Clinical trial NCT04089566: Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
Official title: Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Muscular Atrophy, Spinal
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2019-09-13
Enrollment: 145
Sex: ALL
Minimum age (years): 7
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).


Eligibility criteria: Key Inclusion Criteria:

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)

Part C Cohort 2:

* Participants ≥18 years of age at Screening (can be ambulatory or nonambulatory)
* HFMSE total score ≥4 points at Screening
* RULM entry item A score ≥3 points at Screening

Key Exclusion Criteria:

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:

* Concurrent or previous participation and/or administration of nusinersen in another clinical study
* Concomitant or previous administration of any SMN2-splicing modifier (excluding nusinersen) or gene therapy, either in a clinical study or as part of medical care.
* Concurrent or previous participation in any interventional investigational study for any other drug or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group
timeFrame: Baseline, Day 183
measure: Parts A and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs)
timeFrame: 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
measure: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)
timeFrame: Parts A and C: Baseline up to Day 302
measure: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)
timeFrame: Parts A and C: Baseline up to Day 302
measure: Parts A and C: Number of Participants With Shifts From Baseline in Urinalysis
timeFrame: Parts A and C: Baseline up to Day 302
measure: Parts A and C: Number of Participants With Shifts From Baseline in Cerebrospinal Fluid (CSF) Parameters
timeFrame: Part A: Baseline up to Day 269, Part C: Baseline up to Day 241
measure: Parts A and C: Number of Participants With Shifts From Baseline in Electrocardiograms (ECGs)
timeFrame: Parts A and C: Baseline up to Day 302
measure: Parts A and C: Number of Participants With Abnormalities in Vital Sign Parameters
timeFrame: Parts A and C: Baseline up to Day 302
measure: Parts A and C: Change From Baseline in Growth Parameters (Body Height)
timeFrame: Parts A and C: Baseline, Day 302
measure: Part C: Change From Baseline in Growth Parameters (Head Circumference)
timeFrame: Baseline, Day 302
measure: Part C: Change From Baseline in Growth Parameters (Chest Circumference)
timeFrame: Baseline, Day 302
measure: Part C: Change From Baseline in Growth Parameters (Arm Circumference)
timeFrame: Baseline, Day 302
measure: Parts A and C: Change From Baseline in Growth Parameters (Ulnar Length)
timeFrame: Parts A and C: Baseline, Day 302
measure: Parts A and C: Change From Baseline in Growth Parameters (Weight for Age Percentile)
timeFrame: Parts A and C: Baseline, Day 302
measure: Part C: Change From Baseline in Growth Parameters (Weight for Length Ratio)
timeFrame: Baseline, Day 302
measure: Part C: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)
timeFrame: Baseline, Day 302
measure: Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Activated Partial Thromboplastin Time (aPTT))
timeFrame: Parts A and C: Baseline up to Day 269
measure: Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Prothrombin Time (PT))
timeFrame: Parts A and C: Baseline up to Day 269
measure: Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (International Normalized Ratio (INR))
timeFrame: Parts A and C: Baseline up to Day 269
measure: Parts A and C: Change From Baseline in Urine Total Protein
timeFrame: Parts A and C: Baseline, Day 302
measure: Parts A and C: Number of Participants With Neurological Examination Abnormalities Reported as AEs
timeFrame: Parts A and C: Baseline up to Day 302
measure: Parts A and C: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements
timeFrame: Parts A and C: Baseline up to Day 302
measure: 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
timeFrame: Parts A and C: Baseline up to Day 302
Secondary outcomes:
measure: 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
timeFrame: Baseline, Day 183
measure: 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
timeFrame: Baseline, Day 183
measure: 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
timeFrame: Baseline, Day 183
measure: Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Baseline, Day 302
measure: Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Baseline, Day 302
measure: Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Baseline, Day 64
