An Open-label Safety and Tolerability Study of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA) Who Previously Participated in ISIS 396443-CS2 (NCT01703988) or ISIS 396443-CS10 (NCT01780246)

An Open-label Study to Assess the Safety and Tolerability of ISIS 396443 in Patients With Spinal Muscular Atrophy Who Previously Participated in 396443-CS2 or 396443-CS10

The primary objective of this study is to examine the safety and tolerability of nusinersen (ISIS 396443) administered intrathecally to participants with Spinal Muscular Atrophy (SMA) who previously participated in ISIS 396443-CS2 (NCT01703988) or ISIS 396443-CS10 (NCT01780246). The secondary objective is to examine the plasma and cerebrospinal fluid (CSF) pharmacokinetic(s) (PK) of nusinersen administered intrathecally to participants with SMA who previously participated in ISIS 396443-CS2 or ISIS 396443-CS10.

Study Overview

• Status: Completed
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Drug: nusinersen

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 Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 1

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Texas
    • Dallas, Texas, United States, 75207
      • UT Southwestern Medical Center - Children's Medical Center Dallas
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Clinical signs attributable to Spinal Muscular Atrophy
• Satisfactory completion of dosing and all study visits in ISIS 396443-CS2 (NCT01703988) or ISIS 396443 CS10 (NCT01780246) with an acceptable safety profile, per Investigator judgement.
• Able to complete all study procedures, measurements and visits and parent/participant has adequately supportive psychosocial circumstances, in the opinion of the investigator
• Estimated life expectancy > 2 years from Screening
• Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedure

Key Exclusion Criteria:

• Have any new or worsening of existing condition which in the opinion of the Investigator would make the subject unsuitable for enrollment, or could interfere with the participant participating in or completing the study.
• Dosing in ISIS 396443-CS2 (NCT01703988) or ISIS 396443-CS10 (NCT01780246) within 180 days (6 months) of screening, or longer ago than 396 days (13 months) from screening
• Hospitalization for surgery (i.e. scoliosis surgery) or pulmonary event within 2 months of screening or planned during the duration of the study
• Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy
• Clinically significant abnormalities in hematology or clinical chemistry parameters
• Treatment with another investigational drug, biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Any history of gene therapy or cell transplantation.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: nusinersen	Drug: nusinersen; Administered by intrathecal (IT) injection; Other Names: ISIS 396443; Spinraza; BIIB058; IONIS SMN Rx; ISIS SMNRx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of participants that experience Adverse Events (AEs) and Serious Adverse Events	Up to 24 Months
Number of participants with clinically significant neurological examination abnormalities	Up to 24 Months
Number of participants with clinically significant vital sign abnormalities	Up to 24 Months
Number of participants with clinically significant physical examination abnormalities	Up to 24 Months
Number of participants with clinically significant weight abnormalities	Up to 24 Months
Number of participants with clinically significant laboratory parameters	Up to 24 Months
Number or participants with clinically significant cerbrospinal fluid (CSF) laboratory parameters	Up to Day 176
Number of participants with clinically significant electrocardiograms (ECGs) abnormalities	Up to 24 Months
Change from Baseline in concomitant medications	Up to 24 Months

Secondary Outcome Measures

Outcome Measure	Time Frame
PK parameters of nusinersen (ISIS 396443) in CSF levels: Maximum observed plasma drug concentration (Cmax)	Pre-dose Day 176, Day 358 and Day 540
PK parameters of nusinersen in CSF levels: Time to reach maximum observed concentration (Tmax)	Pre-Dose Day 176, Day 358 and Day 540
PK parameters of nusinersen in CSF levels: Area under the plasma concentrations time curve from the time of the intrathecal (IT) dose to the last collected sample (AUCinf)	Pre-Dose Day 176, Day 358 and Day 540

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• 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.
• Darras BT, Chiriboga CA, Iannaccone ST, Swoboda KJ, Montes J, Mignon L, Xia S, Bennett CF, Bishop KM, Shefner JM, Green AM, Sun P, Bhan I, Gheuens S, Schneider E, Farwell W, De Vivo DC; ISIS-396443-CS2/ISIS-396443-CS12 Study Groups. Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies. Neurology. 2019 May 21;92(21):e2492-e2506. doi: 10.1212/WNL.0000000000007527. Epub 2019 Apr 24.

Helpful Links

• Cure SMA
• Muscular Dystrophy Association
• National Organization for Rare Diseases
• Clinical Study Report (CSR) Synopsis - a results summary

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2014
• Primary Completion (Actual): January 31, 2017
• Study Completion (Actual): January 31, 2017

Study Registration Dates

• First Submitted: January 30, 2014
• First Submitted That Met QC Criteria: January 31, 2014
• First Posted (Estimate): February 3, 2014

Study Record Updates

• Last Update Posted (Actual): February 16, 2021
• Last Update Submitted That Met QC Criteria: February 12, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Spinal Muscular Atrophy; SMA; SMN; SMNRx; ISIS-SMNRx; ISIS 396443; IONIS-SMNRx; IONIS-SMN Rx; Spinraza
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal
• Other Study ID Numbers: ISIS 396443-CS12

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No