Table 1. Salient features of clinical trials of Trofinetide.

Trial description (Ref.)	Age group, years	Comparators	Efficacy	Safety
Glaze DJ, et al. (17)	15.9–44.2	Trofinetide 70 mg/kg and 35 mg/kg twice daily or placebo	MBA change index: -2.01 vs. -0.62 (p = 0.146) CGI-I score: 3.24 vs. 3.64 (p = 0.164) Caregiver Top 3 Concerns total VAS score: -62.59 vs. -23.71 (p = 0.076) In this trial p <0.2 was considered significant.	• The most common encountered TEAE was diarrhoea (39% -35 mg/kg group vs. 15% - placebo group), irritability (22% -35 mg/kg group vs. 15% - placebo group), and somnolence (17% -70 mg/kg group vs. 5% - placebo group) • Most AEs were mild or moderate in intensity and most events were considered not related to study drug SAE: Three subjects experienced serious adverse events, 2 subjects in the 35 mg/kg cohort and 1 subject in the 70 mg/kg cohort. All SAEs were resolved by the end of the study.
Glaze DJ, et al (18)	5–15	Trofinetide 200 mg/kg twice daily vs. placebo.	RSBQ total score: -6.7 vs. -2.3; p = 0.042 CGI-I: 3 vs. 3.5; p = 0.029) RTT-DSC: -76 vs. 25.85; p = 0.025)	• The tolerability of Trofinetide was very good at all 3 dose levels • Diarrhoea: 200 mg (56%); 100 mg (13%), 50 mg (27%), placebo (4%) • Vomiting: 200 mg (22%); 100 mg (13%), 50 mg (7%), placebo (13%) • Upper respiratory tract infection: 200 mg (19%); 100 mg (0%), 50 mg (7%), placebo (13%) • Pyrexia: 200mg (11%); 100mg (19%), 50mg (0%), placebo (8%) SAE: Four SAEs occurred in 3 participants. All the SAEs were deemed not related to study medication and resolved by the end of the study.
Neul LJ, et al (19)	5–20	Trofinetide oral solution (1 g Trofinetide per 5 mL, calculated as per the weight) vs. placebo	RSBQ: -4.9 vs.-1.7; p = 0.018 CGI-I: 3.5 vs. 3.8; p = 0.003 CSBS-DP-IT Social total score: -0.1 vs.-1.1; p = 0.006	• Common treatment-emergent adverse events included diarrhea 80.6% for Trofinetide vs. 19.1% for placebo and vomiting 26.88% for Trofinetide vs. 9.57% for placebo • All the TEAE were of mild to moderate in severity SAE: 1 case of Bacteremia, bronchiolitis, covid-19 pneumonia, urinary tract infection, seizure was reported.

RSBQ: Rett Syndrome Behavior Questionnaire; CGI-I: Clinical Global Impression Scale-Improvement; RTT-DSC: RTT-Clinician Domain Specific Concerns; MBA: Motor Behavior Assessment scale; CSBS-DP-IT: Social Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist - Social Composite Score; TEAE: Treatment Emergent Adverse Event.