Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy

NCT04089566 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 232SM2032019-002663-10
• Study Type: interventional
• Target: 145
• Locations: 17 countries
• Sites: 42

Brief Summary

The primary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA), as measured by change in Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score (Part B); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C). The secondary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A, B and C); to examine the effect of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA, to examine the effect of nusinersen administered intrathecally at higher doses compared to the currently approved dose in participants with SMA (Part B).

Conditions

Muscular Atrophy, Spinal

Outcome Measures

Primary Outcomes (23)

• Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

  The CHOP-INTEND test was designed to evaluate the motor skills of infants with significant motor weakness. It included 16 items (capturing neck, trunk, and proximal and distal limb strength), nine of which were scored 0, 1, 2, 3, or 4, five were scored as 0, 2, or 4, one was scored as 0, 1, 2, or 4, and one as 0, 2, 3, or 4 with higher scores indicating greater muscle strength and function. Total score was calculated as the sum of scores for each item. Total score ranged from 0 (worst possible score) and 64 (best possible score). The change from baseline to Day 183 in the CHOP-INTEND total score was compared to CS3B study (NCT02193074) sham control group using the joint-rank methodology to account for mortality.

  Baseline, Day 183

• Parts A and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs)

  An adverse event (AE) was any unfavorable \& unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with use of an investigational product, whether or not related to investigational product. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of Investigator, placed participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. AE and SAEs were regarded as treatment-emergent if it was present prior to receiving first dose of nusinersen in this current study and subsequently worsened in severity or was not present prior to receiving first dose of nusinersen and subsequently appeared.

  Part A: From the first dose of the study drug up to Day 389, Part C: From the first dose of the study drug up to Day 361

• Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

  Blood chemistry parameters included protein, albumin, creatinine, blood urea nitrogen, bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, bicarbonate, chloride, sodium, potassium, cystatin C, and creatine kinase. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high values postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.

  Parts A and C: Baseline up to Day 302

• Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)

  Hematology parameters included complete blood cell count, with differential and platelet count, and absolute neutrophil count. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline values. The categories with at least one participant with shift from baseline in these parameters are reported.

  Parts A and C: Baseline up to Day 302

• Parts A and C: Number of Participants With Shifts From Baseline in Urinalysis

  Urinalysis included assessments of urine total protein, specific gravity, pH, protein, glucose, ketones, bilirubin, blood, red blood cells (RBC), white blood cells (WBC), epithelial cells, bacteria, casts and crystals. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.

  Parts A and C: Baseline up to Day 302

• Parts A and C: Number of Participants With Shifts From Baseline in Cerebrospinal Fluid (CSF) Parameters

  CSF parameters included cell count, total protein, and glucose. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high values postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.

  Part A: Baseline up to Day 269, Part C: Baseline up to Day 241

• Parts A and C: Number of Participants With Shifts From Baseline in Electrocardiograms (ECGs)

  The ECGs were assessed by the investigator to be normal, abnormal and abnormal AE. The number of participants with ECG shifts from normal to each of the categorical values denoting an abnormal scan (abnormal not AE, abnormal AE) was assessed. Shift from baseline to worst post-baseline values were reported. The categories with at least one participant with shift from baseline in ECG are reported.

  Parts A and C: Baseline up to Day 302

• Parts A and C: Number of Participants With Abnormalities in Vital Sign Parameters

  Vital sign assessment included temperature, pulse rate, systolic blood pressure, diastolic blood pressure, and respiratory rate. As pre-specified in protocol, the criteria for determining potentially clinically relevant abnormalities in vital signs included: temperature \< 36.0 and \> 38.0 degrees Celsius (C), pulse rate \< 60 and \> 100 beats per minute (bpm), systolic blood pressure \[\< 90, \> 140 and \> 160 millimeters of mercury (mmHg)\], diastolic blood pressure \< 50, \> 90 and \> 100 mmHg and respiratory rate \< 12 and \> 20 breaths per minute. The categories with at least one participant with clinically relevant vital sign abnormalities are reported.

  Parts A and C: Baseline up to Day 302

• Parts A and C: Change From Baseline in Growth Parameters (Body Height)

  Parts A and C: Baseline, Day 302

• Part C: Change From Baseline in Growth Parameters (Head Circumference)

  As pre-specified in the protocol, head circumference was measured for participants with infantile-onset SMA only.

