|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Duchenne Muscular Dystrophy (DMD)
|Medical condition in easily understood language
|A neuromuscular disease characterized by rapidly progressive muscle weakness and wasting
|Diseases [C] - Musculoskeletal Diseases [C05]
|E.1.2 Medical condition or disease under investigation
|Duchenne muscular dystrophy
|System Organ Class
|10010331 - Congenital, familial and genetic disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To establish the effects of givinostat versus placebo administered chronically over 18 months to slow disease progression in ambulant DMD subjects
|Secondary objectives of the trial
|To assess the safety and tolerability of givinostat versus placebo administered chronically in DMD subjects.
To evaluate the pharmacokinetic (PK) profile of givinostat administered chronically in DMD subjects.
To evaluate the impact on quality of life and activities of daily living of givinostat versus placebo administered chronically.
To evaluate the correlation between PK profile of givinostat and pharmacodynamics (PD) data.
To explore whether the effects of givinostat versus placebo administered chronically may be related to the type of DMD mutation or to the biomarkers.
|Trial contains a sub-study
|Principal inclusion criteria
|1. Are ambulant males aged ≥6 years at randomisation with DMD characteristic clinical symptoms or signs (e.g., proximal muscle weakness, Gowers’ maneuver, elevated serum creatinine kinase level) already present at screening;
2. Have DMD diagnosis confirmed by genetic testing;
3. Are able to give informed assent and/or consent in writing signed by the subject and/or parent/legal guardian (according to local regulations);
4. Are able to complete 2 Four Stairs Climb test (4SC) screening assessments; the results of these tests must be within ±1 second of each other;
5. Have the mean of 2 screening 4SC assessments ≤8 seconds;
6. Have time to rise from floor between ≥3 and <10 seconds at screening;
7. Have manual muscle testing (MMT) of quadriceps at screening ≥ Grade - 3;
8. Have used systemic corticosteroids for a minimum of 6 months immediately prior to the start of study treatment, with no significant change in corticosteroids type or dosage or dosing regimen (excluding changes related to body weight change) for a minimum of 6 months immediately prior to start of study treatment and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study.
9. Subjects must be willing to use adequate contraception.
Contraceptive methods must be used from Randomization Visit 3 through 3 months after the last dose of study drug, and include the following:
• True abstinence (absence of any sexual intercourse), when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
• Condom with spermicide and the female partner must use an acceptable method of contraception, such as an oral, transdermal, injectable or implanted steroid-based contraceptive, or a diaphragm or a barrier method of contraception in conjunction with spermicidal jelly such as for example cervical cap with spermicide jelly.
|Principal exclusion criteria
|1. Have exposure to another investigational drug within 3 months prior to the start of study treatment (only exception allowed is use of
Deflazacort in US as part of the Expanded Access Program and in Canada
as part of the Special Access Program);
2. Have exposure to idebenone within 3 months prior to the start of study treatment;
3. Have exposure to any dystrophin restoration product (e.g., Ataluren, Exon-skipping) within 6 months prior to the start of study treatment;
4. Use of any pharmacologic treatment, other than corticosteroids, that might have had an effect on muscle strength or function within 3 months prior to the start of study treatment (e.g., growth hormone); Vitamin D, calcium, and any other supplements will be allowed as long as their intake has been stable for 3 months prior to the start of study treatment. Testosterone will also be allowed if it is used as a replacement therapy for the treatment of delayed puberty, and testosterone dose and regimen have been stable for at least 6 months and circulating testosterone levels are within the normal ranges for the subject's age;
5. Have 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;
6. Loss of ≥30 degrees of plantar flexion from the normal range of
movement at the ankle joint due to contracture (i.e. fixed loss of more
than 10 degrees of plantar flexion from plantigrade, assuming normal
range of dorsiflexion of 20 degrees);
7. Change in contracture treatment such as serial casting, contracture control devices, night splints, stretching exercises (passive, active, self) within 3 months prior to enrollment, or expected need for such intervention during the study;
