A Phase 3, Randomized, Double-Blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients With Infantile-onset Spinal Muscular Atrophy
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- Biogen
- 入组人数
- 122
- 试验地点
- 31
- 主要终点
- Percentage of Motor Milestones Responders
研究概览
简要总结
The primary objective of the study is to examine the clinical efficacy of nusinersen (ISIS 396443) administered intrathecally (IT) to participants with infantile-onset with infantile-onset spinal muscular atrophy (SMA). The secondary objective of the study is to examine the safety and tolerability of nusinersen administered intrathecally to participants with infantile-onset SMA.
详细描述
This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc..
In August 2016, sponsorship of the trial was transferred to Biogen.
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
- — 至 210 Days（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Be born (gestational age) between 37 and 42 weeks
- •Be medically diagnosed with spinal muscular atrophy (SMA)
- •Have Survival Motor Neuron2 (SMN2) Copy number = 2
- •Body weight equal to or greater than 3rd percentile for age using appropriate country-specific guidelines
- •Be able to follow all study procedures
- •Reside within approximately 9 hours ground-travel distance from a participating study center, for the duration of the study
排除标准
- •Hypoxemia (oxygen [O2] saturation awake less than 96% or O2 saturation asleep less than 96%, without ventilation support) during screening evaluation
- •Clinically significant abnormalities in hematology or clinical chemistry parameters or Electrocardiogram (ECG), as assessed by the Site Investigator, at the Screening visit that would render the participant unsuitable for participation in the study
- •Participant's parent or legal guardian is not willing to meet standard of care guidelines (including vaccinations and respiratory syncytial virus prophylaxis if available), nor provide nutritional and respiratory support throughout the study
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
nusinersen
干预措施: nusinersen (Drug)
Sham procedure
干预措施: Sham procedure (Procedure)
结局指标
主要结局
Percentage of Motor Milestones Responders
时间窗: assessed at the later of the Day 183, Day 302, or Day 394 study visits
The definition of a motor milestones responder was based on improvement in the motor milestones categories in Section 2 of the Hammersmith Infant Neurological Examination (HINE), with the exclusion of voluntary grasp, as follows: (i) subject demonstrates ≥ 2-point increase in the motor milestones category of ability to kick or achievement of maximal score on that category (touching toes), or a 1-point increase in the motor milestones category of head control, rolling, sitting, crawling, standing, or walking, and (ii) among the motor milestone categories, with the exclusion of voluntary grasp, there are more categories where there is improvement as defined in (i) than worsening. (For the category of ability to kick, worsening is defined as ≥ 2-point decrease or decrease to the lowest possible score of no kicking. For the other categories, worsening is defined as ≥ 1-point decrease.) The lowest possible score for the HINE is 0 (zero), and the highest possible score for the HINE is 28.
Time to Death or Permanent Ventilation
时间窗: Day 91, Day 182, Day 273, Day 364, Day 394
Estimated proportion of participants who died or required permanent ventilation by a given study day, based on the Kaplan-Meier product-limit method. Time to death or permanent ventilation was defined as either tracheostomy or ≥ 16 hours ventilation/day continuously for \> 21 days in the absence of an acute reversible event. This endpoint was adjudicated by a blinded, independent group of experienced clinicians, the Event Adjudication Committee (EAC), based on review of clinical study data and supporting information. Results are based on all available data.
次要结局
- Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration(Day 91, Day 182, Day 273, Day 364, Day 394)
- Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs(Screening through Day 394 (± 7 days) or early termination)
- Number of Participants With AEs Corresponding to Changes in Hematology Values(up to Day 394 (± 7 days) or early termination)
- Summary of Shifts in 12-lead Electrocardiogram (ECG) Results(up to Day 394 (± 7 days) or early termination)
- Percentage of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders(assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits)
- Summary of Time to Death(Day 91, Day 182, Day 273, Day 364, Day 394)
- Percentage of Participants Not Requiring Permanent Ventilation(Up to Day 394)
- Percentage of Compound Muscular Action Potential (CMAP) Responders(assessed at the later of the Day 183, Day 302, or Day 394 study visits)
- Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration(Day 91, Day 182, Day 273, Day 364, Day 394)
- Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values(up to Day 394 (± 7 days) or early termination)
- Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline(up to Day 394 (± 7 days) or early termination)
- Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values(up to Day 394 (± 7 days) or early termination)