A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Fragile X Syndrome - 20/08/20
, Joseph P. Horrigan, MD d, Nicole Tartaglia, MD e, Randi Hagerman, MD f, Alexander Kolevzon, MD g, h, Craig A. Erickson, MD i, Shivkumar Hatti, MD j, Mike Snape, PhD k, Alex Yaroshinsky, PhD l, George Stoms, BA l, FXS-001 Investigators1
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.
Le texte complet de cet article est disponible en PDF.Keywords : Fragile X, Trofinetide, NNZ-2566, Clinical trial, Neurodevelopmental disorders
Plan
| Conflicts of interest: E.B.-K. participated in the Neu-2566-FXS 001 trial, has been a consultant for Seaside Therapeutics, Novartis, Roche, Alcobra, Neuren, Cydan, Fulcrum, GW, Neurotrope, Marinus, Zynerba, BioMarin, and Ovid Pharmaceuticals regarding conduct of clinical trials in FXS and other rare neurological diseases, is on the Scientific Advisory Board for Vtesse/Mallinckrodt to provide guidance on clinical trials in Niemann-Pick type C (NP-C), has received research funding to conduct clinical trials in FXS from Novartis, Roche, Seaside Therapeutics, Alcobra, Neuren, Ovid, and Zynerba to conduct a clinical trial in NP-C from Vtesse/Mallinckrodt, and to develop FMR1 testing standards from Asuragen. She was also a participating principal investigator on a clinical trial in Rett syndrome sponsored by Neuren Pharmaceuticals. She has research finding through grants from NIH, CDC, FRAXA Research Foundation, International Rett Syndrome Foundation, and the Phelan McDermid Foundation. She was consultant to GCC on the project funded by Neuren Pharmaceuticals for the psychometric analysis of the FXRS. J.P.H. was an employee at Neuren Pharmaceuticals, Inc. during the conduct of the research. He is currently an employee at AMO Pharma Ltd., which was not involved in the clinical trial reported in this manuscript. N.T. participated in the Neu-2566-FXS 001 trial and has received research funding from NICHD and CDC, and for industry-sponsored clinical trials in autism and/or fragile X from Seaside Therapeutics, Roche, Neuren, Alcobra, Zynerba, and Ovid. She has consulted with Zynerba and Ovid on clinical trial design and outcome measures in FXS. R.H. participated in the Neu-2566-FXS 001 trial and receives research funding from NICHD, Azrieli Foundation, Curemark, and Zynerba currently regarding studies in FXS, autism, or premutation involvement. She has consulted with Zynerba, Fulcrum, Ovid, Novartis, and Roche in the past and has carried out studies funded by Marinus, Roche, Novartis, Seaside Therapeutics, Forest, and the National Fragile X Foundation in the past. A.K. participated in the Neu-2566-FXS 001 trial and receives research funding from the National Institute of Neurological Disorders and Stroke, New York Community Trust, AMO Pharma, and the Seaver Foundation. He has been a consultant for Ovid Therapeutics, Genentech, Supernus Pharmaceuticals, Fulcrum Therapeutics, Coronis, 5AM Ventures, Labcorp, and sema4. C.A.E. participated in the Neu-2566-FXS 001 trial. He has received current or past funding from Confluence Pharmaceuticals, Novartis, F. Hoffmann-La Roche Ltd., Seaside Therapeutics, Riovant Sciences, Inc., Fulcrum Therapeutics, Neuren Pharmaceuticals Ltd., Alcobra Pharmaceuticals, Neurotrope, Zynerba Pharmaceuticals, Inc., and Ovid Therapeutics Inc. to consult on trial design or development strategies and/or conduct clinical trials in FXS or other neurodevelopmental disorders. C.A.E. is additionally the inventor or coinventor on several patents held by Cincinnati Children's Hospital Medical Center or Indiana University School of Medicine describing methods of treatment in FXS or other neurodevelopmental disorders. S.H. participated in the Neu-2566-FXS 001 trial. M.S. was a consultant for Neuren Pharmaceuticals for the reported study. He is an employee of AMO Pharma Ltd., which was not involved in the presently reported study. A.Y. is a Biostatistician for Vital Systems, Inc., a contract research organization utilized by Neuren for the trial described in this article. G.S. is President of Vital Systems, Inc., a contract research organization utilized by Neuren Pharmaceuticals for the conduct and analysis of this clinical trial, the Rett-001 and Rett 002 trials of trofinetide in Rett syndrome, and trials in traumatic brain injury sponsored by Neuren. L.G. and N.E.J. are executives at Neuren Pharmaceuticals Ltd. |
Vol 110
P. 30-41 - septembre 2020 Retour au numéro
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