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    Clinical Trial Results:
    A PHASE II RANDOMIZED AND CONTROLLED INVESTIGATION OF SIX WEEKS OF ORAL VALGANCICLOVIR THERAPY IN INFANTS AND CHILDREN WITH CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS.

    Summary
    EudraCT number
    		 2014-001920-31
    Trial protocol
    		 GB  
    Global end of trial date
    03 Jan 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2022
    First version publication date
    21 Dec 2022
    Other versions
    Summary report(s)
    		 Summary report

    Trial information

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    Trial identification
    Sponsor protocol code
    DMID11-0069
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01649869
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 The UK Sponsor is: UCL: 08-0172
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Gower Street, London, United Kingdom,
    Public contact
    Prof Paul Griffiths, University College London, p.griffiths@ucl.ac.uk
    Scientific contact
    Prof Paul Griffiths, University College London, p.griffiths@ucl.ac.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
    15 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess whether a six week course of oral valganciclovir can stabilize the hearing of children with congenital CMV infection who present with hearing loss. This will be accomplished by evaluating changes in hearing in either ear at 6 months from baseline.
    Protection of trial subjects
    N/A
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Sep 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: 24
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    35
    EEA total number of subjects
    0
    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)
    24
    Children (2-11 years)
    11
    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
    		 For this study, subjects were enrolled once they signed the informed consent form (ICF). It was not until after hearing loss was confirmed by audiology testing and confirmation of congenital CMV by dried blood spot that a subject was randomized and started on study drug. This reduced protocol enrolment from 54 to 35.

    Pre-assignment
    Screening details
    		 Hearing loss was confirmed by audiology testing and congenital CMV was confirmed by dried blood spot.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 27 Children between 1 month and 3 years of age (up to 4th birthday) with sensoneural hearing loss and documented CMV infection will receive placebo orally twice a day for 6 weeks Placebo: Simple Syrup as 60-90% sucrose in purified water: given orally twice a day for 6 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Simple Syrup as 60-90% sucrose in purified water: given orally twice a day for 6 weeks.

    Arm title
    		 Active
    Arm description
    		 27 Children between 1 month and 3 years of age (up to 4th birthday) with sensoneural hearing loss and documented CMV infection will receive valganciclovir HCl 16.0 mg/kg orally twice a day for 6 weeks Valganciclovir: Valcyte (valganciclovir hydrochloride) 50 mg of valganciclovir free base per 1 mL, oral solution: given at 16.0 mg/kg, twice a day for 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Valganciclovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Valcyte (valganciclovir hydrochloride) 50 mg of valganciclovir free base per 1 mL, oral solution: given at 16.0 mg/kg, twice a day for 6 weeks

    Number of subjects in period 1
    		Placebo Active
    Started
    18
    17
    Completed
    16
    16
    Not completed
    2
    1
         Required treatment outside protocol
    1
    -
         Family member illness
    1
    -
         Severe hearing loss borderline eligible
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 27 Children between 1 month and 3 years of age (up to 4th birthday) with sensoneural hearing loss and documented CMV infection will receive placebo orally twice a day for 6 weeks Placebo: Simple Syrup as 60-90% sucrose in purified water: given orally twice a day for 6 weeks

    Reporting group title
    Active
    Reporting group description
    		 27 Children between 1 month and 3 years of age (up to 4th birthday) with sensoneural hearing loss and documented CMV infection will receive valganciclovir HCl 16.0 mg/kg orally twice a day for 6 weeks Valganciclovir: Valcyte (valganciclovir hydrochloride) 50 mg of valganciclovir free base per 1 mL, oral solution: given at 16.0 mg/kg, twice a day for 6 weeks.

    Reporting group values
    		 Placebo Active Total
    Number of subjects
    		 18 17 35
    Age categorical
    27 Children between 1 month and 3 years of age (up to 4th birthday) with sensoneural hearing loss and documented CMV infection will receive placebo orally twice a day for 6 weeks Placebo: Simple Syrup as 60-90% sucrose in purified water: given orally twice a day for 6 weeks
    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: months
        median (standard deviation)
    		 19.5 ± 13.1 17.8 ± 5.8 -
    Gender categorical
    Units: Subjects
        Female
    		 8 6 14
        Male
    		 10 11 21

