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    Clinical Trial Results:
    CONgenital Cytomegalovirus: Efficacy of antiviral treatment in a non-Randomized Trial with historical control group

    Summary
    EudraCT number
    2013-003068-30
    Trial protocol
    NL  
    Global end of trial date
    17 May 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Oct 2022
    First version publication date
    22 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CMV-MM-2
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02005822
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Leiden University Medical Center
    Sponsor organisation address
    Albinusdreef 2, Leiden, Netherlands, 2333 ZA
    Public contact
    Aloysius Cornelis Maria Kroes, MD PhD, Leiden University Medical Center, 0031 71526 3931, A.C.M.Kroes@lumc.nl
    Scientific contact
    Aloysius Cornelis Maria Kroes, MD PhD, Leiden University Medical Center, 0031 71526 3931, A.C.M.Kroes@lumc.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
    04 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Investigate whether early valganciclovir treatment of children with SNHL of ≥ 20 dB, unilateral or bilateral, and a confirmed congenital CMV infection can prevent deterioration of the hearing loss at 18-22 months follow­-up.
    Protection of trial subjects
    - By participating in the study, parents learned their child had cCMV while this might otherwise have been undetected. This knowledge could have posed a possible extra burden. We have tried to diminish stress by providing clear information before consent, providing time to consider and ask questions. The advantages of the awareness of the presence of the congenital CMV infection were explained, for instance additional hearing evaluations. We provided contact information of the lead investigator and an independent pediatrician to answer any questions at any time. - Potential side effects of the study drug were monitored by regular blood tests - Regular blood tests were performed at the home of the study subject to minimise burden burden of travel and stress for the child - Blood tests in control subjects were only performed at baseline and 7 weeks after inclusion - Urine samples were collected on filter paper by parents at home and sent via postal service to minimise burden of travel - Parents of historic controles approached for the study might have experienced distress from realising their child could have been treated in the CONCERT 2.0 trial if the trial were started earlier. We stressed the advantages of the possibility of follow-up with the extra physical examination, extra developmental tests and extra hearing evaluation for the children in the historical control group.
    Background therapy
    no medicinal treatment, regular care and follow-up by pediatrician, audiologist and possible other specialists such as ophthalmologists.
    Evidence for comparator
    Current views on treatment are based on two seminal randomized controlled trials (Kimberlin 2003, Kimberlin 2015), which show that antiviral treatment has a favorable effect on long-term neurodevelopmental and audiologic outcome, the latter more notably in those with evidence of CNS disease. While there is widespread consensus on the treatment of infants with cCMV and clinically detectable symptoms and CNS involvement (Luck 2017), evidence from prospective controlled trials for antiviral treatment of cCMV infants with isolated hearing loss was long lacking. An observational study reported favorable long term hearing outcome in infants with cCMV and isolated hearing loss, after treatment with (val)ganciclovir (Pasternak 2018)
    Actual start date of recruitment
    02 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Scientific research
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 37
    Worldwide total number of subjects
    37
    EEA total number of subjects
    37
    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)
    37
    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 September 1 2013 and 19 December 2016, subjects were recruited through a nationwide targeted screening approach using the national Newborn Hearing Screening (NHS) program. Parents or legal guardians of infants who failed three subsequent rounds of the NHS were informed about the trial and offered CMV testing.

    Pre-assignment
    Screening details
    1381 infants tested for CMV, of which 1374 (99%) were successfully tested; 59 (4.3%) CMV positive, of which 35 were included in the prospective trial; 24 were not: 19 were ineligible due to exclusion criteria and 5 due to procedural(1) or logistical reasons(2) or no interest(2).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    A blinded audiologist reassessed all raw data from baseline and follow-up audiological tests. Blinded psychologists assessed (performed and interpreted) the developmental tests at follow-up. Data was subsequently analysed by non-blinded investigator.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment group
    Arm description
    Infants in the treatment group received valgancivlovir 16mg/kg bid during six weeks. Per protocol, dosages were fixed for the entire treatment period. Initial home visit at inclusion: medical history taking, physical examination, child development test (van Wiechen), blood sampling (complete blood count with differential, liver function tests and viral load). Hereafter, weekly visits until one week after treatment for blood and urine filter paper sampling. Parents were asked keep diaries with abnormalities or signs during treatment and instructed to contact investigators in case of possible adverse events. Follow-up visit ate age 18-22 months: physical examination, developmental examination (BSID-III) and BERA.
    Arm type
    Experimental

    Investigational medicinal product name
    Valcyte
    Investigational medicinal product code
    SUB16471MIG
    Other name
    Valganciclovir
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    16mg/kg twice daily (32 mg/kg daily) during six weeks. The specific dosage was determined at inclusion according to the weight of the infant, registered at inclusion. The dosage remained unchanged during the 6 weeks treatment. Suspension was prepared by pharmacy and supplied to parents, along with (needleless) syringes for administration, which were marked to ensure that the correct dosage is administered by the parents.

