Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome

• Published in: Contemporary clinical trials 2022-03, Vol.114, p.106704-106704, Article 106704
• Main Authors: Neul, Jeffrey L., Percy, Alan K., Benke, Timothy A., Berry-Kravis, Elizabeth M., Glaze, Daniel G., Peters, Sarika U., Jones, Nancy E., Youakim, James M.
• Format: Article
• Language: English
• Subjects: Adolescent; Caregiver rating scale; Child; Child, Preschool; Clinician rating scale; Double-Blind Method; Female; Glutamates; Humans; LAVENDER; Outcome Assessment, Health Care; Quality of Life; Rett syndrome; Rett Syndrome - drug therapy; Rett Syndrome Behaviour Questionnaire; Trofinetide
• ISSN: 1551-7144; 1559-2030
• DOI: 10.1016/j.cct.2022.106704

Rett syndrome (RTT) is a debilitating neurodevelopmental disorder with no approved treatments. Trofinetide is a synthetic analog of glycine–proline–glutamate, the N-terminal tripeptide of insulin-like growth factor 1. In a phase 2, placebo-controlled trial in 82 females with RTT aged 5–15 years, a significant (p ≤ 0.042) improvement over placebo was observed with the highest trofinetide dose (200 mg/kg twice daily [BID]) on three measures: Rett Syndrome Behaviour Questionnaire (RSBQ), Clinical Global Impression-Improvement (CGI-I), and RTT-Clinician Domain Specific Concerns-Visual Analog Scale (RTT-DSC-VAS). Trofinetide was well tolerated at all doses (50, 100, and 200 mg/kg BID). A phase 3 trial utilizing disease-specific and novel scales was designed to investigate the efficacy and safety of trofinetide in girls and women with RTT. This 12-week, double-blind, randomized, placebo-controlled study (LAVENDER; NCT04181723) will evaluate trofinetide in 187 females, aged 5–20 years, with RTT. Co-primary endpoints are the RSBQ and CGI-I scales. Clinical domains of the CGI-I include communication, ambulation, hand use, seizures, attentiveness, and social (eye contact) and autonomic (breathing) aspects. Secondary endpoints will leverage four novel RTT-specific clinician ratings (derived from the RTT-DSC-VAS) of hand function, ambulation, ability to communicate, and verbal communication, and existing scales, to evaluate other core symptoms of RTT, quality of life and caregiver burden. A 40-week, open-label extension study will follow. This study was designed using disease-specific scales optimized to demonstrate changes in core symptoms of RTT and may provide the first phase 3 data demonstrating drug efficacy in individuals with RTT. Trial registration: Clinicaltrials.govNCT04181723 •Rett syndrome (RTT) is a neurodevelopmental disorder without approved treatment.•Trofinetide is an investigational drug for the treatment of RTT.•LAVENDER utilizes clinician- and caregiver-rating scales to assess efficacy.•LAVENDER utilizes novel RTT-specific scales optimized for distinct RTT domains.•LAVENDER will provide the first prospectively powered study of trofinetide efficacy.