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NCT02193074: ENDEAR

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

Terminated Phase 3 Results posted Last updated 17 February 2021
What this trial tests

Phase 3 trial testing nusinersen in Spinal Muscular Atrophy in 122 participants. Terminated before completion.

Timeline
19 August 2014
Primary endpoint
21 November 2016
21 November 2016

Quick facts

Lead sponsorBiogen
PhasePhase 3
StatusTerminated
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment122
Start date19 August 2014
Primary completion21 November 2016
Estimated completion21 November 2016
Sites31 locations across France, Italy, Japan, Belgium, Sweden, United Kingdom, Germany, South Korea

Drugs / interventions tested

Conditions studied

Sponsor

Biogen — full company profile →

Who can join

Under 210 Days, any sex, with Spinal Muscular Atrophy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Motor Milestones Responders Primary · 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,

GroupValue95% CI
Control0
Nusinersen51
Time to Death or Permanent Ventilation Primary · 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.

By Day 91 (13 weeks/3 months)
GroupValue95% CI
Control0.268
Nusinersen0.240
By Day 182 (26 weeks/6 months)
GroupValue95% CI
Control0.605
Nusinersen0.294
By Day 273 (39 weeks/9 months)
GroupValue95% CI
Control0.702
Nusinersen0.404
By Day 364 (52 weeks/12 months)
GroupValue95% CI
Control0.735
Nusinersen0.447
By Day 394 (13 months)
GroupValue95% CI
Control0.735
Nusinersen0.447
Percentage of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders Secondary · 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.

GroupValue95% CI
Control3
Nusinersen71
Summary of Time to Death Secondary · 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.

by Day 91
GroupValue95% CI
Control0.195
Nusinersen0.101
by Day 182
GroupValue95% CI
Control0.348
Nusinersen0.141
by Day 273
GroupValue95% CI
Control0.382
Nusinersen0.173
by Day 364
GroupValue95% CI
Control0.419
Nusinersen0.173
by Day 394
GroupValue95% CI
Control0.419
Nusinersen0.173
Percentage of Participants Not Requiring Permanent Ventilation Secondary · Up to Day 394
GroupValue95% CI
Control68
Nusinersen77
Percentage of Compound Muscular Action Potential (CMAP) Responders Secondary · 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.

GroupValue95% CI
Control5
Nusinersen36
Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration Secondary · 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.

by Day 91
GroupValue95% CI
Control0.238
Nusinersen0.128
by Day 182
GroupValue95% CI
Control0.546
Nusinersen0.128
by Day 273
GroupValue95% CI
Control0.697
Nusinersen0.228
by Day 364
GroupValue95% CI
Control0.773
Nusinersen0.271
by Day 394
GroupValue95% CI
Control0.773
Nusinersen0.271
Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration Secondary · 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.

by Day 91
GroupValue95% CI
Control0.300
Nusinersen0.350
by Day 182
GroupValue95% CI
Control0.670
Nusinersen0.462
by Day 273
GroupValue95% CI
Control0.725
Nusinersen0.584
by Day 364
GroupValue95% CI
Control0.725
Nusinersen0.625
by Day 394
GroupValue95% CI
Control0.725
Nusinersen0.625
Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs Secondary · 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 abili

Any event
GroupValue95% CI
Control40
Nusinersen77
Moderate or severe event
GroupValue95% CI
Control39
Nusinersen70
Severe event
GroupValue95% CI
Control33
Nusinersen45
Possibly related or related event
GroupValue95% CI
Control6
Nusinersen9
Related event
GroupValue95% CI
Control0
Nusinersen0
Serious event
GroupValue95% CI
Control39
Nusinersen61
Related serious event
GroupValue95% CI
Control0
Nusinersen0
Treatment discontinuation due to an event
GroupValue95% CI
Control16
Nusinersen13
Number of Participants With AEs Corresponding to Changes in Hematology Values Secondary · up to Day 394 (± 7 days) or early termination
Anemia
GroupValue95% CI
Control1
Nusinersen1
Neutrophil count increased
GroupValue95% CI
Control0
Nusinersen1
Leukocytosis
GroupValue95% CI
Control1
Nusinersen0
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values Secondary · up to Day 394 (± 7 days) or early termination
Blood potassium decreased
GroupValue95% CI
Control0
Nusinersen2
Liver function test abnormal
GroupValue95% CI
Control0
Nusinersen1
Alanine aminotransferase increased
GroupValue95% CI
Control0
Nusinersen1
Aspartate aminotransferase increased
GroupValue95% CI
Control0
Nusinersen1
Blood chloride decreased
GroupValue95% CI
Control0
Nusinersen1
Blood iron decreased
GroupValue95% CI
Control0
Nusinersen1
Blood sodium decreased
GroupValue95% CI
Control0
Nusinersen1
C-reactive protein increased
GroupValue95% CI
Control1
Nusinersen2
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline Secondary · up to Day 394 (± 7 days) or early termination
Systolic blood pressure <90 mmHg
GroupValue95% CI
Control36
Nusinersen74
Systolic blood pressure >140 mmHg
GroupValue95% CI
Control4
Nusinersen4
Systolic blood pressure >160 mmHg
GroupValue95% CI
Control0
Nusinersen0
Diastolic blood pressure <50 mmHg
GroupValue95% CI
Control26
Nusinersen71
Diastolic blood pressure >90 mmHg
GroupValue95% CI
Control13
Nusinersen12
Diastolic blood pressure >100 mmHg
GroupValue95% CI
Control3
Nusinersen0
Pulse rate <60 bpm
GroupValue95% CI
Control0
Nusinersen0
Pulse rate >100 bpm
GroupValue95% CI
Control41
Nusinersen80

Adverse events — posted to ClinicalTrials.gov

Time frame: Screening through Day 394 (± 7 days) or early termination. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Control
Serious: 39/41 (95%)
Deaths:
Nusinersen
Serious: 61/80 (76%)
Deaths:

Serious adverse events (92 terms)

ReactionSystemControlNusinersen
Respiratory distressRespiratory, thoracic and mediastinal disorders
Respiratory failureRespiratory, thoracic and mediastinal disorders
PneumoniaInfections and infestations
AtelectasisRespiratory, thoracic and mediastinal disorders
Acute respiratory failureRespiratory, thoracic and mediastinal disorders
Pneumonia aspirationRespiratory, thoracic and mediastinal disorders
Rhinovirus infectionInfections and infestations
Pneumonia viralInfections and infestations
Respiratory tract infectionInfections and infestations
Viral upper respiratory tract infectionInfections and infestations
Cardio-respiratory arrestCardiac disorders
Viral infectionInfections and infestations
Bronchial secretion retentionRespiratory, thoracic and mediastinal disorders
Respiratory arrestRespiratory, thoracic and mediastinal disorders
PyrexiaGeneral disorders
BronchiolitisInfections and infestations
BronchitisInfections and infestations
Lower respiratory tract infectionInfections and infestations
Respiratory syncytial virus bronchiolitisInfections and infestations
Upper respiratory tract infectionInfections and infestations
DyspnoeaRespiratory, thoracic and mediastinal disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
VomitingGastrointestinal disorders
Bronchitis viralInfections and infestations
Pneumonia bacterialInfections and infestations
Other adverse events (51 terms — click to expand)

ReactionSystemControlNusinersen
PyrexiaGeneral disorders
ConstipationGastrointestinal disorders
Upper respiratory tract infectionInfections and infestations
TeethingGastrointestinal disorders
NasopharyngitisInfections and infestations
DiarrhoeaGastrointestinal disorders
VomitingGastrointestinal disorders
Gastrooesophageal reflux diseaseGastrointestinal disorders
DysphagiaGastrointestinal disorders
Oxygen saturation decreasedInvestigations
AtelectasisRespiratory, thoracic and mediastinal disorders
CoughRespiratory, thoracic and mediastinal disorders
RashSkin and subcutaneous tissue disorders
Nasal congestionRespiratory, thoracic and mediastinal disorders
TachycardiaCardiac disorders
Oral candidiasisInfections and infestations
PneumoniaInfections and infestations
Salivary hypersecretionGastrointestinal disorders
Urinary tract infectionInfections and infestations
Viral upper respiratory tract infectionInfections and infestations
Respiratory distressRespiratory, thoracic and mediastinal disorders
Respiratory failureRespiratory, thoracic and mediastinal disorders
RhinorrhoeaRespiratory, thoracic and mediastinal disorders
Upper respiratory tract congestionRespiratory, thoracic and mediastinal disorders
Dermatitis diaperSkin and subcutaneous tissue disorders
ConjunctivitisInfections and infestations
Ear infectionInfections and infestations
InfluenzaInfections and infestations
BradycardiaCardiac disorders
FlatulenceGastrointestinal disorders
Bacterial tracheitisInfections and infestations
BronchiolitisInfections and infestations
Respiratory tract infectionInfections and infestations
Rhinovirus infectionInfections and infestations
Viral infectionInfections and infestations
Weight decreasedInvestigations
ScoliosisMusculoskeletal and connective tissue disorders
Bronchial secretion retentionRespiratory, thoracic and mediastinal disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
HypoxiaRespiratory, thoracic and mediastinal disorders

Most-reported serious reactions: Respiratory distress, Respiratory failure, Pneumonia, Atelectasis, Acute respiratory failure, Pneumonia aspiration, Rhinovirus infection, Pneumonia viral.

Data from ClinicalTrials.gov NCT02193074 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy.
    Finkel RS, Mercuri E, Darras BT, Connolly AM, et al · · 2017 · cited 1659× · PMID 29091570 · DOI 10.1056/nejmoa1702752
  2. Splice-switching antisense oligonucleotides as therapeutic drugs.
    Havens MA, Hastings ML. · · 2016 · cited 402× · PMID 27288447 · DOI 10.1093/nar/gkw533
  3. A walk through tau therapeutic strategies.
    Jadhav S, Avila J, Schöll M, Kovacs GG, et al · · 2019 · cited 216× · PMID 30767766 · DOI 10.1186/s40478-019-0664-z
  4. Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases.
    Schoch KM, Miller TM. · · 2017 · cited 211× · PMID 28641106 · DOI 10.1016/j.neuron.2017.04.010
  5. LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model.
    Zhao HT, John N, Delic V, Ikeda-Lee K, et al · · 2017 · cited 179× · PMID 28918051 · DOI 10.1016/j.omtn.2017.08.002
  6. Neurofilament as a potential biomarker for spinal muscular atrophy.
    Darras BT, Crawford TO, Finkel RS, Mercuri E, et al · · 2019 · cited 173× · PMID 31139691 · DOI 10.1002/acn3.779
  7. Clinical Evidence Supporting Early Treatment Of Patients With Spinal Muscular Atrophy: Current Perspectives.
    Dangouloff T, Servais L. · · 2019 · cited 149× · PMID 31632042 · DOI 10.2147/tcrm.s172291
  8. Gene-based therapies for neurodegenerative diseases.
    Sun J, Roy S. · · 2021 · cited 126× · PMID 33526943 · DOI 10.1038/s41593-020-00778-1

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing