E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 1 Spinal Muscular Atrophy (SMA) |
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E.1.1.1 | Medical condition in easily understood language |
SMA is a muscular disease that affects child's muscular development leading to muscle weakness and progressive loss of movement. Type 1 children are usually diagnosed before 6 months of age. |
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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 | 20.1 |
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 |
Part 1
•To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of RO7034067 in infants with Type 1 SMA and to select the dose for Part 2
Part 2
•To assess the efficacy of RO7034067 measured as the proportion of infants sitting without support after 12 months of treatment
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E.2.2 | Secondary objectives of the trial |
To assess:
•Safety and tolerability of RO7034067
•Pharmacokinetics of RO7034067
•Pharmacodynamic effects of RO7034067
•Effect on motor development milestones
•Effect on sitting without support and further motor development
milestones
•Impact of treatment with RO7034067 on time to event (death,
permanent ventilation)
•Change from baseline in the total raw score of the BSID-III gross
motor scale
•To assess the proportion of infants:
•Who achieve a score of 40 or higher in the Children's Hospital of
Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND)
•Who achieve an increase of at least 4 points on their CHOP-INTEND
score from baseline
•Who achieve head control
•Who achieve a reduction of at least 30 degrees in phase angle
(respiratory inductance plethysmography)
•Who are alive without permanent ventilation
•Who do not require invasive or non-invasive respiratory support |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Males and females aged between 28 days (1 month) of life and 210 days (7 months) (inclusive) at enrollment
- A legally authorized representative must be able to consent for the patient according to International Conference on Harmonisation and local regulations
- Gestational age of 37 to 42 weeks
- Confirmed diagnosis of 5q-autosomal recessive SMA, including:
•Genetic confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the survival motor neuron 1 (SMN1) gene
•Clinical history, signs or symptoms attributable to Type 1 SMA, i.e., hypotonia, absent deep tendon reflexes and/or tongue fasciculations with onset after the age of 28 days, but prior to the age of 3 months (inclusive), and inability to sit independently (without support) at the time of screening
- Infant has two SMN2 gene copies, as confirmed by central testing
- Body weight >= 3rd percentile for age, using appropriate country-specific guidelines (for the first infant only > 7 kg)
- Receiving adequate nutrition and hydration (with or without gastrostomy) at the time of screening, in the opinion of the Investigator
- Adequately recovered from any acute illness at the time of screening and considered well-enough to participate in the opinion of the Investigator |
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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 or 5 half-lives, whichever is longer
- Concomitant or previous Administration of a SMN2 targeting antisense oligonucleotide or SMN2 splicing modifier or gene therapy either in a clinical study or as part of medical care.
- Any history of cell therapy
- Hospitalization for pulmonary event within the last 2 months, or planned at the time of screening
- Unstable gastrointestinal, renal, hepatic, endocrine or cardiovascular system diseases
- Inadequate venous or capillary blood access for the study procedures
- Patients requiring invasive ventilation or tracheostomy
- Patients requiring awake non-invasive ventilation or with awake hypoxemia (arterial oxygen saturation < 95%) with or without ventilator support
- Patients with a history of respiratory failure or severe pneumonia, and have not fully recovered their pulmonary function at the time of screening
- Multiple or fixed contractures and/or hip subluxation or dislocation at birth
- Presence of non-SMA related concurrent syndromes or diseases
- Confirmed (2 consecutive measurements) systolic blood pressure or diastolic blood pressure outside the 95th percentile for age; resting heart rate < 70 bpm or > 170 bpm
- Presence of clinically relevant electrocardiogram (ECG) abnormalities before study drug administration
- History of malignancy if not considered cured
- Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first dose administration
- Taking any nutrients known to modulate cytochrome [CYP] 3A activity within 2 weeks prior to administration of study drugs
- The infant (and the mother, if breastfeeding the infant):
• Any inhibitor of CYP3A4 taken within 2 weeks (or within 5 times the elimination half life, whichever is longer) prior to dosing, including but not limited to ketoconazole, miconazole, itraconazole, fluconazole, erythromycin, clarithromycin, ranitidine, cimetidine
• Any inducer of CYP3A4 taken within 4 weeks (or within 5 times the elimination half-life, whichever is longer) prior to dosing, including but not limited to rifampicin, rifabutin, glucocorticoids, carbamazepine, phenytoin, phenobarbital, St. John's wort
• Any organic cation transporter-2 and multidrug and toxic compound extrusion substrates shall be avoided
• Any known flavin containing monooxygenase (FMO) 1 or FMO3 inhibitors or substrates
- Clinically significant abnormalities in laboratory test results
- Ascertained or presumptive hypersensitivity to RO7034067 or the constituents of its formulation
- Prior use, (at any time in the patients' life) and/or, anticipated need for quinolones (chlororquine and hydroxychloroquine), thioridazine, hydroxychloroquine, vigabatrin, retigabine, or any other drug known to cause retinal toxicity during the study. Infants exposed to chloroquine, hydroxychloroquine, thioridazine, vigabatrin, retigabine or drugs with known retinal toxicity given to mothers during pregnancy (and lactation) should not be enrolled.
