Spinal Muscular Atrophy
Conditions
Keywords
Type 1 Spinal Muscular Atrophy
Brief summary
An open-label, multi-part, first-in-human study of oral branaplam in infants with Type 1 spinal muscular atrophy. The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy after 13 weeks; and to estimate the Maximum Tolerated Dose (MTD) of orally administered branaplam; and to identify the dose that was safe for long term use as well as that can provide durable efficacy optimal dosing regimen in patients with Type 1 SMA.
Detailed description
This was an open-label, multi-part, first-in-human, proof of concept study in infants with Type 1 spinal muscular atrophy who have exactly 2 copies of SMN2, to evaluate safety, tolerability, PK, PD and efficacy of oral branaplam after 13 weeks treatment. Parts 1,2 and 3 were intended to be non-confirmatory. In Part 1 of the study, patients were dosed once weekly with branaplam. The branaplam dose was escalated in subsequent cohorts until MTD was determined or when sufficient PK results confirmed that the MTD could not be reached due to a potential pharmacokinetic plateau at higher doses. A decision to dose escalate the next cohort was made after safety data was collected for 14 days following the first dose (14-day DLT window). PK was used to confirm that there was no accumulation of the compound. After 13 weeks treatment, participants in part 1 could enter an extension treatment phase until they discontinued from the study or were transferred into part 3. Part 2 of the study enrolled new patients into one 2 dose cohorts with once weekly dosing for 52 weeks. The branaplam dose was escalated in subsequent cohorts after 6 patients were enrolled and at least 3 patients from the previous cohort completed 13 weeks of treatment. After 52 weeks, patients may have continued treatment in part 3 if it was in the best interest of the patient. Part 3, participants from part 1 and 2 who have completed at least 52 weeks of banaplam treatment were elegible to continue receiving treatment as long as in the best interest of the patient. In all cases continuation of the treatment was done at a dose selected as optimum, considering existing safety as well as efficacy data.
Interventions
DRUGbranaplam
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Days to 182 Days
Healthy volunteers
No
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
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 nusinersen or gene transfer at any time or other investigational drugs within 14 days. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLT) in Part 1 - Safety Analysis Set (SAS) | Baseline up to 2 weeks for Part 1 | A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant therapies that occurs within the first 14 days of treatment with LMI070 and meets any of the criteria for blood and lymphatic system disorders, gastrointestinal disorders, investigations and other toxicities considered clinically significant. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Baseline up to approximately 83 months | TEAEs are defined as adverse events starting on or after the first dose of study treatment that were absent pre-treatment, or events present prior to the first dose but increased in severity after the first dose. Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post last treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Plasma Pharmacokinetic (PK) Parameter Cmax After a Single Dose - Part 1 - PAS | from 0 h to 168 h after first/single dose | The observed maximum plasma concentration following drug administration \[mass / volume). |
| Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 1 - PAS | from 0 h to 168 h after first/single dose | The observed maximum plasma (or serum or blood) concentration following drug administration \[mass / volume |
| Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) After a Single Dose - Part 2 - PAS | from 0 h to 168 h after first/single dose | The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume) |
| Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) for All Observation Periods - Part 2 - PAS | from 0 h to 168 h after first/single dose | The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume). AUC values used for comparison are combined from AUCinf values after single dose and AUC0-168h values after repeated administration. |
| Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for a Single Dose - Part 2 - PAS | from 0 h to 168 h after first/single dose | The observed maximum plasma (or serum or blood) concentration following drug administration \[mass / volume) |
| Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 2 - PAS | from 0 h to 168 h after first/single dose | The observed maximum plasma (or serum or blood) concentration following drug administration \[mass / volume) |
| Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Baseline, Week 52 and Month 6 of Part 3 | The effect of branaplam on growth parameters: Length (measured from the top of the head to the sole of the foot), Head circumference and Chest circumference (measured across nipple line). Mean change from baseline in cm is presented In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration. |