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 27 Children between 1 month and 3 years of age (up to 4th birthday) with sensoneural hearing loss and documented CMV infection will receive placebo orally twice a day for 6 weeks Placebo: Simple Syrup as 60-90% sucrose in purified water: given orally twice a day for 6 weeks

    Reporting group title
    Active
    Reporting group description
    		 27 Children between 1 month and 3 years of age (up to 4th birthday) with sensoneural hearing loss and documented CMV infection will receive valganciclovir HCl 16.0 mg/kg orally twice a day for 6 weeks Valganciclovir: Valcyte (valganciclovir hydrochloride) 50 mg of valganciclovir free base per 1 mL, oral solution: given at 16.0 mg/kg, twice a day for 6 weeks.

    Subject analysis set title
    Randomized
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Randomized children between 1 month and 3 years of age (up to 4th birthday) with sensoneural hearing loss and documented CMV infection will receive placebo orally twice a day for 6 weeks

    Primary: Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing.

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    End point title
    		 Number of Ears That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing.
    End point description
    A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss. Not both ears are evaluable for all subjects. In some subjects, only one ear is evaluable.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 180
    End point values
    		 Placebo Active
    Number of subjects analysed
    16
    15
    Units: Ears
        Improve + no change
    27
    20
        Worsened
    1
    6
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0859
    Method
    		 Generalized linear model for binary outc
    Confidence interval

    Secondary: Number of Best Ear That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing [ex. Improved+ no Change (Normal to Normal) Versus Other].

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    End point title
    		 Number of Best Ear That Had (1) Improved Hearing or no Change in Hearing (2) Worsened Hearing [ex. Improved+ no Change (Normal to Normal) Versus Other].
    End point description
    A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss. For this outcome, we combine the improved hearing and no change for the special case only of normal to normal. Other category include worsened and no change from (1) mild to mild hearing loss, (2) moderate to moderate hearing loss, or (3) severe to severe hearing loss.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 180
    End point values
    		 Placebo Active
    Number of subjects analysed
    15
    12
    Units: Participants
        Improved + normal to normal
    9
    6
        No change abnormal or worsened
    6
    6
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7068
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Adverse Event (AE) Resulting in Unanticipated Medically Attended Visit

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    End point title
    		 Adverse Event (AE) Resulting in Unanticipated Medically Attended Visit
    End point description
    Adverse event resulting in unanticipated medically attended visit. This outcome summarizes the number of adverse events (AEs) that resulted in the unanticipated medically attended visit.
    End point type
    Secondary
    End point timeframe
    Day 1 thru day 70
    End point values
    		 Placebo Active
    Number of subjects analysed
    18
    17
    Units: Participants
        No
    15
    17
        Yes
    3
    0
    No statistical analyses for this end point

    Secondary: Adverse Event (AE) Resulting in Unresolved Outcome

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    End point title
    		 Adverse Event (AE) Resulting in Unresolved Outcome
    End point description
    Adverse event resulting in unresolved outcome. This outcome summarizes the number of adverse events (AEs) that resulted in unresolved outcome of that AE.
    End point type
    Secondary
    End point timeframe
    Day 1 thru day 70
    End point values
    		 Placebo Active
    Number of subjects analysed
    18
    17
    Units: Participants
        No
    18
    17
        Yes
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Adverse Events in the Active Group That Resulted in Discontinuation of Valganciclovir

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    End point title
    		 Number of Adverse Events in the Active Group That Resulted in Discontinuation of Valganciclovir [1]
    End point description
    AE resulting in discontinuation of valganciclovir (active group only). This outcome summarizes the number of adverse events (AEs) that resulted in the discontinuation of valganciclovir in the active group only.
    End point type
    Secondary
    End point timeframe
    Day 1 thru day 70
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was just for the participants who had randomised to receive the IMP.
    End point values
    		 Active
    Number of subjects analysed
    17
    Units: Participants
        No
    17
        Yes
    0
    No statistical analyses for this end point

    Secondary: The Quantitative Log Reduction in CMV in Saliva Detected After 6 Weeks of Therapy

