children treated in Part 2 will be asked to continue in the extension phase and if no 
safety concern is raised, they will receive Givinostat at the same ongoing dose (during the 
last visit planned at 12 months) for a maximum of up to an additional 12 months 
(Extension 1). 
Extension 2: A second extension study phase is foreseen because of the positive 
histology results. 
All children treated in Extension 1 will be asked to continue in the extension phase and if 
no safety concern is raised, they will receive Givinostat at the appropriate dose for a 
maximum of up to an additional 12 months. 
A recent PK population analysis was performed with the aim to develop a population PK 
model and support dosing recommendation in DMD clinical development plan (for more 
details, see the IB n. 14 – par 6.3.2.1). 
Pharmacokinetic parameter estimates were used to simulate exposure in children across a 
wide weight range following different doses of Givinostat. The aim was to identify doses 
of the compound that warranted comparable exposures with acceptable efficacy and 
safety profiles. The dose increase of 5 mg was considered feasible in clinical practice of 
the compound. The results are shown in Table 6 and Table 7. 
Extension 3: All children treated in Extension 2 will be asked to continue in the 
extension phase and if no safety concern is raised, they will receive Givinostat at the 
appropriate dose for a maximum of up to an additional 12 months. 


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Table 6 
Simulation Cmax (ng/mL) After Different Oral Doses of Givinostat to 
Patients Weighing 10-70 kg (1200 Simulations for Each Patient 
Weight) 
Dose (mg) BID 
Cmax (ng/mL) 
Weight (kg) 
10 
12.5 
15 
20 
25 
30 
40 
50 
60 
70 
20 
25 
25 
30 
35 
40 
50 
55 
60 
70 
Mean 
74.5 81.2 76.8 84.7 84.9 90.3 
105 
101 
101 
114 
Median 
69.5 74.9 70.4 80.6 77.8 84.5 97.5 94.0 96.3 
106 
Standard deviation 28.5 32.6 30.9 32.0 34.1 35.6 41.7 40.0 38.5 43.4 
CV% 
38.3 40.2 40.2 37.8 40.2 39.4 39.6 39.8 38.0 38.2 
5P 
37.9 39.1 37.7 40.7 42.4 44.5 50.6 50.2 
49 
59.2 
25P 
54.5 57.2 54.7 61.7 60.6 63.7 75.1 72.3 
74 
82.0 
75P 
89.8 99.4 93.6 
102 
103 
111 
128 
121 
122 
139 
95P 
127 
143 
135 
144 
152 
156 
183 
174 
174 
195 
BID=twice daily; Cmax=maximum plasma concentration; CV%=coefficient of variation percent. 
Note: Compound administered as an oral suspension at the doses of 20 (10 kg), 25 (12.5 kg), 25 (15 kg), 
30 (20 kg), 35 (25 kg), 40 (30 kg), 50 (40 kg), 55 mg (50 kg), 60 mg (60 kg) and 70 mg bid (70 kg). 


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Table 7 
Simulation AUC0-12 (ng h/mL) after Different Oral Doses of 
Givinostat to Patients Weighing 10-70 kg (1200 Simulations for Each 
Patient Weight) 
Dose (mg) BID 
AUC0-12  (ng h/mL) 
Weight (kg) 
10 
12.5 
15 
20 
25 
30 
40 
50 
60 
70 
20 
25 
25 
30 
35 
40 
50 
55 
60 
70 
Mean 
595 
624 
571 
598 
562 
579 
627 
588 
572 
600 
Median 
531 
561 
502 
539 
507 
520 
558 
522 
512 
534 
Standard 
deviation 
289 
305 
292 
288 
273 
286 
316 
293 
281 
298 
CV % 
48.6 48.9 51.1 48.2 
48.5 49.4 50.4 
49.9 49.2 
49.6 
5P 
254 
248 
235 
243 
229 
236 
253 
242 
241 
252 
25P 
393 
408 
366 
387 
363 
370 
412 
381 
378 
385 
75P 
738 
769 
693 
752 
687 
717 
780 
722 
708 
743 
95P 
114 
1 
120 
9 
112 
8 
115 
5 
109 
9 
112 
2 
122 
6 
114 
5 
109 
0 
118 
7 
AUC0-12=area under the plasma–concentration time curve from 0 to 12 hours; BID=twice daily; 
CV%=coefficient of variation percent. 
Note: Compound administered as an oral suspension at the doses of 20 (10 kg), 25 (12.5 kg), 25 (15 kg), 
30 (20 kg), 35 (25 kg), 40 (30 kg), 50 (40 kg), 55 (50 kg), 60 (60 kg) and 70 mg BID (70 kg) 
During the Extension 2, the dose administered will be adjusted depending on the weight 
of the child, according the tables above (Table 6 and Table 7). 
2 Study Objectives 
Primary Objective 
The primary objective of this study is as follows: 
•
To establish the histologic effects of Givinostat administered chronically at
the selected daily dose


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Secondary Objectives 
The secondary objectives of this study are as follows: 
•
To establish the effects of Givinostat administered chronically at the selected
daily dose on functional parameters, such as the 6MWT, North Star
Ambulatory Assessment (NSAA), and performance of upper limb (PUL)
•
To establish the safety and tolerability of Givinostat administered chronically
at the selected daily dose in children with DMD
•
To explore the effects of Givinostat administered chronically at the selected
daily dose on parameters such as MRI and biomarkers
•
To explore the acceptability/palatability of the oral suspension
•
To explore whether the effects of Givinostat on disease progression may be
related to the type of DMD mutation (Pane M et al. 2014)
Extension phases: 
The primary objective is to evaluate the safety and tolerability of long-term 
administration of Givinostat administered chronically at the selected daily dose in 
children with DMD. 
The secondary objectives are: 
•
To establish the effects of Givinostat administered chronically at the selected
daily dose on other functional parameters, such as the 6MWT, NSAA, and
PUL (Extension 1, 2, 3)
•
To explore the effects of Givinostat administered chronically at the selected
daily dose on parameters such as MRI (Extension 1)
•
To collect information related to 2 biomarkers, LTBP4 and osteopontin
genotype (at the beginning of Extension 2 only)
•
To collect information related to time to wheelchair and how much time the
children spend in wheelchair (Extension 3 – only for the children that are not
able to complete the 6MWT)
Primary Endpoint 
The primary endpoint of this study is as follows: 
•
Change in the value of muscle fiber area % (MFA%) comparing the histology
biopsies before and after 12 months of treatment with Givinostat


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The primary endpoints of the extension phases are: 
•
Number of children experiencing treatment-emergent AEs and serious adverse
events (SAEs)
•
Type, incidence, and severity of treatment-emergent AEs and SAEs correlated
with dose
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study are as follows: 
•
Change in additional histological endpoints (i.e., cross-sectional area,
inflammation, necrosis, fibrosis, and muscle regeneration) after 12 months of
treatment with Givinostat at the selected daily dose
•
Change in muscular function after 12 months of treatment with Givinostat at
the selected daily dose based on the 6MWT
•
Change in muscular function after 12 months of treatment with Givinostat at
the selected daily dose based on the NSAA
•
Change in muscular function after 12 months of treatment with Givinostat at
the selected daily dose based the PUL
The secondary efficacy endpoints of the extension phases are as follows: 
•
Change of muscular function (including loss of ambulation) after 24, 36, and
52 months of treatment with Givinostat at the selected daily dose based on the
6MWT
•
Change in muscular function after 24, 36, and 52 months of treatment with
Givinostat at the selected daily dose based on the NSAA
•
Change in muscular function after 24, 36, and 52 months of treatment with
Givinostat at the selected daily dose based on the PUL
•
Time to wheelchair and how much time the children spend in wheelchair
(Extension 3 – only for the children that are not able to complete the 6MWT)
Safety Endpoints 
The safety endpoints of this study are as follows: 
•
Number of children experiencing treatment-emergent AEs and SAEs
•
Type, incidence, and severity of treatment-related AEs and SAEs
•
Measures of vital signs, clinical laboratory tests (blood chemistry,
hematology, disease serologies), echocardiographs (ECHOs), pulmonary
function tests (PFTs; forced expiratory volume at 1 second [FEV1], forced
vital capacity [FVC], FEV1/FVC, and peak expiratory flow [PEF])


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(Suárez AA et al. 2002), and 12-lead ECGs. 
Pharmacokinetic Endpoints 
The PK endpoints of this study are as follows: 
•
Individual Givinostat concentrations tabulated by dose cohort along with
descriptive statistics for Part 1 and tabulated along with descriptive statistics
for Part 2.
Exploratory Endpoints 
The exploratory endpoints of this study are as follows: 
•
Change in muscle, fat, and fibrosis content after treatment with Givinostat as
measured by MRI (also evaluated during Extension 1)
•
Change in muscle biomarkers (e.g., miRNA) following treatment with
Givinostat (Part 1 and Part 2 of the study)
•
Evaluation of LTBP4 and osteopontin genotype (at the beginning of
Extension 2 only)
•
PK–PD correlations
•
Evaluation of any correlation between the effects of Givinostat on disease
progression and the type of DMD mutation patients may have in relation to
their disease
3 Investigational Plan 
3.1 Description of Overall Study Design and Plan 
This is a 2-part, phase 2 study to assess the effects of Givinostat on muscle histologic 
parameters and on clinical parameters in ambulant children with DMD. The safety, 
tolerability, and pharmacokinetics of Givinostat will also be assessed. 
Children who assent to participate in this study (if capable of doing so) and whose 
parent/guardian signs the informed consent to participate will undergo pre-study 
screening assessments up to 4 weeks (±2 weeks) before the first scheduled dose of study 
drug. In addition, patients will be asked to share information concerning the type of 
mutation they carry in relation to DMD. 
Approximately 20 children will be enrolled in the study as follows: the first 4 children 
will be treated at a low dose level of Givinostat (25 mg BID in children who weigh 
20-49 kg and 37.5 mg BID in children who weigh ≥50 kg).


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If none of the stopping criteria (see Section 3.3.5 for stopping criteria) are met after 
2 weeks of treatment at the low dose, the review team will determine the escalated dose 
level (i.e., intermediate dose level) to be used for the treatment of an additional 8 children 
who will be treated at the intermediate dose. The 4 children previously treated at the low 
dose level will also be switched to the intermediate dose level. 
If none of the stopping criteria are met after 2 weeks of treatment at the intermediate 
dose, the review team will determine the subsequent escalated dose level to be used for 
the treatment of an additional 8 children who will be treated at the high dose. All 
children treated at the intermediate dose level will be switched to the high dose level. 
Once all 20 children enrolled during the Part 1 of the study have been treated for at least 
2 weeks, the review team will determine the RD to be used in Part 2 based on the safety 
and tolerability profile observed and on the PK analyses. All the children enrolled will 
switch to the RD level, which will be administered for the subsequent 12 months of the 
study (Part 2). 
As of July 2013, the safety and tolerability assessments of Givinostat from Part 1 of the 
study were completed and the Safety Review Team determined the RD to be 37.5 mg 
BID. The Safety Review Team also recommended performing additional platelet count 
assessments every week to maintain a stricter control and to monitor this parameter for 
safety reasons. 
In addition, as of September 2013, after assessing approximately 2 months of data on the 
platelet counts, the Safety Review Team decided to reduce the RD in subjects with 
platelet count ≤150 x 109/L to 25mg BID Givinostat. Subjects with platelet count 
>150 x 109/L will continue on 37.5mg Givinostat.
After the 20 baseline biopsies are collected, an interim analysis aimed at checking the 
real variability of MFA% observed in the study will be implemented, the within-subject 
standard deviation of MFA% will be calculated, and the final sample size will be adjusted 
based on this interim analysis and in particular on the observed standard deviation. A 
conservative approach will be adopted, where the sample size may be increased but not 
decreased. 
The additional children (if any) will be enrolled during Part 2 of the study and will 
receive the RD of Givinostat up to 40 months. 
A treatment table for the study is presented in Table 8. 


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Table 8 
Treatment Table – Part 1 and Part 2 
PART 1 
PART 2 
Treatment Visitc 
Treatment Visitc 
Subject 
1 
2a 
3 
4a
5 
6a
1 
2 
3 
4 
5 
6 
7 
8 
9 
10b 
1–4 
5–12 
13–20 
Additional 
children 
(if any) 
a At the end of Week 2 (Visit 2) at every dose level, a safety check is foreseen. 
b At the end of Month 12, an efficacy analysis on biopsy results and functional tests is foreseen, and a decision 
to consider the study complete or to continue the study for up to another 40 months (extension phases 
[Extension 1, 12 months and Extension 2, 12 months and Extension 3, 16 months]) will be taken. 
c The visits during Part 1 will be performed every 7 days (±1 day); the visits during Part 2 will be performed 
periodically every 1 – 1.5 months (±7 days). 
Legend: 
25 – 37.5 mg BID – low dose level 
Intermediate dose level 
High dose level 
Recommended dose level 
During Part 1 of the study, children will visit the center once a week.  During Part 2 of 
the study, children will visit the study center per the schedule of assessments for a total of 
10 visits, not including follow up. Children may be evaluated more often if necessary for 
safety reasons. Children who discontinue the study drug early will be asked to come in 
for an end-of-study visit within 2 weeks after the last dose of study drug. Children who 
have ongoing AEs at discontinuation will be followed until resolution or stabilization. 
Efficacy will be assessed through changes from baseline in biopsy at 1 year (Part 2) and 
changes from baseline in the 6MWT, PUL, and NSAA at 1 year (Part 2); at 2 years (for 
Extension 1), at 3 years (for Extension 2), and at 4 years (for Extension 3). Exploratory 
efficacy parameters will include changes from baseline in MRI results, PK–PD 
correlations, and measures of miRNA. In addition, exploratory analysis will be 
performed to investigate whether the effects of Givinostat on disease progression may be 
related to the type of DMD mutation. Safety will be assessed by number of children 
experiencing treatment-emergent AEs and SAEs; type, incidence, and severity of 
treatment-emergent AEs and SAEs; and measures of vital signs, clinical laboratory tests 


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(blood chemistry, hematology, disease serologies, and urinalysis), ECHOs, PFTs (FEV1, 
FVC, FEV1/FVC, and PEF), and 12-lead ECGs. 
During Part 1, after 1 week of treatment, blood samples for PK measurements will be 
collected pre-dose in the morning before drug intake and at 1, 2, 4, and 8 hours post-dose. 
PK samples will also be collected during Part 2 of the study. At Visit 2, blood samples 
for PK analysis should be taken pre-dose and between 6 and 8 hours post-dose. At 
Visit 3, blood samples for PK analysis should be collected pre-dose in the morning before 
drug intake and between 0 and 2 hours post-dose. At Visit 4, blood samples for PK 
analysis should be taken pre-dose and between 2 and 4 hours post-dose. At Visit 6, blood 
samples for PK analysis should be taken pre-dose and between 4 and 6 hours post-dose. 
At Visit 10, blood samples for PK analysis should be taken pre-dose and at 1, 2, 4, and 
8 hours post-dose. 
3.1.1 
Extension Phases 
EXTENSION 1 
A first extension phase study treatment is foreseen in order to allow the patients to 
continue study treatment at least until the final analysis is performed (Part 2; after 
12 months of treatment). Part 2 was originally planned with a 12-month study drug 
treatment. At 12 months, an efficacy and safety analysis will be conducted. If the results 
show a positive effect on patients, and no safety concern is raised, then patients will 
continue study treatment for up to another 12 months to evaluate the safety and 
tolerability of long-term administration of Givinostat and to evaluate the effect of 
treatment on muscle function. 
EXTENSION 2 
In February 2015, the results were available and they have shown that the treatment with 
Givinostat significantly increases the amount of muscle in the biopsies and significantly 
reduces the amount of fibrotic tissue. Moreover treatment with Givinostat significantly 
reduces tissue necrosis and fatty replacement, 2 other parameters related to disease 
progression. Function tests have shown overall stability, although the sample size of the 
study is too small to draw definitive conclusions. Finally, the drug was well tolerated. 
Based on these results, a second extension phase is foreseen in order to allow the patients 
to continue a study treatment that supports a beneficial effect of Givinostat in DMD. The 
children on treatment in the Extension 1 will be asked to continue in the Extension 2 and 
will receive Givinostat at the same ongoing dose for a maximum of an additional 
12 months. 


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The patient will receive Givinostat at the same ongoing dose, during the last visit planned 
at 12 months, and will be treated for a maximum of an additional 28 months (Month 40). 
The dose can be reduced or increased according to the dose modification criteria, 
specified below (Section 3.3.5). 
EXTENSION 3 
In February 2015, the results were available and they have shown that the treatment with 
Givinostat significantly increases the amount of muscle in the biopsies and significantly 
reduces the amount of fibrotic tissue. Moreover treatment with Givinostat significantly 
reduces tissue necrosis and fatty replacement, 2 other parameters related to disease 
progression. Function tests have shown overall stability, although the sample size of the 
study is too small to draw definitive conclusions. Finally, the drug was well tolerated. 
Based on these results, a third extension phase is foreseen in order to allow the patients to 
continue a study treatment that supports a beneficial effect of Givinostat in DMD. The 
children on treatment in the Extension 2 will be asked to continue in the Extension 3 and 
will receive Givinostat at the same ongoing dose for a maximum of an 
additional16 months. 
The extension 3 will be additionally extended by 4 months, until the activation of the 
Long Term Safety Study (Study NDSC/14/2357/51 - EUDRACT: 2017-000397-10). 
The patient will receive Givinostat at the same ongoing dose, during the last visit planned 
at 12 months (at PART 2), and will be treated for a maximum of an additional 40 months 
(Month 52). The dose can be reduced or increased according to the dose modification 
criteria, specified below (Section 3.3.5). 
During the extension phases 1 and 2 of the study, children will visit the center every 
2 months, for a total of 6 visits during Extension 1 (from Visit 11 to Visit 16) and a 
further 6 visits for Extension 2 (Visit 17 to Visit 22), and every 4 months during 
Extension 3 for 4 visits (Visit 23 to Visit 26). 
3.2 Selection of Study Population 
This study will enroll approximately 20 ambulatory male children with an established 
diagnosis of DMD who are at least 7 years of age but <11 years of age. Additional 
children could be enrolled in the second part of the study, after the interim evaluation of 
baseline biopsies if the observed variability is higher than the one used for the current 
sample size estimate. Children will be enrolled at approximately 5 study sites in Italy. 
Specific entry criteria are detailed in Section 3.2.1 and Section 3.2.2. 


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3.2.1 
Inclusion Criteria 
Children meeting all of the following inclusion criteria are eligible for inclusion in the 
study: 
1.
Male children aged 7 to <11 years with an immunohistochemical and
molecular diagnosis of DMD.
2.
Parent/guardian has signed the informed consent form and child has assented
to be in the study (if applicable).
3.
Able to complete the 2 screening 6MWTs with a minimal distance of at least
250 m each. In addition, the results of theses 2 tests must be within ±30 m of
each other.
4.
On a stable dose of systemic corticosteroids for at least 6 months.
5.
At least 6 months worth of data on the 6MWT (this will be the “historical”
6MWT). From the moment of the historical 6MWT assessment(s), the child
must not have received any compound that could potentially affect the
6MWT, with the exception of the stable steroid treatment.
6.
A parent/guardian and child can comply with all study evaluations/procedures
and return for all study activities.
3.2.2 
Exclusion Criteria 
Children meeting any of the following exclusion criteria will not be enrolled in the study. 
1.
Initiation of systemic corticosteroid therapy within 6 months prior to the start
of study drug or change in systemic corticosteroid therapy (e.g., initiation,
change in type of drug, dose modification not related to body weight change,
schedule modification, interruption, discontinuation, or re-initiation) within
6 months prior to the start of study drug.
2.
Use of any pharmacologic treatment, other than corticosteroids, that might
have an effect on muscle strength since the time of the historical 6MWT and
in any case within 3 months prior to the start of study treatment (e.g., growth
hormone). Vitamin D, calcium, and integrators will be allowed.
3.
Surgery that might have an effect on muscle strength or function within 3
months before study entry or planned surgery at any time during the study.
4.
Exposure to another investigational drug since the time of the historical
6MWT and in any case within 3 months prior to the start of study treatment.


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5.
History of participation in gene therapy, cell-based therapy or oligonucleotide
therapy.
6.
Presence of other clinically significant disease that in the opinion of the
investigator places the child in unacceptable risk for an adverse outcome or
that could affect study results.
7.
Symptomatic cardiomyopathy or heart failure. If child has a left ventricular
ejection fraction <45% at screening, the investigator should discuss inclusion
of child in the study with the medical monitor.
8.
Inadequate hematological function.
9.
Absolute neutrophil count: <1.5 x 109/L.
10. Platelets: <100 x 109/L.
11. Current or history of liver disease or impairment, including but not limited to
an elevated total bilirubin.
12. Inadequate renal function, as defined by serum creatinine >2 x the upper limit
of normal.
13. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human
immunodeficiency virus at screening
14. A baseline QTc >450 msec, (as the mean of 3 consecutive readings 5 minutes
apart) or history of additional risk factors for torsades de pointes (e.g., heart
failure, hypokalemia, family history of long QT syndrome).
15. Psychiatric illness/social situations rendering the potential child unable to
understand and comply with the study protocol.
3.2.3 
Removal of Children from Therapy or Assessment 
A child will be considered to have completed the study when he completes the 
12- month/end-of-study visit (Visit 10) in Part 2. If a child is discontinued at any time
after entering the study, the investigator will make every effort to see the child and
complete the early termination and follow-up assessments as shown in Section 3.4.10. All
AEs should be followed until the child recovers or his condition stabilizes.
A termination electronic case report form (eCRF) should be completed for every child 
who receives study drug, whether or not the child completes the study. The reason for any 
early discontinuation should be indicated on this form. The primary reason for a child 


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withdrawing prematurely should be selected from the following standard categories of 
early termination: 
•
Adverse Event (Adverse Reaction): Clinical or laboratory events occurred
that, in the medical judgment of the investigator for the best interest of the
child, are grounds for discontinuation. This includes serious adverse events
(SAEs) and non-serious AEs, regardless of relation to study drug.
•
Death: The child died.
•
Withdrawal of Consent: The child or his parent/guardian desired to withdraw
from further participation in the study in the absence of an
investigator-determined medical need to withdraw. If the child or
parent/guardian gave a reason for withdrawing, it should be recorded in the
eCRF.
•
Protocol Violation: The child’s findings or conduct failed to meet the
protocol entry criteria or failed to adhere to the protocol requirements (e.g.,
drug noncompliance, failure to return for defined number of visits). The
violation necessitated premature termination from the study.
•
Lost to Follow-Up: The child stopped coming for visits, and study personnel
were unable to contact the child.
•
Other: The child was terminated for a reason other than those listed above,
such as theft or loss of study drugs or termination of study by sponsor.
The children included in the extension phases will be considered to have completed the 
study when they complete the 12-month end-of-extension study visit (Visit 16) for 
Extension phase 1, the 36-month end-of-extension study visit (Visit 22) for 
Extension phase 2, and the 52-month-end-of-extension study visit (Visit 26) for 
Extension phase 3. If the extension phases are stopped due to negative results of Part 2 or 
the child is discontinued from the study treatment, the child will be asked to attend the 
early termination and follow-up assessments as shown in Section 3.4.6 and 
Section 3.4.10, respectively. 
3.3 Treatments 
3.3.1 
Details of Study Treatment 
Details about study drug are provided in Table 9. 


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Table 9 
Details of Study Treatment 
Givinostat^ 
Drug name 
Givinostat 
Manufacturer 
Italfarmaco S.p.A. 
Dose(s) 
1st  dose level: 
25 mg (children 20–49 kg) 
37.5 mg (children ≥50 kg) 
2nd dose level: 
50 mg (children 20–49 kg) 
75 mg (children ≥ 50 kg)* 
3rd dose level: 
75 mg (children 20–49 kg) 
100 mg (children ≥ 50 kg)* 
Dose frequency 
BID 
Route 
Oral under fed conditions 
Formulation 
Oral suspension and/or capsules 
^Givinostat is used to indicate the whole study drug name Givinostat hydrochloride monohydrate. The 
dosages / concentrations of the study drug are expressed as Givinostat hydrochloride monohydrate. 
* Estimated doses based on current knowledge.
BID=twice daily
3.3.2 
Dosage Schedule 
Study drug will be administered as 2 oral doses daily while the child is in the fed state. 
Children who enroll during Part 1 of the study will receive their assigned dose until the 
RD is determined. They will then receive up to 12 months of treatment with Givinostat 
at the RD. Additional children may be enrolled as needed during Part 2 to reach the 
sample size calculated after the interim analysis. Children who will be included in the 
extension phase, will continue Givinostat up to a total of 48 months of treatment. The 
RD should be reduced in case of platelet count ≤150 x 109/L as described in 
Section 3.3.5.1. 


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3.3.3 
Treatment Assignment 
All children will receive study drug. Children enrolled in Part 1 of the study will start to 
take either the low, intermediate, or high dose, depending on the needs of the study at the 
time of enrollment and they will switch to the RD when the review team decide that this 
dose is safe (see Table 8). 
When the safety review team has determined the RD, all children currently on study drug 
will be switched to that dose (the RD), and Part 2 of the study will commence. All 
children who enroll during Part 2 (if applicable) of the study will be given the RD of 
Givinostat. 
Children who will be included in the extension phases will be treated at the same ongoing 
dose during the last visit planned at 12 months and will be treated for a maximum of an 
additional 40 months (Month 52). During Extension 2 and Extension 3, the dose will be 
adjusted based on the weight of the children. 
3.3.4 
Drug Packaging, Labeling, Storage, Dispensing, Investigational Medicinal Product 
Accountability, and Blinding 
Drug Packaging - Oral Suspension 
The primary packaging will consist of an amber plastic bottle containing the suspension. 
The secondary packaging will be a carton box containing 1 amber bottle and a syringe 
dosing system for dispensing the suspension. 
Drug Packaging - Capsules 
Capsules will be supplied as 50 mg and 25 mg hard gelatin capsules for oral 
administration in white plastic bottles containing 30 capsules each. 
Labeling 
The primary and secondary labels will show all the information requested according to 
the Annex 13 of the Good Manufacturing Practice. Bottles containing Givinostat will be 
labeled in local language (i.e., Italian). 
Storage 
The investigational medicinal product (IMP; Givinostat) will be stored at Italfarmaco until 
distribution to the investigational sites. The investigational site will store the IMP under 
the conditions specified in the label (i.e., 5 ± 3°C for the oral suspension and <30°C for 
the capsules), ensuring that it is not accessible to unauthorized persons until it is 
dispensed to the child’s parents/legal guardians. 


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Dispensing 
The investigational site will be supplied initially with a congruous number of suspension 
bottles and capsule bottles, in order to have sufficient supply of study drug to treat the 
children who are enrolled in the study. 
All IMP supplies are to be used only for this protocol and for no other purpose. 
The investigator will be responsible for the delivery of IMP to the child’s parents/legal 
guardians according to the protocol. 
Children will be administered the IMP on an outpatient basis. 
At each scheduled visit, the investigator will supply the children with the appropriate 
number of suspension bottles and/or capsules bottles, sufficient to cover the treatment 
until the following visit (i.e., 1 week of treatment during Part 1 of the study and 1 to 
1.5 months, during Part 2 of the study). 
Italfarmaco will provide to the investigator a table with volume of suspension and/or 
number of capsules to be administered according to body weight and dose level. 
The investigator will provide to the child’s parent/legal guardian written instruction on 
the dosage and corresponding volume in milliliters of suspension and/or number of 
capsules to be taken at each administration. Refer to the relevant Clinical Study 
Operations Manual (CSOM) for more detailed information. 
For the extension phases (Extension 1 [12 months], Extension 2 [12 months], and 
Extension 3 [16 months]), at each scheduled visit, the investigator will supply the 
children with the appropriate number of suspension bottles sufficient to cover the 
treatment for 2 months during Extensions 1 and 2 and every 4 months during 
Extension 3. 
Blinding 
Not applicable. This is an open-label study. 
Emergency Procedure for Unblinding 
Not applicable. This is an open-label study. 


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3.3.5 
Dose Modifications 
3.3.5.1 
Child Stopping and Dose Reduction Safety Rules 
Permanent Stopping Rule 
Study drug should be permanently stopped if any of the following occur: 
•
Severe diarrhea (i.e., increase of ≥7 stools per day)
•
Any drug-related SAE
•
QTc >500 msec
•
Platelets ≤50 x 109/L
Temporary Stopping and Dose Reduction Safety Rule 
Study drug should be temporarily stopped if any of the following occur: 
•
Platelets ≤75 x 109/L but >50 x 109/L
•
Moderate diarrhea (i.e., increase of 4 to 6 stools per day)
Study drug may be resumed at a reduced dose level once the event resolves. Such a dose 
reduction can happen only once per child. The treatment can be temporarily interrupted 
for a maximum of 4 weeks. If the child has not recovered from the AE after this period, 
the treatment should be permanently discontinued. 
If a child has a medical event not necessarily drug related that requires interruption of 
study drug dosing for >4 weeks, the review team will determine if the child may resume 
study drug treatment. 
Cohort Expansion Safety Rules 
The review team can decide to expand the first cohort of children and enroll additional 
4 children (for a total of 8 children treated at the first dose level), on the basis of safety, 
tolerability, and PK results in the children treated in that cohort, according to but not 
limited to the following rules: 
•
If 1 child experiences any type of stopping criterion (as defined in the permanent
and temporary stopping rules), or
•
If 2 children experience different types of stopping criterion (e.g., 1 child
experiences hematological toxicity and another child experiences GI toxicity).


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3.3.5.2 
Cohort Abandoned Safety Rules 
The review team can also decide to abandon a given dose level on the basis of safety, 
tolerability and PK results in the children treated at that dose level, according to but not 
limited to the following rules: 
•
If >2 children experience any type of stopping criterion, or
•
If ≥2 or more children experience the same type of stopping criterion
3.3.5.3 
Cohort Dose Escalation Safety Rules 
During Part 1 of the study, each child will receive study drug at a specific dose level. 
Once the first 4 children have been treated for at least 2 weeks, the review team will 
examine safety and tolerability data and PK results and decide if the children can be 
switched to the escalated dose level and if the second group of children can start the 
treatment at the escalated dose level. 
After a further 2 weeks, the review team will decide if the already treated children at the 
lower and intermediate dose levels can switch to the highest dose and if the third and last 
group of children can start the treatment at the highest dose level. 
The children should be switched to the escalated dose level (i.e., intermediate or high 
dose level) only if no or only 1 stopping criterion per dose level occurred. 
For more details, see Figure 1. 
3.3.5.4 
Study Stopping Safety Rules 
If 2 or more stopping criteria occur in the lower dose, the study will be temporarily 
stopped to allow a reassessment of the risks and benefits of the compound. 


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Figure 1 
Cohort expansion, Cohort Abandoned and Dose Escalation Safety 
Rules for Part 1 
SC=stopping criterion, as defined under permanent and temporary stopping rules. 
The review team will include: the Principal Investigators, the Study Chair, the Medical 
Monitor, and other Italfarmaco representatives. 
Dose Increase Rule – Extension 2 and Extension 3 
Study drug should be increased if the following occur: 
•
Weight gain
And
•
Platelets >150 x 109/L in the last 4 months of treatment;
•
No severe drug-related AEs occurred;
•
No drug-related SAE occurred.
The dose should be increased only after the discussion of the data and approval by the 
Medical Monitor, according to Table 10 and Table 11, below. 
0 SC 
YES 
GO to the escalated dose level 
3 or more 
SC 
YES 
CLOSE the dose level  
N 
N  
N 
YES, 2 SC of a different type 
2 SC 
YES, 2 SC of the same type 
YES 
EXPAND the dose level to 8 
children (if applicable, i.e., low 
dose level) or ESCALATE to 
next dose level 
CLOSE the dose level 
1 SC 
EXPAND the dose level to 8 
children (if applicable, i.e., low 
dose level) or ESCALATE to 
next dose level 


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Table 10 
Starting Dose: 37.5 mg BID 
Starting Dose – Extension 2: 37.5 mg BID 
Weight (Kg) 
20 
25 
30 
40 
50 
60 
70 
Dose (BID) 
40 mg 
50 mg 
55 mg 
60 mg 
70 mg 
BID=twice daily. 
Table 11 
Starting Dose: 25 mg BID 
Starting Dose – Extension 2: 25 mg BID 
Weight (Kg) 
20 
25 
30 
40 
50 
60 
70 
Dose (BID) 
27 mg 
33 mg 
37 mg 
40 mg 
47 mg 
BID=twice daily. 
3.3.6 
Treatment Compliance and IMP Accountability 
At each visit, the child’s parents/legal guardians will bring back to the study site all the 
bottles previously received (used, partially used, and unused) and receive a new supply of 
the IMP. 
All unused IMP will be not re-dispensed by the investigator to another child. 
The investigator will maintain accurate records of the disposition of all IMP received, 
distributed to children (including date and time), and accidentally lost or destroyed. 
When dispensing the bottles to the children, the investigator will attach the relevant 
tear-off label to the relevant form. 
Oral Suspension Accountability 
The investigator will count the bottles of suspension used and empty, partially used and 
unused and insert this information in the Drug Accountability Form and in the eCRF. 
Capsule Accountability 
The investigator will count the capsules unused for each bottle and insert the number in 
the Drug Accountability Form and in the eCRF. 
Periodically throughout and at the conclusion of the study, a representative of Italfarmaco 
S.p.A. or its delegate will conduct an inventory of all study drug supplies and the bottles
of oral suspension and/or capsules used, partially used, and unused will be destroyed at
the site, if possible, or sent back to Italfarmaco.
Missed doses are not to be recovered and they should be recorded in the eCRF and in the 
Drug Accountability Form, specifying the reason for any missed dose. 


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For more detailed procedures, please refer to the relevant CSOM. 
3.3.7 
Prior and Concomitant Illnesses and Treatments 
Prior and Concomitant Illnesses 
Investigators should document all significant illnesses that the child has experienced 
within 6 months of screening. Additional illnesses present at the time informed consent 
is given are to be regarded as concomitant illnesses. Illnesses first occurring or detected 
during the study and/or worsening of a concomitant illness during the study are to be 
documented as AEs in the eCRF. 
Prior and Concomitant Treatments 
Prior treatments, defined as those taken within 6 months prior to screening, should be 
recorded in the eCRF as prior medications. 
Concomitant treatments are defined as treatments taken after study drug administration. 
Children should be on stable systemic corticosteroid therapy for at least 6 months prior to 
initiation of study drug. That is, there have been no changes in systemic corticosteroid 
therapy (e.g., initiation, change in type of drug, dose modification not related to body 
weight change, schedule modification, interruption, discontinuation, or re-initiation) 
during the previous 6 months. 
Supportive treatments, such as anti-emetics, anti-diarrheals, anti-pyretics, anti-allergics, 
analgesics, and antibiotics are allowed. 
Use of Vitamin D, calcium and integrators if clinically indicated before enrolment and for 
duration of the trial are allowed. 
The following medications are prohibited prior to (as noted below) and during study 
treatment: 
•
Other investigational agents within 3 months of start of study drug, since time
historical 6MWT data was obtained, or while on study
•
Prior gene therapy or cell-based therapy or oligonucleotide therapy prior to study
treatment or while on study
•
Any pharmacologic treatments (other than stable doses of corticosteroids) that
might have an effect on muscle strength since the time of the historical 6MWT
and in any case within 3 months prior to the start of study treatment (e.g., growth
hormone) or while on study
•
Drugs that prolong the QTc interval (see Appendix 1: Drugs Known to Prolong
the QTc Interval)


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3.4 Assessments 
3.4.1 
Schedule of Assessments 
The procedures to be performed during the study are outlined in the Schedule of 
Assessments (Table 12, Table 13, and Table 14). A detailed description of each 
assessment may be found in Section 3.4.2. 


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Table 12 
Schedule of Assessments: Part 1 (Dose Escalation) 
Assessment 
Screen/ 
Pre-Studya
Part 1 (Approximately 20 Children) 
Week 
-4 (±2 weeks)
0 
1 
2 
3 
4 
5 
Visit (1-day window) 
0 
1 
2 
3 
4 
5 
6 
Informed consent and 
assent 
X 
Medical history/ 
eligibility 
X 
Concomitant 
medications 
Xb
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
12-lead ECGc
X 
X 
X 
X 
X 
X 
X 
ECHOc 
X 
PFTs (FEV1, FVC, 
FEV1/FVC)c 
X 
Clinical laboratory 
testsc,d 
X 
X 
X 
X 
X 
X 
X 
Urinalysisb,c 
X 
X 
X 
X 
X 
X 
X 
miRNA 
X 
Serologye
X 
Quality of Life test 
X 
Muscle evaluations 
(6MWTf, NSAAg, 
PULg) 
X 
Muscle biopsy 
X 
MRI 
Xi 
PK assessmenth 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Study drug 
administration 
X 
X 
X 
X 
X 
X 
6MWT=6-Minute Walk Test; CMV=cytomegalovirus; EBV=Epstein Barr virus; ECG=electrocardiogram; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; MRI=magnetic resonance imaging; 
NSAA=North Star Ambulatory assessment; PFTs=pulmonary function tests; PK=pharmacokinetic. 
a During the pre-study visit, historical function data (from 6 months before the pre-study visit) will be 
collected. 
b Obtain prior medications at screening as well. 
c To be performed more frequently, if clinically indicated. 
d The following laboratory parameters will be assessed: hematology: RBC, hemoglobin, hematocrit, WBC 
with differential, platelets, and abnormal cells; blood chemistry: total bilirubin, alkaline phosphatase, 
amylase, ALT, AST, LDH, CRP, creatine kinase, total protein, albumin, uric acid, sodium, potassium, 
chloride, calcium, glucose, creatinine, BUN, and CrCl (CrCl will be calculated by the Cockcroft and Gault 
formula); urinalysis: pH, specific gravity, protein, glucose, ketones, cytology, and myoglobin. 
e The following serology tests will be conducted: ELISA for HIV-Ab, HCV-Ab, HbsAg, HbeAg, 
anti-EBV, and anti-CMV IgM. 


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f During the pre-study visit, the historical function data relevant to 6MWTs will be collected: (1) result 
from 6MWT performed at least 6 months before the pre-study visit, and (2) result from 2 6MWT 
performed within 4 weeks prior to treatment start will be necessary and inserted into the eCRF. 
g During the pre-study visit, the functional data relevant to the NSAA and PUL will be collected: results 
performed within 4 weeks prior to treatment start will be necessary and inserted into the eCRF. 
h After 1 week of treatment, blood samples for PK analysis should be collected pre-dose in the morning 
before drug intake and at 1, 2, 4, and 8 hours post-dose. It is important to record the time of PK 
assessments and the time of the last drug intake in the evening before the PK assessment. 
i Obtain an MRI of muscle (initially on the muscles of the lower limb and, if possible, on the muscles of the 
upper limb). MRI does not need to be repeated if obtained within 4 ± 2 weeks prior to the start of 
treatment. 


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Table 13 
Schedule of Assessments: Part 2 (Proof of Mechanism) 
Assessment 
Part 2 (All Children)j
12/ 
EOS Visiti 
Month of Study: 
0 
1 
2 
3 
4.5 
6 
7.5 
9 
10.5 
12 
Visit (1 week window) 
1a
2 
3 
4 
5 
6 
7 
8 
9 
10 
Informed Consent and 
assent 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGc
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECHOc 
X 
PFTs (FEV1, FVC, 
FEV1/FVC, PEF)c 
X 
Clinical laboratory 
testsc,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisc,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serologye
Quality of life test 
X 
Acceptability/ 
Palatability evaluation 
X 
X 
Muscle evaluations 
(6MWTf, NSAAg, 
PULg) 
X 
X 
X 
X 
Muscle biopsy 
X 
MRI 
X 
miRNA 
X 
X 
X 
X 
PK assessmenth 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6MWT=6-Minute Walk Test; CMV=cytomegalovirus; EBV=Epstein Barr virus; ECG=electrocardiogram; 
EOS=end of study; HCV=hepatitis C virus; HIV=human immunodeficiency virus; MRI=magnetic 
resonance imaging; PEF=peak expiratory flow; NSAA=North Star Ambulatory assessment; 
PK=pharmacokinetic. 
Note: A subject may return for an unscheduled visit at the discretion of Investigator to undergo additional 
safety evaluations (i.e., laboratory re-testing, AE assessments), or for additional medical evaluations. 
Platelet count may be assessed at an unscheduled visit if deemed necessary by the Investigator. 
The Safety Review Team recommended performing additional platelet count assessment each week, other 
than the scheduled Part 2 assessments, to maintain a strict control and monitor this parameter for safety 
reasons. 


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a Children newly enrolled in Part 2 have to perform the screening visit (see Table 8 – screening/pre-study). 
b Obtain prior medications at screening as well. 
c To be performed more frequently, if clinically indicated. 
d The following laboratory parameters will be assessed: Hematology: RBC, hemoglobin, hematocrit, WBC 
with differential, platelets, ANC, and abnormal cells; Blood chemistry: total bilirubin, alkaline phosphatase, 
amylase, ALT, AST, LDH, CRP, creatine kinase, total protein, albumin, uric acid, sodium, potassium, 
chloride, calcium, glucose, creatinine, BUN, and CrCl (CrCl will be calculated by the Cockcroft and Gault 
formula). Urinalysis: pH, specific gravity, protein, glucose, ketones, cytology, and myoglobin 
e The following serology tests will be conducted: ELISA for HIV-Ab, HCV-Ab, HbsAg, HbeAg, 
anti-EBV, and anti-CMV IgM. 
f During the pre-study visit, the historical function data relevant to 3 6MWTs will be collected: (1) result 
from 6MWT performed at least 6 months before the pre-study visit, and (2) result from 6MWT performed 
within 4 ± 2 weeks prior to treatment start will be necessary and inserted into the eCRF. 
g During the pre-study visit, the functional data relevant to the NSAA and PUL will be collected: results 
performed within 4 ± 2 weeks prior to treatment start will be necessary and inserted into the eCRF. 
h At Visit 2, blood samples for PK analysis should be taken pre-dose and between 6 and 8 hours post-dose. 
At Visit 3, blood samples for PK analysis should be collected pre-dose in the morning before drug intake 
and between 0 and 2 hours post-dose. At Visit 4, blood samples for PK analysis should be taken pre-dose 
and between 2 and 4 hours post-dose. At Visit 6, blood samples for PK analysis should be taken pre-dose 
and between 4 and 6 hours post-dose. At Visit 10, blood samples for PK analysis should be taken pre-dose 
and at 1, 2, 4, and 8 hours post-dose. It is important to record the time of PK assessments. 
i Children who discontinue participation prior to completion the study should perform the Early 
Termination Visit within 2 weeks after the last drug intake. For the assessments to be performed, see 
“12/EOS visit.” 
j Once all 20 children enrolled during the Part 1 of the study have been treated for at least 2 weeks, the 
review team will determine the RD to be used in Part 2 based on the safety and tolerability profile observed 
and on the PK analyses. All the children enrolled will switch to the RD level, which will be administered 
for the subsequent 12 months of the study (Part 2). 


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Table 14 Schedule of Assessments: Extension Phases 
Assessment 
Extension Phase 1 
Extension Phase 2 
Extension Phase 3 
Months 
14 
16 
18 
20 
22 
24/ 
EOSc
FU* 
26 
28 
30 
32 
34 
36/ 
EOSc
FU* 
40 
44 
48 
52/ 
EOSc
FU 
Visit N. 
(1-week window for V11-V24; 
1 month window for V25 and 
V26) 
11 
12 
13 
14 
15 
16 
NA 
17* 
* 
18 
19 
20 
21 
22 
NA 
23 
24 
25 
26 
NA 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGa
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECHOa 
X 
X 
X 
PFTs (FEV1, FVC, FEV1/FVC, 
PEF)a
X 
X 
X 
Clinical laboratory testsa,b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisa,b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xd 
Xd 
Xd 
Xd 
Xd
Quality of life test 
X 
X 
X 
Muscle evaluations (6MWT, 
NSAA, PUL) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; 6MWT=6-Minute Walk Test; ECG=electrocardiogram; EOS=end of study; FEV1= forced expiratory volume at 1 second; FU=follow up; FVC= forced vital 
capacity; MRI=magnetic resonance imaging; NA=Not applicable; NSAA=North Star Ambulatory assessment; PEF=peak expiratory flow; PFT=pulmonary function test; PUL= 
performance of upper limb 


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* To be performed only if the child does not continue the treatment in Extension 2 after Extension 1 and Extension 3 after Extension 2.
** LTBP4 and osteopontin genotype information Note: A subject may return for an unscheduled visit at the discretion of Investigator to undergo additional safety evaluations (i.e.,
laboratory re-testing, AE assessments), or for additional medical evaluations. Platelet count may be assessed at an unscheduled visit if deemed necessary by the Investigator.
a To be performed more frequently, if clinically indicated. 
b The following laboratory parameters will be assessed: Hematology: RBC, hemoglobin, hematocrit, WBC with differential, platelets, ANC, and abnormal cells; Blood chemistry: 
total bilirubin, alkaline phosphatase, amylase, ALT, AST, LDH, CRP, creatine kinase, total protein, albumin, uric acid, sodium, potassium, chloride, calcium, glucose, creatinine, 
BUN, and CrCl (CrCl will be calculated by the Cockcroft and Gault formula). Urinalysis: pH, specific gravity, protein, glucose, ketones, cytology, and myoglobin. 
c If the child is discontinued from the study treatment, the child will be asked to return for the early termination procedures. For the assessments to be performed, see “EOS visit”. 
Discontinued children will also have follow-up procedures performed within 4 weeks of the last dose of study drug. 
d Urinalysis: pH, specific gravity, protein, glucose, ketones and cytology. 


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3.4.2 
Study Procedures 
3.4.2.1 
Pre-Study (Screening)—(Day -28 [±2 Weeks]) 
The assessments during the pre-study phase will determine the child’s eligibility for the 
study and also their ability to comply with protocol requirements by completing all 
screening assessments. All children will undergo all screening assessments, regardless 
of whether they are enrolled during Part 1 or Part 2 of the study. 
The following procedures will be performed and recorded during the screening period: 
•
Obtain written informed consent from the child’s parent/legal guardian and assent
from the child, if applicable.
•
Collect medical history.
•
Review inclusion and exclusion criteria.
•
Obtain and record current and prior medications (taken in the past 6 months).
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Measure height and weight.
•
Obtain a 12-lead ECG in triplicate.
•
Obtain an ECHO.
•
Obtain PFT measurements: FEV1, FVC, FEV1/FVC.
•
Obtain blood samples for hematology, blood chemistry, and disease serology tests.
•
Obtain a urine sample for urinalysis.
•
Obtain blood sample for miRNA.
•
Perform a quality of life test
•
Perform the muscle evaluations:
o
6MWT (collect historical data on tests performed at least 6 months prior to
the pre-study visit and within 4 ± 2 weeks of pre-study visit).
o
NSAA and PUL (collect results from within 4 ± 2 weeks prior to treatment
start).
•
Obtain a muscle biopsy (brachial biceps; please refer to Section 3.4.11 for
instructions; obtained within 4 ± 2 weeks prior to the start of treatment).
•
Obtain an MRI of muscle (initially on the muscles of the lower limb and, if
possible, on the muscles of the upper limb; MRI does not need to be repeated if
obtained within 4 ± 2 weeks prior to the start of treatment).
•
Assess AEs


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3.4.2.2 
Weekly Visits (Part 1; Weeks 0 to 6) 
Children will visit the study center weekly during Part 1 of the study. Children will 
continue to come in weekly (i.e., every 7 ± 1 days) until they are switched to Part 2 of the 
study when the RD is selected. At each visit (unless otherwise indicated), the following 
assessments will be performed and recorded: 
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Measure weight.
•
Obtain a 12-lead ECG in triplicate.
•
Obtain blood samples for hematology and blood chemistry.
•
Obtain a urine sample for urinalysis.
•
Obtain blood for PK assessments at Visit 2 only as noted in the schedule of
assessments.
•
Dispense IMP and perform accountability.
•
Assess AEs.
3.4.2.3 
Part 2 Visits (Months 1 to 10.5) 
Children will visit the study center as noted in the schedule of assessments during Part 2 
of the study (i.e., every 1 to 1.5 months ± 1 week). At each visit (unless otherwise 
indicated), the following assessments will be performed and recorded: 
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Measure height and weight.
•
Obtain a 12-lead ECG in triplicate.
•
Obtain blood sample for hematology and blood chemistry.
•
Obtain blood samples for miRNA (Visits 4 and 6 only).
•
Obtain a urine sample for urinalysis.
•
Obtain blood for a PK assessments at Visits 2, 3, 4, and 6 only as noted in the
schedule of assessments.
•
Obtain muscle evaluations (6MTW, NSAA, and PUL; Visits 4 and 6 only).
•
Dispense IMP and perform accountability.
•
Assess AEs.
•
Acceptability/palatability evaluation (Visit 8 only)


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3.4.3 
Unscheduled Visits 
A subject may return for an unscheduled visit at the discretion of Investigator to undergo 
additional safety evaluations (i.e., laboratory re-testing, AE assessments), or for 
additional medical evaluations. Platelet count may be assessed at an unscheduled visit if 
deemed necessary by the Investigator. 
Subjects who experience a hematological toxicity will be monitored closely until 
resolution of the event. 
3.4.4 
Assessments for End of Study Part 2 (Visit 10 [Month 12])/Beginning of Extension 
Phase 1 
Children who remain in the study will continue to take study drug through Visit 10. The 
end of study (EOS) visit overlaps with the 12-month visit, if the child completes 
treatment. 
The following assessments will be performed and recorded: 
•
Ask for the written informed consent from the child’s parent/legal guardian and
assent from the child, if applicable, for the continuation in Extension 1
(12 months).
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Measure height and weight.
•
Obtain a 12-lead ECG in triplicate.
•
Obtain an ECHO.
•
Obtain PFT measurements: FEV1, FVC, FEV1/FVC, and PEF.
•
Obtain blood samples for hematology and blood chemistry.
•
Obtain a urine sample for urinalysis.
•
Perform a quality of life test.
•
Obtain muscle evaluations (6MWT, NSAA, PUL).
•
Perform a muscle biopsy (please refer to Section 3.4.11 for instructions).
•
Obtain an MRI of dystrophic muscle.
•
Obtain blood sample for miRNA.
•
Obtain blood for PK assessment.
•
Perform accountability.
•
Assess AEs.
•
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•
Dispense IMP and perform accountability for children continuing into the
extension phases.
The extension phases will be followed only for children whose parent/guardian has given 
their written consent and the child has assented to participate in these phases. 
3.4.5 
Extension Phase 1 Visits (Months 12 to 22) 
Extension phase 1 will start at the EOS visit (Visit 10 [Month 12]). As noted in the 
schedule of assessments during Extension 1, for Months 14 to 22, children will visit the 
study center at Visits 11 to 15 (i.e., every 2 months ± 1 week). At each visit (unless 
otherwise indicated), the following assessments will be performed and recorded: 
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Measure weight.
•
Obtain a 12-lead ECG in triplicate.
•
Obtain blood sample for hematology and blood chemistry.
•
Obtain a urine sample for urinalysis.
•
Obtain muscle evaluations (6MTW, NSAA, and PUL) at Visit 12 and Visit 14
only.
•
Dispense IMP and perform accountability.
•
Assess AEs.
3.4.6 
Assessments for End of Extension Phase 1 (Visit 16 [Month 24])/Beginning of 
Extension Phase 2 
For children who continue in Extension 1, the end of the extension phase visit will be 
performed on Month 24 (Visit 16). The following assessments will be performed and 
recorded: 
•
Ask for the written informed consent from the child’s parent/legal guardian and
assent from the child, if applicable, for the continuation in Extension 2
(12 months).
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Measure height and weight.
•
Obtain a 12-lead ECG in triplicate.
•
Obtain an ECHO.


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•
Obtain PFT measurements: FEV1, FVC, FEV1/FVC, and PEF.
•
Obtain blood samples for hematology and blood chemistry.
•
Obtain a urine sample for urinalysis.
•
Obtain muscle evaluations (6MWT, NSAA, PUL).
•
Obtain an MRI of dystrophic muscle.
•
Perform accountability.
•
Perform a quality of life test.
•
Assess AEs.
•
Collect LTBP4 and osteopontin genotype information.
3.4.7 
Extension Phase 2 Visits (Months 24 to 34) 
Extension phase 2 will start at the EOS visit (Visit 16 [Month 24]). As noted in the 
schedule of assessments during Extension 2, for Months 26 to 34, children will visit the 
study center at Visits 17 to 21 (i.e., every 2 months ± 1 week). At each visit (unless 
otherwise indicated), the following assessments will be performed and recorded: 
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Measure weight.
•
Obtain a 12-lead ECG in triplicate.
•
Obtain blood sample for hematology and blood chemistry.
•
Obtain a urine sample for urinalysis.
•
Obtain muscle evaluations (6MTW, NSAA, and PUL) at Visit 18 and Visit 20
only.
•
Dispense IMP and perform accountability.
•
Assess AEs.
3.4.8 
Assessments for End of Extension Phase 2 (Visit 22 [Month 36]/Beginning of 
Extension Phase 3) 
For children who continue in Extension 2, the end of the extension phase visit will be 
performed on Month 36 (Visit 22). The following assessments will be performed and 
recorded: 
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Measure height and weight.


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•
Obtain a 12-lead ECG in triplicate.
•
Obtain an ECHO.
•
Obtain PFT measurements: FEV1, FVC, FEV1/FVC, and PEF.
•
Obtain blood samples for hematology and blood chemistry.
•
Obtain a urine sample for urinalysis.
•
Obtain muscle evaluations (6MWT, NSAA, and PUL).
•
Perform accountability.
•
Perform a quality of life test.
•
Assess AEs.
3.4.9 
Extension Phase 3 Visits (Months 40 to 48) 
Extension phase 3 will start at the EOS visit (Visit 22 [Month 36]). As noted in the 
schedule of assessments during Extension 3, for Months 40 to 52, children will visit the 
study center at Visits 23 to 26 (i.e., every 4 months). The time window for Visits 23 and 
24 is ± 1 week; the time window for Visits 25 and 26 is ± 1 month. 
At each visit (unless otherwise indicated), the following assessments will be performed 
and recorded: 
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Measure weight.
•
Measure height (Visit 25 [Month 48] only)
•
Obtain a 12-lead ECG in triplicate.
•
Obtain blood sample for hematology and blood chemistry.
•
Obtain a urine sample for urinalysis.
•
Obtain muscle evaluations (6MTW, NSAA, and PUL)
•
Dispense IMP and perform accountability.
•
Assess AEs.
3.4.10 Assessments for End of Extension Phase 3 (Visit 26 [Month 52]) 
For children who continue in Extension 3, the end of the extension phase visit will be 
performed on Month 52 (Visit 26) ± 1 month. 
The following assessments will be performed and recorded: 
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.


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•
Measure height and weight.
•
Obtain a 12-lead ECG in triplicate.
•
Obtain an ECHO.
•
Obtain PFT measurements: FEV1, FVC, FEV1/FVC, and PEF.
•
Obtain blood samples for hematology and blood chemistry.
•
Obtain a urine sample for urinalysis.
•
Obtain muscle evaluations (6MWT, NSAA, and PUL).
•
Perform accountability.
•
Perform a quality of life test.
•
Assess AEs.
3.4.11 Early Termination Visit 
Children who discontinue participation prior to completion of all study drug 
administration (i.e., 12 months of treatment or 48 months of treatment if the children 
continue in the extension phases) will be asked to return to the hospital within 2 weeks 
after the last dose of study drug for completion of the same assessments given at the EOS 
visit (for details, see Section 3.4.4 or Section 3.4.6, if applicable). 
3.4.12 Follow-up Visit 
All children, regardless of whether they complete the study (including the extension 
phase) or terminate early in Part 1, Part 2, or from the extension phases (if applicable), 
should return to the study center within 4 weeks of the last dose of study drug for the 
follow-up visit. 
The following assessments will be performed and recorded: 
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Obtain a 12-lead ECG in triplicate.
•
Obtain blood samples for hematology and blood chemistry.
•
Obtain a urine sample for urinalysis.
•
Assess AEs.
3.4.13 Description of Assessments 
Unless otherwise indicated, all assessments will be performed by the investigator or other 
regular study personnel. Assessments are to be performed according to the schedule 


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shown in Section 3.4.1. The assessments at the end-of-study and follow-up visits should 
also be performed if the child terminates the study early. 
Efficacy Assessments 
Muscle Biopsies: A first brachial biceps biopsy (baseline) will be taken prior to the first 
dose of study drug. A second brachial biceps biopsy will be taken at Visit 10 
(12 months) from the opposite arm. 
The muscle biopsy samples from the biceps muscle will be collected by open biopsy 
according to standard hospital procedures for obtaining muscle biopsies from children. 
The minimum amount of muscle tissue required is a small piece of muscle of at least 
0.5 x 0.5 x 0.5 cm. The muscle sample, embedded with tragacanth gum on a piece of 
cork, must be frozen in liquid nitrogen-cooled 2-methylbutane and stored at -80°C 
or -70ºC until shipment. 
The collection, processing, and shipment of these muscle biopsy samples to the Ospedale 
Pediatrico Bambino Gesù laboratory will be described in detail in the study-specific 
laboratory manual. 
6- Minute Walk Test: A modified version of the 6MWT recommended by American
Thoracic Society (2002) for use in adults will be performed.
North Star Ambulatory Assessment: The NSAA will be graded using the standard 
scorecard with each assessment rated as 0 – unable to achieve independently, 1 – 
modified method but achieves goal independent of physical assistance from another, or 2 
– normal with no obvious modification of activity.
Performance of Upper Limb: The PUL was devised to assess motor performance in the 
upper limb for patients with Becker and Duchenne muscular dystrophy.  The purpose is 
to assess change that occurs in motor performance of the upper limb over time from when 
a child is still ambulant until he loses all arm function when non-ambulant. The PUL will 
be administered according to the guidelines developed by the Physiotherapy Working 
Group (Mayhew A et al. 2012, Mercuri E et al. 2012). 
MRIs: MRIs will be taken of muscle (initially on the muscles of the lower limb and, if 
possible, on the muscles of the upper limb) and evaluated per the specifications in the 
CSOM. 
miRNA: miR-1, miR-133, and miR-206 may be evaluated. Additional miRNA 
parameters may be evaluated if warranted. Evaluation of miRNA will be documented in 
a separate report. 


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Other assessments – exploratory analysis regarding type of mutation: the DMD gene 
mutation will be evaluated in the study to explore whether the effects of Givinostat on 
disease progression may be related to the underlying type of mutation. 
Other efficacy assessments – exploratory analysis of muscle biopsies: Muscle biopsies 
will be analyzed in 2 distinct steps, by using different complementary approaches 
(fluorescence-activated cell sorting [FACS]-mediated isolation of cells and functional 
characterization ex vivo and staining of frozen sections) that are finalized to the 
identification and functional/molecular characterization of specific cell types that 
contribute to the regeneration or fibro-adipogenic degeneration of dystrophic muscles. 
These cells include muscle satellite cells (MuSCs) and a heterogeneous population that is 
referred to as “fibro-adipogenic progenitors” (FAPs). These cell types can be isolated by 
FACS in mouse and human muscle samples as distinct populations, based on specific 
combination of surface antigens. 
In the mouse system, MuSCs can be isolated from skeletal muscles by FACS, as 
CD34pos/α7-integrinpos/Sca1neg cells (Sacco A et al. 2008), while FAPs are isolated either 
as CD34pos/α7integrinneg/Sca1pos cells or platelet-derived growth factor receptor (PDGFR) 
PDGFR- α pos cells (Joe AW et al. 2010; Uezumi A et al. 2010). In muscle biopsies of 
human patients or normal individuals, MuSCs are isolated as PDGFR- α 
neg/α7-integrinpos/N-CAM pos cells, while FAPs can be isolated as PDGFR- α 
neg/α7-integrinpos/N-CAM pos cells. 
Pre-clinical studies have demonstrated that functional interactions between these cell 
types contributes to the disease progression in mouse models of DMD (mdx mice) and 
that HDAC inhibitors promote the FAP property of stimulating muscle regeneration at 
the expense of fibro-adipogenic degeneration. The sponsor has identified a novel nuclear 
network that regulates FAP lineage identity and ability to support regeneration or 
fibro-adipogenic degeneration in dystrophic muscles. This network consists of an 
HDAC-repressed miRNA (the myomiRs 1.2, 133a and 206) that target 2 specific 
sub-units (BAF60a and b) of the switch/sucrose non-fermentable (SWI/SNF) chromatin 
remodeling complex, which promotes the expression of fibro-adipogenic genes. Upon 
treatment with HDAC inhibitors, de-repression of myomiRs 1.2, 133a and 206 causes the 
down regulation of BAF60a and b, and the simultaneous activation of BAF60c, leading 
to the formation of BAF60c-based SWI/SNF complex that promotes skeletal myogenesis 
in FAPs. The sponsor has found that mdx mice that respond to HDAC inhibitors, such as 
Givinostat, show increased levels of BAF60c and myomiRs 1.2, 133a and 206. 
1. FACS-sorting of MuSCs and FAPs from biopsies of children before and at the
end of the treatment will be used to measure: a) the relative amount of these cell
populations; b) their ability to differentiate in culture, in myogenic and adipogenic


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media, and their functional interactions by co-culture experiments; c) gene and 
miRNA expression analysis by quantitative polymerase chain reaction. 
It should be emphasized that in vitro exposure to Givinostat of MuSCs and FAPs 
from biopsies of children before the treatment might provide a useful measure 
predictive of child response that can be used to better select children in a 
follow-up trial. 
2. Histologic analysis of muscle sections from biopsies of children before and at the
end of the treatment will be used to measure: a) the expression levels of BAF60
a, b, and c variants, and myomiRs 1.2, 133a and 206 in MuSCs and FAPs, which
will be identified as Pax7pos or PDGFR- α pos, respectively.
Safety Assessments 
Physical Examination: Physical examination will include examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, heart, lungs, 
abdomen, lymph nodes, extremities, and nervous system. An AE form must be 
completed for all changes identified as clinically noteworthy. Height without shoes and 
weight will be recorded as noted in the schedule of assessments. 
Vital Signs: Vital signs will include body temperature (ºC), pulse rate, and blood 
pressure. 
Electrocardiogram: Standard 12-lead ECGs will be conducted in triplicate per the 
schedule of assessments and more often if clinically indicated. ECG will be acquired at 
the sites, then ECG data will be transmitted and a central reading will be performed. For 
details, see the relevant CSOM. 
ECHOs: Standard ECHOs will be conducted as per the schedule of assessments and 
more often if clinically indicated. 
Pulmonary function tests: FEV1, FVC, FEV1/FVC, and PEF, will be collected per the 
site’s standard process as noted in the schedule of assessments and more often if 
clinically indicated. 
Laboratory Parameters: The following laboratory tests are to be performed as indicated 
in the schedule of assessments and more often if clinically indicated: 
1. Hematology: red blood cell (RBC) count, hemoglobin, hematocrit, WBC count
with differential, platelets, ANC, and abnormal cells. Additional platelet counts
may be assessed for subjects in Part 2, at an unscheduled visit, if deemed
necessary by the Investigator (refer Section 3.4.3 for details).


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2. Blood chemistry: total bilirubin, alkaline phosphatase, amylase, alanine
aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase
(LDH), C-reactive protein (CRP), creatine kinase, total protein, albumin, uric
acid, sodium, potassium, chloride, calcium, glucose, creatinine, blood urea
nitrogen (BUN), and creatine phosphokinase (CPK) (creatinine clearance [CrCl]
will be calculated by the Cockcroft and Gault formula.)
3. Urinalysis: pH of freshly voided specimen, specific gravity, protein, glucose,
ketones, cytology, and myoglobin (myoglobin not assessed during Extension 3).
4. Other: enzyme-linked immunosorbent assay (ELISA) for HIV- Ab, HCV-Ab,
HbsAg, hepatitis B e antigen (HbeAg), anti-EBV, and anti-cytomegalovirus
(CMV) immunoglobulin M (IgM).
Lab tests will be performed and analyzed by a local laboratory to ensure consistent 
interpretation of results. In the event of an unexplained clinically noteworthy abnormal 
laboratory test value, the test should be repeated immediately and followed up until it has 
returned to the normal range and/or an adequate explanation of the abnormality is found. 
Adverse Events: An AE is “any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment (International Conference on 
Harmonisation [ICH] E2A).” All medical and psychiatric conditions (except those 
related to the indication under study) present at screening will be documented on the 
Prior Illnesses eCRF. Changes in these conditions and new symptoms, physical signs, 
syndromes, or diseases should be noted on the AE eCRF during the rest of the study. 
Laboratory abnormalities should be recorded as AEs only if they meet the criteria for an 
SAE, result in discontinuation of the study drug, require medical intervention, or are 
judged by the investigator to be clinically significant changes from baseline values. See 
Section 4, for additional information. 
Pharmacokinetic Assessments 
Blood samples for PK assessments will be collected as indicated in the schedule of 
assessments. Additional information about the PK time points will be provided in the 
relevant CSOM. 
Quality of Life Assessment 
The PedsQL Test will be performed before treatment start, at Visit 10 (12 months), and at 
the end of the extension phases at 24, 36 and 52 months for Extension 1, 2 and 3, 
respectively, if applicable. 
Acceptability/Palatability Evaluation 


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At Visits 8 and 10 of the study Part 2, the palatability of the oral suspension will be 
evaluated using the Five-Point Hedonic Scale palatability. 
The investigator will explain to the child that he would be asked “how much did you like 
the taste of this medicine?” and encouraged to indicate his preference by pointing to the 
appropriate face that depicts five degrees of pleasure: 
•
5 = like very much
•
4 = like a little
•
3 = not sure
•
2 = dislike a little
•
1 = dislike very much
The explanation will be repeated if the child did not understand. 
Figure 2 
Five-Point Hedonic Scale – Face Depictions 
In addition, the palatability/patient acceptability will be also indirectly assessed in parents 
with two questions: 
1. “On the basis of reaction ⁄ facial expression of your child, do you think that the
medication is: pleasant = 3; not sure = 2; or unpleasant = 1?”
2. “Do you sometimes have problems in giving the medication to your child because
he refuses to take it or throws it up? (Yes⁄No)
3.4.14 Appropriateness of Measurements 
All assessments to be used in this study are commonly used, standard measurements 
frequently seen in DMD studies. 


