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

• ClinicalTrials.gov Identifier: NCT03238235
• Recruitment Status: Completed
• First Posted: August 3, 2017
• Last Update Posted: January 26, 2022
• Sponsor: Italfarmaco
• Information provided by (Responsible Party): Italfarmaco

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Becker Muscular Dystrophy	Drug: givinostat; Drug: placebo	Phase 2

Detailed Description:

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: December 12, 2017
• Actual Primary Completion Date: March 19, 2021
• Actual Study Completion Date: March 19, 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: givinostat; Givinostat oral suspension (10 mg/mL) twice daily in a fed state	Drug: givinostat; suspension of givinostat (10 mg/mL); Other Name: Active Comparator: givinostat
Placebo Comparator: placebo; Placebo oral suspension (10 mg/mL) twice daily in a fed state	Drug: placebo; suspension manufactured to mimic givinostat; Other Name: Placebo Comparator: placebo

Outcome Measures

Primary Outcome Measures :

1. Mean change in total fibrosis (%) [ Time Frame: 12 months ]
   Mean change in total fibrosis (%) comparing the histology of muscle biopsies before and after 12 months of treatment with givinostat versus placebo

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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 change) for a minimum of 6 months immediately prior to start of study treatment.
5. 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:

1. Exposure to another investigational drug within 3 months prior to the start of study treatment.
2. 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.
3. Surgery that might affect 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 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.
5. A diagnosis of other neurological diseases or presence of relevant somatic disorders that are not related to BMD.
6. 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.
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 ULN), unless secondary to Gilbert's disease or pattern consistent with Gilbert's disease.
9. 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.
10. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening.
11. 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).
12. 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.
13. Hypersensitivity to the components of study medication.
14. Sorbitol intolerance or sorbitol malabsorption, or the hereditary form of fructose intolerance.
15. Contraindications to muscle biopsy.
16. Contraindications to MRI/MRS (e.g., claustrophobia, metal implants, or seizure disorder).
17. 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

Contacts and Locations

Locations

Italy

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, UOS

Milan, Italy, 20122

Netherlands

Leiden University Medical Center LUMC

Leiden, Netherlands, ZH 2300 RC

Sponsors and Collaborators

Italfarmaco

Investigators

• Principal Investigator: Giacomo Comi, MD; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano

More Information

• Responsible Party: Italfarmaco
• ClinicalTrials.gov Identifier: NCT03238235
• Other Study ID Numbers: DSC/15/2357/53
• First Posted: August 3, 2017
• Last Update Posted: January 26, 2022
• Last Verified: January 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked