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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02193074




Registration number
NCT02193074
Ethics application status
Date submitted
14/07/2014
Date registered
17/07/2014
Date last updated
28/07/2017

Titles & IDs
Public title
A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy
Scientific 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
Secondary ID [1] 0 0
2013-004422-29
Secondary ID [2] 0 0
ISIS 396443-CS3B
Universal Trial Number (UTN)
Trial acronym
ENDEAR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Spinal Muscular Atrophy 0 0
Condition category
Condition code
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Neurological 0 0 0 0
Other neurological disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - nusinersen
Treatment: Surgery - Sham procedure

Experimental: nusinersen -

Sham Comparator: Sham procedure -


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

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

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
assessed at the later of the Day 183, Day 302, or Day 394 study visits
Primary outcome [2] 0 0
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.
Timepoint [2] 0 0
Day 91, Day 182, Day 273, Day 364, Day 394
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits
Secondary outcome [2] 0 0
Summary of Time to Death - Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method.
Timepoint [2] 0 0
Day 91, Day 182, Day 273, Day 364, Day 394
Secondary outcome [3] 0 0
Percentage of Participants Not Requiring Permanent Ventilation
Timepoint [3] 0 0
Up to Day 394
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
assessed at the later of the Day 183, Day 302, or Day 394 study visits
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
Day 91, Day 182, Day 273, Day 364, Day 394
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
Day 91, Day 182, Day 273, Day 364, Day 394
Secondary outcome [7] 0 0
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.
Timepoint [7] 0 0
Screening through Day 394 (± 7 days) or early termination
Secondary outcome [8] 0 0
Number of Participants With AEs Corresponding to Changes in Hematology Values
Timepoint [8] 0 0
up to Day 394 (± 7 days) or early termination
Secondary outcome [9] 0 0
Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values
Timepoint [9] 0 0
up to Day 394 (± 7 days) or early termination
Secondary outcome [10] 0 0
Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline
Timepoint [10] 0 0
up to Day 394 (± 7 days) or early termination
Secondary outcome [11] 0 0
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'.
Timepoint [11] 0 0
up to Day 394 (± 7 days) or early termination
Secondary outcome [12] 0 0
Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values
Timepoint [12] 0 0
up to Day 394 (± 7 days) or early termination

Eligibility
Key inclusion criteria
Key

- 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
Minimum age
No limit
Maximum age
210 Days
Gender
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Sydney
Recruitment hospital [2] 0 0
Royal Children's Hospital, Children's Neuroscience Centre - Parkville
Recruitment postcode(s) [1] 0 0
2031 - Sydney
Recruitment postcode(s) [2] 0 0
3052 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Illinois
Country [5] 0 0
United States of America
State/province [5] 0 0
Massachusetts
Country [6] 0 0
United States of America
State/province [6] 0 0
Missouri
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
North Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Oregon
Country [10] 0 0
United States of America
State/province [10] 0 0
Pennsylvania
Country [11] 0 0
United States of America
State/province [11] 0 0
Texas
Country [12] 0 0
United States of America
State/province [12] 0 0
Utah
Country [13] 0 0
Belgium
State/province [13] 0 0
Brussels
Country [14] 0 0
Canada
State/province [14] 0 0
British Columbia
Country [15] 0 0
Canada
State/province [15] 0 0
Ontario
Country [16] 0 0
France
State/province [16] 0 0
Paris
Country [17] 0 0
Germany
State/province [17] 0 0
Essen
Country [18] 0 0
Germany
State/province [18] 0 0
Freiburg
Country [19] 0 0
Italy
State/province [19] 0 0
Genova
Country [20] 0 0
Italy
State/province [20] 0 0
Rome
Country [21] 0 0
Japan
State/province [21] 0 0
Hyogo
Country [22] 0 0
Japan
State/province [22] 0 0
Tokyo
Country [23] 0 0
Korea, Republic of
State/province [23] 0 0
Seoul
Country [24] 0 0
Spain
State/province [24] 0 0
Barcelona
Country [25] 0 0
Spain
State/province [25] 0 0
Madrid
Country [26] 0 0
Sweden
State/province [26] 0 0
Gothenburg
Country [27] 0 0
Turkey
State/province [27] 0 0
Ankara
Country [28] 0 0
United Kingdom
State/province [28] 0 0
London
Country [29] 0 0
United Kingdom
State/province [29] 0 0
Newcastle

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Biogen
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02193074
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Biogen
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02193074