measure: Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group
timeFrame: Screening up to Day 399
measure: Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group
timeFrame: Screening up to Day 399
measure: Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Screening up to Day 399
measure: Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Screening up to Day 399
measure: Part B Later-onset SMA: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Baseline, Day 302
measure: Part B Later-onset SMA: Change From Baseline in Revised Upper Limb Module (RULM) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Baseline, Day 302
measure: Part B Later-onset SMA: Number of New World Health Organization (WHO) Motor Milestones Achieved Per Participant for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Baseline, Day 302
measure: Part B Later-onset SMA: Change From Baseline in Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Baseline, Day 302
measure: Part B Later-onset SMA: Change From Baseline in Pediatric Quality of Life Inventory™ (PedsQL) for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Baseline, Day 302
measure: Part B Later-onset SMA: Change From (Ratio to) Baseline in CSF Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Baseline, Day 279
measure: Part B Later-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen
timeFrame: Baseline, Day 302
measure: Part B: Number of Participants With TEAEs and TESAEs
timeFrame: From the first dose of the study drug up to Day 399
measure: Part B: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)
timeFrame: Baseline up to Day 302
measure: Part B: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)
timeFrame: Baseline up to Day 302
measure: Part B: Number of Participants With Shifts From Baseline in Urinalysis
timeFrame: Baseline up to Day 302
measure: Part B: Number of Participants With Shifts From Baseline in CSF Parameters
timeFrame: Baseline up to Day 302
measure: Part B: Number of Participants With Shift From Baseline in ECGs
timeFrame: Baseline up to Day 302
measure: Part B: Number of Participants With Abnormalities in Vital Sign Parameters
timeFrame: Baseline up to Day 302
measure: Part B: Change From Baseline in Growth Parameters (Body Height)
timeFrame: Baseline, Day 302
measure: Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Head Circumference)
timeFrame: Baseline, Day 302
measure: Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Chest Circumference)
timeFrame: Baseline, Day 302
measure: Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Arm Circumference)
timeFrame: Baseline, Day 302
measure: Part B: Change From Baseline in Growth Parameters (Ulnar Length)
timeFrame: Baseline, Day 302
measure: Part B: Change From Baseline in Growth Parameters (Weight for Age Percentile)
timeFrame: Baseline, Day 302
measure: Part B: Change From Baseline in Growth Parameters (Weight for Length Percentile)
timeFrame: Baseline, Day 302
measure: Part B: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)
timeFrame: Baseline, Day 302
measure: Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (aPTT)
timeFrame: Baseline up to Day 279
measure: Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (PT)
timeFrame: Baseline up to Day 279
measure: Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (INR)
timeFrame: Baseline up to Day 279
measure: Part B: Change From Baseline in Urine Total Protein
timeFrame: Baseline, Day 302
measure: Part B: Number of Participants With Neurological Examination Abnormalities Reported as AEs
timeFrame: Baseline up to Day 302
measure: Part B: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements
timeFrame: Baseline up to Day 302
measure: Part B: Percentage of Participants With a Postbaseline QTcF of > 500 Msec and an Increase From Baseline to Any Postbaseline Timepoint in QTcF of > 60 Msec
timeFrame: Baseline up to Day 302
measure: Parts A, B and C: Number of Participants With Hospitalizations
timeFrame: Parts A, B, and C: Baseline up to Day 302
measure: Parts A, B and C: Percentage of Time of Hospitalization
timeFrame: Parts A, B, and C: Baseline up to Day 302
measure: Parts A, B and C: Number of Participants With Clinical Global Impression of Change (CGIC)
timeFrame: Parts A, B, and C: Day 302
measure: Parts A, B and C: Number of Serious Respiratory Events
timeFrame: Parts A, B, and C: Baseline up to Day 399
measure: Part B Infantile-onset SMA: Percentage of Time on Ventilation
timeFrame: Baseline up to Day 302
measure: Parts A, B and C: Number of Participants With Ventilator Use
