A Study to Assess Safety/Tolerability, pk, Effects on Histology, Clinical Parameters of Givinostat in Children With DMD

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)

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).

Eligibility 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 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.