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 |
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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 objective of Part 1 of this study is to assess the safety and tolerability of Nusinersen in participants with SMA who are not eligible to participate in the clinical studies ISIS 396443-CS3B (NCT02193074) or ISIS 396443-CS4 (NCT02292537).
The primary objective of Part 2 of this study is to assess the long-term safety and tolerability of Nusinersen in participants with SMA who participated in Part 1 and completed their End of Part 1 Evaluation assessments. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of Part 1 of this study is to examine the pharmacokinetics (PK) of Nusinersen in participants with SMA.
The secondary objective of Part 2 of this study is to examine the PK of Nusinersen in participants with SMA who participated in Part 1 and completed their End of Part 1 Evaluation assessments. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Genetic documentation of 5q SMA homozygous gene deletion, mutation, or compound heterozygote.
- Onset of clinical signs and symptoms consistent with SMA at ≤6 months of age and have documentation of 3 SMN2 copies OR onset of clinical signs and symptoms consistent with SMA at ≤6 months of age, >7 months of age (211 days) at screening, and have documentation of 2 SMN2 copies OR onset of clinical signs and symptoms consistent with SMA at >6 months of age, are ≤18 months of age at screening, and have documentation of 2 or 3 SMN2 copies.
- Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedures.
- Medical care, such as routine immunizations meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA, in the opinion of the Investigator.
- Subjects with 2 SMN2 copies must reside within approximately 9 hours’ ground-travel distance from a participating study site for the duration of the study.
For Part 2 only:
- Participation in Part 1 and completion of the End of Part 1 Evaluation assessments.
- Ability of parent(s) or legal guardian(s) to understand the purpose and risks of the study and to provide signed and dated informed consent on the Part 2 informed consent form (ICF) and authorization to use confidential health information in accordance with national and local participant privacy
regulations.
- Able to complete all study procedures, measurements, and visits, and parent or legal guardian/participant has adequately supportive psychosocial circumstances, in the opinion of the Investigator.
NOTE: Other protocol defined Inclusion criteria may apply. |
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E.4 | Principal exclusion criteria |
- Meets additional study related criteria.
- Any previous exposure to ISIS 396443; previous dosing in this study or previous studies with ISIS 396443.
- Signs or symptoms of SMA present at birth or within the first week after birth.
- Ventilation for ≥16 hours per day continuously for >21 days at screening.
- Permanent tracheostomy, implanted shunt for CSF drainage, or implanted central nervous system (CNS) catheter at screening.
- History of brain or spinal cord disease that would interfere with the LP procedure, CSF circulation, or safety assessments.
- Hospitalization for surgery (e.g., scoliosis surgery), pulmonary event, or nutritional support within 2 months prior to screening, or hospitalization for surgery planned during the study.
- Clinically significant abnormalities in hematology or clinical chemistry parameters or Electrocardiogram (ECG), as assessed by the Investigator.
- Treatment with an investigational drug for SMA (e.g., albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, hydroxyurea), biological agent, or device within 30 days prior to screening. Any history of gene therapy, prior antisense oligonucleotide (ASO) treatment, or cell transplantation.
For Part 2 only
- Any significant change in clinical status, including laboratory tests that, in the opinion of the Investigator, would make them unsuitable to participate in Part 2. The Investigator must reassess the subject’s medical fitness for participation and
consider any diseases that would preclude treatment.
NOTE: Other protocol defined Exclusion criteria may
apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Number of participants with adverse events and serious adverse events up to 44 months
- Change from Baseline in clinical laboratory parameters at Baseline and 14 months (Part 1) and 30 months (Part 2)
- Change from Baseline in electrocardiograms (ECGs) at Baseline and 14 months (Part 1) and 30 months (Part 2)
- Change from Baseline in vital signs at Baseline and 14 months (Part 1) and 30 months (Part 2)
- Change from Baseline in neurological examination outcomes at Baseline and 14 months (Part 1) and 30 months (Part 2)
- Change from Baseline in growth parameters at Baseline (Part 1) and 30 months (Part 2)
- Activated partial thromboplastin time (aPTT) at Baseline
- Partial thromboplastin time (PTT) at Baseline
- International normalized ratio (INR) at Baseline
- Urine total protein at Baseline |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Nusinersen plasma concentration up to Day 897
- Nusinersen cerebrospinal fluid (CSF) concentration up to Day 897
- Nusinersen plasma antibodies up to Day 897
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1: Day 1 post dose, Days 64, 183, and end of Part 1
Part 2 (participants randomized to drug): Day 1 post dose, Days 239, 477, 715, and Part 2 final follow-up Part 2 (participants randomized to sham): Day 1 post dose, Days 64, 183, 540, 778, and Part 2 Final follow-up
Part 1: Predose Days 1, 15, 29, 64, 183, 302
Part 2 (participants randomized to drug): Predose Days 1, 120, 239, 358, 477, 596, 715 Part 2 (participants randomized to sham): Predose Days 1, 15, 29,
64, 183, 302, 421, 540, 659, 778 |
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity assessments |
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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) | No |
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 | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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 |
sham-procedure controlled |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
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 |
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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 | 4 |
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 | 4 |