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4 Adverse Event Reporting 
Throughout the course of the study, all AEs will be monitored and reported in the AE 
eCRF, including the event’s seriousness, severity, action taken, and relationship to the 
IMP. If AEs occur, the first concern will be the safety of the children. All AEs will be 
followed until resolved or stable and the outcome documented on the appropriate eCRF. 
In order to avoid vague, ambiguous, or colloquial expressions, all AEs should be 
recorded in standard medical terminology rather than the child’s or parent’s/legal 
guardian’s own words. 
4.1 Definitions and Criteria 
4.1.1 
Adverse Events 
An AE is “any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment (ICH E2A)”. 
AEs include: 
1. Onset of any clinical sign or symptom
2. Worsening (change in nature, severity or frequency) of conditions present at the
start of the trial
3. Subject deterioration due to the primary illness
4. Intercurrent illness(es)
5. Drug interactions
6. Events related or possibly related to concomitant medications
7. Abnormal laboratory values, as well as significant shifts from baseline within the
range of normal that the investigator considers to be clinically significant
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
4.1.2 
Adverse Drug Reactions 
In the pre-approval clinical experience with a new medicinal product: “all noxious and 
unintended responses to a medicinal product related to any dose should be considered 
Adverse Drug Reaction.” 


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4.1.3 
Unexpected Adverse Drug Reactions 
An unexpected adverse drug reaction is an event in which the nature or severity is not 
consistent with the applicable product information (e.g., Investigator’s Brochure for an 
unapproved IMP). 
4.1.4 
Serious Adverse Events 
An SAE (experience) or reaction is any untoward medical occurrence that at any dose: 
•
Is fatal (results in the outcome death)
•
Is life-threatening*
•
Requires inpatient hospitalization or prolongs existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect
•
Is medically significant or requires intervention to prevent one or other of the
outcomes listed above
*The term life-threatening refers to an event in which the subject was at risk of death at the time of the
event; it does not refer to an event which hypothetically might have caused death if it were more severe.
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the child or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
An SAE is not necessarily severe; e.g., an overnight hospitalization for a diagnostic 
procedure must be reported as an SAE even though the occurrence is not medically 
serious. By the same token, a severe AE is not necessarily serious: nausea of several 
hours’ duration may be rated as severe but may not be considered serious. 
4.1.5 
Assessing Intensity and Relationship 
All AEs will be assessed on 2 descriptive parameters: intensity and relationship to study 
drug: 
Intensity refers to the “severity” of an event and references impact on a child’s 
functioning. 


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Relationship refers to the likelihood that the event being assessed was caused by the 
study drug. 
Intensity 
Each AE will be classified according to the following criteria: 
Mild: 
The AE does not interfere in a significant manner with the 
child’s normal functioning level. 
Moderate: 
The AE produces some impairment of functioning, but is 
not hazardous to health. 
Severe: 
The AE produces significant impairment of functioning or 
incapacitation and is a definite hazard to the child’s health. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the experience should be noted. If the intensity category changes 
over a number of days, those changes should be recorded separately (with distinct onset 
dates). 
Relationship 
Each AE will be assessed as to its relationship to study drug based on the following 
criteria. Although investigator attribution will be collected for reported events, for 
analytic purposes a temporal association with the use of study drug will be assumed 
sufficient for at least plausible association. 
Not 
related: 
No causal relationship exists between the investigational 
product and the AE, but an obvious alternative cause 
exists, e.g., the child’s underlying medical condition or 
concomitant therapy. 
Related: 
There is a reasonable/plausible possibility that the AE 
may have been caused by the investigational product. 
When assessing the relationship to study drug, the follow criteria will be considered: 
•
Positive rechallenge
•
Positive dechallenge (resolution upon stopping suspect product, in absence of
other intervention or treatment)
•
Known class effect
•
Biological plausibility


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•
Lack of alternative explanation—concomitant drug or disease
Factors to be considered in assessing the relationship of the AE to study drug include: 
•
The temporal sequence from IMP administration
•
The recovery on discontinuation and recurrence on reintroduction
•
The concomitant diseases
•
The evolution of the treated disease
•
The concomitant medication(s)
•
The pharmacology and pharmacokinetics of the IMP
4.2 Reporting Procedures and Requirements 
4.2.1 
Adverse Events 
The investigator or his/her designees are requested to collect and assess any spontaneous 
AE reported by the child and to question the child about AEs and intercurrent illnesses at 
each visit during the treatment period and follow-up. The questioning of children 
regarding AEs is generalized such as “How have you been feeling since your last visit?” 
Any AE occurring after the informed consent form/assent has been signed and up to the 
follow-up study visit, whether volunteered by the child; discovered during general 
questioning by the investigators; or detected through physical examination, laboratory 
test, or other means will be recorded on the specific section of the eCRF. Each AE will 
be described by: 
•
Seriousness
•
Duration (start and end dates)
•
Severity
•
Relationship to the IMP
•
Action taken
•
Outcome
The severity of AE should be assessed and graded according to the most recently 
published National Cancer Institute Common Terminology Criteria for AEs (v. 4.0). 
The relationship to the investigational drug should be assessed as: 
•
Related to IMP
•
Not related to IMP
•
Unknown


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The assessment of the relationship of an AE to the administration of IMP is a clinical 
decision based on all available information at the time of the completion of the eCRF. 
An assessment of ‘not related’ would include the existence of a clear alternative 
explanation, or non-plausibility. 
An assessment of ‘related’ indicates that there is a reasonable suspicion that the AE is 
associated with the use of the IMP. 
4.2.1.1 
Abnormal Laboratory Findings and Other Objective Measurements 
Abnormal laboratory findings and other objective measurements should not be routinely 
captured and reported as AEs in the eCRF as they will be collected and analyzed 
separately. However, abnormal laboratory findings and other objective measurements 
that meet the criteria for an SAE, result in discontinuation of the IMP, require medical 
intervention, or are judged by the investigator to be clinically significant changes from 
baseline values should be captured and reported as AEs in the eCRF. 
When reporting an abnormal laboratory finding as an AE in the eCRF, a clinical 
diagnosis should be recorded in addition to the abnormal value itself, if this is available 
(for example “anemia” in addition to “hemoglobin = 10.5 g/dL”). 
4.2.1.2 
Baseline Medical Conditions 
Medical conditions present at the screening visit that do not worsen in severity or 
frequency during the study are defined as baseline medical conditions and are not AEs. 
These medical conditions should be adequately documented on the appropriate page of 
the eCRF (i.e., the medical history page). However, medical conditions present at the 
initial study visit that worsen in severity or frequency during the study should be recorded 
and reported as AEs. 
4.2.2 
Serious Adverse Events 
Any SAE, including death from any cause that occurs after a child has signed the 
informed consent /assent and up to the final follow-up visit (regardless of relationship to 
study drug) must be reported by the investigators to the sponsor within 24 hours of 
learning of its occurrence. 
Related SAEs MUST be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed. 
The investigators are required to complete the SAE form provided by the sponsor. 
Sufficient details must be provided to allow for a complete medical assessment of the AE 
and independent determination of possible causality. The investigators are obliged to 


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pursue and provide additional information as requested by the sponsor’s drug safety 
manager, or study director, or designee. 
The investigator must send notification of the SAE to the sponsor’s Drug Safety Unit by 
faxing the SAE form, within 24 hours of a SAE, at the number specified below; then, the 
investigator must confirm any SAE notifications by mailing to the mail address or 
phoning to the phone number specified below: 
Drug Safety Unit, Italfarmaco S.p.A. 
Via dei Lavoratori 
54 20092 Cinisello Balsamo (MI), Italy 
Fax: 02 6610 6538 (or Fax 02 6443 2955 as backup) 
phone: +39 02 6443 2510, mobile +39 333 9262611 
e-mail: drug-safety@italfarmaco.com
The same procedure must be applied to the SAE follow-up information. 
The sponsor’s drug safety manager will report all serious and unexpected AE that are 
related to the use of the study drug to the competent authority within the required time 
and following procedures required by applicable laws. It is imperative that the sponsor 
be informed as soon as possible, so that reporting can be done within the required time 
frame. 
The SAEs will also be recorded in the AE section of the eCRF. 
Overdose and Other Situations Putting the Child at Risk of an Adverse Reaction 
Any instance of overdose (suspected or confirmed) must be reported to the sponsor 
within 24 hours and be fully documented as a SAE. Details of any signs or symptoms 
and their management should be recorded including details of any antidote(s) or 
systematic treatment administered. Any signs or symptoms of overdose will be treated 
symptomatically. 
Any other situations putting the child at risk of adverse reaction, such as misuse and 
abuse, medication errors, suspicion of transmission of infective agents must be reported 
to the sponsor within 24 hours and be fully documented as a SAE. 
5 Data Management and Statistical Analysis 
5.1 Data Management Considerations 
Electronic CRFs will be employed for this study. Completed eCRFs for this study will be 
forwarded to the sponsor or its representative where editing and construction of a 


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quality-assured database will occur. The statistical analysis of these data will be 
performed by the sponsor or its representative. 
Data Analysis of the Biopsies 
All images will be digitally captured, using both light microscopy (hematoxylin and eosin 
[H&E] and Gomori trichrome stain) and fluorescence microscopy coupled to the 
Olympus Fluoview FV1000 confocal microscope. Fields for fluorescent imaging will be 
randomly selected while viewing the laminin-dystrophin signal. 
In the only step involving operator discretion, all image parameters including pinhole 
size, detector gain, amplifier offset, amplifier gain, and laser intensity will be first set for 
the dystrophin and laminin channels using normal control tissue, and the same setting 
used for all samples imaged on a given day. Frame size, scan speed, and averaging will 
be the same for all images. For each sample 4 non-overlapping images for each channel 
will be acquired and stored as 12-bit fluorescent images (.TIFF) for analysis. A single 
technician will perform all sectioning, staining, and morphometry steps, while another 
operator will execute the confocal imaging. 
Image processing and quantitative analyses will be done using Metamorph (Molecular 
Devices, Inc.) software program using a custom script. Additional details are provided in 
the relevant CSOM. 
5.2 Statistical Considerations 
The statistical analysis will be undertaken by the contract research organization 
Worldwide Clinical Trials (WCT) in collaboration with the sponsor. 
Any deviations from the analyses described below will be included in the Statistical 
Analysis Plan (SAP). 
5.2.1 
General Considerations 
Data will be provided in data listings sorted by treatment group and child number. 
Tabular summaries will be presented by treatment group for Part 1. Categorical data will 
be summarized by the number and percentage of children in each category. Continuous 
variables will be summarized by descriptive statistics, including mean, standard 
deviation, median, minimum, and maximum. Confidence intervals (CIs) will be 2-sided, 
unless otherwise stated. Details of endpoint analyses will be described in the SAP. 
For analyses of change from baseline, baseline will generally be defined as the value 
collected before any Givinostat treatment is administered. If this value is unavailable, the 
last non-missing value prior to dosing will be used. Otherwise, missing observations will 


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be treated as missing at random, and no data imputation will be performed. All data from 
the CRFs, as well as any derived variables, will be presented in data listings. 
All hypothesis tests will be two-sided with a 5% significance level, and 95% CIs will be 
used, unless stated otherwise. As this is a Phase 2 exploratory study, no adjustments for 
multiplicity will made. 
5.2.2 
Sample Size Justification 
A minimum of 20 evaluable children will be enrolled in this study. 
5.2.2.1 
Part 1 
Approximately 20 children will be enrolled in Part 1 (dose-finding) of this study. 
5.2.2.2 
Part 2 
Muscle fibers: a sample size of 20 children from part 1 completing the treatment period 
of part 2 should provide 90% power (at a 2-sided alpha level of 5%) to detect at least a 
12.5% increase in MFA% between pre- and post-treatment (which corresponds 
approximately to a 26% relative increase given the observed mean in the Desguerre 
publication of 48% [Desguerre I et al. 2009]), the “worst case” standard deviation of 
16%, which assumes that there is no correlation within a subject in the muscle area fiber 
percentage between pre- and post-treatment. This sample size is based on a paired t-test 
and the assumption of normal distribution of MFA%. 
After the first 20 baseline biopsies are collected, an interim analysis aimed at checking 
the real variability observed in the study will be implemented: the within-subject 
standard deviation of MFA% will be calculated, the actual distribution of MFA% will be 
checked and the final sample size will be adjusted based on the observed standard 
deviation and actual distribution of MFA%. Results by Al-Sunduqchi and Guenther 
(1990) indicate that power calculations for the Wilcoxon test may be made using the 
standard t-test formulations with a simple adjustment to the sample size. The size of the 
adjustment depends upon the actual distribution of the data. They give sample size 
adjustment factors for four distributions. These are 1 for the uniform distribution, 2/3 for 
the double exponential distribution, 9/π2 for the logistic distribution, and π/3 for the 
normal distribution. So depending on the actual distribution of MFA%, sample size 
re-calculation will be based on a Wilcoxon Signed Rank test with the corresponding 
adjustment if the observed distribution of MFA% is not normal. 


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5.2.3 
Analysis Populations 
The intent-to-treat (ITT) population includes all children who are enrolled in the Part 1 
portion or entered the Part 2 portion of the study. The efficacy analysis will be conducted 
based on the ITT population. 
The evaluable population will include all children who are in the Part 2 of the study, 
receive Givinostat of at least 80% dose, have at least one baseline and one post-baseline 
assessment of biopsies, and have no major protocol violations. The evaluable population 
will be identified prior to database lock. A sensitivity analysis may be conducted based 
on the evaluable population. 
The safety population will include all children who receive any investigational product. 
The safety analysis will be conducted based on the safety population. 
The PK population will include all children with at least one quantifiable post-dose 
concentration datum available. All statistical analyses of PK data will be performed 
using the PK population. 
5.2.4 
Primary Endpoint 
The primary endpoint of this study is change in the value of MFA% comparing the 
histology biopsies before and after 12 months of treatment with Givinostat. 
The primary endpoints of the extension phases are: 
•
Number of children experiencing treatment-emergent AEs and SAEs
•
Type, incidence, and severity of treatment-emergent AEs and SAEs correlated
with dose.
5.2.5 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following: 
•
Change in additional histological endpoints (i.e., cross-sectional area,
inflammation, necrosis, fibrosis, and muscle regeneration) after 12 months of
treatment with Givinostat at the selected daily dose
•
Change in muscular function after 12 months of treatment with Givinostat at the
selected daily dose based on the 6MWT
•
Change in muscular function after 12 months of treatment with Givinostat at the
selected daily dose based on the NSAA
•
Change in muscular function after 12 months of treatment with Givinostat at the
selected daily dose based on the PUL


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The secondary efficacy endpoints of the extension phases are the change of muscular 
function (including loss of ambulation) after 24, 36, and 52 months of treatment 
(Extension 1, Extension 2, and Extension 3, respectively) with Givinostat as assessed by 
6MWT, NSAA, and PUL. For the children who are not able to complete the 6MWT, the 
time to wheelchair and how much time the children spend in wheelchair were assessed. 
Additional details on secondary efficacy endpoints will be provided in the SAP. 
5.2.6 
Safety Endpoints 
The safety endpoints will include the following: 
•
The number of children experiencing AEs
•
The type, incidence, and severity of AEs correlated with dose
•
ECG, ECHO, vital sign, physical examination, PFTs, and clinical laboratory
parameter findings
5.2.7 
Secondary Pharmacokinetic Endpoints 
Individual Givinostat concentrations will be tabulated by dose cohort along with 
descriptive statistics for Part 1 and tabulated along with descriptive statistic for Part 2. 
Noncompartmental PK data analysis will be performed for data obtained from each dose 
cohort with scheduled PK sample collection. If data allow, descriptive statistics of 
noncompartmental PK parameters (area under the plasma–concentration time curve, 
maximum plasma concentration, clearance, terminal elimination half-life) will be 
provided. 
5.2.8 
Exploratory Endpoints 
The exploratory endpoints will include the following: 
•
Changes in muscle, fat, and fibrosis content after treatment with Givinostat as
measured by MRI (also evaluated during Extension 1)
•
Change in muscle biomarkers (e.g., miRNA) following treatment with Givinostat
•
Evaluation of LTBP4 and osteopontin genotype
•
PK–PD correlations
•
Evaluation of acceptability/palatability of the oral suspension
•
Evaluation of any correlation between the effects of Givinostat on disease
progression and the type of DMD mutation patients may have in relation to their
disease.


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5.2.8.1 
Magnetic Resonance Imaging 
MRI will be collected via T1w imaging and quantitative Dixon imaging (the fat content 
of the image as a percentage of the total signal per voxel). Additional details will be 
provided in the SAP. 
5.2.8.2 
miRNA 
miR-1, miR-133, and miR-206 will be evaluated. Other miRNA may be evaluated as 
appropriate. Additional details will be provided in the SAP. 
5.2.8.3 
LTBP4 and Osteopontin Genotype 
The genotype of LFTP4 and osteopontin will be assessed. Additional details will be 
provided in the SAP. 
5.2.8.4 
DMD Gene 
DMD gene in relation to the disease will be evaluated. Additional details will be 
provided in the SAP. 
5.2.8.5 
Acceptability/Palatability of the Oral Suspension 
Summary statistics of palatability score assessed with Five-Point Hedonic Scale 
palatability and patient acceptability will be reported. Additional details will be provided 
in the SAP. 
5.2.9 
Efficacy Analyses 
Efficacy analyses will be conducted on the evaluable population. 
All values will be expressed as means ± standard deviation or standard error of the mean. 
Each of all efficacy endpoints will be subject to normality test and formal statistical test 
performed will be based on whether it is normally distributed. If normal, statistical 
differences will be calculated using the paired t test; if not normal, Wilcoxon signed rank 
test will be used to assess the statistical significance of differences between groups. 
P<0.05 will be set as significant. 
5.2.10 Safety Analyses 
Safety analyses will be conducted on the safety population. 
The safety of Givinostat will be assessed primarily by summarizing treatment-emergent 
AEs and SAEs. Other safety data (e.g., laboratory, ECG, PFTs, physical examination, 
and vital sign findings) will be summarized. Treatment-emergent AEs and SAEs that 
occur after administration of Givinostat will be summarized by system organ class and 
preferred terms, by severity, and by relationship to investigational product. Change from 


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baseline in laboratory values, ECG findings, PFTs, physical examination findings, and 
vital signs measurements will be summarized. 
5.2.11 Pharmacokinetic Analyses 
The PK analysis will be conducted on the PK population. 
Plasma concentrations from Part 1 will be listed and tabulated by dose and time point for 
all children and time points with at least 1 PK assessment. Plasma concentrations from 
Part 2 will be listed and tabulated by time point for all children and time points with at 
least 1 PK assessment. 
Descriptive statistics for all PK parameters for Part 1 will be calculated by treatment. 
Descriptive statistics for all PK parameters for Part 2 will also be calculated. These 
tables will include number of observations, mean, standard deviation, median, minimum 
and maximum and additionally the geometric mean and coefficient of variation (not for 
time to maximum plasma concentration). 
5.2.12 Interim Analyses 
The following interim analyses will be conducted: 
•
After the first 20 baseline biopsies are collected, the between-subject standard
deviation of MFA% fraction will be calculated, the actual distribution of MFA%
will be checked. The within-subject standard deviation will be estimated by
between-subject standard deviation under the “worst case” scenario, which
assumes that there is no correlation within a subject in the muscle area fiber
percentage between pre- and post-treatment.
•
Based on the standard deviation obtained above, the final sample size will be
adjusted. A conservative approach will be adopted, where the sample size may be
increased but not decreased.
5.2.13 Analysis at Month 12 
At 12 months, efficacy and safety analysis will be conducted, on the primary and 
secondary endpoints. If results show a positive effect on patients, and no safety concern 
is raised, then patients will continue study treatment for up to an additional 40 months 
(Extension 1 [12 months], Extension 2 [12 months], and Extension 3 [16 months]) to 
evaluate the safety and tolerability of long-term administration of Givinostat and to 
evaluate the effect of treatment on muscle function. If, on the other hand, the final 
analysis of the results of the first 12 months of treatment does not support a beneficial 
effect of Givinostat in DMD, the study will be considered complete. 


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6 Study Management 
6.1 Approval and Consent 
6.1.1 
Regulatory Guidelines 
The study will be performed in accordance with local national laws (as applicable), the 
guidelines of the ICH, and the guidelines of the Declaration of Helsinki adopted by the 
18th World Medical Assembly in Helsinki, Finland in 1964 and amended by subsequent 
assemblies in Tokyo, Japan in 1975; Venice, Italy in 1983; Hong Kong in 1989; Somerset 
West, South Africa in 1996, and in Edinburgh, Scotland in October 2000. These 
guidelines are on file at WCT. 
This clinical study has been designed to comply with the Good Clinical Practice 
guidelines. 
6.1.2 
Institutional Review Board/Independent Ethics Committees 
This study will be undertaken only after approval of the protocol has been obtained from 
the appropriate Independent Ethics Committee (IEC), and a copy of the approval has 
been received by Italfarmaco S.p.A. 
The IEC must be informed of all subsequent protocol amendments and should be asked 
whether a re-evaluation of the ethical aspects of the study is necessary. 
If applicable, interim reports on the study and reviews of its progress will be submitted to 
the IEC by the investigator at intervals stipulated in their guidelines. 
6.1.3 
Informed Consent 
For each trial subject, written informed consent from the legally accepted representative 
will be obtained prior to any protocol-related activities. Informed assent may be obtained 
from children who are capable of providing assent. As part of this procedure, the 
principal investigator or a designated representative must explain orally and in writing the 
nature, duration, and purpose of the study, and the action of the drug in such a manner 
that the child and (if applicable) appointed guardian are aware of the potential risks, 
inconveniences, or adverse effects that may occur. Children and their legally accepted 
representatives should be given ample time and opportunity to inquire about the details of 
the study prior to deciding whether to participate in the study. It is the responsibility of 
the investigator to ensure that all questions about the study are answered to the 
satisfaction of the children and their legally accepted representatives. 


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Children and their legally accepted representatives should be informed that children may 
withdraw from the study at any time. They will receive all information that is required 
by local regulations and ICH guidelines. The principal investigator or a designated 
representative will provide the sponsor or its representative with a copy of the 
IEC-approved informed consent form prior to the start of the study. 
The informed consent form should be signed and dated by the child’s legally accepted 
representative and the investigator on the same day. If the child and/or legally accepted 
representative are not able to read, an impartial witness should be present during the 
informed consent discussion, and the witness must co-sign and date the informed consent 
form. The child’s legally accepted representative and/or impartial witness should receive 
a copy of the signed documents. 
For details of the information provided, refer to the informed consent form. 
6.2 Discontinuation of the Study by the Sponsor 
The sponsor reserves the right to discontinue the study at this site or at multiple sites for 
safety or administrative reasons at any time. In particular, a site that does not recruit at a 
reasonable rate may be discontinued. Should the study be terminated and/or the site 
closed for whatever reason, all documentation and study medication pertaining to the 
study must be returned to the sponsor or its representative. 
6.3 Study Documentation 
The investigator will supply the sponsor with: 
•
Curricula vitae for all investigators
•
Signed protocol signature page
•
List of IEC members and their occupations/affiliations or multiple assurance
number
•
Letter indicating IEC approval to conduct the protocol
•
Copy of IEC-approved informed consent form
•
Laboratory certification records and reference ranges
The main documents that will be supplied by the Sponsor to investigator are: 
•
Clinical study protocol
•
Investigational drug brochure
•
Sample informed consent form
•
eCRFs/instruction manual
•
Insurance letter


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6.4 Study Monitoring and Auditing 
This study will be monitored at all stages of its development by the clinical research 
personnel employed by the sponsor or its representative. Monitoring will include 
personal visits and telephone communication to assure that the investigation is conducted 
according to protocol and in order to comply with guidelines of Good Clinical Practice. 
On-site review of eCRFs will include a review of forms for completeness and clarity, and 
consistency with source documents available for each child. Note that a variety of 
original documents, data, and records will be considered as source documents in this trial. 
The eCRF itself is not to be used as a source document under any circumstances. 
Medical advisors and clinical research associates or assistants may request to witness 
child evaluations occurring as part of this protocol. The investigator and appropriate 
personnel will be periodically requested to attend meetings/workshops organized by the 
sponsor to assure acceptable protocol execution. The study may be subject to audit by 
the sponsor or by regulatory authorities. If such an audit occurs, the investigator must 
agree to allow access to required child records. By signing this protocol, the investigator 
grants permission to personnel from the sponsor, its representatives, and appropriate 
regulatory authorities for on-site monitoring of all appropriate study documentation, as 
well as on-site review of the procedures employed in eCRF generation, where clinically 
appropriate. 
6.5 Retention of Records 
The investigator must arrange for retention of study records at the site. The nature of the 
records and the duration of the retention period must meet the requirements of the 
relevant regulatory authority. In addition, because this is an international study, the 
retention period must meet the requirements of the most stringent authority. The 
investigator should take measures to prevent accidental or premature destruction of these 
documents. 
6.6 Use of Study Findings 
By signing the study protocol, the investigator agrees to the use of results of the study for 
the purposes of national and international registration. If necessary, the authorities will 
be notified of the investigator’s name, address, qualifications, and extent of involvement. 
Reports covering clinical and biometric aspects of the study will be prepared by the 
sponsor or its representative. 
6.7 Publications 
The sponsor assures that the key design elements of this protocol will be posted in a 
publicly accessible database, such as clinicaltrials.gov. In addition, upon study 
completion and finalization of the study report the results of this study will be either 


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submitted for publication and/or posted in a publicly accessible database of clinical study 
results. 


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7 References 
Al-Sunduqchi MS. 1990. Determining the Appropriate Sample Size for Inferences Based on the 
Wilcoxon Statistics. Ph.D. dissertation under the direction of William C. Guenther, Dept. of 
Statistics, University of Wyoming, Laramie, Wyoming. 
American Thoracic Society. ATS Statement: Guidelines for the 6-Minute Walk Test. Am J Respir 
Crit Care Med 2002;166:111-117. 
Consalvi S, Saccone V, Giordani L, Minetti G, Mozzetta C, Puri PL. Histone deacetylase 
inhibitors in the treatment of muscular dystrophies: epigenetic drugs for genetic diseases. Mol 
Med. 2011 May-Jun;17(5-6):457-65. 
Desguerre I, Mayer M, Leturcq F, Barbet JP, Gherardi RK, Christov C. Endomysial fibrosis in 
Duchenne muscular dystrophy: a marker of poor outcome associated with macrophage alternative 
activation. J Neuropathol Exp Neurol 2009;68:762–773. 
Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne 
muscular dystrophy: improvements in life expectancy since 1967 and the impact of home 
nocturnal ventilation. Neuromuscul Disord. 2002;12(10):926-9. 
Emery AE. The muscular dystrophies. Lancet. 2002;359(9307):687-95. 
Iezzi S, Cossu G, Nervi C, Sartorelli V, Puri PL. Stage-specific modulation of skeletal 
myogenesis by inhibitors of nuclear deacetylases. Proc Natl Acad Sci U S A. 2002 May 
28;99(11):7757-62. 
ITF2357 Investigator’s Brochure. Edition No. 11.0. Release Date January 2012. 
Joe AW, Yi L, Natarajan A, Le Grand F, So L, et al. Muscle injury activates resident 
fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol 2010;12:153-63. 
Mayhew A, Eagle M, Mazzone E, et al. Performance of Upper Limb Module for DMD (PUL for 
DMD). Draft 1. March 31, 2012. 
Mercuri E, McDonald C, Mayhew A, et al. International workshop on assessment of upper limb 
function in Duchenne Muscular Dystrophy: Rome, 15-16 February 2012. Neuromuscul Disord 
2012 Jul 12. [Epub ahead of print] 
McDonald CM, Henricson EK, Abresch RT, et al. The 6-minute walk test and other endpoints in 
DMD: longitudinal natural history observations over 48 weeks from a multicenter study. Muscle 
Nerve. 2013;48(3):343-56 
Minetti GC, Colussi C, Adami R, et al. Functional and morphological recovery of dystrophic 
muscles in mice treated with deacetylase inhibitors. Nat Med. 2006 Oct;12(10):1147-50. 
Pane M, Mazzone ES, Sormani MP, et al. 6 minute walk test in Duchenne MD patients with 
different mutations: 12 month changes. PLoS One. 2014;9(1). 


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Sacco A, Doyonnas R, Kraft P, Vitorovic S, Blau HM. Self-renewal and expansion of single 
transplanted muscle stem cells. Nature. 2008 Nov 27;456(7221):502-6. 
Suárez AA, Pessolano FA, Monteiro SG, et al. Peak flow and peak cough flow in the evaluation 
of expiratory muscle weakness and bulbar impairment in patients with neuromuscular disease. 
Am J Phys Med Rehabil. 2002;81(7):506-11. 
Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct 
from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol 
2010;12:143-52. 