    Arm title
    Combined control group
    Arm description
    2 groups: Refusal control group: Subjects of which parents/guardians refused medicinal treatment. Subjects received regular care after cCMV diagnosis. Referral to pediatrician was advised. Initial home visit at inclusion: medical history taking, physical examination, child development test, blood sampling (complete blood count with differential, liver function tests and viral load). Urine filter papers were collected by parents and mailed, at baseline and during 7 weeks hereafter. Parents were asked to keep diaries. Follow-up visit at age 18-22 months: physical examination, developmental examination (BSID-III) and BERA. Historical control group: Children with hearing loss born between November 2011 and July 2012 were informed by audiologists about CONCERT trial and retrospective dried blood spot (DBS) testing was offered. After retrospective diagnosis, children were included for follow-up visit at age 18-22 months.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Treatment group Combined control group
    Started
    25
    12
    Completed
    25
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    Infants in the treatment group received valgancivlovir 16mg/kg bid during six weeks. Per protocol, dosages were fixed for the entire treatment period. Initial home visit at inclusion: medical history taking, physical examination, child development test (van Wiechen), blood sampling (complete blood count with differential, liver function tests and viral load). Hereafter, weekly visits until one week after treatment for blood and urine filter paper sampling. Parents were asked keep diaries with abnormalities or signs during treatment and instructed to contact investigators in case of possible adverse events. Follow-up visit ate age 18-22 months: physical examination, developmental examination (BSID-III) and BERA.

    Reporting group title
    Combined control group
    Reporting group description
    2 groups: Refusal control group: Subjects of which parents/guardians refused medicinal treatment. Subjects received regular care after cCMV diagnosis. Referral to pediatrician was advised. Initial home visit at inclusion: medical history taking, physical examination, child development test, blood sampling (complete blood count with differential, liver function tests and viral load). Urine filter papers were collected by parents and mailed, at baseline and during 7 weeks hereafter. Parents were asked to keep diaries. Follow-up visit at age 18-22 months: physical examination, developmental examination (BSID-III) and BERA. Historical control group: Children with hearing loss born between November 2011 and July 2012 were informed by audiologists about CONCERT trial and retrospective dried blood spot (DBS) testing was offered. After retrospective diagnosis, children were included for follow-up visit at age 18-22 months.

    Reporting group values
    Treatment group Combined control group Total
    Number of subjects
    25 12 37
    Age categorical
    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)
    25 12 37
        Children (2-11 years)
    0 0 0
        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
    Age continuous
    Age at treatment for treatment group, age at inclusion for control group (excepting the 2 historic controls which were purposefully retrospectively included before at any age before follow-up of 18-22 months).
    Units: weeks
        arithmetic mean (standard deviation)
    8 ( 2.6 ) 7.7 ( 2.7 ) -
    Gender categorical
    Units: Subjects
        Female
    13 7 20
        Male
    12 5 17
    Hearing loss
    Units: Subjects
        Unilateral hearing loss
    13 4 17
        Bilateral hearing loss
    12 8 20
    Best ear hearing loss
    Hearing loss in best ear
    Units: Subjects
        Normal
    13 4 17
        Mild hearing loss
    3 3 6
        Moderate hearing loss
    4 4 8
        Severe hearing loss
    2 0 2
        Profound hearing loss
    3 1 4
    Head circumference
    Units: SD
        arithmetic mean (standard deviation)
    -0.41 ( 1.1 ) -1.05 ( 1 ) -
    Birth weight
    Units: gram(s)
        arithmetic mean (standard deviation)
    3220 ( 470 ) 3107 ( 530 ) -
    Gestational age
    Units: week
        arithmetic mean (standard deviation)
    39.5 ( 1.3 ) 38.9 ( 1.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    Infants in the treatment group received valgancivlovir 16mg/kg bid during six weeks. Per protocol, dosages were fixed for the entire treatment period. Initial home visit at inclusion: medical history taking, physical examination, child development test (van Wiechen), blood sampling (complete blood count with differential, liver function tests and viral load). Hereafter, weekly visits until one week after treatment for blood and urine filter paper sampling. Parents were asked keep diaries with abnormalities or signs during treatment and instructed to contact investigators in case of possible adverse events. Follow-up visit ate age 18-22 months: physical examination, developmental examination (BSID-III) and BERA.

    Reporting group title
    Combined control group
    Reporting group description
    2 groups: Refusal control group: Subjects of which parents/guardians refused medicinal treatment. Subjects received regular care after cCMV diagnosis. Referral to pediatrician was advised. Initial home visit at inclusion: medical history taking, physical examination, child development test, blood sampling (complete blood count with differential, liver function tests and viral load). Urine filter papers were collected by parents and mailed, at baseline and during 7 weeks hereafter. Parents were asked to keep diaries. Follow-up visit at age 18-22 months: physical examination, developmental examination (BSID-III) and BERA. Historical control group: Children with hearing loss born between November 2011 and July 2012 were informed by audiologists about CONCERT trial and retrospective dried blood spot (DBS) testing was offered. After retrospective diagnosis, children were included for follow-up visit at age 18-22 months.

    Primary: Best ear hearing analysis

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    End point title
    Best ear hearing analysis
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to Follow-Up (18-22 months)
    End point values
    Treatment group Combined control group
    Number of subjects analysed
    24
    12
    Units: Subjects
        Improved at follow-up
    3
    0
        Normal hearing at baseline and Follow-up
    12
    2
        Same hearing loss at baseline and Follow-up
    7
    4
        Deteriorated hearing at follow-up
    2
    6
    Statistical analysis title
    Best ear hearing analysis
    Statistical analysis description
    proportional odds model
    Comparison groups
    Treatment group v Combined control group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.003
    Method
    Regression, Logistic
    Confidence interval

    Primary: Best ear hearing analysis, numerical

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    End point title
    Best ear hearing analysis, numerical
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to Follow-Up (18-22 months)
    End point values
    Treatment group Combined control group
    Number of subjects analysed
    24
    12
    Units: decibel
        number (not applicable)
    -3.3
    13.7
    Statistical analysis title
    Best ear hearing, numerical
    Comparison groups
    Treatment group v Combined control group
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.02
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.6
         upper limit
    31.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to Follow-Up (18-22 months)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    none
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    Infants in the treatment group received valgancivlovir 16mg/kg bid during six weeks. Per protocol, dosages were fixed for the entire treatment period. Initial home visit at inclusion: medical history taking, physical examination, child development test (van Wiechen), blood sampling (complete blood count with differential, liver function tests and viral load). Hereafter, weekly visits until one week after treatment for blood and urine filter paper sampling. Parents were asked keep diaries with abnormalities or signs during treatment and instructed to contact investigators in case of possible adverse events. Follow-up visit ate age 18-22 months: physical examination, developmental examination (BSID-III) and BERA.

    Serious adverse events
    Treatment group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 25 (4.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    General disorders and administration site conditions
    BRUE
    Additional description: Admitted for observation due to a brief resolved unexplained event (BRUE), consisting of apnea and color change, which had resolved upon arrival of the ambulance. Independent pediatrician assessed the SAE as unlikely to be related to the test product
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 25 (20.00%)
    Blood and lymphatic system disorders
    Anemia
    Additional description: One subject temporarily halted valganciclovir because of anemia (Hb 4.4 mmol/L) and mild leucopenia (4.14 x 10^9/L) and neutropenia (0.82 x 10^9/L), which resolved three days after cessation of the drug.
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    neutropenia
    Additional description: There were three occurrences of neutropenia in the treatment group: one resolved spontaneously without altering the dosage, one necessitated temporary suspension of the drug, and in one subject the dose was halved.
         subjects affected / exposed
    3 / 25 (12.00%)
         occurrences all number
    3
    Gastrointestinal disorders
    reflux
    Additional description: One subject temporarily halted the study drug because of gastrointestinal complaints which were later not ascribed to valganciclovir after restarting the drug.
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2013
    Changes in letter for parents to further explain the home visit. The letter to physicians regarding the participation of a child in the follow-up study has been added to further inform practitioners previously informed in CONCERT 1.0 about the follow-up in CONCERT 2.0
    24 Feb 2014
    Adjustment in the inclusion criterion regarding birth weight. The new criterion is: > -2 SD for gestational age and parentage. Previously, the criterion was ≥ 2500 grams. The new criterion is more accurate and more representative as birth weight is related to parentage and gestational age.
    17 Jul 2014
    - Recruitment method: Parents of children with hearing loss can also hear about the CONCERT study through another route (internet, friends/family or magazine article). Children who come into contact with the CONCERT study via these routes could also participate in CMV diagnostics. So not just with information from an audiologist. - Intention to treat for 6 weeks: In case of side effects, the treatment can be temporarily stopped. As soon as the blood values allow, treatment will be resumed with the intention of completing the 6 weeks of treatment. - Blood collection for neutropenia: after the detection of neutropenia, another blood sample is taken within 5 days. - The change in the letter concerns a textual change that the CMV diagnosis is offered to children older than 3 months.
    28 May 2015
    - Flyer 'Medical Scientific Research': This folder will in future be given by regional coordinators and audiologists who hand over the first information package (CMV diagnostics) to parents in the event of a referral in the hearing screening (region coordinator) or who are diagnosed with hearing loss (audiologist). - Inclusion of children of minor parents (<18 years): Excluding a child of minor parents is not in the best interests of the child itself. If the guardian(s) have been assigned and known to the researcher, the child can be included. - Change in letter information CMV diagnostics: In the letter it is added that parents have also received the flyer 'Medical Scientific Research' together with the letter. This is referred to in the consent form. - Change of consent forms: Two things have been added to the forms. Firstly, having the doctor (researcher) sign it for providing information to parents. Secondly, a textual addition that by signing the form parents / guardians also give permission for access to the research data by persons named in the folder 'Medical Scientific Research'.

    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.
    Non-randomised trial; this summary is written by another person than the lead researcher who initiated and coordinated the trial.
    For support, Contact us.
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