A Study for Participants With Spinal Muscular Atrophy (SMA) Who Previously Participated in Nusinersen (ISIS 396443) Investigational Studies (SHINE)

An Open-Label Extension Study for Patients With Spinal Muscular Atrophy Who Previously Participated in Investigational Studies of ISIS 396443

The primary objective is to evaluate long-term safety and tolerability of nusinersen (ISIS 396443) administered by intrathecal (IT) injection to participants with Spinal Muscular Atrophy (SMA) who previously participated in investigational studies of nusinersen. The secondary objective is to examine the long-term efficacy of nusinersen administered by IT injection to participants with SMA who previously participated in investigational studies of nusinersen.

Study Overview

• Status: Completed
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Drug: nusinersen

Detailed Description

This study was initiated and the protocol was registered by Ionis Pharmaceuticals, Inc.

In August 2016, Biogen assumed responsibility for this study.

• Study Type: Interventional
• Enrollment (Actual): 292
• Phase: Phase 3

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2031
      • Sydney Children's Hospital Clinical Research Centre
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital
• Belgium
  • Brussels, Belgium, 1020
    • Universitair Kinderziekenhuis Koningin Fabiola
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • BC Children's Hospital / UBC
  • Ontario
    • Brussel, Ontario, Canada, N6A 5W9
      • Children's Health Research Institute
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre
• France
  • Paris 9
    • Paris, Paris 9, France, 75012
      • Armand Trousseau Hospital, I-Motion
• Germany
  • Essen, Germany, 45147
    • Universitätsklinikum Essen
  • Freiburg, Germany, 79106
    • Universitaetsklinikum Freiburg
  • Bayern
    • Muenchen, Bayern, Germany, 80337
      • LMU-Campus Innenstadt
• Hong Kong
  • Hong Kong SAR
    • Hong Kong, Hong Kong SAR, Hong Kong, 999077
      • The University of Hong Kong
• Italy
  • Essen, Italy, 00168
    • Pediatric Neurology Unit, Catholic University
  • Genova, Italy, 16147
    • Istituto Giannina Gaslini, Centro Traslazionale di Miologia
  • Messina, Italy, 98125
    • Department of Neuroscience, Università di Messina, AOU Polic
• Japan
  • Kumamoto, Japan, 860-8556
    • Kumamoto University Hospital
  • Miyagi, Japan, 989-3126
    • Miyagi Prefectural Children Hospital
  • Miyazaki, Japan, 889-1692
    • University of Miyazaki Hospital
  • Aichi
    • Obu, Aichi, Japan, 474-0038
      • Aichi Children's Health and Medical Center
  • Hyogo
    • Nishinomiya, Hyogo, Japan, 663-8501
      • Hyogo College of Medicine
  • Tokyo
    • Shinjuku-ku, Tokyo, Japan, 162-8666
      • Tokyo Women's Medical University
• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of, 3080
      • Seoul National University Hospital
• Spain
  • Barcelona, Spain, 08950
    • Hospital Sant Joan de Déu
  • Hebron, Spain, 08035
    • Hospital Universitario Vall de Hebron
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
• Sweden
  • Gothenburg, Sweden, SE 416 86
    • The Queen Silvia Children's Hospital
• Turkey
  • Ankara, Turkey, 6100
    • Uníversity of Hacettepe
  • Istanbul, Turkey, 34662
    • Marmara University Pendik Training and Research Hospital
• United Kingdom
  • London, United Kingdom, WC1N 1EH
    • UCL Institute of Child Health
  • Northumberland
    • Newcastle, Northumberland, United Kingdom, NE1 3BZ
      • MRC Centre for Neuromuscular Diseases at Newcastle
• United States
  • California
    • Los Angeles, California, United States, 90095-8344
      • David Geffen School of Medicine at UCLA
    • Palo Alto, California, United States, 94305
      • Stanford University School of Medicine
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • Florida
    • Orlando, Florida, United States, 32827
      • Nemours Children's Clinic
  • Illinois
    • New York, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Minnesota
    • Saint Paul, Minnesota, United States, 55101
      • Gillette Children's Specialty Healthcare
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University School of Medicine
    • Miyagi, North Carolina, United States, 27710
      • Duke University School of Medicine
  • Oregon
    • Durham, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center
  • Utah
    • Obu, Aichi, Utah, United States, 84112
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Signed informed consent of parent or guardian and signed informed assent of participant, if indicated per participant's age and institutional guidelines.
• Completion of the index study in accordance with the study protocol or as a result of Sponsor decision (e.g., early termination of the index study) within the preceding 16 weeks

