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    Clinical Trial Results:
    SAFETY AND EFFICACY OF THN102 ON SLEEPINESS IN NARCOLEPTIC PATIENTS

    Summary
    EudraCT number
    		 2015-005035-41
    Trial protocol
    		 BE  
    Global end of trial date
    28 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Oct 2021
    First version publication date
    09 Oct 2021
    Other versions
    Summary report(s)
    		 THN102-201 clinical study report synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    THN102-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02821715
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Theranexus
    Sponsor organisation address
    86 route de Paris, Orsay, France, 91400
    Public contact
    Werner Rein, Theranexus SA, +33 680 02 67 79 , werner.rein@theranexus.fr
    Scientific contact
    Werner Rein, Theranexus SA, +33 680 02 67 79 , werner.rein@theranexus.fr
    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
    28 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the superiority of THN102 (combination modafinil and flecainide acetate) vs modafinil for improving the residual daytime sleepiness assessed by Epworth Sleepiness Scale (ESS) in patients with narcolepsy treated by modafinil
    Protection of trial subjects
    The study was conducted in accordance with applicable laws and regulations, GCP, and the ethical principles that have their origin in the Declaration of Helsinki. All informed consent forms were compliant with the ICH of Technical Requirements for Pharmaceuticals for Human Use guideline on GCP.
    Background therapy
    		 The double-blind 3-period, 3-treatment cross-over was preceded by a baseline period during which the patients were stabilized to 300 mg modafinil administered as open label. This period aimed to stabilize the patient to the same low dose of modafinil investigated during the double-blind periods while still providing potential improvement in sleep parameters when associated with flecainide. There was no wash-out between any of the study period of the cross-over. After the last period of the cross-over, subjects continued to be dosed with modafinil 300 mg only, as open label for an additional week.
    Evidence for comparator
    		 This study design was selected to demonstrate the superiority of each THN102 treatment, as the combination of 300 mg modafinil associated with two different dose levels of flecainide (3 and 27 mg), as compared to modafinil alone (300 mg, control) and to determine which of the two THN102 treatments had best efficacy as based primarily on ESS parameters. The control condition was modafinil alone i.e. associated with placebo of flecainide to ascertain double-blind conditions.
    Actual start date of recruitment
    20 Oct 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: 4
    Country: Number of subjects enrolled
    France: 47
    Worldwide total number of subjects
    51
    EEA total number of subjects
    51
    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)
    51
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 54 patients were screened, 51 patients were randomized and 48 started the double-blind treatment period

    Pre-assignment
    Screening details
    		 Study starts with open-label run in period with modafinil 300 mg/d. 51 patients met study inclusion/exclusion criteria and entered the run-in period, 48 subjects still fulfilled inclusion criteria after run-in and entered the double-blind period.

    Pre-assignment period milestones
    Number of subjects started
    		 51
    Number of subjects completed
    		 48

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 3
    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Capsules of flecainide or Placebo (in vials) could not be differentiated by either the Investigators or the patients. Modafinil was administered as open label (commercial presentation, capsules in blister) throughout the complete study with no corresponding placebo.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 THN102: 300mg/0mg
    Arm description
    		 Participants received either: A Modafinil 300mg/d/Flecainide placebo, B Modafinil 300mg/d/Flecainide 3mg/d C Modafinil 300mg/d/Flecainide 27mg/d
    Arm type
    		 Active comparator

    Investigational medicinal product name
    THN102: 300mg/0mg (Reference)
    Investigational medicinal product code
    THN102: 300mg/0mg
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg modafinil, total daily dose and placebo of flecainide

    Arm title
    		 THN102: 300mg/3mg
    Arm description
    		 THN102: 300mg/3mg, 300 mg modafinil and 3 mg of flecainide acetate, total daily dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    THN102: 300mg/3mg
    Investigational medicinal product code
    THN102: 300mg/3mg
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    THN102: 300mg/3mg, 300 mg modafinil and 3 mg of flecainide acetate, total daily dose

    Arm title
    		 THN102: 300mg/27mg
    Arm description
    		 THN102: 300mg/27mg
    Arm type
    		 Active comparator

