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Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy
study id #: NCT02851797
condition: Duchenne Muscular Dystrophy
it is a randomised, double blind, parallel group, placebo controlled study. A total of 213 male ambulant subjects will be randomised 2:1 (givinostat:placebo). Subjects will be 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 is planned for 19 months.
intervention: givinostat, placebo
mechanism of action: Histone deacetylase (HDAC) inhibitor to reduce inflammation and promote muscle health
last updated: February 15, 2019
start date: June 1, 2017
estimated completion: June 2020
phase of development: Phase 3
size / enrollment: 213
Givinostat or placebo oral suspension (10 mg/mL) will be administered orally as 2 oral doses daily while the subject is in fed state, according to the child's weight.
Study drug should be permanently stopped if any of the following occur:
-severe drug-related diarrhoea;
-any drug-related Serious Adverse Event;
-QTcF >500 msec; -platelets count <=50 x 109/L. Study drug should be temporarily stopped if any of the following occur:
-platelets count <75 x 109/L but >50 x 109/L (the treatment should be temporarily stopped and a platelets count has to be performed and re-tested until platelets will be normalized);
-moderate or severe diarrhoea.
In case the study drug was temporarily stopped, the study drug can be resumed at a level 1/3 smaller than the one at which the Adverse Event leading to temporary stop occurred, once platelets are normalized or diarrhoea is mild (if treatment was stopped for moderate or severe diarrhoea).
Two interim analyses are planned and will be conducted by the IDMC in order to ensure study integrity.
- mean change in 4 standard stairs climb [ Time Frame: 18 months ]
the primary endpoint is the mean change in 4 standard stairs climb test results before and after 18 months of treatment of givinostat versus placebo
- Other functional test as 6MWT [ Time Frame: 18 months ]
the mean change in 6MWT
- time to rise from floor [ Time Frame: 18 months ]
the mean change in time to rise from floor
- Magnetic Resonance Spetroscopy [ Time Frame: 18 months ]
the mean change in fat fraction of vastus lateralis muscles at MRS
• Are an ambulant male 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;
• Have DMD diagnosis confirmed by genetic testing;
• Are able to give informed assent and/or consent in writing signed by the subject and/or parent/legal guardian (according to local regulations);
• 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;
• Have the mean of 2 screening 4SC assessments <=8 seconds;
• Have time to rise from floor of <10 seconds at screening;
• Have manual muscle testing (MMT) of quadriceps at screening >= Grade 3;
• Are eligible according to the protocol-specified functional algorithm* predictive of vastus lateralis muscle fat fraction (VL MFF) that should be in the range >10% but <30% (see section 4.2.3);
• Have used systemic corticosteroids for a minimum of 6 months immediately prior to the start of study treatment, with no significant change in 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.
• The protocol-specific functional algorithm will consider results relevant Four stairs climb test and knee extensor peak torque measurement.
• Have exposure to another investigational drug within 3 months prior to the start of study treatment;
• Have exposure to idebenone within 3 months prior to the start of study treatment;
• Have exposure to any dystrophin restoration product (e.g., Ataluren, Exon skipping) within 6 months prior to the start of study treatment;
• 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;
• 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;
• Ankle joint contractures due to a fixed loss of >=10 degrees of dorsiflexion from plantagrade assuming a normal range of dorsiflexion of 20 degree;
• 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;
• Have presence of other clinically significant disease, which, in the Investigator's opinion, could adversely affect the safety of the subject, making it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results;
• Have a diagnosis of other neurological diseases or presence of relevant somatic disorders that are not related to DMD;
• Have platelets count at screening < Lower Limit of Normal (LLN);
• Have symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction <50% at screening;
• Have a current or history of liver disease or impairment;
• Have inadequate renal function, as defined by serum Cystatin C >2 x the upper limit of normal (ULN);
• Have a positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening;
• Have a baseline QTcF >450 msec, or history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, or family history of long QT syndrome);
• 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;
• Have any known allergic reaction to givinostat or any of its excipients.
-For the subgroup of subjects who will undergo MRI and MRS (i.e., MR Cohort):
• Have contraindications to MRI or MRS (e.g., claustrophobia, metal implants, or seizure disorder).
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