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    Clinical Trial Results:
    International Collaborative Infantile Spasms Study (ICISS)

    Summary
    EudraCT number
    		 2006-000788-27
    Trial protocol
    		 GB   DE  
    Global end of trial date
    31 Dec 2017

    Results information
    Results version number
    		 v1
    This version publication date
    16 Jul 2018
    First version publication date
    16 Jul 2018
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RD01273
    Additional study identifiers
    ISRCTN number
    		 ISRCTN54363174
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Royal United Hospitals Bath NHS Foundation Trust
    Sponsor organisation address
    Combe Park, Bath, United Kingdom, BA1 3NG
    Public contact
    The ICISS Trial Office, The Childrens Centre, Royal United Hospital, Combe Park, Bath, BA1 3NG, United Kingdom, iciss@ruh-bath.swest.nhs.uk
    Scientific contact
    The ICISS Trial Office, The Childrens Centre, Royal United Hospital, Combe Park, Bath, BA1 3NG, United Kingdom, iciss@ruh-bath.swest.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
    21 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to examine if combining hormonal treatment and vigabatrin is better at early control of infantile spasms (day 14-42 of treatment) and at helping development at 18 months of age than taking a hormonal treatment alone.
    Protection of trial subjects
    The trial was conducted in compliance with the approved protocol and adhered to the principles of good clinical practice as stated in European Commission Directive 2005/28/EC and data protection regulations. A clinical trial risk assessment was undertaken by the Sponsor prior to commencement of recruitment and a Data Monitoring and Ethics Committee (DMEC) was appointed who met once a year to review study recruitment, serious adverse reactions (SARs) and approve the annual safety reports. A Trial Steering Committee (TSC) met approximately every 3 months to oversee the progress of the trial. The TSC and the Sponsor could both request the DMEC to assess the progress of the trial, including safety and drop out. The DMEC could recommend to the TSC and/or Sponsor whether to continue, modify or stop the trial. Any SAR or Suspected Unexpected Serious Adverse Reaction (SUSAR) was reported to the relevant authorities within the required time-frames. Informed signed consent was obtained for each child and the parents or guardians were informed they were free to withdraw their child from the trial at any time without giving a reason and without affecting the care they receive. Central monitoring of data was undertaken by the Trial Centre.
    Background therapy
    		 -
    Evidence for comparator
    		 Vigabatrin and hormonal therapies are the two most commonly used and investigated treatments for the treatment of infantile spasms (see Hancock EC, Osborne JP, Edwards SW. Treatment of Infantile Spasms. Cochrane Database Syst Rev. 2013 Jun 5;6:CD001770. DOI: 10.1002/14651858.CD001770.pub3. PubMed ID: 23740534). Our previous study demonstrated that hormonal therapy was superior to vigabatrin at stopping spasms (see Lux AL et al., Lancet 2004; 364: 1773–1778. PubMed ID: 15541450). However, it was also evident from the UKISS study that some patients who failed on their initially randomised therapy (either hormonal therapy or vigabatrin) responded to the other therapy when they were crossed over. Consequently we formed the hypothesis that combining hormonal therapy with vigabatrin may be more effective than hormonal therapy alone at stopping spasms and may therefore also be associated with better developmental outcomes.
    Actual start date of recruitment
    07 Mar 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 42 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 285
    Country: Number of subjects enrolled
    Germany: 31
    Country: Number of subjects enrolled
    Australia: 25
    Country: Number of subjects enrolled
    New Zealand: 16
    Country: Number of subjects enrolled
    Switzerland: 20
    Worldwide total number of subjects
    377
    EEA total number of subjects
    316
    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)
    377
    Children (2-11 years)
    0
    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
    		 Between March 7 2007 and May 22 2014, 766 infants were assessed for eligibility, of whom 377 met the inclusion criteria and were randomly assigned. Recruitment took place in Australia, Germany, New Zealand, Switzerland and the United Kingdom.

    Pre-assignment
    Screening details
    		 Incl:Clinical features of Infantile Spasms confirmed by clinician, EEG hypsarrhythmic or similar compatible with diagnosis.Signed informed consent Excl:Age<2mths or >14mths, >7 days since diagnosis, TS, prev treatment for IS,prev hormonal or vgb treatment,potentially lethal condition, can't follow-up @18mths,language difficulty,in concurrent trial

    Pre-assignment period milestones
    Number of subjects started
    		 377
    Number of subjects completed
    		 377

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Blinding of outcome measures: The pre-treatment and post-treatment EEGs were assessed by investigators masked to treatment and to clinical outcome: a majority view of three of four assessors was accepted for determination of the resolution of EEG features supporting the diagnosis. Aetiology was determined masked to treatment through clinical history, examination, and investigation. A study radiologist masked to treatment reviewed MRI scans done after the primary clinical outcome was determined

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Hormonal therapy and Vigabatrin (Combination therapy)
    Arm description
    		 Combination therapy is hormonal therapy (prednisolone OR tetracosactide depot) with vigabatrin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vigabatrin
    Investigational medicinal product code
    Other name
    Sabril Sachets
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Vigabatrin was given orally in two doses per day: 50 mg/kg per day for the first two doses; increasing to 100 mg/kg per day after 24 h and, if spasms continued after a further 72 h, to 150 mg/kg per day. Vigabatrin was given at the same dose on a bodyweight basis until 3 months from the start of treatment, and then the dose was reduced over 4 weeks.

    Investigational medicinal product name
    Tetracosactide Depot
    Investigational medicinal product code
    Other name
    Synacthen Depot
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Tetracosactide depot was given intramuscularly (0·5 mg [40 IU] on alternate days) for 2 weeks. If spasms continued on day 7 or reappeared between day 8 and day 14 inclusive, the dose was increased to 0·75 mg on alternate days. After 2 weeks of treatment, hormonal therapy was tapered: all children received a reduced dose of prednisolone, with reductions of 10 mg every 5 days or, if on the higher dose of treatment, 40 mg daily, then 20 mg, then 10 mg. Hormonal therapy ceased after day 29.

    Investigational medicinal product name
    Prednisolone (Soluble tablets)
    Investigational medicinal product code
    Other name
    Soluble Prednisolone Tablets
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisolone was given orally (10 mg four times a day) for 2 weeks. If spasms continued on day 7 or reappeared between day 8 and day 14 inclusive, the dose was increased to 20 mg three times a day. After 2 weeks of treatment, hormonal therapy was tapered: all children received a reduced dose of prednisolone, with reductions of 10 mg every 5 days or, if on the higher dose of treatment, 40 mg daily, then 20 mg, then 10 mg. Hormonal therapy ceased after day 29.

    Arm title
    		 Hormonal therapy alone
    Arm description
    		 Hormonal therapy alone is either prednisolone OR tetracosactide depot
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tetracosactide Depot
    Investigational medicinal product code
    Other name
    Synacthen Depot
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Tetracosactide depot was given intramuscularly (0·5 mg [40 IU] on alternate days) for 2 weeks. If spasms continued on day 7 or reappeared between day 8 and day 14 inclusive, the dose was increased to 0·75 mg on alternate days. After 2 weeks of treatment, hormonal therapy was tapered: all children received a reduced dose of prednisolone, with reductions of 10 mg every 5 days or, if on the higher dose of treatment, 40 mg daily, then 20 mg, then 10 mg. Hormonal therapy ceased after day 29.

    Investigational medicinal product name
    Prednisolone (Soluble tablets)
    Investigational medicinal product code
    Other name
    Soluble Prednisolone Tablets
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisolone was given orally (10 mg four times a day) for 2 weeks. If spasms continued on day 7 or reappeared between day 8 and day 14 inclusive, the dose was increased to 20 mg three times a day. After 2 weeks of treatment, hormonal therapy was tapered: all children received a reduced dose of prednisolone, with reductions of 10 mg every 5 days or, if on the higher dose of treatment, 40 mg daily, then 20 mg, then 10 mg. Hormonal therapy ceased after day 29.

    Number of subjects in period 1
    		Hormonal therapy and Vigabatrin (Combination therapy) Hormonal therapy alone
    Started
    186
    191
    Completed
    186
    191

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Hormonal therapy and Vigabatrin (Combination therapy)
    Reporting group description
    		 Combination therapy is hormonal therapy (prednisolone OR tetracosactide depot) with vigabatrin

    Reporting group title
    Hormonal therapy alone
    Reporting group description
    		 Hormonal therapy alone is either prednisolone OR tetracosactide depot

    Reporting group values
    		 Hormonal therapy and Vigabatrin (Combination therapy) Hormonal therapy alone Total
    Number of subjects
    		 186 191 377
    Age categorical
    Units: Subjects
        60-119 days
    		 17 8 25
        120-179 days
    		 42 57 99
        180-239 days
    		 70 63 133
        >=240 days
    		 57 63 120
    Gender categorical
    Units: Subjects
        Female
    		 87 80 167
        Male
    		 99 111 210
    Lead time to treatment
    Units: Subjects
        Up to 7 days
    		 54 56 110
        8-14 days
    		 36 36 72
        15-28 days
    		 37 42 79
        29 days to 2 months
    		 33 27 60
        More than 2 months
    		 24 29 53
        Not known
    		 2 1 3
    Risk of developmental impairment
    Units: Subjects
        Yes
    		 103 104 207
        No
    		 83 87 170
    Antiepileptic drugs for other seizure types
    Units: Subjects
        None
    		 156 166 322
        One
    		 19 20 39
        Two or more
    		 11 5 16
    Pyridoxine given to exclude dependent seizures
    Units: Subjects
        Yes
    		 20 12 32
        No
    		 166 179 345

    End points

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    End points reporting groups
    Reporting group title
    Hormonal therapy and Vigabatrin (Combination therapy)
    Reporting group description
    		 Combination therapy is hormonal therapy (prednisolone OR tetracosactide depot) with vigabatrin

    Reporting group title
    Hormonal therapy alone
    Reporting group description
    		 Hormonal therapy alone is either prednisolone OR tetracosactide depot

    Primary: Cessation of spasms

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    End point title
    		 Cessation of spasms
    End point description
    The primary early outcome was cessation of spasms which was defined as no witnessed spasms on and between Days 14 and Day 42 from trial entry.
    End point type
    Primary
    End point timeframe
    Between Day 14 and Day 42 after enrolment
    End point values
    		 Hormonal therapy and Vigabatrin (Combination therapy) Hormonal therapy alone
    Number of subjects analysed
    186
    191
    Units: number
        Responder
    133
    108
        Non-responder
    53
    83
    Statistical analysis title
    		 Early primary outcome - Chi-squared
    Comparison groups
    Hormonal therapy and Vigabatrin (Combination therapy) v Hormonal therapy alone
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Chi-squared
    Parameter type
    		 Percentage difference in response
    Point estimate
    15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.1
         upper limit
    		 24.9
    Statistical analysis title
    		 Early primary outcome - logistic regression
    Statistical analysis description
    Sensitivity analysis using logistic regression to control for stratification variables and potential confounders
    Comparison groups
    Hormonal therapy and Vigabatrin (Combination therapy) v Hormonal therapy alone
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.3
         upper limit
    		 3.2

    Secondary: Time to response

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    End point title
    		 Time to response
    End point description
    Defined as the first day after initiation of trial treatment on which spasms were not seen and after which response was maintained until Day 42 of treatment.
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 42
    End point values
    		 Hormonal therapy and Vigabatrin (Combination therapy) Hormonal therapy alone
    Number of subjects analysed
    186
    191
    Units: day
        median (inter-quartile range (Q1-Q3))
    2 (2 to 4)
    4 (3 to 6)
    Statistical analysis title
    		 Secondary outcome - time to response analysis
    Comparison groups
    Hormonal therapy and Vigabatrin (Combination therapy) v Hormonal therapy alone
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 2.6

    Secondary: Electro-clinical response

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    End point title
    		 Electro-clinical response
    End point description
    Defined as cessation of spasms and resolution of the EEG features supporting the diagnosis (i.e. hysarrythmia or similar, compatible with the diagnosis of infantile spasms).
    End point type
    Secondary
    End point timeframe
    Between Day 14 and Day 42 after enrolment
    End point values
    		 Hormonal therapy and Vigabatrin (Combination therapy) Hormonal therapy alone
    Number of subjects analysed
    185 [1]
    189 [2]
    Units: Number
        Responder
    123
    104
        Non-responder
    62
    85
    Notes
    [1] - 1 missing value from total of 186
    [2] - 2 missing values from total of 191
    Statistical analysis title
    		 Electro-clinical response analysis
    Comparison groups
    Hormonal therapy and Vigabatrin (Combination therapy) v Hormonal therapy alone
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023
    Method
    		 Chi-squared
    Parameter type
    		 Percentage difference in response
    Point estimate
    11.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 21.6
    Statistical analysis title
    		 Electro-clinical response logistic regression
    Statistical analysis description
    Sensitivity analysis controlling for stratification variables and potential confounders
    Comparison groups
    Hormonal therapy and Vigabatrin (Combination therapy) v Hormonal therapy alone
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 2.8

    Secondary: Absence of spasms on Days 13 and 14

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    End point title
    		 Absence of spasms on Days 13 and 14
    End point description
    Absence of spasms on Days 13 and 14
    End point type
    Secondary
    End point timeframe
    Day 13 to Day 14 inclusive
    End point values
    		 Hormonal therapy and Vigabatrin (Combination therapy) Hormonal therapy alone
    Number of subjects analysed
    186
    191
    Units: Number
        Responder
    166
    132
        Non responders
    20
    59
    Statistical analysis title
    		 Cessation at Days 13 and 14 analysis
    Comparison groups
    Hormonal therapy and Vigabatrin (Combination therapy) v Hormonal therapy alone
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Parameter type
    		 Percentage difference in response
    Point estimate
    20.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.8
         upper limit
    		 28.6

    Secondary: Number of responders if single spasms are allowed in responders from Day 14 to Day 42 inclusive

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    End point title
    		 Number of responders if single spasms are allowed in responders from Day 14 to Day 42 inclusive
    End point description
    Number of responders if single spasms are allowed in responders from Day 14 to Day 42 inclusive
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 42
    End point values
    		 Hormonal therapy and Vigabatrin (Combination therapy) Hormonal therapy alone
    Number of subjects analysed
    186
    191
    Units: Number
        Responder
    141
    121
        Non responder
    45
    70
    Statistical analysis title
    		 Responders if single spasms allowed analysis
    Comparison groups
    Hormonal therapy and Vigabatrin (Combination therapy) v Hormonal therapy alone
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 Chi-squared
    Parameter type
    		 Percentage difference in response
    Point estimate
    12.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.9
         upper limit
    		 21.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 0 to Day 42 inclusive from trial entry
    Adverse event reporting additional description
    **PLEASE NOTE: All adverse events were assessed by the local investigator to determine whether in their view they were adverse reactions. Only adverse reactions were reported to the trial centre using the classification stated in the ICISS protocol. Therefore ADVERSE REACTIONS ONLY are presented in this report.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICISS Protocol
    Dictionary version
    1.3
    Reporting groups
    Reporting group title
    Hormonal therapy and Vigabatrin (Combination therapy)
    Reporting group description
    		 Combination therapy is hormonal therapy (prednisolone OR tetracosactide depot) with vigabatrin

    Reporting group title
    Hormonal therapy alone
    Reporting group description
    		 Hormonal therapy alone is either prednisolone OR tetracosactide depot

