Protocol Title: A randomised, double-blind, placebo-controlled study to evaluate the micro-macroscopic effects on muscles, the safety and tolerability, and the efficacy of givinostat in patients with Becker Muscular Dystrophy

The concept of disease modification in DMD/BMD is characterized by slowing down
or stopping the accumulation and the progression of disability. This includes
the delay of symptoms of weakness, or loss of function, in certain muscle
groups, the delay of general loss of energy, as well as the delay in time to
milestone events (e.g. time to wheelchair, time to loss of upper limb use, time
to assisted ventilation). Nonclinical studies have shown that givinostat has a
potent anti-inflammatory effect (see (current IB) and that HDACi regulate the
transcription of key factors in muscle regeneration such as follistatin.
ITF2357 significantly counteracts histological disease progression in children
with Duchenne Muscle dystrophy aged 7 to 10 years, increasing muscle fibers,
reducing necrosis, fatty replacement and fibrosis and decreasing the number of
hypercontracted fibers. Although underpowered, the function tests (6MWT, NSAA
and PUL) and the pulmonary function tests show an overall stability. These
results indicate that the induction of an active regeneration program, the
reduction of adipose replacement and the enlargement of pre-existing muscle
fibers are all key elements of givinostat*s mechanism of action (MoA),
supporting the potential therapeutic role of givinostat in counteracting muscle
tissue degeneration. On the basis of its putative MoA as described above,
givinostat is expected to act at all stages of the disease and to counter the
disease pathogenetic events in all muscular districts. As the pathogenetic
mechanism of BMD is similar to DMD (i.e. same gene mutated, but different
mutation), givinostat is expected to counter the disease pathogenetic events
also in BMD. The rational of this study is to replicate the histologic findings
collected during the phase II clinical trial (DSC/11/2357/43) in DMD (Bettica
et al. 2016). The primary endpoint was
selected on the basis of the results of study DSC/11/2357/43, where fiber CSA
enlargement appeared key in givinostat*s pharmacological effect.
Considering the recent recommendations outlined in the EMA *Guideline on the
clinical investigation of medicinal products for the treatment of Duchenne and
Becker muscular dystrophy* (December 2015) and in the Federal Drug
Administration (FDA) draft guidance for industry *Duchenne Muscular Dystrophy
and related dystrophinopathies: developing drugs for treatment* (June 2015),
some functional tests have been chosen to evaluate the efficacy of givinostat
in slowing down disease progression. Unlike DMD, there is scarce data in BMD
about standardized functional measures such as the Six Minute Walk Test (6MWT),
the North Star Ambulatory Assessment (NSAA), and Timed Function Tests (TFTs:
run/walk 10 m, rise from the floor, climb four standard steps), therefore the
functional endpoints were selected on the basis of few literature data (Bello
et al, 2016; Mendell et al, 2015; Fischer et al, 2016) and clinical practice.
The functional secondary endpoints included in this trial are MFM, 6MWT, and
TFTs; as described by Fisher (Fischer et al, 2016), they are reliable tests to
assess disability in an ambulant BMD population, showing a high
inter-correlation. Even if no data are available on muscle strength in BMD
patients, it has been included as secondary endpoint in light of givinostat*s
MoA (e.g., increase fibers CSA) and is expected to be appropriate for
evaluating the efficacy of givinostat. Concerning the imaging endpoints,
previous studies have shown that MRI can visualize structural alterations of
muscle in muscular dystrophies (Tasca et al, 2012, Willcocks et al,
2016, Triplett et al, 2014, Bonati et al, 2015) and that fat fraction measured
by MRI or magnetic resonance spectroscopy (MRS) highly correlates with lower
limb function. Although longitudinal data on MRI/MRS particularly from
randomised clinical trials are still limited, fatty degeneration of the muscle,
in particular Muscle Fat Fraction (MFF) evaluated by MRI Dixon technique of the
thigh muscles showed excellent correlation with clinical function in BMD
patients (Fischer et al, 2016), assessed by MFM, 6MWT and TFTs and might be a
promising surrogate outcome marker in clinical trials. For the reason described
above, MFF evaluated by MRI with Dixon technique as well as MRS are secondary
endpoints of the study.
Finally, safety and tolerability and pharmacokinetics will be also assessed in
the study for a proper risk-benefit evaluation of givinostat.

The primary objective of the present study is to establish the histological
effects of givinostat
versus placebo administered over 12 months.

The secondary objectives of this study are the following:
- To establish the macroscopic muscle effects of givinostat versus placebo
administered chronically over 12 months assessed by MRI/MRS.
- To establish the other histological effects of givinostat versus placebo
administered over 12 months.
- To establish the efficacy of givinostat versus placebo administered
chronically over 12 months in slowing disease progression
- To assess the safety and tolerability of givinostat versus placebo
administered chronically.
- To evaluate the pharmacokinetic (PK) profile of givinostat administered
chronically in the target population.
- To evaluate the impact of givinostat versus placebo administered chronically
on quality of life and activities of daily living.