Key Exclusion Criteria:

• Have any condition or worsening condition which in the opinion of the Investigator would make the participant unsuitable for enrollment, or could interfere with the participant participating in or completing the study
• 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 or able to meet standard of care guidelines (including vaccinations and respiratory syncytial virus prophylaxis if available), nor provide nutritional and respiratory support throughout the study
• Treatment with another investigational agent, biological agent, or device within one month of Screening, or 5 half-lives of study agent, whichever is longer

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; Participants transitioned from ISIS 396443-CS3B (NCT02193074)	Drug: nusinersen; Administered by intrathecal (IT) injection; Other Names: ISIS 396443; Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx
Experimental: Group 2; Participants transitioned from ISIS 396443-CS4 (NCT02292537)	Drug: nusinersen; Administered by intrathecal (IT) injection; Other Names: ISIS 396443; Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx
Experimental: Group 3; Participants transitioned from ISIS 396443-CS12 (NCT02052791)	Drug: nusinersen; Administered by intrathecal (IT) injection; Other Names: ISIS 396443; Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx
Experimental: Group 4; Participants transitioned from ISIS 396443-CS3A (NCT01839656)	Drug: nusinersen; Administered by intrathecal (IT) injection; Other Names: ISIS 396443; Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx
Experimental: Group 5; Participants transitioned from 232SM202 (NCT02462759)	Drug: nusinersen; Administered by intrathecal (IT) injection; Other Names: ISIS 396443; Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	AE:unfavorable and unintended sign, symptom, or disease temporally associated with study/use of an investigational drug, whether or not it's considered related to investigational drug. SAE:AE that in view of either Investigator/Sponsor, meets any of the following criteria: results in death;is life-threatening:i.e.poses risk of death, hospitalization/it's prolongation;results in a persistent or significant incapacity or substantial disruption of normal life functions;results in congenital anomaly or birth defect in offspring;is an important event in the opinion of Investigator/Sponsor. TEAE: if it was present prior to first dose of nusinersen or first sham procedure in index study and subsequently worsened in severity/was not present prior to first dose of nusinersen or first sham procedure in index study but subsequently appeared.	From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Vital Sign Abnormalities Reported as AEs	The vital sign assessments included blood pressure, temperature, pulse rate, and respiratory rate. Participants with abnormalities in these assessments recorded as AEs were reported.	From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Weight Abnormalities Reported as AEs	Weight decrease was characterized by a decrease of >=7% from baseline and weight increase was characterized by an increase of >=7% from baseline. Participants with these abnormalities recorded as AEs were reported.	From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Neurological Abnormalities Reported as AEs	Participants with abnormalities in neurological examinations recorded as AEs were reported.	From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Laboratory Abnormalities Reported as AEs	Laboratory investigations included hematology, coagulation, serum chemistry and urinalysis parameters. Participants with abnormalities in these laboratory investigations recorded as AEs were reported.	From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Coagulation Parameters Reported as AEs	Coagulation parameters included activated partial thromboplastin time (aPTT) and international normalized ratio (INR). Participants with abnormalities in these coagulation parameters recorded as AEs were reported.	From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Clinically Significant Shifts in12 Lead Electrocardiogram (ECG) Results	Clinical significance of abnormalities in 12 lead ECG was determined based on the investigator's discretion.	From Day 1 up to the end of the study (up to 2848 days)
Number of Participants Taking Any Concomitant Medication	A concomitant therapy is any non-protocol-specified drug or substance (including over-the-counter medications, herbal medications, and vitamin supplements) administered between the beginning of screening and the last telephone contact or study visit.	From Day 1 up to the end of the study (up to 2848 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Number of New Motor Milestones Achieved as Assessed by World Health Organization (WHO) Criteria	The WHO motor milestones are a set of six milestones in motor development, all of which would be expected to be attained by 24 months of age in healthy children. The individual milestones are: sitting without support, standing with assistance, hands and knees crawling, walking with assistance, standing alone and walking alone. Mean of number of new milestones achieved was calculated and reported in this outcome measure.	MMDR Period: At Day 1800
