Open label, long-term safety, tolerability, and efficacy study of GIVINOSTAT in all DMD patients who have been previously treated in one of the GIVINOSTAT studies.

Although different interventions have now become standard of practice and have
prolonged life expectation and time to wheelchair, DMD prognosis still provides
little hope and even with the best supportive care basic life achievements are
thrown into question. Currently only one product, Ataluren, is approved for
this serious debilitating and life threatening disease. However the approval is
for the treatment of DMD resulting from a nonsense mutation in the dystrophin
gene, in ambulatory patients aged 2 years and older, which only accounts for
13% of the population. In addition, FDA has granted an accelerated approval to
Eteplirsen, which targets DMD gene mutations skippable with exon 51 skipping,
which are relevant for only 13% of DMD population, or approximately 2,000
patients in the United States (US) and 2,500 patients in the European Union
(EU). Thus a significant unmet therapeutic need exists for DMD patients. Since
GIVINOSTAT treatment in DMD is expected to be a chronic treatment, the aim of
this long-term study is to formally evaluate long term safety and tolerability
and to continue monitoring signs of efficacy of GIVINOSTAT in this patients*
population until the Marketing Authorization will be granted and the product
will become available. Moreover, non clinical data indicate that GIVINOSTAT has
shown to produce functional and morphological beneficial effects in the mdx
mice. Histological data from DMD children treated with GIVINOSTAT for 1 year
showed the same morphological effect as was seen in the mdx mouse model. This
evidence supports the potential therapeutic role of GIVINOSTAT in slowing down
DMD progression, it is considered ethical to continue the treatment with
GIVINOSTAT in this rare disease with an unmet medical need.

Moreover, the treatment with GIVINOSTAT showed a statistically significant
(p=0.035) reduction in the decline in 4SC compared to placebo in the patient
treated in the phase III, randomized, double-blind, placebo controlled,
DSC/14/2357/48 trial. The study meets the primary endpoint and the results
demonstrate the clinical benefit of GIVINOSTAT to slow disease progression in
ambulant DMD patients after 18 months of treatment.

This study has been transitioned to CTIS with ID 2023-504520-26-00 check the CTIS register for the current data.

Primary objective:
To assess the long term safety and tolerability of GIVINOSTAT in patients with
DMD following core protocols program and with naïve GIVINOSTAT DMD subjects ,
i.e. subjects screened in study DSC/14/2357/48 who met:
- all the inclusion criteria and none of the exclusion criteria, and
- never been randomized because, the enrollment in the off-target group was
completed.

Secondary objective:
To evaluate the effects of long-term administration of GIVINOSTAT on muscular
function and strength;
To evaluate the effects of long-term administration of GIVINOSTAT on
respiratory function;
To evaluate the impact on daily activities and quality of life following
long-term administration of GIVINOSTAT.

Exploratory Objective(s):
Sparse PK sampling will be also collected to continue the evaluation of
GIVINOSTAT PK.
To compare the functional effects of long-term administration of GIVINOSTAT
between the *delayed GIVINOSTAT* and *GIVINOSTAT* treatment groups. The former
group comprises those patients randomised to placebo in their previous
GIVINOSTAT study; the latter group comprises those patients randomised to
GIVINOSTAT in their previous GIVINOSTAT study.

This is an open label, long-term safety, tolerability, and efficacy study of
GIVINOSTAT in all DMD patients who have been previously treated in one of the
GIVINOSTAT studies

GIVINOSTAT oral suspension (10 mg/mL) has to be administered orally as 2 oral
doses daily while the subject is in a fed state. The starting dose of
GIVINOSTAT in the present long term study will be the same that the subject was
receiving at the end of the previous DMD GIVINOSTAT study ((DSC / 14/2357/48).

The research will last approximately several years, until Givinostat receives
marketing authorization and is available on the market or until the Sponsor
and/or the competent authorities provide different instructions due to safety
and/or efficacy issues. Throughout the treatment period, the patient has to
attend a series of visits, the frequency of which will differ according to
whether the patient is already participating in a study that also involves the
administration of a placebo (DSC/14/2357/48 or DSC/14/2357/50) or a study that
only involves the administration of Givinostat. The initial study visit will
coincide with the final visit of the previous study, whilst subsequent visits
are scheduled every four months throughout the study. If the patient is
currently undergoing treatment in a study that also involves a placebo, given
that we do not know which treatment the patient is receiving, the patient will
need to attend weekly visits for the first month, every two weeks visits for
the second month and then visits at the end of the third and fourth months.
This is because the study doctor needs to check how the patients body responds
to the Givinostat treatment, in the event that the patients is receiving it for
the first time. From month four, visits will be every four months until the end
of the study. Most study visits will last between two and four hours. However,
some visits may take longer. The patients will undergo the following
examinations: - Physical examination and monitoring of vital functions (blood
pressure, heart rate, body temperature, body height (baseline and then annual)
and weight, electrocardiogram (every visit) & echocardiogram (baseline and
then annually)) - A lung function examination (every year as patients can walk
and every 4 years if they can not walk) - Detailed examination about the
medical history - Question about previous used and current medication and
possible side effects. - Blood samples and urine samples will be taken. Blood
sample for haematology, blood coagulation and biochemistry (18 ml each during
each visit) and for pharmacokinetics (2.5 ml each time during the visit every 8
months). Urine samples also during each visit. - Completing questionnaires
(quality of life, with respect to mobility, physical activity and pain) -
Taking study medication twice a day depending on body weight during the course
of the study. - If the patients can walk, their muscular strength is tested,
some tests are done on time (ie climbing stairs of 4 steps, standing up from
the floor, running / running 10 meters and walking distance for 6 minutes). -
If patients can not walk, physical capabilities and muscle strength are
measured by determining daily activities. -General determination of the motor
capacitance, especially the arm function. Blood collection: some known risks
are, although rare, that the blood collection procedure may involve, pain,
(after) bleeding, burning, discomfort, or bruise or infection at the site where
the needle is inserted. Blood pressure measurement: the cuff that is inflated
can possibly feel unpleasant to the arm. ECG: the cures and removal of the ECG
patch (small sticky pads) can cause a transient skin reaction, such as a red
house or itching. Local skin discomfort and / or hair loss can also occur by
applying the electrodes. Echocardiogram: patients may suffer from the sounds
that are part of the Doppler signal. The position the patients must adopt / the
body must turn may cause inconvenience. The patient may feel the cooling of the
gel on the transducer and a slight pressure of the transducer on the chest.
There are no special risks associated with the administration of GIVINOSTAT.
Very common side effects of GIVINOSTAT (equal to or greater than 10% of the
subjects) are: - Thrombocytopenia, accompanied by a nose bleed or bleeding
gums, blood in the urine or faces, purple or red bruises and small red or
purple spots on the skin - Diarrhea Common side effects (more than 2% to 10% of
the subjects): - Nausea, anemia, vomiting, headache, neutropenia, asthenia,
abdominal pain, anorexia, ECG abnormality (ie QTc prolongation), fatigue and
fever. The above mentioned side effects are generally mild to moderate and are
reversible after stopping the study medication.