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

Objectives:

Primary objective: to establish the histological effects of Givinostat versus placebo administered over 12 months.

Secondary Objectives:

* To establish the macroscopic muscle effects of Givinostat versus placebo administered over 12 months assessed by Magnetic Resonance Imaging (MRI)/Magnetic Resonance Spectroscopy (MRS).
* To determine the other histological effects of Givinostat versus placebo administered over 12 months.
* To establish the efficacy of Givinostat versus placebo administered chronically over 12 months in slowing disease progression.
* To assess the safety and tolerability of Givinostat versus placebo administered chronically.
* To evaluate the pharmacokinetic (PK) profile of Givinostat administered chronically in the target population.
* To evaluate the impact of Givinostat versus placebo administered chronically on quality of life and activities of daily living.

This was a phase 2, randomised, double-blind, placebo-controlled study. Eligible patients were randomized in a 2:1 ratio to receive Givinostat or placebo for 12 months. Randomization was stratified by concomitant steroid use at baseline (yes or no). The study comprised twelve (12) visits: screening (V1, V2), randomization (V3), treatment (V4-V10), end of study (V11) and follow-up (V12). Visits during treatment took place every 12 weeks, except for the first 2 months, when they occurred every 2 weeks to allow closer monitoring of safety.

Givinostat (ITF2357) oral suspension (10 mg/mL) was initially administered as 2 daily doses of 40-70 mg according to body weight after a meal (high dose). With amendment 2 of the protocol, a lower starting dose was implemented to address cases of thrombocytopenia reported following the treatment of the first 21 patients and corresponded to the reduced dose of the original protocol (i.e., 26.7-46.7 mg b.i.d according to body weight, i.e., low dose).

51 patients were to be enrolled to provide a sample size of 48 patients with evaluable baseline biopsies. Seventy patients provided written informed consent, 51 (72.86%) completed screening successfully and were randomized; 34 patients (66.67%) to the Givinostat group and 17 (33.33%) to the placebo group.

Eligibility Criteria:
Inclusion Criteria:

1. Ambulant patients with BMD diagnosis confirmed by genetic testing.
2. Able and willing to give informed consent in writing.
3. Able to perform 6MWT at screening with a minimum distance of 200 m and maximum distance of 450 m.
4. 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) was to be presented for a minimum of 6 months prior to start of study treatment.
5. Patients had to be willing to use adequate contraception from randomization until 3 months after the last dose of study treatment, and included the following:

   * True abstinence when in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar ovulation, symptothermal, post ovulation methods) and withdrawal were not acceptable methods of contraception.
   * Condom with spermicide, with the female partner using 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 a cervical cap with spermicide jelly.

Exclusion Criteria:

1. Exposure to another investigational drug within 3 months prior to the start of study treatment.
2. Use of any pharmacological treatment, other than corticosteroids, that could have affected muscle strength or function within 3 months prior to the start of study treatment (e.g., growth hormone). vitamin D, calcium, and other supplements were allowed.
3. Surgery that could have affected muscle strength or function within 3 months before study entry or planned surgery at any time during the study.
4. Presence of other clinically significant disease that in the Investigator's opinion could have adversely affected the safety of the patient or could have impaired the assessment of study results.
5. A diagnosis of other uncontrolled neurological diseases or presence of relevant somatic disorders not related to BMD that could have interfered with the ability to perform the muscle function tests and/or to comply with the study protocol procedures.
6. Platelet count, white blood cell (WBC) count and hemoglobin at screening less than the lower limit of normal (LLN). If laboratory screening results were \< LLN, platelet count, WBC count and hemoglobin were to be repeated once, and if again \< LLN became exclusionary.
7. 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.
8. Current liver disease or impairment, including but not limited to elevated total bilirubin (\>. 1.5 x upper limit of normal \[ULN\]), unless secondary to Gilbert's disease or pattern consistent with Gilbert's disease.
9. Inadequate renal function defined by serum cystatin C \> 2 x ULN. If the value was \> 2 x ULN, serum Cystatin C was to be repeated once, and if again \> 2 x ULN became exclusionary.
10. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening.
11. Baseline corrected QT interval using 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).
12. Current psychiatric illness/social situations rendering the patient unable to understand or comply with the muscle function tests and/or with the study protocol procedures.
13. Hypersensitivity to the components of the study medication.
14. Sorbitol intolerance or sorbitol malabsorption, or the hereditary form of fructose intolerance.
15. Contraindications for muscle biopsy.
16. Contraindications forMRI/MRS (e.g., claustrophobia, metal implants or seizure disorders).
17. Hypertriglyceridemia (˃ 1.5 x ULN). At screening, patients with hypertriglyceridemia could be enrolled if on stable treatment and with controlled levels of triglycerides (i.e., within normal range) for at least six months.