An Open Label Study of LMI070 (Branaplam) in Type 1 Spinal Muscular Atrophy (SMA)

Spinal Muscular Atrophy Clinical Trial

Official title:

An Open Label Multi-part First-in-human Study of Oral LMI070 in Infants With Type 1 Spinal Muscular Atrophy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02268552
• Other study ID #: CLMI070X2201
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 2, 2015
• Est. completion date: December 29, 2022

Study information

• Verified date: April 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 is 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 is safe for long term use as well as that can provide durable efficacy optimal dosing regimen in patients with Type 1 SMA.

Description:

This is 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 and 2 are intended to be non-confirmatory. In Part 1 of the study, patients will be dosed once weekly with branaplam. The branaplam dose will be escalated in subsequent cohorts until MTD is determined or when sufficient PK results confirm that the MTD cannot be reached due to a potential pharmacokinetic plateau at higher doses. A decision to dose escalate the next cohort will be made after safety data have been collected for 14 days following the first dose (14-day DLT window). PK will be used to confirm that there is no accumulation of the compound.

Part 2 of the study will enroll new patients into one of up to 3 dose cohorts with once weekly dosing for 52 weeks. The branaplam dose will be escalated in subsequent cohorts after 6 patients have been enrolled and at least 3 patients from the previous cohort will have completed 13 weeks of treatment. After 52 weeks, patients may continue treatment if Novartis, the investigator and the independent DMC agree that this is in the best interest of the patient.

In all cases continuation of the treatment will be done at a dose selected as optimum, considering existing safety as well as efficacy data

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: December 29, 2022
• Est. primary completion date: December 29, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 28 Days to 182 Days

Eligibility

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.

Related Conditions & MeSH terms

• Atrophy
• Muscular Atrophy
• Muscular Atrophy, Spinal
• Spinal Muscular Atrophy

Intervention

Drug:
• branaplam

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Leuven
Bulgaria	Novartis Investigative Site	Sofia
Denmark	Novartis Investigative Site	Copenhagen
Germany	Novartis Investigative Site	Essen
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Roma	RM
Poland	Novartis Investigative Site	Warsaw
Poland	Novartis Investigative Site	Wroclaw
Russian Federation	Novartis Investigative Site	Ekaterinburg
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Saint Petersburg
Russian Federation	Novartis Investigative Site	Volgograd

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Belgium,  Bulgaria,  Denmark,  Germany,  Italy,  Poland,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with adverse events (AEs), serious adverse events (SAEs)	Participants are monitored for safety throughout the study	13 weeks
Primary	Number of participants with adverse events (AEs), serious adverse events (SAEs)	Participants are monitored for safety throughout the study	52 weeks
Secondary	Change from baseline in length	To evaluate the effect of branaplam on length in cm	Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study.
Secondary	Change from baseline in pulse oximetry	To evaluate the effect of branaplam on respiratory function by measurement of Pulse oximetry in percentage (%) of oxygen saturation	Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study.
Secondary	Change from baseline in Hammersmith Infant Neurology Examination (HINE) section 2	To evaluate the effect of branaplam on infant motor development using HINE section 2	Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study.
Secondary	Pharmacokinetic: AUC	To evaluate branaplam pharmacokinetics in plasma after single and repeated doses of branaplam by determination of AUC.	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 (Pre-dose + 4 & 24 hours post-dose), 94, 99, 274 (Pre-dose + 4 & 24 hours post-dose), 276, 281
Secondary	In addition to the above for Part 2 - Change from baseline in feeding status	To evaluate the efficacy of branaplam on preservation of oral feeding	Baseline, Day 15, Day 36, Day 57, Day 88 + End of Study
Secondary	In addition to the above for Part 2 - Changes in Ulnar Nerve Compound Motor Action Potential (CMAP) from baseline	To evaluate the efficacy of branaplam on Ulnar and Peroneal Nerve Compound Motor Action Potentials (CMAPs) in terms of % increase from baseline	Baseline, Day 88 + End of Study
Secondary	In addition to the above for Part 2 - Changes from baseline on the ability to site without support	To evaluate the efficacy of branaplam on the ability to sit without support	52 weeks
Secondary	Change from baseline in weight	To evaluate the effect of branaplam on weight in kilograms	Screening, Day 1, Day 8 to Day 85. Extended treatment periods: every 4 weeks and at the End of Study
Secondary	Change from baseline in head circumference	To evaluate the effect of branaplam on head circumference in cm	Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study.
Secondary	Change from baseline in chest circumference	To evaluate the effect of branaplam on chest circumference	Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study.
Secondary	Change from baseline in Children's Hospital of Philadelphia Infant Neuromuscular Disorders (CHOP INTEND)	To evaluate the effect of branaplam on infant motor development using CHOP INTEND	Part 1: Baseline, Day 36, Day 85, and every 6 to 7 weeks in the extended treatment periods, and at the End of Study. Part 2: Baseline, Day 36, Day 85, Day 127, Day 176, Day 218, Day 267, Day 309, Day 358 and End of Study
Secondary	Change from baseline in respiratory rate	To evaluate the effect of branaplam on respiratory function by measurement of the respiratory rate	Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study.
Secondary	Change from baseline in chest circumference during quiet breathing	To evaluate the effect of branaplam on respiratory function by measurement of the chest circumference in cm during expiration and during inspiration	Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study.
Secondary	Change from baseline in paradoxical breathing	To evaluate the effect of branaplam on respiratory function by evaluation of the presence of absence of paradoxical breathing	Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study.
Secondary	Pharmacokinetic: Cmax	To evaluate branaplam pharmacokinetics in plasma after single and repeated doses of branaplam by determination of Cmax.	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 (Pre-dose + 4 & 24 hours post-dose), 94, 99, 274 (Pre-dose + 4 & 24 hours post-dose), 276, 281