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

Muscular Atrophy, Spinal Clinical Trial

— DEVOTE  

Official title:

Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04089566
• Other study ID #: 232SM203
• Secondary ID: 2019-002663-10
• Status: Completed
• Phase: Phase 3
• Start date: March 26, 2020
• Est. completion date: May 30, 2024

Study information

• Verified date: June 2024
• Source: Biogen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 145
• Est. completion date: May 30, 2024
• Est. primary completion date: February 21, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 7 Days and older

Eligibility

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.

Related Conditions & MeSH terms

• Atrophy
• Muscular Atrophy
• Muscular Atrophy, Spinal

Intervention

Drug:
• Nusinersen
Administered as specified in the treatment arm

Locations

Country	Name	City	State
Australia	Royal Children's Hospital	Parkville	Victoria
Brazil	HC-UFMG - Hospital das Clinicas da Universidade Federal de Minas Gerais	Belo Horizonte	Minas Gerais
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital das Clínicas da Faculdade de Medicina da USP	São Paulo	Sao Paulo
Canada	London Health Sciences Centre (LHSC) - Children's Hospital	London	Ontario
Canada	McGill University Health Centre/Glen Site/Montreal Children's Hospital	Montreal	Quebec
Canada	BC Children's Hospital	Vancouver	British Columbia
Chile	Clinica Las Condes	Santiago
Chile	Clinica MEDS La Dehesa	Santiago
Chile	Hospital Luis Calvo Mackenna	Santiago
China	Beijing Children's Hospital	Beijing	Beijing
China	Peking University First Hospital	Beijing	Beijing
China	Xiangya Hospital, Central South University	Changsha	Hunan
China	The Second Hospital affiliated to West China Medical University	Chendu	Sichuan
China	Children's Hospital Chongqing University of Medical Science	Chongqing	Chongqing
China	Guangzhou Woman and Children's Medical Center	Guangzhou	Guangzhou
China	Qilu Hospital of Shandong University	Jinan	Shandong
Colombia	Hospital Universitario San Ignacio	Bogota
Colombia	Fundacion Hospitalaria San Vicente de Paul	Medellin
Estonia	Tallinn Children's Hospital	Tallinn
France	Hôpital Raymond Poincaré	Garches	Hauts De Seine
France	Hopital Purpan	Toulouse cedex 9	Haute Garonne
Germany	Universitaetsklinikum Freiburg	Freiburg	Baden Wuerttemberg
Germany	Universitaetsklinikum Giessen und Marburg GmbH	Giessen	Hessen
Greece	University General Hospital "Attikon"	Athens
Greece	General Hospital of Thessaloniki "Hippokration"	Thessaloniki
Hungary	Magyarorszagi Reformatus Egyhaz Bethesda Gyermekkorhaz	Budapest
Hungary	Semmelweis Egyetem	Budapest
Ireland	The Children's University Hospital	Dublin
Israel	Schneider Children's Medical Center	Petach-Tikva
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	Fondazione Serena Onlus - Centro Clinico Nemo	Milano
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Roma
Japan	Kurume University Hospital	Kurume-shi	Fukuoka-Ken
Japan	Hyogo College of Medicine Hospital	Nishinomiya-shi	Hyogo-Ken
Japan	Tokyo Women's Medical University Hospital	Shinjuku-ku	Tokyo-To
Korea, Republic of	Kyungpook National University Chilgok Hospital	Daegu	Gyeongsangbuk-do
Korea, Republic of	Seoul National University Hospital	Seoul
Latvia	Children's Clinical University Hospital	Riga
Lebanon	Saint George University Hospital Medical Center	Beirut
Mexico	Antiguo Hospital Civil de Guadalajara Fray Antonio Alcalde	Guadalajara	Jalisco
Mexico	Hospital Infantil de Mexico Federico Gomez	Mexico	Distrito Federal
Mexico	Instituto Nacional de Pediatria	Mexico City	Distrito Federal
Netherlands	UMC Utrecht	Utrecht
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Instytut Pomnik - Centrum Zdrowia Dziecka	Warszawa
Russian Federation	Regional Pediatric Clinical Hospital #1	Ekaterinburg
Russian Federation	Russian Children Neuromuscular Center of Veltischev	Moskva
Saudi Arabia	King Fahad Specialist Hospital	Dammam
Saudi Arabia	National Guard Health Affairs: King Abdulaziz Medical City	Jeddah
Saudi Arabia	King Faisal Specialist Hospital & Research Center	Riyadh
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Sant Joan de Deu	Esplugues Del Llobregat	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	National Taiwan University Hospital	Taipei
Turkey	Akdeniz Univesity Medical Faculty	Antalya
United Kingdom	Great Ormond Street Hospital for Children	London	Greater London
United States	Children's Hospital Colorado	Aurora	Colorado
United States	The Johns Hopkins Hospital	Baltimore	Maryland
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	The University of Texas Southwestern Medical Center	Dallas	Texas
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Stanford Hospital and Clinics	Palo Alto	California

Sponsors (1)

Lead Sponsor	Collaborator
Biogen

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Chile,  China,  Colombia,  Estonia,  France,  Germany,  Greece,  Hungary,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Latvia,  Lebanon,  Mexico,  Netherlands,  Poland,  Russian Federation,  Saudi Arabia,  Spain,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part B Infantile-onset SMA: Change from Baseline in CHOP-INTEND Total Score	The CHOP-INTEND test is designed to evaluate the motor skills of infants with significant motor weakness. It includes 16 items (capturing neck, trunk, and proximal and distal limb strength) structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0-4.	Baseline up to Day 183
Primary	Part A and C: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that at any dose results in death, in the view of the Investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect.	Screening up to Day 389
Primary	Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters		Screening up to Day 302
Primary	Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs)		Screening up to Day 302
Primary	Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs		Screening up to Day 302
Primary	Part A and C: Change from Baseline in Body Length/Height		Baseline up to Day 302
Primary	Part C Infantile-onset SMA: Change from Baseline in Head Circumference		Baseline up to Day 302
Primary	Part C Infantile-onset SMA: Change from Baseline in Chest Circumference		Baseline up to Day 302
Primary	Part C Infantile-onset SMA: Change from Baseline in Arm Circumference		Baseline up to Day 302
Primary	Part A and C Later-onset SMA: Change from Baseline in Ulnar Length		Baseline up to Day 302
Primary	Part A and C: Ratio of Weight for Age		Baseline up to Day 302
Primary	Part A and C: Ratio of Weight for Length		Baseline up to Day 302
Primary	Part C: Ratio of Head-to-chest Circumference		Baseline up to Day 302
Primary	Part A and C: Change from Baseline in Activated Partial Thromboplastin Time (aPTT)		Baseline up to Day 269
Primary	Part A and C: Change from Baseline in Prothrombin Time (PT)		Baseline up to Day 269
Primary	Part A and C: Change from Baseline in International Normalized Ratio (INR)		Baseline up to Day 269
Primary	Part A and C: Change in Urine Total Protein		Baseline up to Day 302
Primary	Part A and C: Change from Baseline in Neurological Examination Outcomes		Baseline up to Day 302
Primary	Part A and C: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements		Baseline up to Day 302
Primary	Part 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		Baseline up to Day 302
Secondary	Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders	Section 2 of the HINE is used to assess motor milestones of the participants It is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking.	Day 302
Secondary	Part B Infantile-onset SMA: Change from Baseline in HINE Section 2 Motor Milestones Total Score	Section 2 of the HINE is used to assess motor milestones of the participants. It is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking.	Baseline up to Day 302
Secondary	Part B Infantile-onset SMA: Time to Death or Permanent Ventilation	Permanent ventilation is defined as tracheostomy or = 16 hours of ventilation/day continuously for > 21 days in the absence of an acute reversible event.	Screening up to Day 302
Secondary	Part B Infantile-onset SMA: Time to Death (Overall Survival)		Screening up to Day 399
Secondary	Part A and B Later-onset SMA: Change from Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score	HFMSE scale is a tool to assess motor function in children with SMA. The original 20 item Hammersmith Functional Motor Scale was expanded to include 13 additional adapted items from the Gross Motor Function Measure to improve sensitivity for the higher functioning ambulant population.	Baseline up to Day 302
Secondary	Part A and B Later-onset SMA: Change from Baseline in Revised Upper Limb Module (RULM) Score	The RULM is developed to assess upper limb functional abilities participants with SMA. This test consists of upper limb performance items that are reflective of activities of daily living.	Baseline up to Day 302
Secondary	Part A and B Later-onset SMA: Total Number of New WHO Motor Milestones		Baseline up to Day 302
Secondary	Part A and B Later-onset SMA: Change from Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND)	ACEND is designed to quantify the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases. It includes domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance).	Baseline up to Day 302
Secondary	Part A and B Later-onset SMA: Change from Baseline in Pediatric Quality of Life Inventory™ (PedsQL)	PedsQL is used to measure health related quality of life (HRQOL) in children and adolescents. The PedsQL Measurement 4.0 Generic Core Scales include assessment of physical functioning, emotional functioning, social functioning, and school functioning and the PedsQL 3.0 Neuromuscular Module measures HRQOL.	Baseline up to Day 302
Secondary	Part B: Number of Participants with AEs and SAEs	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that at any dose results in death, in the view of the Investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect.	Screening up to Day 399
Secondary	Part B: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters		Screening up to Day 302
Secondary	Part B: Number of Participants with Clinically Significant Shifts from Baseline in ECGs		Day 1 up to Day 302
Secondary	Part B: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs		Screening up to Day 302
Secondary	Part B: Change from Baseline in Body Length/Height		Baseline up to Day 302
Secondary	Part B Infantile-onset SMA: Change from Baseline in Head Circumference		Baseline up to Day 302
Secondary	Part B Infantile-onset SMA: Change from Baseline in Chest Circumference		Baseline up to Day 302
Secondary	Part B Infantile-onset SMA: Change from Baseline in Arm Circumference		Baseline up to Day 302
Secondary	Part B Later-onset SMA: Change from Baseline in Ulnar Length		Baseline up to Day 302
Secondary	Part B: Ratio of Weight for Age		Baseline up to Day 302
Secondary	Part B: Ratio of Weight for Length		Baseline up to Day 302
Secondary	Part B: Ratio of Head-to-chest Circumference		Baseline up to Day 302
Secondary	Part B: Change from Baseline in aPTT		Baseline up to Day 279
Secondary	Part B: Change from Baseline in PT		Baseline up to Day 279
Secondary	Part B: Change from Baseline in INR		Baseline up to Day 279
Secondary	Part B: Change in Urine Total Protein		Baseline up to Day 302
Secondary	Part B: Change from Baseline in Neurological Examination Outcomes		Baseline up to Day 302
Secondary	Part B: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements		Baseline up to Day 302
Secondary	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		Baseline up to Day 302
Secondary	Part A, B and C: Number of Hospitalizations		Day 1 to Day 302
Secondary	Part A, B and C: Duration of Hospitalizations		Day 1 to Day 302
Secondary	Part A, B and C: Clinical Global Impression of Change (CGIC)	The CGIC scale is a 7 point scale that requires the clinician to assess how much the participant's illness has changed relative to a baseline state at the beginning of the intervention, where 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. Higher rating will indicate worsening of the condition.	Day 302
Secondary	Part A, B and C: Number of Participants with Serious Respiratory Events		Screening up to Day 399
Secondary	Part B Infantile-onset SMA: Percentage of Time on Ventilation		Screening up to Day 302
Secondary	Parts A, B and C: Ventilator Use		Screening up to Day 302
Secondary	Parts A and B: Change from Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale	PASA questionnaire is developed to assess the signs and symptoms of dysphagia. It includes 33 items across 4 domains. General feeding, drinking liquids and eating solid foods will be assessed with 5 levels of response (Never, Rarely, Sometimes, Often, and Always), and 2 items will be assessed with 'Yes'/'No'. The assessment of swallowing concerns has 4 levels of response: Strongly Agree, Agree, Disagree, and Strongly Disagree. For Part A, it will be assessed in participants with later-onset SMA and in Part B, it will be assessed in participants with infantile- and later-onset SMA.	Baseline up to Day 302
Secondary	Part C: Change from Baseline in HFMSE Score	HFMSE scale is a tool to assess motor function in children with SMA. The original 20 item Hammersmith Functional Motor Scale was expanded to include 13 additional adapted items from the Gross Motor Function Measure to improve sensitivity for the higher functioning ambulant population.	Baseline up to Day 302
Secondary	Part C: Change from Baseline in RULM Score	The RULM is developed to assess upper limb functional abilities participants with SMA. This test consists of upper limb performance items that are reflective of activities of daily living.	Baseline up to Day 302
Secondary	Part C: Total Number of New WHO Motor Milestones		Baseline up to Day 302
Secondary	Part C: Change from Baseline in ACEND	ACEND is designed to quantify the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases. It includes domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance).	Baseline up to Day 302
Secondary	Part C: Change from Baseline in PedsQL™	PedsQL is used to measure healthrelated quality of life (HRQOL) in children and adolescents. The PedsQL Measurement 4.0 Generic Core Scales include assessment of physical functioning, emotional functioning, social functioning, and school functioning and the PedsQL 3.0 Neuromuscular Module measures HRQOL.	Baseline up to Day 302
Secondary	Part C: Change from Baseline in CHOP-INTEND Total Score	The CHOP-INTEND test is designed to evaluate the motor skills of infants with significant motor weakness. It includes 16 items (capturing neck, trunk, and proximal and distal limb strength) structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0-4.	Baseline to up Day 302
Secondary	Part C: Change from Baseline in HINE Section 2 Motor Milestones Total Score	Section 2 of the HINE is used to assess motor milestones of the participants. It is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking.	Baseline up to Day 302

External Links

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