Secondary Exploratory Objectives:
- To evaluate the correlation between the PK profile of givinostat and
pharmacodynamics (PD) data.
- To evaluate a possible disease-related biomarker.
- To explore additional disease-related MRI biomarkers.

Phase 2, randomised, double-blind, placebo-controlled study. Ambulant patients
who have provided written informed consent will undergo a 4-week screening
period to determine eligibility for the study. Approximately 48 eligible
patients will then be randomized in a 2:1 ratio to be treated with givinostat
or placebo for a period of 12 months. The randomization process will be
stratified by the factor related to concomitant steroid use at baseline (yes
vs. no). Patients who complete the study (i.e. 12 months of treatment) will be
asked to return for a follow-up visit 4 weeks after the end of treatment. A
total of 12 visits will take place during the study: Screening (V1, V2),
Randomization (V3), Treatment (V4-V10), End of Study (V11) and Follow-up (V12).
Visits during the treatment period will take place every 12 weeks except for
the first 2 months, when they will occur every 2 weeks to allow close
monitoring of hematological safety parameters. Patients may be evaluated more
often if necessary for safety reasons. Patients who discontinue the study
treatment early will be asked to come in for an Early Withdrawal Visit within 4
weeks after the last dose of study treatment. Patients who have ongoing AEs at
discontinuation will be followed until resolution or stabilization.

The investigational study drug to be used in this study is givinostat (ITF2357)
and a placebo.
Givinostat oral suspension (10 mg/mL) and placebo oral suspension is to be
administered orally as 2 oral doses daily in a fed condition (e.g. in the
morning after breakfast and in the evening after dinner). The suspension is
administered by means of a graduated dosing syringe. The dosage to be
administered is based on patient weight (see protocol page 45).

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness Givinostat is a histone deacetylase (HDAC)
inhibitor.
Givinostat has already been evaluated in several clinical studies in adult and
pediatric populations. The most commonly observed adverse events were
thrombocytopenia, anemia, neutropenia, diarrhea, nausea, abdominal pain,
vomiting, QTc prolungation, respiratory infections, fever and worsening of
general conditions. These events were usually of mild or moderate intensity and
disappeared following interruption of the study drug. Doses up to
approximately 100 mg bid were generally well tolerated in adults.
Concerning the risks of study procedures foreseen in this clinical trial, blood
samples collection may cause fainting and/or swelling, pain, redness, bruising
or infection (infections are rare) where the needle is inserted.
Electrocardiogram (ECG)/Echocardiogram (ECHO): skin irritations are rare but
may occur during an ECG/ECHO because of the electrodes or gel that are used.
Magnetic resonance: the exam does not have any particular risks. Some people
feel claustrophobic. Subject cannot do this exam if they have metal parts in
their body (pacemakers, jewelry that cannot be removed, hearing aids, hip
prosthesis, etc.)
Muscle biopsy: the biopsy may cause pain and there is a chance of infection or
bruising.
Moreover, it is unknown if the use of study drug is harmful to a fetus or
newborn. Therefore, subject and her partner must be willing to use highly
effective contraceptive methods constantly and correctly up to 3 months
following the last dose of the study drug.
Subjects might not receive any benefits from participating in this study and
BMD symptoms may worsen.

However, nonclinical studies have shown that givinostat has a potent
anti-inflammatory effect (see (current IB) and that HDACi regulate the
transcription of key factors in muscle regeneration such as follistatin.
Concerning the clinical experience in dystrophinopathies a phase II clinical
trial (DSC/11/2357/43) has been conducted to evaluate the safety and the
potential of ITF2357 as a treatment for Duchenne Muscular Disease (i.e. DMD).
The results of that study showed an increase of the muscle fiber fraction and a
reduction of muscle necrosis, fat tissue replacement and fibrosis. As the
pathogenetic mechanism of BMD is similar to DMD (i.e. same gene mutated, but
different mutation), givinostat is expected to counter the disease pathogenetic
events also in BMD, potentially slowing down the disease progression and
relieve some symptoms.
The risk/benefit ratio of the proposed study is postulated to be favorable for
both the results of the clinical safety and pre-clinical toxicology studies and
for the efficacy results in the previous Phase 2 DMD study.
To date, a significant increase of the fat level in the blood (triglycerides)
has been reported for 4 patients who have already entered the study, although
for 2 of these patients the increase of such level was already present at the
beginning of the study. The relationship between the increase of the fat level
in the blood, Becker muscular dystrophy and the study treatment is currently
being studied. Meanwhile, to ensure your safety, in case of an increase of
triglycerides the study doctor could prescribe a suitable treatment (including
food supplements), and the relevant cost will be borne by the Sponsor. Should
your level of triglycerides in the blood be above a set threshold (300 mg/dL),
the study treatment could be temporarily interrupted.