Rett Syndrome
Conditions
Keywords
Fenfluramine HCl, RTT
Brief summary
The purpose of this study is to investigate the efficacy of fenfluramine hydrochloride (HCl) versus placebo in study participants with Rett syndrome (RTT).
Interventions
Oral solution
OTHERPlacebo
Oral solution
Sponsors
UCB BIOSCIENCES, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
The study consists of a Double-Blind and an Open-Label (OL) Intervention Period. During OL Intervention Period, the sponsor, participants, caregivers, and Investigators will be unblinded to treatment assignment.
Eligibility
Sex/Gender
ALL
Age
5 Years to 35 Years
Healthy volunteers
No
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 or deletion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression of Change (CGIC) Score at Week 14 | 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". |
| Change from Baseline to Week 14 in Rett Syndrome Behaviour Questionnaire (RSBQ) Total Score | From Baseline (Day 1) to Week 14 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of serious TEAEs during the double-blind intervention period | From Baseline (Day 1) up to Week 14 | 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. |
| Incidence of TEAEs leading to discontinuation during the double-blind intervention period | From Baseline (Day 1) up to Week 14 | 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. |
| Incidence of related TEAEs during the double-blind intervention period | From Baseline (Day 1) up to Week 14 | 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. |
| Change from Baseline in QT interval corrected using Fridericia's formula (QTcF) interval on 12-lead ECG by visit during the double-blind intervention period | From Baseline (Day 1) up to Week 14 | Change from Baseline in QTcF interval as measured by 12-lead ECG up to Week 14 by visit will be reported |
| Change from Baseline to Week 14 in Patient-Reported Outcomes Measurement Information System-Sleep Disturbance (PROMIS-SD) score | From Baseline (Day 1) to Week 14 | 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. |
| Change from Baseline to Week 14 in Observer-Reported Communication Ability (ORCA) score | From Baseline (Day 1) to Week 14 | 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. |
| Incidence of treatment-emergent Doppler Echocardiogram (ECHO) results meeting the Food and Drug Administration (FDA) case definition of drug-associated valvular heart disease (VHD) during the double-blind intervention period | From Baseline (Day 1) up to Week 14 | 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. |
| Incidence of treatment-emergent Doppler ECHO results meeting the FDA case definition of PAH (defined as a PASP >35mmHg) during the double-blind intervention period | From Baseline (Day 1) up to Week 14 | ECHO readings related to pulmonary arterial hypertenstion (PAH) will be reported based on Pulmonary artery systolic pressure (PASP). |
| Incidence of treatment-emergent adverse events (TEAEs) from baseline to end of safety follow up | From Baseline (Day1) to the End of Safety Follow Up (up to 3 years and 10 months) | 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. |
| Incidence of serious TEAEs from baseline to end of safety follow up | From Baseline (Day1) to the End of Safety Follow Up (up to 3 years and 10 months) | 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. |
| Incidence of TEAEs leading to discontinuation from baseline to end of safety follow up | From Baseline (Day1) to the End of Safety Follow Up (up to 3 years and 10 months) | 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. |
| Incidence of related TEAEs from baseline to end of safety follow up | From Baseline (Day1) to the End of Safety Follow Up (up to 3 years and 10 months) | 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. |
| Change from Baseline in QT interval corrected using Fridericia's formula (QTcF) interval on 12-lead ECG by visit from baseline to end of safety follow up | From Baseline (Day1) to the End of Safety Follow Up (up to 3 years and 10 months) | Change from Baseline in QTcF interval as measured by 12-lead ECG up to Week 98 by visit will be reported |
| Incidence of treatment-emergent Doppler Echocardiogram (ECHO) results meeting the Food and Drug Administration (FDA) case definition of drug-associated valvular heart disease (VHD) from baseline to end of safety follow up | From Baseline (Day1) to the End of Safety Follow Up (up to 3 years and 10 months) | 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. |
| Caregiver Global Impression of Change - Seizure (CaGIC-Seizure) score at Week 14 | 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". |
| Incidence of treatment-emergent Doppler ECHO results meeting the FDA case definition of PAH (defined as a PASP >35mmHg) from baseline to end of safety follow up | From Baseline (Day1) to the End of Safety Follow Up (up to 3 years and 10 months) | ECHO readings related to pulmonary arterial hypertenstion (PAH) will be reported based on Pulmonary artery systolic pressure (PASP). |
| Incidence of treatment-emergent adverse events (TEAEs) during the double-blind intervention period | From Baseline (Day 1) up to Week 14 | 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. |
Countries
Belgium, France, Hungary, Italy, Japan, Poland, Spain, United States
Contacts
CONTACTUCB Cares
STUDY_DIRECTORUCB Cares
0018445992273
Outcome results
None listed