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    Clinical Trial Results:
    A Phase III, Double Blinded, Randomised, Placebo Controlled Clinical Trial of High Dose Oral Genistein Aglycone in Patients with Sanfilippo Syndrome (Mucopolysaccharidosis III)

    Summary
    EudraCT number
    2013-001479-18
    Trial protocol
    GB  
    Global end of trial date
    30 Jun 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    21 May 2020
    First version publication date
    21 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GENiSIS2013
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    REC reference: 14/NI/0006, Protocol number: GENiSIS2013
    Sponsors
    Sponsor organisation name
    Manchester University NHS Foundation Trust
    Sponsor organisation address
    Oxford Road, Manchester, United Kingdom, M13 9WL
    Public contact
    Lynne Webster, Manchester University NHS Foundation Trust, +44 161 2764125, research.sponsor@mft.nhs.uk
    Scientific contact
    Lynne Webster, Manchester University NHS Foundation Trust, +44 161 2764125, research.sponsor@mft.nhs.uk
    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
    30 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to evaluate oral genistein aglycone therapy in patients between 2 and 15 years old with MPS III A, B or C
    Protection of trial subjects
    A local anaesthetic (usually a cream) will be used to minimise the discomfort when blood is taken. There is a small risk of infection but every effort will be made to minimise this risk. The amount of blood taken will be carefully monitored to ensure too much blood is not taken. General anaesthesia: Anaesthesia affects the whole body, including the brain, heart, and lungs. The child will be under the supervision of the anaesthesia team from the time the medication is given until the child is again fully awake. Lumbar puncture: A sample of spinal fluid will be taken by performing a lumbar puncture. After a lumbar puncture, some people will have a headache and there is also the risk of pain at the injection site, meningitis, bleeding, spinal fluid leakage, nerve damage, and paralysis. Every effort will be made to minimise these risks. If a child has not had genetic testing to confirm their diagnosis of MPS III, this will be offered to them. Learning these results may be useful for the child’s health care. The risks of learning genetic test results may include emotional upset and/or family conflicts from learning unknown information about you, your child, your parents or blood relatives. Having the test or the results can be discussed with a genetic counsellor who can help explain the possible risks and benefits of learning this information.
    Background therapy
    Although this study is placebo controlled, no treatment will be withheld. After the initial 12 months period all patients will move on to an open label phase where all patients will be given the study drug.
    Evidence for comparator
    -
    Actual start date of recruitment
    01 May 2014
    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
    United Kingdom: 21
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    14
    Adolescents (12-17 years)
    7
    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
    UK only, recruitment period from 01/08/2014 - 31/01/2017.

    Pre-assignment
    Screening details
    Genotyping, demographics, medical history

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Genistein
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Genistein aglycone
    Investigational medicinal product code
    500 0500 0
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    160mg/kg per day for maximum duration of 104 weeks (including a 52 week open label treatment period)

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    N/A - placebo.

    Number of subjects in period 1
    Genistein Placebo
    Started
    9
    12
    Completed
    9
    11
    Not completed
    0
    1
         Logistical reasons
    -
    1
    Period 2
    Period 2 title
    Placebo controlled phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Genistein
    Arm description
    160mg/kg/day genistein aglycone
    Arm type
    Experimental

    Investigational medicinal product name
    Genistein aglycone
    Investigational medicinal product code
    500 0500 0
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    160mg/kg per day for maximum duration of 104 weeks (including a 52 week open label treatment period)

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    N/A - placebo.

    Number of subjects in period 2
    Genistein Placebo
    Started
    9
    11
    Completed
    9
    11
    Period 3
    Period 3 title
    Open label extension
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Genistein
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Genistein aglycone
    Investigational medicinal product code
    500 0500 0
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    160mg/kg per day for maximum duration of 104 weeks (including a 52 week open label treatment period)

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    N/A - placebo.

    Number of subjects in period 3
    Genistein Placebo
    Started
    9
    11
    Completed
    9
    10
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Genistein
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    Genistein Placebo Total
    Number of subjects
    9 12 21
    Age categorical
    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)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    7.2 (5.1 to 15.9) 5.9 (3.1 to 15.2) -
    Gender categorical
    Units: Subjects
        Female
    3 7 10
        Male
    6 5 11
    MPS group
    Units: Subjects
        IIIA
    5 7 12
        IIIB
    3 1 4
        IIIC
    1 4 5
    CSF HS
    Units: ng/ml
        arithmetic mean (standard deviation)
    1632 ± 362 1499 ± 284 -
    Plasma HS
    Units: ng/ml
        arithmetic mean (standard deviation)
    1680 ± 426 1500 ± 310 -
    Urine HS
    Units: mg/mmol creatinine
        arithmetic mean (standard deviation)
    33.2 ± 28.2 36.4 ± 25.1 -
    Urine GAG
    Units: mg/mmol creatinine
        arithmetic mean (standard deviation)
    57.9 ± 23.8 66.3 ± 35.2 -
    BSID-III DQ
    Units: Scale
        arithmetic mean (standard deviation)
    17 ± 10 29 ± 24 -
    Beck Depression Inventory
    Units: Scale
        arithmetic mean (standard deviation)
    10.9 ± 8.1 14.1 ± 9.1 -
    Parents PedsQL
    Units: Percentage
        arithmetic mean (standard deviation)
    61.3 ± 14.4 55.8 ± 16.4 -
    PedsQL Family Impact
    Units: Percentage
        arithmetic mean (standard deviation)
    42.3 ± 14.2 48.8 ± 15.8 -

    End points

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    End points reporting groups
    Reporting group title
    Genistein
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -
    Reporting group title
    Genistein
    Reporting group description
    160mg/kg/day genistein aglycone

    Reporting group title
    Placebo
    Reporting group description
    -
    Reporting group title
    Genistein
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: CSF Heparan sulphate

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    End point title
    CSF Heparan sulphate
    End point description
    End point type
    Primary
    End point timeframe
    52 weeks
    End point values
    Genistein Placebo Genistein Placebo Genistein Placebo
    Number of subjects analysed
    9
    11
    9
    11
    7
    7
    Units: ng/ml
        arithmetic mean (standard deviation)
    1632 ± 362
    1499 ± 284
    1597 ± 373
    1580 ± 303
    1649 ± 468
    1578 ± 403
    Statistical analysis title
    Estimated effect of Genistein
    Statistical analysis description
    % Difference between groups at 12 months, adjusted for baseline
    Comparison groups
    Genistein v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.26
    Method
    ANCOVA
    Parameter type
    Percentage difference
    Point estimate
    -5.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.7
         upper limit
    4.7

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events will be reported at screening (day -21) baseline (day -21 to -1), and weeks 0, 4, 13, 26, 39, 52, 56, 65, 78, 91, 104 & 108
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Genistein
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Genistein Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 11 (9.09%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Gastrostomy tube placement
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Bullous impetigo
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Genistein Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    11 / 11 (100.00%)
    Immune system disorders
    Tonsillectomy and/or adenoidectomy
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    2
    Social circumstances
    Accidental injuries
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 11 (9.09%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Febrile illness, unspecified
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 11 (18.18%)
         occurrences all number
    2
    5
    Emotional lnability
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    0
    3
    Dental decay
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Dental extractions
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Ingrowing toenail
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Increasing aggressive behaviour
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Sleep disturbance
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Breast tissue development (Tanner stage II)
         subjects affected / exposed
    3 / 9 (33.33%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Needlestick injury
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Stress fracture of foot
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infections
         subjects affected / exposed
    8 / 9 (88.89%)
    8 / 11 (72.73%)
         occurrences all number
    15
    15
    Hay fever
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Sleep disordered breathing
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Shortness of breath
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Nervous system disorders
    New onset seizures / increasing seizure frequency
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 11 (9.09%)
         occurrences all number
    4
    1
    Decreased responsiveness
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Dystonia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Increasing hyperactivity
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Sleep myoclonus
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Vacant episodes
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eyelid infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Deteriorating hearing loss
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    3 / 9 (33.33%)
    2 / 11 (18.18%)
         occurrences all number
    7
    3
    Vomiting
         subjects affected / exposed
    2 / 9 (22.22%)
    6 / 11 (54.55%)
         occurrences all number
    2
    7
    Constipation
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Abnormal liver function tests (not present at baseline)
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 11 (18.18%)
         occurrences all number
    2
    1
    Skin and subcutaneous tissue disorders
    Skin infection
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Knee dislocation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Abnormal thyroid function tests (not present at baseline)
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 11 (27.27%)
         occurrences all number
    2
    3
    Elevated testosterone levels (not present at baseline)
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Precocious puberty
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Chicken pox
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Glandular fever
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Infected gastrostomy site
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 11 (0.00%)
         occurrences all number
    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.
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