Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Biogen
- 入组人数
- 145
- 试验地点
- 45
- 主要终点
- Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group
研究概览
简要总结
The primary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA), as measured by change in Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score (Part B); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C).
The secondary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A, B and C); to examine the effect of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA, to examine the effect of nusinersen administered intrathecally at higher doses compared to the currently approved dose in participants with SMA (Part B).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Care Provider)
入排标准
- 年龄范围
- 7 Days 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Part A, B and C:
- •Genetic documentation of 5q SMA (homozygous gene deletion, mutation, or compound heterozygote)
- •Onset of clinical signs and symptoms consistent with SMA at > 6 months (> 180 days) of age (i.e., later-onset SMA)
- •Age 2 to ≤ 15 years, inclusive, at the time of informed consent
- •Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset) should have age > 1 week to ≤ 7 months (≤ 210 days) at the time of informed consent
- •Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):
- •Age 2 to < 10 years at the time of informed consent
- •Can sit independently but has never had the ability to walk independently
- •HFMSE score ≥ 10 and ≤ 54 at Screening
- •Currently on nusinersen treatment at the time of Screening, with the first dose being at least 1 year prior to Screening
- •Part C Cohort 1:
- •Participants of any age (individuals ≥18 years of age at Screening must be ambulatory)
- •Part C Cohort 2:
- •Participants ≥18 years of age at Screening (can be ambulatory or nonambulatory)
- •HFMSE total score ≥4 points at Screening
- •RULM entry item A score ≥3 points at Screening
排除标准
- •Part A, B and C:
- •Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the Screening period
- •Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or of an implanted central nervous system (CNS) catheter
- •Hospitalization for surgery, pulmonary event, or nutritional support within 2 months prior to Screening or planned within 12 months after the participant's first dose
- •Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
- •Medical necessity for a gastric feeding tube
- •Treatment with an investigational drug given for the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any survival motor neuron-2 gene (SMN2)-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
- •Treatment with an investigational drug including but not limited to the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any SMN2-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
- •Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):
- •Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
- •Medical necessity for a gastric feeding tube
- •Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset): Signs or symptoms of SMA present at birth or within the first week after birth
- •Concurrent or previous participation and/or administration of nusinersen in another clinical study
- •Concomitant or previous administration of any SMN2-splicing modifier (excluding nusinersen) or gene therapy, either in a clinical study or as part of medical care.
- •Concurrent or previous participation in any interventional investigational study for any other drug or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
28/28 Milligram (mg) Safety Group
Part A: Participants with later-onset SMA will receive loading doses of 28 mg of nusinersen intrathecally on Days 1, 15 and 29 followed by maintenance doses of 28 mg on Days 149 and 269.
干预措施: Nusinersen (Drug)
12/12 mg Active Control Group
Part B: Participants with infantile- or later-onset SMA will receive loading doses of 12 mg of nusinersen intrathecally on Days 1, 15, 29, and 64 followed by maintenance doses of 12 mg on Days 183 and 279. Sham procedure will be administered on Day 135.
干预措施: Nusinersen (Drug)
50/28 mg Active Treatment Group
Part B: Participants with infantile- or later-onset SMA will receive loading doses of 50 mg of nusinersen intrathecally on Days 1 and 15 followed by maintenance doses of 28 mg on Days 135 and 279. Sham procedure will be administered on Days 29, 64 and 183.
干预措施: Nusinersen (Drug)
12/50/28 mg Titration Group
Part C: Participants who have been receiving the approved dose of 12 mg for at least 1 year prior to entry, will receive a single bolus dose of 50 mg of nusinersen intrathecally on Day 1 (4 months after their most recent maintenance dose of 12 mg) followed by maintenance doses of 28 mg on Days 121 and 241.
干预措施: Nusinersen (Drug)
结局指标
主要结局
Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group
时间窗: Baseline, Day 183
The CHOP-INTEND test was designed to evaluate the motor skills of infants with significant motor weakness. It included 16 items (capturing neck, trunk, and proximal and distal limb strength), nine of which were scored 0, 1, 2, 3, or 4, five were scored as 0, 2, or 4, one was scored as 0, 1, 2, or 4, and one as 0, 2, 3, or 4 with higher scores indicating greater muscle strength and function. Total score was calculated as the sum of scores for each item. Total score ranged from 0 (worst possible score) and 64 (best possible score). The change from baseline to Day 183 in the CHOP-INTEND total score was compared to CS3B study (NCT02193074) sham control group using the joint-rank methodology to account for mortality.
Parts A and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs)
时间窗: Part A: From the first dose of the study drug up to Day 389, Part C: From the first dose of the study drug up to Day 361
An adverse event (AE) was any unfavorable \& unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with use of an investigational product, whether or not related to investigational product. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of Investigator, placed participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. AE and SAEs were regarded as treatment-emergent if it was present prior to receiving first dose of nusinersen in this current study and subsequently worsened in severity or was not present prior to receiving first dose of nusinersen and subsequently appeared.
Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)
时间窗: Parts A and C: Baseline up to Day 302
Blood chemistry parameters included protein, albumin, creatinine, blood urea nitrogen, bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, bicarbonate, chloride, sodium, potassium, cystatin C, and creatine kinase. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high values postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.
Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)
时间窗: Parts A and C: Baseline up to Day 302
Hematology parameters included complete blood cell count, with differential and platelet count, and absolute neutrophil count. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline values. The categories with at least one participant with shift from baseline in these parameters are reported.
Parts A and C: Number of Participants With Shifts From Baseline in Urinalysis
时间窗: Parts A and C: Baseline up to Day 302
Urinalysis included assessments of urine total protein, specific gravity, pH, protein, glucose, ketones, bilirubin, blood, red blood cells (RBC), white blood cells (WBC), epithelial cells, bacteria, casts and crystals. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.
Parts A and C: Number of Participants With Shifts From Baseline in Cerebrospinal Fluid (CSF) Parameters
时间窗: Part A: Baseline up to Day 269, Part C: Baseline up to Day 241
CSF parameters included cell count, total protein, and glucose. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high values postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.
Parts A and C: Number of Participants With Shifts From Baseline in Electrocardiograms (ECGs)
时间窗: Parts A and C: Baseline up to Day 302
The ECGs were assessed by the investigator to be normal, abnormal and abnormal AE. The number of participants with ECG shifts from normal to each of the categorical values denoting an abnormal scan (abnormal not AE, abnormal AE) was assessed. Shift from baseline to worst post-baseline values were reported. The categories with at least one participant with shift from baseline in ECG are reported.
Parts A and C: Number of Participants With Abnormalities in Vital Sign Parameters
时间窗: Parts A and C: Baseline up to Day 302
Vital sign assessment included temperature, pulse rate, systolic blood pressure, diastolic blood pressure, and respiratory rate. As pre-specified in protocol, the criteria for determining potentially clinically relevant abnormalities in vital signs included: temperature \< 36.0 and \> 38.0 degrees Celsius (C), pulse rate \< 60 and \> 100 beats per minute (bpm), systolic blood pressure \[\< 90, \> 140 and \> 160 millimeters of mercury (mmHg)\], diastolic blood pressure \< 50, \> 90 and \> 100 mmHg and respiratory rate \< 12 and \> 20 breaths per minute. The categories with at least one participant with clinically relevant vital sign abnormalities are reported.
Parts A and C: Change From Baseline in Growth Parameters (Body Height)
时间窗: Parts A and C: Baseline, Day 302
Part C: Change From Baseline in Growth Parameters (Head Circumference)
时间窗: Baseline, Day 302
As pre-specified in the protocol, head circumference was measured for participants with infantile-onset SMA only.
Part C: Change From Baseline in Growth Parameters (Chest Circumference)
时间窗: Baseline, Day 302
As pre-specified in protocol, chest circumference was measured for participants with infantile-onset SMA only.
Part C: Change From Baseline in Growth Parameters (Arm Circumference)
时间窗: Baseline, Day 302
As pre-specified in the protocol, arm circumference was measured for participants with infantile-onset SMA. Here, negative change from baseline indicated reduction in arm circumference.
Parts A and C: Change From Baseline in Growth Parameters (Ulnar Length)
时间窗: Parts A and C: Baseline, Day 302
As pre-specified in the protocol, ulnar length was measured for participants with later-onset SMA.
Parts A and C: Change From Baseline in Growth Parameters (Weight for Age Percentile)
时间窗: Parts A and C: Baseline, Day 302
World Health Organization (WHO) child growth standards (2006) was used to calculate the weight for age percentile in the infantile-onset participants while the 2000 Centers for Disease Control and Prevention (CDC) Growth Charts was used to calculate the weight for age percentile for later-onset participants. Negative change from baseline indicates low weight for age percentile.
Part C: Change From Baseline in Growth Parameters (Weight for Length Ratio)
时间窗: Baseline, Day 302
As pre-specified in the protocol, weight for length ratio was assessed only for the participants with infantile-onset SMA.
Part C: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)
时间窗: Baseline, Day 302
As pre-specified in the protocol, head to chest circumference ratio was assessed only for the participants with infantile-onset SMA.
Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Activated Partial Thromboplastin Time (aPTT))
时间窗: Parts A and C: Baseline up to Day 269
Activated partial thromboplastin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of aPTT at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of aPTT at baseline to high values postbaseline.
Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Prothrombin Time (PT))
时间窗: Parts A and C: Baseline up to Day 269
Prothrombin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of PT at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of PT at baseline to high values postbaseline.
Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (International Normalized Ratio (INR))
时间窗: Parts A and C: Baseline up to Day 269
INR was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of INR at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of INR at baseline to high values postbaseline. The category with at least one participant with shift from baseline in INR ratio is reported.
Parts A and C: Change From Baseline in Urine Total Protein
时间窗: Parts A and C: Baseline, Day 302
Parts A and C: Number of Participants With Neurological Examination Abnormalities Reported as AEs
时间窗: Parts A and C: Baseline up to Day 302
Participants with abnormalities in neurological examinations recorded as AEs were reported.
