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    Clinical Trial Results:
    Palatability testing of a new paediatric formulation of valacyclovir for the prophylaxis and treatment of VZV and HSV infections in children – VALID 0

    Summary
    EudraCT number
    		 2012-000577-22
    Trial protocol
    		 NL  
    Global end of trial date
    30 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Nov 2020
    First version publication date
    19 Nov 2020
    Other versions
    Summary report(s)
    		 paper

    Trial information

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    Trial identification
    Sponsor protocol code
    AKF-UMCN11.05
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboudumc
    Sponsor organisation address
    Geert Grooteplein Zuid 10, Nijmegen, Netherlands,
    Public contact
    David Burger, Radboud University Nijmegen Medical Centre, 31 243616405, d.bastiaans@akf.umcn.nl
    Scientific contact
    Diane Bastiaans, Radboud University Nijmegen Medical Centre, 31 243616405, david.burger@radboudumc.nl
    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
    10 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine which of three newly developed formulations of valacyclovir is accepted best in children.
    Protection of trial subjects
    The burden of this study is very low: a single dose, or less, exposure to pharmaceutical active substance. The substance has solely antiviral activity and therefore does not influence normal physiological processes in the human body. The total dose of the drug that will be administered to the subject during one taste assessment is 270 mg (4 ml of the 20 mg/ml solution, the 25 mg/ml suspension and the mixed formulation (22.5 mg/ml)) for children of 4-8 years and 540 mg for children of 8-12 years and the parent(s). The dose of valacyclovir in immunocompromised children for the treatment of VZV and HSV infection is 60-90 mg/kg daily, divided in two to three doses. The estimated bodyweight of a child of 4 years of age is 15-19 kg and for a child of 8 years of age 25-28 kg. The lowest single therapeutic dose would be 300 mg (15 kg * 20 mg/kg). For children 4-8 years of age the administered dose during the taste assessment (270 mg) is comparable to a single therapeutic dose and less than 1/3 of a total daily therapeutic dose for a child of 15 kg. For children 8-12 years of age the dose administered (540 mg) is comparable to a single therapeutic dose for a child of 27 kg, and 1/3 or less of a total daily therapeutic dose. The taste assessment will be performed combined with a regular visit to the outpatient clinic. Subjects don’t have to come to the hospital separately to participate in this study. DNA will be collected through obtaining a 2 ml saliva sample. This is a non-invasive and patient friendly way of obtaining DNA.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2012
    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
    Netherlands: 64
    Worldwide total number of subjects
    64
    EEA total number of subjects
    64
    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)
    33
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    31
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 30 children and their parent(s). Inclusion criteria: 1. Subject is at least 4 years of age. 2. Subject weighs at least 15 kg. 3. Subject is capable of performing the taste assessment, according to the investigator’s judgement. 4. The child and parent(s) are willing to participate in the taste assessment. 5. Signed informed consent

    Pre-assignment
    Screening details
    		 No tests have to be performed to decide whether the subject is allowed to participate in the taste assessment. The capability to perform the palatability testing is judged by the investigator. The investigator will also determine whether the in- and exclusion criteria are met.

    Period 1
    Period 1 title
    treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The subject performing the taste assessment cannot be fully blinded for the different formulations, since the appearance of a solution and suspension is different. All formulations will be presented in similar plastic medication cups. The investigator is not blinded, because in case of spillage, solution can be replaced.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 test
    Arm description
    		 20 mg/ml valacyclovir solution
    Arm type
    		 Experimental

    Investigational medicinal product name
    valacyclovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Children of 4-8 years will taste 4 ml of each solution and children of 8-12 years and the parent(s) will taste 8 ml of each solution.

    Arm title
    		 reference
    Arm description
    		 20 mg/ml valacyclovir solution from crushed tablets
    Arm type
    		 Active comparator

    Investigational medicinal product name
    valacyclovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Crushed and suspended tablet. Children of 4-8 years will taste 4 ml of each solution and children of 8-12 years and the parent(s) will taste 8 ml of each solution.

    Number of subjects in period 1
    		test reference
    Started
    64
    40
    Completed
    40
    40
    Not completed
    24
    0
         Consent withdrawn by subject
    24
    -

    Baseline characteristics

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

    Reporting group values
    		 treatment Total
    Number of subjects
    		 64 64
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 33 33
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 31 31
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 40 40
        Male
    		 24 24
    Subject analysis sets

    Subject analysis set title
    evaluable
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    evaluable child parent pairs

    Subject analysis sets values
    		 evaluable
    Number of subjects
    40
    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)
    20
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    20
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    17
        Male
    23

    End points

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    End points reporting groups
    Reporting group title
    test
    Reporting group description
    		 20 mg/ml valacyclovir solution

    Reporting group title
    reference
    Reporting group description
    		 20 mg/ml valacyclovir solution from crushed tablets

    Subject analysis set title
    evaluable
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    evaluable child parent pairs

    Primary: VAS score

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    End point title
    		 VAS score [1]
    End point description
    End point type
    Primary
    End point timeframe
    entire study, 1 day
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: only descriptive difference was reported, no formal test was done
    End point values
    		 test reference
    Number of subjects analysed
    40 [2]
    40 [3]
    Units: mm
        arithmetic mean (confidence interval 95%)
    26 (18 to 34)
    24 (16 to 32)
    Notes
    [2] - children only
    [3] - results of children only
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    entire study
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    1
    Reporting groups
    Reporting group title
    ae group
    Reporting group description
    		 -

    Serious adverse events
    		 ae group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 64 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ae group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 64 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: only very limited exposure to medication, no adverse events were reported

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Mar 2013
    1. Change from single centre to multicentre study. 2. Include two additional investigators to the list. 3. Adding description of a specific group of children that can be included. 4. Further clarify the exclusion criteria. 5. Minor changes
    12 Dec 2014
    1. Restart of the trial 2. Addition of second phase of the trial In the first phase of the trial, children and one of their parents tested three newly developed, saccharose based, formulations. Twelve children and one of their parents were included into the first phase of this trial, of which 8 had evaluable data. In the second phase of the trial, two different valacyclovir liquids will be tested: one newly developed, glycerol based formulation (solution, concentration 20 mg/mL) and a reference formulation (suspension, concentration 25 mg/mL). 3. Change of primary objective in the second phase of the trial 4. Changes in trial set-up 5. Addition of secondary objective

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    22 Oct 2014
    problems with stability of oral formulation
    08 May 2015

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Only the VAS results for the children were reported, this template does not allow for two different groups.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28800385
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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
    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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