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8 Appendices 


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Appendix 1: Drugs Known to Prolong the QTc Interval 
Generic Name 
Drug Class / Clinical Usage 
Comments 
Risk List 
(Brand Name) 
Albuterol (Proventil®;Ventolin®) 
ß2-receptor agonist/Asthma 
Congenital QT Avoid 
Alfuzosin (Uroxatral®) 
Alpha1-blocker/Benign prostatic hyperplasia 
Possible Risk of TdP 
Amantadine (Symmetrel®) 
Dopaminergic/Anti-viral/Anti-infective/ 
Parkinson's Disease 
Possible Risk of TdP 
Amiodarone (Cordarone®) 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males,TdP risk regarded as 
low 
Risk of TdP 
Amiodarone (Pacerone®) 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males,TdP risk regarded as 
low 
Risk of TdP 
Amitriptyline (Elavil®) 
Tricyclic Antidepressant/depression 
Risk of TdP with overdosage 
Conditional TdP Risk 
Amphetamine (Dexedrine®) 
CNS stimulant/ADHD 
This includes dextroamphetamine and 
amphetamine / dextroamphetamine 
combinations. 
Congenital QT Avoid 
Amphetamine (Adderall® ) 
CNS stimulant/ADHD 
This includes dextroamphetamine and 
amphetamine / dextroamphetamine 
combinations. 
Congenital QT Avoid 
Arsenic trioxide (Trisenox®) 
Anti-cancer/Leukemia 
Risk of TdP 
Astemizole (Hismanal®) 
Antihistamine/Allergic rhinitis 
No Longer available in U.S. 
Risk of TdP 
Atazanavir (Reyataz® ) 
Protease inhibitor/HIV 
Possible Risk of TdP 
Atomoxetine (Strattera®) 
norepinephrine reuptake inhibitor /ADHD 
Congenital QT Avoid 
Azithromycin (Zithromax®) 
Antibiotic/bacterial infection 
Risk of TdP 
Bepridil (Vascor®) 
Anti-anginal/heart pain 
Females>Males 
Risk of TdP 
Chloral hydrate (Noctec®) 
Sedative/sedation/ insomnia 
Possible Risk of TdP 
Chloroquine (Aralen®) 
Anti-malarial/malaria infection 
Risk of TdP 
Chlorpromazine (Thorazine®) 
Anti-psychotic/ Anti-emetic/schizophrenia/ 
nausea 
Risk of TdP 
Ciprofloxacin (Cipro®) 
Antibiotic/bacterial infection 
Drug metabolism inhibitor- Risk for 
drug interactions 
Conditional TdP Risk 


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Generic Name 
Drug Class / Clinical Usage 
Comments 
Risk List 
(Brand Name) 
Cisapride (Propulsid®) 
GI stimulant/heartburn 
No longer available in the U.S.; 
available in Mexico 
Risk of TdP 
Citalopram (Celexa®) 
Anti-depressant/depression 
Risk of TdP 
Clarithromycin (Biaxin®) 
Antibiotic/bacterial infection 
Risk of TdP 
Clomipramine (Anafranil®) 
Tricyclic Antidepressant/depression 
Conditional TdP Risk 
Clozapine (Clozaril®) 
Anti-psychotic/schizophrenia 
Possible Risk of TdP 
Cocaine (Cocaine) 
Local anesthetic/ 
Cardiac stimulant 
Congenital QT Avoid 
Desipramine (Pertofrane®) 
Tricyclic Antidepressant/depression 
Risk of TdP with overdosage 
Conditional TdP Risk 
Dexmethylphenidate (Focalin®) 
CNS stimulant/ADHD 
Congenital QT Avoid 
Diphenhydramine (Benadryl®) 
Antihistamine/Allergic rhinitis, insomnia 
Risk of QT increase/TdP in 
overdosages 
Conditional TdP Risk 
Diphenhydramine (Nytol®) 
Antihistamine/Allergic rhinitis, insomnia 
Risk of QT increase/TdP in 
overdosages 
Conditional TdP Risk 
Disopyramide (Norpace®) 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Risk of TdP 
Dobutamine (Dobutrex®) 
Catecholamine/heart failure and shock 
Congenital QT Avoid 
Dofetilide (Tikosyn®) 
Anti-arrhythmic/abnormal heart rhythm 
Risk of TdP 
Dolasetron (Anzemet®) 
Anti-nausea/nausea, vomiting 
Possible Risk of TdP 
Domperidone (Motilium®) 
Anti-nausea/nausea 
Not available in the U.S. 
Risk of TdP 
Dopamine (Intropine®) 
Inotropic agent/heart failure; hypotension; 
shock 
Congenital QT Avoid 
Doxepin (Sinequan®) 
Tricyclic Antidepressant/depression 
Conditional TdP Risk 
Dronedarone (Multaq®) 
Anti-arrhythmic/Atrial Fibrillation 
Possible Risk of TdP 
Droperidol (Inapsine®) 
Sedative;Anti-nausea/anesthesia adjunct, 
nausea 
Risk of TdP 
Ephedrine (Broncholate®) 
Bronchodilator, decongestant/Allergies, 
sinusitis, asthma 
Congenital QT Avoid 
Ephedrine (Rynatuss®) 
Bronchodilator, decongestant/Allergies, 
sinusitis, asthma 
Congenital QT Avoid 


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Generic Name 
Drug Class / Clinical Usage 
Comments 
Risk List 
(Brand Name) 
Epinephrine (Primatene®) 
catecholamine, vasoconstrictor/anaphylaxis, 
allergic reactions 
Cardiac stimulant 
Congenital QT Avoid 
Epinephrine (Bronkaid®) 
catecholamine, vasoconstrictor/anaphylaxis, 
allergic reactions 
Cardiac stimulant 
Congenital QT Avoid 
Eribulin (Halaven® ) 
Anti-cancer/metastatic breast neoplasias 
Possible Risk of TdP 
Erythromycin (E.E.S.® ) 
Antibiotic;GI stimulant/bacterial infection; 
increase GI motility 
Females>Males 
Risk of TdP 
Erythromycin (Erythrocin®) 
Antibiotic;GI stimulant/bacterial infection; 
increase GI motility 
Females>Males 
Risk of TdP 
Escitalopram (Cipralex®) 
Anti-depressant/Major depression/ Anxiety 
disorders 
Possible Risk of TdP 
Escitalopram (Lexapro®) 
Anti-depressant/Major depression/ Anxiety 
disorders 
Possible Risk of TdP 
Famotidine (Pepcid®) 
H2-receptor antagonist/Peptic ulcer/ GERD 
Possible Risk of TdP 
Felbamate (Felbatrol®) 
Anti-convulsant/seizure 
Possible Risk of TdP 
Fenfluramine (Pondimin®) 
Appetite suppressant/dieting, weight loss 
Congenital QT Avoid 
Fingolimod (Gilenya®) 
Immunosuppressant/Multiple Sclerosis 
Possible Risk of TdP 
Flecainide (Tambocor®) 
Anti-arrhythmic/abnormal heart rhythm 
Risk of TdP 
Fluconazole (Diflucan®) 
Anti-fungal/fungal infection 
Drug metabolism inhibitor- Risk for 
drug interactions 
Conditional TdP Risk 
Fluoxetine (Prozac®) 
Anti-depressant/depression 
Conditional TdP Risk 
Fluoxetine (Sarafem®) 
Anti-depressant/depression 
Conditional TdP Risk 
Foscarnet (Foscavir®) 
Anti-viral/HIV infection 
Possible Risk of TdP 
Fosphenytoin (Cerebyx®) 
Anti-convulsant/seizure 
Possible Risk of TdP 
Galantamine (Reminyl®) 
Cholinesterase inhibitor/ Dementia, Alzheimer's 
Conditional TdP Risk 
Gatifloxacin (Tequin®) 
Antibiotic/bacterial infection 
Possible Risk of TdP 
Gemifloxacin (Factive®) 
Antibiotic/bacterial infection 
Possible Risk of TdP 
Granisetron (Kytril®) 
Anti-nausea/nausea and vomiting 
Possible Risk of TdP 
Halofantrine (Halfan®) 
Anti-malarial/malaria infection 
Females>Males 
Risk of TdP 


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Generic Name 
Drug Class / Clinical Usage 
Comments 
Risk List 
(Brand Name) 
Haloperidol (Haldol®) 
Anti-psychotic/schizophrenia, agitation 
When given intravenously or at 
higher-than- recommended doses, risk 
of sudden death, QT prolongation and 
torsades increases. 
Risk of TdP 
Ibutilide (Corvert®) 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Risk of TdP 
Iloperidone (Fanapt®) 
Antipsychotic, atypical/Schizophrenia 
Possible Risk of TdP 
Imipramine (Norfranil®) 
Tricyclic Antidepressant/depression 
Risk of TdP in overdosage 
Conditional TdP Risk 
Indapamide (Lozol®) 
Diuretic/stimulate urine & salt loss 
Possible Risk of TdP 
Isoproterenol (Isupres®) 
Catecholamine/allergic reaction 
Congenital QT Avoid 
Isoproterenol (Medihaler-Iso®) 
Catecholamine/allergic reaction 
Congenital QT Avoid 
Isradipine (Dynacirc®) 
Anti-hypertensive/high blood pressure 
Possible Risk of TdP 
Itraconazole (Sporanox®) 
Anti-fungal/fungal infection 
Drug metabolism inhibitor- Risk for 
drug interactions 
Conditional TdP Risk 
Ketoconazole (Nizoral®) 
Anti-fungal/fungal infection 
Drug metabolism inhibitor 
Conditional TdP Risk 
Lapatinib (Tykerb®) 
Anti-cancer/breast cancer, metastatic 
Possible Risk of TdP 
Lapatinib (Tyverb®) 
Anti-cancer/breast cancer, metastatic 
Possible Risk of TdP 
Levalbuterol (Xopenex® ) 
Bronchodilator/asthma 
Congenital QT Avoid 
Levofloxacin (Levaquin®) 
Antibiotic/bacterial infection 
Possible Risk of TdP 
Levomethadyl (Orlaam®) 
Opiate agonist/pain control, narcotic 
dependence 
Not available in the U.S. 
Risk of TdP 
Lisdexamfetamine (Vyvanse® ) 
CNS stimulant/ADHD 
Congenital QT Avoid 
Lithium (Eskalith®) 
Anti-mania/bipolar disorder 
Possible Risk of TdP 
Lithium (Lithobid®) 
Anti-mania/bipolar disorder 
Possible Risk of TdP 
Mesoridazine (Serentil®) 
Anti-psychotic/schizophrenia 
Risk of TdP 
Metaproterenol (Alupent®) 
Bronchodilator/asthma 
Congenital QT Avoid 
Metaproterenol (Metaprel®) 
Bronchodilator/asthma 
Congenital QT Avoid 
Methadone (Dolophine®) 
Opiate agonist/pain control, narcotic 
dependence 
Females>Males 
Risk of TdP 


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Generic Name 
Drug Class / Clinical Usage 
Comments 
Risk List 
(Brand Name) 
Methadone (Methadose®) 
Opiate agonist/pain control, narcotic 
dependence 
Females>Males 
Risk of TdP 
Methylphenidate (Ritalin®) 
CNS stimulant/ADHD 
Congenital QT Avoid 
Methylphenidate (Concerta® ) 
CNS stimulant/ADHD 
Congenital QT Avoid 
Midodrine (ProAmatine®) 
Vasoconstrictor/low blood pressure, fainting 
Congenital QT Avoid 
Moexipril/HCTZ (Uniretic®) 
Anti-hypertensive/high blood pressure 
Possible Risk of TdP 
Moxifloxacin (Avelox®) 
Antibiotic/bacterial infection 
Risk of TdP 
Nicardipine (Cardene®) 
Anti-hypertensive/high blood pressure 
Possible Risk of TdP 
Nilotinib (Tasigna® ) 
Anti-cancer/Leukemia 
Possible Risk of TdP 
Norepinephrine (Levophed®) 
Vasoconstrictor, Inotrope/shock, low blood 
pressure 
Congenital QT Avoid 
Nortriptyline (Pamelor®) 
Tricyclic Antidepressant/depression 
Conditional TdP Risk 
Octreotide (Sandostatin®) 
Endocrine/acromegaly, carcinoid diarrhea 
Possible Risk of TdP 
Ofloxacin (Floxin®) 
Antibiotic/bacterial infection 
Possible Risk of TdP 
Ondansetron (Zofran®) 
Anti-emetic/nausea and vomiting 
Possible Risk of TdP 
Oxytocin (Pitocin®) 
Oxytocic/Labor stimulation 
Possible Risk of TdP 
Paliperidone (Invega®) 
Antipsychotic, atypical/Schizophrenia 
Possible Risk of TdP 
Paroxetine (Paxil®) 
Anti-depressant/depression 
Conditional TdP Risk 
Pentamidine (NebuPent®) 
Anti-infective/pneumocystis pneumonia 
Females>Males 
Risk of TdP 
Pentamidine (Pentam®) 
Anti-infective/pneumocystis pneumonia 
Females>Males 
Risk of TdP 
Perflutren lipid microspheres 
(Definity® ) 
Imaging contrast agent/Echocardiography 
Possible Risk of TdP 
Phentermine (Fastin®) 
Appetite suppressant/dieting, weight loss 
Congenital QT Avoid 
Phentermine (Adipex®) 
Appetite suppressant/dieting, weight loss 
Congenital QT Avoid 
Phenylephrine (Neosynephrine®) 
Vasoconstrictor, decongestant/low blood 
pressure, allergies, sinusitis, asthma 
Congenital QT Avoid 
Phenylpropanolamine (Acutrim®) 
Decongestant/allergies, sinusitis, asthma 
No longer available in the U.S. 
Congenital QT Avoid 
Phenylpropanolamine (Dexatrim®) 
Decongestant/allergies, sinusitis, asthma 
No longer available in the U.S. 
Congenital QT Avoid 


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Generic Name 
Drug Class / Clinical Usage 
Comments 
Risk List 
(Brand Name) 
Pimozide (Orap® ) 
Anti-psychotic/Tourette's tics 
Females>Males 
Risk of TdP 
Probucol (Lorelco®) 
Antilipemic/Hypercholesterolemia 
No longer available in U.S. 
Risk of TdP 
Procainamide (Pronestyl®) 
Anti-arrhythmic/abnormal heart rhythm 
Risk of TdP 
Procainamide (Procan® ) 
Anti-arrhythmic/abnormal heart rhythm 
Risk of TdP 
Protriptyline (Vivactil®) 
Tricyclic Antidepressant/depression 
Conditional TdP Risk 
Pseudoephedrine (PediaCare®) 
Decongestant/allergies, sinusitis, asthma 
Congenital QT Avoid 
Pseudoephedrine (Sudafed®) 
Decongestant/allergies, sinusitis, asthma 
Congenital QT Avoid 
Quetiapine (Seroquel® ) 
Anti-psychotic/schizophrenia 
Possible Risk of TdP 
Quinidine (Quinaglute®) 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Risk of TdP 
Quinidine (Cardioquin® ) 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Risk of TdP 
Ranolazine (Ranexa® ) 
Anti-anginal/chronic angina 
Possible Risk of TdP 
Risperidone (Risperdal® ) 
Anti-psychotic/schizophrenia 
Possible Risk of TdP 
Ritodrine (Yutopar®) 
Uterine relaxant/prevent premature labor 
Congenital QT Avoid 
Ritonavir (Norvir®) 
Protease inhibitor/HIV 
Conditional TdP Risk 
Roxithromycin* (Rulide®) 
Antibiotic/bacterial infection 
*not available in the United States
Possible Risk of TdP 
Salmeterol (Serevent® ) 
Sympathomimetic/asthma, COPD 
Congenital QT Avoid 
Sertindole (Serdolect®) 
Antipsychotic, atypical/Anxiety, Schizophrenia 
Possible Risk of TdP 
Sertindole (Serlect®) 
Antipsychotic, atypical/Anxiety, Schizophrenia 
Possible Risk of TdP 
Sertraline (Zoloft®) 
Anti-depressant/depression 
Conditional TdP Risk 
Sibutramine (Meridia®) 
Appetite suppressant/dieting, weight loss 
Congenital QT Avoid 
Solifenacin (VESIcare®) 
muscarinic receptor antagonist/treatment of 
overactive bladder 
Conditional TdP Risk 
Sotalol (Betapace® ) 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Risk of TdP 
Sparfloxacin (Zagam® ) 
Antibiotic/bacterial infection 
Risk of TdP 
Sunitinib (Sutent®) 
Anti-cancer/RCC, GIST 
Possible Risk of TdP 
Tacrolimus (Prograf®) 
Immunosuppressant/Immune suppression 
Possible Risk of TdP 
Tamoxifen (Nolvadex® ) 
Anti-cancer/breast cancer 
Possible Risk of TdP 


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Generic Name 
Drug Class / Clinical Usage 
Comments 
Risk List 
(Brand Name) 
Telithromycin (Ketek®) 
Antibiotic/bacterial infection 
Possible Risk of TdP 
Terbutaline (Brethine®) 
Bronchodilator/asthma 
Congenital QT Avoid 
Terfenadine (Seldane®) 
Antihistamine/Allergic rhinitis 
No longer available in U.S. 
Risk of TdP 
Thioridazine (Mellaril® ) 
Anti-psychotic/schizophrenia 
Risk of TdP 
Tizanidine (Zanaflex® ) 
Muscle relaxant/ 
Possible Risk of TdP 
Tolterodine (Detrol®) 
Bladder Antispasmodic/ 
Congenital QT Avoid 
Tolterodine (Detrol LA®) 
Bladder Antispasmodic/ 
Congenital QT Avoid 
Trazodone (Desyrel®) 
Anti-depressant/Depression, insomnia 
Conditional TdP Risk 
Trimethoprim-Sulfa (Bactrim®) 
Antibiotic/bacterial infection 
Conditional TdP Risk 
Trimethoprim-Sulfa (Sulfa®) 
Antibiotic/bacterial infection 
Conditional TdP Risk 
Trimipramine (Surmontil®) 
Tricyclic Antidepressant/depression 
Conditional TdP Risk 
Vandetanib (Caprelsa®) 
Anti-cancer/Thyroid cancer 
Risk of TdP 
Vardenafil (Levitra® ) 
phosphodiesterase inhibitor/vasodilator 
Possible Risk of TdP 
Venlafaxine (Effexor® ) 
Anti-depressant/depression 
Possible Risk of TdP 
Voriconazole (VFend® ) 
Anti-fungal/anti-fungal 
Possible Risk of TdP 
Ziprasidone (Geodon® ) 
Anti-psychotic/schizophrenia 
Possible Risk of TdP 
Source: Arizona Center for Education and Research on Therapeutics. Link: http://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/. The last revision date: 22 
Sep 2013. Accessed 02 Oct 2013. 


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Protocol Amendment 7 
Summary of Changes 
Italfarmaco S.p.A 
A Two-Part Study to Assess the Safety and Tolerability, Pharmacokinetics, and Effects on 
Histology and Different Clinical Parameters of Givinostat in Ambulant Children with 
Duchenne Muscular Dystrophy 
Protocol No.:  DSC/11/2357/43 
Rationale for Amendment 
1. The amendment is planned to allow the patients on treatment in the third extension phase of the
study to continue for additional 4 months until the activation of the Long Term Safety study
(Study N. DSC/14/2357/51 - EUDRACT: 2017-000397-10), that will be submitted to the Ethic
Committees and for which the Sponsor estimates to obtain the approval within October 2017.
In this way the patients who accept to be included in the Long Term Safety study will continue
the treatment with Givinostat, without any interruptions.
The Long Term Safety Study will be submitted on April 2017 to AIFA and to the participating
sites in study DSC/11/2357/43 and it will be activated as soon as the approval is available.
2. Minor editorial changes were made throughout the document for maintaining accuracy,
consistency, and clarity.


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Summary of Changes 
The following changes were made to the protocol. Additions to the protocol are denoted in bold. 
Deletions are in strikethrough. Order of paragraphs and section numbering reflect the amended 
protocol. 
SYNOPSIS 
Design: 
[…] EXTENSION 3 
A third extension phase is foreseen in order to allow the patients to continue a study treatment that 
supports a beneficial effect of Givinostat in DMD. The children on treatment in the Extension 2 will 
be asked to continue in the Extension 3 and will receive Givinostat at the same ongoing dose for a 
maximum of an additional 12 months. During Extension 3, the dose will be adjusted based on the 
weight of the children. 
This part of the study will be additionally extended until the activation of the Long Term 
Safety Study (Study N. DSC/14/2357/51 - EUDRACT: 2017-000397-10). 
Treatments: 
[…] Moreover, children who will be enrolled in the extension phases will receive Givinostat at the 
same ongoing dose (during the last visit planned at 12 months of treatment) for a maximum of an 
additional 36 40 months (12 months for Extension 1, 12 months for Extension 2, and 12 16 months 
for Extension 3). 
Additional children may be enrolled as needed during Part 2 to reach the sample size calculated after 
the interim analysis. Children who enroll during Part 2 will receive up to 12 or 48 months (if they 
will be enrolled in the extension phases) of treatment with Givinostat at the RD. During Extensions 
2 and 3, the dose will be adjusted based on the weight of the children.  The total duration of the 
study is anticipated to be 15 months, and an additional 36 40 months for Extension 1 (12 months), 
Extension 2 (12 months), and Extension 3 (12 16 months). 
Main Parameters of Efficacy: 
Extension Phases: 
As secondary endpoints, the change in muscular function after 24 months, 36 months, and 48 
52 months (Extension 1, Extension 2, and Extension 3, respectively) of treatment with Givinostat as 
assessed by 6MWT, NSAA, and PUL will be investigated. For the children that are not able to 
complete the 6MWT, the time to wheelchair and how much time the children spend in wheelchair 
were assessed. 


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2.
Study Objectives
Secondary Efficacy Endpoints
The secondary efficacy endpoints of the extension phases are as follows:
•
Change of muscular function (including loss of ambulation) after 24, 36, and 48 52 months
of treatment with Givinostat at the selected daily dose based on the 6MWT
•
Change in muscular function after 24, 36, and 48 52 months of treatment with Givinostat
at the selected daily dose based on the NSAA
•
Change in muscular function after 24, 36, and 48 52 months of treatment with Givinostat
at the selected daily dose based on the PUL
3. Investigational Plan
3.1 Description of Overall Study Design and Plan
[…] The additional children (if any) will be enrolled during Part 2 of the study and will receive the 
RD of Givinostat up to 36 40 months. 


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Table 1 
Treatment Table – Part 1 and Part 2 
PART 1 
PART 2 
Treatment Visitc 
Treatment Visitc 
Subject 
1 
2a 
3 
4a
5 
6a
1 
2 
3 
4 
5 
6 
7 
8 
9 
10b 
1–4 
5–12 
13–20 
Additional 
children 
(if any) 
a At the end of Week 2 (Visit 2) at every dose level, a safety check is foreseen. 
b At the end of Month 12, an efficacy analysis on biopsy results and functional tests is foreseen, and a decision to consider the 
study complete or to continue the study for up to another 36 40 months (extension phases [Extension 1, 12 months and Extension 
2, 12 months and Extension 3, 12 16 months]) will be taken. 
c The visits during Part 1 will be performed every 7 days (±1 day); the visits during Part 2 will be performed periodically every 1 – 
1.5 months (±7 days). 
Legend: 
25 – 37.5 mg BID – low dose level 
Intermediate dose level 
High dose level 
Recommended dose level 
3.1.1 Extension Phases 
EXTENSION 2 
[…] The patient will receive Givinostat at the same ongoing dose, during the last visit planned at 
12 months, and will be treated for a maximum of an additional 24 28 months (Month 36 40). The 
dose can be reduced or increased according to the dose modification criteria, specified below 
(Section 3.3.5). 
EXTENSION 3 
In February 2015, the results were available and they have shown that the treatment with Givinostat 
significantly increases the amount of muscle in the biopsies and significantly reduces the amount of 
fibrotic tissue. Moreover treatment with Givinostat significantly reduces tissue necrosis and fatty 
replacement, 2 other parameters related to disease progression. Function tests have shown overall 


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stability, although the sample size of the study is too small to draw definitive conclusions. Finally, 
the drug was well tolerated. 
Based on these results, a third extension phase is foreseen in order to allow the patients to continue a 
study treatment that supports a beneficial effect of Givinostat in DMD. The children on treatment in 
the Extension 2 will be asked to continue in the Extension 3 and will receive Givinostat at the same 
ongoing dose for a maximum of an additional 12 16 months. 
The extension 3 will be additionally extended by 4 months, until the activation of the Long 
Term Safety Study (Study N. DSC/14/2357/51 - EUDRACT: 2017-000397-10). 
The patient will receive Givinostat at the same ongoing dose, during the last visit planned at 
12 months (at PART 2), and will be treated for a maximum of an additional 36 40 months (Month 
48 52). The dose can be reduced or increased according to the dose modification criteria, specified 
below (Section 3.3.5). 
During the extension phases 1 and 2 of the study, children will visit the center every 2 months, for a 
total of 6 visits during Extension 1 (from Visit 11 to Visit 16) and a further 6 visits for Extension 2 
(Visit 17 to Visit 22), and every 4 months during Extension 3 for 3 4 visits (Visit 23 to Visit 25 26). 
3.2.3 Removal of Children from Therapy or Assessment 
[…] The children included in the extension phases will be considered to have completed the study 
when they complete the 12-month end-of-extension study visit (Visit 16) for Extension phase 1, the 
36-month end-of-extension study visit (Visit 22) for Extension phase 2, and the 48 52-month-end-of- 
extension study visit (Visit 25 26) for Extension phase 3. If the extension phases are stopped due to
negative results of Part 2 or the child is discontinued from the study treatment, the child will be asked
to attend the early termination and follow-up  assessments  as  shown  in  Section  3.4.6  and  Section
3.4.10, respectively.
3.3.3 Treatment Assignment 
All children will receive study drug. Children enrolled in Part 1 of the study will start to take either 
the low, intermediate, or high dose, depending on the needs of the study at the time of enrollment and 
they will switch to the RD when the review team decide that this dose is safe (see Table 8). 
When the safety review team has determined the RD, all children currently on study drug will be 
switched to that dose (the RD), and Part 2 of the study will commence. All children who enroll during 
Part 2 (if applicable) of the study will be given the RD of Givinostat. 
Children who will be included in the extension phases will be treated at the same ongoing dose during 
the last visit planned at 12 months and will be treated for a maximum of an additional 36 40 months 


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(Month 48 52). During Extension 2 and Extension 3, the dose will be adjusted based on the weight of 
the children. 
3.3.4 Treatment Assignment 
[…] For the extension phases (Extension 1 [12 months], Extension 2 [12 months], and Extension 3 
[12 16 months]), at each scheduled visit, the investigator will supply the children with the appropriate 
number of suspension bottles sufficient to cover the treatment for 2 months during Extensions 1 and 
2 and every 4 months during Extension 3. 


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Table 2 
Schedule of Assessments: Extension Phases 
Assessment 
Extension Phase 1 
Extension Phase 2 
Extension Phase 3 
Months 
14 
16 
18 
20 
22 
24/ 
EOSc
FU* 
26 
28 
30 
32 
34 
36/ 
EOSc
FU* 
40 
44 
48/ 
EOS 
52/ 
EOSc
FU 
Visit N. 
(1-week window for V11-V24; 
1 month window for V25 and V26) 
11 
12 
13 
14 
15 
16 
NA 
17* 
* 
18 
19 
20 
21 
22 
NA 
23 
24 
25 
25 26 
NA 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGa
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECHOa
X 
X 
X 
X 
PFTs (FEV1, FVC, FEV1/FVC, 
PEF)a
X 
X 
X 
X 
Clinical laboratory testsa,b
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisa,b
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xd 
Xd 
Xd 
Xd
Xd
Quality of life test 
X 
X 
X 
X 
Muscle evaluations (6MWT, NSAA, 
PUL) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; 6MWT=6-Minute Walk Test; ECG=electrocardiogram; EOS=end of study; FEV1= forced expiratory volume at 1 second; FU=follow up; FVC= 
forced vital capacity; MRI=magnetic resonance imaging; NA=Not applicable; NSAA=North Star Ambulatory assessment; PEF=peak expiratory flow; PFT=pulmonary 
function test; PUL= performance of upper limb 
* To be performed only if the child does not continue the treatment in Extension 2 after Extension 1 and Extension 3 after Extension 2.
** LTBP4 and osteopontin genotype information Note: A subject may return for an unscheduled visit at the discretion of Investigator to undergo additional safety


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evaluations (i.e., laboratory re-testing, AE assessments), or for additional medical evaluations. Platelet count may be assessed at an unscheduled visit if deemed 
necessary by the Investigator. 
a To be performed more frequently, if clinically indicated. 
b The following laboratory parameters will be assessed: Hematology: RBC, hemoglobin, hematocrit, WBC with differential, platelets, ANC, and abnormal cells; Blood 
chemistry: total bilirubin, alkaline phosphatase, amylase, ALT, AST, LDH, CRP, creatine kinase, total protein, albumin, uric acid, sodium, potassium, chloride, 
calcium, glucose, creatinine, BUN, and CrCl (CrCl will be calculated by the Cockcroft and Gault formula). Urinalysis: pH, specific gravity, protein, glucose, ketones, 
cytology, and myoglobin. 
c If the child is discontinued from the study treatment, the child will be asked to return for the early termination procedures. For the assessments to be performed, see 
“EOS visit”. Discontinued children will also have follow-up procedures performed within 4 weeks of the last dose of study drug. 
d Urinalysis: pH, specific gravity, protein, glucose, ketones and cytology. 


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3.4.9 Extension Phase 3 Visits (Months 40 to 44 48) 
Extension phase 3 will start at the EOS visit (Visit 22 [Month 36]). As noted in the schedule of 
assessments during Extension 3, for Months 40 to 48 52, children will visit the study center at Visits 
23 to 25 26 (i.e., every 4 months). The time window for Visits 23 and 24 is ± 1 week; the time 
window for Visits 25 and 26 is ± 1 month. 
At each visit (unless otherwise indicated), the following assessments will be performed and 
recorded: 
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Measure weight.
•
Measure height (Visit 25 [Month 48] only)
•
Obtain a 12-lead ECG in triplicate.
•
Obtain blood sample for hematology and blood chemistry.
•
Obtain a urine sample for urinalysis.
•
Obtain muscle evaluations (6MTW, NSAA, and PUL) at Visit 40 and Visit 44 only
•
Dispense IMP and perform accountability.
•
Assess AEs.
3.4.10 Assessments for End of Extension Phase 3 (Visit 25 26 [Month 48 52]) 
For children who continue in Extension 3, the end of the extension phase visit will be performed on 
Month 48 52 (Visit 25 26) ± 1 month. 
The following assessments will be performed and recorded: 
•
Obtain and record concomitant medications.
•
Perform a physical examination.
•
Measure vital signs: blood pressure, pulse rate, body temperature.
•
Measure height and weight.
•
Obtain a 12-lead ECG in triplicate.
•
Obtain an ECHO.
•
Obtain PFT measurements: FEV1, FVC, FEV1/FVC, and PEF.
•
Obtain blood samples for hematology and blood chemistry.
•
Obtain a urine sample for urinalysis.
•
Obtain muscle evaluations (6MWT, NSAA, and PUL).
•
Perform accountability.


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•
Perform a quality of life test.
•
Assess AEs.
3.4.11 Early Termination Visit 
Children who discontinue participation prior to completion of all study drug administration (i.e., 
12 months of treatment or 36 months 52 months of treatment if the children continue in the 
extension phases) will be asked to return to the hospital within 2 weeks after the last dose of study 
drug for completion of the same assessments given at the EOS visit (for details, see Section 3.4.4 or 
Section 3.4.6, if applicable). 
3.4.13 Description of Assessments 
[…] 
Safety Assessments 
Adverse Events: An AE is any is “any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment (International Conference on Harmonisation [ICH] E2A).” 
Quality of Life Assessment 
The PedsQL Test will be performed before treatment start, at Visit 10 (12 months), and at the end of 
the extension phases at 24, 36 and 52 months for Extension 1, 2 and 3 and Extension 2, respectively, 
if applicable. 
5.2.5 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following: 
[…] 
Change in muscular function after 12 months of treatment with Givinostat at the selected daily dose 
based on the PUL. 
The secondary efficacy endpoints of the extension phases are the change of muscular function 
(including loss of ambulation) after 24, 36, and 48 52 months of treatment (Extension 1, Extension 
2, and Extension 3, respectively) with Givinostat as assessed by 6MWT, NSAA, and PUL. For the 
children who are not able to complete the 6MWT, the time to wheelchair and how much time the 
children spend in wheelchair were assessed. 


