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

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Berry-Kravis, Elizabeth, Horrigan, Joseph P., Tartaglia, Nicole, Hagerman, Randi, Kolevzon, Alexander, Erickson, Craig A., Hatti, Shivkumar, Snape, Mike, Yaroshinsky, Alex, Stoms, George, Sanders, Kevin, Frazier, Jean, Challman, Thomas, Innis, Jeffrey, King, Bryan, Cubells, Joseph, Visootsak, Jeannie, Skinner, Steven, Treadwell-Deering, Dianne, Vinson, Sherry Sellers, Needelman, Howard, Glass, Larry, Jones, Nancy E.·2020·Pediatric Neurology

DOI 10.1016/j.pediatrneurol.2020.04.019

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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.

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Snape M, Horrigan J, Glass L, et al. Improving outcome measures for fragile X syndrome clinical trials: development of fragile X syndrome-specific rating scales. Presented at 17th Society for the Study of Behavioural Phenotypes International Research Symposium. October 2014; New York, NY.

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Additional file 1 of Is trofinetide a future treatment for Rett syndrome? A comprehensive systematic review and meta-analysis of randomized controlled trials
Mohammed, H. E., Bady, Z. A. M., Haseeb, M. E., Aboeldahab, H. A., Sharaf-Eldin, W. E., & Zaki, M. S. (2024) · Figshare · doi:10.6084/m9.figshare.26322596

Authors: 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., Vinson, S. S., Needelman, H., Glass, L., & Jones, N. E.
Affiliations: Duke University (US)
Children's Hospital Colorado (US)
University of California, Davis (US)
Mount Sinai Hospital (US)
Cincinnati Children's Hospital Medical Center (US)
Suburban Research Associates (US)
AMO Pharma (United Kingdom) (GB)
ORCID: Horrigan, Joseph P.
Tartaglia, Nicole
Hagerman, Randi
Kolevzon, Alexander
Erickson, Craig A.
Snape, Mike
Yaroshinsky, Alex
Stoms, George
Sanders, Kevin
Frazier, Jean
Challman, Thomas
Innis, Jeffrey
Cubells, Joseph
Visootsak, Jeannie
Skinner, Steven
Needelman, Howard
Glass, Larry
Jones, Nancy E.
Venue: Pediatric Neurology
Publisher: Elsevier BV
Published: 2020-09
Volume: 110
Pages: 30-41
ISSN: 0887-8994 (ISSN-L)
DOI: 10.1016/j.pediatrneurol.2020.04.019
OpenAlex: W2734032654
Cited by: 102
References: 50
Citations by year: 2026: 3 · 2025: 6 · 2024: 25 · 2023: 18 · 2022: 12 · 2021: 13 · 2020: 15
FWCI: 8.50
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Pediatric Neurology (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: Neuren Pharmaceuticals, Ltd
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords: trofinetide, fragile X syndrome, FMRP, safety and tolerability, efficacy, symptom domains, dose comparison
MeSH terms: Adolescent, Adult, Child, Double-Blind Method, Fragile X Syndrome, Glutamates, Humans, Male, Outcome Assessment, Health Care, Young Adult

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

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