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 the study is to assess the safety and tolerability of ISIS 396443 in participants with SMA who are not eligible to participate in the clinical studies ISIS 396443-CS3B (NCT02193074) or ISIS 396443-CS4 (NCT02292537). |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is to examine the pharmacokinetics of ISIS 396443 in participants with SMA. |
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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.
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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.
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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 at 14 months - Change from Baseline in clinical laboratory parameters at Baseline and 14 months - Change from Baseline in electrocardiograms (ECGs) at Baseline and 14 months - Change from Baseline in vital signs at Baseline and 14 months - Change from Baseline in neurological examination outcomes at Baseline and 14 months
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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) |
1. ISIS 396443 plasma concentration 2. ISIS 396443 cerebrospinal fluid (CSF) concentration
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 4 hours post-dose on Day 1 and pre-dose on Days 64, 183 and 422. 2. Pre-dose on Days 1, 15, 29, 64, 183 and 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 | 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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 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 | 4 |