This is a Phase 2 Open-label (Core Phase Plus Extension Phase) With 2 Cohorts Study to Assess the Pharmacokinetics and Safety of Givinostat in younger DMD Patients. * Planned screening duration: approximately 4 weeks * Planned Core Treatment duration: approximately 48 weeks * Planned Extension Treatment duration: approximately 96 weeks * Planned Follow Up duration: approximately 4 weeks (± 7 days) * Total duration of study participation: up to 151 weeks (ie, 37-38 months)
This is an open-label, multicentre, multicountry, 2 cohorts study to evaluate the PK profile and safety of givinostat in subjects with DMD aged ≥4 to \<6 years for Cohort 1 and aged ≥2 to \<4 years for Cohort 2. The starting dose for Cohort 2 will be confirmed/adjusted with results of the interim analysis of Cohort 1. The study will consist of 2 phases, a Core Phase and an Extension Phase. Two final analyses will be conducted, the first at the end of the Core Phase and the second at the end of the Extension Phase (core and extension data will be combined). The study will enrol approximately 18 subjects (approximately 9 subjects \[aged ≥4 to \<6 years\] in Cohort 1 and approximately 9 subjects \[aged ≥2 to \<4 years\] in Cohort 2).
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
Cohort 1 - from 4 to 6 years old
Cohort 2 - from 2 to 4 years old
Queen Fabiola Children's University Hospital HUDERF
Brussels, Belgium
RECRUITINGFondazione Serena Onlus - Azienda Ospedaliera Niguarda Ca' Granda - NeuroMuscolar Omnicenter
Milan, Italy
RECRUITINGOspedale Pediatrico Bambino Gesù
Roma, Italy
RECRUITINGPoliclinico Universitario Agostino Gemelli - Università Cattolica del Sacro Cuore
Roma, Italy
RECRUITINGLeids Universitair Medisch Centrum (LUMC)
Leiden, Netherlands
RECRUITINGLeeds Teaching Hospital NHS Trust
Leeds, England, United Kingdom
NOT_YET_RECRUITINGGreat Ormond Street Hospital - GOSH
London, England, United Kingdom
NOT_YET_RECRUITINGNewcastle upon Tyne Hospitals NHS Foundation Trust - Newcastle University
Newcastle upon Tyne, England, United Kingdom
RECRUITINGOxford University Hospitals NHS Foundation Trust
Oxford, England, United Kingdom
RECRUITINGCore Phase: Cohort 1 - Change from baseline of the pharmacokinetic (PK) parameter Area under the concentration-time curve from dosing (time 0) to time t at steady state (AUC0-T,ss).
Pharmacokinetic samples will be collected 1 pre-dose in the morning and 3 post-dose (0-2 h, 4-6 h, 6-8 h) after 1 week (Visit 3) and after 6 months (Visit 10). Sampling times will be randomly assigned to each subject to collect at least 1 pre-dose sample and 2 post-dose samples in each subject. At these timepoints, the subject will be asked to take the morning dose at the site. Samples collected after 1 week of treatment will be used for the exploratory PK analysis.
Time frame: Baseline up to week 48
Core Phase: Cohort 1 - Change from baseline of the pharmacokinetic (PK) parameter maximum plasma concentration at steady state (Cmax,ss).
Pharmacokinetic samples will be collected 1 pre-dose in the morning and 3 post-dose (0-2 h, 4-6 h, 6-8 h) after 1 week (Visit 3) and after 6 months (Visit 10). Sampling times will be randomly assigned to each subject to collect at least 1 pre-dose sample and 2 post-dose samples in each subject. At these timepoints, the subject will be asked to take the morning dose at the site. Samples collected after 1 week of treatment will be used for the exploratory PK analysis.
Time frame: Baseline up to week 48
Core Phase: Cohort 1 - Change from baseline of the pharmacokinetic (PK) parameter elimination half-life (t1/2) assessed after at least 7 days of dosing.
Pharmacokinetic samples will be collected 1 pre-dose in the morning and 3 post-dose (0-2 h, 4-6 h, 6-8 h) after 1 week (Visit 3) and after 6 months (Visit 10). Sampling times will be randomly assigned to each subject to collect at least 1 pre-dose sample and 2 post-dose samples in each subject. At these timepoints, the subject will be asked to take the morning dose at the site. Samples collected after 1 week of treatment will be used for the exploratory PK analysis.
Time frame: Baseline up to week 48
Core Phase: Cohort 2 - Change from baseline of the pharmacokinetic (PK) parameter Area under the concentration-time curve from dosing (time 0) to time t at steady state (AUC0-T,ss).
Pharmacokinetic samples will be collected 1 pre-dose in the morning and 3 post-dose (0-2 h, 4-6 h, 6-8 h) after 1 week (Visit 3) and after 6 months (Visit 10). Sampling times will be randomly assigned to each subject to collect at least 1 pre-dose sample and 2 post-dose samples in each subject. At these timepoints, the subject will be asked to take the morning dose at the site. Samples collected after 1 week of treatment will be used for the exploratory PK analysis.
Time frame: Baseline up to week 48
Core Phase: Cohort 2 - Change from baseline of the pharmacokinetic (PK) parameter maximum plasma concentration at steady state (Cmax,ss).
Pharmacokinetic samples will be collected 1 pre-dose in the morning and 3 post-dose (0-2 h, 4-6 h, 6-8 h) after 1 week (Visit 3) and after 6 months (Visit 10). Sampling times will be randomly assigned to each subject to collect at least 1 pre-dose sample and 2 post-dose samples in each subject. At these timepoints, the subject will be asked to take the morning dose at the site. Samples collected after 1 week of treatment will be used for the exploratory PK analysis.
Time frame: Baseline up to week 48
Core Phase: Cohort 2 - Change from baseline of the pharmacokinetic (PK) parameter elimination half-life (t1/2) assessed after at least 7 days of dosing
Pharmacokinetic samples will be collected 1 pre-dose in the morning and 3 post-dose (0-2 h, 4-6 h, 6-8 h) after 1 week (Visit 3) and after 6 months (Visit 10). Sampling times will be randomly assigned to each subject to collect at least 1 pre-dose sample and 2 post-dose samples in each subject. At these timepoints, the subject will be asked to take the morning dose at the site. Samples collected after 1 week of treatment will be used for the exploratory PK analysis.
Time frame: Baseline up to week 48
Extension Phase: Type, incidence, and severity of treatment-emergent adverse events
Time frame: postbaseline up to Week 144
Extension Phase: Proportion of patients experiencing treatment-emergent adverse events
Time frame: postbaseline up to Week 144
Core Phase: Type, incidence, and severity of treatment-emergent adverse events
Time frame: Baseline up to week 48
Core Phase: Proportion of patients experiencing treatment-emergent adverse events
Time frame: Baseline up to week 48
Core Phase: Change from baseline as measured by North Star Ambulatory Assessment (NSAA) in cohort 1 after 48 weeks of treatment of givinostat.
Time frame: Baseline up to week 48
Core Phase: Change from baseline as measured by Bayley III Gross Motor in cohort 2 after 48 weeks of treatment of givinostat.
Time frame: Baseline up to week 48
Core Phase: Change from baseline in quality of life (as measured by health-related quality of life, HRQOL) at week 48 of treatment of givinostat
Time frame: Baseline up to week 48
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