Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Becker Muscular Dystrophy

Study Overview
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Brief Summary
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This is a phase 2, randomised, double-blind, placebo controlled study to evaluate the micro-macroscopic effects on muscles, the safety and tolerability, and the efficacy of givinostat in patients with Becker Muscular Dystrophy. Approximately 48 eligible patients will be randomized in a 2:1 ratio to be treated with givinostat or placebo for a period of 12 months.

Detailed Description
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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 subject's weight. Study drug should be permanently stopped if any of the following occur: severe drug-related diarrhoea; any drug-related Serious Adverse Event (SAE); QTcorrected by Fridericia's formulas (QTcF) >500 msec; platelets (PLT) count ≤50 x 1.000.000.000/L (10E9/L); White blood cell (WBC) ≤ 2.0 x 10E9/L; Hemoglobin (Hb) ≤ 8.0 g/dL. Study drug should be temporarily stopped if any of the following occur: PLT count <75 x 10E9/L but >50 x 10E9/L; WBC < 3.0 x 10E9/L but > 2.0 x 10E9/L; Hb < 10.0 g/dL but > 8.0 g/dL; moderate or severe diarrhoea. tryglicerides >300 mg/dL In case the study drug was temporarily stopped, the study drug can be resumed at a level 20% smaller than the dose at which the Adverse Event leading to temporary stop occurred, once platelets and/or WBC and/or Hb and/or tryglicerides are normalized or when diarrhoea is mild

Official Title
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A Randomised, Double Blind, Placebo Controlled Study to Evaluate the Micro-macroscopic Effects on Muscles, the Safety and Tolerability, and the Efficacy of Givinostat in Patients With Becker Muscular Dystrophy (BMD)

Conditions
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Becker Muscular Dystrophy

Intervention / Treatment
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* Drug: givinostat
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ambulant patients with BMD diagnosis confirmed by genetic testing. Able and willing to give informed consent in writing. Able to perform 6MWT at screening with a minimum distance of 200 m and maximum distance of 450 m. If in treatment with systemic corticosteroids and/or angiotensin-converting-enzyme (ACE) inhibitor , and/or β or α adrenergic receptor blocker, 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. Patients must be willing to use adequate contraception. Contraceptive methods must be used from Randomization through 3 months after the last dose of study treatment. Exclusion Criteria: Exposure to another investigational drug within 3 months prior to the start of study treatment. Use of any pharmacologic treatment, other than corticosteroids, that might have 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. Surgery that might affect muscle strength or function within 3 months before study entry or planned surgery at any time during the study. Presence of other clinically significant disease that in the Investigator's opinion could adversely affect the safety of the patient, making it unlikely that the course of treatment or follow-up is completed, or could impair the assessment of study results. A diagnosis of other neurological diseases or presence of relevant somatic disorders that are not related to BMD. Platelet count, WBC count and hemoglobin at screening < Lower Limit of Normal (LLN). If laboratory screening results are < LLN, platelet count, WBC count and hemoglobin are to be repeated once, and if again < LLN become exclusionary. Symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction < 50% at screening or with heart transplant. Current liver disease or impairment, including but not limited to elevated total bilirubin (> 1.5 x ULN), unless secondary to Gilbert's disease or pattern consistent with Gilbert's disease. Inadequate renal function, as defined by serum Cystatin C > 2 x the upper limit of normal (ULN). If the value is > 2 x ULN, serum Cystatin C will be repeated once, and if again > 2 x ULN becomes exclusionary. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening. Baseline corrected 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). Current psychiatric illness/social situations rendering the potential patient unable to understand and comply with the muscle function tests and/or with the study protocol procedures. Hypersensitivity to the components of study medication. Sorbitol intolerance or sorbitol malabsorption, or the hereditary form of fructose intolerance. Contraindications to muscle biopsy. Contraindications to MRI/MRS (e.g., claustrophobia, metal implants, or seizure disorder). Hypertrygliceridemia (<1.5 per upper limit of normal)* * at screening, patient with hypertrygliceridemia can be enrolled if in stable treatment and with controlled level of tryglicerides (i.e. within normal range) for at least 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: givinostat<br>Givinostat oral suspension (10 mg/mL) twice daily in a fed state | Drug: givinostat<br>* suspension of givinostat (10 mg/mL)<br>* Other names: Active Comparator: givinostat;|
| Placebo Comparator: placebo<br>Placebo oral suspension (10 mg/mL) twice daily in a fed state | Drug: placebo<br>* suspension manufactured to mimic givinostat<br>* Other names: Placebo Comparator: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in total fibrosis (%) | Mean change in total fibrosis (%) comparing the histology of muscle biopsies before and after 12 months of treatment with givinostat versus placebo | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in fat fraction of vastus lateralis and soleus | Evaluation will be performed comparing Magnetic Resonance Spectroscopy (MRS) before and after 12 months of treatment with givinostat versus placebo. | 12 months | 
| Mean change in fat fraction of pelvic girdle and lower limb muscles | Evaluation will be performed comparing Magnetic Resonance Imaging (MRI) before and after 12 months of treatment with givinostat versus placebo | 12 months | 
| Mean CSA of pelvic girdle and lower limb muscles | Evaluation will be performed comparing MRI before and after 12 months of treatment with givinostat versus placebo | 12 months | 
| Mean change in other histology parameters (e.g. Muscle Fibers Area Fraction [MFAF]%, % of total fibrosis, regenerative fibers) | Evaluation will be performed comparing the histology biopsies before and after 12 months of treatment with givinostat | 12 months | 
| Mean change in Motor Function Measurement (MFM) | Evaluation will be performed using the Motor Function Measurement scale before and after 12 months of treatment with givinostat versus placebo | 12 months | 
| Mean change in 6 Minute Walking Test (6MWT) | Evaluation will be performed before and after 12 months of treatment with givinostat versus placebo | 12 months | 
| Proportion of patients with < 10% worsening in 6MWT at the end of study. | Proportion of patients with < 10% worsening in 6MWT at the end of study. | 12 months | 
| Proportion of patients who lose the ability to rise from floor (Baseline through end of study). | Proportion of patients who lose the ability to rise from floor (Baseline through | 12 months | 
| Proportion of patients who lose ambulation during the study | Proportion of patients who lose ambulation during the study | 12 months | 
| Mean change in muscle strength evaluated by knee extension, elbow flexion as measured by Hand Held Myometry (HHM), | Evaluation will be performed before and after 12 months of treatment with givinostat versus placebo | 12 months | 
| Mean changes in quality of life (assessed by the 36-item Short Form survey [SF36]) | Evaluation will be performed before and after 12 months of treatment with givinostat as compared to placebo | 12 months | 
| Number of patients experiencing treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) from Baseline through end of study (EOS). | Number of patients experiencing treatment-emergent adverse events (TEAEs) | 12 months | 
| Type, incidence, and severity of TEAEs and SAEs (Baseline through EOS). | Type, incidence, and severity of TEAEs and SAEs (Baseline through EOS). | 12 months | 
| Changes from baseline to end of study of vital sign and clinical laboratory tests | number of participants with abnormal laboratory values | 12 months | 
| Changes from baseline to end of study of physical examination | number of participants with abnormal physical examination assessments | 12 months | 
| Mean change in Time Function Test | Evaluation will be performed before and after 12 months of treatment with givinostat as compared to placebo | 12 months |