Overview
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.
Principal investigator
Eligibility criteria
Exclusion Criteria: 1. Have exposure to another investigational drug within 3 months prior to the start of study treatment; 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 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; 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 at screening \< Lower Limit of Normal (LLN); 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; 13. Have inadequate renal function, as defined by serum Cystatin C \>2 x the upper limit of normal (ULN); 14. Have Triglycerides \> 300 mg/dL (3.42 mmol/L) in fasting condition at screening visit; 15. Have a positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening15. 16. 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); 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.
For Referring Providers
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