  Baseline, Day 302

• Part C: Change From Baseline in Growth Parameters (Chest Circumference)

  As pre-specified in protocol, chest circumference was measured for participants with infantile-onset SMA only.

  Baseline, Day 302

• Part C: Change From Baseline in Growth Parameters (Arm Circumference)

  As pre-specified in the protocol, arm circumference was measured for participants with infantile-onset SMA. Here, negative change from baseline indicated reduction in arm circumference.

  Baseline, Day 302

• Parts A and C: Change From Baseline in Growth Parameters (Ulnar Length)

  As pre-specified in the protocol, ulnar length was measured for participants with later-onset SMA.

  Parts A and C: Baseline, Day 302

• Parts A and C: Change From Baseline in Growth Parameters (Weight for Age Percentile)

  World Health Organization (WHO) child growth standards (2006) was used to calculate the weight for age percentile in the infantile-onset participants while the 2000 Centers for Disease Control and Prevention (CDC) Growth Charts was used to calculate the weight for age percentile for later-onset participants. Negative change from baseline indicates low weight for age percentile.

  Parts A and C: Baseline, Day 302

• Part C: Change From Baseline in Growth Parameters (Weight for Length Ratio)

  As pre-specified in the protocol, weight for length ratio was assessed only for the participants with infantile-onset SMA.

  Baseline, Day 302

• Part C: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)

  As pre-specified in the protocol, head to chest circumference ratio was assessed only for the participants with infantile-onset SMA.

  Baseline, Day 302

• Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Activated Partial Thromboplastin Time (aPTT))

  Activated partial thromboplastin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of aPTT at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of aPTT at baseline to high values postbaseline.

  Parts A and C: Baseline up to Day 269

• Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Prothrombin Time (PT))

  Prothrombin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of PT at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of PT at baseline to high values postbaseline.

  Parts A and C: Baseline up to Day 269

• Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (International Normalized Ratio (INR))

  INR was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of INR at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of INR at baseline to high values postbaseline. The category with at least one participant with shift from baseline in INR ratio is reported.

  Parts A and C: Baseline up to Day 269

• Parts A and C: Change From Baseline in Urine Total Protein

  Parts A and C: Baseline, Day 302

• Parts A and C: Number of Participants With Neurological Examination Abnormalities Reported as AEs

  Participants with abnormalities in neurological examinations recorded as AEs were reported.

  Parts A and C: Baseline up to Day 302

• Parts A and C: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements

  Parts A and C: Baseline up to Day 302

• Parts A and C: Percentage of Participants With a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of > 500 Millisecond (Msec) and an Increase From Baseline to Any Postbaseline Timepoint in QTcF of > 60 Msec

  Parts A and C: Baseline up to Day 302

Secondary Outcomes (56)

• Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group

  Baseline, Day 183

• Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group

  Baseline, Day 183

• Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of Neurofilament Light Chain (NF-L) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

  Baseline, Day 183

• Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

  Baseline, Day 302

• Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

  Baseline, Day 302

Study Arms (4)

28/28 Milligram (mg) Safety Group

EXPERIMENTAL

Part A: Participants with later-onset SMA will receive loading doses of 28 mg of nusinersen intrathecally on Days 1, 15 and 29 followed by maintenance doses of 28 mg on Days 149 and 269.

Drug: Nusinersen

12/12 mg Active Control Group

ACTIVE COMPARATOR

Part B: Participants with infantile- or later-onset SMA will receive loading doses of 12 mg of nusinersen intrathecally on Days 1, 15, 29, and 64 followed by maintenance doses of 12 mg on Days 183 and 279. Sham procedure will be administered on Day 135.

Drug: Nusinersen

50/28 mg Active Treatment Group

EXPERIMENTAL

Part B: Participants with infantile- or later-onset SMA will receive loading doses of 50 mg of nusinersen intrathecally on Days 1 and 15 followed by maintenance doses of 28 mg on Days 135 and 279. Sham procedure will be administered on Days 29, 64 and 183.

