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

NCT02193074 | Terminated Phase 3 Results DMC

• 2 other identifiers: ISIS 396443-CS3B2013-004422-29
• Study Type: interventional
• Target: 122
• Locations: 13 countries
• Sites: 31

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.

Conditions

Spinal Muscular Atrophy

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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.

  assessed at the later of the Day 183, Day 302, or Day 394 study visits

• 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.

  Day 91, Day 182, Day 273, Day 364, Day 394

Secondary Outcomes (12)

• Percentage of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders

  assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits

• Summary of Time to Death

  Day 91, Day 182, Day 273, Day 364, Day 394

• Percentage of Participants Not Requiring Permanent Ventilation

  Up to Day 394

• Percentage of Compound Muscular Action Potential (CMAP) Responders

  assessed at the later of the Day 183, Day 302, or Day 394 study visits

• Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration

  Day 91, Day 182, Day 273, Day 364, Day 394

Study Arms (2)

nusinersen

EXPERIMENTAL

Drug: nusinersen

Sham procedure

SHAM COMPARATOR

Procedure: Sham procedure

Interventions

nusinersen DRUG

Administered by intrathecal (IT) injection as specified in the treatment arm.

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

nusinersen

Sham procedure PROCEDURE

Small needle prick on the lower back at the location where the IT injection is normally made

Sham procedure

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Biogen: lead

Study Sites (31)

UCLA Medical Center

Los Angeles, California, 90095, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Nemours Children's Hospital

Orlando, Florida, 32827, United States

Location

Ann and Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, 60611, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Duke Children's Hospital

Durham, North Carolina, 27710, United States

Location

Doernbecher Children's Hospital

Portland, Oregon, 97239, United States

Location

Children's Hospital of Philadelphia - Neurology

Philadelphia, Pennsylvania, 19104, United States

Location

UT Southwestern Medical Center/Children's Medical Center Dallas

Dallas, Texas, 75235, United States

Location

Primary Children's Medical Center (University of Utah)

Salt Lake City, Utah, 84112, United States

Location

Sydney Children's Hospital

Sydney, New South Wales, 2031, Australia

Location

Royal Children's Hospital, Children's Neuroscience Centre

Parkville, Victoria, 3052, Australia

Location

Hôpital Universitaire des Enfants Reine FABIOLA (HUDERF)

Brussels, 15 - 1020, Belgium

Location

British Columbia Children's Hospital/UBC

Vancouver, British Columbia, V6H 3N1, Canada

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Institut de Myologie

Paris, 75012, France

Location

Universitatsklinikum Essen

Essen, 45147, Germany

Location

Universtatsklinikum Freiburg, Zentrum fur Kinder-und Jugendmedizin , Abteilung Neuropadiatrie und Muskelerkrankungen

Freiburg im Breisgau, 79106, Germany

Location

Istituto Giannina Gaslini, Centro Traslazionale di Miologia e Patologie Neurodegenerative

Genova, 16148, Italy

Location

Pediatric Neurology Unit, Catholic University

Rome, 00153, Italy

Location

Hyogo College of Medicine

Nishinomiya, Hyōgo, 663-8131, Japan

Location

Tokyo Women's Medical University

Tokyo, 162-8666, Japan

Location

Seoul National University Hospital

Seoul, South Korea

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario La Paz, Pediatric Neurology Department

Madrid, 28046, Spain

Location

University of Gothenburg, The Queen Silvia Children's Hospital

Gothenburg, Sweden

Location

Hacettepe Children's Hospital

Ankara, 06230, Turkey (Türkiye)

Location

UCL Institute of Child Health/Great Ormond Street

London, WC1N 1EH, United Kingdom

Location

MRC Centre for Neuromuscular Diseases at Newcastle, Institute of Genetic Medicine Newcastle University

Newcastle, NE1 3BZ, United Kingdom

Location

Related Publications (4)

• 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

• Dabbous O, Maru B, Jansen JP, Lorenzi M, Cloutier M, Guerin A, Pivneva I, Wu EQ, Arjunji R, Feltner D, Sproule DM. Survival, Motor Function, and Motor Milestones: Comparison of AVXS-101 Relative to Nusinersen for the Treatment of Infants with Spinal Muscular Atrophy Type 1. Adv Ther. 2019 May;36(5):1164-1176. doi: 10.1007/s12325-019-00923-8. Epub 2019 Mar 16.

  PMID: 30879249 DERIVED

• Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC; ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1723-1732. doi: 10.1056/NEJMoa1702752.

  PMID: 29091570 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: Biogen Study Medical Director
• Organization: Biogen

clinicaltrials@biogen.com

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 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: July 14, 2014
• First Posted: July 17, 2014
• Study Start: August 19, 2014
• Primary Completion: November 21, 2016
• Study Completion: November 21, 2016
• Last Updated: February 17, 2021
• Results First Posted: July 28, 2017

Record last verified: 2021-02

Locations

TU (1); KR (1); BE (1); FR (1); AU (2); DE (2); JP (2); ES (2); GB (2); IT (2); US (12); CA (2); SE (1)