Back to resultsA Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy (ENDEAR)
Primary Purpose
Spinal Muscular Atrophy
Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
nusinersen
Sham procedure
Sponsored by
About this trial
This is an interventional treatment trial for Spinal Muscular Atrophy focused on measuring Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS-SMN Rx, ISIS 396443, IONIS-SMNRx, IONIS-SMN Rx, Spinraza, ENDEAR
Eligibility Criteria
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.
Sites / Locations
- UCLA Medical Center
- Children's Hospital Colorado
- Nemours Children's Hospital
- Ann and Robert H. Lurie Children's Hospital of Chicago
- Boston Children's Hospital
- Washington University School of Medicine
- Columbia University Medical Center
- Duke Children's Hospital
- Doernbecher Children's Hospital
- Children's Hospital of Philadelphia - Neurology
- UT Southwestern Medical Center/Children's Medical Center Dallas
- Primary Children's Medical Center (University of Utah)
- Sydney Children's Hospital
- Royal Children's Hospital, Children's Neuroscience Centre
- Hôpital Universitaire des Enfants Reine FABIOLA (HUDERF)
- British Columbia Children's Hospital/UBC
- Hospital for Sick Children
- Institut de Myologie
- Universitatsklinikum Essen
- Universtatsklinikum Freiburg, Zentrum fur Kinder-und Jugendmedizin , Abteilung Neuropadiatrie und Muskelerkrankungen
- Istituto Giannina Gaslini, Centro Traslazionale di Miologia e Patologie Neurodegenerative
- Pediatric Neurology Unit, Catholic University
- Hyogo College of Medicine
- Tokyo Women's Medical University
- Seoul National University Hospital
- Hospital Universitario Vall d'Hebron
- Hospital Universitario La Paz, Pediatric Neurology Department
- University of Gothenburg, The Queen Silvia Children's Hospital
- Hacettepe Children's Hospital
- UCL Institute of Child Health/Great Ormond Street
- MRC Centre for Neuromuscular Diseases at Newcastle, Institute of Genetic Medicine Newcastle University
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Sham Comparator
Arm Label
nusinersen
Sham procedure
Arm Description
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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.
Summary of Time to Death
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
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.
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.
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.
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.
Number of Participants With AEs Corresponding to Changes in Hematology Values
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline
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'.
Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02193074
Brief Title
A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy
Acronym
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
Study Type
Interventional
2. Study Status
Record Verification Date
February 2021
Overall Recruitment Status
Terminated
Why Stopped
After a positive interim analysis, the decision was made to terminate the study early to allow for participants to enroll into an open label study
Study Start Date
August 19, 2014 (Actual)
Primary Completion Date
November 21, 2016 (Actual)
Study Completion Date
November 21, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Biogen
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spinal Muscular Atrophy
Keywords
Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS-SMN Rx, ISIS 396443, IONIS-SMNRx, IONIS-SMN Rx, Spinraza, ENDEAR
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
122 (Actual)
8. Arms, Groups, and Interventions
Arm Title
nusinersen
Arm Type
Experimental
Arm Title
Sham procedure
Arm Type
Sham Comparator
Intervention Type
Drug
Intervention Name(s)
nusinersen
Other Intervention Name(s)
ISIS 396443, BIIB058, Spinraza, IONIS-SMN Rx, ISIS SMNRx
Intervention Description
Administered by intrathecal (IT) injection as specified in the treatment arm.
Intervention Type
Procedure
Intervention Name(s)
Sham procedure
Intervention Description
Small needle prick on the lower back at the location where the IT injection is normally made
Primary Outcome Measure Information:
Title
Percentage of Motor Milestones Responders
Description
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 Frame
assessed at the later of the Day 183, Day 302, or Day 394 study visits
Title
Time to Death or Permanent Ventilation
Description
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.
Time Frame
Day 91, Day 182, Day 273, Day 364, Day 394
Secondary Outcome Measure Information:
Title
Percentage of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders
Description
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.
Time Frame
assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits
Title
Summary of Time to Death
Description
Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method.
Time Frame
Day 91, Day 182, Day 273, Day 364, Day 394
Title
Percentage of Participants Not Requiring Permanent Ventilation
Time Frame
Up to Day 394
Title
Percentage of Compound Muscular Action Potential (CMAP) Responders
Description
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 Frame
assessed at the later of the Day 183, Day 302, or Day 394 study visits
Title
Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration
Description
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.
Time Frame
Day 91, Day 182, Day 273, Day 364, Day 394
Title
Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration
Description
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.
Time Frame
Day 91, Day 182, Day 273, Day 364, Day 394
Title
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs
Description
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.
Time Frame
Screening through Day 394 (± 7 days) or early termination
Title
Number of Participants With AEs Corresponding to Changes in Hematology Values
Time Frame
up to Day 394 (± 7 days) or early termination
Title
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values
Time Frame
up to Day 394 (± 7 days) or early termination
Title
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline
Time Frame
up to Day 394 (± 7 days) or early termination
Title
Summary of Shifts in 12-lead Electrocardiogram (ECG) Results
Description
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'.