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    End point title
    		 The Quantitative Log Reduction in CMV in Saliva Detected After 6 Weeks of Therapy
    End point description
    The quantitative log reduction in CMV in saliva (urine) detected after 6 weeks of therapy. Quantitative viral load by PCR in log 10 units measured in urine after 6 weeks of therapy; if undetectable, viral load is assigned a value of 10 (1 in log 10 units)
    End point type
    Secondary
    End point timeframe
    Baseline thru months 6
    End point values
    		 Placebo Active
    Number of subjects analysed
    17
    17
    Units: log10 IU/ml
        least squares mean (confidence interval 95%)
    0.0057 (-0.6395 to 0.6508)
    1.3202 (0.6894 to 1.9509)
    No statistical analyses for this end point

    Secondary: The Quantitative Log Reduction in Viruria Detected After 6 Weeks of Therapy

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    End point title
    		 The Quantitative Log Reduction in Viruria Detected After 6 Weeks of Therapy
    End point description
    The quantitative log reduction in viruria (urine) detected after 6 weeks of therapy. Quantitative viral load by PCR in log 10 units measured in urine after 6 weeks of therapy; if undetectable, viral load is assigned a value of 10 (1 in log 10 units)
    End point type
    Secondary
    End point timeframe
    Baseline thru months 6
    End point values
    		 Placebo Active
    Number of subjects analysed
    13
    15
    Units: log10 IU/ml
        least squares mean (confidence interval 95%)
    0.8390 (-0.05057 to 1.7286)
    1.2152 (0.5274 to 1.9029)
    No statistical analyses for this end point

    Secondary: The Quantitative Log Change in Viremia From Baseline to Month 6.

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    End point title
    		 The Quantitative Log Change in Viremia From Baseline to Month 6.
    End point description
    The quantitative change (Month 6 minus baseline) in viremia (blood) Quantitative viral load by PCR in log 10 units measured in urine after 6 weeks of therapy; if undetectable, viral load is assigned a value of 10 (1 in log 10 units).
    End point type
    Secondary
    End point timeframe
    Baseline to month 6
    End point values
    		 Placebo Active
    Number of subjects analysed
    17
    17
    Units: log10 IU/ml
        least squares mean (confidence interval 95%)
    -0.1528 (-0.5721 to 0.2664)
    0.4908 (0.08108 to 0.9005)
    No statistical analyses for this end point

    Secondary: Detection of CMV in Saliva PCR Six Month After Trial Entry

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    End point title
    		 Detection of CMV in Saliva PCR Six Month After Trial Entry
    End point description
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.
    End point type
    Secondary
    End point timeframe
    At 6 months
    End point values
    		 Placebo Active
    Number of subjects analysed
    16
    16
    Units: Participants
        Positive
    8
    7
        Negative
    8
    9
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Detection of CMV in Saliva by PCR Six Weeks After Trial Entry

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    End point title
    		 Detection of CMV in Saliva by PCR Six Weeks After Trial Entry
    End point description
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.
    End point type
    Secondary
    End point timeframe
    At 6 weeks (Day 42)
    End point values
    		 Placebo Active
    Number of subjects analysed
    16
    16
    Units: Participants
        Positive
    9
    3
        Negative
    7
    13
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0659
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Detection of Viremia (Blood) by PCR Six Month After Trial Entry

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    End point title
    		 Detection of Viremia (Blood) by PCR Six Month After Trial Entry
    End point description
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.
    End point type
    Secondary
    End point timeframe
    At 6 months
    End point values
    		 Placebo Active
    Number of subjects analysed
    15
    15
    Units: Participants
        Positive
    4
    3
        Negative
    11
    12
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Detection of Viremia (Blood) by PCR Six Weeks After Trial Entry

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    End point title
    		 Detection of Viremia (Blood) by PCR Six Weeks After Trial Entry
    End point description
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.
    End point type
    Secondary
    End point timeframe
    At 6 weeks (Day 42)
    End point values
    		 Placebo Active
    Number of subjects analysed
    15
    14
    Units: Participants
        Positive
    4
    2
        Negative
    11
    12
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6513
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Detection of Viruria (Urine) by PCR Six Month After Trial Entry

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    End point title
    		 Detection of Viruria (Urine) by PCR Six Month After Trial Entry
    End point description
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.
    End point type
    Secondary
    End point timeframe
    At 6 months
    End point values
    		 Placebo Active
    Number of subjects analysed
    11
    14
    Units: Participants
        Positive
    10
    11
        Negative
    1
    3
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6043
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Detection of Viruria (Urine) by PCR Six Weeks After Trial Entry

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    End point title
    		 Detection of Viruria (Urine) by PCR Six Weeks After Trial Entry
    End point description
    Each subject either has positive or negative PCR results. Virus is detected if the PCR is positive.
    End point type
    Secondary
    End point timeframe
    At 6 weeks (Day 42)
    End point values
    		 Placebo Active
    Number of subjects analysed
    12
    12
    Units: Participants
        Positive
    11
    1
        Negative
    1
    11
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Change in Total Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6.

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    End point title
    		 Change in Total Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6.
    End point description
    A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 180
    End point values
    		 Placebo Active
    Number of subjects analysed
    16
    15
    Units: Ears
        Worsened
    1
    6
        Other
    27
    20
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0859
    Method
    		 Generalized linear model for binary outc
    Confidence interval

    Secondary: Change in Total Ear Hearing Assessments [Worse+ no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6.

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    End point title
    		 Change in Total Ear Hearing Assessments [Worse+ no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6.
    End point description
    A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 180
    End point values
    		 Placebo Active
    Number of subjects analysed
    16
    15
    Units: Ears
        worse + no change (abnormal to abnormal)
    19
    20
        Other
    9
    6
    No statistical analyses for this end point

    Secondary: Change in Total Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6.

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    End point title
    		 Change in Total Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6.
    End point description
    A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 180
    End point values
    		 Placebo Active
    Number of subjects analysed
    16
    15
    Units: Ears
        Improved
    0
    0
        Other
    28
    26
    No statistical analyses for this end point

    Secondary: Change in Best Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6.

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    End point title
    		 Change in Best Ear Hearing Assessments [Worse Versus Other] Between Baseline and Study Month 6.
    End point description
    A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 180
    End point values
    		 Placebo Active
    Number of subjects analysed
    15
    12
    Units: Participants
        Worsened
    0
    3
        Other
    15
    9
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0752
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Change in Best Ear Hearing Assessments [Worse + no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6.

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    End point title
    		 Change in Best Ear Hearing Assessments [Worse + no Change (Abnormal to Abnormal) Versus Other] Between Baseline and Study Month 6.
    End point description
    A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 180
    End point values
    		 Placebo Active
    Number of subjects analysed
    15
    12
    Units: Participants
        No change abnormal to abnormal + worsened
    6
    6
        Improved + normal to normal
    9
    6
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7068
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Change in Best Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6.

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    End point title
    		 Change in Best Ear Hearing Assessments [Improved Versus Other] Between Baseline and Study Month 6.
    End point description
    A single, independent study audiologist who is masked (blinded) to treatment assignment will assess the audiology test battery for each subject and assign the classifications of normal hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear and one for the right ear), giving "total ear" classifications. At the analyses stage, the "best ear" classification for the subject at that study visit will be determined; for example, if a subject had mild hearing loss in their left ear and severe hearing loss in their right ear, then the "best ear" classification will be mild hearing loss.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 180
    End point values
    		 Placebo Active
    Number of subjects analysed
    15
    12
    Units: Participants
        Improved
    0
    0
        No change or worsened
    15
    12
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Association of Change in Viral Load (Blood) With Change in Total Ear Hearing at 6 Months

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    End point title
    		 Association of Change in Viral Load (Blood) With Change in Total Ear Hearing at 6 Months
    End point description
    Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.
    End point type
    Secondary
    End point timeframe
    At 6 months
    End point values
    		 Randomized
    Number of subjects analysed
    31
    Units: Ears
    log mean (standard deviation)
        Improved + normal to normal
    1.396 ± 0.542
        No change abnormal + worsened
    1.326 ± 0.566
    No statistical analyses for this end point

    Secondary: Association of Change in Viral Load (Saliva) With Change in Total Ear Hearing at 6 Months

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    End point title
    		 Association of Change in Viral Load (Saliva) With Change in Total Ear Hearing at 6 Months
    End point description
    Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units or log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.
    End point type
    Secondary
    End point timeframe
    At 6 months
    End point values
    		 Randomized
    Number of subjects analysed
    31
    Units: log 10 copies/ml
    log mean (standard deviation)
        Improved + normal to normal
    2.447 ± 1.715
        No change abnormal + worsened
    2.290 ± 1.349
    No statistical analyses for this end point

    Secondary: Association of Change in Viral Load (Urine) With Change in Total Ear Hearing at 6 Months

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    End point title
    		 Association of Change in Viral Load (Urine) With Change in Total Ear Hearing at 6 Months
    End point description
    Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.
    End point type
    Secondary
    End point timeframe
    At 6 months
    End point values
    		 Randomized
    Number of subjects analysed
    29
    Units: log 10 copies/ml
    log mean (standard deviation)
        Improved + normal to normal
    3.562 ± 1.139
        No change abnormal + worsened
    3.583 ± 1.370
    No statistical analyses for this end point

    Secondary: Association of Change in Viral Load (Blood) With Change in Best Ear Hearing at 6 Months

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    End point title
    		 Association of Change in Viral Load (Blood) With Change in Best Ear Hearing at 6 Months
    End point description
    Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.
    End point type
    Secondary
    End point timeframe
    At 6 months
    End point values
    		 Randomized
    Number of subjects analysed
    27
    Units: log 10 copies/ml
    log mean (standard deviation)
        Improved + normal to normal
    1.396 ± 0.542
        No change abnormal + worsened
    1.359 ± 0.668
    No statistical analyses for this end point

    Secondary: Association of Change in Viral Load (Saliva) With Change in Best Ear Hearing at 6 Months

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    End point title
    		 Association of Change in Viral Load (Saliva) With Change in Best Ear Hearing at 6 Months
    End point description
    Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.
    End point type
    Secondary
    End point timeframe
    At 6 months
    End point values
    		 Randomized
    Number of subjects analysed
    27
    Units: log 10 copies/ml
    log mean (standard deviation)
        Improved + normal to normal
    2.447 ± 1.715
        No change abnormal + worsened
    2.423 ± 1.484
    No statistical analyses for this end point

    Secondary: Association of Change in Viral Load (Urine) With Change in Best Ear Hearing at 6 Months

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    End point title
    		 Association of Change in Viral Load (Urine) With Change in Best Ear Hearing at 6 Months
    End point description
    Analysis of actual viral load was done using log base 10 transformation. Undetectable viral load value was replaced by a value of 10. A summary measure of the viral load over time considers all time points available by calculating the average area under the curve (AUC) (trapezoidal rule) applied to the log base 10 viral load. Average is based on the maximum period of time with viral load data for a given subject. The average or standardize AUC units is therefore the original AUC units of log 10 copies/ml*days divided by days in study which equals log 10 copies/ml.
    End point type
    Secondary
    End point timeframe
    At 6 months
    End point values
    		 Randomized
    Number of subjects analysed
    25
    Units: log 10 copies/ml
    log mean (standard deviation)
        Improved + normal to normal
    3.562 ± 1.139
        No change abnormal + worsened
    3.831 ± 1.570
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were recorded from Study Day 1 until 4 weeks after last dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Active Group
    Reporting group description
    		 Participants received study drug.

    Reporting group title
    Placebo Group
    Reporting group description
    		 Participants received placebo.

    Serious adverse events
    		 Active Group Placebo Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Active Group Placebo Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 17 (76.47%)
    12 / 18 (66.67%)
    General disorders and administration site conditions
    Hypermetropia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    2 / 17 (11.76%)
    4 / 18 (22.22%)
         occurrences all number
    2
    4
    Condition aggravated
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 18 (11.11%)
         occurrences all number
    2
    6
    Rhinorrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Bronchiolitis
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Nasal congestion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 18 (11.11%)
         occurrences all number
    2
    3
    Rhinovirus infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Asthma
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Screaming
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Hallucination
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Agitation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Crying
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Investigations
    Blood urine present
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Protein urine present
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 18 (11.11%)
         occurrences all number
    1
    4
    Monocytopenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear infection
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Auditory disorder
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Otitis media
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 18 (11.11%)
         occurrences all number
    1
    3
    Vomiting
         subjects affected / exposed
    5 / 17 (29.41%)
    2 / 18 (11.11%)
         occurrences all number
    5
    5
    Decreased appetite
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Teething
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 18 (11.11%)
         occurrences all number
    2
    2
    Diarrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    Gastroenteritis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Reflux gastritis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Petechiae
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Dermatitis diaper
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Rash erythematous
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Impetigo
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Rash papular
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Pallor
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Osteopenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Viral infection
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 18 (11.11%)
         occurrences all number
    1
    3
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Tonsillitis
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Postoperative wound infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Varicella
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 18 (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 reported
    For support, Contact us.
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    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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