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] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
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 evaluate the safety and tolerability of 12 weeks treatment with RO6885247 in adult and pediatric patients with spinal muscular atrophy (SMA) |
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E.2.2 | Secondary objectives of the trial |
Pharmacokinetics
•To investigate the multiple-dose pharmacokinetics of RO6885247 and its metabolite(s), if appropriate
•To assess the potential effect of food on the pharmacokinetics of RO6885247
Pharmacodynamics
•To investigate pharmacodynamic (PD) effects of RO6885247 as assessed by Survival of Motor Neuron 2 (SMN2) splicing modification and increase in SMN protein
•To investigate the pharmacokinetic (PK)/PD relationship of RO6885247 by PK/PD modeling (PD to include SMN2 messenger RNA (mRNA) and SMN protein)
•To investigate the effect of 12 weeks of treatment with RO6885247 on muscle electrophysiology as assessed by Compound Muscle Action Potential (CMAP)
•To investigate the effect of 12 weeks of treatment with RO6885247 on Electrical Impedance Myography (EIM) (optional) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Males and females, aged 2 to 55 years inclusive
- Confirmed diagnosis of 5q-autosomal recessive SMA (Types 1 to 3)
- Able and willing to provide informed consent and to comply with the study protocol. Alternatively, a legally authorized representative must be able to consent for the patient and assent must be given by the subject wherever possible.
- Female patients of childbearing potential and male patients with a female partner of childbearing potential must agree with the required contraceptive methods as defined per protocol. |
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E.4 | Principal exclusion criteria |
- Concomitant or previous participation in any investigational drug or device study within 90 days prior to screening
- Concomitant or previous participation in a SMN2-targeting antisense oligonucleotide study within 12 months prior to screening
- Concomitant or previous participation at any time in a gene therapy study
- Hospitalization for pulmonary event within the last 2 months or planned at the time of screening
- Surgery for scoliosis in the last 6 months from screening or planned within 6 months from screening
- Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system disease
- Clinically relevant ECG abnormalities at screening or baseline; personal or family history (first degree relatives) of congenital long QT syndrome
- Clinically significant abnormalities in laboratory test results at screening
- Any concomitant disease or condition that could interfere with the conduct of the study, or pose an unacceptable risk to the subject in this study
- Use of prohibited medications as per protocol within 90 days prior to randomization. Patients who are on inhaled corticosteroids, administered either through a nebulizer or an inhaler, are allowed.
- Recently initiated treatment (within <6 months prior to randomization) with oral salbutamol or another beta2-adrenergic agonist taken orally is not allowed. Patients who have been on oral salbutamol (or another beta2-adrenergic agonist) for at least 6 months before randomization are allowed. Use of inhaled beta2-adrenergic agonists is allowed. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety: Incidence of adverse events (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) |
1. Pharmacokinetics: RO6885247 plasma concentrations
2. Pharmacokinetics: RO6885247 exposure, area under the concentration-time curve (AUC-tau, over the 24-hour dosing interval)
3. Pharmacodynamics: SMN protein levels in blood
4. Effect of RO6885247 on muscle electrophysiology, as assessed by Compound Muscle Action Potential (CMAP)
5. Effect of RO6885247 on Electrical Impedance Myography
6. Pharmacodynamics: In vivo splicing modification of SMN2 mRNA in blood |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 16 weeks
2. Up to 12 weeks
3-6: Up to 20 weeks |
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability, clinical genotyping |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | Yes |
E.8.2.3 | Other | No |
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 | 4 |
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 |
Italy |
Netherlands |
Switzerland |
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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The date when the last patient’s last visit (LPLV) occurs |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |