A Study to Assess Safety/Tolerability, pk, Effects on Histology, Clinical Parameters of Givinostat in Children With DMD

Study Overview
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Brief Summary
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The primary objective of Parts 1 and 2 of the study were to establish the histologic effects of givinostat administered chronically at the selected daily dose. The secondary objectives of Parts 1 and 2 of the study were as follows: To establish the effects of givinostat administered chronically at the selected daily dose on functional parameters, such as the 6-Minute Walk Test (6MWT), North Star Ambulatory Assessment (NSAA), and performance of upper limb (PUL) To establish the safety and tolerability of givinostat administered chronically at the selected daily dose in children with Duchenne muscular dystrophy (DMD) To explore the effects of givinostat administered chronically at the selected daily dose on parameters such as magnetic resonance imaging (MRI) and biomarkers To explore the acceptability/palatability of the oral suspension To explore whether the effects of givinostat on disease progression may be related to the type of DMD mutation. The primary objective of the Extension of the study was to evaluate the safety and tolerability of long-term administration of givinostat administered chronically at the selected daily dose in children with DMD. The secondary objectives of the Extensions were: To establish the effects of givinostat administered chronically at the selected daily dose on muscular functional parameters, such as the 6MWT, NSAA, and PUL (Extensions 1, 2, and 3) To explore the effects of givinostat administered chronically at the selected daily dose on parameters such as MRI (Extension 1) To collect information related to 2 biomarkers, latent Transforming growth factor β (TGFβ) binding protein 4 (LTBP4) and osteopontin genotype (at the beginning of Extension 2 only) To collect information related to time to wheelchair and how much time the children spend in wheelchair (Extension 3 - only for the children who were not able to complete the 6MWT)

Detailed Description
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This is a 2-part, phase II study to assess the effects of Givinostat on muscle histologic parameters and on clinical parameters in ambulant children with DMD. The safety, tolerability, and pharmacokinetics of Givinostat will also be assessed. Approximately 20 children were to be enrolled in the study as follows: the first 4 children were to be treated at a low dose level of givinostat (25 mg twice daily [BID] in children who weighed 20 kg to 49 kg and 37.5 mg BID in children who weighed ≥ 50 kg). If none of the stopping criteria were met after 2 weeks of treatment at the low dose, the review team was to determine the escalated dose level (ie, intermediate dose level) to be used for the treatment of an additional 8 children who were to be treated at the intermediate dose. The 4 children previously treated at the low dose level were also switched to the intermediate dose level. If none of the stopping criteria were met after 2 weeks of treatment at the intermediate dose, the review team was to determine the subsequent escalated dose level to be used for the treatment of an additional 8 children who were to be treated at the high dose. All children treated at the intermediate dose level were to be switched to the high dose level. Once all 20 children enrolled during Part 1 of the study had been treated for at least 2 weeks, the review team was to determine the recommended dose (RD) to be used in Part 2 based on the safety and tolerability profile observed and on the pharmacokinetic (PK) analyses. All the children enrolled were switched to the RD level (37.5 mg BID), which was administered for the subsequent 12 months of the study (Part 2). At the end of Part 2 of the study, parents were asked to consent and patients to assent to continuing their participation in the Extension to receive the study treatment at least until the final analysis was performed (Part 3-Extensions; after 52 months of treatment). The patients received givinostat at the same ongoing dose, during the last visit planned at 12 months, and were treated for additional 40 months (Extensions 1, 2, and 3 up to month 52).

Official Title
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A Two-Part Study to Assess the Safety and Tolerability, Pharmacokinetics, and Effects on Histology and Different Clinical Parameters of Givinostat in Ambulant Children With Duchenne Muscular Dystrophy

Conditions
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Duchenne Muscular Dystrophy (DMD)