| Change From Baseline in Growth Parameter: Body Weight - FAS | Baseline, Week 52 and Month 6 of Part 3 | The effect of Branaplam on body weight in Kg was measured using a weight scale. Mean change from baseline in Kg is presented In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration. |
| Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) After a Single Dose - Part 1 - Pharmacokinetics Analysis Set (PAS) | from 0 h to 168 h after first/single dose | The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume\] |
| Change From Baseline in Respiratory Function: Respiratory Rate - FAS | Baseline, Week 52 and Month 6 of Part 3 | The effect of branaplam on respiratory rate was evaluated by counting the number of breaths for one minute. Mean change from baseline in breaths per minute is reported In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration. |
| Number of Participants With Presence of Paradoxical Breathing - FAS | Baseline, Week 52 and Month 6 of Part 3 | A paradoxical breathing occurs when one compartment moves out of phase compared to another one. In SMA type I, paradoxical breathing is often a sign of breathing problems where the pulmonary ribcage moves inward during inspiration rather than outward while the abdomen expands. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration. |
| Change From Baseline in Respiratory Function: Chest Circumference During Quiet Breathing - End of Inspiration and Expiration - FAS | Baseline, Week 52 and Month 6 of Part 3 | The effect of branaplam on respiratory status was evaluated by measuring the circumference of the ribcage while taking a breathe in and out while quiet or sleeping. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration. |
| Summary of CHOP INTEND Total Score - Parts 1 and 3 and Parts 2 and 3 - FAS | Baseline, Week 52 and Month 6 of Part 3 | CHOP INTEND is a motor test measure for SMA Type 1 and similarly weak infants with neuromuscular disease. The CHOP INTEND provides a useful measure of motor skills and strength in this population. It is a 16 item, 64 point scale. Each item (motor skill) is given a score from zero to 4: zero indicates can't complete the movement, 1 to 3 indicates partial performance and a 4 indicates person can complete the movement on their own without assistance. These scores are added up to a possible total score of 64 and higher scores indicate better outcomes. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration. |
| Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS | Baseline up Week 78 | To evaluate the efficacy of branaplam on preservation of oral feeding In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration. |
| Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Week 52 and Month 6 of Part 3 | HINE Section 2 is a standardized evaluation of motor function. It evaluates 8 items; grasp, head control, kicking, rolling over, sitting up, crawling, standing and walking. Motor skills are assigned a score of 0 to 3 to 5 points and zero means the child lacks that motor skill. The maximum score is 26 which is dependent on age, level of development and severity of disease. A higher score is a better outcome. This assessment was added with amendment 6, therefore no baseline was available. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration. |
| Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS | Week 52 and Month 6 of Part 3 | HINE Section 2 is a standardized evaluation of motor function. It evaluates 8 items; grasp, head control, kicking, rolling over, sitting up, crawling, standing and walking. Motor skills are assigned a score of 0 to 3 to 5 points and zero means the child lacks that motor skill. The maximum score is 26 which is dependent on age, level of development and severity of disease. A higher score is a better outcome. This assessment was added with amendment 6, therefore no baseline was available. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration. |
| Ventilation Use for Parts 1 and 3 and Parts 2 and 3 - FAS | Baseline up to 82 months | BiBAP (bilevel positive airway pressure) ventilation is a 2 level breathing support which has a tube that connects to a mask. It provides a different level of air pressure for inhalation vs. exhalation, whereas a CPAP (continuous positive airway pressure) only pumps one level of air pressure but is also non-invasiive. Invasive ventilation is delivered via an endotracheal or tracheostomy tube. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration. |
| Change From Baseline in Respiratory Function: Pulse Oximetry - FAS | Baseline, Week 52 and Month 6 of Part 3 | The effect of branaplam on pulse oximetry in percentage of oxygen saturation was evaluated using a probe that measures oxygen in the blood. Mean change from baseline in percentage of oxygen saturation is reported. Negative numbers indicate a decrease from baseline In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration. |
| Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) for All Observation Periods - Part 1 - PAS | from 0 h to 168 h after first/single dose | The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume\] for all observations. AUC values used for comparison are combined from AUCinf values after single dose and AUC 0-168h values after repeated administration. |
Countries
Belgium, Bulgaria, Denmark, Germany, Italy, Poland, Russia
Participant flow
Pre-assignment details
Cohorts in Part 1 were enrolled sequentially following a 14 day dose-limiting toxicity (DLT) window for each cohort before escalating to the next level. Forty participants were enrolled but only 38 received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 LMI070 6mg/m2 Enteral dosing using nasogastric or nasojejunal or percutaneous endoscopic gastrostomy feeding tubes for 13 weeks | 2 |
| Part 1 LMI070 12mg/m2 Single weekly dose for 13 weeks via e teral dosing using nasogastric or nasojejunal or percutaneous endoscopic gastrostomy feeding tubes | 2 |
| Part 1 LMI070 24mg/m2 Single weekly dose for 13 weeks via enteral dosing using nasogastric or nasojejunal or percutaneous endoscopic gastrostomy feeding tubes | 2 |
| Part 1 LMI070 48mg/m2 Single weekly dose for 13 weeks via enteral dosing using nasogastric or nasojejunal or percutaneous endoscopic gastrostomy feeding tubes | 4 |
| Part 1 LMI070 60mg/m2 Single weekly dose for 13 weeks via enteral dosing using nasogastric or nasojejunal or percutaneous endoscopic gastrostomy feeding tubes | 3 |
| Part 2 LMI070 0.625 mg/kg LMI070 0.625 mg/kg by enteral route via feeding tube or oral | 10 |
| Part 2 LMI070 2.5 mg/kg LMI070 2.5 mg/kg by enteral route via feeding tube or oral | 15 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Part 1 | Death | 1 | 1 | 1 | 2 | 0 | 0 | 0 |
| Part 1 | Subject/guardian decision | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Part 2 | Death | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Part 2 | Subject/guardian decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 3 Extension | Death | 0 | 1 | 1 | 1 | 1 | 1 | 0 |
| Part 3 Extension | Early termination of trial | 1 | 0 | 0 | 0 | 2 | 9 | 11 |
| Part 3 Extension | Subject/guardian decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part 1 LMI070 6mg/m2 | Part 1 LMI070 12mg/m2 | Part 1 LMI070 24mg/m2 | Part 1 LMI070 48mg/m2 | Part 1 LMI070 60mg/m2 | Part 2 LMI070 0.625 mg/kg | Part 2 LMI070 2.5 mg/kg | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 3.0 months STANDARD_DEVIATION 1.41 | 4.5 months STANDARD_DEVIATION 0.71 | 3.5 months STANDARD_DEVIATION 2.12 | 3.8 months STANDARD_DEVIATION 1.71 | 5.3 months STANDARD_DEVIATION 2.08 | 4.38 months STANDARD_DEVIATION 1.521 | 3.81 months STANDARD_DEVIATION 1.188 | 4.21 months STANDARD_DEVIATION 1.481 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 2 Participants | 10 Participants | 14 Participants | 34 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 2 Participants | 5 Participants | 9 Participants | 22 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 5 Participants | 6 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 2 / 2 | 2 / 2 | 3 / 4 | 1 / 3 | 1 / 10 | 2 / 15 |
| other Total, other adverse events | 2 / 2 | 2 / 2 | 2 / 2 | 4 / 4 | 3 / 3 | 10 / 10 | 15 / 15 |
| serious Total, serious adverse events | 2 / 2 | 2 / 2 | 2 / 2 | 4 / 4 | 3 / 3 | 8 / 10 | 11 / 15 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities (DLT) in Part 1 - Safety Analysis Set (SAS)
A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant therapies that occurs within the first 14 days of treatment with LMI070 and meets any of the criteria for blood and lymphatic system disorders, gastrointestinal disorders, investigations and other toxicities considered clinically significant.
Time frame: Baseline up to 2 weeks for Part 1
Population: Safety analysis set. No DLTs were observed, therefore maximum tolerated dose could not be determined.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 LMI070 6mg/m2 | Number of Participants With Dose Limiting Toxicities (DLT) in Part 1 - Safety Analysis Set (SAS) | 0 Participants |
| Part 1 LMI070 12mg/m2 | Number of Participants With Dose Limiting Toxicities (DLT) in Part 1 - Safety Analysis Set (SAS) | 0 Participants |
| Part 1 LMI070 24mg/m2 | Number of Participants With Dose Limiting Toxicities (DLT) in Part 1 - Safety Analysis Set (SAS) | 0 Participants |
| Part 1 LMI070 48mg/m2 | Number of Participants With Dose Limiting Toxicities (DLT) in Part 1 - Safety Analysis Set (SAS) | 0 Participants |
| Part 1 LMI070 60mg/m2 | Number of Participants With Dose Limiting Toxicities (DLT) in Part 1 - Safety Analysis Set (SAS) | 0 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS
TEAEs are defined as adverse events starting on or after the first dose of study treatment that were absent pre-treatment, or events present prior to the first dose but increased in severity after the first dose. Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post last treatment.
