Discussion
diarrhea, antiseizure, TEAEs, vomiting, constipation, neurodevelopmental disorders, RTT
SECONDARY, RARE DISEASE, SYNDROME, PATHOPHYSIOLOGY
In this phase 3 study in a large cohort of girls and women 5–20 years of age with RTT, trofinetide demonstrated a statistically significant improvement over placebo for both the coprimary and key secondary efficacy endpoints. Treatment with trofinetide improved key symptoms of the syndrome from the perspective of both the caregiver (RSBQ) and clinician (CGI-I). All RSBQ subscores were directionally in favor of trofinetide, suggesting broad improvement across key symptoms of the syndrome.Cohen’s The efficacy endpoints are complementary and reflect functionally important dimensions of RTT, including the ability to communicate. The RSBQ shows correlations with functioning, is validated across a range of ages (2–47 years) in RTTMild or moderate diarrhea was frequently associated with trofinetide and was responsible for the majority of discontinuations due to TEAEs; however, diarrhea was self-limited and resolved soon after withdrawal of trofinetide. The implementation of a diarrhea-management plan partway through the study, which involved the adjustment or discontinuation of laxative medications commonly taken for RTT-associated constipation, the initiation of fiber supplements and antidiarrheal medication and dose reduction or interruption of trofinetide, if necessary, appeared to mitigate this risk, as 75% of participants receiving trofinetide completed the study. Furthermore, analyses indicate that the risk of functional unblinding due to an imbalance of TEAEs of diarrhea did not bias the efficacy data in favor of trofinetide. Given that most participants were using concomitant antiseizure medication, many of which cause changes in liver enzymesThe exclusion of individuals without a documented disease-causing In conclusion, statistically significant differences were demonstrated between trofinetide and placebo for efficacy endpoints relevant to RTT, suggesting that trofinetide is potentially capable of modifying core symptoms consistent with the underlying pathophysiology of the syndrome. Furthermore, this study demonstrated an acceptable safety profile for trofinetide. When we evaluate the benefit versus risk associated with trofinetide, it is important to consider the medium effect size that was demonstrated for the efficacy endpoints, which can be interpreted as clinically meaningful, particularly as this is a rare disease with a high burden for patients and families. When we consider the risk element, it is important to note that diarrhea and vomiting were issues of tolerability, not safety. Almost all TEAEs of diarrhea and vomiting were mild or moderate in severity and can be managed with appropriate interventions. Given that numerous phase 2 and 3 studies in neurodevelopmental disorders including RTT have failed to meet efficacy endpoints