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5.2.13. Analysis at Month 12 
At 12 months, efficacy and safety analysis will be conducted, on the primary and secondary endpoints. 
If results show a positive effect on patients, and no safety concern is raised, then patients will continue 
study treatment for up to an additional 36  40  months  (Extension  1  [12  months],  Extension  2  [12 
months], and Extension 3 [12 16 months]) to evaluate the safety and tolerability of long-term 
administration of Givinostat and to evaluate the effect of treatment on muscle function. If, on the other 
hand, the final analysis of the results of the first 12 months of treatment does not support a beneficial 
effect of Givinostat in DMD, the study will be considered complete. 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A Two-Part Study to Assess the Safety and Tolerability, Pharmacokinetics, 
and Effects on Histology and Different Clinical Parameters of Givinostat in 
Ambulant Children with Duchenne Muscular Dystrophy 
Protocol Ref: DSC/11/2357/43 
Version: Final Version 3.0 
Date effective: 10-January-18 
NCT01761292 
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16.1.9 
Documentation of Statistical Methods 
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Table of Contents
16.1.9 Documentation of Statistical Methods ................................................................................
Table of Contents .....................................................................................................................
STATISTICAL ANALYSIS PLAN DSC/11/2357/43, Version 3.0 - 10 January 2018 .........
1
2
3
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STATISTICAL ANALYSIS PLAN 
A Two-Part Study to Assess the Safety and Tolerability, Pharmacokinetics, and Effects on 
Histology and Different Clinical Parameters of Givinostat in Ambulant Children with 
Duchenne Muscular Dystrophy 
Protocol Ref: DSC/11/2357/43 
Version: Final Version 3.0 
Date effective:  10-January-18 
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SUMMARY OF SECTIONS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................... 5
1.
INTRODUCTION ............................................................................................................... 8
2.
SAMPLE SIZE.................................................................................................................. 10
3.
RANDOMIZATION .......................................................................................................... 10
4.
INTERIM ANALYSIS ....................................................................................................... 10
5.
Statistical methods ............................................................................................................. 11
5.1 Continuous ................................................................................................................... 11
5.2 Categorical ................................................................................................................... 11
6.
Analysis Plan .................................................................................................................... 12
6.1 General ........................................................................................................................ 12
6.2 Derived Data ................................................................................................................ 12
6.3 Analysis populations ...................................................................................................... 17
6.4 Protocol Deviations ....................................................................................................... 18
6.5 Data Summaries ............................................................................................................ 18
6.6 Disposition of Subjects .................................................................................................. 19
6.7 Baseline Comparability .................................................................................................. 20
6.7.1
Variables Considered ........................................................................................ 20
6.8 Concomitant medications ............................................................................................... 35
6.9 Measurement of Treatment Compliance ........................................................................... 36
6.10 
Primary Endpoint........................................................................................................ 36
6.11 
Principal Analysis ....................................................................................................... 36
6.11.1 
Sensitivity Analysis ............................................................................................. 37
6.11.2 
Exploratory Analysis ............................................................................................ 37
6.12 
Secondary Endpoints ................................................................................................... 37
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6.12.1
Additional histological endpoints ........................................................................... 37
6.12.2
Change in muscular function based on the 6MWT at End of Study/End of Extension phases
6.12.3
Change in muscular function based on the NSAA at End of Study/End of Extension phases
6.12.4
By Osteopontin (TT vs GT+GG) Change in muscular function based on the PUL at End of 
Extension phase ................................................................................................................. 40
6.12.5
Change in muscular function based on the Histology parameters at End of Study ........ 40
6.12.6
Proportion of patients who loss the ambulation at End of Study/End of Extension phases
6.13 
Exploratory Analysis ................................................................................................... 41
6.14 
Multiplicity ................................................................................................................ 42
6.15 
Safety analysis ........................................................................................................... 42
6.15.1
Extent of exposure ............................................................................................... 42
6.15.2
Adverse Events ................................................................................................... 42
6.15.3
Clinical Laboratory Evaluations ............................................................................ 43
6.15.4
Pulmonary function tests (PFTs) ............................................................................ 44
6.15.5
Echocardiographs ................................................................................................ 44
6.15.6
Vital Signs ......................................................................................................... 44
6.15.7
ECG .................................................................................................................. 44
6.15.8
Physical Examination ........................................................................................ 45
6.15.9
Concomitant medications .................................................................................. 45
6.16
Pharmacokinetic Analysis ............................................................................................ 46
6.17
Key Data Items ........................................................................................................... 47
6.18
Change to Planned Protocol Analysis ............................................................................ 47
6.19
Post-Hoc Analysis ...................................................................................................... 47
7.
TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT .................................... 49
......................................................................................................................................... 40 
........................... ................................................................................................................. 40 
......................................................................................................................................... 40 
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8.
FIGURES TO BE INCLUDED IN THE CLINICAL STUDY REPORT .................................. 68
9.
APPENDIX 16.2 LISTINGS ............................................................................................... 72
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
6MWT 
6-Minute Walk Test
6MWD 
6-Minute Walk Distance
Ab 
Antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma–
concentration time curve 
BID 
twice daily 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CL 
clearance 
CL/F 
volume of distribution 
cm 
Centimeter 
Cmax 
maximum plasma concentration 
CMV 
Cytomegalovirus 
CPK 
creatine phosphokinase 
CrCl 
creatinine clearance 
CRP 
C-reactive protein
CSA 
cross-sectional area 
CSOM 
Clinical Study Operations 
Manual  
DMD 
Duchenne muscular dystrophy 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECHO 
Echocardiograph 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent 
assay  
EOS 
end of study 
FACS 
fluorescence-activated cell 
sorting  
FAP 
fibroadipongenic progenitors 
FEV1 
forced expiratory volume at 1 
second  
FU 
follow up 
FVC 
forced vital capacity 
GI 
Gastrointestinal 
h 
hour 
H&E 
hematoxylin and eosin 
HbeAg 
hepatitis B e antigen 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HDAC 
histone deacetylase 
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HIV 
human immunodeficiency virus 
ICH 
International Conference on 
Harmonisation  
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IL 
interleukin 
IMP 
investigational medicinal product 
ITT 
intent to treat 
JIA 
juvenile idiopathic arthritis 
KA 
absorption rate constant 
kg 
kilogram 
L 
liter 
LDH 
lactate dehydrogenase 
LTBP4 
latent transforming growth factor 
beta binding protein 4  
m 
Meter 
MFA% 
muscle fibers area % 
mg 
Milligram 
miRNA 
micro ribonucleic acid 
mL 
Milliliter 
MRI 
magnetic resonance imaging 
msec 
Millisecond 
MTD 
maximum-tolerated dose 
MuSC 
muscle satellite cells 
ng 
nanogram 
nmol 
nanomole 
NOAEL 
no observed adverse effect level 
NSAA 
North Star Ambulatory 
Assessment  
PD 
Pharmacodynamic 
PDGFR 
platelet-derived growth factor 
receptor  
PEF 
peak expiratory flow 
PET 
polyethylene terephthalate 
PFT 
pulmonary function tests 
PK 
Pharmacokinetic 
PUL 
performance of upper limb 
QT 
QT interval 
QTc 
QT interval – corrected 
RBC 
red blood cells 
RD 
recommended dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOJIA 
systemic onset juvenile idiopathic 
arthritis  
SWI/SNF 
switch/sucrose non-fermentable 
TNF-α 
tumor necrosis factor-alpha 
V/F 
plasma volume 
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V2/F 
peripheral volume 
WBC 
white blood cells 
WCT 
Worldwide Clinical Trials 
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1.
INTRODUCTION
This document details the statistical analysis of the data that will be performed for the 
Italfarmaco S.p.A. study DSC/11/2357/43.  
The proposed analysis is based on the contents of the Final Version of the protocol (dated       
01 Aug 2012) and amendments 1, 2, 3, 4, 5, 6 and 7 (dated 05 Dec 2012, 25 Mar 2013, 23 
Oct 2013, 17 Apr 2014, 16 Mar 2015, 06 Jan 2016 and 11 Apr 2017 respectively). 
The Clinical Study Report (CSR) will be written by WCT following the guidelines in the 
ICH E3 document. 
The efficacy and safety analyses will be performed by Worldwide Clinical Trials (WCT). 
The pharmacokinetic (PK) analyses will be performed by Accelera. 
The primary objectives of this study are as follows: 

To establish the histologic effects of Givinostat administered chronically at the
selected daily dose
The secondary objectives of this study are as follows: 

To establish the effects of Givinostat administered chronically at the selected
daily dose on functional parameters, such as the 6-Minute Walk Test (6MWT),
North Star Ambulatory Assessment (NSAA), and performance of upper limb
(PUL)

To establish the safety and tolerability of Givinostat administered chronically at
the selected daily dose in children with Duchenne muscular dystrophy (DMD)

To explore the effects of Givinostat administered chronically at the selected
daily dose on parameters such as magnetic resonance imaging (MRI) and
biomarkers

To explore the acceptability/palatability of the oral suspension

To explore whether the effects of Givinostat on disease progression may be
related to the type of DMD mutation
Extension phase: 

The primary objective is to evaluate the safety and tolerability of long-term
administration of Givinostat administered chronically at the selected daily dose
in children with DMD.
The secondary objectives are: 
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
To establish the effects of Givinostat administered chronically at the selected
daily dose on other functional parameters, such as the 6MWT, NSAA, and PUL

To explore the effects of Givinostat administered chronically at the selected
daily dose on parameters such as MRI

To collect information related to 2 biomarkers, LTBP4 and osteopontin genotype
(at the beginning of Extension 2 only).
The analysis populations of this study are as follows (see section 6.3 for definition): 

Intent-to-treat (ITT) Population

Evaluable Population

Completers Population

Safety Population

PK Population
This is a 2-part, phase 2 study to assess the effects of Givinostat on muscle histologic 
parameters and on clinical parameters in ambulant children with DMD. The safety, 
tolerability, and pharmacokinetics of Givinostat will also be assessed. 
Approximately 20 children will be enrolled in the study as follows:  
The first 4 children will be treated at a low dose level of Givinostat. 
If none of the stopping criteria are met after 2 weeks of treatment at the low dose, the 
review team will determine the escalated dose level (i.e., intermediate dose level) to be used 
for the treatment of an additional 8 children who will be treated at the intermediate dose. 
The 4 children previously treated at the low dose level will also be switched to the 
intermediate dose level. 
If none of the stopping criteria are met after 2 weeks of treatment at the intermediate dose, 
the review team will determine the subsequent escalated dose level to be used for the 
treatment of an additional 8 children who will be treated at the high dose. All children 
treated at the intermediate dose level will be switched to the high dose level.  
Once all 20 children enrolled during the Part 1 of the study have been treated for at least 2 
weeks, the review team will determine the RD to be used in Part 2 based on the safety and 
tolerability profile observed and on the PK analyses. All the children enrolled will switch to 
the RD level, which will be administered for the subsequent 12 months of the study (Part 2). 
The additional children (if any) will be enrolled during Part 2 of the study and will receive 
the RD of Givinostat for 12 months. 
At 12 months, efficacy and safety analysis will be conducted. If the results show a positive 
effect on patients, and no safety concern is raised, then patients will continue study 
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treatment for another 12 months (Extension phase 1) to evaluate the safety and tolerability 
of long-term administration of Givinostat and to evaluate the effect of treatment on muscle 
function. If, on the other hand, the final analysis of the results of the first 12 months of 
treatment does not support a beneficial effect of Givinostat in DMD, the study will be 
considered complete and the patient will be asked to discontinue the treatment and return to 
the site for early termination assessments (within 2 weeks after the last study drug intake) 
and follow up assessments (within 4 weeks after the last study drug intake). This extension 
phase will be up to 24 months. 
Since the histology results of the first 12 months of treatment are positive, a second 
extension phase is foreseen in order to allow the patients to continue a study treatment that 
supports a beneficial effect of Givinostat in DMD. The children on treatment in the 
Extension 1 will be asked to continue in the Extension 2 and will receive Givinostat at the 
same ongoing dose for a maximum of an additional 12 months. During Extension 2, the 
dose will be adjusted based on the weight of the children. This extension phase will be up to 
36 months. 
A third extension phase is foreseen in order to allow the patients to continue a study 
treatment that supports a beneficial effect of Givinostat in DMD. The children on treatment 
in the Extension 2 will be asked to continue in the Extension 3 and will receive Givinostat 
at the same ongoing dose for a maximum of an additional 16 months. During Extension 3, 
the dose will be adjusted based on the weight of the children. This extension phase will be 
up to 52 months. 
2.
SAMPLE SIZE
The sample size estimation was based on the following assumptions: 
A minimum of 20 evaluable children will be enrolled in this study.  
In part 1 approximately 20 children will be enrolled in Part 1 (dose-finding) of this study. 
A sample size of 20 children from part 1 completing the treatment period of part 2 should 
provide 90% power (at a 2-sided alpha level of 5%) to detect at least a 12.5% increase in 
muscle fiber area% (MFA%) between pre- and post-treatment (which corresponds 
approximately to a 26% relative increase given the observed mean in the Desguerre1 
publication of 48%), the “worst case” standard deviation of 16%, which assumes that there 
is no correlation within a subject in the muscle area fiber percentage between pre- and post-
treatment. This sample size is based on a paired t-test and the assumption of normal 
distribution of MFA%.  
3.
RANDOMIZATION
This is a non-randomized trial, all subjects will receive study drug. 
4.
INTERIM ANALYSIS
After the first 20 baseline biopsies were collected, an interim analysis aimed at checking the 
real variability observed in the study was conducted: the within-subject standard deviation 
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of MFA% was calculated, the actual distribution of MFA% was checked and the final 
sample size was adjusted based on the observed standard deviation and actual distribution 
of MFA%. Results by Al-Sunduqchi2 and Guenther indicate that power calculations for the 
Wilcoxon test may be made using the standard t-test formulations with a simple adjustment 
to the sample size. The size of the adjustment depended upon the actual distribution of the 
data. They gave sample size adjustment factors for four distributions. These were 1 for the 
uniform distribution, 2/3 for the double exponential distribution, 9/π2 for the logistic 
distribution, and π/3 for the normal distribution. So depending on the actual distribution of 
MFA%, sample size re-calculation was based on a Wilcoxon Signed Rank test with the 
corresponding adjustment if the observed distribution of MFA% was not normal. 
The resulted sample size was smaller than the original and included 19 enrolled subjects. 
5.
STATISTICAL METHODS
5.1 
Continuous
For continuous variables, the number of non-missing observations, mean, median, SD, 
minimum and maximum will be presented. For all tabulations of change from baseline data, 
the 95% confidence interval (CI) for the mean will also be provided. 
Individual raw data will be presented to the precision in which it is recorded. The number of 
decimal places to display for individual derived data will be determined by the scale of 
measurement using the following rules unless otherwise stated in Section 6.2:  

No decimal places will be displayed if the smallest calculated value is ≥ 100;

One decimal place will be displayed when the smallest value is within the interval
(10, 100), with 10 being inclusive;

Two decimal places are displayed when the smallest value is within (1, 10), with 1
being inclusive; and so on for even smaller scale of measurement.
For both raw and derived data, means and medians will be displayed to one more decimal 
places, the individual data and dispersion statistics (e.g SD) will have two more decimal 
places, and the minimum and maximum will be displayed to the same number of decimal 
places as reported in the individual data. Change from baseline will be reported to the same 
precision as the observed values. 
5.2 
Categorical 
Categorical data will be presented in contingency tables with cell frequencies and 
percentages for the subject population. Percentages will be presented to one decimal place 
and will be calculated using the number of subjects with non-missing data as the 
denominator unless otherwise stated.  The number of missing data points will also be 
presented where applicable. 
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6.
ANALYSIS PLAN
6.1 
General
All statistical tests will be performed using a two-tailed 5% overall significance level, 
unless otherwise stated.  The null hypothesis at all times will be that the pre-treatment and 
post-treatment values are equivalent.  All comparisons between pre-treatment and post-
treatment measurements will be reported with 95% CIs for the difference. For each 
statistical test, an observed significance level will be quoted.  Where this value is less than 
0.05, 0.01 or 0.001, attention will be drawn to the fact using the conventional “*”, “**” or 
“***” annotation, respectively. P-values will be rounded to four decimal places. 
Normality assumptions will be evaluated by an examination of the residual plots and the 
Shapiro-Wilk test of normality. Depending on the degree of departure from these 
assumptions, an alternate nonparametric approach may be used for supportive purposes. 
With the exception of some hematology parameters (see section 6.15.3), post-baseline 
repeat/unscheduled assessments will be disregarded, although they will be listed in the 
relevant appendices to the report, in particular all clinically significant values will be noted. 
All calculations and figures for the efficacy and safety analyses will be produced using 
SAS® Version 9.3. 
PK analyses will be performed using Phoenix WinNonlin Version 6.3. 
All summaries and analyses documented below will be presented in the final integrated 
statistical/clinical report and tables that will be based on the E3 guidelines published by 
ICH.  However, it is noted here that no analysis plan prepared in advance of the data can be 
absolutely definitive and so the final report may contain additional tables or statistical tests 
if warranted by the data obtained.  The justification for any such additional analyses will be 
fully documented in the final report. 
6.2 
Derived Data 

Baseline
Baseline is defined as the last value collected (from either a scheduled or
unscheduled visit) before the first Givinostat treatment

Early Termination
Subjects who discontinue participation prior to completing the study should perform
the Early Termination Visit within 2 weeks after the last drug intake.

End of Study
The end-of-study visit is defined as Visit 10 of part 2 (Month 12)/early termination..

End of Extension
End of Extension 1 is defined as Visit 16 (Month 24) of the Extension part of the
study.
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End of Extension 2 is defined as Visit 22 (Month 36) of the second Extension part of 
the study. 
End of Extension 3 is defined as Visit 26 (Month 52) of the third Extension part of 
the study. 
For subjects that had an early termination during one of the extensions, the end of the respective 
extension is defined as the date of the early termination. 
•
MFA% change
Change in the value of MFA% at End of Study is calculated as the difference
between MFA% at End of Study and its baseline value.
•
Other histological endpoints
The same definition is used for the other histological endpoints: Perimysial Fibrosis
%, Endomysial Fibrosis %, Total fibrosis %, Necrosis %, Inflammation: Total N° of
Myofiber, Total of M2, Total of M1, Total of M2M1, single stained cells M2, single
stained cells M1, Total Macrophages, Total of single stained M2 / total n. of fields,
Total of single stained M1 / total n. of fields, Total of M2M1 / total n. of fields,
Total of single stained M2 / total macrophages, Total of single stained M1 / total
macrophages, Total of M2M1 / total macrophages, Muscle Regeneration: 1) Total n°
of Develop Myosin positive cells – all fields / Total fibers biopsy – all fields,  2)
Total n° of SC (sublaminal and extralaminal) – all fields /Total fibers biopsy – all
fields,  3) Total n° of SC (sublaminal) – all field / Total fibers biopsy – all fields,  4)
Total n° of SC (sublaminal) – all field / Total n° of SC (sublaminal and
extralaminal) – all fields, 5) Total n° of sublaminal SC positive Ki67 – all fields /
Total n° of SC (sublaminal) – all fields, 6) Total n° of SC (extralaminal ) – all
fields /Total n° of fibers – all fields, 7) Total n° of SC (extralaminal) – all fields /
Total n°of SC (sublaminal and extralaminal) – all fields, 8) Total n° of extralaminal
SC positive Ki67 – all fields /Total n° of SC (extralaminal) – all fields.
•
MRI
The MRI results are centrally scored as ‘Stage 0’, ‘Stage 1’, ‘Stage 2a’, ‘Stage 2b’,
‘Stage 3’, ‘Stage 4’ (please see ‘DSC_11_2357_43_MRI
Manual_Final_5Feb2013_final.pdf’ for further information). The frequency of the
MRI scores at Baseline, End of Study and End of Extension 1 calculated and
presented per body location. Change in the MRI at End of Study/End of Extension 1
is determined by comparing the MRI score given at baseline to the MRI score given
at End of Study/End of Extension 1.
•
miRNA
Changes from baseline to End of Study will be calculated for the following
parameters – miR-1, miR-133, miR-206.
•
Changes in muscular function
o
Change in muscular function based on the 6MWT at End of Study/End of
Extension phases is calculated as the difference between the distance after 6
minutes (meters) at End of Study/End of Extension phases and its baseline
value. If more than one value is recorded for the baseline, the mean value
rounded to the integer will be taken.  Calculation method is specified in
section 6.12.
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o
Change in muscular function based on the NSAA at End of Study/End of
Extension phases is calculated as the difference between Total NSAA Score
at End of Study/End of Extension phases and its baseline value. Total NSAA
score is achieved by summing the scores for all 17 individual items.
Calculation method is specified in section 6.13.
o
Change in muscular function based on the PUL at End of Study/End of
Extension phases is calculated as the difference between the PUL at End of
Study/End of Extension phases and its baseline value. Calculation method is
specified in section 6.14.

Missing observations
o
Unless specified, missing observations will be treated as missing at random,
and no data imputation will be performed. All data from the CRFs, as well as
any derived variables, will be presented in data listings
o
For 6MWT (but not for Number of falls), Time to stand up from floor
(seconds), and Time to walk 10m (seconds, the rule for missing data
handling is shown in Table 1 and specified as follows:
Table 1 Rule for missing data handling 
Subje
ct 
Ambulat
ory at 
baseline 
4SC 
basel
ine 
Amb
ulato
ry at 
visit1 
4SC 
visit1 
Ambulat
ory at 
baseline 
4SC 
base
line 
Amb
ulato
ry at 
visit1 
4SC 
visit
1 
change 
from 
baseline 
low 
up 
001 
y 
15 
y 
10 
y 
15 
y 
10 
-5
-5
-5
002 
y 
miss 
y 
8 
y 
14.8 
y 
8 
-6.8
-6.8
-6.8
003 
y 
25 
y 
miss 
y 
25 
y 
12.9 
-12.1
-12.1
-12.1
004 
y 
miss 
y 
miss 
y 
14.8 
y 
12.9 
-1.9
-1.9
-1.9
005 
n 
miss 
y 
22 
n 
>25
y 
22 
<-3 
. 
-3
006 
n 
miss 
y 
miss 
n 
>25
y 
12.9 
<-12.1 
. 
-12.1
007 
y 
13 
n 
miss 
y 
13 
n 
>22
>9
9 
. 
008 
y 
miss 
n 
miss 
y 
14.8 
n 
>22
>7.2
7.2 
. 
009 
n 
miss 
n 
miss 
n 
>25
n 
>22
. 
. 
. 
010 
y 
7 
y 
13 
y 
7 
y 
13 
6 
6 
6 
011 
y 
4 
y 
12 
y 
4 
y 
12 
8 
8 
8 
012 
y 
15 
y 
8 
y 
15 
y 
8 
-7
-7
-7
013 
y 
17 
y 
12 
y 
17 
y 
12 
-5
-5
-5
014 
y 
15 
y 
10 
y 
15 
y 
10 
-5
-5
-5
015 
y 
22 
y 
21 
y 
22 
y 
21 
-1
-1
-1
max 
25 
22 
mean 
14.8 
12.9 
1) missing values will be imputed to:
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(a)  worst result observed in parts 1, 2 and the extension 1 for the extension 1
analysis, and
(b)≥ worst result observed in parts 1, 2, extension 1 and extension 2 for extension 2
analysis.
(c)≥ worst result observed in parts 1, 2, extension 1, extension 2 and extension 3 for
extension 3 analysis.
For Time to Walk and Time to Stand up worst result is the maximal value, while for 
all other scores (excluding Total Score) worst result in the minimal value. 
2) if missing not due to ambulation at visit x, then we impute using the mean of
patients with values at visit x (and not the mean across all visits)
In addition, for missing values without reason of missing at Baseline, the mean of all 
baseline values will be imputed except subject 512 – “Time to stand up from floor”. 
For Subject 512, missing values for test “Time to stand up from floor” at baseline and 
post-baseline (e.g., 12 months) the worst value collected during the trial for this 
subject will be used for imputation.  
Missing values of 'time to walk 10 m' and 'time to stand up from floor' were imputed 
according to whether the subject was ambulatory or not. If a subject was ambulatory 
then the result was imputed to the mean result of the specific visit, and if the subject 
was not ambulatory, the result was imputed to the maximal result collected. 
Missing score results were imputed to the minimal result collected. Missing 'Total 
score' was imputed as the sum of all non-missing score results per visit. 
3) when both baseline and post baseline visit(s) values are both left or right censored,
then the visit change from baseline will be set to missing
Such imputation necessarily leads to censored observations and therefore means and 
standard deviations will be estimated using PROC LIFEREG which provides a 
mechanism for handling right (and/or left) censored data when the underlying 
probability density function is Normal.  In the absence of covariates, the mean is given 
by the intercept term and the SD by the scale parameter. See below for details. 
-
Identify the worst/maximum observed value (i.e., Time to stand up from floor
(seconds)) from subjects with available data; apply this value to those patients will
missing data due to an inability to perform the task; identify these patients as right
censored in the dataset in accordance with SAS PROC LIFEREG
instruction..   The SAS® code for this model is given below:
PROC lifereg DATA= Datasetname covout outEST=lifeout; 
MODEL y*cens(0) = / dist=normal;   
run; 
The estimated mean and its standard deviation are the estimates of the intercept and 
the scale from following SAS output (i.e. 10.0021 and 4.4734 in this example, 
respectively).  
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-
Identify the worst/minimum observed value (i.e., 6MWT) from subjects with
available data;   apply this value to those patients will missing data due to an
inability to perform the task; identify these patients as left censored in the dataset
in accordance with SAS PROC LIFEREG instruction. The SAS® code for left
censoring is given below:
DATA leftcensored; set data; 
   if y=. then do; lower=.;y=minobs;end; else lower=y; 
run; 
PROC lifereg DATA=leftcensored  covout outEST=lifeoutleft; 
  MODEL (lower,y) = / dist=normal;   
run; 
-
Identify an interval data for change from baseline (i.e., 6MWT, time to walk 10m
and time to stand up from floor) in accordance with SAS PROC LIFEREG with
interval censoring to estimate mean and standard error. The SAS® code for left
censoring is given below:
    PROC lifereg DATA=CHG; 
      MODEL (low, up) =   / dist=normal; 
run; 
For the NSAA scores the missing score is imputed with worst score, missing NSAA 
‘Total Score’ observations were imputed as the sum of all test results per visit, 
regardless of whether the subject was ambulatory or not. 

Incomplete dates
All incomplete dates will be entered on the database as they were recorded in the
CRF.  Thereafter for calculation purposes only, the incomplete dates will be
completed using pre-defined rules.  If a day or month is recorded as NK or NA it
will be replaced by the first day of the month or January respectively, provided this
does not contradict any other dates recorded.  For missing adverse events (AEs) and
medications dates/times during the trial, the worst-case date will be used (e.g. the
end of the month for a stop date and 23:59 for the stop time, the date/time of initial
dose for start of AE i.e. all events with missing start dates will be assumed to be
treatment emergent).

Ambiguous values
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In the case where a variable is recorded as “>x”, “≥x”, “<x” or “≤x”, then for 
analysis purposes a value of x will be taken. Where a range of values is quoted the 
midpoint of the range will be taken. In the case where a subject records more than 
one score at a timepoint for any particular efficacy measure, the worst of the 
recorded scores will be taken for analysis purposes. 

ECG data
For ECG data recorded on continuous scales, if more than one value is recorded, the
mean value rounded to the integer will be presented. For overall interpretation if
more than one value is recorded, then take most severe of the respective readings
will be taken.
o QT Intervals
The analysis will use QT intervals that have been corrected for heart rate 
by the Bazett’s1 and Fridericia’s2 formula (QTcB = QT/ [RR]1/2 and QTcF 
= QT/[RR]1/3 respectively), as recorded on the CRF.  

Pulmonary function tests (PFTs)
For PFT data recorded on continuous scales, if more than one value is recorded, the
mean value rounded to the integer will be presented

Secondary Efficacy Assessment
Efficacy will be assessed through paired t-tests to test the changes from baseline in
biopsy at End of Study and through descriptive statistics of changes from baseline in
the MRI, 6MWT, PUL, and NSAA at End of Study and Extension Phases.

BMI
BMI will be calculated using the following equation –
 
BMI (Kg/m2)=weight(kg)/Height(meters)2 
6.3 
Analysis populations 
The intent-to treat (ITT) population will include all children who are enrolled in the Part 1 
portion or entered the Part 2 portion of the study. Subjects will be analyzed according to the 
dose level to which they are allocated. 
The Completers population will include all children who successfully completed Part 2 
portion of the study. Subjects will be analysed according to the dose level to which they are 
allocated. 
The evaluable population will include all subjects who are in Part 2 of the study, receive 
Givinostat of at least 80% dose in Part 2, have at least one baseline and one post-baseline 
assessment of biopsies, and have no major protocol violations. All protocol deviations will 
be assessed and documented on a case-by-case basis prior to the database lock, and 
deviations considered having a serious impact on the efficacy results will lead to the 
relevant subject being excluded from the population.  Major protocol deviations include 
(but are not limited to): 

Not meeting inclusion criteria/meeting an exclusion criteria
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
Taking an inadmissible concomitant medication likely to effect the primary efficacy
endpoints

Any other deviations likely to have an impact on the primary efficacy endpoint:
o
Unstable  dose of systemic corticosteroids during the trial (e.g. change in
type of drug, dose modification not related to body weight change, schedule
modification, interruption, discontinuation, or re initiation)

Visit 1 not performed

Biopsy not Evaluable
Prior to the database lock, subject evaluability will be reviewed by the sponsor and detailed 
in the study evaluability document. A listing of all subjects excluded from the evaluable 
population and the reason for their exclusion should be included. The dose level under 
which a subject is analysed will be the dose of investigational product that is actually 
received. 
The safety population will include all children who receive any investigational product. The 
dose level under which the subject is analysed will be the dose of investigational product that 
is actually received. 
The PK population will include all children with at least one quantifiable post-dose 
concentration datum.  
6.4 
Protocol Deviations 
A listing of protocol deviations will be provided within Appendix 16.2. Summaries of key 
protocol deviations will be provided. Major protocol violations will lead to exclusion from 
the evaluable population. 
6.5 
Data Summaries 
Categorical data will be summarized by the number and percentage of children in each 
category.  Continuous variables will be summarized by descriptive statistics, including 
mean, standard deviation, median, minimum, and maximum.  CIs will be 2-sided.  
All data will be summarized separately for part 1, part 2 and Extension phases. Data will be 
summarized by the initial dose level of part1 of the study (there will be 3 groups: 25.0 mg, 
37.5 mg and 50.0 mg). For part 2 there will be only one group: 37.5 – 25.0 mg BID). For 
Extension phases (1, 2 and 3), data will be summarized by the initial dose at start of each 
Extension phase except for AE data which will be summarized by the dose level assigned to 
the adverse event in question (see Section 6.2 for details). Data will also be summarized for 
the appropriate population overall. 
Appendix 16.2 listings will be sorted by initial dose level and subject number with subject 
level data presented in chronological order within each parameter or measurement as 
appropriate. 
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 Subject disposition will be summarized using the ITT Population. The primary efficacy 
endpoint will be analysed using the Evaluable Population, with the Completers and the ITT 
populations used for sensitivity analysis. The secondary efficacy endpoints will be analysed 
using the ITT Population only. The safety endpoints will be summarized using the Safety 
Population. The PK endpoints will be summarized using the PK Population. 
6.6 
Disposition of Subjects 

The number of subjects in the ITT population who completed Part 1, Part 2 and the
extension phases of the study based on the protocol will be summarized.

The number of subjects in each population will be summarized

A subject will be considered to have completed Part 1 when the subject has
completed Week 11 of part 1.

A subject is considered to have completed Part 2 when the subject has completed 12
month visit of Part 2.

The subject is considered to have completed the extension 1 study when the subject
has completed after 12-month the end-of-extension study visit (Visit 16).

The subject is considered to have completed the extension 2 study when the subject
has completed after 12-month the end-of-extension 2 study visit (Visit 22).

The subject is considered to have completed the extension 3 study when the subject
has completed after 16-month the end-of-extension 3 study visit (Visit 26).
Reasons for early termination should be summarized.
o
Death
o
Lost to follow up
o
Patient withdrew consent
o
Protocol violation
o
Adverse event
o
Other

The number of subjects that entered the study, the numbers of subjects that
completed each phase of the study should be summarized.

Reason and timing (days since first dose) for withdrawal should be tabulated.