Time frame: Baseline up to approximately 83 months
Population: Safety analysis set, all enrolled participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Deaths | 1 Participants |
| Part 1 LMI070 6mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with serious adverse events | 2 Participants |
| Part 1 LMI070 6mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with adverse events | 2 Participants |
| Part 1 LMI070 12mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with serious adverse events | 2 Participants |
| Part 1 LMI070 12mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with adverse events | 2 Participants |
| Part 1 LMI070 12mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Deaths | 2 Participants |
| Part 1 LMI070 24mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Deaths | 2 Participants |
| Part 1 LMI070 24mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with adverse events | 2 Participants |
| Part 1 LMI070 24mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with serious adverse events | 2 Participants |
| Part 1 LMI070 48mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with serious adverse events | 4 Participants |
| Part 1 LMI070 48mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with adverse events | 4 Participants |
| Part 1 LMI070 48mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Deaths | 3 Participants |
| Part 1 LMI070 60mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with serious adverse events | 3 Participants |
| Part 1 LMI070 60mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with adverse events | 3 Participants |
| Part 1 LMI070 60mg/m2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Deaths | 1 Participants |
| Part 2 LMI070 0.625 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with adverse events | 10 Participants |
| Part 2 LMI070 0.625 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Deaths | 1 Participants |
| Part 2 LMI070 0.625 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with serious adverse events | 8 Participants |
| Part 2 LMI070 2.5 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Deaths | 2 Participants |
| Part 2 LMI070 2.5 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with serious adverse events | 11 Participants |
| Part 2 LMI070 2.5 mg/kg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS | Participants with adverse events | 15 Participants |
Secondary
Change From Baseline in Growth Parameter: Body Weight - FAS
The effect of Branaplam on body weight in Kg was measured using a weight scale. Mean change from baseline in Kg is presented In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration.
Time frame: Baseline, Week 52 and Month 6 of Part 3
Population: Full analysis set - Number of patients who have an assessment available at Baseline and the relevant post-baseline visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Change From Baseline in Growth Parameter: Body Weight - FAS | Week 52 | 2.739 kg | Standard Deviation 1.3545 |
| Part 1 LMI070 6mg/m2 | Change From Baseline in Growth Parameter: Body Weight - FAS | P3 Month 6 | 9.546 kg | Standard Deviation 3.5069 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Growth Parameter: Body Weight - FAS | Week 52 | 3.145 kg | Standard Deviation 1.5089 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Growth Parameter: Body Weight - FAS | P3 Month 6 | 4.402 kg | Standard Deviation 1.325 |
Secondary
Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS)
The effect of branaplam on growth parameters: Length (measured from the top of the head to the sole of the foot), Head circumference and Chest circumference (measured across nipple line). Mean change from baseline in cm is presented In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration.
Time frame: Baseline, Week 52 and Month 6 of Part 3
Population: Full analysis set - Number of patients who have an assessment available at Baseline and the relevant post-baseline visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Chest - Week 52 | 4.68 cm | Standard Deviation 2.4769 |
| Part 1 LMI070 6mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Head -Week 52 | 5.030 cm | Standard Deviation 1.1235 |
| Part 1 LMI070 6mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Length - Week 52 | 16.950 cm | Standard Deviation 3.7825 |
| Part 1 LMI070 6mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Chest - P3 Month 6 | 14.750 cm | Standard Deviation 548 |
| Part 1 LMI070 6mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Length - P3 Month 6 | 52.140 cm | Standard Deviation 9.8766 |
| Part 1 LMI070 6mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Head -P3 Month 6 | 9.717 cm | Standard Deviation 1.8766 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Length - P3 Month 6 | 22.944 cm | Standard Deviation 3.7686 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Chest - P3 Month 6 | 8.582 cm | Standard Deviation 2.7423 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Head -Week 52 | 5.111 cm | Standard Deviation 1.3407 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Head -P3 Month 6 | 6.359 cm | Standard Deviation 1.2971 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Length - Week 52 | 16.942 cm | Standard Deviation 4.5806 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS) | Chest - Week 52 | 5.656 cm | Standard Deviation 3.0167 |
Secondary
Change From Baseline in Respiratory Function: Chest Circumference During Quiet Breathing - End of Inspiration and Expiration - FAS
The effect of branaplam on respiratory status was evaluated by measuring the circumference of the ribcage while taking a breathe in and out while quiet or sleeping. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration.
Time frame: Baseline, Week 52 and Month 6 of Part 3
Population: Full analysis set - Number of patients who have an assessment available at Baseline and the relevant post-baseline visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 LMI070 12mg/m2 | Change From Baseline in Respiratory Function: Chest Circumference During Quiet Breathing - End of Inspiration and Expiration - FAS | Week 52 - end of inspiration | 5.964 cm | Standard Deviation 3.6345 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Respiratory Function: Chest Circumference During Quiet Breathing - End of Inspiration and Expiration - FAS | P3 Month 6 - end of inspiration | 8.535 cm | Standard Deviation 3.3083 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Respiratory Function: Chest Circumference During Quiet Breathing - End of Inspiration and Expiration - FAS | Week 52 - end of expiration | 6.033 cm | Standard Deviation 3.9466 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Respiratory Function: Chest Circumference During Quiet Breathing - End of Inspiration and Expiration - FAS | P3 Month 6 - end of expiration | 9.147 cm | Standard Deviation 3.5755 |
Secondary
Change From Baseline in Respiratory Function: Pulse Oximetry - FAS
The effect of branaplam on pulse oximetry in percentage of oxygen saturation was evaluated using a probe that measures oxygen in the blood. Mean change from baseline in percentage of oxygen saturation is reported. Negative numbers indicate a decrease from baseline In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration.
Time frame: Baseline, Week 52 and Month 6 of Part 3
Population: Full analysis set - Number of patients who have an assessment available at Baseline and the relevant post-baseline visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Change From Baseline in Respiratory Function: Pulse Oximetry - FAS | Week 52 | -0.8 percentage | Standard Deviation 2.59 |
| Part 1 LMI070 6mg/m2 | Change From Baseline in Respiratory Function: Pulse Oximetry - FAS | P3 Month 6 | -0.7 percentage | Standard Deviation 2.58 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Respiratory Function: Pulse Oximetry - FAS | Week 52 | -0.1 percentage | Standard Deviation 1.56 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Respiratory Function: Pulse Oximetry - FAS | P3 Month 6 | 0.0 percentage | Standard Deviation 1.83 |
Secondary
Change From Baseline in Respiratory Function: Respiratory Rate - FAS
The effect of branaplam on respiratory rate was evaluated by counting the number of breaths for one minute. Mean change from baseline in breaths per minute is reported In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration.
Time frame: Baseline, Week 52 and Month 6 of Part 3
Population: Full analysis set - Number of patients who have an assessment available at Baseline and the relevant post-baseline visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Change From Baseline in Respiratory Function: Respiratory Rate - FAS | Week 52 | 41.3 breaths per minute | Standard Deviation 7.57 |
| Part 1 LMI070 6mg/m2 | Change From Baseline in Respiratory Function: Respiratory Rate - FAS | P3 Month 6 | 29.2 breaths per minute | Standard Deviation 6.59 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Respiratory Function: Respiratory Rate - FAS | Week 52 | 40.5 breaths per minute | Standard Deviation 13.46 |
| Part 1 LMI070 12mg/m2 | Change From Baseline in Respiratory Function: Respiratory Rate - FAS | P3 Month 6 | 37.2 breaths per minute | Standard Deviation 8.95 |
Secondary
Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS
HINE Section 2 is a standardized evaluation of motor function. It evaluates 8 items; grasp, head control, kicking, rolling over, sitting up, crawling, standing and walking. Motor skills are assigned a score of 0 to 3 to 5 points and zero means the child lacks that motor skill. The maximum score is 26 which is dependent on age, level of development and severity of disease. A higher score is a better outcome. This assessment was added with amendment 6, therefore no baseline was available. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration.
Time frame: Week 52 and Month 6 of Part 3
Population: Full analysis set - Number of patients who have an assessment available at Baseline and the relevant post-baseline visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Week 52 Sitting - Stable independent sit or Pivots (rotates) | 1 participants |
| Part 1 LMI070 6mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Week 52 Standing - Supports weight | 0 participants |
| Part 1 LMI070 6mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Week 52: Walking - Makes any attempt (i.e., bounces) | 0 participants |
| Part 1 LMI070 6mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Part 3, Month 6: Sitting - Stable independent sit or Pivots (rotates) | 0 participants |
| Part 1 LMI070 6mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Part 3, Month 6: Standing - Supports weight | 0 participants |
| Part 1 LMI070 6mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Part 3, Month 6: Walking - Makes any attempt (i.e., bounces) | 0 participants |
| Part 1 LMI070 12mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Part 3, Month 6: Standing - Supports weight | 5 participants |
| Part 1 LMI070 12mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Week 52 Sitting - Stable independent sit or Pivots (rotates) | 1 participants |
| Part 1 LMI070 12mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Part 3, Month 6: Sitting - Stable independent sit or Pivots (rotates) | 4 participants |
| Part 1 LMI070 12mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Week 52 Standing - Supports weight | 2 participants |
| Part 1 LMI070 12mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Part 3, Month 6: Walking - Makes any attempt (i.e., bounces) | 2 participants |
| Part 1 LMI070 12mg/m2 | Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS | Week 52: Walking - Makes any attempt (i.e., bounces) | 1 participants |
Secondary
Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS
To evaluate the efficacy of branaplam on preservation of oral feeding In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration.
