Clinical Trial: An Open Label Study of LMI070 in Type 1 Spinal Muscular Atrophy (SMA)

Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional

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

Brief Summary: An open-label, multi-part, first-in-human study of oral LMI070 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) and optimal dosing regimen of orally administered LMI070 in patients with Type 1 SMA.

Detailed Summary:

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 LMI070 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 LMI070. The LMI070 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 dosing regimens (depending on the results of Part 1) for 12 weeks. Patients who complete the first 13 weeks of Part 1 and are, in the opinion of the Investigator and Sponsor benefiting and/or tolerating LMI070, may continue treatment with higher doses of LMI070 that have been shown to be well tolerated.


Sponsor: Novartis Pharmaceuticals

Current Primary Outcome: Parts 1 & 2 Safety & Tolerability [ Time Frame: 13 weeks ]

To evaluate the effect of LMI070 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


Original Primary Outcome: Parts 1 & 2 Safety & Tolerability [ Time Frame: 13 weeks ]

To evaluate the effect of LMI070 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 cardiac function at all dose levels


Current Secondary Outcome:

  • Changes in Growth Parameters from baseline [ Time Frame: Screening, Day 1, Day 8 to Day 85 & End of Study ]
    To evaluate the effect of LMI070 on the following growth measurements; - Body Weight & Length - Head & Chest Circumference
  • Changes in respiratory function from baseline [ Time Frame: Baseline, Day 8 to Day 85 & End of Study ]

    To evaluate the effect of LMI070 on respiratory function as change from Baseline by measurement of the following;

    • Infant cry vital capacity (optional)
    • Pulse oximetry
    • Respiratory rate
    • Paradoxical breathing assessment
    • Chest circumference during quiet breathing
  • Changes in Infant motor development from baseline [ Time Frame: Baseline, Day 36, Day 85 + End of Study ]
    To evaluate the effect of LMI070 on Infant Motor Development as in change from Baseline
  • 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 ]
    To evaluate LMI070 pharmacokinetics in plasma after single and repeated doses of LMI070 by determination of AUC & Cmax
  • 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 ]
    To evaluate the efficacy of LMI070 on motor and development milestones using the CHOP INTEND Infant Motor Scale
  • 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 ]
    To evaluate the efficacy of LMI070 on Ulnar Nerve Compound Motor Action Potential (CMAP) in terms of % increase from baseline
  • 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 ]
    To evaluate the efficacy of LMI070 on motor and development milestones by physical examination including assessment of oral feeding, head control, rolling, sitting up


Original Secondary Outcome:

  • Changes in quadriceps muscle thickness from baseline [ Time Frame: Baseline, Day 85 & End of Study ]
    To evaluate the effect of LMI070 on quadriceps muscle thickness by ultrasound.
  • Changes in Growth Parameters from baseline [ Time Frame: Screening, Day 1, Day 8 to Day 85 & End of Study ]
    To evaluate the effect of LMI070 on the following growth measurements; - Body Weight & Length - Head & Chest Circumference
  • Changes in respiratory function from baseline [ Time Frame: Baseline, Day 8 to Day 85 & End of Study ]

    To evaluate the effect of LMI070 on respiratory function as in change from Baseline by measurement of the following;

    • Infant cry vital capacity
    • Pulse oximetry
    • Respiratory rate
    • Paradoxical breathing assessment
  • Changes in Infant motor development from baseline [ Time Frame: Baseline, Day 36, Day 85 + End of Study ]
    To evaluate the effect of LMI070 on Infant Motor Development as in change from Baseline
  • 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 ]
    To evaluate LMI070 pharmacokinetics in serum after single and repeated doses of LMI070 by determination of AUC & Cmax
  • 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 ]
    To evaluate the efficacy of LMI070 on motor and development milestones using the CHOP INTEND Infant Motor Scale
  • In addition to the above for Part 2 - Changes in Ulnar Nerve Compound Action Potential from baseline [ Time Frame: Baseline, Day 88 + End of Study ]
    To evaluate the efficacy of LMI070 on ulnar nerve compound action potential in terms of % increase from baseline
  • 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 ]
    To evaluate the efficacy of LMI070 on motor and development milestones by physical exmaniation including assessment of oral feeding, head control, rolling, sitting up


Information By: Novartis

Dates:
Date Received: October 1, 2014
Date Started: April 2015
Date Completion: August 2017
Last Updated: January 24, 2017
Last Verified: January 2017