timeFrame: Parts A, B, and C: Screening up to Day 302
measure: Part A: Change From Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale
timeFrame: Baseline, Day 302
measure: Part A: Number of Participants With Shift From Baseline in PASA Scale Items - Attempted to Drink Liquids and Attempted to Eat Solid Foods
timeFrame: Baseline, Day 302
measure: Part B: Change From Baseline in the PASA Scale
timeFrame: Baseline, Day 302
measure: Part B: Infantile SMA-onset: Change From (Ratio to) Baseline in CSF Concentration of NF-L
timeFrame: Baseline, Day 279
measure: Parts A and C: Change From Baseline in HFMSE Total Score
timeFrame: Parts A and C: Baseline, Day 302
measure: Parts A and C: Change From Baseline in RULM Total Score
timeFrame: Parts A and C: Baseline, Day 302
measure: Parts A and C: Number of Participants With WHO Motor Milestones Status
timeFrame: Parts A and C: Baseline up to Day 302
measure: Parts A and C: Change From Baseline in ACEND Total Score
timeFrame: Parts A and C: Baseline, Day 302
measure: Parts A and C: Change From Baseline in PedsQL™ Total Score
timeFrame: Parts A and C: Baseline, Day 302
measure: Part C: Change From Baseline in CHOP-INTEND Total Score
timeFrame: Baseline, Day 302
measure: Part C: Change From Baseline in HINE Section 2 Motor Milestones Total Score
timeFrame: Baseline, Day 302
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Belo Horizonte
country: Brazil
facility: HC-UFMG - Hospital das Clinicas da Universidade Federal de Minas Gerais
state: Minas Gerais
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande Do Sul
city: São Paulo
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina da USP
state: Sao Paulo
city: London
country: Canada
facility: London Health Sciences Centre (LHSC) - Children's Hospital
state: Ontario
city: Santiago
country: Chile
facility: Hospital Luis Calvo Mackenna
city: Santiago
country: Chile
facility: Clinica Las Condes
city: Santiago
country: Chile
facility: Clinica MEDS La Dehesa
city: Beijing
country: China
facility: Peking University First Hospital
state: Beijing
city: Hangzhou
country: China
facility: The Children's Hospital of Zhejiang University school of Med_Hangzhou
state: Binjiang
city: Guangzhou
country: China
facility: Guangzhou Woman and Children's Medical Center
state: Guangzhou
city: Changsha
country: China
facility: Xiangya Hospital, Central South University
state: Hunan
city: Bogota
country: Colombia
facility: Hospital Universitario San Ignacio
city: Medellin
country: Colombia
facility: Fundacion Hospitalaria San Vicente de Paul
city: Tallinn
country: Estonia
facility: Tallinn Children's Hospital
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
state: Baden Wuerttemberg
city: Giessen
country: Germany
facility: Universitaetsklinikum Giessen und Marburg GmbH
state: Hessen
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Budapest
country: Hungary
facility: Magyarorszagi Reformatus Egyhaz Bethesda Gyermekkorhaz
city: Milano
country: Italy
facility: Fondazione Serena Onlus - Centro Clinico Nemo
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Kurume-shi
country: Japan
facility: Kurume University Hospital
state: Fukuoka-Ken
city: Nishinomiya-shi
country: Japan
facility: Hyogo College of Medicine Hospital
state: Hyogo-Ken
city: Shinjuku-ku
country: Japan
facility: Tokyo Women's Medical University Hospital
state: Tokyo-To
city: Beirut
country: Lebanon
facility: Saint George University Hospital Medical Center
city: Mexico City
country: Mexico
facility: Instituto Nacional de Pediatria
state: Distrito Federal
city: Mexico
country: Mexico
facility: Hospital Infantil de Mexico Federico Gomez
state: Distrito Federal
city: Guadalajara
country: Mexico
facility: Antiguo Hospital Civil de Guadalajara Fray Antonio Alcalde
state: Jalisco
city: Warszawa
country: Poland
facility: Instytut Pomnik - Centrum Zdrowia Dziecka
city: Ekaterinburg
country: Russian Federation
facility: Regional Pediatric Clinical Hospital #1
city: Moskva
country: Russian Federation
facility: Russian Children Neuromuscular Center of Veltischev
city: Dammam
country: Saudi Arabia
facility: King Fahad Specialist Hospital
city: Jeddah
country: Saudi Arabia
facility: National Guard Health Affairs: King Abdulaziz Medical City
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital & Research Center
city: Esplugues Del Llobregat
country: Spain
facility: Hospital Sant Joan de Deu
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
Study officials:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.