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    Clinical Trial Results:
    Evaluation of the efficiency of folinic acid in children with autism spectrum disorders: a pilot study "EFFET"

    Summary
    EudraCT number
    		 2015-000955-25
    Trial protocol
    		 FR  
    Global end of trial date
    31 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Feb 2023
    First version publication date
    23 Feb 2023
    Other versions
    Summary report(s)
    		 EFFET_Article-Abstract

    Trial information

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    Trial identification
    Sponsor protocol code
    PSS2015/EFFET-LEHEUP/SKJ
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02551380
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CHRU Nancy
    Sponsor organisation address
    Rue du MORVAN, Vandoeuvre les Nancy, France, 54511
    Public contact
    El Mehdi SIAGHY, Délégation à la Recherche clinique et à l'Innovation, 0033 383155285, dripromoteur@chru-nancy.fr
    Scientific contact
    El Mehdi SIAGHY, Délégation à la Recherche clinique et à l'Innovation, 0033 383155285, dripromoteur@chru-nancy.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
    31 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the efficiencyof folinic acid, as folinate calicum (FOLINORAL®) 5 mg two times a day during 12 weeks, on the reduction of autism disorder especially on the communication and social interactions.
    Protection of trial subjects
    No specific protection mesures were set for the study
    Background therapy
    		 No curative medical treatment are available in children with autism sprectrum disorders. Children beneficit of psychotherapy and reeducative care (speech therapy, psychomotricity...).
    Evidence for comparator
    		 Placebo
    Actual start date of recruitment
    02 Oct 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    19
    Adolescents (12-17 years)
    0
    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
    		 Date of start: 02/10/2015 Date of last visit of last participated patient: 31/08/2018 Place of recruitment: FRANCE/ CHRU Nancy/ Médecine infantile et génétique clinique

    Pre-assignment
    Screening details
    		 Children aged 3 to 10 years with autism spectrum disorders defined by : Autism Diagnostic Observation Schedule (ADOS), Autism Diagnostic Interview (ADI), Childhood Autism Rating Scale (CARS) or diagnosed by a physician (pediatrician, child psychiatrist)

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 folinic acid group
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Calcium Folinate, 5mg
    Investigational medicinal product code
    Marketing authorisation number: 3400933073770
    Other name
    FOLINORAL® or Calcium Folinate Pentahydrate
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Buccal use
    Dosage and administration details
    Calcium Folinate, 10 mg per day

    Arm title
    		 placebo group
    Arm description
    		 Lactose
    Arm type
    		 Placebo

    Investigational medicinal product name
    lactose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Buccal use
    Dosage and administration details
    capsule of lactose twice a day

    Number of subjects in period 1
    		folinic acid group placebo group
    Started
    9
    10
    Completed
    9
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    folinic acid group
    Reporting group description
    		 -

    Reporting group title
    placebo group
    Reporting group description
    		 Lactose

    Reporting group values
    		 folinic acid group placebo group Total
    Number of subjects
    		 9 10 19
    Age categorical
    mean age of patient 6 years 2 months +/- 2 years old (min 3 years, max 10 years old)
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 9 10 19
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        children
    		 0 0 0
    Age continuous
    Units: months
        median (standard deviation)
    		 65.3 ( 27 ) 67.5 ( 28.8 ) -
    Gender categorical
    4 girls et 15 boys
    Units: Subjects
        Female
    		 3 1 4
        Male
    		 6 9 15
    ADOS score
    ADOS score at baseline
    Units: points
        arithmetic mean (standard deviation)
    		 16.8 ( 4.4 ) 16.3 ( 3.2 ) -
    SRS score at baseline
    Units: points
        arithmetic mean (standard deviation)
    		 92.2 ( 13.6 ) 93.4 ( 16 ) -
    ADOS score Week 12
    Units: points
        arithmetic mean (standard deviation)
    		 14 ( 5 ) 15.9 ( 3.7 ) -
    SRS score week 12
    Units: points
        arithmetic mean (standard deviation)
    		 83.9 ( 14.6 ) 85.5 ( 16.3 ) -
    serum folates at weeks 12
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 123.1 ( 83.3 ) 31.4 ( 31.2 ) -
    Blocking FRA antibodies at T0
    Units: pmol/mL
        arithmetic mean (standard deviation)
    		 1 ( 2.2 ) 1.3 ( 2.1 ) -
    Subject analysis sets

    Subject analysis set title
    XXX
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The analyses were conducted successively in intention-to-treat and per protocol.

    Subject analysis sets values
    		 XXX
    Number of subjects
    19
    Age categorical
    mean age of patient 6 years 2 months +/- 2 years old (min 3 years, max 10 years old)
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    19
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
        children
    0
    Age continuous
    Units: months
        median (standard deviation)
    66.3 ( 27.2 )
    Gender categorical
    4 girls et 15 boys
    Units: Subjects
        Female
    4
        Male
    15
    ADOS score
    ADOS score at baseline
    Units: points
        arithmetic mean (standard deviation)
    16,5 ( 3.7 )
    SRS score at baseline
    Units: points
        arithmetic mean (standard deviation)
    92.3 ( 14.5 )
    ADOS score Week 12
    Units: points
        arithmetic mean (standard deviation)
    15 ( 4.3 )
    SRS score week 12
    Units: points
        arithmetic mean (standard deviation)
    84.7 ( 15 )
    serum folates at weeks 12
    Units: nmol/L
        arithmetic mean (standard deviation)
    123 ( 83 )
    Blocking FRA antibodies at T0
    Units: pmol/mL
        arithmetic mean (standard deviation)
    ( )

    End points

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    End points reporting groups
    Reporting group title
    folinic acid group
    Reporting group description
    		 -

    Reporting group title
    placebo group
    Reporting group description
    		 Lactose

    Subject analysis set title
    XXX
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The analyses were conducted successively in intention-to-treat and per protocol.

    Primary: ADOS score evolution

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    End point title
    		 ADOS score evolution
    End point description
    End point type
    Primary
    End point timeframe
    ADOS score evolution between T0 and Week 12 of treatment
    End point values
    		 folinic acid group placebo group
    Number of subjects analysed
    9
    10
    Units: points
        arithmetic mean (standard deviation)
    -2.8 ( 1.9 )
    -0.4 ( 2.2 )
    Statistical analysis title
    		 statiscal comparison between groups
    Comparison groups
    folinic acid group v placebo group
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Variability estimate
    Standard deviation

    Secondary: ADOS social interaction score evolution

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    End point title
    		 ADOS social interaction score evolution
    End point description
    in folinic acid group : mean score evolution -1.8 (1.3) versus 0.2 (0.2 sd) p= 0.19
    End point type
    Secondary
    End point timeframe
    evolution between baseline and weeks 12 of treatment
    End point values
    		 folinic acid group placebo group
    Number of subjects analysed
    9
    10
    Units: points
        arithmetic mean (standard deviation)
    -1.8 ( 1.3 )
    0.2 ( 2.2 )
    Statistical analysis title
    		 statiscal comparison between groups
    Comparison groups
    folinic acid group v placebo group
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Secondary: ADOS communication score evolution

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    End point title
    		 ADOS communication score evolution
    End point description
    Mean ADOS communication score : in folinic acid group -1.2 (1.3 SD), versus in placebo group -0.4 (1.1sd) ; p =0.02
    End point type
    Secondary
    End point timeframe
    between baseline T0 and W12
    End point values
    		 folinic acid group placebo group
    Number of subjects analysed
    9
    10
    Units: points
        arithmetic mean (standard deviation)
    -1.2 ( 1.3 )
    -0.4 ( 1.1 )
    Statistical analysis title
    		 statiscal comparison between groups
    Comparison groups
    folinic acid group v placebo group
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Secondary: SRS score evolution

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    End point title
    		 SRS score evolution
    End point description
    End point type
    Secondary
    End point timeframe
    between baseline T0 and W12
    End point values
    		 folinic acid group placebo group
    Number of subjects analysed
    9
    10
    Units: points
        arithmetic mean (standard deviation)
    -8.3 ( 13.4 )
    -7.9 ( 12.7 )
    Statistical analysis title
    		 statiscal comparison between groups
    Comparison groups
    placebo group v folinic acid group
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The AEs and SAEs were collected and reported to the sponsor from enrolment to the end of the study (week 24).
    Adverse event reporting additional description
    Children's parents were contacted by telephone at 3 and 6 weeks after the start of the study to check for any adverse treatment effects and to verify compliance. Parents were provided with a telephone number for the principal investigator to report any adverse events. A reassessment took place 12 weeks after the end of treatment (at week 24 ).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    folinoral
    Reporting group description
    		 -

    Reporting group title
    placebo
    Reporting group description
    		 -

    Serious adverse events
    		 folinoral placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 folinoral placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    8 / 9 (88.89%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthmatic crisis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 9 (22.22%)
         occurrences all number
    2
    2
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    agression
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Sleep disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    anger
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Influenza
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    2
    Rhinolaryngitis
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    1
    Influenza like illness
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    Otitis media
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jun 2016
    Request for an additional 18-month extension of the inclusion period
    07 Feb 2018
    Request for an additional visit specific to the inclusion in the protocol when it is not possible to do so during the usual follow-up visit

    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.
    -absence of double-blindness, -carried out on a small number of children, a larger multicenter study over a longer period would be necessary.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32387472
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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