Expert Consensus on Real-World Use of Trofinetide for Rett Syndrome Using a Modified Delphi Method

Trofinetide is the first approved treatment for Rett syndrome (RTT) in the United States and Canada. Trofinetide improved the core symptoms of RTT in clinical trials, and real-world evidence supports the findings of clinical trials. As RTT experts in the United States have now gained nearly 3 years of real-world experience with trofinetide, a modified Delphi process was conducted in the United States to establish consensus recommendations for the practical use of trofinetide in the treatment of RTT.

A multidisciplinary steering group of five trofinetide-experienced RTT experts practicing at an International Rett Syndrome Foundation (IRSF)-designated center of excellence convened and developed 72 consensus statements across six domains: first-line use, pre-treatment assessment, initiation, benefit evaluation, tolerability management, and discontinuation strategies. The statements were then assigned a 4-point Likert scale for testing via email by the Delphi panel identified by the steering group. Consensus was reached for individual statements if they met the pre-specified consensus threshold of ≥ 75% agreement.

Two rounds of assessments were completed by 25 respondents in each round, resulting in agreement ≥ 75% being reached across the final statement set. The consensus supports trofinetide as the standard of care for eligible patients with early initiation and an individualized approach to titration to maximize efficacy and tolerability. The panel reflected the steering group's view that trofinetide is efficacious. While side effects can emerge with trofinetide, they are manageable in most cases.

Recommendations highlight a flexible, patient-centered approach to trofinetide use to optimize efficacy while addressing tolerability challenges and supporting adherence.