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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Spinal Muscular Atrophy	Drug: nusinersen	Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	21 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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
Actual Study Start Date :	May 8, 2013
Actual Primary Completion Date :	August 21, 2017
Actual Study Completion Date :	August 21, 2017

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Nusinersen 6 mg	Drug: nusinersen; Administered by intrathecal (IT) injection; Other Names: ISIS 396443; Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx
Experimental: Nusinersen 12 mg	Drug: nusinersen; Administered by intrathecal (IT) injection; Other Names: ISIS 396443; Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx

Outcome Measures

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Primary Outcome Measures :

1. Percent of Participants Who Achieved Improvement in Motor Milestones as Assessed by Section 2 of the HINE at the Last Visit [ Time Frame: Day 1352 or Early Termination ]
   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 :

1. Event-free Survival at the End of Study [ Time Frame: Up to Day 1638 ]
   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.
2. Percent of Participants With Improved Motor Function at the Last Visit as Assessed by the CHOP-INTEND Motor Function Scale [ Time Frame: Day 1352 or Early Termination ]
   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.
3. Change in Neuromuscular Electrophysiology at the Last Visit as Assessed by the Change From Baseline in CMAP Amplitude [ Time Frame: Baseline, Day 1072 ]
   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.
4. Number of Participants Experiencing Adverse Events (AEs) and/or Serious Adverse Events (SAEs) [ Time Frame: Up to Day 1352 ]
   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.
5. Concentration of Nusinersen in Cerebrospinal Fluid (CSF) [ Time Frame: Day 1135 (Predose) ]
   The concentration of nusinersen in CSF was measured by using standard laboratory assays.
6. PK Parameters of Nusinersen in Plasma: Maximum Concentration (Cmax) [ Time Frame: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose ) ]
   Cmax is the maximum observed concentration of study drug in plasma.
7. PK Parameters of Nusinersen in Plasma: Time to Reach Cmax (Tmax) [ Time Frame: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose ) ]
   Tmax is the time at which Cmax occurs.
8. 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) [ Time Frame: Day 1 (Predose and 1, 2, and 4 hours [hr] Postdose) and Day 2 (24 hr Postdose ) ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	up to 210 Days (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

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Locations

United States, California
Stanford University Medical Center
Stanford, California, United States, 94305
United States, Florida
Nemours Children's Hospital
Orlando, Florida, United States, 32827
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
Canada, Ontario
The Hospital for Sick Children (SickKids)
Toronto, Ontario, Canada, M5G 1X8

Sponsors and Collaborators

Biogen

Investigators

Study Director:	Medical Director	Biogen

  Study Documents (Full-Text)

Documents provided by Biogen:

Study Protocol  [PDF] January 25, 2016

Statistical Analysis Plan  [PDF] February 10, 2016

More Information

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Additional Information:

Cure SMA  Muscular Dystrophy Association  National Organization for Rare Diseases 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Responsible Party:	Biogen
ClinicalTrials.gov Identifier:	NCT01839656 History of Changes
Other Study ID Numbers:	ISIS 396443-CS3A; 2017-000621-12 ( EudraCT Number )
First Posted:	April 25, 2013
Results First Posted:	October 30, 2018
Last Update Posted:	October 30, 2018
Last Verified:	October 2018

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Biogen:

Spinal Muscular Atrophy; SMA; SMN; SMNRx; ISIS-SMNRx	ISIS 396443; IONIS-SMNRx; Spinraza; Nusinersen

Additional relevant MeSH terms:

Atrophy; Muscular Atrophy; Muscular Atrophy, Spinal; Spinal Cord Diseases; Pathological Conditions, Anatomical; Neuromuscular Manifestations; Neurologic Manifestations	Nervous System Diseases; Signs and Symptoms; Central Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases