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

JRCT ID: jRCT2061200040

Registered date:25/12/2020

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Spinal Muscular Atrophy
• Date of first enrollment: 03/08/2021
• Target sample size: 152
• Countries of recruitment: Colombia,Japan,Estonia,Japan,Ireland,Japan,Latvia,Japan,Spain,Japan,Taiwan,Japan,United States,Japan
• Study type: Interventional

Intervention(s)

- 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.

- 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.

- 50/28 mg 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.

- Part C: Participants who have been receiving the approved dose 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) followed by maintenance doses of 28 mg on Days 121 and 241.

Outcome(s)

Primary Outcome

1. Part B Infantile-onset SMA: Change from Baseline in CHOP INTEND Total Score [Time Frame: Baseline up to Day 183]

2. Part A and C: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

3. Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters
4. Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs)
5. Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs

6. Part A and C: Change from Baseline in Body Length/Height
7. Part C Infantile-onset SMA: Change from Baseline in Head Circumference
8. Part C Infantile-onset SMA: Change from Baseline in Chest Circumference
9. Part C Infantile-onset SMA: Change from Baseline in Arm Circumference
10. Part A and C Later-onset SMA: Change from Baseline in Ulnar Length
11. Part A and C: Ratio of Weight for Age
12. Part A and C: Ratio of Weight for Length
13. Part C: Ratio of Head-to-chest Circumference

14. Part A and C: Change from Baseline in Activated Partial Thromboplastin Time (aPTT)
15. Part A and C: Change from Baseline in Prothrombin Time (PT)
16. Part A and C: Change from Baseline in International Normalized Ratio (INR)

17. Part A and C: Change in Urine Total Protein

18. Part A and C: Change from Baseline in Neurological Examination Outcomes

19. Part A and C: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements

20. 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

Secondary Outcome

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

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

3. Part B Infantile-onset SMA: Time to 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.

4. Part B Infantile-onset SMA: Time to Death (Overall Survival)

5. Part A and Part B Later-onset SMA: Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score

6. Part A and Part B Later-onset SMA: Change from Baseline in Revised Upper Limb Module (RULM) Score

7. Part A and Part B Later-onset SMA: Total Number of New WHO Motor Milestones

8. Part A and Part B Later-onset SMA: Change from Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND)

9. Part A and Part B Later-onset SMA: Change from Baseline in Pediatric Quality of Life Inventory(TM) (PedsQL)

10. Part B: Number of Participants with AEs and SAEs

11. Part B: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters
12. Part B: Number of Participants with Clinically Significant Shifts from Baseline in ECGs
13. Part B: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs

14. Part B: Change from Baseline in Body Length/Height
15. Part B Infantile-onset SMA: Change from Baseline in Head Circumference
16. Part B Infantile-onset SMA: Change from Baseline in Chest Circumference
17. Part B Infantile-onset SMA: Change from Baseline in Arm Circumference
18. Part B Later-onset SMA: Change from Baseline in Ulnar Length
19. Part B: Ratio of Weight for Age
20. Part B: Ratio of Weight for Length
21. Part B: Ratio of Head-to-chest Circumference

22. Part B: Change from Baseline in aPTT
23. Part B: Change from Baseline in PT
24. Part B: Change from Baseline in INR

25. Part B: Change in Urine Total Protein

26. Part B: Change from Baseline in Neurological Examination Outcomes

27. Part B: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements

28. 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

29. Part A, B and C: Number of Hospitalizations
30. Part A, B and C: Duration of Hospitalizations

31. Part A, B and C: Clinical Global Impression of Change (CGIC) [Time Frame: Day302]

32. Part A, B and C: Number of Participants with Serious Respiratory Events

33. Part B Infantile-onset SMA: Percentage of Time on Ventilation

34. Parts A, B and C: Ventilator Use

35. Part B Infantile-onset SMA: Change from Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale

36. Part C: Change from Baseline in HFMSE Score

37. Part C: Change from Baseline in RULM Score

38. Part C: Total Number of New WHO Motor Milestones

39. Part C: Change from Baseline in ACEND

40. Part C: Change from Baseline in PedsQL(TM)

41. Part C: Change from Baseline in CHOP INTEND Total Score

42. Part C: Change from Baseline in HINE Section 2 Motor Milestones Total Score

43. Part A and B Later-onset SMA: Change from Baseline in the PASA Scale

Key inclusion & exclusion criteria

• Age minimum: Not applicable
• Age maximum: Not applicable
• Gender: Both

Include 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:
- 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

NOTE: Other protocol defined Inclusion criteria may apply.

Exclude 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 (SMN2)-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation

Part B:
- 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 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

NOTE: Other protocol defined Exclusion criteria may apply.

Related Information

• Primary Sponsor: Berger Zdenek
• Secondary ID(s): NCT04089566