Givinostat in Duchenne's Muscular Dystrophy Long-term Safety and Tolerability Study

Prior treatment

• Use of any current investigational drug other than Givinostat;

Other illness

• Have presence of other clinically significant disease, which, in the Investigator's opinion, could adversely affect the safety of the subject, making it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results;
• Have a diagnosis of other uncontrolled neurological diseases or presence of relevant uncontrolled somatic disorders that are not related to DMD;
• Have heart failure (New York Heart Association Class III or IV)
• Have a psychiatric illness/social situation rendering the potential subject unable to understand and comply with the muscle function tests and/or with the study protocol procedures.
• Have any hypersensitivity to the components of study medication;

Lab values

• Use of any pharmacologic treatment, other than corticosteroids, that might have had an effect on muscle strength or function within 3 months prior to be enrolled in this study (e.g., growth hormone); Vitamin D, calcium, and any other supplements will be allowed;
• Have platelets count, White Blood Cell and Hemoglobin at screening \< Lower Limit of Normal (LLN)\* (for abnormal screening laboratory test results (\<LLN), the platelets count, White Blood Cell and Hemoglobin will be repeated once; if the repeat test result is still \<LLN, then exclusionary);
• Have Triglycerides \> 300 mg/dL (3.42 mmol/L) in fasting condition at screening visit\* (for abnormal screening laboratory test results (\>300 mg/dL), the triglycerides will be repeated once; if the repeat test result is still \>300 mg/dL, then exclusionary);
• Have inadequate renal function, as defined by serum Cystatin C \>2 x the upper limit of normal (ULN) at screening visit\*. If the value is \>2 x ULN, the serum Cystatin C will be repeated once; if the repeated test result is still \>2 x ULN, the subject should be excluded);
• Have a current liver disease or impairment, including but not limited to an elevated total bilirubin\* (i.e. \> 1.5 x ULN), unless secondary to Gilbert disease or pattern consistent with Gilbert's;
• Have a baseline QTcF \>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, or family history of long QT syndrome);
• Have a sorbitol intolerance or sorbitol malabsorption or have the hereditary form of fructose intolerance.
  • the Investigators to evaluate these exclusion criteria can use the laboratory results obtained within 5 months from V1, to allow the continuity of the treatment. It is worth noting, as soon as the site will receive the laboratory results done in screening/baseline (Visit 1) visit they will check the GIVINOSTAT dose and modify it as per protocol safety rules and/or dosage modifications rules.

• Must have participated in one of the previous studies with GIVINOSTAT in DMD and have attended the End of Study Visit or must have been screened in study DSC/14/2357/48 and met:
  • all the inclusion criteria and none of the exclusion criteria,
  • had a baseline vastus lateralis muscle fat fraction (VL MFF) assessed by MRS in the range ≤5% or \>30%, i.e. included in"off-target" group,
  • never been randomized because, the enrollment in the off target group was completed.
• Aged ≥6 years old;
• Are able to give informed assent and/or consent in writing signed by the subject and/or parent/legal guardian (according to localregulations);
• Subjects must be willing to use adequate contraception:
  • Contraceptive methods must since the previous GIVINOSTAT study through 3 months after the last dose of study drug, and include the following:
  • True abstinence (absence of any sexual intercourse), when in line with the preferred and usual lifestyle of the subject.
  • Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
  • Condom with spermicide and the female partner must use an acceptable method of contraception, such as an oral,
  • transdermal, injectable or implanted steroid-basedcontraceptive, or a diaphragm or a barrier method of contraception in conjunction with spermicidal jelly such asfor example cervical cap with spermicide jelly.