Reasons for Screening Failures will be tabulated.
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6.7 
Baseline Comparability 
The baseline data will be summarized in appropriate tables using the ITT population. The 
comparability of initial dose levels with respect to the subject demographics and baseline 
characteristics will be assessed in a descriptive manner, no formal statistical testing will be 
performed. 
6.7.1 
Variables Considered 
Standard continuous or categorical variable summaries will be presented for the following 
variables based on the ITT population. 
6.7.1.1 
Demography 

Age at screening visit (years)

Sex (Male)

Race (American Indian or Alaska Native, Asian, Black or African American, Native
Hawaiian or Other Pacific Islander, White, Other)

Height (cm)

Body Weight (kg)

BMI (kg/m2)

Mutation Type
6.7.1.2 
Medical and Surgical History  
Separate tabulations will be produced for previous and ongoing conditions with all 
conditions coded using MedDRA Version 20.1 (primary system organ class and 
preferred term). 
6.7.1.3 
Physical Examination at Screening 

Cardiovascular (Normal, Abnormal [Not Clinically Significant {NCS}], Abnormal
[Clinically Significant {CS}], Not done)

Abdomen (Normal, Abnormal [NCS], Abnormal [CS], Not done)

Ear/Eye/Nose/Throat (Normal, Abnormal [NCS], Abnormal [CS], Not done)

Neck and Thyroid (Normal, Abnormal [NCS], Abnormal [CS], Not done)
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
Spine (Normal, Abnormal Abnormal [NCS], Abnormal [CS], Not done)

Lymph Nodes  (Normal, Abnormal [NCS], Abnormal [CS], Not done)

Skin and Mucosa (Normal, Abnormal [NCS], Abnormal [CS], Not done)

Chest and Lungs  (Normal, Abnormal [NCS], Abnormal [CS], Not done)

Musculoskeletal system (Normal, Abnormal [NCS], Abnormal [CS], Not done)

Neurological system (Normal, Abnormal [NCS], Abnormal [CS], Not done)

Extremities (Normal, Abnormal [NCS], Abnormal [CS], Not done)

Genitourinary (Normal, Abnormal [NCS], Abnormal [CS], Not done)

Other (Normal, Abnormal [NCS], Abnormal [CS], Not done)
When calculating the percentage reporting each category, the “Not Done” category will not 
be included in the denominator. 
6.7.1.4 
 Muscle biopsy at Screening 

MFAF%

Perimysial Fibrosis %

Endomysial Fibrosis %

Total fibrosis %

Necrosis %

Fiber dimension distribution (CSA)

No. of hypercontracted fibers [Number of fibers per microscopic field (20x)]

Fatty replacement %

N° of fiber [Number of fibers per microscopic field (20x)]

Inflammation: (Total N° of Myofiber

Inflammation: (Total of M2)
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
Inflammation: (Total of M1

Inflammation: (Total of M2M1)

Inflammation: (single stained cells M2)

Inflammation: (single stained cells M1)

Inflammation: (Total Macrophages)

Inflammation: (Total of single stained M2 / total n. of fields)

Inflammation: (Total of single stained M1 / total n. of fields)

Inflammation: (Total of M2M1 / total n. of fields)

Inflammation: (Total of single stained M2 / total macrophages)

Inflammation: (Total of single stained M1 / total macrophages)

Inflammation: (Total of M2M1 / total macrophages)

Muscle Regeneration: ( Total n° of Develop Myosin positive cells – all fields / Total
fibers biopsy – all fields)

Muscle Regeneration: (Total n° of SC (sublaminal and extralaminal) – all fields /Total
fibers biopsy – all fields)

Muscle Regeneration: (Total n° of SC (sublaminal) – all field / Total fibers biopsy – all
fields)

Muscle Regeneration: (Total n° of SC (sublaminal) – all field / Total n° of SC
(sublaminal and extralaminal) – all fields)

Muscle Regeneration: (Total n° of sublaminal SC positive Ki67 – all fields / Total n° of
SC (sublaminal) – all fields)

Muscle Regeneration: (Total n° of SC (extralaminal ) – all fields /Total n° of fibers – all
fields)

Muscle Regeneration: (Total n° of SC (extralaminal) – all fields / Total n° of SC
(sublaminal and extralaminal) – all fields)
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
Muscle Regeneration: (Total n° of extralaminal SC positive Ki67 – all fields /Total n° of
SC (extralaminal) – all fields)
6.7.1.5 
miRNA at Screening 

miR-1 (copies/mL)

miR-133 (copies/mL)

miR-206 (copies/mL)
6.7.1.6 
MRI at Screening 

MRI central score
6.7.1.7 
Quality Tests – PedsQL at Screening 

Multidimensional Fatigue Scale (CHILD and PARENT Reports):
o
General Fatigue
Feel tired (Never, Almost Never, Sometimes, Often, Almost Always)
Feel physically weak (Never, Almost Never, Sometimes, Often, Almost
Always)
Too tired to do things I like to do (Never, Almost Never, Sometimes,
Often, Almost Always)
Too tired to spend time with friends (Never, Almost Never, Sometimes,
Often, Almost Always)
Trouble finishing things (Never, Almost Never, Sometimes, Often, Almost
Always)
Trouble starting things (Never, Almost Never, Sometimes, Often, Almost
Always)
o
Sleep/Rest Fatigue:
Sleep a lot (Never, Almost Never, Sometimes, Often, Almost Always)
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Hard to sleep through the night (Never, Almost Never, Sometimes, Often,
Almost Always)
Tired when waking up in the morning (Never, Almost Never, Sometimes,
Often, Almost Always)
Rest a lot (Never, Almost Never, Sometimes, Often, Almost Always)
Take a lot of naps(Never, Almost Never, Sometimes, Often, Almost
Always)
Spend a lot of time in bed (Never, Almost Never, Sometimes, Often,
Almost Always)
o
Cognitive Fatigue:
Hard to stay attentive(Never, Almost Never, Sometimes, Often, Almost
Always)
Hard to remember what people tell me (Never, Almost Never, Sometimes,
Often, Almost Always)
Hard to remember what I just heard (Never, Almost Never, Sometimes,
Often, Almost Always)
Hard to think quickly (Never, Almost Never, Sometimes, Often, Almost
Always)
Have trouble remembering what I was just thinking (Never, Almost Never,
Sometimes, Often, Almost Always)
Have trouble remembering more than one thing at a time (Never, Almost
Never, Sometimes, Often, Almost Always)

Neuromuscular Module (CHILD and PARENT Reports):
o
About my neuromuscular disease:
Hard to breathe (Never, Almost Never, Sometimes, Often, Almost Always)
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Get sick easily (Never, Almost Never, Sometimes, Often, Almost Always)
Get sores and/or rashes (Never, Almost Never, Sometimes, Often, Almost
Always)
Legs hurt (Never, Almost Never, Sometimes, Often, Almost Always)
Feel tired (Never, Almost Never, Sometimes, Often, Almost Always)
Back feels stiff (Never, Almost Never, Sometimes, Often, Almost Always)
Wake up tired (Never, Almost Never, Sometimes, Often, Almost Always)
Hands are weak (Never, Almost Never, Sometimes, Often, Almost
Always)
Hard to use the bathroom (Never, Almost Never, Sometimes, Often,
Almost Always)
Hard to gain or lose weight (Never, Almost Never, Sometimes, Often,
Almost Always)
Hard to use hands (Never, Almost Never, Sometimes, Often, Almost
Always)
Hard to swallow food (Never, Almost Never, Sometimes, Often, Almost
Always)
Takes a long time to bathe or shower (Never, Almost Never, Sometimes,
Often, Almost Always)
Get hurt accidentally (Never, Almost Never, Sometimes, Often, Almost
Always)
Take a long time to eat (Never, Almost Never, Sometimes, Often, Almost
Always)
Hard to turn during the night (Never, Almost Never, Sometimes, Often,
Almost Always)
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Hard to go places with my equipment (Never, Almost Never, Sometimes,
Often, Almost Always)
o
Communication:
Hard to tell doctors and nurses how I feel (Never, Almost Never,
Sometimes, Often, Almost Always)
Hard to ask the doctors and nurses questions (Never, Almost Never,
Sometimes, Often, Almost Always)
Hard to explain the illness to other people (Never, Almost Never,
Sometimes, Often, Almost Always)
o
Family Resources:
Hard for the family to plan activities (Never, Almost Never, Sometimes,
Often, Almost Always)
Hard for the family to get enough rest (Never, Almost Never, Sometimes,
Often, Almost Always)
Money is a problem (Never, Almost Never, Sometimes, Often, Almost
Always)
The family has a lot of problems (Never, Almost Never, Sometimes, Often,
Almost Always)
Don’t have the needed equipment (Never, Almost Never, Sometimes,
Often, Almost Always)

Pediatric Quality of Life Inventory (generic core scales) (CHILD and PARENT
Reports):
o
Physical functioning:
Hard to walk (Never, Almost Never, Sometimes, Often, Almost Always)
Hard to run (Never, Almost Never, Sometimes, Often, Almost Always)
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Hard to play sports or exercise (Never, Almost Never, Sometimes, Often,
Almost Always)
Hard to lift something heavy (Never, Almost Never, Sometimes, Often,
Almost Always)
Hard to take a bath or shower by myself (Never, Almost Never,
Sometimes, Often, Almost Always)
Hard to do chores around the house (Never, Almost Never, Sometimes,
Often, Almost Always)
Hurt or ache (Never, Almost Never, Sometimes, Often, Almost Always)
Have low energy (Never, Almost Never, Sometimes, Often, Almost
Always)
o
About my feelings:
Feel afraid or scared (Never, Almost Never, Sometimes, Often, Almost
Always)
Feel sad or blue (Never, Almost Never, Sometimes, Often, Almost
Always)
Feel angry (Never, Almost Never, Sometimes, Often, Almost Always)
Have trouble sleeping (Never, Almost Never, Sometimes, Often, Almost
Always)
Worry what will happen to me (Never, Almost Never, Sometimes, Often,
Almost Always)
o
Getting along with others:
Have trouble getting along with other kids (Never, Almost Never,
Sometimes, Often, Almost Always)
Other kids don’t want to be my friend (Never, Almost Never, Sometimes,
Often, Almost Always)
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Other kids tease me (Never, Almost Never, Sometimes, Often, Almost
Always)
Cannot do things other kids my age can do (Never, Almost Never,
Sometimes, Often, Almost Always)
Hard to keep up when playing with other kids (Never, Almost Never,
Sometimes, Often, Almost Always)
o
About school:
Hard to pay attention in class (Never, Almost Never, Sometimes, Often,
Almost Always)
Forget things (Never, Almost Never, Sometimes, Often, Almost Always)
Have trouble keeping up with school work (Never, Almost Never,
Sometimes, Often, Almost Always)
Miss school because of not feeling well (Never, Almost Never, Sometimes,
Often, Almost Always)
Miss school to go to the doctor or hospital (Never, Almost Never,
Sometimes, Often, Almost Always)
6.7.1.8 
Vital Signs at Screening 

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

Systolic/Diastolic blood pressure significance (normal/abnormal)

Pulse rate (bpm)

Pulse rate significance (normal/abnormal)

Body temperature (degrees Celsius)

Body temperature significance (normal/abnormal)
6.7.1.9 
ECG (12-lead) at Screening 
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As stated in section 6.2, for data recorded on continuous scales, if more than one value is 
recorded, the mean value rounded to the integer will be presented. For the Overall 
Interpretation (Normal, Abnormal (NCS), Abnormal (CS)) if more than one value is recorded 
for a given visit, then the most severe interpretation of the respective readings will be taken. 

PR interval (ms)

RR interval (ms)

QRS duration (ms)

QT interval (ms)

QTc interval (ms) [Bazett’s formula - QTcB]

QTcF  interval (ms) [Fridericia’s formula - QTcF]

Overall interpretation of the ECG (Normal, Abnormal (NCS), Abnormal (CS))
6.7.1.10 
  Pulmonary function tests (PFTs) at Screening 
As stated in section 6.2, for data recorded on continuous scales, if more than one value 
is recorded, the mean value rounded to the integer will be presented.  

Forced expiratory volume at 1 second [FEV1] (L)

Forced vital capacity [FVC]  (L)

FEV1/FVC (ratio)

Peak Expiratory Flow [PEF] (L/min)
6.7.1.11 
Echocardiographs at Screening 

M Mode
o
Left atrial (LA) dimension (cm)
o
Left ventricular end-diastolic internal dimension (LVEDD) (cm)
o
Left ventricular end-systolic internal dimension (LVESD) (cm)
o
Left ventricular septal (LVS) wall thickness:(mm)
o
Left ventricular posterior wall (PW) thickness:(mm)

2D
o
Left ventricular end-diastolic (LVED) volume (ml)
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o
Left ventricular end-systolic (LVES) volume (4-ch) (ml)
o
Left ventricular end-systolic (LVES) volume (2-ch) (ml)
o
Left ventricular end-systolic (LVES) volume (Biplane) (ml)
o
Left atrial (LA) volume (ml)
o
Left ventricular outflow tract (LVOT) diameter (cm)
o
Maximal LV wall thickness (cm)
o
Left Ventricular Ejection Fraction (LVEF) (%)

Colour Doppler:
o
Semi qualitative grade of mitral regurgitation reg (1,2,3,4)
o
Semi qualitative grade of tricuspid regurgitation reg (1,2,3,4)

Pulse wave Doppler:
o
Mitral E max (m/s)
o
A max (m/s)
o
A duration (ms)
o
Pulmonary S max (m/s)
o
D max (m/s)
o
A pulm duration (ms)

Continuous wave Doppler:
o
Tricuspid regurgitation v max (m/s)
o
Isovolumic relaxation time (ms)
o
Stroke volume (ml)
6.7.1.12 
Haematology at Screening 

Hemoglobin (g/L)

Hematocrit (%)

Red blood cell count (10^12/L)

White blood cell count (10^9/L)

Platelets (10^9/L)
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
Absolute Neutrophil Count (10^9/L)

Neutrophil (%)

Lymphocytes (10^9/L) / (%)

Monocytes (10^9/L) / (%)

Basophils (10^9/L) / (%)

Eosinophils (10^9/L) / (%)

Abnormal cells (10^9/L) / (%)
6.7.1.13 
Chemistry at Screening 

Alanine transaminase (ukat/L)

Albumin (g/L)

Alkaline phosphatase (ukat/L)

Amylase (ukat/L)

Aspartate transaminase (ukat/L)

Total bilirubin (umol/L)

Blood urea nitrogen (mmol/L)

C-reactive Protein (mmol/L)

Calcium (mmol/L)

Chloride (mmol/L)

Creatine Phosphokinase

Creatine kinase (ukat/L)

Creatinine (umol/L)

Creatinine Clearance (mL/Sec)
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
Glucose (mmol/L)

Lactate dehydrogenease (ukat/L)

Potassium (mmol/L)

Total protein (g/L)

Sodium (mmol/L)

Uric acid (umol/L)
6.7.1.14 
Urinalysis at Screening 

Specific gravity

pH

Protein (Positive, Negative, Trace)

Glucose (Positive, Negative, Trace)

Ketones Cytology – results will only be listed.

Myoglobin (mmol/L)
6.7.1.15 
Serology at Screening 

HIV Antibody (HIV-Ab)

Hepatitis C (antibody HCV-Ab)

Hepatitis B: surface antigen (HbsAg)

Hepatitis B: surface e antigen (HbeAg)

Anti Epstein Barr Virus (anti-EBV)

Anti Cytomegalovirus antibody (anti-CMV IgM)
6.7.1.16 
Six Minutes Walk Test at Screening (6MWT) at Screening 

Falls (Distance, Time of fall (minutes and seconds), restart time (minutes and seconds))

Distance reached in 6 minutes (meters)
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
Percentage of predicted value at screening. The predictive value is calculated using the
following equation by Geiger7:
m
pred
height
age
age
MWT
*
28
.
132
*
36
.1
*
81
.
39
72
.
196
6
2 



6.7.1.17 
North Star Ambulatory Assessment (NSAA) at Screening 
Scores (0, 1, or 2) for each of the following: 

Stand

Walk (10m)
o
Score
o
Time (seconds)

Stand-up after seating

Stand on 1 leg – R

Stand on 1 Leg – L

Climb one step – R

Climb one step – L

Step down from a step – R

Step down from a step – L

Seating and supine

Stand up from floor
o
Score
o
Time (seconds)
o
Comments (A,B,C,D,E)

Rise head
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
Stand on heels

Jumps

Hops on one leg – R

Hops on one leg – L

Run
o
Score
o
Comments (A,B,C,D,E)

Total score
6.7.1.18 
Performance of Upper Limb (PUL) at Screening 

Item A. Entry item
o
This item defines the gross ability of an individual and is based on the Brooke
Scale. It directs the evaluator to the appropriate items to assess next
(0,1,2,3,4,5,6)

High level shoulder dimension (for left arm, right arm or both arms):
o
Item B. Shoulder abduction to shoulder height  (0,1,2,3,4)
o
Item C. Shoulder abduction above shoulder height (0,1,2,3,4)
o
Item D. Shoulder flexion to shoulder height (0,1,2,3,4)
o
Item E. Shoulder flexion above shoulder height (0,1,2,3,4)

Mid level elbow dimension (for left arm, right arm or both arms)::
o
Item F. Hand(s) to mouth (0,1,2,3)
o
Item G. Hand(s) from lap to table (0,1,2,3)
o
Item H. Move weight on table (0,1,2,3,4,5)
o
Item I. Lifting light cans (0,1,2,3,4,5)
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o
Item J. Lifting heavy cans (0,1,2,3,4,5)
o
Item K. Stacking light cans (0,1,2,3,4)
o
Item L. Stacking heavy cans (0,1,2,3,4)
o
Item M. Remove lid from container (0,1)
o
Item N. Tearing paper (0,1,2,3,4)

Distal size of wrist and hand
o
Item O. Tracking a path (0,1,2,3,4)
o
Item P. Push on light (0,1,2,3)
o
Item Q. Supination (0,1,2,3,4)
o
Item R. Picking up coins (0,1,2,3)
o
Item S. Placing finger on number diagram (0,1,2,3)
o
Item T. 2 points pliers or tongs?
Score (0,1,2)
Weight (5 gr, 10 gr)
o
Item U. 3 points pliers
Score (0,1,2)
Weight (5 gr, 10 gr)
o
Item V. Key grip / thumb
Starting position (Hand close, Hand open)
Score (0,1,2,3)
Weight (5 gr, 10 gr)
6.8 Concomitant medications 
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Concomitant medication verbatim terms (as recorded on the CRFs) ongoing at the time of the 
initial dose of study medication will be mapped to and summarized by Anatomical Therapeutic 
Chemical (ATC) Level 2 and Drug Reference Names using the World Health Organization 
(WHO) dictionary (Version September 2017 Enhanced). 
6.9 Measurement of Treatment Compliance 
Medication containers (the bottles of oral suspension and/or capsules used) are returned at each 
visit, for compliance/non-compliance assessment.  Non-compliance is defined as taking less 
than 80% of the study medication during any outpatient evaluation period (visit to visit).   
Treatment compliance will be assessed as part of the protocol deviations. 
The subject compliance with treatment will be summarized by initial dose, Initial dose of study 
drug administered BID based on body weight, exposure to study drug, number and percentage 
of subjects who received the treatment. 
The date/time of IMP dispensed will be also listed for all subjects. 
6.10 Primary Endpoint 
The primary endpoint of this study is change of MFA%, comparing the histology biopsies at 
baseline with the results at the End of Study. 
Null Hypotheses:  
MFA% at Month 12 is equal MFA% at Baseline. 
Alternative Hypotheses:  
MFA% at End of Study is not equal to MFA% at Baseline. 
6.11 Principal Analysis 
Measurements and changes in MFA% will be presented using appropriate summary tables 
by visit.  
The Paired T-test or non-parametric Signed rank test for two means (paired observations) 
(as is appropriate) will be applied for testing the statistical significance of the change from 
baseline to End of Study. MFA% P<0.05 will be set as significant. The SAS® code for this 
model is given below:   
proc ttest data=data sides=2 alpha=0.05 h0=0;  
paired MFAEOS * MFABL;  
run;  
Where MFAEOS is the MFA at the end of Study and MFABL is he MFA at baseline 
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Imputation techniques 
No data imputation will be performed; missing observations will be treated as missing at 
random. 
6.11.1 Sensitivity Analysis 
The primary endpoint analysis will be repeated using Completers and ITT population. 
6.11.2 Exploratory Analysis 

The correlation between change in MFA% and DMD mutation will be assessed using
the ANOVA method:
Proc glm order=internal; 
Ods select OverallANOVA=anova; 
Class DMD; 
Model c_MFA=DMD; 
Means DMD/scheffe; 
Run; 
Quit; 

If possible, change in MFA% will be summarized according to the arm sequence of the
measurements (Left-Right or Right-Left).

MFA% will be summarized by LTBP4 (IAMM vs VTTT+ other)
MFA% will be summarized  by Osteopontin (TT vs GT+GG) 
6.12 Secondary Endpoints 
Analysis of secondary endpoints is done at both End of Study and End of Extension phases 
for the following endpoints:  

6MWT

NSAA

PUL
6.12.1 Additional histological endpoints 
Additional histological endpoints will be analyzed in a similar manner as for the primary 
analysis. 
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
Perimysial Fibrosis %

Endomysial Fibrosis %

Total fibrosis %

Necrosis %

Inflammation: (Total of single stained M2 / total n. of fields)

Inflammation: (Total of single stained M1 / total n. of fields)

Inflammation: (Total of M2M1 / total n. of fields)

Inflammation: (Total of single stained M2 / total macrophages)

Inflammation: (Total of single stained M1 / total macrophages)

Inflammation: (Total of M2M1 / total macrophages)

Muscle Regeneration: ( Total n° of Develop Myosin positive cells – all fields / Total
fibers biopsy – all fields)

Muscle Regeneration: (Total n° of SC (sublaminal and extralaminal) – all fields /Total
fibers biopsy – all fields)

Muscle Regeneration: (Total n° of SC (sublaminal) – all field / Total fibers biopsy – all
fields)

Muscle Regeneration: (Total n° of SC (sublaminal) – all field / Total n° of SC
(sublaminal and extralaminal) – all fields)

Muscle Regeneration: (Total n° of sublaminal SC positive Ki67 – all fields / Total n° of
SC (sublaminal) – all fields)

Muscle Regeneration: (Total n° of SC (extralaminal ) – all fields /Total n° of fibers – all
fields)

Muscle Regeneration: (Total n° of SC (extralaminal) – all fields / Total n° of SC
(sublaminal and extralaminal) – all fields)

Muscle Regeneration: (Total n° of extralaminal SC positive Ki67 – all fields /Total n° of
SC (extralaminal) – all fields)

Fiber dimension distribution (CSA)

No of Hypercontracted fibers

Fatty replacement %
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The analysis methodology for changes in the above endpoints except for CSA will compare 
End of Study to baseline using Paired-T test subject to normality assumption or non-parametric 
Signed rank test for two means (paired observations) as is appropriate. Additionally descriptive 
statistics per visit will be provided. 
The 2.5th, 10th, 25th, 50th, 75th, and 97.5th percentiles will be tabulated for baseline CSA 
score and the end of treatment CSA score. The hypothesis that the median scores are the same 
between the baseline and the end of treatment will be tested using SAS procedure npar1way 
with option ‘median’.  
This will be shown descriptively by plotting the cumulative distribution of all measurements at 
End of Study alongside a cumulative distribution plot for all measurements at Baseline. 
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6.12.2 Change in muscular function based on the 6MWT at End of Study/End of 
Extension phases 
Descriptive statistics (including CI) for the actual values and change from baseline (mean of two 
baseline measurements) will be provided per visit for the total score. The descriptive statistics 
will also be presented by the following categories: 

By age group

By corticosteroids treatment (i.e. continuous vs intermittent regimen)

By LTBP4 (IAMM vs VTTT+ other)

By Osteopontin (TT vs GT+GG)

By predicted value at baseline (≥80% predicted value vs  <80% predicted value)
Additionally a graph of the achieved distance over time for each subject will be presented. 
In addition, descriptive statistics of the change from baseline in the percentage of predicted 
distance (as described in 6.2) per visit will be presented. 
6.12.3 Change in muscular function based on the NSAA at End of Study/End of Extension 
phases 
Descriptive statistics (including CI) for the actual values and change from baseline will be 
provided per visit for each item and total score. The descriptive statistics will also be presented 
by the following categories: 

By LTBP4 (IAMM vs VTTT+ other)
6.12.4 By Osteopontin (TT vs GT+GG) Change in muscular function based on the PUL at 
End of Extension phase 
Descriptive statistics (including CI) for the actual values and change from baseline will be 
provided per visit for each item and total score. 
6.12.5 Change in muscular function based on the Histology parameters at End of Study 
Descriptive statistics will also be presented by the following categories: 

By LTBP4 (IAMM vs VTTT+ other)

By Osteopontin (TT vs GT+GG)
6.12.6 Proportion of patients who loss the ambulation at End of Study/End of Extension 
phases 
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The proportion of subjects who lose ambulation (i.e. who are not able to perform the 6MWT and 
the 10 meter walk test) will be summarized  yearly until the  end of the study (i.e. at 12 month, 
24 month, 36 month and end of study (52 months). 
For patients who lost the ambulation, the time to wheelchair and how much time the children 
spend in wheelchair were assessed and reported in a listing.  
Additionally, the time from first use of study drug to loss of ambulation will be illustrated with a 
Kaplan-Meier plot. Patients who did not lose ambulation will be censored at the time of last 
assessment.  
6.13 
Exploratory Analysis 
The exploratory endpoints will include the following: 

Shift changes of the MRI scores, per muscle and body location,  after treatment with
Givinostat (also evaluated during the extension 1 phase).

Change in muscle biomarkers (e.g., miRNA) following treatment with Givinostat
(Part 1 and Part 2 of the study)
The analysis methodology for changes in the above endpoints will compare month 12
to baseline using Paired-T test subject to normality assumption or non-parametric
Signed rank test for two means (paired observations) as is appropriate. Additionally
descriptive statistics per visit will be provided.

Evaluation of acceptability/palatability of the oral suspension
An incidence table will be presented including the following
o
Taste of medicine

For child (dislike very much, dislike a little, not sure, like a little, like very
much)

For parent (pleasant, not sure, unpleasant)
o
Difficulties in giving medication to child (yes, no)

The exploratory analysis for testing the relations between PK and PD parameters will
be discussed in a separate SAP. Evaluation of any correlation between the effects of
Givinostat on disease progression and the type of DMD mutation subjects may have
in relation to their disease.
Disease progression will be measured by change from baseline to End of Study/End
of Extension phases for 6MWT summarized by DMD mutation type.

PedsQL. Descriptive statistics for the total score and the score of the subscales and
change from baseline will be presented per visit. A listing of PedsQL will be
presented.
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Evaluation of LTBP4 and osteopontin genotype (at the beginning of Extension 2  
only) . An incidence table of all sequences of LTBP4 and Osteopontin will be presented. 
6.14 
Multiplicity 
As this is a Phase 2 exploratory study, no adjustments for multiplicity will be made. 
6.15 
Safety analysis 
All subjects who receive at least one dose of study medication will be included in the analysis 
of safety. 
For all analysis by visit, results at ‘any time post baseline’ will be presented. 
The following visits will be included in the safety analysis –  

Visits 1-6 in Part 1

Visits 1-10 in Part 2

Visits 11-16 and follow-up in the extension 1 phase

Visits 17-22 and follow-up in the extension 2 phase

Visits  23-26 and follow-up in the extension 3 phase
6.15.1 Extent of exposure 
Overall exposure will be calculated, per study part, as the number of days the subject took study 
medication: (last date of dosing - first day of dosing + 1).  No allowance will be made for breaks 
in therapy.  If the date of last dosing is completely missing then the date of last dosing will be 
taken for analysis purposes as the date the relevant medication was last dispensed.  If only the 
month of the last dose is recorded, the first day of the month will be assumed as the last dosing 
date. 
6.15.2  Adverse Events 
A treatment emergent adverse event (TEAE) is defined as any AE that has an onset on or after 
the dose of study treatment, or any pre-existing condition that has worsened during or after the 
first dose of study treatment. Whether TEAEs will be attributed to a treatment or not is a 
clinical decision based on all available information at the time of the completion of the eCRF. 
A treatment-related adverse event is defined as an adverse event as being unlikely, possibly, 
probably or definitely related to the study treatment. If adverse event has missing relationship it 
is assumed to be related to the study treatment for analysis purposes. 
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The number and incidence of TEAEs, Serious adverse events (SAEs), AEs related to study 
treatment, SAEs related to treatment and AEs leading to study discontinuation will be 
summarized by study part (part 1, part 2, extension phases) and treatment. 
The treatment associated with the TEAE will be determined by finding which treatment dates 
the adverse event onset date falls in.  
For the summarization by severity or relationship to the study drug, if more than one event 
occurred with the same Preferred Term for the same patient, the patient will be counted only once 
for that Preferred Term using the most severe or related occurrence respectively. The summary 
will include the number of TEAEs, the total number and percentage of subjects reporting at least 
one event. An individual patient will be counted only once for any specific Preferred Term 
regardless to the number of times that Preferred Term occurred for that patient (First Ever 
Incidence approach). Adverse events will be coded using MedDRA version 17.0.  
Narratives of deaths, serious and other significant adverse events will be provided in the 
relevant section of the study report.  
 A complete subject listing of all adverse events will be provided in Appendix 16.2 to the study 
report. This listing will include treatment, AE verbatim, MedDRA primary system organ class 
and preferred term, the time of onset and cessation of event relative to first dosing of study 
medication, duration of AE (for ongoing AEs use the date of investigator signature as the 
cessation date for calculation purposes), whether serious, severity, relationship to study 
medication, action taken and outcome. 
6.15.3  Clinical Laboratory Evaluations 
Descriptive statistics will be calculated for each follow-up assessment (Visits 1-6 in Part 1, 
Visits 1-10 in Part 2 and Visits 11-26 and follow-up in the extension phases) as well as changes 
from baseline for hematology and serum chemistry. Each measurement will be classed as 
below, within, or above normal range, based on ranges supplied by the laboratory used. Shift 
tables in relation to the normal range from screening to each follow-up visit will be presented. 
In addition, for parts 1 and 2, descriptive statistics of the minimal values, time to nadir and time 
to recovery, will be calculated for Platelets, Red Blood Cells (RBC) and Neutrophils. A graph 
of the results (including normal range reference lines) over time (including unscheduled results) 
for each subject per test will be provided.  
Descriptive statistics for urinalysis will be calculated for each follow-up assessment as well as 
changes from baseline.  
Details of microscopic urinalysis will be provided in Appendix 16.2 of the report. 
A listing of any clinically significant laboratory measurements recorded throughout the study 
will be provided. 
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In addition, a listing of laboratory results will be provided. 
6.15.4  Pulmonary function tests (PFTs) 
Descriptive statistics for forced expiratory volume at 1 second [FEV1], forced vital capacity 
[FVC], FEV1/FVC and PEF will be calculated for each follow-up assessment as well as 
changes from baseline at Month 12 (Part II), Month 24 (Ext 1), Month 36 (Ext 2) and Month 52 
(Ext 3).  If more than one value is recorded, the mean value rounded to the integer will be 
presented. In addition, the percentage of predictive value of FVC, FEV1 and FEV1/FVC will be 
calculated according to the Quanjer Global Lungs Initiative (GLI) 2012 regression 
equation8(http://www.lungfunction.org/tools.html). 
The percentage of predictive value of PEF will be calculated according to the Buyse et al, 2015 
Lancet formula: PEF*100 / (-422.8 + 5.288 * height) 
A listing of PFTs will be provided. 
6.15.5  Echocardiographs 
Descriptive statistics for all the parameters will be presented by the following categories - 
Mode, 2D, Colour Doppler, Pulsed Wave Doppler and Continuous Wave Doppler. 
A listing of echocardiographs will be provided. 
6.15.6 Vital Signs 
Summary statistics for observed and changes from pre-dose in the following vital signs will be 
tabulated at each follow-up: 

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

Heart Rate (bpm)

Body temperature (degrees Celsius)

Weight (Kg)

Height (cm)
An outlier value following dosing for systolic and diastolic blood pressure is defined as an 
increase or decrease from the baseline value of more than 20 mmHg. The number and 
percentage of subjects with outlier values following dosing for systolic and diastolic blood 
pressure at each assessment will be presented. 
Mean profiles by treatment will be presented for each vital sign. 
6.15.7  ECG 
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Summary statistics for observed and changes from pre-dose in the following ECG variables will 
be tabulated at each follow-up: 

RR interval (ms)

PR interval (ms)

QRS complex (ms)

QT interval (ms)

QTc interval (ms) [Bazett’s formula - QTcB]

