Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study

Abstract

Rett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study ( https://clinicaltrials.gov identifier NCT04181723 ), females with Rett syndrome received twice-daily oral trofinetide (n = 93) or placebo (n = 94) for 12 weeks. For the coprimary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire for trofinetide versus placebo was -4.9 versus -1.7 (P = 0.0175; Cohen's d effect size, 0.37), and LSM Clinical Global Impression-Improvement at week 12 was 3.5 versus 3.8 (P = 0.0030; effect size, 0.47). For the key secondary efficacy endpoint, LSM change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist Social Composite score was -0.1 versus -1.1 (P = 0.0064; effect size, 0.43). Common treatment-emergent adverse events included diarrhea (80.6% for trofinetide versus 19.1% for placebo), which was mostly mild to moderate in severity. Significant improvement for trofinetide compared with placebo was observed for the coprimary efficacy endpoints, suggesting that trofinetide provides benefit in treating the core symptoms of Rett syndrome.

Fig. 1. Participant disposition.

Note that the three participants missing from the full analysis set (n = 184), who were included in the randomized analysis set (n = 187), had a baseline assessment but no post-baseline efficacy assessments. *208 unique participants were screened, but some were rescreened, for a total of 227 screenings. COVID-19, coronavirus disease 2019. Source data

Fig. 2. RSBQ total scores, CGI-I scale scores and RSBQ subscores.

a, Mean (s.e.m.) change from baseline in RSBQ total score at each study visit in the full analysis set. b, Mean (s.e.m.) CGI-I scale score at each study visit in the full analysis set. c, LSM treatment differences with 95% CIs for the change in RSBQ subscores from baseline to week 12. In a,b, data are presented as mean values ± s.e.m.; asterisks at week 12 denote significance based on the LSM treatment difference from the MMRM analysis in which adjustments were made for multiple comparisons (two-sided P = 0.0175 and Cohen’s d effect size = 0.37 for the RSBQ change from baseline to week 12 and two-sided P = 0.0030 and Cohen’s d effect size = 0.47 for the CGI-I scale score at week 12). In c, data are presented as LSM treatment difference, and whiskers represent the lower and upper limits of the 95% CI; CI widths have not been adjusted for multiplicity. Sample size for each RSBQ subscore analysis: trofinetide (n = 76) and placebo (n = 85). Source data

Fig. 3. Subgroup analyses of the coprimary efficacy endpoints.

a–c, LSM treatment differences with 95% CIs for the coprimary efficacy endpoints by age (a), baseline RSBQ severity (b) and category of mutation severity (c) based on the MMRM analysis in the full analysis set. In a–c, data are presented as LSM treatment difference, and whiskers represent the lower and upper limits of the 95% CI; CI widths have not been adjusted for multiplicity. Source data

Extended Data Fig. 1. Alanine Aminotransferase Values.

Figure footnote: The dashed vertical line at day 1 indicates when study treatment was initiated. Source data

Extended Data Fig. 2. Score on the CGI-I Scale at Week 12.

Figure footnote: CGI-I denotes Clinical Global Impression-Improvement. Source data