Drug: Nusinersen

12/50/28 mg Titration Group

EXPERIMENTAL

Part C: Participants who have been receiving the approved dose of 12 mg for at least 1 year prior to entry, will receive a single bolus dose of 50 mg of nusinersen intrathecally on Day 1 (4 months after their most recent maintenance dose of 12 mg) followed by maintenance doses of 28 mg on Days 121 and 241.

Drug: Nusinersen

Interventions

Nusinersen DRUG

Administered as specified in the treatment arm

Also known as: BIIB058

12/12 mg Active Control Group; 12/50/28 mg Titration Group; 28/28 Milligram (mg) Safety Group; 50/28 mg Active Treatment Group

Eligibility Criteria

• Age: 7 Days+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Part A, B and C:
• \- Genetic documentation of 5q SMA (homozygous gene deletion, mutation, or compound heterozygote)
• Part A:
• Onset of clinical signs and symptoms consistent with SMA at \> 6 months (\> 180 days) of age (i.e., later-onset SMA)
• Age 2 to ≤ 15 years, inclusive, at the time of informed consent
• Part B:
• Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset) should have age \> 1 week to ≤ 7 months (≤ 210 days) at the time of informed consent
• Participants with SMA symptom onset \> 6 months (\> 180 days) of age (later onset):
• Age 2 to \< 10 years at the time of informed consent
• Can sit independently but has never had the ability to walk independently
• HFMSE score ≥ 10 and ≤ 54 at Screening
• Part C:
• \- Currently on nusinersen treatment at the time of Screening, with the first dose being at least 1 year prior to Screening
• Part C Cohort 1:
• \- Participants of any age (individuals ≥18 years of age at Screening must be ambulatory)

You may not qualify if:

• Part A, B and C:
• Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the Screening period
• Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or of an implanted central nervous system (CNS) catheter
• Hospitalization for surgery, pulmonary event, or nutritional support within 2 months prior to Screening or planned within 12 months after the participant's first dose
• Part A:
• Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for \> 6 hours during a 24-hour period, at Screening
• Medical necessity for a gastric feeding tube
• Treatment with an investigational drug given for the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any survival motor neuron-2 gene (SMN2)-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
• Part B:
• Treatment with an investigational drug including but not limited to the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any SMN2-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
• Participants with SMA symptom onset \> 6 months (\> 180 days) of age (later onset):
• Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for \> 6 hours during a 24-hour period, at Screening
• Medical necessity for a gastric feeding tube
• Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset): Signs or symptoms of SMA present at birth or within the first week after birth
• Part C:

Sponsors & Collaborators

• Biogen: lead

Study Sites (45)

Stanford Hospital and Clinics

Palo Alto, California, 94304, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

