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

NCT01839656 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: ISIS 396443-CS3A2017-000621-12
• Study Type: interventional
• Target: 21
• Locations: 2 countries
• Sites: 4

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.

Conditions

Spinal Muscular Atrophy

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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.

  Day 1352 or Early Termination

Secondary Outcomes (8)

• Event-free Survival at the End of Study

  Up to Day 1638

• Percent of Participants With Improved Motor Function at the Last Visit as Assessed by the CHOP-INTEND Motor Function Scale

  Day 1352 or Early Termination

• Change in Neuromuscular Electrophysiology at the Last Visit as Assessed by the Change From Baseline in CMAP Amplitude

  Baseline, Day 1072

• Number of Participants Experiencing Adverse Events (AEs) and/or Serious Adverse Events (SAEs)

  Up to Day 1352

• Concentration of Nusinersen in Cerebrospinal Fluid (CSF)

  Day 1135 (Predose)

Study Arms (2)

Nusinersen 6 mg

EXPERIMENTAL

Drug: nusinersen

Nusinersen 12 mg

EXPERIMENTAL

Drug: nusinersen

Interventions

nusinersen DRUG

Administered by intrathecal (IT) injection

Also known as: ISIS 396443, Spinraza, BIIB058, IONIS SMN Rx, ISIS SMNRx

Nusinersen 12 mg; Nusinersen 6 mg

Eligibility Criteria

• Age: 21 Days - 210 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Biogen: lead

Study Sites (4)

Stanford University Medical Center

Stanford, California, 94305, United States

Location

Nemours Children's Hospital

Orlando, Florida, 32827, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

The Hospital for Sick Children (SickKids)

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (3)

• 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.

  PMID: 34089650 DERIVED

• 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.

  PMID: 31420846 DERIVED

• 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.

  PMID: 27939059 DERIVED

Related Links

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

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Interventions

nusinersen

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Results Point of Contact

• Title: US Biogen Clinical Trial Center
• Organization: Biogen

clinicaltrials@biogen.com

866-633-4636

Study Officials

• Medical Director

  Biogen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: April 22, 2013
• First Posted: April 25, 2013
• Study Start: May 8, 2013
• Primary Completion: August 21, 2017
• Study Completion: August 21, 2017
• Last Updated: February 17, 2021
• Results First Posted: October 30, 2018

Record last verified: 2021-02

Locations

US (3); CA (1)