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 safety and tolerability of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA) (Parts A and C); to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with SMA, as measured by change in CHOP INTEND total score (Part B). |
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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, 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 (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: - 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 |
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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 - 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
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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 302 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 269 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
Part B and C Infantile-onset SMA: 2) Change from Baseline in HINE Section 2 Motor Milestones Total Score
Part B Infantile-onset SMA: 3) Time to Permanent Ventilation 4) Time to Death (Overall Survival)
Part A, B and C 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) Number of New WHO Motor Milestones Responders 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
Part C Infantile-onset SMA: 34) Ventilator Use Part A and B: 35) Change from Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale
Part A B and C: 36) Cerebrospinal Fluid (CSF) Levels of Nusinersen 37) Plasma Levels of Nusinersen
Part C Infantile-onset SMA: 38) Change from Baseline in CHOP INTEND Total Score
Part C Later-onset SMA: 39) Change from Baseline in 6-Minute Walk Test (6MWT) Distance 40) Change from Baseline in 10-Meter Walk/Run Test (10MWR) 41) Change from Baseline in Spinal Muscular Atrophy-Health Index (SMA-HI) |
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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) and 4) Screening up to Day 302
5) to 9) - Baseline up to Day 302
10) and 11) Screening up 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 25) Baseline up to Day 279 26) to 28) Baseline up to Day 302
29) and 30) Day 1 to Day 279 31) Day 302 32) Screening up to Day 302
33) Screening up to Day 302
34) Screening up to Day 302
35) Baseline up to Day 302
36) Baseline up to Day 279 37) Baseline up to Day 302
38) Baseline to up Day 302
39) to 41) 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 |
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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 |
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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 | 24 |
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 |
Argentina |
Australia |
Brazil |
Canada |
Chile |
Colombia |
Estonia |
Hungary |
Ireland |
Italy |
Korea, Republic of |
Latvia |
Lebanon |
Mexico |
Poland |
Russian Federation |
Saudi Arabia |
Spain |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 1 |