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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
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 |
To examine the clinical efficacy of ISIS 396443 administered intrathecally to patients with later-onset SMA. |
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E.2.2 | Secondary objectives of the trial |
To examine the safety and tolerability of ISIS 396443 administered intrathecally to patients with later-onset SMA. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Parent or guardian signed informed consent and, if indicated per subject’s age and institutional guidelines, subject has signed informed assent.
2. Be medically diagnosed with spinal muscular atrophy (SMA)
3. Have onset of clinical signs and symptoms consistent with SMA at > 6 months of age
4. Be 2 to 12 years of age at screening
5. Be able to sit independently, but has never had the ability to walk independently
6. Have Motor Function Score (Hammersmith Functional Motor Scale – Expanded) ≥ 10 and ≤ 54 at Screening
7. Be able to complete all study procedures, measurements and visits and parent or guardian/subject has adequately supportive psychosocial circumstances, in the opinion of the Investigator
8. Have estimated life expectancy > 2 years from screening, in the opinion of the Investigator
9. Meet age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedures
10. For subjects who have reached reproductive maturity, satisfy study contraceptive requirements. |
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E.4 | Principal exclusion criteria |
1. Respiratory insufficiency, defined by the medical necessity for invasive or non-invasive ventilation for > 6 hours during a 24 hour period, at Screening
2. Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Site Investigator
3. Severe contractures or severe scoliosis evident on X-ray examination at Screening
4. Hospitalization for surgery (i.e., scoliosis surgery, other surgery), pulmonary event, or nutritional support within 2 months of screening or planned during the duration of the study
5. Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
6. History of brain or spinal cord disease, including tumors, or abnormalities by MRI or CT that would interfere with the LP procedures or CSF circulation
7. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter
8. History of bacterial meningitis
9. Dosing with ISIS 396443 in any previous clinical study
10. Prior injury (e.g., upper or lower limb fracture) or surgical procedure which impacts the subject’s ability to perform any of the outcome measure testing required in the protocol and from which the subject has not fully recovered or achieved a stable baseline
11. Clinically significant abnormalities in hematology or clinical chemistry parameters or ECG, as assessed by the Site Investigator, at the Screening visit that would render the subject unsuitable for inclusion
12. Treatment with another investigational drug (e.g., oral albuterol/salbutamol, riluzole, carnitine, creatine, sodium phenylbutyrate, etc.), 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, antisense oligonucleotide therapy, or cell transplantation
13. Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability (e.g., wasting or cachexia, severe anemia, etc.) 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) |
Change from baseline in HFMSE (Hammersmith Functional Motor Scale – Expanded) score at 15 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) |
• Proportion of subjects who achieve a 3 point increase from baseline in Hammersmith Functional Motor Scale – Expanded (HFMSE) score at 15 months
• Proportion of subjects that achieve any new motor milestone at 15 months
• Number of motor milestones achieved per subject at 15 months
• Change from baseline in Upper Limb Module Test at 15 months
• Proportion of subjects that achieve standing alone at 15 months
• Proportion of subjects that achieve walking with assistance at 15 months |
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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) | No |
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 | Yes |
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 | 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 | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
Canada |
France |
Germany |
Hong Kong |
Italy |
Japan |
Korea, Republic of |
Spain |
Sweden |
United Kingdom |
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 | 2 |
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 | 6 |