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

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ClinicalTrials.gov Identifier: NCT04089566
Recruitment Status : Not yet recruiting
First Posted : September 13, 2019
Last Update Posted : October 28, 2019
Sponsor:
Information provided by (Responsible Party):
Biogen

Brief Summary:

The primary objective of the study is to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA).

The secondary objectives of the study are to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA; to examine the effect of nusinersen administered at higher doses compared to the currently approved dose in participants with SMA; and to examine the pharmacokinetic(s) (PK) of nusinersen [cerebrospinal fluid (CSF) and plasma] after intrathecal administration of nusinersen given at higher doses to participants with SMA.


Condition or disease Intervention/treatment Phase
Muscular Atrophy, Spinal Drug: Nusinersen Phase 2 Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 125 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Official Title: Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
Estimated Study Start Date : February 26, 2020
Estimated Primary Completion Date : June 13, 2022
Estimated Study Completion Date : December 18, 2022


Arm Intervention/treatment
Experimental: 28/28 Milligram (mg) Safety Group
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
Administered as specified in the treatment arm
Other Name: BIIB058

Active Comparator: 12/12 mg Randomized Control Group
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
Administered as specified in the treatment arm
Other Name: BIIB058

Experimental: 50/28 mg Randomized Treatment Group
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
Administered as specified in the treatment arm
Other Name: BIIB058

Experimental: 12/50/28 mg Titration Group
Part C: Participants who have been receiving the approved dose of 12 mg for at least 1 year prior to entry in this study, 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
Administered as specified in the treatment arm
Other Name: BIIB058




Primary Outcome Measures :
  1. Part B Infantile-onset SMA: Change from Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Total Score [ Time Frame: Baseline up to Day 183 ]
    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.

  2. Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders [ Time Frame: Day 302 ]
    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.

  3. Part B Infantile-onset SMA: Change from Baseline in HINE Section 2 Motor Milestones Total Score [ Time Frame: Baseline up to Day 302 ]
    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.

  4. Part B Infantile-onset SMA: Time to Permanent Ventilation [ Time Frame: Screening up to Day 302 ]
    Permanent ventilation is defined as tracheostomy or ≥ 16 hours of ventilation/day continuously for > 21 days in the absence of an acute reversible event.

  5. Part B Infantile-onset SMA: Time to Death (Overall Survival) [ Time Frame: Screening up to Day 302 ]
  6. Part A, B and C Later-onset SMA: Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score [ Time Frame: Baseline up to Day 302 ]
    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.

  7. Part A, B and C Later-onset SMA: Change from Baseline in Revised Upper Limb Module (RULM) Score [ Time Frame: Baseline up to Day 302 ]
    The RULM is developed to assess upper limib functional abilities participants with SMA. This test consists of upper limb performance items that are reflective of activities of daily living.

  8. Part A, B and C Later-onset SMA: Number of New WHO Motor Milestones Responders [ Time Frame: Baseline up to Day 302 ]
  9. Part A, B and C Later-onset SMA: Change from Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) [ Time Frame: Baseline up to Day 302 ]
    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).

  10. Part A, B and C Later-onset SMA: Change from Baseline in Pediatric Quality of Life Inventory™ (PedsQL) [ Time Frame: Baseline up to Day 302 ]
    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.

  11. Part C Infantile-onset SMA: Change from Baseline in CHOP INTEND Total Score [ Time Frame: Baseline to up Day 302 ]
    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.

  12. Part C Infantile-onset SMA: Change from Baseline in HINE Section 2 Motor Milestones Total Score [ Time Frame: Baseline up to Day 302 ]
    Section 2 of the HINE is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. The score scale ranges from 0 to 4, where increase in number indicates improvement.

  13. Part C Later-onset SMA: Change from Baseline in 6-Minute Walk Test (6MWT) Distance [ Time Frame: Baseline up to Day 302 ]
    6MWT measures the distance a participant can walk quickly in 6 minutes.

  14. Part C Later-onset SMA: Change from Baseline in 10-Meter Walk/Run Test (10MWR) [ Time Frame: Baseline up to Day 302 ]
    10MWR is a measure of the time required to walk/run 10 meters.

  15. Part C Later-onset SMA: Change from Baseline in Spinal Muscular Atrophy-Health Index (SMA-HI) [ Time Frame: Baseline up to Day 302 ]
    SMA-HI questionnaire measures a participant's perception of total disease burden


Secondary Outcome Measures :
  1. Part A, B and C: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Screening up to Day 302 ]
    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.

  2. Part A, B and C: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters [ Time Frame: Screening up to Day 302 ]
  3. Part A, B and C: Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs) [ Time Frame: Screening up to Day 302 ]
  4. Part A, B and C: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs [ Time Frame: Screening up to Day 302 ]
  5. Part A, B and C: Change from Baseline in Body Length/Height [ Time Frame: Baseline up to Day 302 ]
  6. Part B Infantile-onset SMA: Change from Baseline in Head Circumference [ Time Frame: Baseline up to Day 302 ]
  7. Part B Infantile-onset SMA: Change from Baseline in Chest Circumference [ Time Frame: Baseline up to Day 302 ]
  8. Part B Infantile-onset SMA: Change from Baseline in Arm Circumference [ Time Frame: Baseline up to Day 302 ]
  9. Part A, B and C Later-onset SMA: Change from Baseline in Ulnar Length [ Time Frame: Baseline up to Day 302 ]
  10. Part A, B and C: Ratio of Weight for Age [ Time Frame: Baseline up to Day 302 ]
  11. Part A, B and C: Ratio of Weight for Length [ Time Frame: Baseline up to Day 302 ]
  12. Part A, B and C: Ratio of Head-to-chest Circumference [ Time Frame: Baseline up to Day 302 ]
  13. Part A, B and C: Change from Baseline in Activated Partial Thromboplastin Time [ Time Frame: Baseline up to Day 279 ]
  14. Part A, B and C: Change from Baseline in Prothrombin Time [ Time Frame: Baseline up to Day 279 ]
  15. Part A, B and C: Change from Baseline in International Normalized Ratio [ Time Frame: Baseline up to Day 279 ]
  16. Part A, B and C: Change in Urine Total Protein [ Time Frame: Baseline up to Day 279 ]
  17. Part A, B and C: Change from Baseline in Neurological Examination Outcomes [ Time Frame: Baseline up to Day 302 ]
  18. Part A, B and C: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements [ Time Frame: Baseline up to Day 302 ]
  19. Part A, B 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 [ Time Frame: Baseline up to Day 302 ]
  20. Part A, B and C: Number of Hospitalizations [ Time Frame: Day 1 to Day 279 ]
  21. Part A, B and C: Duration of Hospitalizations [ Time Frame: Day 1 to Day 279 ]
  22. Part A, B and C: Clinical Global Impression of Change (CGIC) [ Time Frame: Baseline up to Day 302 ]
    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.

  23. Part A, B and C: Number of Participants with Serious Respiratory Events [ Time Frame: Screening up to Day 302 ]
  24. Part A and B: Change from Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale [ Time Frame: Baseline up to Day 302 ]
    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.

  25. Part A, B and C: Cerebrospinal Fluid (CSF) Levels of Nusinersen [ Time Frame: Baseline up to Day 279 ]
  26. Part A, B and C: Plasma Levels of Nusinersen [ Time Frame: Baseline up to Day 302 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 ≤ 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:

  • Participants ≥ 18 years of age at Screening must be ambulatory
  • Currently on nusinersen treatment at the time of Screening, with the first dose being at least 1 year prior to 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 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
  • Dosing with onasemnogene abeparvovec-xioi (Zolgensma) within 6 months prior to Screening

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 prior to Screening or anytime during the study; prior treatment with risdiplam or branaplam; or any history of gene therapy, prior antisense oligonucleotide treatment, or cell transplantation

Part B:

  • 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 prior to Screening or anytime during the study; prior treatment with risdiplam or branaplam; or any history of gene therapy, prior antisense oligonucleotide treatment, or cell transplantation

Part C:

- Concurrent participation and/or administration of nusinersen in another clinical study

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04089566


Contacts
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Contact: US Biogen Clinical Trial Center 866-633-4636 clinicaltrials@biogen.com
Contact: Global Biogen Clinical Trial Center clinicaltrials@biogen.com

Sponsors and Collaborators
Biogen
Investigators
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Study Director: Medical Director Biogen

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Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT04089566     History of Changes
Other Study ID Numbers: 232SM203
2019-002663-10 ( EudraCT Number )
First Posted: September 13, 2019    Key Record Dates
Last Update Posted: October 28, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/
URL: http://www.biogenclinicaldatarequest.com/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Muscular Atrophy
Muscular Atrophy, Spinal
Atrophy
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases