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A 2-Part Study to Assess the Safety and Tolerability, pk, Effects on Histology and Some Clinical Parameters of Givinostat in Ambulant Children With DMD
study id #: NCT01761292
condition: Duchenne Muscular Dystrophy (DMD)
This is a 2-part, phase 2 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. All children treated in part 2 continue in the extension phase, for a maximum of an additional 12 months.
mechanism of action: Histone deacetylase (HDAC) inhibitor to reduce inflammation and promote muscle health
start date: May 2013
estimated completion: November 2017
phase of development: Phase 1/Phase 2
size / enrollment: 20
Approximately 20 children will be enrolled in the study as follows: the first 4 children will be treated at a low dose level of Givinostat.
If none of the stopping criteria described in the study protocol are met after 2 weeks of treatment at the low dose, the review team will determine the escalated dose level (i.e., intermediate dose level) to be used for the treatment of an additional 8 children who will be treated at the intermediate dose. The 4 children previously treated at the low dose level will also be switched to the intermediate dose level.
If none of the stopping criteria are met after 2 weeks of treatment at the intermediate dose, the review team will determine the subsequent escalated dose level to be used for the treatment of an additional 8 children who will be treated at the high dose. All children treated at the intermediate dose level will be switched to the high dose level.
Once all 20 children enrolled during the Part 1 of the study have been treated for at least 2 weeks, the review team will 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 will switch to the RD level, which will be administered for the subsequent 12 months of the study (Part 2).
The additional children (if any) will be enrolled during Part 2 of the study and will receive the RD of Givinostat for 12 months.
The total duration of the study is 15 months and an additional 12 months for the extension phase.
- Change in the value of MFA% comparing the histology biopsies before and after 12 months of treatment with Givinostat. [ Time Frame: baseline and 12 months ]
- Change in additional histological endpoints (i.e., cross-sectional area, inflammation, necrosis, fibrosis, and muscle regeneration) after 12 months of treatment with Givinostat at the selected daily dose [ Time Frame: baseline and 12 months ]
- Change in muscular function after 12 months of treatment with Givinostat at the selected daily dose based on the 6MWT, NSAA and PUL [ Time Frame: baseline and 12 months ]
- Type, incidence, and severity of treatment-emergent AEs and SAEs correlated with dose [ Time Frame: baseline and 12 months ]
• Male children aged 7 to <11 years with an immunohistochemical and molecular diagnosis of DMD.
• A parent/guardian and child can comply with all study evaluations/procedures and return for all study activities.
• 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.
• On a stable dose of systemic corticosteroids for at least 6 months.
• 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.
• Parent/guardian has signed the informed consent form and child has assented to be in the study (if applicable).
• 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.
• 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.
• 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.
• 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.
• History of participation in gene therapy, cell-based therapy or oligonucleotide therapy.
• 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.
• 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.
• Inadequate hematological function
• Absolute neutrophil count: <1.5 x 109/L
• Platelets: <100 x 109/L
• Current or history of liver disease or impairment, including but not limited to an elevated total bilirubin.
• Inadequate renal function, as defined by serum creatinine >2 x the upper limit of normal.
• Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening
• 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).
• Psychiatric illness/social situations rendering the potential child unable to understand and comply with the study protocol.
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