A Phase 3 Study of Fenfluramine Hydrochloride in Rett Syndrome

A Phase 3 Randomized, Double-Blind, Placebo Controlled, Parallel Group, Multicenter Study With Open-Label Extension to Evaluate the Efficacy And Safety of Fenfluramine Hydrochloride in Study Participants With Rett Syndrome

The purpose of this study is to investigate the efficacy of fenfluramine hydrochloride (HCl) versus placebo in study participants with Rett syndrome (RTT).

Study Overview

• Status: Not yet recruiting
• Conditions: Rett Syndrome
• Intervention / Treatment: Drug: fenfluramine hydrochloride; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: UCB Cares; Phone Number: 0018445992273; Email: UCBCares@ucb.com
• Study Contact Backup: Name: UCB Cares; Phone Number: +18445992273; Email: ucbcares@ucb.com

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Ep0247 21010
  • Texas
    • Houston, Texas, United States, 77030
      • Ep0247 21005

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participant has typical or classic Rett Syndrome (RTT) according to the RettSearch Consortium 2010 revised criteria
• Participant has a documented disease-causing mutation in the methyl-CpG-binding protein 2 (MECP2) gene
• Participant meets criteria for postregression for at least 6 months prior to Screening, defined as:
• No loss or degradation of ambulation (including gait, coordination, or independence of walking/standing);
• No loss or degradation of hand function; no loss or degradation of speech (including babbling, words, or previously developed communicative vocalizations);
• No loss or degradation of nonverbal communicative or social skills (including eye gaze, using body to indicate communicative intent, or social attentiveness)
• Participant has an Rett Syndrome Clinical Severity Scale (RTT-CSS) rating of 10 to 36 (inclusive)
• Participant has a Clinical Global Impression-Severity (CGIS) score of ≥4
• Participant has a legal representative capable of providing signed informed consent on behalf of the participant as described in the protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
• Participant is aged 5 to 35 years of age (inclusive) at the time of first administration of investigational intervention.
• Male or female.
• Participant has a consistent caregiver who is ≥18 years of age at the Screening Visit. The caregiver needs to be able to complete the caregiver assessments defined for the entire study. Every attempt should be made to have the same evaluator complete the assessments for the duration of the study.

Exclusion Criteria:

• Participant has a history of lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
• Participant has clinically significant abnormality in vital signs according to the Investigator

• Participant has an exclusionary cardiovascular or cardiopulmonary abnormality based on echocardiogram (ECHO), electrocardiogram (ECG), or physical examination, and is not approved for entry by the central cardiac reader. Exclusionary abnormalities include, but are not limited to:

  1. Greater than trace aortic valve regurgitation.
  2. Greater than mild mitral valve regurgitation.
  3. Possible signs of pulmonary arterial hypertension (PAH) with abnormal pulmonary artery systolic pressure (PASP) or PASP ≥35 mmHg.
  4. Evidence of left ventricular dysfunction (systolic or diastolic).
  5. Clinically significant structural cardiac abnormality, including but not limited to mitral valve prolapse, atrial or ventricular septal defects, or patent ductus arteriosus with reversal of shunt (right to left shunt). Note: Patent foramen ovale without a reversal of shunt or a bicuspid aortic valve is not considered exclusionary
• Participant has a clinically significant medical condition, including chronic obstructive pulmonary disease, interstitial lung disease, portal hypertension, or need for invasive mechanical ventilation (eg, via tracheostomy), or has had clinically relevant symptoms or a clinically significant illness currently or in the 4 weeks prior to the Screening Visit that would negatively impact study participation, collection of study data, or pose a risk to the participant
• Participant is taking >4 concomitant antiseizure medications (ASMs). Rescue medications are not included in the count

