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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 4
- 主要终点
- 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.
研究概览
简要总结
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)
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 7 Years 至 11 Years（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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.
研究组 & 干预措施
Givinostat
Givinostat will be administered as 2 oral doses daily while the child is in fed state.
干预措施: Givinostat (Drug)
结局指标
主要结局
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.
时间窗: After12 months of treatment
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.
次要结局
- 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)(At 12 months)
- Change From Baseline to End of Study in Cross Sectional Area (CSA)(At 12 months)
- Change From Baseline to End of Study in Fibrosis, Necrosis, Fatty Replacement(After 12 months)
- Change From Baseline to End of Study in Number of Hypercontracted Fibers(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(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)(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(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)(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)(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(Part 1, Part 2, and Extensions 1, 2, and 3)