QTc interval (ms) [Fridericia’s formula - QTcF]
Mean profiles by treatment will be presented for each ECG variable. 
The incidence of outliers in absolute QT, QTcF and QTcB intervals (>450, >480, and >500 
msec), and the change from baseline in QT, QTcF and QTcB intervals (>30 and >60 msec) will 
be summarized by treatment as defined in ICH E14 guideline4.  
The incidence of outliers of absolute QRS (<75, >110 msec) and absolute PR (<100, >220 
msec) will be summarized by treatment. 
Both the number and percentage of subjects who meet the ECG outlier criteria at each 
assessment will be presented by treatment sequence.  
Moreover, the analysis of outliers will be done dividing the group by age. 
The individual subject ECG data that meets the ECG outlier criteria will be listed in Appendix 
16.2.  
In addition, the change from baseline at each follow-up in the overall interpretation of the ECG 
(Normal, Abnormal NCS, and Abnormal CS) will also be tabulated. 
A listing of ECG will be provided. 
6.15.8  Physical Examination 
The body systems within the physical examination data at the end of the study will be 
summarized by treatment (Normal; Abnormal NCS, Abnormal CS). Changes from baseline will 
also be tabulated.  
A listing of physical examination will be provided. 
6.15.9  Concomitant medications 
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Concomitant medication verbatim terms (as recorded on the CRFs) after the initial dose of 
study drug will be mapped to Anatomical Therapeutic Chemical (ATC) Level 2 and Drug 
Reference Names using the World Health Organization (WHO) dictionary (Version March 
2014  Enhanced).  
Concomitant medication verbatim terms (as recorded on the CRFs) after the initial dose of 
study drug will be summarized by Anatomical Therapeutic Chemical (ATC) Level 2 and Drug 
Reference Names using the World Health Organization (WHO) dictionary (Version March 
2014  Enhanced) and Study Part. 
A listing of concomitant medications will be provided. 
6.16 
Pharmacokinetic Analysis 
The PK analysis will be performed on the PK population. 
Listing of PK concentration data and of PK derived parameters will be provided. 
The following plots will also be provided:  
Individual plasma concentration vs. time profiles of Givinostat following different dose levels 
of the compound. 
Mean (SD) vs. time profile following different dose levels of the compound. 
Descriptive statistics of PK parameters of Givinostat will include mean, SD, coefficient of 
variation (CV), min, median, and max.  
The PK analysis will be conducted as follows: 
Plasma actual sampling times will be used:  
Plasma concentrations below the lower limit of quantification (BLQ) before the first detectable 
concentration will be set equal to zero.  
All BLQ values after the last detectable plasma concentration will be excluded from the PK 
calculation. A BLQ value between two detectable plasma concentrations will be excluded from 
the PK calculations.  
BLQ values will be set equal to zero for the descriptive statistic evaluations. BLQ values 
between two detectable plasma concentrations will be excluded for the descriptive statistics 
evaluations.  
Individual values considered to be anomalous will be excluded from the PK analysis and 
descriptive statistics.Justification for exclusion will be provided in the PK report.  
Plasma Givinostat, Cmax, tmax Clast, tlast will be taken directly from the raw data. 
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Areas under the plasma concentration vs. time curve (AUClast) will be calculated using the 
trapezoidal rule. If the concentration vs. time profile allows, the half-life of the terminal phase 
of LF-BP, t½,z, will be determined by linear regression analysis of the natural-log 
concentration vs. time curve according to the formula:  
t½,z = ln(2)/z  where z is the slope of the regression line. 
6.17 
Key Data Items 
A second statistician within WCT will check all the analyses relating to the primary efficacy 
endpoint and key secondary endpoints.  
The checking procedure will involve writing independent SAS® programs and comparing the 
output produced with the results in the relevant tables. Any disagreements will be reconciled 
appropriately. 
6.18 
Change to Planned Protocol Analysis 
Not applicable, no changes from the planned analysis described in the protocol. 
6.19 
Post-Hoc Analysis 
After database lock for Part 1 and Part 2 data, a post-hoc analysis will be performed to calculate 
the correlations and associated p-values, using the Pearson correlation analysis, between the 
histological parameters (MFAF, Fibrosis %, Necrosis %, Fatty replacement %, Mean CSA, 
Total n° Develop Myosin positive cells / Total fibers) and the demographic and functional 
parameters (age, corticosteroids duration, 6MWT, NSAA total score, time to walk 10m 
(seconds), time to stand up from floor (seconds), PUL: total score, PUL: high level shoulder 
dimension) at baseline value, the value at Visit 10 and the change from baseline. 
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References 
(1)
Desguerre I, Mayer M, Leturcq F, Barbet JP, Gherardi RK, Christov C. Endomysial
fibrosis in Duchenne muscular dystrophy: a marker of poor outcome associated with
macrophage alternative activation. J Neuropathol Exp Neurol 2009;68:762–773.
(2)
Al-Sunduqchi MS. 1990. Determining the Appropriate Sample Size for Inferences
Based on the Wilcoxon Statistics. Ph.D. dissertation under the direction of William C.
Guenther, Dept. of Statistics, University of Wyoming, Laramie, Wyoming
(3)
Bazett HC. An analysis of time relations of the electrocardiogram. Heart 1920; 7: 353-
370.3.
(4)
Fridericia LS. Die systolendauer in elektrokardio-gram bei normalen menschen und bei
herzkranken. Acta Med Scand 1920; 53: 469.
(5)
SAS Institute Inc.  The SAS System, Version 9.3.  Cary, NC, SAS Institute Inc. 2012.
(6)
ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic
Potential for Non-Antiarrhythmic Drugs.
(7)
Henricson E, Abresch R, Han JJ, Nicorici A, Goude Keller E, Elfring G, Reha A, Barth
J, McDonald CM. Percent-predicted 6-minute walk distance in duchenne muscular
dystrophy to account for maturational influences. Version 2. PLoS Curr. 2012 Jan 25
[revised 2012 Feb 2];4:RRN1297. PubMed PMID: 22306689
(8)
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL,
Hankinson JL, Ip MSM, Zheng J, Stocks J, and the ERS Global Lung Function
Initiative. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the
global lung function 2012 equations. Eur Respir J 2012;40 1324-1343
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7.
TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT
14.1.1 
Patient Disposition – ITT population 
14.1.1.1 
Patient Disposition – ITT population– Part 1+2, Extension 1, 2 and 3 
14.1.2 
Datasets Analyzed – ITT population 
14.1.3 
Screening Failures 
14.1.4 
Demography – ITT Population 
14.1.5 
Previous Medical History – ITT Population 
14.1.6 
Ongoing Medical History – ITT Population 
14.1.7a 
Muscle Biopsy at Screening – ITT Population 
14.1.7b 
Muscle Biopsy at Screening Inflammation– ITT Population 
14.1.7c 
Muscle Biopsy at Screening Regeneration– ITT Population 
14.1.8 
miRNA at Screening – ITT Population 
14.1.9 
MRI at Screening – ITT Population 
14.1.10a 
PedsQL-Child at Screening – ITT Population 
14.1.10b 
PedsQL- Parent at Screening – ITT Population 
14.1.11 
Pulmonary Function Tests (PFTs) at Screening – ITT Population 
14.1.12 
Echocardiographs at Screening – ITT Population 
14.1.13 
Six Minutes Walk Test (6MWT) at Screening  – ITT Population 
14.1.14 
North Star Ambulatory Assessment (NSAA) at Screening  – ITT Population 
14.1.15 
Performance of Upper Limb (PUL) at Screening  – ITT Population 
14.1.16 
Vital Signs at Screening – ITT Population 
14.1.17 
12-Lead ECG at Screening – ITT Population
14.1.18 
Physical Examination at Screening – ITT Population 
14.1.19 
Hematology at Screening – ITT Population 
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14.1.20 
Chemistry at Screening – ITT Population 
14.1.21 
Urinalysis at Screening – ITT Population 
14.1.22 
Serology Test at Screening – ITT Population 
14.1.23 
Concomitant Medication Ongoing at Time of the Dose of Study Medication – 
ITT Population 
14.2.1.1.1 
Primary Analysis of Primary Endpoint: Summary Statistics for Change in 
MFA% - Evaluable Population 
14.2.1.1.2 
Primary Analysis of Primary Endpoint: Measurement and changes in MFA% - 
Evaluable Population 
14.2.1.2.1.1 
Sensitivity Analysis of Primary Endpoint: Summary Statistics for Change in 
MFA% - Completers Population 
14.2.1.2.1.2 
Sensitivity Analysis of Primary Endpoint: Measurement and changes in 
MFA% - Completers Population 
14.2.1.2.2.1 
Sensitivity Analysis of Primary Endpoint: Summary Statistics for Change in 
MFA% - ITT Population 
14.2.1.2.2.2 
Sensitivity Analysis of Primary Endpoint: Measurement and changes in 
MFA% - ITT Population 
14.2.1.3.1 
Exploratory Analysis of Primary Endpoint:  Summary Statistics for MFA% by 
DMD - Evaluable Population 
14.2.1.3.2 
Exploratory Analysis of Primary Endpoint: Correlation between changes in 
MFA% and DMD - Evaluable Population 
14.2.1.3.3 
Exploratory Analysis of Primary Endpoint:  Summary Statistics for MFA% by 
Arm Sequence - Evaluable Population 
14.2.1.4.1a 
14.2.1.4.1b 
14.2.1.4.1c 
Analysis of Secondary Endpoint: Summary Statistics for Additional 
Histological Endpoint - ITT Population 
Analysis of Secondary Endpoint: Summary Statistics for Additional 
Histological Endpoint - ITT Population 
Analysis of Secondary Endpoint: Summary Statistics for Additional 
Histological Endpoint - ITT Population 
14.2.1.4.2 
Analysis of Secondary Endpoint: Additional Histological Endpoint - ITT 
Population 
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14.2.1.4.3.1 
Analysis of Exploratory Endpoint: Summary Statistics for Change in MFA% 
and histology at each Follow-up Assessment by Osteopontin - ITT Population 
14.2.1.4.3.2 
Analysis of Exploratory Endpoint: Summary Statistics for Change in MFA% 
and  histology at each Follow-up Assessment by LTBP4  - ITT Population 
14.2.1.5.1 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment - Part 2 - ITT Population 
14.2.1.5.2.1 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment – Extension 1 - ITT Population 
14.2.1.5.2.2 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment – Extension 2 - ITT Population 
14.2.1.5.2.3 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment – Extension 3 - ITT Population 
14.2.1.5.3 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by DMD mutation - Part 2 - ITT Population 
14.2.1.5.4.1 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by DMD mutation – Extension 1 - ITT 
Population 
14.2.1.5.4.2 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by DMD mutation – Extension 2 - ITT 
Population 
14.2.1.5.4.3 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by DMD mutation – Extension 3 - ITT 
Population 
14.2.1.5.5.1 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by Age - Part 2 - ITT Population 
14.2.1.5.5.2.1 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by Age – Extension 1 - ITT Population 
14.2.1.5.5.2.2 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by Age – Extension 2 - ITT Population 
14.2.1.5.5.2.3 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by Age – Extension 3 - ITT Population 
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14.2.1.5.6.1 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by corticosteroids regimen - Part 2 - ITT 
Population 
14.2.1.5.6.2.1 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by Corticosteroids Regimen - Extension 1- ITT 
Population 
14.2.1.5.6.2.2 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by corticosteroids regimen – Extension 2 - ITT 
Population 
14.2.1.5.6.2.3 
Analysis of Secondary Endpoint: Summary Statistics for Change in 6MWT at 
each Follow-up Assessment by corticosteroids regimen – Extension 3 - ITT 
Population 
14.2.1.5.7.1 
Analysis of Exploratory Endpoint: Summary Statistics for Change in 6MWT 
at each Follow-up Assessment by Osteopontin  - ITT Population 
14.2.1.5.7.1.1 
Analysis of Exploratory Endpoint: Summary Statistics for Change in 6MWT 
at each Follow-up Assessment by Osteopontin – Extension 1  - ITT 
Population 
14.2.1.5.7.1.2 
Analysis of Exploratory Endpoint: Summary Statistics for Change in 6MWT 
at each Follow-up Assessment by Osteopontin – Extension 2  - ITT 
14.2.1.5.7.1.3 
Analysis of Exploratory Endpoint: Summary Statistics for Change in 6MWT 
at each Follow-up Assessment by Osteopontin – Extension 3  - ITT 
14.2.1.5.7.2 
Analysis of Exploratory Endpoint: Summary Statistics for Change in 6MWT 
at each Follow-up Assessment by LTBP4  - ITT Population 
14.2.1.5.7.2.1 
Analysis of Exploratory Endpoint: Summary Statistics for Change in 6MWT 
at each Follow-up Assessment by LTBP4 –Extension 1 - ITT Population 
14.2.1.5.7.2.2 
Analysis of Exploratory Endpoint: Summary Statistics for Change in 6MWT 
at each Follow-up Assessment by LTBP4 –Extension 2 - ITT Population 
14.2.1.5.7.2.3 
Analysis of Exploratory Endpoint: Summary Statistics for Change in 6MWT 
at each Follow-up Assessment by LTBP4 –Extension 3 - ITT Population 
14.2.1.6.1.1 
Analysis of Secondary Endpoint: Change in Percentage of Predicted Distance 
6MWT at each Follow-up Assessment - Part 2 - ITT Population 
14.2.1.6.1.2.1 
Analysis of Secondary Endpoint: Change in Percentage of Predicted Distance 
6MWT at each Follow-up Assessment - Extension 1- ITT Population 
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14.2.1.6.1.2.2 
Analysis of Secondary Endpoint: Change in Percentage of Predicted Distance 
6MWT at each Follow-up Assessment - Extension 2- ITT Population 
14.2.1.6.1.2.3 
Analysis of Secondary Endpoint: Change in Percentage of Predicted Distance 
6MWT at each Follow-up Assessment - Extension 3- ITT Population 
 14.2.1.6.2.1 
Analysis of Secondary Endpoint: Change in 6MWT (Absolute Value) at each 
Follow up Assessment by < and >=80% of Predicted Distance 6MWT at 
Baseline - Part 2 - ITT Population  
14.2.1.6.2.2.1 
Analysis of Secondary Endpoint: 6MWT (Absolute Value) at each Follow up 
Assessment by < and >=80% of Predicted Distance 6MWT at Baseline - 
Extension 1- ITT Population 
14.2.1.6.2.2.2 
Analysis of Secondary Endpoint: Change in 6MWT (Absolute Value) at each 
Follow up Assessment by < and >=80% of Predicted Distance 6MWT at 
Baseline - Extension 2- ITT Population 
14.2.1.6.2.2.3 
Analysis of Secondary Endpoint: Change in 6MWT (Absolute Value) at each 
Follow up Assessment by < and >=80% of Predicted Distance 6MWT at 
Baseline - Extension 3- ITT Population 
14.2.1.7.1 
Analysis of Secondary Endpoint: Change in NSAA  at each Follow-up 
Assessment - Part 2 - ITT Population 
14.2.1.7.1b 
Analysis of Secondary Endpoint: Change in NSAA  at each Follow-up 
Assessment  (excluding pt. 219 at End of Part 2)- Part 2 - ITT Population 
14.2.1.7.2.1 
Analysis of Secondary Endpoint: Change in NSAA  at each Follow-up 
Assessment – Extension 1 - ITT Population 
14.2.1.7.2.2 
Analysis of Secondary Endpoint: Change in NSAA  at each Follow-up 
Assessment – Extension 2 - ITT Population 
14.2.1.7.2.3 
Analysis of Secondary Endpoint: Change in NSAA  at each Follow-up 
Assessment – Extension 3 - ITT Population 
14.2.1.7.3.1 
Analysis of Exploratory Endpoint: Summary Statistics for Change in NSAA 
at each Follow-up Assessment by Osteopontin - ITT Population 
14.2.1.7.3.1.1 
Analysis of Exploratory Endpoint: Summary Statistics for Change in NSAA 
at each Follow-up Assessment by Osteopontin- Extension 1 - ITT Population 
14.2.1.7.3.1.2 
Analysis of Exploratory Endpoint: Summary Statistics for Change in NSAA 
at each Follow-up Assessment by Osteopontin- Extension 2 - ITT Population 
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14.2.1.7.3.1.3 
Analysis of Exploratory Endpoint: Summary Statistics for Change in NSAA 
at each Follow-up Assessment by Osteopontin- Extension 3 - ITT Population 
14.2.1.7.3.2 
Analysis of Exploratory Endpoint: Summary Statistics for Change in NSAA 
at each Follow-up Assessment by LTBP4  - ITT Population 
14.2.1.7.3.2.1 
Analysis of Exploratory Endpoint: Summary Statistics for Change in NSAA 
at each Follow-up Assessment by LTBP4 –Extension 1 - ITT Population 
14.2.1.7.3.2.2 
Analysis of Exploratory Endpoint: Summary Statistics for Change in NSAA 
at each Follow-up Assessment by LTBP4 –Extension 2 - ITT Population 
14.2.1.7.3.2.3 
Analysis of Exploratory Endpoint: Summary Statistics for Change in NSAA 
at each Follow-up Assessment by LTBP4 –Extension 3 - ITT Population 
14.2.1.8.1 
Analysis of Secondary Endpoint: Change in PUL at each Follow-up 
Assessment - Part 2 - ITT Population 
14.2.1.8.2.1 
Analysis of Secondary Endpoint: Change in PUL at each Follow-up 
Assessment - Extension 1- ITT Population 
14.2.1.8.2.2 
Analysis of Secondary Endpoint: Change in PUL at each Follow-up 
Assessment - Extension 2- ITT Population 
14.2.1.8.2.3 
Analysis of Secondary Endpoint: Change in PUL at each Follow-up 
Assessment - Extension 3- ITT Population 
14.2.1.8.3.1 
Analysis of Exploratory Endpoint: Summary Statistics for Change in PUL 
from baseline to Extension 3 by LTBP4 - ITT Population 
14.2.1.8.3.2 
Analysis of Exploratory Endpoint: Summary Statistics for Change in PUL 
from baseline to Extension 3 by Osteopontin - ITT Population 
14.2.1.9 
Analysis of Secondary Endpoint: Additional Histological Endpoint, fiber 
dimension distribution (CSA) - Completers Population 
14.2.1.10.1 
Exploratory Analysis: Summary Statistics of Change in miRNA at End of 
Study (Part 2) - ITT Population 
14.2.1.10.2 
Exploratory Analysis: Change in miRNA at End of Study - ITT Population 
14.2.1.11.1 
Exploratory Analysis: Acceptability/Palatability of the Oral Suspension  at 
each Follow-up Assessment - ITT Population 
14.2.1.12.1a 
Exploratory Analysis: Summary Statistics for the Change from Baseline in 
PedsQL-Child at each Follow-up Assessment – Part 2 – ITT Population 
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14.2.1.12.1b 
Exploratory Analysis: Summary Statistics for the Change from Baseline in 
PedsQL- Parent  at each Follow-up Assessment – Part 2 – ITT Population 
14.2.1.12.2.1a 
Exploratory Analysis: Summary Statistics for the Change from Baseline in 
PedsQL-Child at each Follow-up Assessment – Extension 1– ITT Population 
14.2.1.12.2.1b 
Exploratory Analysis: Summary Statistics for the Change from Baseline in 
PedsQL- Parent at each Follow-up Assessment – Extension 1– ITT Population 
14.2.1.12.2.2a 
Exploratory Analysis: Summary Statistics for the Change from Baseline in 
PedsQL-Child at each Follow-up Assessment – Extension 2– ITT Population 
14.2.1.12.2.2b 
Exploratory Analysis: Summary Statistics for the Change from Baseline in 
PedsQL- Parent at each Follow-up Assessment – Extension 2– ITT Population 
14.2.1.12.2.3a 
Exploratory Analysis: Summary Statistics for the Change from Baseline in 
PedsQL-Child at each Follow-up Assessment – Extension 3– ITT Population 
14.2.1.12.2.3b 
Exploratory Analysis: Summary Statistics for the Change from Baseline in 
PedsQL- Parent at each Follow-up Assessment – Extension 3– ITT Population 
14.2.1.13.1 
Exploratory Analysis: MRI Scores Shift from Baseline (Screening) to each 
Follow-up Assessment  Part 2 –ITT Population 
14.2.1.13.2 
Exploratory Analysis: MRI Scores Shift from Baseline (Screening) to each 
Follow-up Assessment – Extension 1–ITT Population 
14.2.1.14.1 
Exploratory Analysis:  Evaluation of LTBP4 and Osteopontin Genotype  -
Extension 1-ITT Population 
14.2.1.14.2 
Exploratory Analysis:  Evaluation of LTBP4 and Osteopontin Genotype  -
Extension 2-ITT Population 
14.2.1.14.3 
Exploratory Analysis:  Evaluation of LTBP4 and Osteopontin Genotype  -
Extension 3-ITT Population 
14.2.15.1 
Number and Percent of Subjects Who Lost Ambulation - ITT Population 
14.3.1.1 
Extent of Exposure to Study Medication - Part 1 - Safety Population 
14.3.1.2 
Extent of Exposure to Study Medication - Part 2 - Safety Population 
14.3.1.3.1 
Extent of Exposure to Study Medication - Extension 1- Safety Population 
14.3.1.3.2 
Extent of Exposure to Study Medication - Extension 2- Safety Population 
14.3.1.3.3 
Extent of Exposure to Study Medication - Extension 3- Safety Population 
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14.3.2.1 
Summary of Treatment-Emergent Adverse Event Reporting  – Part 1 – Safety 
Population 
14.3.2.2 
Summary of Treatment-Emergent Adverse Event Reporting  – Part 2 – Safety 
Population 
14.3.2.3.1 
Summary of Treatment-Emergent Adverse Event Reporting  – Part 1+2 and 
Extension 1– Safety Population 
14.3.2.3.2 
Summary of Treatment-Emergent Adverse Event Reporting  – Part 1+2  
Extension 1 and Extension 2 – Safety Population 
14.3.2.3.3 
Summary of Treatment-Emergent Adverse Event Reporting  – Part 1+2, 
Extension 1, Extension 2 and Extension 3 – Safety Population 
14.3.3.1 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class and Preferred Term – Part 1 – Safety Population 
14.3.3.2 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class and Preferred Term – Part 2 – Safety Population 
14.3.3.3.1 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class and Preferred Term – Part 1+2 and Extension 1 – Safety 
Population 
14.3.3.3.2 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class and Preferred Term – Part 1+2  Extension 1 and 
Extension 2– Safety Population 
14.3.3.3.3 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class and Preferred Term – Part 1+2, Extension 1, Extension 2 
and Extension 3– Safety Population 
14.3.4.1 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Severity – Part 1 – Safety 
Population 
14.3.4.2 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Severity – Part 2 – Safety 
Population 
14.3.4.3.1 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Severity – Part 1+2 and Extension 
1– Safety Population 
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14.3.4.3.2 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Severity – Part 1+2  Extension  and 
Extension 2– Safety Population 
14.3.4.3.3 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Severity – Part 1+2, Extension 1, 
Extension 2 and  Extension 3– Safety Population 
14.3.5.1 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Relationship to Study Drug – Part 1 
– Safety Population
14.3.5.1.2 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Relationship to Study Drug – Part 1 
+ 2 – Safety Population
14.3.5.2 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Relationship to Study Drug – Part 2 
– Safety Population
14.3.5.3.1 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Relationship to Study Drug – Part 
1+2 and Extension 1 – Safety Population 
14.3.5.3.2 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Relationship to Study Drug – Part 
1+2, Extension 1 and Extension 2– Safety Population 
14.3.5.3.3 
MedDRA Summary of Treatment-Emergent Adverse Events by Primary 
System Organ Class, Preferred Term, and Relationship to Study Drug – Part 
1+2, Extension 1, Extension 2 and Extension 3– Safety Population 
14.3.6.1 
MedDRA Summary of Treatment-Emergent Adverse Events Resulting in 
Study Discontinuation by Primary System Organ Class and Preferred Term – 
Part 1 – Safety Population 
14.3.6.2 
MedDRA Summary of Treatment-Emergent Adverse Events Resulting in 
Study Discontinuation by Primary System Organ Class and Preferred Term – 
Part 2 – Safety Population 
14.3.6.3.1 
MedDRA Summary of Treatment-Emergent Adverse Events Resulting in 
Study Discontinuation by Primary System Organ Class and Preferred Term – 
Part 1+2 and Extension 1 – Safety Population 
14.3.6.3.2 
MedDRA Summary of Treatment-Emergent Adverse Events Resulting in 
Study Discontinuation by Primary System Organ Class and Preferred Term – 
Part 1+2, Extension 1 and Extension 2– Safety Population 
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14.3.6.3.3 
MedDRA Summary of Treatment-Emergent Adverse Events Resulting in 
Study Discontinuation by Primary System Organ Class and Preferred Term – 
Part 1+2, Extension 1, Extension 2 and Extension 3– Safety Population 
14.3.7.1 
MedDRA Summary of Treatment-Emergent Serious Adverse Events by 
Primary System Organ Class and Preferred Term – Part 1 – Safety Population 
14.3.7.2 
MedDRA Summary of Treatment-Emergent Serious Adverse Events by 
Primary System Organ Class and Preferred Term – Part 2 – Safety Population 
14.3.7.3.1 
MedDRA Summary of Treatment-Emergent Serious Adverse Events by 
Primary System Organ Class and Preferred Term – Part 1+2 and Extension 1 
– Safety Population
14.3.7.3.2 
MedDRA Summary of Treatment-Emergent Serious Adverse Events by 
Primary System Organ Class and Preferred Term – Part 1+2, Extension 1, and 
Extension 2– Safety Population 
14.3.7.3.3 
MedDRA Summary of Treatment-Emergent Serious Adverse Events by 
Primary System Organ Class and Preferred Term – Part 1+2, Extension 1, 
Extension 2 and Extension 3– Safety Population 
14.3.8.1 
MedDRA Summary of Treatment-Emergent Drug-related Serious Adverse 
Events by Primary System Organ Class and Preferred Term – Part 1 – Safety 
Population 
14.3.8.2 
MedDRA Summary of Treatment-Emergent Drug-related Serious Adverse 
Events by Primary System Organ Class and Preferred Term – Part 2 – Safety 
Population 
14.3.8.3.1 
MedDRA Summary of Treatment-Emergent Drug-related Serious Adverse 
Events by Primary System Organ Class and Preferred Term – Part 1+2 and 
Extension 1 – Safety Population 
14.3.8.3.2 
MedDRA Summary of Treatment-Emergent Drug-related Serious Adverse 
Events by Primary System Organ Class and Preferred Term – Part 1+2, 
Extension 1and Extension 2– Safety Population 
14.3.8.3.3 
MedDRA Summary of Treatment-Emergent Drug-related Serious Adverse 
Events by Primary System Organ Class and Preferred Term – Part 1+2, 
Extension 1, Extension 2 and Extension 3– Safety Population 
14.3.9.1 
Summary Statistics for the Change from Baseline in Hematology at each 
Follow-up Assessment – Part 1 – Safety Population 
14.3.9.2 
Summary Statistics for the Change from Baseline in Hematology at each 
Follow-up Assessment – Part 2 – Safety Population 
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14.3.9.3.1 
Summary Statistics for the Change from Baseline in Hematology at each 
Follow-up Assessment – Extension 1– Safety Population 
14.3.9.3.2 
Summary Statistics for the Change from Baseline in Hematology at each 
Follow-up Assessment – Extension 2– Safety Population 
14.3.9.3.3 
Summary Statistics for the Change from Baseline in Hematology at each 
Follow-up Assessment – Extension 3– Safety Population 
14.3.9.3.4 
Summary Statistics for the Change from Baseline in Hematology  from 
Baseline and at Month 12, 24, 36,  and End of Study Assessment – Safety 
Population    
14.3.10.1 
Summary Statistics for the Minimal Value in Hematology – Part 1 – Safety 
Population 
14.3.10.2 
Summary Statistics for the Minimal Value in Hematology – Part 2 – Safety 
Population 
14.3.11.1 
Summary Statistics for the Change from Baseline in Chemistry at each 
Follow-up Assessment – Part 1 – Safety Population 
14.3.11.2 
Summary Statistics for the Change from Baseline in Chemistry each Follow-
up Assessment – Part 2 – Safety Population 
14.3.11.3.1 
Summary Statistics for the Change from Baseline in Chemistry at each 
Follow-up Assessment – Extension 1– Safety Population 
14.3.11.3.2 
Summary Statistics for the Change from Baseline in Chemistry at each 
Follow-up Assessment – Extension 2– Safety Population 
14.3.11.3.3 
Summary Statistics for the Change from Baseline in Chemistry at each 
Follow-up Assessment – Extension 3– Safety Population 
14.3.11.3.4 
Summary Statistics for the Change from Baseline in Chemistry  from Baseline 
and at Month 12, 24, 36, 48 and End of Study Assessment – Safety Population  
14.3.12.1 
Summary Statistics for the Change from Baseline  in Urinalysis at each 
Follow-up Assessment – Part 1 – Safety Population 
14.3.12.2 
Summary Statistics for the Change from Baseline  in Urinalysis at each 
Follow-up Assessment – Part 2 – Safety Population 
14.3.12.3.1 
Summary Statistics for the Change from Baseline in Urinalysis at each 
Follow-up Assessment – Extension 1– Safety Population 
14.3.12.3.2 
Summary Statistics for the Change from Baseline in Urinalysis at each 
Follow-up Assessment – Extension 2– Safety Population 
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14.3.12.3.3 
Summary Statistics for the Change from Baseline in Urinalysis at each 
Follow-up Assessment – Extension 3– Safety Population 
14.3.12.3.4 
Summary Statistics for the Change from Baseline in Urinalysis from Baseline 
and at Month 12, 24, 36, 48 and End of Study Assessment – Safety Population  
14.3.13.1 
Normal Range Shifts in Hematology from Baseline (Screening) to each 
Follow-up Assessment  – Part 1 – Safety Population 
14.3.13.2 
Normal Range Shifts in Hematology from Baseline (Screening) to each 
Follow-up Assessment  – Part 2 – Safety Population 
14.3.13.3.1 
Normal Range Shifts in Hematology from Baseline (Screening) to each 
Follow-up Assessment  – Extension 1 – Safety Population 
14.3.13.3.2 
Normal Range Shifts in Hematology from Baseline (Screening) to each 
Follow-up Assessment  – Extension 2 – Safety Population 
14.3.13.3.3 
Normal Range Shifts in Hematology from Baseline (Screening) to each 
Follow-up Assessment  – Extension 3 – Safety Population 
14.3.14.1 
Normal Range Shifts in Chemistry from Baseline (Screening) to each Follow-
up Assessment  – Part 1 – Safety Population 
14.3.14.2 
Normal Range Shifts in Chemistry from Baseline (Screening) to each Follow-
up Assessment  – Part 2 – Safety Population 
14.3.14.3.1 
Normal Range Shifts in Chemistry from Baseline (Screening) to each Follow-
up Assessment  – Extension 1 – Safety Population 
14.3.14.3.2 
Normal Range Shifts in Chemistry from Baseline (Screening) to each Follow-
up Assessment  – Extension 2 – Safety Population 
14.3.14.3.3 
Normal Range Shifts in Chemistry from Baseline (Screening) to each Follow-
up Assessment  – Extension 3 – Safety Population 
14.3.15.1 
Normal Range Shifts in Urinalysis from Baseline (Screening) to each Follow-
up Assessment  – Part 1 – Safety Population 
14.3.15.2 
Normal Range Shifts in Urinalysis from Baseline (Screening) to each Follow-
up Assessment  – Part 2 – Safety Population 
14.3.15.3.1 
Normal Range Shifts in Urinalysis from Baseline (Screening) to each Follow-
up Assessment  – Extension 1– Safety Population 
14.3.15.3.2 
Normal Range Shifts in Urinalysis from Baseline (Screening) to each Follow-
up Assessment  – Extension 2– Safety Population 
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14.3.15.3.3 
Normal Range Shifts in Urinalysis from Baseline (Screening) to each Follow-
up Assessment  – Extension 3– Safety Population 
14.3.16.1.1 
Summary Statistics for the Change from Baseline in Pulmonary Function 
Tests at each Follow-up Assessment – Part 2 – Safety Population 
14.3.16.1.2.1 
Summary Statistics for the Change from Baseline in Pulmonary Function 
Tests at each Follow-up Assessment – Extension 1 – Safety Population 
14.3.16.1.2.2 
Summary Statistics for the Change from Baseline in Pulmonary Function 
Tests at each Follow-up Assessment – Extension 2 – Safety Population 
14.3.16.1.2.3 
Summary Statistics for the Change from Baseline in Pulmonary Function 
Tests at each Follow-up Assessment – Extension 3 – Safety Population 
14.3.16.2.1 
