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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02462759
Registration number
NCT02462759
Ethics application status
Date submitted
14/05/2015
Date registered
4/06/2015
Date last updated
17/02/2021
Titles & IDs
Public title
A Study to Assess the Safety and Tolerability of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA).
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Scientific title
A Phase 2, Randomized, Double-blind, Sham-procedure Controlled Study to Assess the Safety and Tolerability and Explore the Efficacy of ISIS 396443 (BIIB058) Administered Intrathecally in Subjects With Spinal Muscular Atrophy Who Are Not Eligible to Participate in the Clinical Studies ISIS 396443-CS3B or ISIS 396443-CS4
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Secondary ID [1]
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2014-003657-33
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Secondary ID [2]
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232SM202
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Universal Trial Number (UTN)
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Trial acronym
EMBRACE
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Spinal Muscular Atrophy
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Condition category
Condition code
Musculoskeletal
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Other muscular and skeletal disorders
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Neurological
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Other neurological disorders
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Intervention/exposure
Study type
Interventional(has expanded access)
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Description of intervention(s) / exposure
Treatment: Drugs - Nusinersen
Treatment: Surgery - Sham Procedure
Experimental: Nusinersen - Administered by intrathecal injection.
Sham Comparator: Sham Procedure - Small needle prick on the lower back at the location where the IT injection is normally made.
Treatment: Drugs: Nusinersen
Administered by intrathecal injection.
Treatment: Surgery: Sham Procedure
Small needle prick on the lower back at the location where the IT injection is normally made.
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Intervention code [1]
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Treatment: Drugs
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Intervention code [2]
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Treatment: Surgery
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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Assessment method [1]
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An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.
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Timepoint [1]
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Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)
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Primary outcome [2]
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Number of Participants With Change From Baseline in Clinical Laboratory Parameters
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Assessment method [2]
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Clinically significant changes in laboratory parameters were evaluated for assessing the safety of ISIS 396443.
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Timepoint [2]
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Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)
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Primary outcome [3]
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Number of Participants With Change From Baseline in Electrocardiograms (ECGs)
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Assessment method [3]
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Clinically significant changes in ECG measurements were evaluated for assessing the safety of ISIS 396443.
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Timepoint [3]
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Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596
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Primary outcome [4]
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Number of Participants With Change From Baseline in Vital Signs
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Assessment method [4]
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Clinically significant changes in vital signs were evaluated for assessing the safety of ISIS 396443. Vital signs that were assessed included resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide.
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Timepoint [4]
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Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596
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Primary outcome [5]
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Change From Baseline in Head Circumference
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Assessment method [5]
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Participants were analyzed for change in growth parameter of head circumference to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the head circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.
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Timepoint [5]
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Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
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Primary outcome [6]
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Change From Baseline in Chest Circumference
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Assessment method [6]
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Participants were analyzed for change in growth parameter of chest circumference to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the chest circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days>1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.
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Timepoint [6]
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Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
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Primary outcome [7]
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Change From Baseline in Arm Circumference
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Assessment method [7]
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Participants were analyzed for change in growth parameter of arm circumference to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the arm circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.
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Timepoint [7]
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Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
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Primary outcome [8]
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Change From Baseline in Weight for Age
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Assessment method [8]
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Participants were analyzed for change in growth parameter of weight for age to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the weight for age percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.
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Timepoint [8]
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Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
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Primary outcome [9]
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Change From Baseline in Weight
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Assessment method [9]
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Participants were analyzed for change in growth parameter of weight to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the weight percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.
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Timepoint [9]
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Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
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Primary outcome [10]
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Change From Baseline in Head to Chest Circumference (HCC) Ratio
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Assessment method [10]
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Participants were analyzed for change in growth parameter of HCC to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the HCC circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.
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Timepoint [10]
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Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
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Primary outcome [11]
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Change From Baseline in Body Length
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Assessment method [11]
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Participants were analyzed for change in growth parameter of body length to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the body length percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline; Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.
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Timepoint [11]
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Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
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Primary outcome [12]
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Number of Participants With Change From Baseline in Neurological Examination Outcomes
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Assessment method [12]
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Neurological examinations included assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, reflexes, mood, speech/language and hearing.
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Timepoint [12]
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Part 1: Baseline to Day 422; Part 2: Baseline to Day 596
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Primary outcome [13]
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Number of Participants With Change From Baseline in Activated Partial Thromboplastin Time [aPTT]
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Assessment method [13]
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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, high and unknown values of aPTT at baseline to high values postbaseline.
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Timepoint [13]
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Part 2: Up to 1080 days
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Primary outcome [14]
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Number of Participants With Change From Baseline in Partial Thromboplastin Time [PTT]
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Assessment method [14]
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PTT was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of PTT at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of PTT at baseline to high values postbaseline.
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Timepoint [14]
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Part 2: Up to 1080 days
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Primary outcome [15]
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Number of Participants With Change From Baseline in International Normalized Ratio [INR])
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Assessment method [15]
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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, high and unknown values of INR at baseline to high values postbaseline.
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Timepoint [15]
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Part 2: Up to 1080 days
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Primary outcome [16]
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Number of Participants With Presence of Urine Total Protein Post-baseline
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Assessment method [16]
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Urine total protein was evaluated to assess safety.
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Timepoint [16]
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Part 2: Up to 1080 days
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Secondary outcome [1]
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Plasma Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study
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Assessment method [1]
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Study days were windowed for integrated analysis and labelled as follows: Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659.
