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 | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051203 |
E.1.2 | Term | Spinal muscular atrophy congenital |
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 |
Part 1: Determine the safety and tolerability of ascending weekly doses and estimate the MTD of branaplam in infants with Type 1 SMA. Part 2: Evaluate the safety and tolerability of ascending weekly doses of branaplam for 52 weeks in patients with Type 1 SMA. |
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E.2.2 | Secondary objectives of the trial |
Part 1: - To evaluate branaplam pharmacokinetics in plasma after single and repeated doses of branaplam. - To evaluate the effect of branaplam on growth parameters - To evaluate the effect of branaplam on respiratory function - To evaluate the effect of branaplam on infant motor development
In addition to the above for Part 2: - To evaluate the efficacy of branaplam on motor and developmental milestones - To evaluate the efficacy of branaplam on the ability to sit without support. - To evaluate the efficacy of LMI070 on ulnar and peroneal nerve compound motor action potential [CMAP] |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Common for both Parts 1 and 2: - Type 1 SMA, diagnosed clinically, with symptom onset <6 months of age and genetic confirmation of mutations in both alleles of the SMN1 gene, and with SMN2 copy number of 2. - Best supportive care in place and stable for at least 14 days before screening. - Must be able to demonstrate antigravity strength in both biceps. At birth gestational age >32 weeks and body weight at birth >2 kg. - Must live within 2 hours drive of study center. Clearance should be obtained from the site investigator and sponsor if the patient resides more than 2 hours ground travel from the study center
Specific for Part 1 - Age at screening between 1 and 7 months - Must have or agree to have placement of feeding tube for enteral access via nasogastric (NG), nasojejunal (NJ), percutaneous gastrostomy (PEG), or percutaneous jejunostomy (PEJ) tube for administration of branaplam (for patients in whom branaplam cannot be administered orally ; NG tube may be removed between doses).
Specific for Part 2 - Age at screening between 30 and 180 days of age - Must have or agree to have placement of feeding tube for enteral access via nasogastric (NG), nasojejunal (NJ), percutaneous gastrostomy (PEG), or percutaneous jejunostomy (PEJ) tube for administration of branaplam (for the first administration only and for patients in whom branaplam cannot be administered orally; NG tube may be removed between doses). - Minimum CHOP INTEND score of 15 at baseline - Must be able to feed orally for all nutritional needs and be greater than the 2nd percentile for weight on the standard growth curves for the country of origin |
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E.4 | Principal exclusion criteria |
Common for both Parts 1 and 2: - Neurologic, or neuromuscular conditions other than SMA. - Anemia, leukopenia, neutropenia or thrombocytopenia - Hepatic dysfunction - Age adjusted renal dysfunction - Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period. - Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period. - Excluding SMA, any medically unstable condition including cardiomyopathy, hepatic dysfunction, kidney disorder, endocrine disorder, GI disorders, prematurity of <32 weeks gestation, metabolic disorders, severe respiratory compromise and significant brain abnormalities or injuries including hypoxic-ischemic encephalopathy. - Current diagnosis of cardiac and/or vascular abnormalities or ECG abnormalities - Acute or ongoing medical condition that, according to the Site Investigator and discussed with sponsor, 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 including be assessed by CHOP INTEND motor scale, changes in hematologic parameters or gastrointestinal dysfunction that would compromise the ability of adequate assessment of safety
Specific for Part 1 - Use of other investigational drugs within 14 days. - Intractable seizure disorder (other than inactive febrile seizures). - Persistent (in the opinion of the Investigator) hypoxemia (O2 saturation awake <92% or O2 saturation asleep <91%, without ventilation support) or requiring oral suctioning >2 per day, or presence of a tracheostomy.
Specific for Part 2 - Use of gene transfer at any time or other investigational drugs within 14 days. - Patients who have received nusinersen at any time prior to screening - Intractable epilepsy - Persistent (in the opinion of the Investigator) hypoxemia (O2 saturation awake <92% or O2 saturation asleep <91%, without ventilation support), or presence of a tracheostomy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1 Safety & Tolerability [Time Frame: 13 Weeks]: To evaluate the effect of branaplam on the following; - Number of adverse events reported at all dose levels - Changes from baseline in existing and newly reported findings on physical examination - Changes from baseline in hematology, blood chemistry and urinalysis results at all dose levels - Changes from baseline in vital signs at all dose levels - Changes from baseline on existing or newly reported ophthalmologic findings at all dose levels - Changes from baseline on existing or newly reported cardiac function at all dose levels - Changes from baseline in existing and newly reported neurological findings at all dose levels - Changes from baseline in existing and newly reported neurophysiological findings at all dose levels
Part 2 Safety & Tolerability [Time Frame: 52Weeks]: To evaluate the effect of branaplam on the following; - Number of adverse events reported at all dose levels - Changes from baseline in existing and newly reported findings on physical examination - Changes from baseline in hematology, blood chemistry and urinalysis results at all dose levels - Changes from baseline in vital signs at all dose levels - Changes from baseline on existing or newly reported ophthalmologic findings at all dose levels - Changes from baseline on existing or newly reported cardiac function at all dose levels - Changes from baseline in existing and newly reported neurological findings at all dose levels - Changes from baseline in existing and newly reported neurophysiological findings at all dose levels |
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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) |
Part 1: - Changes in Growth Parameters from baseline [Time Frame: Screening, Day 1, Day 8 to Day 85. Extended treatment periods: every 4 weeks and at the End of Study] - Changes in respiratory function from baseline [Time Frame: Baseline, Day 8 to Day 85. Extended treatment periods: every 4 weeks and at the End of Study] - Changes in Infant motor development from baseline [Time Frame: Baseline, Day 36, Day 85. Extended treatment periods: every 6 to 7 weeks and at the End of Study] - Collect pharmacokinetic data from single and repeated dosing [Time Frame: Parts 1 and 2: Day 1 (Pre-dose + 1, 2, 4, 8 & 24 hours post-dose), Days 2, 3, 5, 8, 29. Part 1: Day 43. Part 2: Day 57, 57, 92 (Predose + 4 & 24 hours post-dose), 94, 99, 274 (Pre-dose + 4 & 24 hours post-dose), 276, 281]
In addition to the above for Part 2: - Changes in motor and developmental milestones from baseline [Time Frame: Baseline, Day 15, Day 36, Day 57, Day 88 + End of Study] - Changes in Ulnar Nerve Compound Motor Action Potential (CMAP) from baseline [Time Frame: Baseline, Day 88 + End of Study] - Changes from baseline on the ability to site without support [Time Frame: 52 weeks] |
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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 | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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 | 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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Bulgaria |
Czech Republic |
Denmark |
Germany |
Hungary |
Italy |
Poland |
Russian Federation |
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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When the last subject completes their End of Study visit, and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator, or in the event of an early study termination decision, the date of that decision.
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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 | 1 |
E.8.9.1 | In the Member State concerned days | 28 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 4 |