Back to resultsA Study to Assess the Efficacy, Safety and Pharmacokinetics of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy (SMA)
Primary Purpose
Spinal Muscular Atrophy
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
nusinersen
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 396443, IONIS-SMNRx, Spinraza, Nusinersen
Eligibility Criteria
Key Inclusion Criteria:
- Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
- Onset of clinical signs and symptoms consistent with SMA at ≥ 21 days and <6 months (180 days) of age
- At study entry, receiving adequate nutrition and hydration (with or without gastrostomy), in the opinion of the Site Investigator
- Body weight >5th percentile for age using Center of Disease Control and Prevention (CDC) guidelines
- Medical care meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA (Wang et al. 2007), in the opinion of the Site Investigator
- Gestational age of 35 to 42 weeks and gestation body weight ≥2 kg
- Reside within approximately 9 hours ground-travel distance from a participating study center for the duration of the study. Residence >2 hours ground-travel distance from a study center must obtain clearance from the Site Investigator and the study Medical Monitor
- Able to complete all study procedures, measurements and visits and parent or guardian/participant has adequately supportive psychosocial circumstances, in the opinion of the Site Investigator
Exclusion Criteria:
- Hypoxemia (O2 saturation awake <96% or O2 saturation asleep <96%, without ventilation support)
- Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
- History of brain or spinal cord disease that would interfere with the lumbar puncture (LP) procedures, CSF circulation, or safety assessments
- Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
- History of bacterial meningitis
- Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Site Investigator, at screening that would render the participant unsuitable for inclusion
- Treatment with another investigational drug (e.g., albuterol, riluzole, carnitine, creatine, sodium phenylbutyrate, salbutamol, valproate, hydroxyurea etc), biological agent, or device within 90 days prior to enrollment or anytime during the study. Any history of gene therapy or cell transplantation
- The participants parent(s) or legal guardian(s) is unable to understand the nature, scope, and possible consequences of the study, or does not agree to comply with the protocol defined schedule of assessments
- Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere with the assessment of safety or would compromise the ability of the participant to undergo study procedures
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
Sites / Locations
- Stanford University Medical Center
- Nemours Children's Hospital
- Columbia University Medical Center
- The Hospital for Sick Children (SickKids)
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Nusinersen 6 mg
Nusinersen 12 mg
Arm Description
Outcomes
Primary Outcome Measures
Percent of Participants Who Achieved Improvement in Motor Milestones as Assessed by Section 2 of the HINE at the Last Visit
Section 2 of HINE consists of 8 independent milestone categories. Within each of these categories, participants can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. Overall, there are a total of 26 milestones that can be achieved across the 8 categories. Improvement was defined as any of the following: 1. An increase from baseline of 2 milestones or more, or the achievement of pincer grasp in the voluntary grasp category 2. An increase from baseline of 2 milestones or more, or achievement of touching toes in the ability to kick category 3. An increase from baseline of 1 milestone or more in any of the remaining 6 categories: head control, rolling, sitting, crawling, standing, or walking.
Secondary Outcome Measures
Event-free Survival at the End of Study
Event-free survival was defined as the percent of participants who were alive and did not require permanent ventilatory support (defined as tracheostomy or the need for ≥16 hours ventilation/day continuously for at least 2 weeks in the absence of an acute reversible illness) Event-free survival was estimated using Kaplan-Meier methodology.
Percent of Participants With Improved Motor Function at the Last Visit as Assessed by the CHOP-INTEND Motor Function Scale
The CHOP-INTEND test includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0 (worst) to 4 (best). Total scores range from 0 to 64, with higher scores indicating better movement functioning. Improvement was defined as an increase in total CHOP INTEND score ≥4 points from baseline as of the last study visit.
Change in Neuromuscular Electrophysiology at the Last Visit as Assessed by the Change From Baseline in CMAP Amplitude
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 positive change from Baseline indicates that the number of motor neurons increased.
Number of Participants Experiencing Adverse Events (AEs) and/or Serious Adverse Events (SAEs)
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 subject (whether male or female); is an important medical event in the opinion of the Investigator or Sponsor.
Concentration of Nusinersen in Cerebrospinal Fluid (CSF)
The concentration of nusinersen in CSF was measured by using standard laboratory assays.
PK Parameters of Nusinersen in Plasma: Maximum Concentration (Cmax)
Cmax is the maximum observed concentration of study drug in plasma.
PK Parameters of Nusinersen in Plasma: Time to Reach Cmax (Tmax)
Tmax is the time at which Cmax occurs.
PK Parameters of Nusinersen in Plasma: Area Under the Plasma Concentrations Time Curve From the Time of the IT Dose to Four Hours After Dosing (AUC0-4)
AUC is area under the plasma concentration-time curve from zero time (Predose) to 4 hours after IT administration of study drug. AUC was determined by using the linear trapezoidal rule.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01839656
Brief Title
A Study to Assess the Efficacy, Safety and Pharmacokinetics of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy (SMA)
Official Title
A Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients With Infantile-Onset Spinal Muscular Atrophy
Study Type
Interventional
2. Study Status
Record Verification Date
February 2021
Overall Recruitment Status
Completed
Study Start Date
May 8, 2013 (Actual)
Primary Completion Date
August 21, 2017 (Actual)
Study Completion Date
August 21, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Biogen
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The primary objective is to examine the clinical efficacy of multiple doses of nusinersen (ISIS 396443) administered intrathecally to participants with Infantile-Onset Spinal Muscular Atrophy (SMA). The secondary objectives are to examine the safety and tolerability of multiple doses of nusinersen administered intrathecally to participants with infantile-onset SMA and to examine the cerebral spinal fluid (CSF) and plasma Pharmacokinetics (PK) of multiple doses 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 396443, IONIS-SMNRx, Spinraza, Nusinersen
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
21 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Nusinersen 6 mg
Arm Type
Experimental
Arm Title
Nusinersen 12 mg
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
nusinersen
Other Intervention Name(s)
ISIS 396443, Spinraza, BIIB058, IONIS SMN Rx, ISIS SMNRx
Intervention Description
Administered by intrathecal (IT) injection
Primary Outcome Measure Information:
Title
Percent of Participants Who Achieved Improvement in Motor Milestones as Assessed by Section 2 of the HINE at the Last Visit
Description
Section 2 of HINE consists of 8 independent milestone categories. Within each of these categories, participants can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. Overall, there are a total of 26 milestones that can be achieved across the 8 categories. Improvement was defined as any of the following: 1. An increase from baseline of 2 milestones or more, or the achievement of pincer grasp in the voluntary grasp category 2. An increase from baseline of 2 milestones or more, or achievement of touching toes in the ability to kick category 3. An increase from baseline of 1 milestone or more in any of the remaining 6 categories: head control, rolling, sitting, crawling, standing, or walking.
Time Frame
Day 1352 or Early Termination
Secondary Outcome Measure Information:
Title
Event-free Survival at the End of Study
Description
Event-free survival was defined as the percent of participants who were alive and did not require permanent ventilatory support (defined as tracheostomy or the need for ≥16 hours ventilation/day continuously for at least 2 weeks in the absence of an acute reversible illness) Event-free survival was estimated using Kaplan-Meier methodology.
Time Frame
Up to Day 1638
Title
Percent of Participants With Improved Motor Function at the Last Visit as Assessed by the CHOP-INTEND Motor Function Scale
Description
The CHOP-INTEND test includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0 (worst) to 4 (best). Total scores range from 0 to 64, with higher scores indicating better movement functioning. Improvement was defined as an increase in total CHOP INTEND score ≥4 points from baseline as of the last study visit.
Time Frame
Day 1352 or Early Termination
Title
Change in Neuromuscular Electrophysiology at the Last Visit as Assessed by the Change From Baseline in CMAP Amplitude
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 positive change from Baseline indicates that the number of motor neurons increased.
