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    Clinical Trial Results:
    Add-on therapy with low dose fenfluramine in Lennox Gastaut epilepsy

    Summary
    EudraCT number
    		 2015-004008-46
    Trial protocol
    		 BE  
    Global end of trial date
    19 Jul 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jan 2025
    First version publication date
    30 Jan 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FFA-LGS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZ Leuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Lieven Lagae, UZ Leuven, lieven.lagae@uzleuven.be
    Scientific contact
    Lieven Lagae, UZ Leuven, lieven.lagae@uzleuven.be
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To study the potential effect of add-on fenfluramine in refractory Lennox Gastaut epilepsy. ( exploratory dose finding add-on trial). - Dose finding study add on low dose FFA (0,2 or 0,4 or 0,8 mg/kg/day, max 30 mg/day) - Number of responders at each dosage (responder : min 50 % decrease of nr of seizures per 4 weeks compared to baseline period) - Safety of low dose FFA
    Protection of trial subjects
    To minimize stress and pain during blood collections in pediatric study subjects, a combination of psychological and physical strategies is employed. Distraction techniques such as cartoons, toys, or virtual reality headsets help divert the child’s attention, reducing anxiety and perceived discomfort. Topical anesthetics, like numbing creams or sprays, are applied to the skin to desensitize the area before needle insertion. For added comfort, vibrating cold pads or other pain-relief devices may be used near the site to confuse nerve signals and further reduce pain. Staff are trained to use gentle, child-centered communication to reassure and guide the child through the procedure, and allowing parents to be present provides an additional layer of emotional support. These methods collectively ensure that blood collection is as stress-free and painless as possible. To avoid stress during other assessments such as ECG, echo and collection of vital signs, we made sure the communication was gentle and child-centered and that
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    13
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    7
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was recruited on 22 MAR 2016 and the last patient on 20 JUL 2016. A phase 3 study was initiated during this trial and therefore the recruitment officially ended on 6 OCT 2017. The last follow-up visit of the remaining subjects took place in JUL 2024.

    Pre-assignment
    Screening details
    		 1. Electro-clinical epilepsy syndrome compatible with Lennox Gastaut syndrome 2. Drug resistant: at least 4 documented seizures in the last 4 weeks before inclusion 3. Age between 3 and 18 years All the subjects that were screened were enrolled in the study.

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not blinded.

    Arms
    Arm title
    		 Baseline
    Arm description
    		 -
    Arm type
    		 no intervention

    Investigational medicinal product name
    No product
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Auricular use
    Dosage and administration details
    No product

    Number of subjects in period 1
    		Baseline
    Started
    13
    Completed
    13
    Period 2
    Period 2 title
    Overall trial
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IMP dosing
    Arm description
    		 Dosing IMP: starting dosage 0.2 mg/kg/day BID; second step: 0.4 mg/kg/day BID; max dosage 0.8 mg/kg/day BID or 30 mg/day BID. Review of epileptic seizures is performed on each milestone and IMP dose increases if subject is non-responder (< 50% reduction of total number of clinically observable seizures with a motor component (GTC or/and TS or/and AS or/and M or/and FS) compared to baseline).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fenfluramine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    Oral solution of fenfluramine (2.5 mg/mL) Dosage: starting dosage 0.2 mg/kg/day BID; second step: 0.4 mg/kg/day BID; max dosage 0.8 mg/kg/day BID or 30 mg/day BID

    Number of subjects in period 2
    		IMP dosing
    Started
    13
    Week 8
    13
    Week 12
    13
    Week 16
    10
    Completed
    10
    Not completed
    3
         Adverse event, non-fatal
    1
         Lack of efficacy
    2
    Period 3
    Period 3 title
    Extension period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Dosing IMP
    Arm description
    		 Dosing IMP: continuing at IMP dose of end of overall study period (0.2 mg/kg/day BID, 0.4 mg/kg/day BID or 0.8 mg/kg/day BID (max 30 mg/day BID)). Review of epileptic seizures is performed every 3 month. If subject is non-responder (< 50% reduction of total number of clinically observable seizures with a motor component (GTC or/and TS or/and AS or/and M or/and FS) compared to baseline), subjects are excluded from the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fenfluramine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    Oral solution of fenfluramine (2.5 mg/mL) Continuation of dose of overall study period (0.2 mg/kg/day BID, 0.4 mg/kg/day BID or max dosage 0.8 mg/kg/day BID or 30 mg/day BID)

    Number of subjects in period 3 [1]
    		Dosing IMP
    Started
    9
    Completed
    2
    Not completed
    7
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    1
         Lack of efficacy
    4
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 1 subject completed the overall study but chose to not enter the extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline period
    Reporting group description
    		 Collecting baseline seizure frequency for each subject for 4 weeks. This number will be used to compare the seizure frequency with in the next phase of the trial. Drug regimen will remain stable during baseline.

    Reporting group values
    		 Baseline period Total
    Number of subjects
    		 13 13
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 7 7
        Adolescents (12-17 years)
    		 6 6
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.7 ( 4.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 9 9
    Lennox Gastaut epilepsy etiology
    Units: Subjects
        genetic
    		 4 4
        structural
    		 2 2
        unknown
    		 7 7
    Presence of atonic seizures/drop attacks
    Units: Subjects
        present
    		 9 9
        absent
    		 4 4
    seizure frequency
    baseline median seizure frequency per month including multiple seizures types (ie, combinations of tonic, generalized tonic–clonic, myoclonic, absence, and atonic seizures/drop attacks)
    Units: unit(s)
        median (full range (min-max))
    		 61 (21 to 1360) -
    Weight
    Units: kilogram(s)
        median (standard deviation)
    		 45.4 ( 20.2 ) -
    Amount of failed antiepileptic treatments
    Amount of failed antiepileptic treatments
    Units: unit(s)
        median (full range (min-max))
    		 5 (3 to 7) -
    medication treatment duration
    Units: year
        median (full range (min-max))
    		 8 (2 to 15) -
    Amount of current antiepileptic treatments
    Units: unit(s)
        median (full range (min-max))
    		 4 (2 to 4) -

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -
    Reporting group title
    IMP dosing
    Reporting group description
    		 Dosing IMP: starting dosage 0.2 mg/kg/day BID; second step: 0.4 mg/kg/day BID; max dosage 0.8 mg/kg/day BID or 30 mg/day BID. Review of epileptic seizures is performed on each milestone and IMP dose increases if subject is non-responder (< 50% reduction of total number of clinically observable seizures with a motor component (GTC or/and TS or/and AS or/and M or/and FS) compared to baseline).
    Reporting group title
    Dosing IMP
    Reporting group description
    		 Dosing IMP: continuing at IMP dose of end of overall study period (0.2 mg/kg/day BID, 0.4 mg/kg/day BID or 0.8 mg/kg/day BID (max 30 mg/day BID)). Review of epileptic seizures is performed every 3 month. If subject is non-responder (< 50% reduction of total number of clinically observable seizures with a motor component (GTC or/and TS or/and AS or/and M or/and FS) compared to baseline), subjects are excluded from the study.

    Primary: ≥50% reduction in median CS frequency

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    End point title
    		 ≥50% reduction in median CS frequency [1]
    End point description
    End point type
    Primary
    End point timeframe
    In the 20 weeks of IMP treatment.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No specific statistical analyses are used, except for medians and percentages.
    End point values
    		 IMP dosing
    Number of subjects analysed
    13
    Units: %
    62
    No statistical analyses for this end point

    Secondary: Convulsive seizure frequency per month at the last visit

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    End point title
    		 Convulsive seizure frequency per month at the last visit
    End point description
    Median seizure frequency at the last visit for the intent‐to‐treat study population (N = 13)
    End point type
    Secondary
    End point timeframe
    Seizure frequency at the last visit
    End point values
    		 IMP dosing
    Number of subjects analysed
    13
    Units: unit(s)
        median (full range (min-max))
    31 (2 to 890)
    No statistical analyses for this end point

    Secondary: Reduction in convulsive seizure frequency

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    End point title
    		 Reduction in convulsive seizure frequency
    End point description
    End point type
    Secondary
    End point timeframe
    Median reduction seizure frequency at the last visit compared with baseline for the intent‐to‐treat study population.
    End point values
    		 IMP dosing
    Number of subjects analysed
    13
    Units: %
    53
    No statistical analyses for this end point

    Secondary: Convulsive seizure frequency per month at the last visit in patients who completed 20 weeks of IMP treatment

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    End point title
    		 Convulsive seizure frequency per month at the last visit in patients who completed 20 weeks of IMP treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Mean reduction in convulsive seizure frequency at the last visit compared to the baseline in the patients who completed 20 weeks of IMP treatment.
    End point values
    		 IMP dosing
    Number of subjects analysed
    10
    Units: unit(s)
        median (full range (min-max))
    22 (2 to 136)
    No statistical analyses for this end point

    Secondary: Reduction of convulsive seizures at the last visit in patients who completed 20 weeks of IMP treatment

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    End point title
    		 Reduction of convulsive seizures at the last visit in patients who completed 20 weeks of IMP treatment
    End point description
    End point type
    Secondary
    End point timeframe
    The value of the last visit in patients who completed 20 weeks of IMP treatment was compared with baseline.
    End point values
    		 IMP dosing
    Number of subjects analysed
    10
    Units: %
    60
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Possibly related adverse event reported from baseline period, the overall study and extension period until 15 months.
    Adverse event reporting additional description
    Adverse events were reported during every visit and self-reporting by participants
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 UZ Leuven guidelines
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Fenfluramin
    Reporting group description
    		 -

    Serious adverse events
    		 Fenfluramin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Fenfluramin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 13 (46.15%)
    Nervous system disorders
    Decreased alertness
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Sleepiness
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jan 2016
    Adding template of epileptic seizure diary.
    08 Mar 2016
    - Adding recruitment letter to send to potential families. - Adding Sub-I. - Updated investigator brouchure. - Adjustments to the protocol: - Adding information on how to deal with subjects with reproductive potential (adding pregnancy tests, information on sperm and egg donation and contraception use,...) - Adding prohibited food consumptions (grapefruit and seville oranges) - Adding prohibited concomitant medication (felbamate, drugs that interact with central serotonin and drugs that potentially interact with fenfluramin via CYP2D6, CYP3A4 and/or CYP2B6 pathways)
    25 Aug 2017
    Changes to the protocol: - Adding information on not completing ICF's on subjects that become 18 years during the clinical study since they are mentally not capable to. - Adding information on changing the IMP dose in case of adverse events - Adding the possibility on continuing IMP dosing when the subject is a non-responder but has an effect on the severity and/or duration of the epileptic seizures. - Adding the possibility to change the IMP dose in the extension phase regardless of the fact that the subject is a responder or not. - Adding the possibility for non-responder subjects to enter the extension phase - Updating the flowchart for the extension phase so that safety blood samples, blood AED levels and cardiac evaluation are not necessary each visit.
    24 Apr 2018
    Clarifications in the study protocol: - On each on site visit the convulsive seizures are counted starting 28 days before the on site study visit. - Frequency of cardiologic assessments (ECG and echo) and blood collections in the extension period are performed at descretion of the PI but once a year at minimum. - AED levels are determined in the standard of care clinical follow-up. - Visit window of extension phase study visit is 3 months +/- 2 weeks. - Harmonizing seizure type abbreviations. - Dose adjustments during the extension phase are respons/effect dependant with a dose of minimum 0.1 mg/kg/day and a maximum of 30 mg/day. Reasons for dose adjustments need to be document in the source documents and CRF.
    09 Aug 2019
    As part of the European General Data Protection Regulation (GDPR), which has been in force since May 2018, an information letter will be prepared to inform (by phone and/or email) study patients, who are still participating in the study after May 2018, how their personal data will be managed, stored and used.
    13 Feb 2020
    New version of investigator brochure.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This study is limited by the small sample size and lack of a placebo control group.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30146701
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