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: fenfluramine hydrochloride; Participants will receive fenfluramine hydrochloride for 14 weeks in a double-blind period (including titration and maintenance), followed by a 2-week double-blind transition period. This is followed by a 52-week open-label treatment period. Participants may continue treatment until alternative access is available. Those who discontinue without continued access will undergo an 8-day taper and a 26-week follow-up.	Drug: fenfluramine hydrochloride; Oral solution; Other Names: Fintepla, ZX008
Placebo Comparator: Placebo; Participants will receive a matching placebo for 14 weeks in a double-blind period (including titration and maintenance). After this period, they transition into a 2-week double-blind period with fenfluramine hydrochloride, followed by a 52-week open-label treatment period. Participants may continue treatment until alternative access is available. Those who discontinue without continued access will undergo an 8-day taper and a 26-week follow-up.	Other: Placebo; Oral solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline to Week 14 in Rett Syndrome Behaviour Questionnaire (RSBQ) Total Score	The RSBQ is a caregiver-completed, instrument assessing behavioral and emotional features in RTT. The RSBQ consists of 45 items, including 8 subscales: General mood (8 items); Breathing problems (5 items); Hand behavior (6 items); Face movements (4 items); Body rocking and expressionless face (6 items); Nighttime behaviors (3 items); Fear/anxiety (4 items); and Walking/standing (2 items). Caregivers are asked to evaluate each RTT feature based on the current status of the patients on a 3-point scale as 0 ("not true"), 1 ("somewhat or sometimes true"), or 2 ("often true"), with the total score ranging from 0 to 90. Higher scores indicate increased disease severity. Seven items that do not belong under any of the subscales are classed as "uncategorized" but contribute to the overall total score.	From Baseline (Day 1) to Week 14
Clinical Global Impression of Change (CGIC) Score at Week 14	The CGIC is a clinician-rated single item evaluating the degree of improvement or worsening of a participant's condition from Baseline following treatment or intervention. The CGIC uses a 7-point response scale, with the following ratings: "1: Very Much improved", "2: Much improved", "3: Minimally improved", "4: No change", "5: Minimally worse", "6: Much worse", "7: Very Much Worse".	At Week 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline to Week 14 in Patient-Reported Outcomes Measurement Information System-Sleep Disturbance (PROMIS-SD) score	Sleep disturbances will be assessed by the PROMIS-SD parent proxy 8a version. Caregivers are asked to rate 8 items over the past 7 days on a 5-point scale: "1: Never", "2: Almost never", "3: Sometimes", "4: Almost always", and "5: Always", with higher scores indicating more severe sleep disturbances.	From Baseline (Day 1) to Week 14
Change from Baseline to Week 14 in Observer-Reported Communication Ability (ORCA) score	The ORCA is an 84-item, observer-reported measure of communication ability over the past 30 days. The majority of the items included in the ORCA measure have 3 response options: "No or only once," "Sometimes," and "Yes, almost all the time", which enable derivation of an overall communication score and scores for each form of communication (expressive, receptive, and pragmatic), with higher scores indicating greater communication ability.	From Baseline (Day 1) to Week 14
Caregiver Global Impression of Change - Seizure (CaGIC-Seizure) score at Week 14	The CaGIC-Seizure is a caregiver-reported item assessing the change from Baseline in the participant's seizure status. The CaGIC-Seizure uses a 7-point response scale, with the following ratings: "1: Very Much improved", "2: Much improved", "3: Minimally improved", "4: No change", "5: Minimally worse", "6: Much worse", "7: Very Much Worse".	At Week 14
Incidence of Treatment-emergent adverse event (TEAEs)	An AE is any untoward medical occurrence in a clinical study participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment emergent adverse events (TEAEs) are adverse events that are not present prior to the pharmaceutical product administration or an already present event that worsens either in intensity or frequency.	From Baseline (Day 1) up to Week 98
Incidence of serious TEAEs	An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or more of the criteria listed: Results in death; Is life-threatening; Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity; Is a congenital anomaly/birth defect; Other important medical events which based on medical or scientific judgement may jeopardize the patients or may require medical or surgical intervention to prevent any of the above.	From Baseline (Day 1) up to Week 98
Incidence of TEAEs leading to discontinuation	An AE is any untoward medical occurrence in a clinical study participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment emergent adverse events (TEAEs) are adverse events that are not present prior to the pharmaceutical product administration or an already present event that worsens either in intensity or frequency. TEAEs leading to discontinuation will be reported.	From Baseline (Day 1) up to Week 98
Incidence of related TEAEs	An AE is any untoward medical occurrence in a clinical study participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment emergent adverse events (TEAEs) are adverse events that are not present prior to the pharmaceutical product administration or an already present event that worsens either in intensity or frequency. Related TEAEs will be reported.	From Baseline (Day 1) up to Week 98
Change from Baseline in QT interval corrected using Fridericia's formula (QTcF) interval on 12-lead ECG at Week 14	Change from Baseline in QTcF interval as measured by 12-lead ECG at Week 14 will be reported.	At Week 14
Treatment-emergent Doppler Echocardiogram (ECHO) results meeting the Food and Drug Administration (FDA) case definition of drug-associated valvular heart disease (VHD)	The FDA case definition of drug-associated VHD is aortic regurgitation ≥mild and/or mitral regurgitation ≥moderate with restricted valve motion, valve thickening, and/or physical signs or symptoms attributable to valve diseases. ECHO readings related to VHD on any of the 4 valves (aortic, mitral, pulmonary, tricuspid) will be reported with grades of absent, trace, mild, moderate, or severe.	From Baseline (Day 1) up to Week 98
Treatment-emergent Doppler ECHO results meeting the FDA case definition of pulmonary arterial hypertension (PAH) >35mmHg	ECHO readings related to pulmonary arterial hypertension (PAH) on any of the 4 valves (aortic, mitral, pulmonary, tricuspid) will be reported with grades of absent, trace, mild, moderate, or severe.	From Baseline (Day 1) up to Week 98

Collaborators and Investigators

• Sponsor: UCB BIOSCIENCES, Inc.
• Investigators: Study Director: UCB Cares, 0018445992273

Study record dates

Study Major Dates

• Study Start (Estimated): May 31, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): November 15, 2030

Study Registration Dates

• First Submitted: March 25, 2026
• First Submitted That Met QC Criteria: March 25, 2026
• First Posted (Actual): March 31, 2026

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: RTT; Fenfluramine HCl
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, Inborn; Neurobehavioral Manifestations; Heredodegenerative Disorders, Nervous System; Intellectual Disability; Genetic Diseases, X-Linked; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; X-Linked Intellectual Disability; Rett Syndrome; Organic Chemicals; Amines; Phenethylamines; Ethylamines; Fenfluramine
• Other Study ID Numbers: EP0247; 2025-523157-34 (Other Identifier: EU CTR)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal. This plan may change if the risk of re-identifying trial participants is determined to be too high after the trial is completed; in this case and to protect participants, individual patient-level data would not be made available.
• IPD Sharing Time Frame: Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe or global development is discontinued, and 18 months after trial completion.
• IPD Sharing Access Criteria: Qualified researchers may request access to anonymized IPD and redacted study documents which may include: raw datasets, analysis-ready datasets, study protocol, blank case report form, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a pre-specified time, typically 12 months, on a password protected portal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No