Time Frame
Baseline, Day 1072
Title
Number of Participants Experiencing Adverse Events (AEs) and/or Serious Adverse Events (SAEs)
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 subject (whether male or female); is an important medical event in the opinion of the Investigator or Sponsor.
Time Frame
Up to Day 1352
Title
Concentration of Nusinersen in Cerebrospinal Fluid (CSF)
Description
The concentration of nusinersen in CSF was measured by using standard laboratory assays.
Time Frame
Day 1135 (Predose)
Title
PK Parameters of Nusinersen in Plasma: Maximum Concentration (Cmax)
Description
Cmax is the maximum observed concentration of study drug in plasma.
Time Frame
Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
Title
PK Parameters of Nusinersen in Plasma: Time to Reach Cmax (Tmax)
Description
Tmax is the time at which Cmax occurs.
Time Frame
Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
Title
PK Parameters of Nusinersen in Plasma: Area Under the Plasma Concentrations Time Curve From the Time of the IT Dose to Four Hours After Dosing (AUC0-4)
Description
AUC is area under the plasma concentration-time curve from zero time (Predose) to 4 hours after IT administration of study drug. AUC was determined by using the linear trapezoidal rule.
Time Frame
Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose )
10. Eligibility
Sex
All
Minimum Age & Unit of Time
21 Days
Maximum Age & Unit of Time
210 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
Onset of clinical signs and symptoms consistent with SMA at ≥ 21 days and <6 months (180 days) of age
At study entry, receiving adequate nutrition and hydration (with or without gastrostomy), in the opinion of the Site Investigator
Body weight >5th percentile for age using Center of Disease Control and Prevention (CDC) guidelines
Medical care meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA (Wang et al. 2007), in the opinion of the Site Investigator
Gestational age of 35 to 42 weeks and gestation body weight ≥2 kg
Reside within approximately 9 hours ground-travel distance from a participating study center for the duration of the study. Residence >2 hours ground-travel distance from a study center must obtain clearance from the Site Investigator and the study Medical Monitor
Able to complete all study procedures, measurements and visits and parent or guardian/participant has adequately supportive psychosocial circumstances, in the opinion of the Site Investigator
Exclusion Criteria:
Hypoxemia (O2 saturation awake <96% or O2 saturation asleep <96%, without ventilation support)
Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
History of brain or spinal cord disease that would interfere with the lumbar puncture (LP) procedures, CSF circulation, or safety assessments
Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
History of bacterial meningitis
Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Site Investigator, at screening that would render the participant unsuitable for inclusion
Treatment with another investigational drug (e.g., albuterol, riluzole, carnitine, creatine, sodium phenylbutyrate, salbutamol, valproate, hydroxyurea etc), biological agent, or device within 90 days prior to enrollment or anytime during the study. Any history of gene therapy or cell transplantation
The participants parent(s) or legal guardian(s) is unable to understand the nature, scope, and possible consequences of the study, or does not agree to comply with the protocol defined schedule of assessments
Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere with the assessment of safety or would compromise the ability of the participant to undergo study procedures
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
Stanford University Medical Center
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Nemours Children's Hospital
City
Orlando
State/Province
Florida
ZIP/Postal Code
32827
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
The Hospital for Sick Children (SickKids)
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
12. IPD Sharing Statement
Citations:
PubMed Identifier
34089650
Citation
Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Bishop KM, Foster R, Liu Y, Ramirez-Schrempp D, Schneider E, Bennett CF, Wong J, Farwell W. Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. Lancet Child Adolesc Health. 2021 Jul;5(7):491-500. doi: 10.1016/S2352-4642(21)00100-0. Epub 2021 Jun 3.
Results Reference
derived
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
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/CS3A_Biogen.com%20Packet_Redacted.pdf
Description
Clinical Study Report (CSR) Synopsis - a results summary
Learn more about this trial
A Study to Assess the Efficacy, Safety and Pharmacokinetics of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy (SMA)
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