Time frame: Baseline up Week 78
Population: Full analysis set - Number of patients who have an assessment available at Baseline and the relevant post-baseline visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS | Other (mixture of both tube and oral feeding) | 8 participants |
| Part 1 LMI070 6mg/m2 | Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS | Only exclusively orally fed | 3 participants |
| Part 1 LMI070 6mg/m2 | Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS | Only exclusively tube fed | 0 participants |
| Part 1 LMI070 6mg/m2 | Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS | Started on orally fed, switched to tube fed | 0 participants |
| Part 1 LMI070 6mg/m2 | Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS | Started on tube fed, switched to orally fed | 0 participants |
| Part 1 LMI070 12mg/m2 | Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS | Started on tube fed, switched to orally fed | 0 participants |
| Part 1 LMI070 12mg/m2 | Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS | Started on orally fed, switched to tube fed | 2 participants |
| Part 1 LMI070 12mg/m2 | Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS | Only exclusively orally fed | 18 participants |
| Part 1 LMI070 12mg/m2 | Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS | Other (mixture of both tube and oral feeding) | 5 participants |
| Part 1 LMI070 12mg/m2 | Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS | Only exclusively tube fed | 0 participants |
Secondary
Number of Participants With Presence of Paradoxical Breathing - FAS
A paradoxical breathing occurs when one compartment moves out of phase compared to another one. In SMA type I, paradoxical breathing is often a sign of breathing problems where the pulmonary ribcage moves inward during inspiration rather than outward while the abdomen expands. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration.
Time frame: Baseline, Week 52 and Month 6 of Part 3
Population: Full analysis set - Number of patients who have an assessment available at Baseline and the relevant post-baseline visit.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Number of Participants With Presence of Paradoxical Breathing - FAS | P3 Month 6 | 4 Participants |
| Part 1 LMI070 6mg/m2 | Number of Participants With Presence of Paradoxical Breathing - FAS | Week 52 | 5 Participants |
| Part 1 LMI070 12mg/m2 | Number of Participants With Presence of Paradoxical Breathing - FAS | Week 52 | 15 Participants |
| Part 1 LMI070 12mg/m2 | Number of Participants With Presence of Paradoxical Breathing - FAS | P3 Month 6 | 14 Participants |
Secondary
Summary of CHOP INTEND Total Score - Parts 1 and 3 and Parts 2 and 3 - FAS
CHOP INTEND is a motor test measure for SMA Type 1 and similarly weak infants with neuromuscular disease. The CHOP INTEND provides a useful measure of motor skills and strength in this population. It is a 16 item, 64 point scale. Each item (motor skill) is given a score from zero to 4: zero indicates can't complete the movement, 1 to 3 indicates partial performance and a 4 indicates person can complete the movement on their own without assistance. These scores are added up to a possible total score of 64 and higher scores indicate better outcomes. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration.
Time frame: Baseline, Week 52 and Month 6 of Part 3
Population: Full analysis set - Number of patients who have an assessment available at Baseline and the relevant post-baseline visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Summary of CHOP INTEND Total Score - Parts 1 and 3 and Parts 2 and 3 - FAS | Part 3, Month 6 | 26.0 scores on a scale | — |
| Part 1 LMI070 6mg/m2 | Summary of CHOP INTEND Total Score - Parts 1 and 3 and Parts 2 and 3 - FAS | Week 52 | 38.1 scores on a scale | Standard Deviation 8.69 |
| Part 1 LMI070 12mg/m2 | Summary of CHOP INTEND Total Score - Parts 1 and 3 and Parts 2 and 3 - FAS | Week 52 | 43.6 scores on a scale | Standard Deviation 6.79 |
| Part 1 LMI070 12mg/m2 | Summary of CHOP INTEND Total Score - Parts 1 and 3 and Parts 2 and 3 - FAS | Part 3, Month 6 | 44.7 scores on a scale | Standard Deviation 8.73 |
Secondary
Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS
HINE Section 2 is a standardized evaluation of motor function. It evaluates 8 items; grasp, head control, kicking, rolling over, sitting up, crawling, standing and walking. Motor skills are assigned a score of 0 to 3 to 5 points and zero means the child lacks that motor skill. The maximum score is 26 which is dependent on age, level of development and severity of disease. A higher score is a better outcome. This assessment was added with amendment 6, therefore no baseline was available. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration.