Percentage of Participants With <2 Years of Age Who Attained Motor Milestones as Assessed by Section 2 of Hammersmith Infant Neurological Examination (HINE)	HINE is evaluated in infants between 2-24 months of age. It's a simple, standardized instrument including 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of HINE (HINE-2) was assessed, which evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform task and score of 2, 3, or 4 indicating full milestone development. Total score is calculated by summing item scores to give maximum possible score of 26. Higher score indicates good neurological function.	At Day 309
Number of Participants Who Died or Met Permanent Ventilation	Permanent ventilation was defined as tracheostomy or >=16 hours of ventilator support per day continuously for >21 days in the absence of an acute reversible event.	MMDR Period: Up to Day 1800
Number of Participants Not Requiring Permanent Ventilation	Permanent ventilation was defined as tracheostomy or >=16 hours of ventilator support per day continuously for >21 days in the absence of an acute reversible event.	MMDR Period: Up to Day 1800
Change From Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale	The CHOP INTEND test is designed to evaluate the motor skills of infants with significant motor weakness, including infants with SMA. Participants who are ≥2 years will be continued to be assessed until a CHOP INTEND maximum score of 64 is achieved. It includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0 (worst) to 4 (best). Total scores range from 0 to 64, with higher scores indicating better movement functioning.	Baseline, Day 2198
Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Total Score	The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. 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.	MMDR Period: Baseline, MMDR Day 1800
Change From Baseline in Revised Upper Limb Module (RULM) Total Score	RULM Test is used in participants with SMA to assess upper limb functional ability items and has total of 20 items with an entry item that serves as functional class identification and does not contribute to total score. Remaining 19 scorable items reflect different functional domains and graded on 3-point system with score of 0 (unable), 1 (able, with modification), and 2 (able, no difficulty). There is only 1 item that is scored as a can/cannot score, with 1 as the highest score. Scorable items are summed for total score (0-37), higher scores indicating increased upper limb function. Positive change from baseline indicates improvement.	MMDR Period: Baseline, MMDR Day 1800
Change From Baseline in Total Distance Walked Over Time as Assessed by 6-Minute Walk Test (6MWT)	The 6MWT measures the distance an individual can walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes.	Baseline, Day 2670
Number of Participants Who Experienced Contracture Assesment	Contracture assessment is performed to assess the motor performance in SMA. The number of participants who experienced at least one contracture at any location and severe contractures in any of the five locations (hip flexors, knee flexors, ankle planter flexors, elbow flexors, forearm flexors) are reported in this outcome measure.	MMDR Period: At MMDR Day 1800
Change From Baseline in Compound Muscular Action Potential (CMAP)	CMAP is an electrophysiological technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. Peroneal amplitude (PA) and ulnar amplitude (UA) data is reported in this OM. Score <0 indicated worse response and >0 indicated better response than the normal matched population. Score change <0 indicated worsening and >0 indicated improvement as compared to baseline.	MMDR Period: Baseline, MMDR Day 1800
Change From Baseline in Body Length	Participants were analyzed for change in growth parameter of body length to evaluate clinical efficacy. The body length was calculated using either WHO or Centers for Disease Control and Prevention (CDC) scales. The CDC scale allows to calculate the body length up to 20 years, while the WHO scale allows to calculate it only up to 10 years.	MMDR Period: up to Day 1800
Change From Baseline in Weight	Participants were analyzed for change in growth parameter of weight to evaluate clinical efficacy. The weight was calculated using either WHO or CDC scales. The CDC scale allows to calculate the weight up to 20 years, while the WHO scale allows to calculate it only up to 10 years.	MMDR Period: up to Day 1800
Change From Baseline in Weight for Age Percentile	Participants who were below the age of 36 months were analyzed for change in growth parameter of weight for age to evaluate clinical efficacy. The weight for age percentile was calculated using either WHO or CDC scales. The CDC scale allows to calculate the weight for age percentile up to 20 years, while the WHO scale allows to calculate it only up to 10 years.	MMDR Period: up to Day 1800