    Serious adverse events
    		 Hormonal therapy and Vigabatrin (Combination therapy) Hormonal therapy alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 186 (9.14%)
    16 / 191 (8.38%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Obstructive cardiac hypertrophy **
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Drowsiness
         subjects affected / exposed
    4 / 186 (2.15%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertonia
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritability
         subjects affected / exposed
    2 / 186 (1.08%)
    3 / 191 (1.57%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropsychiatric (disturbed sleep)
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Movement disorder **
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    3 / 186 (1.61%)
    0 / 191 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Immunosuppression
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 191 (1.05%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal upset
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 191 (1.05%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Fluid or electrolyte disturbance
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 191 (1.57%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    4 / 186 (2.15%)
    5 / 191 (2.62%)
         occurrences causally related to treatment / all
    5 / 5
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster (chicken pox)*
    Additional description: *Required treatment to prevent infection or was infected
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 191 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Hormonal therapy and Vigabatrin (Combination therapy) Hormonal therapy alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    117 / 186 (62.90%)
    111 / 191 (58.12%)
    Vascular disorders
    Pallor**
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 191 (0.52%)
         occurrences all number
    0
    1
    Immune system disorders
    Allergic rash or anaphylaxis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 191 (0.52%)
         occurrences all number
    0
    2
    Immunosuppression
         subjects affected / exposed
    3 / 186 (1.61%)
    3 / 191 (1.57%)
         occurrences all number
    3
    3
    Respiratory, thoracic and mediastinal disorders
    Abnormal breathing pattern**
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 191 (0.52%)
         occurrences all number
    0
    1
    Hypoxia**
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 191 (0.52%)
         occurrences all number
    0
    1
    Tachypnoea**
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 191 (0.52%)
         occurrences all number
    0
    1
    Cardiac disorders
    Bardycardia**
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 191 (0.00%)
         occurrences all number
    1
    0
    Obstructive cardiac hypertrophy**
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 191 (0.52%)
         occurrences all number
    0
    1
    Nervous system disorders
    Drowsiness
         subjects affected / exposed
    45 / 186 (24.19%)
    3 / 191 (1.57%)
         occurrences all number
    51
    3
    Hypertonia
         subjects affected / exposed
    3 / 186 (1.61%)
    9 / 191 (4.71%)
         occurrences all number
    4
    10
    Hypotonia
         subjects affected / exposed
    7 / 186 (3.76%)
    8 / 191 (4.19%)
         occurrences all number
    10
    9
    Irritability
         subjects affected / exposed
    61 / 186 (32.80%)
    75 / 191 (39.27%)
         occurrences all number
    71
    90
    Neuropsychiatric (disturbed sleep)
         subjects affected / exposed
    29 / 186 (15.59%)
    35 / 191 (18.32%)
         occurrences all number
    37
    44
    High MRI signal in basal ganglia**
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 191 (0.52%)
         occurrences all number
    2
    1
    Movement disorder**
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    14 / 186 (7.53%)
    2 / 191 (1.05%)
         occurrences all number
    15
    2
    Blood and lymphatic system disorders
    Blood disorder (high platelet count)**
    Additional description: **Unexpected adverse reaction
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 191 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Abnormal eye movements**
    Additional description: **Unexpected adverse reaction
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 191 (0.00%)
         occurrences all number
    1
    0
    Not focusing (vision)**
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 191 (0.00%)
         occurrences all number
    1
    0
    Squinting**
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 191 (0.52%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Gastrointestinal upset
         subjects affected / exposed
    23 / 186 (12.37%)
    26 / 191 (13.61%)
         occurrences all number
    26
    30
    Skin and subcutaneous tissue disorders
    Sweating**
    Additional description: ** Unexpected adverse reaction
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 191 (0.52%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Fluid or electrolyte disturbance
         subjects affected / exposed
    12 / 186 (6.45%)
    23 / 191 (12.04%)
         occurrences all number
    13
    28
    Endocrine disorders
    Endocrine or metabolic disturbance
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 191 (1.05%)
         occurrences all number
    2
    2
    Infections and infestations
    Infection
         subjects affected / exposed
    14 / 186 (7.53%)
    19 / 191 (9.95%)
         occurrences all number
    16
    20
    Varicella zoster (chicken pox)*
    Additional description: *Required treatment to prevent infection or was infected
         subjects affected / exposed
    2 / 186 (1.08%)
    4 / 191 (2.09%)
         occurrences all number
    2
    4
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    35 / 186 (18.82%)
    51 / 191 (26.70%)
         occurrences all number
    42
    61
    Weight gain
         subjects affected / exposed
    24 / 186 (12.90%)
    34 / 191 (17.80%)
         occurrences all number
    31
    49

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Apr 2005
    Protocol updated from version 1.0 to version 1.1. This occurred between the original ethics submission in the UK and obtaining final approval. Please see Appendix 1 Section A1 of Protocol Version 1.3 for a description and explanation of all the amendments made to the protocol as part of this amendment. ICISS Protocol Version 1.3 can be downloaded from the trial website at www.iciss.org.uk
    20 Dec 2006
    Protocol updated from version 1.1 to version 1.2. This occurred before the start date of recruitment. Please see Appendix 1 Section A2 of Protocol Version 1.3 for a description and explanation of all the amendments made to the protocol as part of this amendment. ICISS Protocol Version 1.3 can be downloaded from the trial website at www.iciss.org.uk
    05 Jan 2011
    Protocol updated from version 1.2 to version 1.3. Please see Appendix 1 Section A3 of Protocol Version 1.3 for a description and explanation of all the amendments made to the protocol as part of this amendment. ICISS Protocol Version 1.3 can be downloaded from the trial website at www.iciss.org.uk

    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.
    Results Version 1 presents the early outcome measures. Version 2 will include the late outcome measures at 18 months of age (currently in press). Version 3 will include the late outcome measures at 42 months of age.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27838190
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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