Time frame: Week 52 and Month 6 of Part 3
Population: Full analysis set - Number of patients who have an assessment available at Baseline and the relevant post-baseline visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS | Week 52 | 3.3 total scores | Standard Deviation 2.31 |
| Part 1 LMI070 6mg/m2 | Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS | Part 3 Month 6 | 3.0 total scores | Standard Deviation 2.12 |
| Part 1 LMI070 12mg/m2 | Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS | Week 52 | 4.9 total scores | Standard Deviation 3.44 |
| Part 1 LMI070 12mg/m2 | Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS | Part 3 Month 6 | 7.7 total scores | Standard Deviation 4.82 |
Secondary
Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) After a Single Dose - Part 2 - PAS
The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume)
Time frame: from 0 h to 168 h after first/single dose
Population: Pharmacokinetic analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) After a Single Dose - Part 2 - PAS | 1150 h*ng/mL | Standard Deviation 357 |
| Part 1 LMI070 12mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) After a Single Dose - Part 2 - PAS | 4060 h*ng/mL | Standard Deviation 734 |
Secondary
Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) for All Observation Periods - Part 2 - PAS
The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume). AUC values used for comparison are combined from AUCinf values after single dose and AUC0-168h values after repeated administration.
Time frame: from 0 h to 168 h after first/single dose
Population: Pharmacokinetic analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) for All Observation Periods - Part 2 - PAS | 1020 h*ng/mL | Standard Deviation 278 |
| Part 1 LMI070 12mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) for All Observation Periods - Part 2 - PAS | 3470 h*ng/mL | Standard Deviation 909 |
Secondary
Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) After a Single Dose - Part 1 - Pharmacokinetics Analysis Set (PAS)
The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume\]
Time frame: from 0 h to 168 h after first/single dose
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) After a Single Dose - Part 1 - Pharmacokinetics Analysis Set (PAS) | 0.321 mg/kg - Actual | 378 h*ng/mL | Standard Deviation 31.9 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) After a Single Dose - Part 1 - Pharmacokinetics Analysis Set (PAS) | 0.654 mg/kg - Actual | 892 h*ng/mL | Standard Deviation 12.3 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) After a Single Dose - Part 1 - Pharmacokinetics Analysis Set (PAS) | 1.39 mg/kg - Actual | 1820 h*ng/mL | — |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) After a Single Dose - Part 1 - Pharmacokinetics Analysis Set (PAS) | 2.49 mg/kg - Actual | 3310 h*ng/mL | Standard Deviation 1340 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) After a Single Dose - Part 1 - Pharmacokinetics Analysis Set (PAS) | 2.94 mg/kg - Actual | 3800 h*ng/mL | Standard Deviation 1590 |
Secondary
Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) for All Observation Periods - Part 1 - PAS
The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume\] for all observations. AUC values used for comparison are combined from AUCinf values after single dose and AUC 0-168h values after repeated administration.
Time frame: from 0 h to 168 h after first/single dose
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) for All Observation Periods - Part 1 - PAS | 0.299 mg/kg - Actual | 413 h*ng/mL | Standard Deviation 98.3 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) for All Observation Periods - Part 1 - PAS | 0.644 mg/kg - Actual | 761 h*ng/mL | Standard Deviation 170 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) for All Observation Periods - Part 1 - PAS | 1.30 mg/kg - Actual | 1340 h*ng/mL | Standard Deviation 381 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) for All Observation Periods - Part 1 - PAS | 2.52 mg/kg - Actual | 3310 h*ng/mL | Standard Deviation 850 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) for All Observation Periods - Part 1 - PAS | 2.95 mg/kg - Actual | 4210 h*ng/mL | Standard Deviation 1030 |
Secondary
Summary of Plasma Pharmacokinetic (PK) Parameter Cmax After a Single Dose - Part 1 - PAS
The observed maximum plasma concentration following drug administration \[mass / volume).
