E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 |
|
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.
Part 3: Assess long-term safety and tolerability of extended oral/enteral, once a week branaplam treatment in subjects with Type 1 SMA who have had at least 52 weeks of treatment in either Part 1 or 2 of the protocol. |
|
E.2.2 | Secondary objectives of the trial |
Part 1:
- Evaluate branaplam pharmacokinetics in plasma after single and repeated doses of branaplam
- Evaluate the effect of branaplam on growth parameters
- Evaluate the effect of branaplam on respiratory function
- Evaluate the effect of branaplam on infant motor development
-In addition for Part 2:
- Evaluate UFB112 pharmacokinetics in plasma after repeated doses of branaplam
- Evaluate the efficacy of branaplam on motor and developmental Milestones
- Evaluate the efficacy of branaplam on the ability to sit without support
- Evaluate the efficacy of LMI070 on ulnar compound motor action potential
In addition for Part 3:
- Evaluate efficacy of branaplam on the ability to sit without support, stand or walk over time
- Evaluate long-term effect of branaplam on respiratory function
- Assess the impact of treatment with branaplam on death/permanent ventilation
- Investigate branaplam and UFB112 PK in plasma and the impact of increasing age |
|
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
- Type 1 SMA, diagnosed with genetic confirmation of mutations in both alleles of the SMN1 gene, and with SMN2 copy number of 2.
- Impossibility / inappropriateness of treatment with nusinersen for one of the following conditions: unavailability of the drug, clinical choice (motivations expressed by the attending physician) or choice of the patient / caregiver.
- Age at screening up to 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 swallow solid and liquid even if feeding is used to support nutrition intake and must be in the 5th percentile for length or weight on the international growth curves and must be proportional in height and weight.
Specific for Part 3:
- Current participation in Part 1 or 2 of the protocol and completion of at least 52 weeks of treatment
- Further branaplam treatment is in the best interest of the subject as assessed by the Site Investigator
- Able to complete all study procedures, measurements and visits; and parent or guardian/subject has adequately supportive psychosocial circumstances, in the opinion of the Site Investigator |
|
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.
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).
For Part 3:
There are no specific exclusion criteria for Part 3 of the study. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Parts 1 & 2 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 Haematology, blood chemistry and urianalysis 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
Part 3 Long-term Safety & Tolerability [Time Frame: from 52 Weeks
onwards]:
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 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
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 & End of Study]
• Changes in Infant motor development from baseline[Time Frame: Baseline, Day 36, Day 85 + End of Study]
• Changes in quadriceps muscle thickness from baseline[Time Frame: Baseline, Day 85 & End of Study]
• Changes in respiratory function from baseline[Time Frame: Baseline, Day 8 to Day 85 & End of Study]
• Collect pharmacokinetic data from single and repeated dosing[Time Frame: Part 1 Day 1 (Pre-dose + 1, 2, 4, 8 & 24 hours post-dose) and Days 2, 3, 5, 8, 29, 43 Part 2 Day 1 (Pre-dose + 1, 2, 4, 8 & 24 hours
post-dose) and Days 2, 3, 5, 8, 29, 43, 57 (Pre-dose + 2, 4, 8 & 24 hours post-dose), 59, 62]
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]
In addition to the above for Part 2 - Changes in motor and developmental milestones from baseline[Time Frame: Screening, Baseline, Day 1to Day 88 + End of Study]
In addition to the above for Part 2 - 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]
In addition to the above for Part 3:
- Evaluate branaplam PK in plasma at sparse sampling [Time Frame: every 6 months]
- Assess the impact of treatment with branaplam on time-to-event (death/permanent ventilation) [Time Frame: as the event occurs] |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | 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 | 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 | 11 |
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 |
Russian Federation |
United States |
Belgium |
Denmark |
Germany |
Italy |
|
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
|
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.
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 27 |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 10 |