NCT03779334进行中（未招募）2 期
An Open-Label Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 26
- 试验地点
- 9
- 主要终点
- Percentage of Participants With Two Copies of the Survival Motor Neuron (SMN) 2 Gene (Excluding the Known SMN2 Gene Modifier Mutation c.859G>C) and Baseline Compound Muscle Action Potential (CMAP) >=1.5 Millivolt (mV) Who Are Sitting Without Support
研究概览
简要总结
A global study of oral risdiplam in pre-symptomatic participants with spinal muscular atrophy (SMA).
详细描述
The study is an open-label, single-arm, multicenter clinical study to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam in infants aged from birth to 6 weeks who have been genetically diagnosed with SMA but are not yet presenting with symptoms. There will be a screening, treatment, open-label extension (OLE) and a follow-up. All participants will receive risdiplam orally once daily for 2 years followed by an OLE phase of at least 3 years and a follow-up (if applicable), for a total treatment duration of at least 5 years for each participant enrolled.
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
- 1 Day 至 6 Weeks（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males and females aged from birth (1 day) to 6 weeks (42 days) of age at the time of first dose (Day 1); a minimum age of 7 days at first dose is required for the first infant to be enrolled
- •Gestational age of 37-42 weeks for singleton births; gestational age of 34-42 weeks for twins
- •Body weight >= 3rd percentile for age, using appropriate country-specific guidelines
- •Genetic diagnosis of 5q-autosomal recessive SMA, including confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the SMN1 gene
- •Absence of clinical signs or symptoms at screening (Day -42 to Day -2) or at baseline (Day -1) that are, in the opinion of the investigator, strongly suggestive of SMA
- •Receiving adequate nutrition and hydration at the time of screening, in the opinion of the investigator
- •Adequately recovered from any acute illness at baseline and considered well enough to participate in the study, in the opinion of the investigator
- •Able and expected to be able to safely travel to the study site for the entire duration of the study and in accordance to the frequency of required study visits, in the opinion of the investigator
- •Able to complete all study procedures, measurements, and visits, and the parent (or caregiver), in the opinion of the investigator, has adequately supportive psychosocial circumstances
- •Parent (or caregiver) is willing to consider nasogastric, naso-jejunal, or gastrostomy tube placement during the study to maintain safe hydration, nutrition, and treatment delivery, if recommended by the investigator
- •Parent (or caregiver) is willing to consider the use of non-invasive ventilation during the study, if recommended by the investigator
排除标准
- •Concomitant or previous participation in any investigational drug or device study at any time
- •Concomitant or previous administration of an SMN2-targeting antisense oligonucleotide, SMN2-splicing modifier, or gene therapy either in a clinical study or as part of medical care
- •Presence of significant concurrent syndromes or diseases
- •In the opinion of the investigator, inadequate venous or capillary blood access for the study procedures
- •Requiring invasive ventilation, tracheostomy or awake non-invasive ventilation
- •Awake hypoxemia (SaO2 < 95%) with or without ventilator support
- •Multiple or fixed contractures and/or hip subluxation or dislocation at birth
- •Systolic blood pressure or diastolic blood pressure or heart rate considered to be clinically significant by the investigator
- •Presence of clinically relevant ECG abnormalities before study drug administration; corrected QT interval using Bazett's method > 460 ms; personal or family history (first degree relatives) of congenital long QT syndrome indicating a safety risk for patients as determined by the investigator. First-degree atrioventricular block or isolated right bundle branch block are allowed
- •The infant (and the mother, if breastfeeding the infant) taking any inhibitor of CYP3A4 taken within 2 weeks, any inducer of CYP3A4 taken within 4 weeks, any OCT 2 and MATE substrates within 2 weeks and known FMO1 or FMO3 inhibitors or substrates
- •Clinically significant abnormalities in laboratory test results
- •Ascertained or presumptive hypersensitivity to risdiplam or to the constituents of its formulation
- •Treatment with oral salbutamol or another beta-2 adrenergic agonist taken orally for SMA is not allowed. Use of inhaled beta-2 adrenergic agonists is allowed
- •Infants exposed to drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should not be enrolled. Anticipated need for drugs known to cause retinal toxicity during the study.
- •Diagnosis of ophthalmic diseases
研究组 & 干预措施
Open-label Risdiplam
Experimental
Participants will be enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.
干预措施: Risdiplam (Drug)
结局指标
主要结局
Percentage of Participants With Two Copies of the Survival Motor Neuron (SMN) 2 Gene (Excluding the Known SMN2 Gene Modifier Mutation c.859G>C) and Baseline Compound Muscle Action Potential (CMAP) >=1.5 Millivolt (mV) Who Are Sitting Without Support
时间窗: At Month 12
The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Gross Motor Scale is a commonly used measure of infant and toddler development (0 to 42 months). The normed-scores derived from the BSID-III are used in clinical practice to detect infants with developmental delays, as well as to evaluate developmental progress and the impact of therapeutic interventions. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22, "sits without support for 5 seconds", is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. An exact binomial test was performed. If the lower limit of the two-sided 90% CI was above the 5% threshold, the primary objective of the study was considered achieved.