Intervention / Treatment
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* Drug: Givinostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male children aged 7 to <11 years with an immunohistochemical and molecular diagnosis of DMD. A parent/guardian and child can comply with all study evaluations/procedures and return for all study activities. Able to complete the 2 screening 6MWTs with a minimal distance of at least 250 m each. In addition, the results of these tests must be within ±30 m of each other. On a stable dose of systemic corticosteroids for at least 6 months. At least 6 months worth of data on the 6MWT (this will be the historical 6MWT). From the moment of the historical 6MWT assessment(s), the child must not have received any compound that could potentially affect the 6MWT, with the exception of the stable steroid treatment. Parent/guardian has signed the informed consent form and child has assented to be in the study (if applicable). Exclusion Criteria: Initiation of systemic corticosteroid therapy within 6 months prior to the start of study drug or change in systemic corticosteroid therapy (e.g., initiation, change in type of drug, dose modification not related to body weight change, schedule modification, interruption, discontinuation, or re initiation) within 6 months prior to the start of study drug. Use of any pharmacologic treatment, other than corticosteroids, that might have an effect on muscle strength since the time of the historical 6MWT and in any case within 3 months prior to the start of study treatment (e.g., growth hormone). Vitamin D, calcium, and integrators will be allowed. Surgery that might have an effect on muscle strength or function within 3 months before study entry or planned surgery at any time during the study. Exposure to another investigational drug since the time of the historical 6MWT and in any case within 3 months prior to the start of study treatment. History of participation in gene therapy, cell-based therapy or oligonucleotide therapy. Presence of other clinically significant disease that in the opinion of the investigator places the child in unacceptable risk for an adverse outcome or that could affect study results. Symptomatic cardiomyopathy or heart failure. If child has a left ventricular ejection fraction <45% at screening, the investigator should discuss inclusion of child in the study with the medical monitor. Inadequate hematological function Absolute neutrophil count: <1.5 x 109/L Platelets: <100 x 109/L Current or history of liver disease or impairment, including but not limited to an elevated total bilirubin. Inadequate renal function, as defined by serum creatinine >2 x the upper limit of normal. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening A baseline QTc >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, family history of long QT syndrome). Psychiatric illness/social situations rendering the potential child unable to understand and comply with the study protocol.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 11 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Givinostat<br>Givinostat will be administered as 2 oral doses daily while the child is in fed state. | Drug: Givinostat<br>* Givinostat, oral suspension 10 mg/mL or oral capsules 50 mg, administered orally under fed conditions at the dose of 25 mg BID, 37.5 mg BID, and 50 mg BID during Part 1 for two weeks, and 25 mg BID and 37.5 mg BID during Part 2 for 12 months. Givinostat, oral suspension 10 mg/mL, administered orally under fed conditions at the dose of 25 mg BID or 37.5 mg BID during Extension 1, and modified as per patient's weight during Extensions 2 and 3 (up to 52 months).<br>* Other names: ITF2357;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Part 2 in the Value of Muscle Fiber Area (MFA) % Comparing the Histology Biopsies Before and After 12 Months of Treatment With Givinostat. | The primary endpoint was the change in histology comparing the brachial biceps biopsies before and after ≥12 months of treatment with Givinostat. Muscle biopsies: A first brachial biceps biopsy (baseline) was taken prior to the first dose of study drug. A second brachial biceps biopsy was taken at Visit 10 (12 months) from the opposite arm. The muscle biopsy samples from the biceps muscle were collected by open biopsy. The minimum amount of muscle tissue required was a piece of muscle of at least 0.5 × 0.5 × 0.5 cm. | After12 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End of Study in Cross Sectional Area (CSA) | This histological parameter was evaluated on the brachial biceps biopsies taken prior to the first dose of study drug and after 12 months of treatment with givinostat. | At 12 months | 
| Change From Baseline to End of Study in Fibrosis, Necrosis, Fatty Replacement | These histological parameters were evaluated on the brachial biceps biopsies taken prior to the first dose of study drug and after 12 months of treatment with givinostat. | After 12 months | 
| Change From Baseline to End of Study in Number of Hypercontracted Fibers | This histological parameter was evaluated on the brachial biceps biopsies taken prior to the first dose of study drug and after 12 months of treatment with givinostat. The number of fibers is calculated per microscopic field (20x). | At 12 months | 