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Timepoint [1]
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Pre-dose on Days 64, 183, 540 and 659
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Secondary outcome [2]
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Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study
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Assessment method [2]
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Study days were windowed for integrated analysis and labelled as follows: Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138.
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Timepoint [2]
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Pre-dose on Days 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
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Secondary outcome [3]
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Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Participants Who Received Sham Procedure in Part 1 of the Study
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Assessment method [3]
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CSF samples were analyzed for ISIS 396443 concentrations in participants. Study days were windowed for integrated analysis and labelled as follows: Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540.
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Timepoint [3]
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Pre-dose on Days 15, 29, 64, 183, 302, 422 and 540
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Secondary outcome [4]
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CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Participants Who Received ISIS 396443 in Part 1 of the Study
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Assessment method [4]
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CSF samples were analyzed for ISIS 396443 concentrations in participants. Study days were windowed for integrated analysis and labelled as follows: Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018.
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Timepoint [4]
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Pre-dose on Days 15, 29, 64, 183, 302, 422, 540, 659, 778, 898 and 1018
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Secondary outcome [5]
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Number of Participants With Plasma Antibodies to ISIS 396443
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Assessment method [5]
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Timepoint [5]
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Part 2: Baseline to Day 596
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Eligibility
Key inclusion criteria
Key
- Genetic documentation of 5q SMA homozygous gene deletion, mutation, or compound
heterozygote.
- Onset of clinical signs and symptoms consistent with SMA at =6 months of age and have
documentation of 3 SMN2 copies OR onset of clinical signs and symptoms consistent with
SMA at =6 months of age, >7 months of age (211 days) at screening, and have
documentation of 2 SMN2 copies OR onset of clinical signs and symptoms consistent with
SMA at >6 months of age, are =18 months of age at screening, and have documentation of
2 or 3 SMN2 copies.
- Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is
planned for study procedures.
- Medical care, such as routine immunizations meets and is expected to continue to meet
guidelines set out in the Consensus Statement for Standard of Care in SMA, in the
opinion of the Investigator.
- Participants with 2 SMN2 copies must reside within approximately 9 hours'
ground-travel distance from a participating study site for the duration of the study.
Key
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Minimum age
No limit
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Meets additional study related criteria.
- Any previous exposure to ISIS 396443; previous dosing in this study or previous
studies with ISIS 396443.
- Signs or symptoms of SMA present at birth or within the first week after birth.
- Ventilation for =16 hours per day continuously for >21 days at screening.
- Permanent tracheostomy, implanted shunt for CSF drainage, or implanted central nervous
system (CNS) catheter at screening.
- History of brain or spinal cord disease that would interfere with the LP procedure,
CSF circulation, or safety assessments.
- Hospitalization for surgery (e.g., scoliosis surgery), pulmonary event, or nutritional
support within 2 months prior to screening, or hospitalization for surgery planned
during the study.
- Clinically significant abnormalities in hematology or clinical chemistry parameters or
Electrocardiogram (ECG), as assessed by the Investigator.
- Treatment with an investigational drug for SMA (e.g., albuterol/salbutamol, riluzole,
carnitine, sodium phenylbutyrate, valproate, hydroxyurea), biological agent, or device
within 30 days prior to screening. Any history of gene therapy, prior antisense
oligonucleotide (ASO) treatment, or cell transplantation.
For Part 2 only:
To be eligible to participate in Part 2 of this study, participants must meet the following
eligibility criteria at the time of consent to participate in Part 2:
Participation in Part 1 and completion of the End of Part 1 Evaluation assessments.
Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study
and to provide signed and dated informed consent on the Part 2 informed consent form (ICF)
and authorization to use confidential health information in accordance with national and
local participant privacy regulations.
Able to complete all study procedures, measurements, and visits, and parent or legal
guardian/participant has adequately supportive psychosocial circumstances, in the opinion
of the Investigator.
Participants will be excluded from the Part 2 if they meet the following exclusion
criterion at the time of consent into Part 2 of the study:
Any significant change in clinical status, including laboratory tests that, in the opinion
of the Investigator, would make them unsuitable to participate in Part 2. The Investigator
must reassess the subject's medical fitness for participation and consider any diseases
that would preclude treatment.
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
19/08/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
24/09/2018
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Sample size
Target
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Accrual to date
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Final
21
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Recruitment in Australia
Recruitment state(s)
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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United States of America
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State/province [2]
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Connecticut
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Country [3]
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United States of America
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State/province [3]
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Maryland
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Country [4]
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United States of America
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State/province [4]
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Minnesota
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Country [5]
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United States of America
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State/province [5]
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Texas
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Country [6]
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United States of America
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State/province [6]
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Washington
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Country [7]
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Germany
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State/province [7]
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Muenchen
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Biogen
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
The primary objective of Part 1 of this study is to assess the safety and tolerability of
Nusinersen in participants with SMA who are not eligible to participate in the clinical
studies ISIS 396443-CS3B (NCT02193074) or ISIS 396443-CS4 (NCT02292537). The secondary
objective of Part 1 of this study is to examine the pharmacokinetics (PK) of Nusinersen in
participants with SMA. The primary objective of Part 2 of this study is to assess the
long-term safety and tolerability of Nusinersen in participants with SMA who participated in
Part 1 and completed their End of Part 1 Evaluation assessments. The secondary objective of
Part 2 of this study is to examine the PK of Nusinersen in participants with SMA who
participated in Part 1 and completed their End of Part 1 Evaluation assessments.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02462759
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Trial related presentations / publications
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Contacts
Principal investigator
Name
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Medical Director
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Address
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Biogen
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02462759
Download to PDF