Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy
Condition: Duchenne Muscular Dystrophy
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne
Study type: Interventional
Phase: Phase 3

Summary: 
      Primary Objective

      The primary objective of the study was to establish the effects of givinostat versus placebo
      administered chronically over 18 months to slow disease progression in ambulant DMD subjects.

      Secondary Objectives

      The secondary objectives of this study were:

        -  To assess the safety and tolerability of givinostat versus placebo administered
           chronically in DMD subjects

        -  To evaluate the PK profile of givinostat administered chronically in DMD subjects

        -  To evaluate the impact on quality of life (QoL) and activities of daily living of
           givinostat versus placebo administered chronically.
    

Detailed description: 
      This was a phase 3, randomised, double-blind, placebo-controlled, multicentre study to
      evaluate the efficacy and safety of givinostat in ambulant subjects with DMD. This study
      included ambulant male paediatric subjects aged ≥ 6 years at baseline affected by DMD.

      A total of 179 male ambulant subjects was randomized 2:1 (givinostat: placebo).

      Subjects were stratified for their concomitant use of steroids in 4 strata:

        1. Deflazacort daily regimen

        2. Deflazacort intermittent regimen

        3. Other steroids daily regimen

        4. Other steroids intermittent regimen. The study duration was planned to be 19 months.

      Givinostat or placebo oral suspension (10 mg/mL) was administered orally as 2 oral doses
      daily while the subject were in fed state, according to the child's weight.

      Study drug should have been permanently stopped if any of the following occurred:

        -  severe drug-related diarrhoea;

        -  any drug-related Serious Adverse Event;

        -  QTcF >500 msec;

        -  platelets count ≤50 x 10^9/L.

        -  white blood cells ≤2.0 x 10^9/L

        -  hemoglobin ≤8.0 g/dL

      Study drug should have been temporarily stopped if any of the following occurred:

        -  moderate or severe diarrhoea.

        -  platelets count <75 x 10^9/L but >50 x 10^9/L (the treatment should been temporarily
           stopped and a platelets count was to be performed and re-tested until platelets
           normalized);

        -  white blood cell <3.0 x 10^9/L but >2.0 x 10^9/L (the treatment should be temporarily
           stopped and white blood cells had to be measured by 1 week and re-tested until white
           blood cells normalized);

        -  hemoglobin <10.0 g/dL but > 8.0 g/dL (the treatment should be temporarily stopped and
           hemoglobin had to be measured by 1 week and re-tested until hemoglobin normalized);

        -  Triglycerides >300 mg/dL (3.42 mmol/L) in fasting condition (the treatment should be
           temporarily stopped and triglycerides measured every 2 weeks until triglycerides
           returned to levels below 300mg/dL (3.42 mmol/L)

      In case the study drug was temporarily stopped, the study drug could be resumed at a level
      20% smaller than the one at which the Adverse Event leading to temporary stop occurred, once
      platelets and/or white blood cell and/or hemoglobin normalized and/or triglycerides returned
      to levels below 300 mg/dL (3.42 mmol/L) or diarrhoea was mild.

      In addition, in case a subject had a consistent (e.g., at least 2 consecutive evaluations)
      platelets count ≤150 x 10^9/L and didn't meet the stopping criteria for platelets, the
      Investigator should have to reduce the dose by 20% of the current dose.

      Only one dose reduction was allowed during the treatment period.

      This trial design a single planned interim analysis. The interim was governed by an IDMC in
      order to solely assess futility.
    

Intervention name(s): givinostat; placebo
Intervention type(s): Drug; Drug
Intervention description(s): The oral suspension of givinostat (10 mg/mL) was to be dosed in fed condition as described below:
Givinostat or placebo starting dose
> or =10 and < 12.5 kg of weight: 13.3 mg bid = 1.3 ml oral suspension bid
> or =12.5 and < 20 kg: 16.7 mg bid =1.7 ml oral suspension bid
> or = 20 and < 25 kg: 20 mg bid = 2.0 ml oral suspension bid
> or = 25 and < 30 kg: 23.3 mg bid = 2.3 ml oral suspension bid
> or = 30 and < 40 kg: 26.7 mg bid = 2.7 ml oral suspension bid
> or = 40 and < 50 kg: 33.3 mg bid = 3.3 ml oral suspension bid
> or = 50 and < 60 kg: 36.7 mg bid = 3.7 ml oral suspension bid
> or = 60 and < 70 kg: 40 mg bid = 4 ml oral suspension bid
> or = 70 kg: 46.7 mg bid = 4.7 ml oral suspension bid; The oral suspension of placebo, manufactured to mimic givinostat, was to be dosed in fed condition as described for givinostat.
Other intervention name(s): ITF2357
Intervention MeSH terms: Givinostat hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Dystrophy; DMD; Givinostat