| Change From Baseline in Muscular Function After 12 Months of Treatment With Givinostat at the Selected Daily Dose Based on the 6-Minute Walk Test | This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes. The 6-Minute Walk Test is a useful measure of functional capacity targeted at people with at least moderately severe impairment. The longer the walked distance the better the outcome. | At 12 months | 
| Change From Baseline in Muscular Function After 12 Months of Treatment With Givinostat at the Selected Daily Dose Based on the North Star Ambulatory Assessment (NSAA) | The NSAA, which is composed by 17 items, was graded, for each item, using the standard scorecard with each assessment rated as 0 - unable to achieve independently, 1 - modified method but achieves goal independent of physical assistance from another, or 2 - normal with no obvious modification of activity. The subscales scores are summed up to compute a total score, ranging from 0 to 34. The higher the total score, the better the outcome. The mean Change From Baseline to EoS in NSAA total score is reported hereunder. | At 12 months | 
| Change From Baseline in Muscular Function After 12 Months of Treatment With Givinostat at the Selected Daily Dose Based on the Performance of Upper Limb (PUL) | The PUL (version 1.2) was used to assess the change in motor performance of the upper limb over time in patients with Becker and Duchenne muscular dystrophy, from when they are still ambulant, until they loose all arm function when non-ambulant. The revised version of the PUL included 22 items. These include one entry item to define the starting functional level, and 21 items subdivided into: shoulder level (Question B to E; minimum score 0 and maximum score 16) elbow level (Question F to N; minimum score 0 and maximum score 34) distal level dimension (Question O to V; minimum score 0 and maximum score 24) The total score is calculated by the sum of all the scores of the three subscales (total score range: 0-74) (scores from Question A entry item did not contribute). For all items, the higher the score, the better the outcome. | At 12 months | 
| Change From Baseline in Muscular Function After After 24 (Extension 1), 36 (Extension 2), and 52 Months (Extension 3) of Treatment With Givinostat at the Selected Daily Dose Based on the 6-Minute Walk Test | This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes. The 6-Minute Walk Test is a useful measure of functional capacity targeted at people with at least moderately severe impairment. The longer the walked distance the better the outcome. | At 24, 36, and 52 months | 
| Change From Baseline in Muscular Function After 24 (Extension 1), 36 (Extension 2), and 52 Months (Extension 3) of Treatment With Givinostat at the Selected Daily Dose Based on the North Star Ambulatory Assessment (NSAA) | The NSAA, which is composed by 17 items, was graded, for each item, using the standard scorecard with each assessment rated as 0 - unable to achieve independently, 1 - modified method but achieves goal independent of physical assistance from another, or 2 - normal with no obvious modification of activity. The subscales scores are summed up to compute a total score, ranging from 0 to 34. The higher the total score, the better the outcome. The mean Change From Baseline to EoS in NSAA total score is reported hereunder. | At 24, 36, and 52 months | 
| Change From Baseline in Muscular Function After 24 (Extension 1), 36 (Extension 2), and 52 Months (Extension 3) of Treatment With Givinostat at the Selected Daily Dose Based on the Performance of Upper Limb (PUL) | The PUL (version 1.2) was used to assess the change in motor performance of the upper limb over time in patients with Becker and Duchenne muscular dystrophy, from when they are still ambulant, until they loose all arm function when non-ambulant. The revised version of the PUL included 22 items taking. These include one entry item to define the starting functional level, and 21 items subdivided into: shoulder level (Question B to E; minimum score 0 and maximum score 16) elbow level (Question F to N; minimum score 0 and maximum score 34) distal level dimension (Question O to V; minimum score 0 and maximum score 24) The total score is calculated by the sum of all the scores of the three subscales (total score range: 0-74) (scores from Question A entry item did not contribute). For all items, the higher the score, the better the outcome. | At 24, 36, and 52 months | 
| Number of Children Experiencing Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Type and Severity of TEAEs | Summary of Treatment-emergent Adverse Events (TEAE) Reporting from Baseline to the End of Extension 3 (Month 52). In the analysis were included: Any TEAE, Any treatment-related TEAE, Any mild or moderate or severe TEAE, Any life-threatening or disabling TEAE, Any TEAE resulting in death, any serious adverse event, and Any TEAE resulting in study discontinuation. | Part 1, Part 2, and Extensions 1, 2, and 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rare disease