8. Have presence of other clinically significant disease, which, in the Investigator’s opinion, could adversely affect the safetyof the subject, making it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results;
9. Have a diagnosis of other uncontrolled neurological diseases or presence of relevant uncontrolled somatic disorders that are not related to DMD;
10. Have platelets count, White Blood Cell and Hemoglobin at screening <Lower Limit of Normal (LLN) (for abnormal screening laboratory test results (<LLN), the platelets count, White Blood Cell and Hemoglobin will be repeated once; if the repeat test result is still <LLN, then exclusionary);
11. Have symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction <50% at screening;
12. Have a current or history of liver disease or impairment; including but not limited to an elevated total bilirubin (i.e. > 1.5 x ULN), unless secondary to Gilbert disease or pattern consistent with Gilbert's;
13. Have inadequate renal function, as defined by serum Cystatin C >2 x the upper limit of normal (ULN). If the value is >2 x ULN, the serum Cystatin C will be repeated once; if the repeated test result is still >2 x ULN, the subject should be excluded);
14. Have Triglycerides > 300 mg/dL (3.42 mmol/L) in fasting condition at screening visit;15. Have a positive t
15. Have a positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening;
16. Have a baseline corrected QT interval, Fridericia’s correction (QTcF) >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, or family history of long QT syndrome);
17. Have a psychiatric illness/social situations rendering the potential subject unable to understand and comply with the muscle function tests and/or with the study protocol procedures;
18. Have any hypersensitivity to the components of study medication;
19. Have a sorbitol intolerance or sorbitol malabsorption, or have the hereditary form of fructose intolerance.
20. Have contraindications to MRI or MRS (e.g., claustrophobia, metal implants, or seizure disorder).
At the discretion of the Investigator, subjects not meeting inclusion/exclusion criteria may be re-screened twice with an interval of at least 3 months between assessments.
|E.5 End points
|Primary end point(s)
|Mean change in 4SC before and after 18 months of treatment of givinostat versus placebo.
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|Key secondary efficacy endpoints:
• Mean change in time to rise from floor
• Mean change in 6MWT
• Mean change in NSAA
• Cumulative loss of function on the NSAA
• Mean change in muscle strength evaluated by knee extension, elbow flexion as measured by hand-held myometry HHM
Imaging (MR cohort):
• Mean change in vastus lateralis muscles fat fraction ;
- Number of subjects experiencing treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) (Baseline through end of study [EOS]);
- Type, incidence, and severity of TEAEs and SAEs (Baseline through EOS);
- Changes from baseline to end of study of:
o Vital signs and clinical laboratory tests (blood chemistry and hematology);
o Respiratory function evaluated by forced vital capacity (FVC), forced expiratory volume at 1 second (FEV1), FVC/FEV1, Peak Expiratory Flow (PEF);
o Cardiac function evaluated by ECG and ECHO;
o Cognitive function evaluated by the Raven progressive matrices;
o Weight, height, and body mass index (BMI).
o Evaluation of acceptability/palatability of the oral suspension.
- Description of the PK of givinostat and its major metabolites:
ITF2374 and ITF2375 in the subject population;
- Identification of the relevant demographic and pathophysiological covariates influencing the PK of givinostat.
• Mean changes in
o time to walk/run 10 meters;
o PODCI scores.
o %-predicted 6MWT;
o Only in the MR cohort: MRI parameters (e.g., fat fraction of thigh muscles, CSA of vastus lateralis and other thigh muscles).
• Time to 10% persistent worsening in 6MWT (Baseline through end of study);
• Proportion of subjects with ≥10% worsening in 6MWT at end of study;
• Time to loss of standing (Baseline through end of study);
• Proportion of subjects who loose ambulation during the study;
•Evaluation of any correlation between the effect of Givinostat on
disease progression and the type of DMD mutation, LTBP4 and
•Evaluation of any possible DMD serum biomarker;
• PK-PD analyses: relationships between metrics of exposure and efficacy/safety endpoints of givinostat.
|Timepoint(s) of evaluation of this end point
|Key secondary efficacy endpoints: will be formally assessed after 18 months of treatment.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Other scope of the trial description
|Quality of life and daily activities
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days