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

Chicago, Illinois, 60611, United States

Location

The Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

The University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

HC-UFMG - Hospital das Clinicas da Universidade Federal de Minas Gerais

Belo Horizonte, Minas Gerais, 30130-100, Brazil

Location

Hospital de Clínicas de Porto Alegre

Porto Alegre, Rio Grande do Sul, 90035-903, Brazil

Location

Hospital das Clínicas da Faculdade de Medicina da USP

São Paulo, São Paulo, 05403-000, Brazil

Location

London Health Sciences Centre (LHSC) - Children's Hospital

London, Ontario, N6A 5W9, Canada

Location

Hospital Luis Calvo Mackenna

Santiago, 7500539, Chile

Location

Clinica Las Condes

Santiago, 7591046, Chile

Location

Clinica MEDS La Dehesa

Santiago, 7691236, Chile

Location

Peking University First Hospital

Beijing, Beijing Municipality, 100034, China

Location

The Children's Hospital of Zhejiang University school of Med_Hangzhou

Hangzhou, Binjiang, 310052, China

Location

Guangzhou Woman and Children's Medical Center

Guangzhou, Guangzhou, 510623, China

Location

Xiangya Hospital, Central South University

Changsha, Hu'nan, 410008, China

Location

Hospital Universitario San Ignacio

Bogotá, 110231, Colombia

Location

Fundacion Hospitalaria San Vicente de Paul

Medellín, 050010, Colombia

Location

Tallinn Children's Hospital

Tallinn, 13419, Estonia

Location

Universitaetsklinikum Freiburg

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

Universitaetsklinikum Giessen und Marburg GmbH

Giessen, Hesse, 35392, Germany

Location

Semmelweis Egyetem

Budapest, 1094, Hungary

Location

Magyarorszagi Reformatus Egyhaz Bethesda Gyermekkorhaz

Budapest, 1146, Hungary

Location

Fondazione Serena Onlus - Centro Clinico Nemo

Milan, 20162, Italy

Location

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Roma, 00168, Italy

Location

Kurume University Hospital

Kurume-shi, Fukuoka, 830-0011, Japan

Location

Hyogo College of Medicine Hospital

Nishinomiya-shi, Hyōgo, 663-8501, Japan

Location

Tokyo Women's Medical University Hospital

Shinjuku-ku, Tokyo-To, 162-8666, Japan

Location

Saint George University Hospital Medical Center

Beirut, 11 00 2807, Lebanon

Location

Antiguo Hospital Civil de Guadalajara Fray Antonio Alcalde

Guadalajara, Jalisco, 44280, Mexico

Location

Instituto Nacional de Pediatria

Mexico City, Mexico City, 04530, Mexico

Location

Hospital Infantil de Mexico Federico Gomez

Mexico City, Mexico City, 06720, Mexico

Location

Instytut Pomnik - Centrum Zdrowia Dziecka

Warsaw, 04-730, Poland

Location

Russian Children Neuromuscular Center of Veltischev

Moskva, 125412, Russia

Location

Regional Pediatric Clinical Hospital #1

Yekaterinburg, 620149, Russia

Location

King Fahad Specialist Hospital

Dammam, 31444, Saudi Arabia

Location

National Guard Health Affairs: King Abdulaziz Medical City

Jeddah, 21423, Saudi Arabia

Location

King Faisal Specialist Hospital & Research Center

Riyadh, 11211, Saudi Arabia

Location

Hospital Sant Joan de Deu

Esplugues Del Llobregat, Barcelona, 08950, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Universitari i Politecnic La Fe

Valencia, 46026, Spain

Location

Kaohsiung Medical University Chung-Ho Memorial Hospital

Kaohsiung City, 80756, Taiwan

Location

National Taiwan University Hospital

Taipei, 10002, Taiwan

Location

Related Publications (3)

• Finkel RS, Crawford TO, Mercuri E, Sumner CJ, Garcia Romero MDM, Day JW, Montes J, Sun P, Tichler B, Paradis AD, Boesch E, Inra J, Littauer R, Sohn J, Monine M, Gambino G, Foster R, Farewell R, Fradette S. High-dose nusinersen for spinal muscular atrophy: a phase 3 randomized trial. Nat Med. 2026 Feb 3. doi: 10.1038/s41591-025-04193-6. Online ahead of print.

  PMID: 41634391 DERIVED

• Wang X, Zheng Y, Lu J, Li X, Chen S, Xue Y, Hu S, Peng G, Zhang F, Zhao X, Liu Y, Fan Y, Zhou H, Liang C, Liu L, He L, Zhang J, Shi W, Tian J, Han M, Xu K. Musculoskeletal deformities in children with spinal muscular atrophy: a multicenter cross-sectional study with longitudinal follow-up. Ann Phys Rehabil Med. 2026 Jan 8;69(3):102080. doi: 10.1016/j.rehab.2025.102080. Online ahead of print.

  PMID: 41512690 DERIVED

• Finkel RS, Ryan MM, Pascual Pascual SI, Day JW, Mercuri E, De Vivo DC, Foster R, Montes J, Gurgel-Giannetti J, MacCannell D, Berger Z. Scientific rationale for a higher dose of nusinersen. Ann Clin Transl Neurol. 2022 Jun;9(6):819-829. doi: 10.1002/acn3.51562. Epub 2022 May 13.

  PMID: 35567345 DERIVED

Related Links

• SMA Europe
• CureSMA
• Muscular Dystrophy Association
• Study website - US patients only

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 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 11, 2019
• First Posted: September 13, 2019
• Study Start: March 26, 2020
• Primary Completion: February 21, 2024
• Study Completion: May 30, 2024
• Last Updated: June 5, 2025
• Results First Posted: June 5, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

CA (1); ES (1); TW (2); LE (1); SA (3); PL (1); RU (2); US (7); CN (4); HU (2); JP (3); DE (2); CO (2); CL (3); IT (2); ME (3); BR (3)