E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Spinal Muscular Atrophy (SMA) |
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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.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To test the safety and tolerability of escalating doses of nusinersen (ISIS 396443) in participants with spinal muscular atrophy (SMA) |
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E.2.2 | Secondary objectives of the trial |
To test the pharmacokinetics of escalating doses of nusinersen (ISIS 396443) in participants with spinal muscular atrophy (SMA) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Males and Females 2-15 years of age
-Genetic documentation of 5qSMA (homozygous gene deletion or mutation)
-Clinical signs attributable to SMA
-Able to complete all study procedures, measurements, and visits and parent/patient has adequately supportive psychological circumstances, in the opinion of the investigator
-Estimated life expectancy >2 years from Screening
-Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedure |
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E.4 | Principal exclusion criteria |
-Respiratory insufficiency defined by the medical necessity for invasive or non-invasive ventilation during a 24-hour period
-Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Investigator
-Previous scoliosis surgery that would interfere with the lumbar puncture injection procedure
-Hospitalization for surgery (e.g. scoliosis surgery) or pulmonary event within 2 months of screening or planned during the duration of the study
-Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
-History of brain or spinal cord disease that would interfere with lumbar puncture procedures or cerebrospinal fluid (CSF) circulation
-Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter
-History of bacterial meningitis
-Dosing with ISIS 396443 in clinical study ISIS 396443-CS1 Cohorts 2, 3, or 4
-Dosing with ISIS 396443 in clinical study ISIS 396443-CS10
-Clinically significant abnormalities in hematology or clinical chemistry parameters or ECG at the Screening visit, as assessed by the Site Investigator that would render the subject unsuitable for inclusion
-Treatment with investigational drug, biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3-months of screening. Any history of gene therapy or cell transplantation
-Ongoing medical condition that would interfere with the conduct and assessments of the study. Examples are medical disability (e.g. wasting or cachexia, sever anemia) that would interfere with the assessment of safety or would compromise the ability of the patient to undergo study procedures |
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E.5 End points |
E.5.1 | Primary end point(s) |
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs |
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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) |
Plasma Pharmacokinetics, Cerebrospinal Fluid (CSF) Pharmacokinetics, Urine Pharmacokinetics |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
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 | 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 | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA 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.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |