A Study to Assess Safety/Tolerability, pk, Effects on Histology, Clinical Parameters of Givinostat in Children With DMD
Condition: Duchenne Muscular Dystrophy (DMD)
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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)
    

Detailed description: 
      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).
    

Intervention name(s): Givinostat
Intervention type(s): Drug
Intervention description(s): Givinostat, oral suspension 10 mg/mL or oral capsules 50 mg, administered orally under fed conditions at the dose of 25 mg BID, 37.5 mg BID, and 50 mg BID during Part 1 for two weeks, and 25 mg BID and 37.5 mg BID during Part 2 for 12 months. Givinostat, oral suspension 10 mg/mL, administered orally under fed conditions at the dose of 25 mg BID or 37.5 mg BID during Extension 1, and modified as per patient's weight during Extensions 2 and 3 (up to 52 months).
Other intervention name(s): ITF2357
Intervention MeSH terms: Givinostat hydrochloride
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: rare disease