Randomised, Double-blind, Placebo-controlled, Multicentre Study to Evaluate the Efficacy, Safety and Tolerability of Givinostat in Non-ambulant Patients With Duchenne Muscular Dystrophy
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 138
- 试验地点
- 29
- 主要终点
- Change of Performance of Upper Limb 2.0 (PUL) total score at 18 months of treatment of givinostat compared to placebo group.
研究概览
简要总结
This is a randomised, double-blind, placebo-controlled, multicentre study to evaluate the efficacy, safety, and tolerability of givinostat in non-ambulant male paediatric (aged 9 to <18 years) patients with DMD. 138 patients will be randomised 2:1 to givinostat or placebo and will be treated for 18 months.
- Planned screening duration: approximately 4 weeks (±14 days)
- Planned treatment duration: 18 months (approximately 72 weeks)
- Planned follow-up duration: 4 weeks (±7 days) (for patients not participating in the long-term safety study)
- Total duration of study participation: up to 83 weeks (ie, 20-21 months)
详细描述
Duchenne muscular dystrophy is a rare, progressive, debilitating and life-threatening condition for which there is a critical need for novel therapies that are effective and well-tolerated in all DMD patients. Steroids are generally recognised as the standard of care in the general DMD population; however, they are not suitable for all patients.
Givinostat, a HDAC inhibitor, was developed for the treatment of DMD based on: (i) the role that increased HDAC activity is thought to exert in contributing to DMD pathogenesis; and (ii) givinostat's ability to counter the pathophysiological and degenerative mechanisms causing muscle insufficiency in boys with DMD.
This study will evaluate the efficacy, safety, and tolerability of givinostat in non-ambulant patients to further corroborate data from the completed phase 3 pivotal study of givinostat in ambulant patients with DMD (ie, Study DSC/14/2357/48, NCT02851797). Primary Objective of the study is to demonstrate the efficacy of givinostat in reducing muscle decline in non-ambulant DMD patients, as measured by Performance of the Upper Limb (PUL) 2.0. Secondary Objectives of the study are to evaluate the safety and tolerability of givinostat in non-ambulant DMD patients, and to further explore the efficacy of givinostat in non-ambulant DMD patients.
A total of 138 patients are planned for enrolment. Patients will be randomised 2:1 to givinostat or placebo and will be treated for 18 months.
The study will be comprised of:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 9 Years 至 17 Years（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Patients must satisfy all the following criteria:
- •Children and adolescent males aged ≥ 9 to <18 years at screening (patients ≥ 18 years of age at screening will not be enrolled into the study)
- •Are able to give informed assent and/or consent in writing signed by the patient and/or parent/legal guardian (according to local regulations)
- •A genetic diagnosis of DMD
- •Non-ambulant, defined as being wheelchair bound and:
- •Unable to perform the 10-meter walk/run test (10MWT), or
- •Unable to complete the 10MWT in 30 seconds or less, without any support or devices
- •Performance of the Upper Limb test (PUL version 2.0) entry item scores 3 to 6
- •If on medication for DMD-associated cardiomyopathy (eg, ACE inhibitor, β-blocker, diuretics), stable for ≥1 month immediately prior to start of study treatment, if any
- •Stable corticosteroids, defined as:
- •Receiving systemic corticosteroids for a minimum of 6 months immediately prior to start of study treatment
- •No significant change in dose or dosing regimen (except for adjustments due to body weight change) for a minimum of 6 months immediately prior to start of study treatment
- •Willing to use adequate contraception. Effective contraceptive methods must be used from randomisation visit through 3 months after the last dose of study drug, and include the following:
- •True abstinence (ie, absence of any sexual intercourse), when in line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, post-ovulation, and symptothermal methods) and withdrawal are not acceptable methods of contraception
- •Condom with spermicide and the female partner must use an effective method of contraception, such as an oral, transdermal, injectable or implanted hormonal contraceptive; intrauterine device; bilateral tubal occlusion, or a diaphragm or a barrier method of contraception in conjunction with spermicidal jelly such as for example cervical cap with spermicide jelly.
排除标准
- •Patients will be excluded from the study if they satisfy any of the following criteria:
- •1. Exposure to another investigational drug within 3 months prior to start of study treatment.
- •2. Have exposure to any dystrophin restoration product (eg, Ataluren, Exon skipping) within 6 months prior to the start of study treatment
- •3. Having received any gene therapy (eg, AAV Micro-dystrophin delivery) prior to start of study treatment
- •4. Use of any pharmacologic treatment or supplement (other than corticosteroids), that might have had an effect on muscle strength or function within 3 months prior to the start of study treatment (eg, growth hormone); vitamin D, calcium and any other supplements will be allowed
- •5. Use of testosterone, unless used as a replacement therapy for the treatment of delayed puberty. The testosterone dose and regimen should be stable within 6 months prior to the start of study treatment, and circulating testosterone levels should be within the normal ranges for the patient's age
- •6. Elbow-flexion contractures \>30° in the dominant arm
- •7. Inability to perform consistent PUL 2.0 measurement within ±2 points without shoulder domain or within ±3 points with shoulder domain during paired testing at screening
- •8. Forced Vital Capacity % of predicted \<40%
- •9. Requirement for daytime ventilator assistance (Note: Night ventilator assistance and use of bi-level positive airway pressure therapy is allowed)
- •10. Episode of respiratory failure within the 8 weeks prior to screening
- •11. Symptomatic cardiomyopathy or heart failure and/or left ventricular ejection fraction \<45%
- •12. Baseline corrected QT interval using Fredericia's formula (QTcF) \>450 msec (as the mean of 3 consecutive readings 5 minutes apart) or history of additional risk factors for torsades de pointes (eg, heart failure, hypokalaemia, or family history of long QT syndrome)
- •13. Major surgical procedure (including scoliosis surgery) planned within 1 year of the start of study treatment
- •14. Poorly controlled asthma or underlying lung disease such as bronchitis, bronchiectasis, emphysema, recurrent pneumonia that in the opinion of the Investigator might impact respiratory function
- •15. Platelets, white blood cells, and/or haemoglobin \< lower limit of normal (LLN) at screening (Note: for abnormal screening laboratory test results \[\300 mg/dL (3.42 mmol/L) at screening (Note: if the value is \>300 mg/dL, the triglycerides will be repeated once; if the repeated test result is still \>300 mg/dL, the patient should be excluded)
- •17. Current or history of liver disease or impairment, including but not limited to a baseline elevated total bilirubin (ie, \>1.5 × upper limit of normal \[ULN\]), unless secondary to Gilbert disease or pattern consistent with Gilbert disease
- •18. Inadequate renal function, as defined by serum Cystatin C result \>2 × ULN (Note: if the value is \>2 × ULN, the serum Cystatin C will be repeated once; if the repeated test result is still \>2 × ULN, the patient should be excluded)
- •19. Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus at screening
- •20. Hypersensitivity to any component of study medication
- •21. Sorbitol intolerance or malabsorption, or have the hereditary form of fructose intolerance
- •22. Diagnosis of other uncontrolled neurological diseases or presence of relevant uncontrolled somatic disorders that are not related to DMD, based on Investigator judgement
- •23. Psychiatric illness or social situations rendering the potential patient unable to understand and comply with the muscle function tests and/or with the study protocol procedures, based on Investigator judgement
- •24. Have contraindications to MRI scan (eg, claustrophobia, metal implants, or uncontrolled seizure disorder), based on Investigator's judgement.
研究组 & 干预措施
Placebo
Patients will receive concomitant corticosteroid treatment as part of the standard of care.
干预措施: Placebo (Drug)
Givinostat
Patients will receive concomitant corticosteroid treatment as part of the standard of care.
干预措施: Givinostat (Drug)
结局指标
主要结局
Change of Performance of Upper Limb 2.0 (PUL) total score at 18 months of treatment of givinostat compared to placebo group.
时间窗: Baseline and 18 months
The PUL examines 3 major "dimensions" of upper extremity function: shoulder, middle, and distal functions. It includes 22 scored items; a score of 42 (12 for shoulder; 17 for mid-level, and 13 for distal) indicates the highest level of independent function and 0 the lowest.
次要结局
- Change from baseline of Peak Expiratory Flow percent predicted (PEF%p) at 18 months of treatment of givinostat compared to placebo group(Baseline and 18 months)
- Change from baseline of Forced Vital Capacity percent predicted (FVC%p) at 18 months of treatment of givinostat compared to placebo group(Baseline and 18 months)
- Cumulative loss of PUL total score over 18 months of treatment of givinostat compared to placebo group.(Baseline to 18 months)
- Type, incidence, and severity of treatment-emergent adverse events(Baseline to 18 months)
- Proportion of patients experiencing treatment-emergent adverse events(Baseline to 18 months)
- Change from baseline vital signs and clinical laboratory tests(Baseline and 18 months)
- Change from baseline electrocardiogram and echocardiogram(Baseline and 18 months)
- Time to assisted ventilation and rate of respiratory infection including duration, severity of respiratory infection and use of antibiotics, of givinostat compared to placebo group.(Baseline to 18 months)