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 examine the clinical efficacy of multiple doses of ISIS 396443 administered intrathecally to patients with Infantile-Onset SMA. |
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E.2.2 | Secondary objectives of the trial |
To examine the safety and tolerability of multiple doses of ISIS 396443 administered intrathecally to patients with infantile-onset SMA.
To examine the cerebral spinal fluid (CSF) and plasma PK of multiple doses of ISIS 396443 administered intrathecally to patients with infantile-onset SMA. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent of parent(s) or guardian(s)
2. Genetic documentation of 5q SMA homozygous gene deletion or mutation
3. Onset of clinical signs and symptoms consistent with SMA at ≥ 21 days and ≤ 6 months (180 days) of age
4. Males and females between ≥ 21 days and ≤ 7 months (210 days) of age at Screening
5. At study entry, receiving adequate nutrition and hydration (with or without gastrostomy), in the opinion of the Site Investigator
6. Body weight > 5th percentile for age using CDC guidelines
7. Medical care meets and is expected to continue to meet guidelines set out in the Consensus Statement for Standard of Care in SMA (Wang et al. 2007), in the opinion of the Site Investigator
8. Gestational age of 35 to 42 weeks and gestation body weight ≥ 2 kg
9. Reside within approximately 9 hours ground-travel distance from a participating study center for the duration of the study. Residence > 2 hours ground-travel distance from a study center must obtain clearance from the Site Investigator and the study Medical Monitor
10. Able to complete all study procedures, measurements and visits and parent or guardian/subject has adequately supportive psychosocial circumstances, in the opinion of the Site Investigator |
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E.4 | Principal exclusion criteria |
1. Hypoxemia (O2 saturation awake < 96% or O2 saturation asleep < 96%, without ventilation support)
2. Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
3. History of brain or spinal cord disease that would interfere with the LP procedures, CSF circulation, or safety assessments
4. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter
5. History of bacterial meningitis
6. Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Site Investigator, at screening that would render the subject unsuitable for inclusion
7. Treatment with another investigational drug (e.g., albuterol, riluzole, carnitine, creatine, sodium phenylbutyrate, salbutamol, valproate, hydroxyurea, etc.), biological agent, or device within 90 days prior to enrollment or anytime during the study. Any history of gene therapy or cell transplantation
8. The subject’s parent(s) or legal guardian(s) is unable to understand the nature, scope, and possible consequences of the study, or does not agree to comply with the protocol defined schedule of assessments
9. Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere with the assessment of safety or would compromise the ability of the subject to undergo study procedures |
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E.5 End points |
E.5.1 | Primary end point(s) |
-Achieve improvement of motor milestones |
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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 and CSF Pharmacokinetics
-Event-free survival
-Improvement in muscle strength as measured by CHOP-INTEND
-Improvement in neuromuscular electrophysiology
-Safety and tolerability as assessed by adverse events, neurological examinations, vital signs, physical examination and weight, clinical laboratory tests, ECGs, and use of concomitant medications
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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 | 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) | 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 | 2 |
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 | 4 |