Time frame: from 0 h to 168 h after first/single dose
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax After a Single Dose - Part 1 - PAS | 0.321 mg/kg - Actual | 9.10 ng/mL | Standard Deviation 1.22 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax After a Single Dose - Part 1 - PAS | 0.654 mg/kg - Actual | 18.6 ng/mL | Standard Deviation 1.63 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax After a Single Dose - Part 1 - PAS | 1.39 mg/kg - Actual | 55.6 ng/mL | — |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax After a Single Dose - Part 1 - PAS | 2.49 mg/kg - Actual | 53.2 ng/mL | Standard Deviation 9.5 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax After a Single Dose - Part 1 - PAS | 2.94 mg/kg - Actual | 72.4 ng/mL | Standard Deviation 16.7 |
Secondary
Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 1 - PAS
The observed maximum plasma (or serum or blood) concentration following drug administration \[mass / volume
Time frame: from 0 h to 168 h after first/single dose
Population: Pharmacokinetic analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 1 - PAS | 0.299 mg/kg - Actual | 8.84 ng/mL | Standard Deviation 3.58 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 1 - PAS | 0.644 mg/kg - Actual | 15.3 ng/mL | Standard Deviation 4.1 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 1 - PAS | 1.30 mg/kg - Actual | 37.8 ng/mL | Standard Deviation 12.8 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 1 - PAS | 2.51 mg/kg - Actual | 69.1 ng/mL | Standard Deviation 15.7 |
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 1 - PAS | 2.95 mg/kg - Actual | 96.5 ng/mL | Standard Deviation 32.7 |
Secondary
Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 2 - PAS
The observed maximum plasma (or serum or blood) concentration following drug administration \[mass / volume)
Time frame: from 0 h to 168 h after first/single dose
Population: Pharmacokinetic analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 2 - PAS | 21.7 ng/mL | Standard Deviation 5.71 |
| Part 1 LMI070 12mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 2 - PAS | 77.4 ng/mL | Standard Deviation 27.5 |
Secondary
Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for a Single Dose - Part 2 - PAS
The observed maximum plasma (or serum or blood) concentration following drug administration \[mass / volume)
Time frame: from 0 h to 168 h after first/single dose
Population: Pharmacokinetic analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for a Single Dose - Part 2 - PAS | 22.0 ng/mL | Standard Deviation 5.7 |
| Part 1 LMI070 12mg/m2 | Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for a Single Dose - Part 2 - PAS | 82.0 ng/mL | Standard Deviation 22.5 |
Secondary
Ventilation Use for Parts 1 and 3 and Parts 2 and 3 - FAS
BiBAP (bilevel positive airway pressure) ventilation is a 2 level breathing support which has a tube that connects to a mask. It provides a different level of air pressure for inhalation vs. exhalation, whereas a CPAP (continuous positive airway pressure) only pumps one level of air pressure but is also non-invasiive. Invasive ventilation is delivered via an endotracheal or tracheostomy tube. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1&3 and Part 2&3) irrespective of study dose or route of administration.
Time frame: Baseline up to 82 months
Population: Full analysis set - Number of patients who have an assessment available at Baseline and the relevant post-baseline visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1 LMI070 6mg/m2 | Ventilation Use for Parts 1 and 3 and Parts 2 and 3 - FAS | Non-invasive ventilation - BiPAP | 9 participants |
| Part 1 LMI070 6mg/m2 | Ventilation Use for Parts 1 and 3 and Parts 2 and 3 - FAS | Non-invasive ventilation - CPAP | 3 participants |
| Part 1 LMI070 6mg/m2 | Ventilation Use for Parts 1 and 3 and Parts 2 and 3 - FAS | Invasive ventilation | 4 participants |
| Part 1 LMI070 12mg/m2 | Ventilation Use for Parts 1 and 3 and Parts 2 and 3 - FAS | Non-invasive ventilation - BiPAP | 18 participants |
| Part 1 LMI070 12mg/m2 | Ventilation Use for Parts 1 and 3 and Parts 2 and 3 - FAS | Non-invasive ventilation - CPAP | 2 participants |
| Part 1 LMI070 12mg/m2 | Ventilation Use for Parts 1 and 3 and Parts 2 and 3 - FAS | Invasive ventilation | 5 participants |