E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Later Onset Spinal Muscular Atrophy (SMA) |
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E.1.1.1 | Medical condition in easily understood language |
Later Onset Spinal Muscular Atrophy (SMA) is an inherited disease of the motor nerves (the nerves that send signals from your brain to the muscles) causing muscle weakness. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10079415 |
E.1.2 | Term | Spinal muscular atrophy type III |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10079416 |
E.1.2 | Term | Spinal muscular atrophy type II |
E.1.2 | System Organ Class | 100000004850 |
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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 assess safety and tolerability of SRK-015 in patients with later onset (e.g., Type 2 and Type 3) spinal muscular atrophy (SMA) To assess the efficacy of SRK-015 by assessing changes in motor function outcome measures
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E.2.2 | Secondary objectives of the trial |
To characterize the pharmacokinetics (PK) of SRK-015 To evaluate the pharmacodynamic (PD) effects of SRK-015 To evaluate time to therapeutic effect between low and high dose SRK-015 in a predefined cohort (Cohort 3) To evaluate the immunogenicity of SRK-015 To evaluate the effect of SRK-015 on quality of life assessments
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age 5 through 21 years old at the time of screening for Cohorts 1 and 2; Age ≥2 years old at the time of screening for Cohort 3 2. Estimated life expectancy >2 years from screening 3. Informed consent document signed by the patient if the patient is legally an adult. If the patient is legally a minor, informed consent document signed by the patient’s parent or legal guardian and patient’s oral or written assent obtained, if applicable and in accordance with the regulatory and legal requirements of the participating location 4. Documented diagnosis of 5q SMA 5. Diagnosed as later onset (e.g., Type 2 or Type 3) SMA prior to receiving any treatment with therapy approved for SMA 6. Non ambulatory patients must be able to sit independently (sits up straight with head erect for at least 10 seconds; does not use arms or hands to balance body or support position) per World Health Organization (WHO) motor milestones definition at screening. Patients who never had the ability to walk independently will be classified as Type 2. Patients who previously had the ability to walk unaided will be classified as Type 3. 7. Ambulatory patients must have the ability to independently ambulate without aids or orthotics over 10 meters in 30 seconds or less at screening 8. For Cohort 1, Revised Hammersmith Scale (RHS) score no greater than 63 at screening 9. For Cohorts 2 and 3, Hammersmith Functional Motor Scale Expanded (HFMSE) score no less than 10 at screening 10. Receiving the same background SMA therapy (e.g., on an approved survival motor neuron (SMN) upregulator therapy such as nusinersen, or not on any SMA therapy) for at least 6 months prior to screening and anticipated to remain on that therapy throughout the duration of the study 10a. If receiving the SMN upregulator therapy nusinersen, must have completed the loading regimen and initiated maintenance dosing (i.e., completed at least one maintenance dose) with at least 4 weeks after the first maintenance dose having elapsed prior to screening 11. Nutritional status stable over the past 6 months and anticipated to be stable throughout the duration of the study 12. Have no physical limitations that would prevent the patient from undergoing motor function outcome measures throughout the duration of the study 13. Able to receive study drug infusions and provide blood samples through the use of a peripheral intravenous (IV) or a long-term IV access device that the patient has placed for reasons independent from the study (i.e., for background medical care and not for the purpose of receiving SRK-015 in the study), throughout the duration of the study 14. Able to adhere to the requirements of the protocol, including travel to the study center and completing all study procedures and study visits 15. For patients who are expected to have reached reproductive maturity by the end of the study, adhere to study specific contraception requirements 15a. Females of childbearing potential must have a negative pregnancy test at screening and agree to employ highly effective contraceptive measures (failure rate of 1% or less per year when used consistently and correctly) for the duration of the study and for 12 weeks following the last dose of study drug. Effective contraception methods are restricted to abstinence, intrauterine contraceptive devices, bilateral tubal occlusion, vasectomized partner, or a licensed hormonal product in combination with a barrier method. 15b. Male patients with female partners of childbearing potential must be abstinent or agree to employ the use of a condom with or without spermicide throughout the duration of the study and for 12 weeks following the last dose of study drug.
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E.4 | Principal exclusion criteria |
1. Use of tracheostomy with positive pressure 2. Use of chronic daytime non invasive ventilatory support for >16 hours daily in the 2 weeks prior to dosing, or anticipated to regularly receive such daytime ventilator support chronically over the duration of the study 3. Any acute or co morbid condition interfering with the well being of the patient within 14 days of screening, including active systemic infection, the need for acute treatment or inpatient observation due to any reason 4. Severe scoliosis and/or contractures at screening. Based on clinical judgement, any scoliosis or contractures present must be stable over the past 6 months, anticipated to be stable for the duration of the study and not prevent the patient from being evaluated on any functional outcome measures throughout the duration of the study. 5. Pregnant or breastfeeding 6. Major orthopedic or other interventional procedure, including spine or hip surgery, considered to have the potential to substantially limit the ability of the patient to be evaluated on any functional outcome measures, within 6 months prior to screening, or anticipated for the duration of the study 7. Prior history of a hypersensitivity reaction to a monoclonal antibody or recombinant protein bearing an Fc domain (such as a soluble receptor-Fc fusion protein) 8. Use of systemic corticosteroids within 60 days prior to screening. Inhaled or topical steroids are allowed. 9. Treatment with investigational drugs within 3 months prior to screening 10. Use of therapies with potentially significant muscle effects (such as androgens, insulin like growth factor, growth hormone, systemic beta agonist, botulinum toxin, or muscle relaxants) or muscle-enhancing supplements within 60 days prior to screening 11. Patient has any other condition, which in the opinion of the Investigator may compromise safety or compliance, would preclude the patient from successful completion of the study, or interfere with the interpretation of the results
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E.5 End points |
E.5.1 | Primary end point(s) |
Cohort 1; Ambulatory Type 3 patients: Change from Baseline in the revised Hammersmith Scale (RHS). Administration of the RHS includes the timed rise from floor and 10 meter walk/run tests. The RHS is designed for SMA, validated in SMA, and considered clinically meaningful.
Cohort 2 and Cohort 3;Type 2 and non ambulatory Type 3 patients: Change from Baseline in Hammersmith Functional Motor Skills Expanded (HFMSE) Scores. HFMSE is designed for SMA, validated in SMA, and considered clinically meaningful. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Ongoing throughout the study |
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E.5.2 | Secondary end point(s) |
Cohort 1; Ambulatory Type 3 patients: Proportion of patients achieving various magnitudes of change in RHS score from Baseline Change from Baseline in 6 minute walk test (6MWT) Change from Baseline in 30 second sit to stand Change from Baseline in 10 meter walk/run (from the RHS) Change from Baseline in timed rise from floor (from the RHS)
Cohort 2 and Cohort 3;Type 2 and non ambulatory Type 3 patients: Proportion of patients achieving various magnitudes of change in HFMSE score from Baseline Change from Baseline in Revised Upper Limb Module (RULM) Change from Baseline in number of WHO motor development milestones attained Proportion of patients achieving various magnitudes of change in RULM score from Baseline Proportion of patients who attain a new WHO motor development milestone relative to Baseline
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Ongoing throughout the study |
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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 | Yes |
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 | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Cohort 1 and 2 are open label and Cohort 3 is double blind randomized |
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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 |
For Cohort 3: two different doses (2 and 20 Mg/kg) of the study drug |
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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 | 8 |
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 |
Germany |
Italy |
Netherlands |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 8 |
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 | 11 |