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

NCT ID: NCT02292537

Last Updated: 2021-02-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 126 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-11-24
• Study Completion Date: 2017-02-20

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.

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.

Conditions

Spinal Muscular Atrophy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Nusinersen

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

Group Type: EXPERIMENTAL

Nusinersen

Intervention Type: DRUG

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

Sham procedure

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

Group Type: SHAM_COMPARATOR

Sham procedure

Intervention Type: PROCEDURE

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

Interventions

Nusinersen

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

Intervention Type: DRUG

Sham procedure

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

Intervention Type: PROCEDURE

Other Intervention Names

Sprinraza; ISIS 396443; IONIS-SMN Rx; BIIB058

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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
• 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 subject unsuitable for inclusion
• 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.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Biogen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Biogen

Locations

UCLA Clinical and Translational Research Center

Los Angeles, California, United States

Lucile Packard Children's Hospital at Stanford

Palo Alto, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Nemours Children's Hospital

Orlando, Florida, United States

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

Chicago, Illinois, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Washington University School of Medicine

St Louis, Missouri, United States

Columbia University Medical Center

New York, New York, United States

Oregon Health & Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia - Neurology

Philadelphia, Pennsylvania, United States

Children's Medical Center

Dallas, Texas, United States

Children's Hospital - London Health Sciences Centre

London, Ontario, Canada

McGill University Health Centre-Glen Site-CIM

Montreal, Quebec, Canada

Armand Trousseau Hospital, I-Motion, Clinical Trials Platform

Paris, , France

Universitatsklinikum Essen

Essen, , Germany

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

Freiburg im Breisgau, , Germany

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

Hong Kong, Hong Kong SAR, Hong Kong

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

Messina, , Italy

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

Rome, , Italy

Hyogo College of Medicine

Nishinomya-shi, Hyōgo, Japan

Tokyo Women's Medical University

Shinjuku-ku, Tokyo, Japan

Seoul National University Children's Hospital

Seoul, Korea, South Korea

Hospital Sant Joan de Deu

Barcelona, , Spain

University of Gothenburg, The Queen Silvia Children's Hospital

Gothenburg, , Sweden

Countries

United States; Canada; France; Germany; Hong Kong; Italy; Japan; South Korea; Spain; Sweden

References

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.

Reference Type: DERIVED

PMID: 31420846 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29443664 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Related Links

http://www.curesma.org

Cure SMA

http://mda.org/disease/spinal-muscular-atrophy

Muscular Dystrophy Association

https://www.rarediseases.org

National Organization for Rare Diseases

Other Identifiers

2014-001947-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ISIS 396443-CS4

Identifier Type: -

Identifier Source: org_study_id