Percentage of CMAP Responders	CMAP is an electrophysiological technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. A participant was defined as a responder if they had a peroneal amplitude ≥1 mV at last visit (including the amplitude ≥1 mV at baseline and also demonstrated as such at last visit).	MMDR Period: At Day 1800
Number of Participants Who Achieved Motor Milestones	Motor milestones were measured based on WHO criteria. The WHO motor milestones are a set of six milestones in motor development, all of which would be expected to be attained by 24 months of age in healthy children. The individual milestones are: sitting without support (SWS), standing with assistance (SWA), hands and knees crawling (HKC), and walking alone (WA).	MMDR Period: up to Day 1800
Number of Participants Who Achieved Standing Alone and Walking With Assistance	Motor milestones were measured based on WHO criteria. The WHO motor milestones are a set of six milestones in motor development, all of which would be expected to be attained by 24 months of age in healthy children. The individual milestones are: SWS, SWA, HKC, WWA, WA and standing alone (SA). SA and WWA were assessed in this outcome measure.	MMDR Period: up to Day 1800
Total Number of Hospitalizations Due to Serious Respiratory Events	Total number of hospitalizations is total number of serious events that occurred during study for all participants under each group. For a participant with multiple SAEs which started at the same date and led to hospitalization, it is counted as one hospitalization.	Up to day 2520
Total Number of Hospitalizations Due to Serious Adverse Events	Total number of hospitalizations is total number of serious events that occurred during study for all participants under each group. For a participant with multiple SAEs which started at the same date and led to hospitalization, it is counted as one hospitalization.	Up to day 2520
Percent of Time in Hospitalization		Upto day 2160
Change From Baseline in Cobb-Angle on X-Ray of the Thoracolumbar Spine by Visit	Cobb angle is a measurement of the degree of side-to-side spinal curvature used to define scoliosis.	MMDR Period: Baseline, MMDR Day 1800
Pediatric Quality of Life Inventory (PedsQL) Questionnaires Total Score by Domain	Items on the PedsQL generic core scale are reverse scored and transformed to a 0-100 scale. The PedsQL parent (P) and self (S) reported questionnaire was collected for participants from 2 to 25 years of age. Four dimensions were collected: Physical, Emotional, Social and School functioning and each item was scored on a 5 point ordinal scale. 0 (never) =100, 1 (almost never) = 75, 2 (sometimes)= 50, 3 (often) = 25, 4 (almost always) = 0. A total score was calculated as the sum of all the items over the number of items answered on all the scales. If more than 50% of items or more were missing, the scale score was not computed. Higher scores indicated better health related quality of life.	MMDR Period: At Day 1800
Change From Baseline in Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) Questionnaire Total Score	The ACEND is a questionnaire that includes a total of seven domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance) and each domain comprises several items. The total score (TS) for each domain will be calculated on a scale of 0 to 100. Higher scores indicate a greater impact on the caregiver.	MMDR Period: up to Day 1800
Number of Participants With Disease-related Hospitalizations and AEs		MMDR Period: up to Day 1800
Survival Rate	Survival rate was defined as the percentage of participants alive during the study and was estimated from the Kaplan Meier (KM) curve for time to death.	MMDR Period: up to Day 1800

Collaborators and Investigators

• Sponsor: Biogen
• Investigators: Study Director: Medical Director, Biogen

Publications and helpful links

Helpful Links

• Cure SMA
• Muscular Dystrophy Association
• National Organization for Rare Diseases

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2015
• Primary Completion (Actual): August 21, 2023
• Study Completion (Actual): August 21, 2023

Study Registration Dates

• First Submitted: October 30, 2015
• First Submitted That Met QC Criteria: October 30, 2015
• First Posted (Estimated): November 1, 2015

Study Record Updates

• Last Update Posted (Actual): October 22, 2024
• Last Update Submitted That Met QC Criteria: September 27, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: SMA; SMN; SMNRx; ISIS-SMNRx; ISIS 396443; IONIS-SMNRx; IONIS-SMN Rx; Spinraza; SHINE; nusinersen
• Additional Relevant MeSH Terms: Neurologic Manifestations; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; Motor Neuron Disease; Atrophy; Muscular Atrophy; Muscular Atrophy, Spinal
• Other Study ID Numbers: ISIS 396443-CS11; 2015-001870-16 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No