Time Frame
up to Day 394 (± 7 days) or early termination
Title
Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values
Time Frame
up to Day 394 (± 7 days) or early termination
10. Eligibility
Sex
All
Maximum Age & Unit of Time
210 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Biogen
Official's Role
Study Director
Facility Information:
Facility Name
UCLA Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Nemours Children's Hospital
City
Orlando
State/Province
Florida
ZIP/Postal Code
32827
Country
United States
Facility Name
Ann and Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Duke Children's Hospital
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Doernbecher Children's Hospital
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Children's Hospital of Philadelphia - Neurology
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
UT Southwestern Medical Center/Children's Medical Center Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States
Facility Name
Primary Children's Medical Center (University of Utah)
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Facility Name
Sydney Children's Hospital
City
Sydney
State/Province
New South Wales
ZIP/Postal Code
2031
Country
Australia
Facility Name
Royal Children's Hospital, Children's Neuroscience Centre
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3052
Country
Australia
Facility Name
Hôpital Universitaire des Enfants Reine FABIOLA (HUDERF)
City
Brussels
ZIP/Postal Code
15 - 1020
Country
Belgium
Facility Name
British Columbia Children's Hospital/UBC
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6H 3N1
Country
Canada
Facility Name
Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Institut de Myologie
City
Paris
ZIP/Postal Code
75012
Country
France
Facility Name
Universitatsklinikum Essen
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
Universtatsklinikum Freiburg, Zentrum fur Kinder-und Jugendmedizin , Abteilung Neuropadiatrie und Muskelerkrankungen
City
Freiburg
ZIP/Postal Code
79106
Country
Germany
Facility Name
Istituto Giannina Gaslini, Centro Traslazionale di Miologia e Patologie Neurodegenerative
City
Genova
ZIP/Postal Code
16148
Country
Italy
Facility Name
Pediatric Neurology Unit, Catholic University
City
Rome
ZIP/Postal Code
00153
Country
Italy
Facility Name
Hyogo College of Medicine
City
Nishinomiya
State/Province
Hyogo
ZIP/Postal Code
663-8131
Country
Japan
Facility Name
Tokyo Women's Medical University
City
Tokyo
ZIP/Postal Code
162-8666
Country
Japan
Facility Name
Seoul National University Hospital
City
Seoul
Country
Korea, Republic of
Facility Name
Hospital Universitario Vall d'Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital Universitario La Paz, Pediatric Neurology Department
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
University of Gothenburg, The Queen Silvia Children's Hospital
City
Gothenburg
Country
Sweden
Facility Name
Hacettepe Children's Hospital
City
Ankara
ZIP/Postal Code
06230
Country
Turkey
Facility Name
UCL Institute of Child Health/Great Ormond Street
City
London
ZIP/Postal Code
WC1N 1EH
Country
United Kingdom
Facility Name
MRC Centre for Neuromuscular Diseases at Newcastle, Institute of Genetic Medicine Newcastle University
City
Newcastle
ZIP/Postal Code
NE1 3BZ
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
31420846
Citation
Darras BT, Farrar MA, Mercuri E, Finkel RS, Foster R, Hughes SG, Bhan I, Farwell W, Gheuens S. An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. CNS Drugs. 2019 Sep;33(9):919-932. doi: 10.1007/s40263-019-00656-w.
Results Reference
derived
PubMed Identifier
30879249
Citation
Dabbous O, Maru B, Jansen JP, Lorenzi M, Cloutier M, Guerin A, Pivneva I, Wu EQ, Arjunji R, Feltner D, Sproule DM. Survival, Motor Function, and Motor Milestones: Comparison of AVXS-101 Relative to Nusinersen for the Treatment of Infants with Spinal Muscular Atrophy Type 1. Adv Ther. 2019 May;36(5):1164-1176. doi: 10.1007/s12325-019-00923-8. Epub 2019 Mar 16.
Results Reference
derived
PubMed Identifier
29091570
Citation
Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC; ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1723-1732. doi: 10.1056/NEJMoa1702752.
Results Reference
derived
PubMed Identifier
27939059
Citation
Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016 Dec 17;388(10063):3017-3026. doi: 10.1016/S0140-6736(16)31408-8. Epub 2016 Dec 7.
Results Reference
derived
Links:
URL
http://www.curesma.org
Description
Cure SMA
URL
http://mda.org/disease/spinal-muscular-atrophy
Description
Muscular Dystrophy Association
URL
https://www.rarediseases.org
Description
National Organization for Rare Diseases
URL
http://clinicalresearch.biogen.com/Content/Studies/CS3b%20Biogen.com%20Packet.pdf
Description
Clinical Study Report (CSR) Synopsis - a results summary
Learn more about this trial
A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy
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