| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Spinal Muscular Atrophy (SMA) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041582 |
| E.1.2 | Term | Spinal muscular atrophy |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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). |
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| E.2.2 | Secondary objectives of the trial |
| 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). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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:
- 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
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| E.4 | Principal 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
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 survival motor neuron-2 (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
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part B Infantile-onset SMA:
1) Change from Baseline in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Total Score
Part A and C:
2) Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
3) Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters
4) Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs)
5) Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs
6) Change from Baseline in Body Length/Height
Part C Infantile-onset SMA:
7) Change from Baseline in Head Circumference
8) Change from Baseline in Chest Circumference
9) Change from Baseline in Arm Circumference
Part A and C Later-onset SMA:
10) Change from Baseline in Ulnar Length
Part A and C:
11) Ratio of Weight for Age
12) Ratio of Weight for Length
Part C:
13) Ratio of Head-to-chest Circumference
Part A and C:
14) Change from Baseline in Activated Partial Thromboplastin Time (aPTT)
15) Change from Baseline in Prothrombin Time (PT)
16) Change from Baseline in International Normalized Ratio (INR)
17) Change in Urine Total Protein
18) Change from Baseline in Neurological Examination Outcomes
19) Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements
20) 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 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part B Infantile-onset SMA:
1) Baseline up to Day 183
Part A and C:
2) Screening up to Day 389
3) Screening up to Day 302
4) Screening up to Day 302
5) Screening up to Day 302
6) Baseline up to Day 302
Part C Infantile-onset SMA:
7) Baseline up to Day 302
8) Baseline up to Day 302
9) Baseline up to Day 302
Part A and C Later-onset SMA:
10) Baseline up to Day 302
Part A and C:
11) Baseline up to Day 302
12) Baseline up to Day 302
Part C:
13) Baseline up to Day 302
Part A and C:
14) Baseline up to Day 269
15) Baseline up to Day 269
16) Baseline up to Day 269
17) Baseline up to Day 302
18) Baseline up to Day 302
19) Baseline up to Day 302
20) Baseline up to Day 302 |
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| E.5.2 | Secondary end point(s) |
Part B Infantile-onset SMA:
1) Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders
2) Change from Baseline in HINE Section 2 Motor Milestones Total Score
3) Time to Death or Permanent Ventilation
4) Time to Death (Overall Survival)
Part A and B Later-onset SMA:
5) Change from Baseline in Hammersmith Functional Motor Scale – Expanded (HFMSE) Score
6) Change from Baseline in Revised Upper Limb Module (RULM) Score
7) Total number of New WHO Motor Milestones
8) Change from Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND)
9) Change from Baseline in Pediatric Quality of Life Inventory™ (PedsQL)
Part B:
10) Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
11) Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters
12) Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs)
13) Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs
14) Change from Baseline in Body Length/Height
Part B Infantile-onset SMA:
15) Change from Baseline in Head Circumference
16) Change from Baseline in Chest Circumference
17) Change from Baseline in Arm Circumference
Part B Later-onset SMA:
18) Change from baseline in Ulnar Length
Part B:
19) Ratio of Weight for Age
20) Ratio of Weight for Length
21) Ratio of Head-to-chest Circumference
22) Change from Baseline in aPTT
23) Change from Baseline in PT
24) Change from Baseline in INR
25) Change in Urine Total Protein
26) Change from Baseline in Neurological Examination Outcomes
27) Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements
28) Percentage of Participants with a Postbaseline QTcF of > 500 millisecond (msec) and an Increase from Baseline to Any Postbaseline Timepoint in QTcF of > 60 msec
Part A, B and C:
29) Number of Hospitalizations
30) Duration of Hospitalizations
31) Clinical Global Impression of Change (CGIC)
32) Number of Participants with Serious Respiratory Events
Part B Infantile-onset SMA:
33) Percentage of Time on Ventilation
Parts A, B and C:
34) Ventilator Use
Part B Infantile-onset SMA:
35) Change from Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale
Part C :
36) Change from Baseline in HFMSE Score
37) Change from Baseline in RULM Score
38) Total Number of New WHO Motor Milestones
39) Change from Baseline in ACEND
40) Change from Baseline in PedsQL
41) Change from Baseline in CHOP INTEND Total Score
42) Change from Baseline in HINE Section 2 Motor Milestones Total Score
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Day 302
2) Baseline up to Day 302
3) Screening up to Day 302
4) Screening up to Day 399
5) to 9) - Baseline up to Day 302
10) Screening to day 399
11) Screening to Day 302
12) Day 1 up to Day 302
13) Screening up to Day 302
14) Baseline up to Day 302
15) to 17) Baseline up to Day 302
18) Baseline up to Day 302
19) to 21) Baseline up to Day 302
22) to 24) Baseline up to Day 279
25) Baseline up to Day 302
26) to 28) Baseline up to Day 302
29) and 30) Day 1 to Day 302
31) Day 302
32) Screening up to Day 399
33) Screening up to Day 302
34) Screening up to Day 302
35) Baseline up to Day 302
36) to 41) Baseline to up Day 302
42) Baseline up to Day 302
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Sequential Assignment: Part A - Open Label. Part B - Double Blind. Part C - Open Label |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Part B only - commercial Spinraza |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| 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 |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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