A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy

Phase 3

Terminated

• Conditions: Spinal Muscular Atrophy
• Interventions: Procedure: Sham procedure; Drug: nusinersen

• Registration Number: NCT02193074
• Lead Sponsor: Biogen

Brief Summary

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.

Detailed Description

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

In August 2016, sponsorship of the trial was transferred to Biogen.

Study Timeline

• Study First Submitted: 2014-07-14
• Study First Submitted QC: 2014-07-15
• Study First Posted: 2014-07-17
• Study Start: 2014-08-19
• Primary Completion: 2016-11-21
• Study Completion: 2016-11-21
• Results First Submitted: 2017-05-16
• Results First Submitted QC: 2017-06-29
• Results First Posted: 2017-07-28
• Status Verified: 2021-02
• Last Update Submitted: 2021-02-12
• Last Update Posted: 2021-02-17

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 122

Inclusion Criteria

• 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

Key

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Exclusion Criteria

• 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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sham procedure	Sham procedure	-
nusinersen	nusinersen	-

Primary Outcome Measures

Name	Time	Method
Percentage of Motor Milestones Responders	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	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.

Secondary Outcome Measures

Name	Time	Method
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	Estimated proportion of participants who died or required permanent ventilation (EAC-adjudicated events) among participants above the study median disease duration (13.1 weeks), by given duration thresholds, based on the Kaplan-Meier product-limit method.
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs	Screening through Day 394 (± 7 days) or early termination	AE: any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. SAE: any AE that in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening: that is, poses an immediate risk of death at the time of the event; requires in-patient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect in the offspring of the participant (whether male or female); is an important medical event in the opinion of the Investigator or Sponsor.
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	Shift to 'abnormal, not clinically significant' includes 'unknown' or 'normal' to 'abnormal, not clinically significant'. Shift to 'abnormal, clinically significant' includes 'unknown' or 'normal' to 'abnormal, clinically significant'.
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	A participants was considered a CHOP-INTEND responder if the change from baseline in CHOP-INTEND total score is ≥ 4 points based on assessment at the later of the Day 183, Day 302, or Day 394 study visits. CHOP-INTEND tests includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). Total scores range from 0 to 64, with higher scores indicating better movement functioning. Results are based on all available data.
Summary of Time to Death	Day 91, Day 182, Day 273, Day 364, Day 394	Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method.
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	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 CMAP responder if the CMAP amplitude at the peroneal nerve was increasing to or maintained at ≥ 1 mV (comparing to the baseline) based on assessment at the later of the Day 183, Day 302, or Day 394 study visits. Results are based on all available data.
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	Estimated proportion of participants who died or required permanent ventilation (EAC-adjudicated events) among participants below the study median disease duration (13.1 weeks), by given duration thresholds, based on the Kaplan-Meier product-limit method.
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

Trial Locations

Locations (31)

Ann and Robert H. Lurie Children's Hospital of Chicago; 🇺🇸 Chicago, Illinois, United States

Children's Hospital of Philadelphia - Neurology; 🇺🇸 Philadelphia, Pennsylvania, United States

UT Southwestern Medical Center/Children's Medical Center Dallas; 🇺🇸 Dallas, Texas, United States

Boston Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Sydney Children's Hospital; 🇦🇺 Sydney, New South Wales, Australia

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada

Hyogo College of Medicine; 🇯🇵 Nishinomiya, Hyogo, Japan

Children's Hospital Colorado; 🇺🇸 Aurora, Colorado, United States

Nemours Children's Hospital; 🇺🇸 Orlando, Florida, United States

UCLA Medical Center; 🇺🇸 Los Angeles, California, United States

Hacettepe Children's Hospital; 🇹🇷 Ankara, Turkey

Institut de Myologie; 🇫🇷 Paris, France

University of Gothenburg, The Queen Silvia Children's Hospital; 🇸🇪 Gothenburg, Sweden

Istituto Giannina Gaslini, Centro Traslazionale di Miologia e Patologie Neurodegenerative; 🇮🇹 Genova, Italy

MRC Centre for Neuromuscular Diseases at Newcastle, Institute of Genetic Medicine Newcastle University; 🇬🇧 Newcastle, United Kingdom

Columbia University Medical Center; 🇺🇸 New York, New York, United States

Duke Children's Hospital; 🇺🇸 Durham, North Carolina, United States

Primary Children's Medical Center (University of Utah); 🇺🇸 Salt Lake City, Utah, United States

Hôpital Universitaire des Enfants Reine FABIOLA (HUDERF); 🇧🇪 Brussels, Belgium

Hospital Universitario Vall d'Hebron; 🇪🇸 Barcelona, Spain

Pediatric Neurology Unit, Catholic University; 🇮🇹 Rome, Italy

Tokyo Women's Medical University; 🇯🇵 Tokyo, Japan

Universitatsklinikum Essen; 🇩🇪 Essen, Germany

Hospital Universitario La Paz, Pediatric Neurology Department; 🇪🇸 Madrid, Spain

Doernbecher Children's Hospital; 🇺🇸 Portland, Oregon, United States

Royal Children's Hospital, Children's Neuroscience Centre; 🇦🇺 Parkville, Victoria, Australia

Universtatsklinikum Freiburg, Zentrum fur Kinder-und Jugendmedizin , Abteilung Neuropadiatrie und Muskelerkrankungen; 🇩🇪 Freiburg, Germany

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

UCL Institute of Child Health/Great Ormond Street; 🇬🇧 London, United Kingdom

British Columbia Children's Hospital/UBC; 🇨🇦 Vancouver, British Columbia, Canada