Parts A and C: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements
时间窗: Parts A and C: Baseline up to Day 302
Parts A and C: Percentage of Participants With a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of > 500 Millisecond (Msec) and an Increase From Baseline to Any Postbaseline Timepoint in QTcF of > 60 Msec
时间窗: Parts A and C: Baseline up to Day 302
次要结局
- Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group(Baseline, Day 183)
- Part B Later-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Baseline, Day 302)
- Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of Neurofilament Light Chain (NF-L) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group(Baseline, Day 183)
- Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Baseline, Day 302)
- Part B: Change From Baseline in Growth Parameters (Weight for Age Percentile)(Baseline, Day 302)
- Part B: Change From Baseline in Growth Parameters (Weight for Length Percentile)(Baseline, Day 302)
- Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group(Baseline, Day 183)
- Part B: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)(Baseline, Day 302)
- Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Baseline, Day 302)
- Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Baseline, Day 64)
- Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group(Screening up to Day 399)
- Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group(Screening up to Day 399)
- Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Screening up to Day 399)
- Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Screening up to Day 399)
- Part B Later-onset SMA: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Baseline, Day 302)
- Part B Later-onset SMA: Change From Baseline in Revised Upper Limb Module (RULM) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Baseline, Day 302)
- Part B Later-onset SMA: Number of New World Health Organization (WHO) Motor Milestones Achieved Per Participant for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Baseline, Day 302)
- Part B Later-onset SMA: Change From Baseline in Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Baseline, Day 302)
- Part B Later-onset SMA: Change From Baseline in Pediatric Quality of Life Inventory™ (PedsQL) for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Baseline, Day 302)
- Part B Later-onset SMA: Change From (Ratio to) Baseline in CSF Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen(Baseline, Day 279)
- Part B: Number of Participants With TEAEs and TESAEs(From the first dose of the study drug up to Day 399)
- Part B: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)(Baseline up to Day 302)
- Part B: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)(Baseline up to Day 302)
- Part B: Number of Participants With Shifts From Baseline in Urinalysis(Baseline up to Day 302)
- Part B: Number of Participants With Shifts From Baseline in CSF Parameters(Baseline up to Day 302)
- Part B: Number of Participants With Shift From Baseline in ECGs(Baseline up to Day 302)
- Part B: Number of Participants With Abnormalities in Vital Sign Parameters(Baseline up to Day 302)
- Part B: Change From Baseline in Growth Parameters (Body Height)(Baseline, Day 302)
- Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Head Circumference)(Baseline, Day 302)
- Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Chest Circumference)(Baseline, Day 302)
- Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Arm Circumference)(Baseline, Day 302)
- Part B: Change From Baseline in Growth Parameters (Ulnar Length)(Baseline, Day 302)
- Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (aPTT)(Baseline up to Day 279)
- Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (PT)(Baseline up to Day 279)
- Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (INR)(Baseline up to Day 279)
- Part B: Change From Baseline in Urine Total Protein(Baseline, Day 302)
- Part B: Number of Participants With Neurological Examination Abnormalities Reported as AEs(Baseline up to Day 302)
- Part B: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements(Baseline up to Day 302)
- Part B: Percentage of Participants With a Postbaseline QTcF of > 500 Msec and an Increase From Baseline to Any Postbaseline Timepoint in QTcF of > 60 Msec(Baseline up to Day 302)
- Parts A, B and C: Number of Participants With Hospitalizations(Parts A, B, and C: Baseline up to Day 302)
- Parts A, B and C: Percentage of Time of Hospitalization(Parts A, B, and C: Baseline up to Day 302)
- Parts A, B and C: Number of Participants With Clinical Global Impression of Change (CGIC)(Parts A, B, and C: Day 302)
- Parts A, B and C: Number of Serious Respiratory Events(Parts A, B, and C: Baseline up to Day 399)
- Part B Infantile-onset SMA: Percentage of Time on Ventilation(Baseline up to Day 302)
- Parts A, B and C: Number of Participants With Ventilator Use(Parts A, B, and C: Screening up to Day 302)
- Part A: Change From Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale(Baseline, Day 302)
- Part A: Number of Participants With Shift From Baseline in PASA Scale Items - Attempted to Drink Liquids and Attempted to Eat Solid Foods(Baseline, Day 302)
- Part B: Change From Baseline in the PASA Scale(Baseline, Day 302)
- Part B: Infantile SMA-onset: Change From (Ratio to) Baseline in CSF Concentration of NF-L(Baseline, Day 279)
- Parts A and C: Change From Baseline in HFMSE Total Score(Parts A and C: Baseline, Day 302)
- Parts A and C: Change From Baseline in RULM Total Score(Parts A and C: Baseline, Day 302)
- Parts A and C: Number of Participants With WHO Motor Milestones Status(Parts A and C: Baseline up to Day 302)
- Parts A and C: Change From Baseline in ACEND Total Score(Parts A and C: Baseline, Day 302)
- Parts A and C: Change From Baseline in PedsQL™ Total Score(Parts A and C: Baseline, Day 302)
- Part C: Change From Baseline in CHOP-INTEND Total Score(Baseline, Day 302)
- Part C: Change From Baseline in HINE Section 2 Motor Milestones Total Score(Baseline, Day 302)