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

NCT03238235 | Completed Phase 2 Results

• 2 other identifiers: DSC/15/2357/532017-001629-41
• Study Type: interventional
• Target: 51
• Locations: 2 countries
• Sites: 2

Brief Summary

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.

Conditions

Becker Muscular Dystrophy

Keywords

Givinostat; Becker Dystrophy

Outcome Measures

Primary Outcomes (1)

• Mean Change From Baseline to Visit 11 in Total Fibrosis (%) on Log Scale, Comparing the Histology of Muscle Biopsies

  The primary efficacy assessment was the mean total fibrosis (%) on log scale assessed through histological examination of bicep muscle biopsies at two timepoints (At baseline and at Visit 11). More particularly, patients underwent two biopsies of muscle from the brachial biceps: the first before starting the study treatment (Visit 2, baseline), and the second at the end of treatment (Visit 11). For each patient, the percentage of total fibrosis was calculated as log of the least square mean of the available fields at each evaluation.

  after 12 months of treatment (at Visit 11)

Secondary Outcomes (24)

• Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Vastus Lateralis and Soleus

  after 12 months of treatment (at Visit 11)

• Mean Change From Baseline to Visit 11 in the Percentage of Fat Fraction of Lower Limb Muscles

  after 12 months of treatment (at Visit 11)

• Mean Change From Baseline to Visit 11 in Cross-sectional Area (CSA), in cm2 of Lower Limb Muscles

  after 12 months of treatment (Visit 11)

• Mean Change From Baseline to Visit 11 in Contractile Area of Lower Limb Muscles (MRI)

  after 12 months of treatment

• Mean Change From Baseline to Visit 11 in Biopsy Histology Parameters: CSA by Type (I or II Fibers), Total CSA

  After 12 months of treatment (Visit 11)

Study Arms (2)

Givinostat

EXPERIMENTAL

Givinostat oral suspension (10 mg/mL) twice daily in a fed state

Drug: Givinostat

Placebo

PLACEBO COMPARATOR

Placebo oral suspension (10 mg/mL) twice daily in a fed state

Drug: Placebo

Interventions

Givinostat DRUG

suspension of Givinostat (10 mg/mL)

Also known as: ITF2357

Givinostat

Placebo DRUG

suspension manufactured to mimic Givinostat

Also known as: Placebo Comparator: placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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) was to be presented for a minimum of 6 months prior to start of study treatment.
• 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.

You may not qualify if:

• Exposure to another investigational drug within 3 months prior to the start of study treatment.
• 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.
• Surgery that could have affected 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 have adversely affected the safety of the patient or could have impaired the assessment of study results.
• 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.
• 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 upper limit of normal \[ULN\]), unless secondary to Gilbert's disease or pattern consistent with Gilbert's disease.
• Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening.
• 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).
• 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.
• Hypersensitivity to the components of the study medication.
• Sorbitol intolerance or sorbitol malabsorption, or the hereditary form of fructose intolerance.
• Contraindications for muscle biopsy.
• Contraindications forMRI/MRS (e.g., claustrophobia, metal implants or seizure disorders).
• 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.

Sponsors & Collaborators

• Italfarmaco: lead

Study Sites (2)

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

Milan, 20122, Italy

Location

Leiden University Medical Center LUMC

Leiden, ZH 2300 RC, Netherlands

Location

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Interventions

givinostat; givinostat hydrochloride

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Maurizio Caserini, MD
• Organization: Italfarmaco SpA

m.caserini@italfarmacogroup.com

+ 39 02 64431

Study Officials

• Giacomo Comi, MD

  Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Placebo was indistinguishable from the active product in color, appearance, smell and taste. Personnel involved in the study (Investigators, nurses, all other site personnel, clinical research associates \[CRA\], medical monitors, project managers, data managers and statisticians) were blinded at all times unless knowledge of the study treatment was necessary for the patient's safety.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2017
• First Posted: August 3, 2017
• Study Start: January 9, 2018
• Primary Completion: March 19, 2021
• Study Completion: March 19, 2021
• Last Updated: November 18, 2024
• Results First Posted: November 18, 2024

Record last verified: 2024-03

Locations

NL (1); IT (1)