    Investigational medicinal product name
    THN102: 300mg/27mg
    Investigational medicinal product code
    THN102: 300mg/27mg
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    THN102: 300mg/27mg 300 mg modafinil and 27 mg of flecainide acetate, total daily dose

    Number of subjects in period 1
    		THN102: 300mg/0mg THN102: 300mg/3mg THN102: 300mg/27mg
    Started
    48
    48
    48
    Completed
    48
    48
    48

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 51 51
    Age categorical
    The age range of the randomized subjects (n=51) was from 19 to 60 years old at screening (mean of 35.7 years and median of 35.0 years) with 24 men (47%) and 27 women (53%). The BMI range was from 18.00 to 35.80 (mean of 26.753 and median of 26.600). Most of the subjects had diagnostic of narcolepsy Type 1 (n=48, 88%) and 6 subjects (12%) with Type 2 narcolepsy at inclusion; no change of diagnosis (from Type 1 to Type 2) was observed during the study
    Units: Subjects
        Adults (18-64 years)
    		 51 51
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 35.7 ( 9.96 ) -
    Gender categorical
    Units: Subjects
        Female
    		 27 27
        Male
    		 24 24

    End points

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    End points reporting groups
    Reporting group title
    THN102: 300mg/0mg
    Reporting group description
    		 Participants received either: A Modafinil 300mg/d/Flecainide placebo, B Modafinil 300mg/d/Flecainide 3mg/d C Modafinil 300mg/d/Flecainide 27mg/d

    Reporting group title
    THN102: 300mg/3mg
    Reporting group description
    		 THN102: 300mg/3mg, 300 mg modafinil and 3 mg of flecainide acetate, total daily dose

    Reporting group title
    THN102: 300mg/27mg
    Reporting group description
    		 THN102: 300mg/27mg

    Primary: Epworth Sleeping Scale (ESS)

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    End point title
    		 Epworth Sleeping Scale (ESS)
    End point description
    Range of the scale : 0 to 24. A low score indicates a good outcome. Results shown are corresponding to a change from baseline of the ESS score
    End point type
    Primary
    End point timeframe
    14 days after the beginning of treatment period
    End point values
    		 THN102: 300mg/0mg THN102: 300mg/3mg THN102: 300mg/27mg
    Number of subjects analysed
    48
    48
    48
    Units: ESS Score
        least squares mean (standard error)
    14.68 ( 0.689 )
    15.34 ( 0.695 )
    15.34 ( 0.694 )
    Statistical analysis title
    		 THN102 300mg/0mg vs THN102 300mg/3mg
    Comparison groups
    THN102: 300mg/0mg v THN102: 300mg/3mg v THN102: 300mg/27mg
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.319
    Method
    		 mixed linear regression modeL
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.97
         upper limit
    		 0.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.658

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected for each 2 week treatment period during the 3 crossover periods.
    Adverse event reporting additional description
    Adverse events were collected by investigator - open question to patient. No scale or questionnaire based collection of events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    THN102:300mg/0mg
    Reporting group description
    		 -

    Reporting group title
    THN102:300mg/3mg
    Reporting group description
    		 -

    Reporting group title
    THN102:300mg/27mg
    Reporting group description
    		 -

    Serious adverse events
    		 THN102:300mg/0mg THN102:300mg/3mg THN102:300mg/27mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 THN102:300mg/0mg THN102:300mg/3mg THN102:300mg/27mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 48 (18.75%)
    15 / 48 (31.25%)
    13 / 48 (27.08%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    Hunger
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    1
    Sluggishness
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    1
    Nightmare
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    violence related symptom
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Palpitation
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    1
    0
    2
    Dysgeusia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 48 (4.17%)
    1 / 48 (2.08%)
         occurrences all number
    2
    2
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Chalazion
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    abdominal upper pain
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    1
    Dry mouth
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    1
    Toothache
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 48 (4.17%)
    0 / 48 (0.00%)
         occurrences all number
    0
    2
    0
    Influenza
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 48 (4.17%)
    0 / 48 (0.00%)
         occurrences all number
    0
    2
    0
    Laryngitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 48 (4.17%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    2
    Tracheitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Pain in extremity
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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