- Recent history (less than 6 months) of ophthalmic disease that would interfere with the conduct of the study as assessed by an ophthalmologist |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1 and 2: Safety
1. Incidence and severity of adverse events (AE) and serious adverse events
2. Incidence of treatment discontinuations due to AE
3. Incidence of abnormal laboratory and ECG values
4. Vital signs abnormalities
5. Anthropometric and ophthalmological examination
Part 1
Pharmacokinetics
6.Plasma concentrations of RO7034067, and its metabolite(s)
Pharmacodynamic
7. Assessment of SMN protein in blood
8.Assessment of SMN messenger ribonucleic acid (mRNA) in blood
Part 2: Efficacy
9.Proportion of infants who are sitting without support at 12 months of treatment assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler development – Third Edition (BSID-III)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-4. Up to 2 years
5. Screening (D [Day] -30 to D -2), D56, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
6. D1, D2, D7, D14, D28, D56, D84, D119, D182, D245, D301, D364, D427, D490, D546, D609, D672, D728
7. D1, D14, D28, D119, D245, D364, D609, D728
8. D1, D14, D28, D245, D364, D609, D728
9. At Month 12 |
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E.5.2 | Secondary end point(s) |
Part 2
1. Plasma concentrations of RO7034067 and its metabolite (s)
2. Assessment of SMN protein in blood
3. Assessment of SMN mRNA in blood
4. Change from baseline in the Total Raw Score of the BSID-III gross
motor scale at Month 12 and 24
5. Proportion of infants who achieve the attainment levels of the motor
milestones assessed in the Hammersmith Infant Neurological
Examination Module 2 (HINE-2) at Month 12 and 24
6. Proportion of infants who achieve a score of 40 or higher in the
Children's Hospital of Philadelphia Infant Test of Neuromuscular
Disorders (CHOP INTEND) at Month 12
7. Proportion of infants who achieve an increase of at least 4 points in
their CHOP-INTEND score from baseline at Month 8 and Month 12
8. Proportion of infants who achieve head control at Month 8, Month 12,
and Month 24
9. Proportion of infants who achieve a reduction of at least 30 degrees in
their phase angle from baseline, as measured by respiratory inductance
plethysmography, at Month 12
10. Time to permanent ventilation (from enrollment)
11. Proportion of infants who are alive at Month 12 and 24
12. Proportion of infants who are alive without permanent ventilation at
Month 12 and 24
13. Proportion of infants who do not require invasive or non-invasive
respiratory support at Month 12 and Month 24
14. Ability to swallow and to feed orally at Month 12 and Month 24 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. D1, D2, D14, D28, D56, D119, D182, D245, D301, D364, D427, D490,
D546, D609, D672, D728
2. D1, D28, D119, D245, D364, D609, D728
3. D1, D28, D245, D364, D609, D728
4. Baseline, Month 12 and 24
5. Month 12 and 24
6. Month 12
7. Month 8 and 12
8. Month 8, Month 12 and 24
9. Baseline and Month 12
10. Up to 2 years
11-14. At Month 12 and 24 |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 25 |
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 |
Belgium |
Brazil |
Canada |
China |
Croatia |
France |
Germany |
Italy |
Japan |
Lebanon |
Poland |
Russian Federation |
Saudi Arabia |
Serbia |
Spain |
Switzerland |
Turkey |
Ukraine |
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 end of this study is defined as the date when the last patient last visit (LPLV) occurs.
The study will continue until RO7034067 is commercially available in the infant’s country, or as per local regulation, or per the Sponsor’s decision to terminate RO7034067 development. However, the study will not exceed 4 years (or less as per country specific requirements) after the last infant is enrolled in the study.
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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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |