A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Fragile X Syndrome

Elizabeth Berry-Kravis, Joseph P. Horrigan, Nicole Tartaglia, Randi Hagerman, Alexander Kolevzon, Craig A. Erickson, Shivkumar Hatti, Mike Snape, Alex Yaroshinsky, George Stoms, Kevin Sanders, Jean Frazier, Thomas Challman, Jeffrey Innis, Bryan King, Joseph Cubells, Jeannie Visootsak, Steven Skinner, Dianne Treadwell-Deering, Sherry Sellers VinsonHoward Needelman, Larry Glass, Nancy E. Jones

Research output: Contribution to journalArticle

Abstract

Background: We analyze the safety and tolerability of trofinetide and provide a preliminary evaluation of its efficacy in adolescent and adult males with fragile X syndrome. Methods: This study was an exploratory, phase 2, multicenter, double-blind, placebo-controlled, parallel group study of the safety and tolerability of orally administered trofinetide in 72 adolescent and adult males with fragile X syndrome. Subjects were randomly assigned in a 1:1:1 ratio to 35 or 70 mg/kg twice daily trofinetide or placebo for 28 days. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and concomitant medications. Efficacy measurements were categorized into four efficacy domains, which related to clinically relevant phenotypic dimensions of impairment associated with fragile X syndrome. Results: Both 35 and 70 mg/kg dose levels of trofinetide were well tolerated and appeared to be generally safe. Trofinetide at the 70 mg/kg dose level demonstrated efficacy compared with placebo based on prespecified criteria. On the basis of a permutation test, the probability of a false-positive outcome for the achieved prespecified success was 0.045. In the group analysis, improvement from treatment baseline was demonstrated on three fragile X syndrome–specific outcome measures. Conclusions: Trofinetide was well tolerated in adolescent and adult males with fragile X syndrome. Despite the relatively short duration of the study, a consistent signal of efficacy at the higher dose was observed in both caregiver and clinician assessments, based on a novel analytical model incorporating evaluation of multiple key symptom areas of fragile X syndrome. This finding suggests a potential for trofinetide treatment to provide clinically meaningful improvement in core fragile X syndrome symptoms.

Original languageEnglish (US)
JournalPediatric Neurology
DOIs
StateAccepted/In press - 2020
Externally publishedYes

Keywords

  • Clinical trial
  • Fragile X
  • Neurodevelopmental disorders
  • NNZ-2566
  • Trofinetide

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Neurology
  • Developmental Neuroscience
  • Clinical Neurology

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  • Cite this

    Berry-Kravis, E., Horrigan, J. P., Tartaglia, N., Hagerman, R., Kolevzon, A., Erickson, C. A., Hatti, S., Snape, M., Yaroshinsky, A., Stoms, G., Sanders, K., Frazier, J., Challman, T., Innis, J., King, B., Cubells, J., Visootsak, J., Skinner, S., Treadwell-Deering, D., ... Jones, N. E. (Accepted/In press). A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Fragile X Syndrome. Pediatric Neurology. https://doi.org/10.1016/j.pediatrneurol.2020.04.019