A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA)

NCT02292537 | Completed Phase 3 Results DMC

• 2 other identifiers: ISIS 396443-CS42014-001947-18
• Study Type: interventional
• Target: 126
• Locations: 10 countries
• Sites: 24

Brief Summary

The primary objective of this study is to examine the clinical efficacy of nusinersen (ISIS 396443) administered intrathecally to participants with later-onset Spinal Muscular Atrophy (SMA). The secondary objective is to examine the safety and tolerability of nusinersen administered intrathecally to participants with later-onset SMA.

Conditions

Spinal Muscular Atrophy

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15

  The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. The scale was originally developed with 20 scored activities and was devised for use in children with SMA Type 2 and Type 3 with limited ambulation to give objective information on motor ability and clinical progression. The expanded scale includes an additional module of 13 items developed to allow for evaluation of ambulatory SMA patients. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.

  Baseline and Month 15

Secondary Outcomes (14)

• Proportion of Participants Who Achieved a 3-Point Increase From Baseline in HFMSE Score at Month 15

  Baseline and Month 15

• Proportion of Participants That Achieved Any New Motor Milestone at Month 15

  Month 15

• Number of New Motor Milestones Achieved Per Participant

  Month 15

• Change From Baseline in Revised Upper Limb Module (RULM) Test

  Baseline and Month 15

• Proportion of Participants That Achieved Standing Alone

  Month 15

Study Arms (2)

Nusinersen

EXPERIMENTAL

Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.

Drug: Nusinersen

Sham procedure

SHAM COMPARATOR

Sham comparator on Days 1, 29, 85 and 274.

Procedure: Sham procedure

Interventions

Nusinersen DRUG

Administered by intrathecal (IT) lumbar puncture (LP) injection

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

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: 2 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Parent or guardian has signed informed consent and, if indicated per participant's age and institutional guidelines, participant has signed informed assent
• Be medically diagnosed with Spinal Muscular Atrophy (SMA)
• Have onset of clinical signs and symptoms consistent with SMA at greater than 6 months of age
• Be able to sit independently, but has never had the ability to walk independently
• Have Motor Function Score (Hammersmith Functional Motor Scale - Expanded) greater than or equal to 10 and less than or equal to 54 at Screening
• Be able to complete all study procedures, measurements and visits and parent or guardian and subject has adequately supportive psychosocial circumstances, in the opinion of the Investigator
• Have an estimated life expectancy of greater than 2 years from Screening, in the opinion of the Investigator
• Meet age-appropriate institutional criteria for use of anesthesia and sedation, if use is planned for study procedures
• For subjects who have reached reproductive maturity, satisfy study contraceptive requirements

You may not qualify if:

• Respiratory insufficiency, defined by the medical necessity for invasive or non-invasive ventilation for greater than 6 hours during a 24 hour period, at Screening
• Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Site Investigator
• Severe contractures or severe scoliosis evident on X-ray examination at Screening
• Hospitalization for surgery (i.e., scoliosis surgery, other surgery), pulmonary event, or nutritional support 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 at any time during the screening period
• History of brain or spinal cord disease, including tumors, or abnormalities by magnetic resonance imaging (MRI) or computed tomography (CT) that would interfere with the LP procedures or cerebrospinal fluid (CSF) circulation
• Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system (CNS) catheter
• History of bacterial meningitis
• Dosing with IONIS-SMN Rx in any previous clinical study
• Prior injury (e.g., upper or lower limb fracture) or surgical procedure which impacts the subject's ability to perform any of the outcome measure testing required in the protocol and from which the subject has not fully recovered or achieved a stable baseline
• Treatment with another investigational drug (e.g., oral albuterol or salbutamol, riluzole, carnitine, creatine, sodium phenylbutyrate, et.c), biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3-months of Screening. Any history of gene therapy, antisense oligonucleotide therapy, or cell transplantation.
• Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability (e.g., wasting or cachexia, severe anemia, etc.) that would interfere with the assessment of safety or would compromise the ability of the subject to undergo study procedures.

Sponsors & Collaborators

• Biogen: lead

Study Sites (24)

UCLA Clinical and Translational Research Center

Los Angeles, California, 90095, United States

Location

Lucile Packard Children's Hospital at Stanford

Palo Alto, California, 94304, 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

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Children's Hospital of Philadelphia - Neurology

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Medical Center

Dallas, Texas, 75235, United States

Location

Children's Hospital - London Health Sciences Centre

London, Ontario, N6A 5W9, Canada

Location

McGill University Health Centre-Glen Site-CIM

Montreal, Quebec, H4A 3JI, Canada

Location

Armand Trousseau Hospital, I-Motion, Clinical Trials Platform

Paris, France

Location

Universitatsklinikum Essen

Essen, Germany

Location

University Hospital Freiberg, Center for Paediatrics and Adolescent Medicine, Department of Neuropaediatrics and Muscular Disease

Freiburg im Breisgau, Germany

Location

The University of Hong Kong, Queen Mary Hospital, Department of Paediatrics and Adolescent Medicine

Hong Kong, Hong Kong SAR, Hong Kong

Location

AOU Policlinico G. Martino Dipartimento di Neuroscienze e Centro Clinico Nemo Sud

Messina, Italy

Location

Fondazione Policlinico Universitario Agostino Gemelli-Universita Cattolica de Sacro Cuore-UOC Neuropsichiatre Infantile

Rome, Italy

Location

Hyogo College of Medicine

Nishinomya-shi, Hyōgo, Japan

Location

Tokyo Women's Medical University

Shinjuku-ku, Tokyo, Japan

Location

Seoul National University Children's Hospital

Seoul, Korea, South Korea

Location

Hospital Sant Joan de Deu

Barcelona, Spain

Location

University of Gothenburg, The Queen Silvia Children's Hospital

Gothenburg, Sweden

Location

Related Publications (2)

• 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

• Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, Iannaccone ST, Kirschner J, Kuntz NL, Saito K, Shieh PB, Tulinius M, Mazzone ES, Montes J, Bishop KM, Yang Q, Foster R, Gheuens S, Bennett CF, Farwell W, Schneider E, De Vivo DC, Finkel RS; CHERISH Study Group. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018 Feb 15;378(7):625-635. doi: 10.1056/NEJMoa1710504.

  PMID: 29443664 DERIVED

Related Links

• Cure SMA
• Muscular Dystrophy Association
• National Organization for Rare Diseases

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

Limitations and Caveats

After the interim analysis of the study, the decision was made in October 2016 to terminate the study early and participants were invited for end-of-study visits.

Results Point of Contact

• Title: Biogen Study Medical Director
• 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 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: November 12, 2014
• First Posted: November 17, 2014
• Study Start: November 24, 2014
• Primary Completion: February 20, 2017
• Study Completion: February 20, 2017
• Last Updated: February 17, 2021
• Results First Posted: February 22, 2018

Record last verified: 2021-02

Locations

DE (2); JP (2); US (11); HK (1); KR (1); IT (2); ES (1); FR (1); SE (1); CA (2)