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

Spinal Muscular Atrophy Clinical Trial

— ENDEAR  

Official title:

A Phase 3, Randomized, Double-Blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients With Infantile-onset Spinal Muscular Atrophy

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02193074
• Other study ID #: ISIS 396443-CS3B
• Secondary ID: 2013-004422-29
• Status: Terminated
• Phase: Phase 3
• Start date: August 19, 2014
• Est. completion date: November 21, 2016

Study information

• Verified date: February 2021
• Source: Biogen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 122
• Est. completion date: November 21, 2016
• Est. primary completion date: November 21, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 210 Days

Eligibility

Key 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 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.

Related Conditions & MeSH terms

• Atrophy
• Muscular Atrophy
• Muscular Atrophy, Spinal
• Spinal Muscular Atrophy

Intervention

Drug:
• nusinersen
Administered by intrathecal (IT) injection as specified in the treatment arm.

Procedure:
• Sham procedure
Small needle prick on the lower back at the location where the IT injection is normally made

Locations

Country	Name	City	State
Australia	Royal Children's Hospital, Children's Neuroscience Centre	Parkville	Victoria
Australia	Sydney Children's Hospital	Sydney	New South Wales
Belgium	Hôpital Universitaire des Enfants Reine FABIOLA (HUDERF)	Brussels
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital/UBC	Vancouver	British Columbia
France	Institut de Myologie	Paris
Germany	Universitatsklinikum Essen	Essen
Germany	Universtatsklinikum Freiburg, Zentrum fur Kinder-und Jugendmedizin , Abteilung Neuropadiatrie und Muskelerkrankungen	Freiburg
Italy	Istituto Giannina Gaslini, Centro Traslazionale di Miologia e Patologie Neurodegenerative	Genova
Italy	Pediatric Neurology Unit, Catholic University	Rome
Japan	Hyogo College of Medicine	Nishinomiya	Hyogo
Japan	Tokyo Women's Medical University	Tokyo
Korea, Republic of	Seoul National University Hospital	Seoul
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitario La Paz, Pediatric Neurology Department	Madrid
Sweden	University of Gothenburg, The Queen Silvia Children's Hospital	Gothenburg
Turkey	Hacettepe Children's Hospital	Ankara
United Kingdom	UCL Institute of Child Health/Great Ormond Street	London
United Kingdom	MRC Centre for Neuromuscular Diseases at Newcastle, Institute of Genetic Medicine Newcastle University	Newcastle
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Ann and Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	UT Southwestern Medical Center/Children's Medical Center Dallas	Dallas	Texas
United States	Duke Children's Hospital	Durham	North Carolina
United States	UCLA Medical Center	Los Angeles	California
United States	Columbia University Medical Center	New York	New York
United States	Nemours Children's Hospital	Orlando	Florida
United States	Children's Hospital of Philadelphia - Neurology	Philadelphia	Pennsylvania
United States	Doernbecher Children's Hospital	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Primary Children's Medical Center (University of Utah)	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Biogen

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Spain,  Sweden,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Motor Milestones Responders	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.	assessed at the later of the Day 183, Day 302, or Day 394 study visits
Primary	Time to Death or Permanent Ventilation	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.	Day 91, Day 182, Day 273, Day 364, Day 394
Secondary	Percentage of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders	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.	assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits
Secondary	Summary of Time to Death	Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method.	Day 91, Day 182, Day 273, Day 364, Day 394
Secondary	Percentage of Participants Not Requiring Permanent Ventilation		Up to Day 394
Secondary	Percentage of Compound Muscular Action Potential (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 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.	assessed at the later of the Day 183, Day 302, or Day 394 study visits
Secondary	Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration	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.	Day 91, Day 182, Day 273, Day 364, Day 394
Secondary	Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration	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.	Day 91, Day 182, Day 273, Day 364, Day 394
Secondary	Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs	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.	Screening through Day 394 (± 7 days) or early termination
Secondary	Number of Participants With AEs Corresponding to Changes in Hematology Values		up to Day 394 (± 7 days) or early termination
Secondary	Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values		up to Day 394 (± 7 days) or early termination
Secondary	Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline		up to Day 394 (± 7 days) or early termination
Secondary	Summary of Shifts in 12-lead Electrocardiogram (ECG) Results	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'.	up to Day 394 (± 7 days) or early termination
Secondary	Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values		up to Day 394 (± 7 days) or early termination

External Links

•   Clinical Study Report (CSR) Synopsis - a results summary
•   Cure SMA
•   Muscular Dystrophy Association
•   National Organization for Rare Diseases