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    Clinical Trial Results:
    Pharmacokinetics and safety of valganciclovir in pediatric heart transplant recipients < 4 months of age.

    Summary
    EudraCT number
    2010-021172-28
    Trial protocol
    ES  
    Global end of trial date
    30 Sep 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NP22523
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01165580
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, CH-4070, Basel, Basel, Switzerland,
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 061 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 061 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000072-PIP01-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to characterize the pharmacokinetics of ganciclovir (GCV) following oral administration of valganciclovir (VGCV) in pediatric heart transplant recipients less than (<) 4 months of age.
    Protection of trial subjects
    The investigator ensured that this study was conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 May 2011
    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
    Spain: 2
    Country: Number of subjects enrolled
    United States: 15
    Worldwide total number of subjects
    17
    EEA total number of subjects
    2
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    1
    Infants and toddlers (28 days-23 months)
    16
    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
    -

    Pre-assignment
    Screening details
    Participants who were heart transplant recipients, aged < 4 months (<125 days), considered hemodynamically stable, at risk of cytomegalovirus (CMV) disease and are being treated with intravenous GCV or VGCV oral solution for the prevention of CMV disease.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    VGCV: All treated participants
    Arm description
    Participants aged < 4 months received 2 doses (one dose per day on 2 consecutive days) of VGCV orally according to the following dosing algorithm: Dose of VGCV is equal to 7 times the multiplied value of the subject's body surface area (BSA) and creatinine clearance estimated by modified Schwartz formula (CrCLS) in milligrams (mg). If the calculated dose was greater than (>) 900 mg then dose given was 900 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    Valganciclovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 2 doses of VGCV orally (one dose per day) according to the following dosing algorithm. Dose of VGCV is equal to 7 times the multiplied value of the subject's BSA and CrCLS. If the calculated dose was >900 mg then dose given was 900 mg.

    Number of subjects in period 1
    VGCV: All treated participants
    Started
    17
    Completed
    16
    Not completed
    1
         Physician decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study
    Reporting group description
    -

    Reporting group values
    Overall study Total
    Number of subjects
    17 17
    Age categorical
    Units: Subjects
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    85.06 ± 33.39 -
    Gender categorical
    Units: Subjects
        Female
    7 7
        Male
    10 10

    End points

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    End points reporting groups
    Reporting group title
    VGCV: All treated participants
    Reporting group description
    Participants aged < 4 months received 2 doses (one dose per day on 2 consecutive days) of VGCV orally according to the following dosing algorithm: Dose of VGCV is equal to 7 times the multiplied value of the subject's body surface area (BSA) and creatinine clearance estimated by modified Schwartz formula (CrCLS) in milligrams (mg). If the calculated dose was greater than (>) 900 mg then dose given was 900 mg.

    Primary: Area Under the Concentration-Time Curve Over the Dosing Interval (AUC 0-24 hours) for GCV

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    End point title
    Area Under the Concentration-Time Curve Over the Dosing Interval (AUC 0-24 hours) for GCV [1]
    End point description
    An integrated population pharmacokinetics (PopPK) model was used to characterize the pharmacokinetics (PK) of GCV which combined the results of this study in pediatric heart transplant participants along with other 3 studies (WP16296, WP16303 and WV16726). The PopPK model is a 2-compartment PK model with first order formation following administration of VGCV with a lag time.
    End point type
    Primary
    End point timeframe
    On study Days 2 and 3: pre-dose, 1-3 hours, 3-7 hours, 7-12 hours and 24 hours post-dose.
    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: No statistical analysis was performed as this was not part of the planned primary endpoint analysis.
    End point values
    VGCV: All treated participants
    Number of subjects analysed
    14 [2]
    Units: microgram(s)*hour/millilitre
        arithmetic mean (standard deviation)
    68.1 ± 19.8
    Notes
    [2] - PopPK analysis was performed in the initial 14 participants, not all treated participants.
    No statistical analyses for this end point

    Primary: Apparent Volume of Distribution of GCV

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    End point title
    Apparent Volume of Distribution of GCV [3]
    End point description
    PopPK model was used to characterize the PK of GCV which combined the results of this study in pediatric heart transplant participants along with other 3 studies (WP16296, WP16303 and WV16726). The PopPK model is a 2-compartment PK model with first order formation following administration of VGCV with a lag time.
    End point type
    Primary
    End point timeframe
    On study days 2 and 3: pre-dose, 1-3 hours, 3-7 hours, 7-12 hours and 24 hours post-dose.
    Notes
    [3] - 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: No statistical analysis was performed as this was not part of the planned primary endpoint analysis.
    End point values
    VGCV: All treated participants
    Number of subjects analysed
    14 [4]
    Units: litre(s)
    arithmetic mean (standard deviation)
        Central volume
    2.13 ± 0.396
        Peripheral volume
    2.09 ± 0.456
    Notes
    [4] - PopPK analysis was performed in the initial 14 participants, not all treated participants.
    No statistical analyses for this end point

    Primary: Terminal Half-life of GCV

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    End point title
    Terminal Half-life of GCV [5]
    End point description
    PopPK model was used to characterize the PK of GCV which combined the results of this study in pediatric heart transplant participants along with other 3 studies (WP16296, WP16303 and WV16726). The PopPK model is a 2-compartment PK model with first order formation following administration of VGCV with a lag time.
    End point type
    Primary
    End point timeframe
    On study days 2 and 3: pre-dose, 1-3 hours, 3-7 hours, 7-12 hours and 24 hours post-dose.
    Notes
    [5] - 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: No statistical analysis was performed as this was not part of the planned primary endpoint analysis.
    End point values
    VGCV: All treated participants
    Number of subjects analysed
    14 [6]
    Units: hour(s)
        arithmetic mean (standard deviation)
    1.97 ± 0.185
    Notes
    [6] - PopPK analysis was performed in the initial 14 participants, not all treated participants.
    No statistical analyses for this end point

    Primary: Maximum Observed Concentration (Cmax) of GCV

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    End point title
    Maximum Observed Concentration (Cmax) of GCV [7]
    End point description
    PopPK model was used to characterize the PK of GCV which combined the results of this study in pediatric heart transplant participants along with other 3 studies (WP16296, WP16303 and WV16726). The PopPK model is a 2-compartment PK model with first order formation following administration of VGCV with a lag time.
    End point type
    Primary
    End point timeframe
    On study days 2 and 3: pre-dose, 1-3 hours, 3-7 hours, 7-12 hours and 24 hours post-dose.
    Notes
    [7] - 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: No statistical analysis was performed as this was not part of the planned primary endpoint analysis.
    End point values
    VGCV: All treated participants
    Number of subjects analysed
    14 [8]
    Units: microgram(s)/millilitre
        arithmetic mean (standard deviation)
    10.5 ± 3.35
    Notes
    [8] - PopPK analysis was performed in the initial 14 participants, not all treated participants.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were assessed throughout the study period up to 7 (+/-2) days, post 2nd VGCV dose.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    VGCV: All treated participants
    Reporting group description
    Participants aged < 4 months received 2 doses (one dose per day on 2 consecutive days) of VGCV POS according to dosing using the dosing algorithm: Dose of VGCV = 7 * BSA * CrCLS. If the calculated dose was >900 mg then dose given was 900 mg.

    Serious adverse events
    VGCV: All treated participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 17 (11.76%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Postoperative wound infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    VGCV: All treated participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 17 (47.06%)
    Cardiac disorders
    Ventricular tachycardia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Tachypnoea
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 17 (23.53%)
         occurrences all number
    4
    Thrombocytosis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Flatulence
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Haematochezia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Metabolic acidosis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Tracheitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
         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
    30 Sep 2010
    This protocol amendment documented that two doses would be received, added a 24-hour PK sample collection, specified a 5-part differential cell count, added an upper limit to the CrCL, updated and specified route of administration, updated the adverse event intensity to a 3-point scale, updated serious adverse event reporting requirements, and added an interim analysis to be performed after four participants have been enrolled in the birth to < 6 weeks age group to assess the effectiveness of the dosing algorithm in this age group.
    30 Mar 2012
    This protocol amendment documented that dosing would not be automatically calculated on the electronic case report form (eCRF), added a window for the post-dosing assessment timeframe, specified when to start collecting previous/concurrent diseases and treatments in the screening assessments, clarified the supplies that would be provided for the administration of the Investigational Medicinal Product (IMP), and modified the inclusion criteria to state participants had to be < 125 days at the time of the last PK assessment and participants with any form of tube feeding can be included.
    28 Dec 2012
    This protocol amendment provided clarification regarding enrollment of 16 participants in the study but recruitment has not been met in the age group birth to < 6 weeks changed the participant numbers to permit a minimum of 16 and a maximum of 24 participants to be enrolled into the study. A maximum recruitment number (24 participants) was provided, allowing for a minimum of four, and maximum of eight participants in the birth to < 6 weeks of age group. The total number of participants to be enrolled in this younger group is dependent on results from ongoing PK data analysis, and whether the data are consistent (within agreed variability boundaries) with those observed in participants at least 4 months of age. The planned recruitment period has been extended to approximately 3 years to allow sufficient time to recruit the required number of participants within the birth to < 6 weeks of age group to facilitate dosing recommendations in this age group.

    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 reported
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