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    Clinical Trial Results:
    An Open-Label, Multicenter, Extension Study to Evaluate the Safety and Efficacy of Padsevonil as Adjunctive Treatment of Focal-Onset Seizures in Adult Subjects with Drug-Resistant Epilepsy

    Summary
    EudraCT number
    2017-003241-26
    Trial protocol
    GB   DE   HU   ES   CZ   BG   FR   LT   BE   PT   EE   NL   DK   AT   GR   FI   NO   SE   HR   IT   RO  
    Global end of trial date
    22 Dec 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Dec 2021
    First version publication date
    16 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EP0093
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03370120
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Biopharma SRL
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, 1070
    Public contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    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
    19 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the long-term safety and tolerability of padsevonil administered at individualized doses as adjunctive treatment for subjects with focal-onset seizures and drug-resistant epilepsy.
    Protection of trial subjects
    During the conduct of the study all participants were closely monitored.
    Background therapy
    Background therapy as permitted in the protocol.
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 4
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Czechia: 24
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Japan: 33
    Country: Number of subjects enrolled
    Lithuania: 9
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Poland: 32
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Spain: 50
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    United States: 41
    Country: Number of subjects enrolled
    Bulgaria: 44
    Country: Number of subjects enrolled
    Ireland: 1
    Worldwide total number of subjects
    406
    EEA total number of subjects
    284
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    395
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study started to enroll study participants in August 2018 and concluded in December 2020.

    Pre-assignment
    Screening details
    Participant Flow refers to the Safety Set. Participants who had completed a padsevonil (PSL) parent study (EP0091 [NCT03373383] or EP0092 [NCT03739840]) were enrolled in this study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Padsevonil
    Arm description
    Participants received padsevonil tablets at a dose of 100 milligrams/day (mg/day) to 800 mg/day up to approximately 2 years.
    Arm type
    Experimental

    Investigational medicinal product name
    UCB0942
    Investigational medicinal product code
    Other name
    PSL
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received padsevonil tablets at a dose of 100 mg/day to 800 mg/day up to approximately 2 years.

    Number of subjects in period 1
    Padsevonil
    Started
    406
    Completed
    0
    Not completed
    406
         End of sponsor decision
    1
         Lack of efficacy
    37
         Per sponsor's instructions
    1
         Trial terminated by sponsor
    2
         Early termination of studies
    5
         The study was interrupted by sponsor
    4
         Sponsor prematurely terminated this study
    2
         End of project
    4
         Study ended prematurely
    1
         Early termination by order of sponsor
    2
         The study was ended by the promoter
    3
         Sponsor study closure
    10
         Clinical trial has been cancelled
    1
         End of clinical trial discontinuation
    1
         The protocol was interrupted by sponsor
    1
         Study terminated by sponsor
    33
         Consent withdrawn by subject
    6
         Promoter ended the study
    3
         The trial has been suspended
    3
         The study was terminated prematurely by study lead
    1
         Sponsor stopped PSL development based on data
    3
         Premature program termination
    1
         Discontinuation of the study
    5
         Padsenovil program closed
    3
         Study stopped by sponsor
    2
         Development discontinued
    5
         Because the clinical trial ended halfway
    4
         Lost to follow-up
    1
         Decision of sponsor
    6
         Sponsor decision
    62
         Sponsor decision to stop the protocol
    1
         Promoter's decision
    2
         Adverse event, non-fatal
    24
         Program closure
    3
         Study ended
    15
         End of padsevonil program
    2
         Study was terminated by parent company UCB
    2
         Trial discontinued by sponsor
    2
         This study is ended early
    1
         Asked by the sponsor
    3
         End of study per sponsor decision
    2
         Premature study close by sponsor's decision
    4
         PI decision poor compliance from participant
    1
         Sponsor decision to terminate study
    63
         Premature study closure
    2
         Premature study termination
    7
         Termination of project
    1
         Program termination
    55
         Discontinuation of drug development
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Padsevonil
    Reporting group description
    Participants received padsevonil tablets at a dose of 100 milligrams/day (mg/day) to 800 mg/day up to approximately 2 years.

    Reporting group values
    Padsevonil Total
    Number of subjects
    406 406
    Age Categorical
    Units: participants
        <=18 years
    0 0
        Between 18 and 65 years
    395 395
        >=65 years
    11 11
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    40.8 ± 12.5 -
    Sex: Female, Male
    Units: participants
        Female
    231 231
        Male
    175 175

    End points

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    End points reporting groups
    Reporting group title
    Padsevonil
    Reporting group description
    Participants received padsevonil tablets at a dose of 100 milligrams/day (mg/day) to 800 mg/day up to approximately 2 years.

    Subject analysis set title
    Padsevonil (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received PSL tablets at a dose of 100 mg/day to 800 mg/day up to approximately 2 years. Participants formed the Safety Set (SS).

    Subject analysis set title
    Padsevonil (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received PSL tablets at a dose of 100 mg/day to 800 mg/day up to approximately 2 years. Participants formed the Full Analysis Set (FAS).

    Primary: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) reported by the participant and/or caregiver or observed by the investigator during the entire study

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    End point title
    Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) reported by the participant and/or caregiver or observed by the investigator during the entire study [1]
    End point description
    An Adverse Event is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any event that was not present prior to the initiation of the first dose of study treatment in this study or any unresolved event already present before initiation of the first dose that worsens in intensity following exposure to the treatment. The SS consisted of all enrolled participants who were administered at least 1 dose of PSL, based on the first dose date from the first administration of study medication Case Report Form (CRF).
    End point type
    Primary
    End point timeframe
    From Entry Visit (Week 0) until the Safety Follow-up Visit (up to approximately 2 years)
    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: Please note that this is an open label study with only 1 treatment arm. Thus no statistical comparison is possible.
    End point values
    Padsevonil (SS)
    Number of subjects analysed
    406
    Units: percentage of participants
        number (not applicable)
    72.2
    No statistical analyses for this end point

    Primary: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) leading to study withdrawal

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    End point title
    Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) leading to study withdrawal [2]
    End point description
    An Adverse Event is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any event that was not present prior to the initiation of the first dose of study treatment in this study or any unresolved event already present before initiation of the first dose that worsens in intensity following exposure to the treatment. The SS consisted of all enrolled participants who were administered at least 1 dose of PSL, based on the first dose date from the first administration of study medication CRF.
    End point type
    Primary
    End point timeframe
    From Entry Visit (Week 0) until the Safety Follow-up Visit (up to approximately 2 years)
    Notes
    [2] - 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: Please note that this is an open label study with only 1 treatment arm. Thus no statistical comparison is possible.
    End point values
    Padsevonil (SS)
    Number of subjects analysed
    406
    Units: percentage of participants
        number (not applicable)
    5.2
    No statistical analyses for this end point

    Primary: Change from Baseline (from the respective parent study [EP0091 or EP0092]) in observable focal-onset seizure frequency over the Evaluation Period

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    End point title
    Change from Baseline (from the respective parent study [EP0091 or EP0092]) in observable focal-onset seizure frequency over the Evaluation Period [3]
    End point description
    Seizure frequency refers to 28-day adjusted frequency. Observable focal-onset seizures refer to Type IAl, IB, and IC (according to the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures, 1981). Focal-onset seizures include all Type I seizures. FAS consisted of all enrolled participants who were administered at least 1 dose of PSL or a partial dose of PSL and completed at least 1 seizure diary during the Evaluation Period.
    End point type
    Primary
    End point timeframe
    From Baseline in respective parent study over the Evaluation Period (up to approximately 2 years) in this study
    Notes
    [3] - 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: Please note that this is an open label study with only 1 treatment arm. Thus no statistical comparison is possible.
    End point values
    Padsevonil (FAS)
    Number of subjects analysed
    406
    Units: seizures per 28 days
        arithmetic mean (standard deviation)
    -7.73 ± 27.52
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Entry Visit (Week 0) until the Safety Follow-up Visit (up to approximately 2 years)
    Adverse event reporting additional description
    A TEAE was defined as any event that was not present prior to the initiation of the first dose of study treatment in this study or any unresolved event already present before initiation of the first dose that worsens in intensity following exposure to the treatment.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Padsevonil (SS)
    Reporting group description
    Participants received PSL tablets at a dose of 100 mg/day to 800 mg/day up to approximately 2 years. Participants formed the SS.

    Serious adverse events
    Padsevonil (SS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 406 (11.82%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Vagal nerve stimulator implantation
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Phyllodes tumour
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Mycoplasma test positive
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cervical radiculopathy
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    7 / 406 (1.72%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    5 / 406 (1.23%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    4 / 406 (0.99%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Postictal state
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure cluster
         subjects affected / exposed
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Status epilepticus
         subjects affected / exposed
    5 / 406 (1.23%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal discomfort
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvi-ureteric obstruction
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug Eruption
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Corona virus infection
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Padsevonil (SS)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    184 / 406 (45.32%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    66 / 406 (16.26%)
         occurrences all number
    76
    Headache
         subjects affected / exposed
    59 / 406 (14.53%)
         occurrences all number
    138
    Dizziness
         subjects affected / exposed
    43 / 406 (10.59%)
         occurrences all number
    63
    Memory impairment
         subjects affected / exposed
    21 / 406 (5.17%)
         occurrences all number
    38
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    47 / 406 (11.58%)
         occurrences all number
    56
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    23 / 406 (5.67%)
         occurrences all number
    27
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    29 / 406 (7.14%)
         occurrences all number
    42

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Oct 2018
    The following major changes were introduced in Protocol Amendment 1 dated 26 Oct 2018: • The original protocol allowed study participants without access to a Managed Access Plan to continue participation in EP0093 after the second year and until a Marketing Authorization was granted by any health authority for the adjunctive treatment of FOS in adults with drug-resistant epilepsy. This amendment limited the duration of participation of all study participants to 2 years. Study participants without access to a Managed Access Plan were offered the option to transfer to another study if approved by the relevant country agencies. • The number of sites increased from 150 to approximately 350. • The proposed indication statement was modified (drug-resistant was removed). • The study objectives specified that study participants had FOS as well as drug-resistant epilepsy. • In the analysis of the primary efficacy variable, the observable FOS frequency instead of the log-transformed observable FOS frequency was measured. • The “other” efficacy variable, time to discontinuation, was added. • It was specified that follow-up echocardiograms at 1 and 6 months after the last PSL intake were required. • China was added to the anticipated regions and countries in which the study was conducted. • The Schedule of Study Assessments was revised consistent with the main change in the amendment. This included a split of the EDV and EOT (called End of Study) visits into separate visits. • Valvular abnormality grading criteria, withdrawal criterion pertaining to echocardiographic findings, description of the measurements and observations included in the echocardiograms, laboratory measurements and prohibited concomitant treatments were made consistent with the feeder studies. • The prohibited concomitant treatments were revised to make them consistent with the feeder studies.
    26 Oct 2018
    Continuation of Protocol Amendment 1 • A clarification of the description of the interpretation of echocardiograms was made. The local physician was required to examine the echocardiograms for suitability for central reading and for determination if an expedited review by the central reader was required. It was made explicit that the central reader is a cardiologist. • The Treatment Satisfaction Questionnaire for Medication (TSQM)-9 was added to study assessments. • A preference was specified for the QOLIE-31-P, SSG, and HADS questionnaires to be completed by the study participants. However, assistance from the study staff or caregiver was permitted.
    04 Feb 2020
    The following major changes were introduced in Protocol Amendment 2 dated 04 Feb 2020: • The primary rationale for this global amendment was to update the name of the legal form of the Sponsor, UCB Biopharma. Belgium adopted a new Code of Companies and Associations, resulting in a mandatory change of the name of the legal form of the entity “société privée à responsabilité limitée”, abbreviated “SPRL”, to “société à responsabilité limitée”, abbreviated “SRL”. This change did not involve any change to the legal form itself, and the company name, company number and VAT number of UCB Biopharma remained the same. • A benefit risk assessment to comply with Section 6 of the ICH-GCP was added. • The specified dosage of 400mg/day as starting dose was deleted to allow more flexibility when adding further parent studies. The individual starting dose of each study participant was the one recommended at the end of the parent study.
    20 May 2020
    Protocol Amendment 2 Addendum A dated 20 May 2020 was introduced in Bulgaria, Finland, France, and Norway due to the exceptional circumstances of the evolving COVID-19 pandemic. UCB proposed to implement measures to reduce the impact on the local health care provision and reduce the inherent risk of study driven hospital/site visits. For details on the visit schedule, drug accountability, and Investigational Medicinal Product (IMP) distribution under exceptional circumstances, see Protocol Amendment 2 Addendum A.

    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.
    None reported
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