次要结局
- Time to Permanent Ventilation and/or Death(Up to 7 years)
- Percentage of Participants Who Meet CHOP INTEND Stopping Criteria at Any Point(Up to Month 24)
- Percentage of Participants Developing Clinically Manifested SMA(At Month 12 and 24)
- Percentage of Participants Who Are Alive Without Permanent Ventilation(At Month 12 and 24)
- Percentage of Participants Alive(At Month 12 and 24)
- Percentage of Participants Who Achieve the Attainment Level of the Motor Milestones as Assessed in the Hammersmith Infant Neurological Examination-2 (HINE-2)(At Month 12 and 24)
- Percentage of Participants With Two Copies of the SMN2 Gene Sitting Without Support for 5 Seconds (Independent of the CMAP Value at Baseline).(At Month 12)
- Percentage of Participants Sitting Without Support for 5 Seconds(At Month 24)
- Percentage of Participants Demonstrating the Ability to Achieve a Scaled Score on BSID-III Gross Motor Subtests Within 1.5 Standard Deviations of Chronological Reference Standard(At Month 24 and 42)
- Change From Baseline Score in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale at Month 12(Baseline, Month 12)
- Percentage of Participants Who Achieve a Score of 40 or Higher, 50 or Higher, and 60 or Higher in the CHOP INTEND Motor Function Scale at Month 12(At Month 12)
- Change From Baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) Score(At Month 60)
- Number and Percentage of Participants Within 3rd Percentile of Normal Range for Weight-for-Age, Length/Height-for-Age and Weight-for-Length/Height(At Month 12, 24, 36, 48 and 60)
- Number and Percentage of Participants Within 3rd Percentile of Normal Range for Head Circumference-for-age(At Month 12 and 24)
- Change From Baseline Percentiles for Weight-for-age, Length/Height-for-age, and weight-for- Length/Height(At Month 12, 24, 36, 48 and 60)
- Change From Baseline Percentiles for Head Circumference- For-age(At Month 12 and 24)
- Change From Baseline in Chest Circumference(At Month 12 and 24)
- Ratio Between Chest and Head Circumferences(At Month 12 and 24)
- Percentage of Participants With the Ability to Swallow and to Feed Orally(At Month 12, 24, 36, 48 and 60)
- Percentage of Participants Sitting Without Support for 30 Seconds(At Month 12 and 24)
- Percentage of Participants Standing for at Least 3 Seconds(At Month 24)
- Change From Baseline in Compound Muscle Action Potential (CMAP) Amplitude(At Month 12 and 24)
- Measurement of Pharmacodynamic Marker Levels in Blood(Day 1, 56, 196, 364, 728 and at early withdrawal)
- Percentage of Participants With Adverse Events(Up to 7 years)
- Ophthalmological Examination as Appropriate for Age(Up to 7 years)
- Plasma Concentration of Risdiplam and Its Metabolites to Characterize the PK Profile(Up to 7 years)
- Percentage of Participants Walking (Takes at Least 3 Steps)(At Month 24)
研究者
研究点 (9)
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相关资讯
Evrysdi Demonstrates Significant Motor Milestone Improvement in Infants with SMA- In a Phase II trial, Roche's Evrysdi (risdiplam) enabled pre-symptomatic babies with SMA to reach key motor milestones after two years of treatment.
- All children in the study were able to swallow and feed orally, and none required permanent ventilation, contrasting sharply with the natural history of untreated Type 1 SMA.
- Cognitive development in the children treated with Evrysdi was comparable to that of babies without SMA, as measured by standardized scales.
- The study confirms the potential of early intervention with Evrysdi, highlighting its non-invasive administration and compatibility with newborn screening programs.last yearEvrysdi Approved in Japan for Pre-Symptomatic SMA and Infants Under 2 Months- Chugai's Evrysdi (risdiplam) gains approval in Japan for treating pre-symptomatic spinal muscular atrophy (SMA) and infants under two months of age.
- The approval is based on Phase II RAINBOWFISH study results, demonstrating Evrysdi's efficacy and safety in pre-symptomatic SMA infants.
- Evrysdi, an oral SMN2 splicing modifier, becomes the first oral treatment option available for SMA patients of all ages after birth in Japan.
- This approval enables earlier intervention, potentially maximizing treatment benefits for SMA patients diagnosed through genetic testing.2 years ago