Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome

To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available. This was a phase 2, multicente...

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Bibliographic Details
Published in:Neurology Vol. 92; no. 16; p. e1912
Main Authors: Glaze, Daniel G, Neul, Jeffrey L, Kaufmann, Walter E, Berry-Kravis, Elizabeth, Condon, Sean, Stoms, George, Oosterholt, Sean, Della Pasqua, Oscar, Glass, Larry, Jones, Nancy E, Percy, Alan K
Format: Journal Article
Language:English
Published: United States 16.04.2019
Subjects:
Adolescent
Anti-Inflammatory Agents, Non-Steroidal - adverse effects
Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics
Anti-Inflammatory Agents, Non-Steroidal - therapeutic use
Child
Child, Preschool
Double-Blind Method
Female
Glutamates - adverse effects
Glutamates - pharmacokinetics
Glutamates - therapeutic use
Glutamic Acid - adverse effects
Glutamic Acid - pharmacokinetics
Glutamic Acid - therapeutic use
Humans
Rett Syndrome - drug therapy
Treatment Outcome
ISSN:1526-632X, 1526-632X
Online Access:Get more information
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Summary:To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available. This was a phase 2, multicenter, double-blind, placebo-controlled, parallel-group study, in which safety/tolerability, pharmacokinetics, and clinical response to trofinetide were characterized in 82 children/adolescents with RTT, aged 5 to 15 years. Sixty-two participants were randomized 1:1:1:1 to receive placebo twice a day (bid) for 14 days, followed by placebo, 50, 100, or 200 mg/kg bid of trofinetide for 42 days. Following blinded safety data review, 20 additional participants were randomized 1:1 to the 200 mg/kg or placebo bid groups. Safety assessments included adverse events, clinical laboratory tests, physical examinations, and concomitant medications. Clinician- and caregiver-based efficacy measurements assessed clinically relevant, phenotypic dimensions of impairment of RTT. All dose levels were well tolerated and generally safe. Trofinetide at 200 mg/kg bid showed statistically significant and clinically relevant improvements relative to placebo on the Rett Syndrome Behaviour Questionnaire, RTT-Clinician Domain Specific Concerns-Visual Analog Scale, and Clinical Global Impression Scale-Improvement. Exploratory analyses suggested that observed changes correlated with trofinetide exposure. These results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials. This study provides Class I evidence that for children/adolescents with RTT, trofinetide was safe, well-tolerated, and demonstrated improvement over placebo at 200 mg/kg bid in functionally important dimensions of RTT.
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ISSN:1526-632X
1526-632X
DOI:10.1212/WNL.0000000000007316