Phase 3 Randomized, Double‑Blind, Placebo‑Controlled Study of Oral Fenfluramine Hydrochloride in Participants with Rett Syndrome

The primary objective of the study is to evaluate the efficacy of Rett syndrome participants receiving fenfluramine hydrochloride compared with placebo, addressing a critical need for disease‑modifying therapeutics in this rare neurodevelopmental disorder. Secondary objectives assess additional clinically relevant outcomes:

• Efficacy on sleep quality.
• Efficacy on communication abilities.
• Efficacy on seizure frequency in participants with concurrent seizures.
• Safety and tolerability of fenfluramine hydrochloride versus placebo.

The trial enrolled 139 participants diagnosed with Rett syndrome, encompassing both male and female individuals aged 5 to 35 years at first administration of the investigational product. Eligibility required confirmation of a disease‑causing mutation in the MECP2 gene and classification as typical or classic Rett syndrome according to the RettSearch Consortium 2010 revised criteria. Candidates had to demonstrate a stable post‑regression status for at least six months, without loss of ambulation, hand function, speech, or non‑verbal communicative and social skills. Additional inclusion parameters included a Rett Syndrome Clinical Severity Scale score between 10 and 36, a Clinical Global Impression‑Severity score of 4 or higher, and the presence of a legal representative able to provide informed consent. Participants were required to have a consistent caregiver aged 18 years or older capable of completing study assessments throughout the trial. The population comprised generally healthy individuals with Rett syndrome meeting the specified clinical and genetic criteria, selected from the broader patient community without further lifestyle restrictions noted.

The study is a Phase 3 randomized, double‑blind, placebo‑controlled, parallel group multicenter trial with an optional open‑label extension designed to evaluate the efficacy and safety of fenfluramine hydrochloride oral solution in participants with Rett syndrome. After an initial screening visit to confirm eligibility criteria, participants are randomized to receive either the investigational oral solution (0.8 mg/kg) or matching placebo and begin treatment at the baseline visit. Follow‑up assessments are scheduled at Weeks 2, 4, 8, and 14, during which clinical, safety, and electrocardiographic data are collected; the primary efficacy assessments (change in Rett Syndrome Behaviour Questionnaire total score and Clinical Global Impression of Change) constitute the primary endpoint at Week 14. An end‑of‑study visit concludes the double‑blind phase, after which eligible participants may enter the open‑label extension for additional observation. Participant involvement therefore spans at least 14 weeks, with the overall trial recruitment period projected from March 2026 to September 2031. Early termination may occur for serious treatment‑emergent adverse events, drug‑related safety concerns, non‑compliance with study procedures, or withdrawal of consent.

The investigational product is Fintepla 2.2 mg/ml oral solution, a sterile aqueous formulation containing fenfluramine hydrochloride. Each participant receives the medication by oral administration at a dose of 0.8 mg per kilogram of body weight. The dose is calculated based on the individual’s most recent weight measurement and prepared according to the study’s dosing algorithm. Administration is performed under supervision at each study visit, and the oral solution is delivered using a calibrated dosing syringe.

The comparator is a matching placebo that is identical in appearance, volume, and administration device to the active oral solution but contains no active substance. The placebo is supplied in the same packaging and is administered by the same route and schedule as the investigational product to maintain blinding.

Dosing occurs according to the protocol‑specified schedule, with each dose administered at the same time of day throughout the treatment period. Participant compliance is monitored by completing a medication diary, performing drug‑accountability checks at each visit, and confirming adherence through residual volume assessment of the delivered dose. Any deviations from the prescribed regimen are documented and addressed according to predefined compliance procedures.

Efficacy will be evaluated by comparing changes from baseline to Week 14 between the fenfluramine hydrochloride and placebo arms. The primary efficacy parameters are the change in Rett Syndrome Behaviour Questionnaire (RSBQ) total score and the Clinical Global Impression of Change (CGIC) score at Week 14. Secondary efficacy assessments include the change from baseline to Week 14 in the Patient‑Reported Outcomes Measurement Information System‑Sleep Disturbance (PROMIS‑SD) score, the Observer‑Reported Communication Ability (ORCA) score, and the Caregiver Global Impression of Change – Seizure (CaGIC‑Seizure) score. Efficacy data will be collected using validated questionnaires and scales administered at baseline and at the Week 14 visit, with scores analyzed for between‑group differences.