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Givinostat in Duchenne’s Muscular Dystrophy Long-term Safety and Tolerability Study
study id #: NCT03373968
condition: Duchenne Muscular Dystrophy
This is an open label, long-term safety, tolerability, and efficacy study of GIVINOSTAT in all DMD (Duchenne’s muscular dystrophy) patients who have been previously treated in one of the GIVINOSTAT studies.
mechanism of action: Histone deacetylase (HDAC) inhibitor to reduce inflammation and promote muscle health
last updated: December 04, 2019
start date: October 24, 2017
estimated completion: December 2023
phase of development: Phase 2/Phase 3
size / enrollment: 100
GIVINOSTAT oral suspension (10 mg/mL) has to be administered orally as 2 oral doses daily while the subject is in a fed state. The starting dose of GIVINOSTAT in the present long term study will be the same that the subject was receiving at the end of the previous DMD GIVINOSTAT study.
As weight affects GIVINOSTAT exposures, the dosage will be modified based on subject weight according the rules detailed in the study protocol section 220.127.116.11.
In addition, in case a subject will have a consistent (e.g., at least 2 consecutive evaluations) platelets count =<150 x 109/L and not meet the stopping criteria for platelets, the Investigator will have to reduce the dose of 1/3 or 20% less of the current dose as described in the study protocol section 10.5.1.3. During the first month of treatment, platelets count assessment will be performed weekly, while during the second month it will be performed every 2 weeks, in order to strictly monitor this parameter for safety reasons, with the exclusion of subjects coming from study DSC/11/2357/43 for which the first visit will be 4 months after the Visit 1/baseline visit.
Study drug should be permanently interrupted if any of the following occurs:
• severe drug-related diarrhoea (i.e., increase of >=7 stools per day);
• any drug-related SAE;
• QTcF >500 msec;
• platelets count =<50 x 109/L;
• white blood cells =<2.0 x 109/L;
hemoglobin =<8.0 g/dL; To avoid laboratory errors and anomalous values, test must be confirmed with a repeated test performed on the next working day. The treatment should be stopped until the retest result becomes available. If the repeated test is still under the stopping limit value, study drug must be permanently discontinued. If the repeated test is acceptable, the subject can resume treatment.
The Investigator will follow up the patient until resolution or acceptable stabilization of the event occurs and document all the relevant information, as applicable. After the resolution/stabilization of the event, the subject will be withdrawn from the study and the EOS Visit (see Section 12.1.10) will be performed.
Any decision relevant to the dose adjustment and/or modification of schedule of assessments can be discussed with the Medical Monitor, but the final decision remains with the Investigator only or its authorized designee.
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [Time Frame: Through study completion, an average of 1 year]
Type, incidence, and severity of treatment related/not related adverse events(AEs) and serious adverse event (SAEs)
• Eligible Sexes: male
• Must have participated in one of the previous studies with GIVINOSTAT in DMD and have attended the End of Study Visit;
• Aged >=7 years and 6 months old
• Are able to give informed assent and/or consent in writing signed by the subject and/or parent/legal guardian (according to local regulations);
• Subjects must be willing to use adequate contraception.
• Use of any pharmacologic treatment, other than corticosteroids, that might have had an effect on muscle strength or function within 3 months prior to be enrolled in this study (e.g., growth hormone); Vitamin D, calcium, and any other supplements will be allowed;
• Use of any current investigational drug other than Givinostat;
• 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, 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);
• Have Triglycerides > 300 mg/dL (3.42 mmol/L) in fasting conditionat screening visit (for abnormal screening laboratory test results (>300 mg/dL), the triglycerides will be repeated once;if the repeat test result is still >300 mg/dL , then exclusionary).
• Have inadequate renal function, as defined by serum Cystatin C >2 x the upper limit of normal (ULN) at screening visit. 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);
• Have heart failure (New York Heart Association Class III or IV)
• Have a current 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;
• Have a baseline QT interval, Fredericia'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);
• 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 hypersensitivity to the components of study medication;
• Have a sorbitol intolerance or sorbitol malabsorption, or have the hereditary form of fructose intolerance.
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