Long-term Safety, Tolerability, and Efficacy Evaluation of Givinostat in Duchenne Muscular Dystrophy Patients Previously Enrolled in Givinostat Trials

Trial ID: 2023-504520-26-00
Protocol: DSC/14/2357/51
Sponsor: Italfarmaco S.p.A.

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Diseases & Conditions

Duchenne muscular dystrophy

Objectives

The primary objective of this study is to assess the long-term **safety** and tolerability of GIVINOSTAT in patients with Duchenne Muscular Dystrophy (DMD). This evaluation is crucial as it ensures that the therapeutic benefits of GIVINOSTAT do not come at the expense of patient safety, particularly in a chronic condition like DMD where long-term treatment is often necessary. Understanding the safety profile of GIVINOSTAT will aid in determining its viability as a long-term treatment option for DMD patients.

Secondary objectives include:

Evaluating the effects of long-term administration of GIVINOSTAT on muscular function and strength, which is significant for maintaining patient mobility and independence.
Assessing the effects on respiratory function, a critical aspect given the progressive nature of DMD affecting respiratory muscles.
Determining the impact on daily activities and quality of life, which are essential measures of treatment success from a patient-centered perspective.

Participants

The clinical trial involves a total of **102 participants** diagnosed with **Duchenne Muscular Dystrophy (DMD)**. The study population consists exclusively of male subjects, aged 6 years and older, who have either participated in previous studies with GIVINOSTAT or were screened in study DSC/14/2357/48. These participants are characterized by their ability to provide informed assent or consent, as per local regulations, and are required to adhere to specific contraceptive measures throughout the study duration and for three months following the last dose of the study drug. The trial population was selected based on their previous involvement in related studies and specific baseline muscle fat fraction criteria. Participants are expected to maintain their usual lifestyle, with true abstinence being an acceptable form of contraception if it aligns with their lifestyle. The study does not include female subjects and focuses on a vulnerable population, given the nature of the condition being studied.

Plans and Procedures

The clinical trial is designed to evaluate the long-term safety, tolerability, and efficacy of **givinostat** in patients with **Duchenne Muscular Dystrophy (DMD)** who have previously participated in one of the givinostat studies. This is an open-label, phase III study, where all participants will receive the investigational drug, ITF2357, administered as an oral suspension. The trial is expected to run from July 2017 to December 2027, with the primary objective of assessing the type, incidence, and severity of treatment-related and unrelated adverse events (AEs) and serious adverse events (SAEs).

Participants eligible for inclusion must have either completed a previous givinostat study or been screened in study DSC/14/2357/48, meeting all inclusion criteria without any exclusion criteria. The study will involve multiple visits, starting with a screening visit to confirm eligibility. Follow-up visits will occur at week 48 and then annually until the study's conclusion. These visits will assess changes in physical function, muscle strength, respiratory function, and quality of life, using various measures such as the 6-Minute Walk Test (6MWT), North Star Ambulatory Assessment (NSAA), and Performance of Upper Limb (PUL).

The expected duration of participant involvement is approximately ten years, with conditions for early termination including withdrawal of consent, non-compliance with study procedures, or the occurrence of significant adverse events. Participants are required to use adequate contraception throughout the study and for three months after the last dose of the study drug. The study aims to provide comprehensive data on the long-term effects of givinostat in DMD patients, contributing valuable insights into the management of this rare disease.

Treatment

The clinical trial involves the administration of **GIVINOSTAT**, an experimental medication, under the product name ITF2357. GIVINOSTAT is formulated as an **oral suspension** and is administered via the oral route. The maximum daily dose of GIVINOSTAT is 140 mg, and the treatment period is limited to a maximum of one day. The active substance, GIVINOSTAT, is of chemical origin and is classified as an orphan drug, with the designation number EU/3/12/1009. The pharmaceutical form of the medication is specifically designed for oral use, and it is not a pediatric formulation. The medication is provided by ITALFARMACO SPA.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on the administration of GIVINOSTAT to assess its long-term safety, tolerability, and efficacy in patients with Duchenne Muscular Dystrophy (DMD) who have previously participated in GIVINOSTAT studies. Participant compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen. The trial is open-label, allowing for direct observation of the effects of GIVINOSTAT in the study population.

Efficacy

The efficacy of GIVINOSTAT in patients with Duchenne Muscular Dystrophy (DMD) will be assessed through a series of secondary endpoints designed to evaluate changes in physical and respiratory functions, muscle strength, and quality of life. For ambulant patients, efficacy will be measured by changes from baseline in physical function using the 6-Minute Walk Test (6MWT), North Star Ambulatory Assessment (NSAA), and time function tests such as time to rise from the floor, time to climb four stairs, and time to complete a 10-meter walk. These assessments will occur at week 48 and then annually until the end of the study. Muscle strength in ambulant patients will be evaluated through knee extension and elbow flexion using handheld myometry (HHM) at the same intervals.

For non-ambulant patients, changes in physical function will be assessed using the Egen Klassifikation (EK) score, and activities of daily living will be evaluated through patient and/or parent/caregiver reports using the Barthel Index. Upper limb muscle strength in non-ambulant patients will also be measured by HHM. For all patients, changes from baseline in physical function will be assessed using the Performance of Upper Limb (PUL) and Motor Function Measure (MFM), while respiratory function will be evaluated through parameters such as Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 second (FEV1), and Peak Expiratory Flow (PEF). Additionally, quality of life will be measured using the Pediatric Quality of Life Inventory (PedsQL) for pediatric patients and the SF-36 for adult patients. These assessments will be conducted at week 48 and then annually until the study concludes.

Furthermore, the study will track the age at which patients reach major disease milestones, including the age at loss of ambulation, the age at which respiratory support is needed during the day, the age at scoliosis surgery, and the age at death. These comprehensive assessments will provide a detailed evaluation of the long-term efficacy of GIVINOSTAT in managing DMD.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subjects must have participated in one of the previous studies with GIVINOSTAT in DMD and have attended the End of Study Visit or must have been screened in study DSC/14/2357/48 and met: all the inclusion criteria and none of the exclusion criteria, had a baseline vastus lateralis muscle fat fraction (VL MFF) assessed by MRS in the range ≤5% or >30%, i.e. included in "off-target" group, never been randomized because the enrollment in the off-target group was completed
Subjects aged ≥6 years
Subjects 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: Contraceptive methods must since the previous GIVINOSTAT study through 3 months after the last dose of study drug, and include the following: -True abstinence (absence of any sexual intercourse), when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. -Condom with spermicide and the female partner must use 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 for example cervical cap with spermicide jelly.

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Exclusion Criteria

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 uncontrolled neurological diseases or presence of relevant uncontrolled 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 (
Have Triglycerides > 300 mg/dL (3.42 mmol/L) in fasting condition at screening visit* (for abnormal screening laboratory test results (>300mg/dl), the triglycerides will be repeated once; if the repeat test result is still >300mg/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 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

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	03 Jul 2017	9
France	Recruiting	03 Jul 2017	11
Germany	Recruiting	03 Jul 2017	13
Italy	Recruiting	03 Jul 2017	58
The Netherlands	Recruiting	03 Jul 2017	—
Spain	Recruiting	03 Jul 2017	5
Netherlands	—	—	24