Summary Statistics for the Change from Baseline in Percent of Predicted 
Pulmonary Function Tests at each Follow-up Assessment – Part 2 – Safety 
Population 
14.3.16.2.2.1 
Summary Statistics for the Change from Baseline in Percent of Predicted 
Pulmonary Function Tests at each Follow-up Assessment – Extension 1 – 
Safety Population 
14.3.16.2.2.2 
Summary Statistics for the Change from Baseline in Percent of Predicted 
Pulmonary Function Tests at each Follow-up Assessment – Extension 2 – 
Safety Population 
14.3.16.2.2.3 
Summary Statistics for the Change from Baseline in Percent of Predicted 
Pulmonary Function Tests at each Follow-up Assessment – Extension 3 – 
Safety Population 
14.3.17.1 
Summary Statistics for the Change from Baseline in Echocardiographs at each 
Follow-up Assessment – Part 2 – Safety Population 
14.3.17.2.1 
Summary Statistics for the Change from Baseline in Echocardiographs at each 
Follow-up Assessment – Extension 1– Safety Population 
14.3.17.2.2 
Summary Statistics for the Change from Baseline in Echocardiographs at each 
Follow-up Assessment – Extension 2– Safety Population 
14.3.17.2.3 
Summary Statistics for the Change from Baseline in Echocardiographs at each 
Follow-up Assessment – Extension 3– Safety Population 
14.3.18.1 
Summary Statistics for the Change from Baseline in Systolic Blood Pressure 
(mmHg) at each Follow-up Assessment – Part 1 – Safety Population 
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14.3.18.2 
Summary Statistics for the Change from Baseline in Systolic Blood Pressure 
(mmHg) at each Follow-up Assessment – Part 2 – Safety Population 
14.3.18.3.1 
Summary Statistics for the Change from Baseline in Systolic Blood Pressure 
(mmHg) at each Follow-up Assessment – Extension 1– Safety Population 
14.3.18.3.2 
Summary Statistics for the Change from Baseline in Systolic Blood Pressure 
(mmHg) at each Follow-up Assessment – Extension 2– Safety Population 
14.3.18.3.3 
Summary Statistics for the Change from Baseline in Systolic Blood Pressure 
(mmHg) at each Follow-up Assessment – Extension 3– Safety Population 
14.3.19.1 
Summary Statistics for the Change from Baseline in Diastolic Blood Pressure 
(mmHg) at each Follow-up Assessment – Part 1 – Safety Population 
14.3.19.2 
Summary Statistics for the Change from Baseline in Diastolic Blood Pressure 
(mmHg) at each Follow-up Assessment – Part 2 – Safety Population 
14.3.19.3.1 
Summary Statistics for the Change from Baseline in Diastolic Blood Pressure 
(mmHg) at each Follow-up Assessment – Extension 1– Safety Population 
14.3.19.3.2 
Summary Statistics for the Change from Baseline in Diastolic Blood Pressure 
(mmHg) at each Follow-up Assessment – Extension 2– Safety Population 
14.3.19.3.3 
Summary Statistics for the Change from Baseline in Diastolic Blood Pressure 
(mmHg) at each Follow-up Assessment – Extension 3– Safety Population 
14.3.20.1 
Summary Statistics for the Change from Baseline in Heart Rate (bpm) at each 
Follow-up Assessment – Part 1 – Safety Population 
14.3.20.2 
Summary Statistics for the Change from Baseline in Heart Rate (bpm) at each 
Follow-up Assessment – Part 2 – Safety Population 
14.3.20.3.1 
Summary Statistics for the Change from Baseline in Heart Rate (bpm) at each 
Follow-up Assessment – Extension 1– Safety Population 
14.3.20.3.2 
Summary Statistics for the Change from Baseline in Heart Rate (bpm) at each 
Follow-up Assessment – Extension 2– Safety Population 
14.3.20.3.3 
Summary Statistics for the Change from Baseline in Heart Rate (bpm) at each 
Follow-up Assessment – Extension 3– Safety Population 
14.3.21.1 
Summary Statistics for the Change from Baseline in Body Temperature 
(degrees C) at each Follow-up Assessment – Part 1 – Safety Population 
14.3.21.2 
Summary Statistics for the Change from Baseline in Body Temperature 
(degrees C) at each Follow-up Assessment – Part 2 – Safety Population 
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14.3.21.3.1 
Summary Statistics for the Change from Baseline in Body Temperature 
(degrees C) at each Follow-up Assessment – Extension 1– Safety Population 
14.3.21.3.2 
Summary Statistics for the Change from Baseline in Body Temperature 
(degrees C) at each Follow-up Assessment – Extension 2– Safety Population 
14.3.21.3.3 
Summary Statistics for the Change from Baseline in Body Temperature 
(degrees C) at each Follow-up Assessment – Extension 3– Safety Population 
14.3.22.1 
Summary Statistics for the Change from Baseline in Body Weight (kg) at each 
Follow-up Assessment – Part 1 
14.3.22.2 
Summary Statistics for the Change from Baseline in Body Weight (kg) at each 
Follow-up Assessment – Part 2 
14.3.22.3.1 
Summary Statistics for the Change from Baseline in Body Weight (kg) at each 
Follow-up Assessment – Extension 1 
14.3.22.3.2 
Summary Statistics for the Change from Baseline in Body Weight (kg) at each 
Follow-up Assessment – Extension 2 
14.3.22.3.3 
Summary Statistics for the Change from Baseline in Body Weight (kg) at each 
Follow-up Assessment Extension 3 
14.3.23.1 
Summary Statistics for the Change from Baseline in Body Height (cm) at End 
of Study 
14.3.23.1.1 
Summary Statistics for the Change from Baseline in Body Height (cm) to end 
of Extension 3 
14.3.24.1.1 
Summary Statistics for the Change from Baseline in ECG PR Interval (ms) at 
each Follow-up Assessment by Initial Dose– Part 1 – Safety Population 
14.3.24.1.2 
Summary Statistics for the Change from Baseline in ECG PR Interval (ms) at 
each Follow-up Assessment  – Part 2 – Safety Population 
14.3.24.1.3.1 
Summary Statistics for the Change from Baseline  in ECG PR Interval (ms) at 
each Follow-up Assessment– Extension 1– Safety Population 
14.3.24.1.3.2 
Summary Statistics for the Change from Baseline  in ECG PR Interval (ms) at 
each Follow-up Assessment– Extension 2– Safety Population 
14.3.24.1.3.3 
Summary Statistics for the Change from Baseline  in ECG PR Interval (ms) at 
each Follow-up Assessment– Extension 3– Safety Population 
14.3.24.2.1 
Summary Statistics for the Change from Baseline in ECG PR Interval (ms) at 
each Follow-up Assessment by Age – Part 1 – Safety Population 
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14.3.24.2.2 
Summary Statistics for the Change from Baseline in ECG PR Interval (ms) at 
each Follow-up Assessment by Age – Part 2 – Safety Population 
14.3.24.2.3.1 
Summary Statistics for the Change from Baseline  in ECG PR Interval (ms) at 
each Follow-up Assessment by Age – Extension 1– Safety Population 
14.3.24.2.3.2 
Summary Statistics for the Change from Baseline  in ECG PR Interval (ms) at 
each Follow-up Assessment by Age – Extension 2– Safety Population 
14.3.24.2.3.3 
Summary Statistics for the Change from Baseline  in ECG PR Interval (ms) at 
each Follow-up Assessment by Age – Extension 3– Safety Population 
14.3.25.1.1 
Summary Statistics for the Change from Baseline in ECG RR Interval (ms) at 
each Follow-up Assessment by Initial Dose – Part 1 – Safety Population 
14.3.25.1.2 
Summary Statistics for the Change from Baseline in ECG RR Interval (ms) at 
each Follow-up Assessment  – Part 2 – Safety Population 
14.3.25.1.3.1 
Summary Statistics for the Change from Baseline  in ECG RR Interval (ms) at 
each Follow-up Assessment– Extension 1– Safety Population 
14.3.25.1.3.2 
Summary Statistics for the Change from Baseline  in ECG RR Interval (ms) at 
each Follow-up Assessment– Extension 2– Safety Population 
14.3.25.1.3.3 
Summary Statistics for the Change from Baseline  in ECG RR Interval (ms) at 
each Follow-up Assessment– Extension 3– Safety Population 
14.3.25.2.1 
Summary Statistics for the Change from Baseline in ECG RR Interval (ms) at 
each Follow-up Assessment by Age – Part 1 – Safety Population 
14.3.25.2.2 
Summary Statistics for the Change from Baseline in ECG RR Interval (ms) at 
each Follow-up Assessment by Age – Part 2 – Safety Population 
14.3.25.2.3.1 
Summary Statistics for the Change from Baseline  in ECG RR Interval (ms) at 
each Follow-up Assessment by Age – Extension 1– Safety Population 
14.3.25.2.3.2 
Summary Statistics for the Change from Baseline  in ECG RR Interval (ms) at 
each Follow-up Assessment by Age – Extension 2– Safety Population 
14.3.25.2.3.3 
Summary Statistics for the Change from Baseline  in ECG RR Interval (ms) at 
each Follow-up Assessment by Age – Extension 3– Safety Population 
14.3.26.1.1 
Summary Statistics for the Change from Baseline in ECG QRS Interval (ms) 
at each Follow-up Assessment by Initial Dose – Part 1 – Safety Population 
14.3.26.1.2 
Summary Statistics for the Change from Baseline in ECG QRS Interval (ms) 
at each Follow-up Assessment  – Part 2 – Safety Population 
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14.3.26.1.3.1 
Summary Statistics for the Change from Baseline in ECG QRS Interval (ms) 
at each Follow-up Assessment  – Extension 1– Safety Population 
14.3.26.1.3.2 
Summary Statistics for the Change from Baseline in ECG QRS Interval (ms) 
at each Follow-up Assessment  – Extension 2– Safety Population 
14.3.26.1.3.3 
Summary Statistics for the Change from Baseline in ECG QRS Interval (ms) 
at each Follow-up Assessment  – Extension 3– Safety Population 
14.3.26.2.1 
Summary Statistics for the Change from Baseline in ECG QRS Interval (ms) 
at each Follow-up Assessment by Age– Part 1 – Safety Population 
14.3.26.2.2 
Summary Statistics for the Change from Baseline in ECG QRS Interval (ms) 
at each Follow-up Assessment by Age – Part 2 – Safety Population 
14.3.26.2.3.1 
Summary Statistics for the Change from Baseline in ECG QRS Interval (ms) 
at each Follow-up Assessment by Age – Extension 1– Safety Population 
14.3.26.2.3.2 
Summary Statistics for the Change from Baseline in ECG QRS Interval (ms) 
at each Follow-up Assessment by Age – Extension 2– Safety Population 
14.3.26.2.3.3 
Summary Statistics for the Change from Baseline in ECG QRS Interval (ms) 
at each Follow-up Assessment by Age – Extension 3– Safety Population 
14.3.27.1.1 
Summary Statistics for the Change from Baseline in ECG QT Interval (ms) at 
each Follow-up Assessment by Initial Dose – Part 1 – Safety Population 
14.3.27.1.2 
Summary Statistics for the Change from Baseline in ECG QT Interval (ms) at 
each Follow-up Assessment  – Part 2 – Safety Population 
14.3.27.1.3.1 
Summary Statistics for the Change from Baseline in ECG QT Interval (ms) at 
each Follow-up Assessment  – Extension 1– Safety Population 
14.3.27.1.3.2 
Summary Statistics for the Change from Baseline in ECG QT Interval (ms) at 
each Follow-up Assessment  – Extension 2– Safety Population 
14.3.27.1.3.3 
Summary Statistics for the Change from Baseline in ECG QT Interval (ms) at 
each Follow-up Assessment  – Extension 3– Safety Population 
14.3.27.2.1 
Summary Statistics for the Change from Baseline in ECG QT Interval (ms) at 
each Follow-up Assessment by Age – Part 1 – Safety Population 
14.3.27.2.2 
Summary Statistics for the Change from Baseline in ECG QT Interval (ms) at 
each Follow-up Assessment by Age – Part 2 – Safety Population 
14.3.27.2.3.1 
Summary Statistics for the Change from Baseline in ECG QT Interval (ms) at 
each Follow-up Assessment by Age – Extension 1– Safety Population 
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14.3.27.2.3.2 
Summary Statistics for the Change from Baseline in ECG QT Interval (ms) at 
each Follow-up Assessment by Age – Extension 2– Safety Population 
14.3.27.2.3.3 
Summary Statistics for the Change from Baseline in ECG QT Interval (ms) at 
each Follow-up Assessment by Age – Extension 3– Safety Population 
14.3.28.1.1 
Summary Statistics for the Change from Baseline in ECG QTcF Interval (ms) 
at each Follow-up Assessment by Initial Dose – Part 1 – Safety Population 
14.3.28.1.2 
Summary Statistics for the Change from Baseline in ECG QTcF Interval (ms) 
at each Follow-up Assessment  – Part 2 – Safety Population 
14.3.28.1.3.1 
Summary Statistics for the Change from Baseline in ECG QTcF Interval (ms) 
at each Follow-up Assessment – Extension 1– Safety Population 
14.3.28.1.3.2 
Summary Statistics for the Change from Baseline in ECG QTcF Interval (ms) 
at each Follow-up Assessment – Extension 2– Safety Population 
14.3.28.1.3.3 
Summary Statistics for the Change from Baseline in ECG QTcF Interval (ms) 
at each Follow-up Assessment – Extension 3– Safety Population 
14.3.28.2.1 
Summary Statistics for the Change from Baseline in ECG QTcF Interval (ms) 
at each Follow-up Assessment by Age – Part 1 – Safety Population 
14.3.28.2.2 
Summary Statistics for the Change from Baseline in ECG QTcF Interval (ms) 
at each Follow-up Assessment by Age – Part 2 – Safety Population 
14.3.28.2.3.1 
Summary Statistics for the Change from Baseline in ECG QTcF Interval (ms) 
at each Follow-up Assessment by Age – Extension 1– Safety Population 
14.3.28.2.3.2 
Summary Statistics for the Change from Baseline in ECG QTcF Interval (ms) 
at each Follow-up Assessment by Age – Extension 2– Safety Population 
14.3.28.2.3.3 
Summary Statistics for the Change from Baseline in ECG QTcF Interval (ms) 
at each Follow-up Assessment by Age – Extension 3– Safety Population 
14.3.29.1.1 
Summary Statistics for the Change from Baseline in ECG QTcB Interval (ms) 
at each Follow-up Assessment by Initial Dose – Part 1 – Safety Population 
14.3.29.1.2 
Summary Statistics for the Change from Baseline in ECG QTcB Interval (ms) 
at each Follow-up Assessment – Part 2 – Safety Population 
14.3.29.1.3.1 
Summary Statistics for the Change from Baseline in ECG QTcB Interval (ms) 
at each Follow-up Assessment – Extension 1– Safety Population 
14.3.29.1.3.2 
Summary Statistics for the Change from Baseline in ECG QTcB Interval (ms) 
at each Follow-up Assessment– Extension 2 – Safety Population 
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14.3.29.1.3.3 
Summary Statistics for the Change from Baseline in ECG QTcB Interval (ms) 
at each Follow-up Assessment– Extension 3 – Safety Population 
14.3.29.2.1 
Summary Statistics for the Change from Baseline in ECG QTcB Interval (ms) 
at each Follow-up Assessment by Age – Part 1 – Safety Population 
14.3.29.2.2 
Summary Statistics for the Change from Baseline in ECG QTcB Interval (ms) 
at each Follow-up Assessment by Age – Part 2 – Safety Population 
14.3.29.2.3.1 
Summary Statistics for the Change from Baseline in ECG QTcB Interval (ms) 
at each Follow-up Assessment by Age – Extension 1– Safety Population 
14.3.29.2.3.2 
Summary Statistics for the Change from Baseline in ECG QTcB Interval (ms) 
at each Follow-up Assessment by Age – Extension 2– Safety Population 
14.3.29.2.3.3 
Summary Statistics for the Change from Baseline in ECG QTcB Interval (ms) 
at each Follow-up Assessment by Age – Extension 3– Safety Population 
14.3.30.1.1 
Summary Statistics for the Change from Baseline in the Overall Interpretation 
of the ECG at each Follow-up Assessment by Initial Dose – Part 1 – Safety 
Population 
14.3.30.1.2 
Summary Statistics for the Change from Baseline in the Overall Interpretation 
of the ECG at each Follow-up Assessment  – Part 2 – Safety Population 
14.3.30.1.3.1 
Summary Statistics for the Change from Baseline in the Overall Interpretation 
of the ECG at each Follow-up Assessment– Extension 1– Safety Population 
14.3.30.1.3.2 
Summary Statistics for the Change from Baseline in the Overall Interpretation 
of the ECG at each Follow-up Assessment– Extension 2– Safety Population 
14.3.30.1.3.3 
Summary Statistics for the Change from Baseline in the Overall Interpretation 
of the ECG at each Follow-up Assessment– Extension 3– Safety Population 
14.3.30.2.1 
Summary Statistics for the Change from Baseline in the Overall Interpretation 
of the ECG at each Follow-up Assessment by Age – Part 1 – Safety 
Population 
14.3.30.2.2 
Summary Statistics for the Change from Baseline in the Overall Interpretation 
of the ECG at each Follow-up Assessment by Age – Part 2 – Safety 
Population 
14.3.30.2.3.1 
Summary Statistics for the Change from Baseline in the Overall Interpretation 
of the ECG at each Follow-up Assessment by Age – Extension 1– Safety 
Population 
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14.3.30.2.3.2 
Summary Statistics for the Change from Baseline in the Overall Interpretation 
of the ECG at each Follow-up Assessment by Age – Extension 2– Safety 
Population 
14.3.30.2.3.3 
Summary Statistics for the Change from Baseline in the Overall Interpretation 
of the ECG at each Follow-up Assessment by Age – Extension 3– Safety 
Population 
14.3.31.1 
Summary Statistics for the Change from Baseline in Physical Examination at 
each Follow-up Assessment – Part 1 – Safety Population 
14.3.31.2 
Summary Statistics for the Change from Baseline in Physical Examination at 
each Follow-up Assessment – Part 2 – Safety Population 
14.3.31.3.1 
Summary Statistics for the Change from Baseline in Physical Examination at 
each Follow-up Assessment – Extension 1– Safety Population 
14.3.31.3.2 
Summary Statistics for the Change from Baseline in Physical Examination at 
each Follow-up Assessment – Extension 2– Safety Population 
14.3.31.3.3 
Summary Statistics for the Change from Baseline in Physical Examination at 
each Follow-up Assessment – Extension 3– Safety Population 
14.3.32.1 
Concomitant Medication Commencing After the Dose of Study Medication – 
Parts 1 and 2 – Safety Population 
14.3.32.2.1 
Concomitant Medication Commencing After the Dose of Study Medication – 
Part 1+2 and Extension 1 – Safety Population 
14.3.32.2.2 
Concomitant Medication Commencing After the Dose of Study Medication – 
Part 1+2 , Extension 1 and Extension 2– Safety Population 
14.3.32.2.3 
Concomitant Medication Commencing After the Dose of Study Medication – 
Part 1+2 , Extension 1, Extension 2 and Extension 3– Safety Population 
8.
FIGURES TO BE INCLUDED IN THE CLINICAL STUDY REPORT
14.2.1.1 
6MWT Achieved Distance per Subject Over Time - Parts 1 and 2 - 
Completers Population 
14.2.1.2.1 
6MWT Achieved Distance per Subject Over Time - Extension 1- ITT 
Population 
14.2.1.2.2 
6MWT Achieved Distance per Subject Over Time - Extension 2- ITT 
Population 
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14.2.1.2.3 
6MWT Achieved Distance per Subject Over Time - Extension 3- ITT 
Population 
14.2.1.1.1 
6MWT Achieved Distance per Subject Over Time to end of Extension 
3 – Completers Population 
14.2.2 
6MWT Mean Changes from Baseline to All Time Points - Parts 1 and 
2 - Completers Population 
14.2.3.1.1 
Mean of the PEF percentage of predicted values at Baseline, End of 
part 2 (visit 10) and End of Extension 1- Completers Population 
14.2.3.1.2 
Mean of the PEF percentage of predicted values at Baseline, End of 
part 2 (visit 10), End of Extension 1 (visit 16) and Extension 2 - 
Completers Population 
14.2.3.1.3 
Mean of the PEF percentage of predicted values at Baseline, End of 
part 2 (visit 10), End of Extension 1 (visit 16) , Extension 2 (visit 22) 
and Extension 3 (visit 26) - Completers Population 
14.2.3.2 
FVC predicted values at Baseline, End of part 2 (visit 10) and 
Extension- Completers Population 
14.2.3.2.1 
FVC predicted values at Baseline, End of part 2 (visit 10) and End of 
Extension 1- Completers Population 
14.2.3.2.2 
Mean of the FVC percentage of predicted values at Baseline, End of 
part 2 (visit 10), End of Extension 1 (visit 16) and Extension 2- 
Completers Population 
14.2.3.2.3 
Mean of the FVC percentage of predicted values at Baseline, End of 
part 2 (visit 10), End of Extension 1 (visit 16) , Extension 2 (visit 22) 
and Extension 3 (visit 26) - Completers Population 
14.2.3.3 
FEV predicted values at Baseline, End of part 2 (visit 10) and 
Extension- Completers Population 
14.2.3.3.1 
FEV predicted values at Baseline, End of part 2 (visit 10) and End of 
Extension 1- Completers Population 
14.2.3.3.2 
Mean of the FEV percentage of predicted values at Baseline, End of 
part 2 (visit 10), End of Extension 1 (visit 16) and Extension 2- 
Completers Population 
14.2.3.3.3 
Mean of the FEV percentage of predicted values at Baseline, End of 
part 2 (visit 10), End of Extension 1 (visit 16) , Extension 2 (visit 22) 
and Extension 3 (visit 26) - Completers Population 
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14.2.3.4.3 
Mean of the PEF absolute values at Baseline, End of part 2 (visit 10), 
End of Extension 1 (visit 16) , Extension 2 (visit 22) and Extension 3 
(visit 26) - Completers Population 
14.2.3.5.3 
Mean of the FVC absolute values at Baseline, End of part 2 (visit 10), 
End of Extension 1 (visit 16) , Extension 2 (visit 22) and Extension 3 
(visit 26) - Completers Population 
14.2.3.6.3 
Mean of the FEV absolute values at Baseline, End of part 2 (visit 10), 
End of Extension 1 (visit 16) , Extension 2 (visit 22) and Extension 3 
(visit 26) - Completers Population 
14.2.4 
Kaplan- Meier Curve for Patient Who Lost Ambulation - Baseline to 
End of Extension 3 – ITT Population 
14.3.1.1 
Platelets Results per Subject Over Time - Part 1- Safety Population 
14.3.1.2 
Platelets Results per Subject Over Time - Part 2 - Safety Population 
14.3.1.1.1 
Mean Platelets Results Over Time - Baseline to end of Extension 3 – 
Safety Population 
14.3.2.1 
RBC Results per Subject Over Time - Part 1 - Safety Population 
14.3.2.2 
RBC Results per Subject Over Time - Part 2- Safety Population 
14.3.3.1 
Neutrophils Results per Subject Over Time - Part 1- Safety Population 
14.3.3.2 
Neutrophils Results per Subject Over Time - Part 2 - Safety Population 
14.3.4.1.1 
Mean Profile for Systolic Blood Pressure (mmHg) – Part 1 – Safety 
Population 
14.3.4.1.2 
Mean Profile for Systolic Blood Pressure (mmHg) – Part 2 – Safety 
Population 
14.3.5.1.1 
Mean Profile for Diastolic Blood Pressure (mmHg) – Part 1 – Safety 
Population 
14.3.5.1.2 
Mean Profile for Diastolic Blood Pressure (mmHg) – Part 2 – Safety 
Population 
14.3.6.1.1 
Mean Profile for Heart Rate (bpm) – Part 1 – Safety Population 
14.3.6.1.2 
Mean Profile for Heart Rate (bpm) – Part 2 – Safety Population 
14.3.7.1.1 
Mean Profile for Body Weight (kg) – Part 1 – Safety Population 
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14.3.7.1.2 
Mean Profile for Body Weight (kg) – Part 2 – Safety Population 
14.3.7.1.3.1 
Mean Profile for Body Weight (kg) – Extension 1– Safety Population 
14.3.7.1.3.2 
Mean Profile for Body Weight (kg) – Extension 2– Safety Population 
14.3.7.1.3.3 
Mean Profile for Body Weight (kg) – Extension 3– Safety Population 
14.3.7.1.3.1.1 
Mean Profile for Body Weight (kg) – Baseline to end of Extension 3– 
Safety Population 
14.3.8.1.1 
Mean Profile for ECG PR Interval (ms) – Part 1 – Safety Population 
14.3.8.1.2 
Mean Profile for ECG PR Interval (ms) – Part 2 – Safety Population 
14.3.9.1.1 
Mean Profile for ECG QRS Interval (ms) – Part 1 – Safety Population 
14.3.9.1.2 
Mean Profile for ECG QRS Interval (ms) – Part 2 – Safety Population 
14.3.10.1.1 
Mean Profile for ECG QT Interval (ms) – Part 1 – Safety Population 
14.3.10.1.2 
Mean Profile for ECG QT Interval (ms) – Part 2 – Safety Population 
14.3.10.1.3.1 
Mean Profile for ECG QT Interval (ms) – Extension 1– Safety 
Population 
14.3.10.1.3.2 
Mean Profile for ECG QT Interval (ms) – Extension 2– Safety 
Population 
14.3.10.1.3.3 
Mean Profile for ECG QT Interval (ms) – Extension 3– Safety 
Population 
14.3.10.1.1.1 
Mean Profile for ECG QT Interval (ms) – Baseline to end of Extension 
3 – Safety Population 
14.3.11.1.1 
Mean Profile for ECG QTcF Interval (ms) – Part 1 – Safety Population 
14.3.11.1.2 
Mean Profile for ECG QTcF Interval (ms) – Part 2 – Safety Population 
14.3.11.1.3.1 
Mean Profile for ECG QTcF Interval (ms) – Extension 1– Safety 
Population 
14.3.11.1.3.2 
Mean Profile for ECG QTcF Interval (ms) – Extension 2– Safety 
Population 
14.3.11.1.3.3 
Mean Profile for ECG QTcF Interval (ms) – Extension 3– Safety 
Population 
14.3.11.1.1.1 
Mean Profile for ECG QTcF Interval (ms) – Baseline to end of 
Extension 3 – Safety Population 
14.3.12.1.1 
Mean Profile for ECG QTcB Interval (ms) – Part 1 – Safety Population 
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14.3.12.1.2 
Mean Profile for ECG QTcB Interval (ms) – Part 2 – Safety Population 
14.3.12.1.3.1 
Mean Profile for ECG QTcB Interval (ms) – Extension 1– Safety 
Population 
14.3.12.1.3.2 
Mean Profile for ECG QTcB Interval (ms) – Extension 2– Safety 
Population 
14.3.12.1.3.3 
Mean Profile for ECG QTcB Interval (ms) – Extension 3– Safety 
Population 
14.3.12.1.1.1 
Mean Profile for ECG QTcB Interval (ms) – Baseline to end of 
Extension 3 – Safety Population 
14.3.13a 
Comparison of CSA Cumulative Distribution at End of Study and 
Baseline - Completers Population 
14.3.13b 
Comparison of CSA Cumulative Distribution at End of Study and 
Baseline -  Completers Population 
14.3.13c 
Comparison of CSA1 Cumulative Distribution at End of Study and 
Baseline - Completers Population 
9.
APPENDIX 16.2 LISTINGS
16.2.1.1 
Patients Disposition – ITT Population 
16.2.1.1.1 
Patients Disposition – Extension 1 – ITT Population 
16.2.1.1.2 
Patients Disposition – Extension 2 – ITT Population 
16.2.1.1.3 
Patients Disposition – Extension 3 – ITT Population 
16.2.1.2 
Datasets Analyzed – ITT population 
16.2.1.2.1 
Datasets Analyzed –Part 1+2, Extension 1, 2 and 3  ITT population 
16.2.2.1 
Protocol Deviations – ITT Population 
16.2.2.1.1 
Protocol Deviations – Extension 1 – ITT Population 
16.2.2.1.2 
Protocol Deviations – Extension 2 – ITT Population 
16.2.2.1.3 
Protocol Deviations – Extension 3 – ITT Population 
16.2.4.1 
Demographics – ITT Population 
16.2.4.2 
Previous Medical History – ITT Population 
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16.2.4.3 
Ongoing Medical History – ITT Population 
16.2.5.1 
Dosing Information – ITT Population 
16.2.5.1.1 
Dosing Information – Extension 1 – ITT Population 
16.2.5.1.2 
Dosing Information – Extension 2 – ITT Population 
16.2.5.1.3 
Dosing Information – Extension 3 – ITT Population 
16.2.5.2 
Study Drug Dose Modification – ITT Population 
16.2.5.2.1 
Study Drug Dose Modification – Extension 1 – ITT Population 
16.2.5.2.2 
Study Drug Dose Modification – Extension 2 – ITT Population 
16.2.5.2.3 
Study Drug Dose Modification – Extension 3– ITT Population 
16.2.6.1 
MFA% – ITT Population 
16.2.6.2 
6MWT – ITT Population 
16.2.6.2.1 
6MWT – Extension 1 – ITT Population 
16.2.6.2.2 
6MWT – Extension 2 – ITT Population 
16.2.6.2.3 
6MWT – Extension 3 – ITT Population 
16.2.6.3 
NSAA – ITT Population 
16.2.6.3.1 
NSAA – Extension 1 – ITT Population 
16.2.6.3.2 
NSAA – Extension 2 – ITT Population 
16.2.6.3.3 
NSAA – Extension 3 – ITT Population 
16.2.6.4 
PUL – ITT Population 
16.2.6.4.1 
PUL – Extension 1 – ITT Population 
16.2.6.4.2 
PUL – Extension 2–  ITT Population 
16.2.6.4.3 
PUL – Extension 3–  ITT Population 
16.2.6.5 
Biopsy Collection Information – ITT Population 
16.2.6.6 
miRNA Results - ITT Population 
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16.2.6.7 
MRI Results – ITT Population 
16.2.6.8 
Acceptability/Palatability of the Oral Suspension – ITT Population 
16.2.6.9 
Histological Parameters – ITT Population 
16.2.6.10 
General Comments of Wheelchair - Subjects Who Lost Ambulation 
16.2.7.1 
All Adverse Events – Safety Population 
16.2.7.1.1 
All Adverse Events – Extension 1 – Safety Population 
16.2.7.1.2 
All Adverse Events – Extension 2 – Safety Population 
16.2.7.1.3 
All Adverse Events – Extension 3 – Safety Population 
16.2.7.2 
All Adverse Events Coding – Safety Population 
16.2.7.2.1 
All Adverse Events Coding – Extension 1 – Safety Population 
16.2.7.2.2 
All Adverse Events Coding – Extension 2 – Safety Population 
16.2.7.2.3 
All Adverse Events Coding – Extension 3 – Safety Population 
16.2.7.3 
Drug-Related Treatment Emergent Adverse Events – Safety Population 
16.2.7.3.1 
Drug-Related Treatment Emergent Adverse Events – Extension 1 – Safety 
Population 
16.2.7.3.2 
Drug-Related Treatment Emergent Adverse Events – Extension 2 – Safety 
Population 
16.2.7.3.3 
Drug-Related Treatment Emergent Adverse Events – Extension 3 – Safety 
Population 
16.2.7.4 
Serious Adverse Events – Safety Population 
16.2.7.4.1 
Serious Adverse Events – Extension 1 – Safety Population 
16.2.7.4.2 
Serious Adverse Events – Extension 2 – Safety Population 
16.2.7.4.3 
Serious Adverse Events – Extension 3 – Safety Population 
16.2.8.1 
Hematology – Safety Population 
16.2.8.1.1 
Hematology – Extension 1 – Safety Population 
16.2.8.1.2 
Hematology – Extension 2 – Safety Population 
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16.2.8.1.3 
Hematology – Extension 3 – Safety Population 
16.2.8.2 
Serum Chemistry – Safety Population 
16.2.8.2.1 
16.2.8.2.2 
Serum Chemistry– Extension 1  – Safety Population 
Serum Chemistry – Extension 2 – Safety Population 
16.2.8.2.3 
Serum Chemistry – Extension 3 – Safety Population 
16.2.8.3 
Urinalysis – Safety Population 
16.2.8.3.1 
Urinalysis – Extension 1 – Safety Population 
16.2.8.3.2 
Urinalysis– Extension 2 – Safety Population 
16.2.8.3.3 
Urinalysis– Extension 3 – Safety Population 
16.2.8.4 
Serology – Safety Population 
16.2.8.4.1 
Serology – Extension 1 – Safety Population 
16.2.8.4.2 
Serology – Extension 2 – Safety Population 
16.2.8.4.3 
Serology – Extension 3 – Safety Population 
16.2.8.5 
Clinically Significant Laboratory Results – Safety Population 
16.2.8.5.1 
Clinically Significant Laboratory Results – Extension 1 – Safety Population 
16.2.8.5.2 
Clinically Significant Laboratory Results – Extension 2 – Safety Population 
16.2.8.5.3 
Clinically Significant Laboratory Results – Extension 3 – Safety Population 
16.2.8.6 
Pulmonary Function Tests – Safety Population 
16.2.8.6.1 
Pulmonary Function Tests – Extension 1 – Safety Population 
16.2.8.6.2 
Pulmonary Function Tests – Extension 2 – Safety Population 
16.2.8.6.3 
Pulmonary Function Tests – Extension 3 – Safety Population 
16.2.8.7 
Echocardiographs – Safety Population 
16.2.8.7.1 
Echocardiographs – Extension 1 – Safety Population 
16.2.8.7.2 
Echocardiographs – Extension 2 – Safety Population 
16.2.8.7.3 
Echocardiographs – Extension 3 – Safety Population 
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16.2.8.8 
PedsQL – ITT Population 
16.2.8.8.1 
PedsQL – Extension 1 – ITT Population 
16.2.8.8.2 
PedsQL – Extension 2 – ITT Population 
16.2.8.8.3 
PedsQL – Extension 3 – ITT Population 
16.2.8.9 
Vital Signs Data – Safety Population 
16.2.8.9.1 
Vital Signs Data – Extension 1 – Safety Population 
16.2.8.9.2 
Vital Signs Data – Extension 2 – Safety Population 
16.2.8.9.3 
Vital Signs Data – Extension 3 – Safety Population 
16.2.8.10 
ECG Data – Safety Population 
16.2.8.10.1 ECG Data – Extension 1 – Safety Population 
16.2.8.10.2 ECG Data – Extension 2 – Safety Population 
16.2.8.10.3 ECG Data – Extension 3 – Safety Population 
16.2.8.11 
Physical Examination – Safety Population 
16.2.8.11.1 Physical Examination – Extension 1 – Safety Population 
16.2.8.11.2 Physical Examination – Extension 2 – Safety Population 
16.2.8.11.3 Physical Examination – Extension 3 – Safety Population 
16.2.8.12 
Concomitant Medication – Safety Population 
16.2.8.12.1 Concomitant Medication – Extension 1 – Safety Population 
16.2.8.12.2 Concomitant Medication – Extension 2 – Safety Population 
16.2.8.12.3 Concomitant Medication – Extension 3 – Safety Population 
16.2.8.13 
Biomarkers: LTBP4 and Osteopontin –Safety Population 
16.2.8.13.1 Biomarkers: LTBP4 and Osteopontin – Extension 1 –Safety Population 
16.2.8.13.2 Biomarkers: LTBP4 and Osteopontin – Extension 2 –Safety Population 
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