Efficacy, Safety and Tolerability of Givinostat in Non-ambulant Patients With Duchenne Muscular Dystrophy

Inclusion Criteria:

Patients must satisfy all the following criteria:

1. Children and adolescent males aged ≥ 9 to <18 years at screening (patients ≥ 18years of age at screening will not be enrolled into the study)

2. Are able to give informed assent and/or consent in writing signed by the patientand/or parent/legal guardian (according to local regulations)

3. A genetic diagnosis of DMD

4. Non-ambulant, defined as being wheelchair bound and:

5. Unable to perform the 10-meter walk/run test (10MWT), or

6. Unable to complete the 10MWT in 30 seconds or less, without any support ordevices

7. Performance of the Upper Limb test (PUL version 2.0) entry item scores 3 to 6

8. If on medication for DMD-associated cardiomyopathy (eg, ACE inhibitor, β-blocker,diuretics), stable for ≥1 month immediately prior to start of study treatment, ifany

9. Stable corticosteroids, defined as:

10. Receiving systemic corticosteroids for a minimum of 6 months immediately priorto start of study treatment

11. No significant change in dose or dosing regimen (except for adjustments due tobody weight change) for a minimum of 6 months immediately prior to start ofstudy treatment

12. Willing to use adequate contraception. Effective contraceptive methods must be usedfrom randomisation visit through 3 months after the last dose of study drug, andinclude the following:

13. True abstinence (ie, absence of any sexual intercourse), when in line with thepreferred and usual lifestyle of the patient. Periodic abstinence (eg,calendar, ovulation, post-ovulation, and symptothermal methods) and withdrawalare not acceptable methods of contraception

14. Condom with spermicide and the female partner must use an effective method ofcontraception, such as an oral, transdermal, injectable or implanted hormonalcontraceptive; intrauterine device; bilateral tubal occlusion, or a diaphragmor a barrier method of contraception in conjunction with spermicidal jelly suchas for example cervical cap with spermicide jelly.

Exclusion Criteria:

Patients will be excluded from the study if they satisfy any of the following criteria:

1. Exposure to another investigational drug within 3 months prior to start of studytreatment.

2. Have exposure to any dystrophin restoration product (eg, Ataluren, Exon skipping)within 6 months prior to the start of study treatment

3. Having received any gene therapy (eg, AAV Micro-dystrophin delivery) prior to startof study treatment

4. Use of any pharmacologic treatment or supplement (other than corticosteroids), thatmight have had an effect on muscle strength or function within 3 months prior to thestart of study treatment (eg, growth hormone); vitamin D, calcium and any othersupplements will be allowed

5. Use of testosterone, unless used as a replacement therapy for the treatment ofdelayed puberty. The testosterone dose and regimen should be stable within 6 monthsprior to the start of study treatment, and circulating testosterone levels should bewithin the normal ranges for the patient's age

6. Elbow-flexion contractures >30° in the dominant arm

7. Inability to perform consistent PUL 2.0 measurement within ±2 points withoutshoulder domain or within ±3 points with shoulder domain during paired testing atscreening

8. Forced Vital Capacity % of predicted <40%

9. Requirement for daytime ventilator assistance (Note: Night ventilator assistance anduse of bi-level positive airway pressure therapy is allowed)

10. Episode of respiratory failure within the 8 weeks prior to screening

11. Symptomatic cardiomyopathy or heart failure and/or left ventricular ejectionfraction <45%

12. Baseline corrected QT interval using Fredericia's formula (QTcF) >450 msec (as themean of 3 consecutive readings 5 minutes apart) or history of additional riskfactors for torsades de pointes (eg, heart failure, hypokalaemia, or family historyof long QT syndrome)

13. Major surgical procedure (including scoliosis surgery) planned within 1 year of thestart of study treatment

14. Poorly controlled asthma or underlying lung disease such as bronchitis,bronchiectasis, emphysema, recurrent pneumonia that in the opinion of theInvestigator might impact respiratory function

15. Platelets, white blood cells, and/or haemoglobin < lower limit of normal (LLN) atscreening (Note: for abnormal screening laboratory test results [<LLN], theplatelets count, white blood cell, and haemoglobin will be repeated once; if therepeat test result is still <LLN, the patient should be excluded)

16. Fasting triglycerides >300 mg/dL (3.42 mmol/L) at screening (Note: if the value is >300 mg/dL, the triglycerides will be repeated once; if the repeated test result isstill >300 mg/dL, the patient should be excluded)

17. Current or history of liver disease or impairment, including but not limited to abaseline elevated total bilirubin (ie, >1.5 × upper limit of normal [ULN]), unlesssecondary to Gilbert disease or pattern consistent with Gilbert disease

18. Inadequate renal function, as defined by serum Cystatin C result >2 × ULN (Note: ifthe value is >2 × ULN, the serum Cystatin C will be repeated once; if the repeatedtest result is still >2 × ULN, the patient should be excluded)

19. Positive test for hepatitis B surface antigen, hepatitis C antibody, or humanimmunodeficiency virus at screening

20. Hypersensitivity to any component of study medication

21. Sorbitol intolerance or malabsorption, or have the hereditary form of fructoseintolerance

22. Diagnosis of other uncontrolled neurological diseases or presence of relevantuncontrolled somatic disorders that are not related to DMD, based on Investigatorjudgement

23. Psychiatric illness or social situations rendering the potential patient unable tounderstand and comply with the muscle function tests and/or with the study protocolprocedures, based on Investigator judgement

24. Have contraindications to MRI scan (eg, claustrophobia, metal implants, oruncontrolled seizure disorder), based on Investigator's judgement.