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 Later-onset Spinal Muscular Atrophy
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Biogen
- 入组人数
- 126
- 试验地点
- 24
- 主要终点
- Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15
研究概览
简要总结
The primary objective of this study is to examine the clinical efficacy of nusinersen (ISIS 396443) administered intrathecally to participants with later-onset Spinal Muscular Atrophy (SMA). The secondary objective is to examine the safety and tolerability of nusinersen administered intrathecally to participants with later-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
- 2 Years 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Parent or guardian has signed informed consent and, if indicated per participant's age and institutional guidelines, participant has signed informed assent
- •Be medically diagnosed with Spinal Muscular Atrophy (SMA)
- •Have onset of clinical signs and symptoms consistent with SMA at greater than 6 months of age
- •Be able to sit independently, but has never had the ability to walk independently
- •Have Motor Function Score (Hammersmith Functional Motor Scale - Expanded) greater than or equal to 10 and less than or equal to 54 at Screening
- •Be able to complete all study procedures, measurements and visits and parent or guardian and subject has adequately supportive psychosocial circumstances, in the opinion of the Investigator
- •Have an estimated life expectancy of greater than 2 years from Screening, in the opinion of the Investigator
- •Meet age-appropriate institutional criteria for use of anesthesia and sedation, if use is planned for study procedures
- •For subjects who have reached reproductive maturity, satisfy study contraceptive requirements
排除标准
- •Respiratory insufficiency, defined by the medical necessity for invasive or non-invasive ventilation for greater than 6 hours during a 24 hour period, at Screening
- •Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Site Investigator
- •Severe contractures or severe scoliosis evident on X-ray examination at Screening
- •Hospitalization for surgery (i.e., scoliosis surgery, other surgery), pulmonary event, or nutritional support within 2 months of Screening or planned during the duration of the study
- •Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
- •History of brain or spinal cord disease, including tumors, or abnormalities by magnetic resonance imaging (MRI) or computed tomography (CT) that would interfere with the LP procedures or cerebrospinal fluid (CSF) circulation
- •Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system (CNS) catheter
- •History of bacterial meningitis
- •Dosing with IONIS-SMN Rx in any previous clinical study
- •Prior injury (e.g., upper or lower limb fracture) or surgical procedure which impacts the subject's ability to perform any of the outcome measure testing required in the protocol and from which the subject has not fully recovered or achieved a stable baseline
- •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 subject unsuitable for inclusion
- •Treatment with another investigational drug (e.g., oral albuterol or salbutamol, riluzole, carnitine, creatine, sodium phenylbutyrate, et.c), biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3-months of Screening. Any history of gene therapy, antisense oligonucleotide therapy, or cell transplantation.
- •Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability (e.g., wasting or cachexia, severe anemia, etc.) that would interfere with the assessment of safety or would compromise the ability of the subject to undergo study procedures.
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Nusinersen
Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.
干预措施: Nusinersen (Drug)
Sham procedure
Sham comparator on Days 1, 29, 85 and 274.
干预措施: Sham procedure (Procedure)
结局指标
主要结局
Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15
时间窗: Baseline and Month 15
The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. The scale was originally developed with 20 scored activities and was devised for use in children with SMA Type 2 and Type 3 with limited ambulation to give objective information on motor ability and clinical progression. The expanded scale includes an additional module of 13 items developed to allow for evaluation of ambulatory SMA patients. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.
次要结局
- Number of Participants With Clinically Significant Physical Examination Abnormalities(Baseline through Month 15)
- Change From Baseline in Revised Upper Limb Module (RULM) Test(Baseline and Month 15)
- Number of Participants That Experienced Adverse Events (AEs) and Serious Adverse Events (SAEs)(Baseline through Month 15)
- Number of Participants With Clinically Significant Vital Sign Abnormalities(Baseline through Month 15)
- Number of Participants With Clinically Significant Neurological Examination Abnormalities(Baseline through Month 15)
- Proportion of Participants That Achieved Any New Motor Milestone at Month 15(Month 15)
- Proportion of Participants That Achieved Standing Alone(Month 15)
- Number of Participants With Clinically Significant Weight Abnormalities(Baseline through Month 15)
- Number of New Motor Milestones Achieved Per Participant(Month 15)
- Proportion of Participants That Achieved Walking With Assistance(Month 15)
- Number of Participants With Abnormal, Clinically Relevant Post-Baseline Worsening in Electrocardiogram (ECG) in Results(Baseline through Month 15)
- Number of Participants Taking Any Concomitant Medication Related to Dosing Procedure or Sham Procedure(Baseline through Month 15)
- Proportion of Participants Who Achieved a 3-Point Increase From Baseline in HFMSE Score at Month 15(Baseline and Month 15)
- Number of Participants With Clinically Significant Laboratory Parameter Abnormalities(Baseline through Month 15)