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    Clinical Trial Results:
    Feasibility and effects on markers in spinal fluid in persons with early Alzheimer's disease when treated with Valaciklovir - open Fas II pilot study (VALZ-Pilot)

    Summary
    EudraCT number
    2016-002317-22
    Trial protocol
    SE  
    Global end of trial date
    14 Jun 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Dec 2021
    First version publication date
    25 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VALZ-Pilot
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Region Västerbotten
    Sponsor organisation address
    Umeå University hospital, Umeå, Sweden,
    Public contact
    Hugo Lövheim, Umeå University hospital - Geriatric centre, 0046 907850000, hugo.lovheim@umu.se
    Scientific contact
    Hugo Lövheim, Umeå University hospital - Geriatric centre, 0046 907850000, hugo.lovheim@umu.se
    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
    01 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objectives in this study are to evaluate change in the measured markers for Alzheimer’s disease between first and second measurement (before and after 28 days of treatment with Valaciklovir), and to evaluate if [18F]-FHBG-PET/CT can be used to show replicating HSV in the brain at early Alzheimer’s disease. Another primary objective is to evaluate safety and feasibility for the thorough examinations and treatment.
    Protection of trial subjects
    The study participant were followed from first dose of studymedication and up to 30 days after after last dose of studymedication both by study visits and by phone calls. Inclusions and exclusion criterias were carefully reviewed. Before start of study drug the protocol stated that bloodsamples were taken in order to exclude patients in risk. If the patient experienced any adverse events during the study these events were carefully evaluated and if necessary the patient was taken of study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Dec 2016
    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
    Sweden: 73
    Worldwide total number of subjects
    73
    EEA total number of subjects
    73
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    68
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were recruited via advertisement i local newspapers and via ordinary doctors visits at geriatric center in Umeå, Skellefteå and Uppsala.

    Pre-assignment
    Screening details
    In total 136 patients were screened for participating in the study and 73 patients were enrolled in the study.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Baseline period
    Arm description
    Before starting studydrug treatment all patients went through a baseline period which included bloodtesting and exams to evaluate if the patient was eligible to start study drug.
    Arm type
    Inclusion period

    Investigational medicinal product name
    9-[4-[18]F-Fluoro- 3(hydroxymethyl)butyl]guaine
    Investigational medicinal product code
    PR2
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single bolus injection at two occasions, total dose 3.5 MBq/kg

    Number of subjects in period 1
    Baseline period
    Started
    73
    Study treatment
    33
    Completed
    33
    Not completed
    40
         Physician decision according to protocol
    40
    Period 2
    Period 2 title
    Study treatment
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Study site A and B
    Arm description
    All patients enrolled into study site A and B were treated with study drug valaciclovir (n=33). A subgroup from studisite A were treated with [18F]-FHBG-PET/CT to evaluate if [18F]-FHBG-PET/CT can be used to show replicating HSV in the brain.
    Arm type
    Experimental

    Investigational medicinal product name
    Valaciklovir
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    First 7 days 500mg x 3/day, if tolerated an increased dose of 1000 mg x3/day was done at day 7 and this dose were keept until study completion (day 28).

    Investigational medicinal product name
    9-[4-[18]F-Fluoro- 3(hydroxymethyl)butyl]guaine
    Investigational medicinal product code
    PR2
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single bolus injection at two occasions, total dose 3.5 MBq/kg

    Number of subjects in period 2
    Study site A and B
    Started
    33
    Completed
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    Baseline characteristics are reported for all enrolled patients regardless study site A or B since all patients went though the same baseline procedures.

    Reporting group values
    Baseline Total
    Number of subjects
    73 73
    Age categorical
    All patients enrolled in the studie were elderly patients.
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    0 0
        From 65-84 years
    68 68
        85 years and over
    5 5
    Gender categorical
    Units: Subjects
        Female
    35 35
        Male
    38 38
    Subject analysis sets

    Subject analysis set title
    [18F]-FHBG-PET/CT
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A subgroup from study site A (n=9) were asked to evaluate if [18F]- FHBG-PET/CT can be used to show replicating HSV in the brain at early Alzheimer's disease.

    Subject analysis set title
    Administrative group for single arm study
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Because this is a single arm study this subject analysis set is done only for administrative reasons. There are no patients to report in this group however the system does not allow a subject analysis set, number of subjects to be zero.

    Subject analysis sets values
    [18F]-FHBG-PET/CT Administrative group for single arm study
    Number of subjects
    9
    1
    Age categorical
    All patients enrolled in the studie were elderly patients.
    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
    9
        85 years and over
    0
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    4
        Male
    5

    End points

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    End points reporting groups
    Reporting group title
    Baseline period
    Reporting group description
    Before starting studydrug treatment all patients went through a baseline period which included bloodtesting and exams to evaluate if the patient was eligible to start study drug.
    Reporting group title
    Study site A and B
    Reporting group description
    All patients enrolled into study site A and B were treated with study drug valaciclovir (n=33). A subgroup from studisite A were treated with [18F]-FHBG-PET/CT to evaluate if [18F]-FHBG-PET/CT can be used to show replicating HSV in the brain.

    Subject analysis set title
    [18F]-FHBG-PET/CT
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A subgroup from study site A (n=9) were asked to evaluate if [18F]- FHBG-PET/CT can be used to show replicating HSV in the brain at early Alzheimer's disease.

    Subject analysis set title
    Administrative group for single arm study
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Because this is a single arm study this subject analysis set is done only for administrative reasons. There are no patients to report in this group however the system does not allow a subject analysis set, number of subjects to be zero.

    Primary: To evaluate change in brain damage markers total-Tau for Alzheimer's disease between first and second measurement (before and after 28 days of treatment with Valaciklovir)

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    End point title
    To evaluate change in brain damage markers total-Tau for Alzheimer's disease between first and second measurement (before and after 28 days of treatment with Valaciklovir)
    End point description
    To evaluate change in brain damage markers total-Tau for Alzheimer's disease between first and second measurement (before and after 28 days of treatment with Valaciklovir)
    End point type
    Primary
    End point timeframe
    Evaluates by comparing first and second measurement day 1 and day 28.
    End point values
    Study site A and B Administrative group for single arm study
    Number of subjects analysed
    33
    1
    Units: units
    33
    1
    Statistical analysis title
    Statistical differences between two measurements
    Statistical analysis description
    Statistical differences between two measurements are analyzeded with intention to treat. Simple statistical tests to compare paired values ​​(e.g. paired t-test) will be used to compare the level of markers in spinal fluid before and after treatment, and to evaluate other outcome measures. Each individual is it´s own control.
    Comparison groups
    Study site A and B v Administrative group for single arm study
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.653 [1]
    Method
    t-test, 2-sided
    Confidence interval
    Notes
    [1] - t-tau before and after (mean +- SD): 720.8 ± 342.8 och 727.7 ± 326.6 pg/mL

    Primary: Feasibility

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    End point title
    Feasibility
    End point description
    Is treatment with Valaciklovir 1500 mg/day or 3000 mg/day feasible in elderly patients with Alzheimer's disease? Is [18F]-FHBG-PET/CT a feasible examination in patients with Alzheimer's disease
    End point type
    Primary
    End point timeframe
    Evaluates at v 2, v3, v4, v5 and v6, there will also be two telephone calls between v 3 and v4 where adverse events will be recorded.
    End point values
    Study site A and B Administrative group for single arm study
    Number of subjects analysed
    33
    1
    Units: units
        number (not applicable)
    33
    1
    Statistical analysis title
    CSF acyclovir koncentration
    Statistical analysis description
    “The intervention’s feasibility and by assessing the CSF acyclovir concentration on intervention day 28.”
    Comparison groups
    Study site A and B v Administrative group for single arm study
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    5.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.47
         upper limit
    6.11
    Variability estimate
    Standard deviation
    Dispersion value
    2.31
    Notes
    [2] - CSF acyclovir konc = mean 5.29 ± 2.31 µmol/L.

    Primary: To evaluate change in brain damage markers NFL (Neorofilament light chain) for Alzheimer's disease between first and second measurement (before and after 28 days of treatment with Valaciklovir)

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    End point title
    To evaluate change in brain damage markers NFL (Neorofilament light chain) for Alzheimer's disease between first and second measurement (before and after 28 days of treatment with Valaciklovir)
    End point description
    To evaluate change in brain damage markers NFL (Neorofilament light chain) for Alzheimer's disease between first and second measurement (before and after 28 days of treatment with Valaciklovir)
    End point type
    Primary
    End point timeframe
    Evaluates by comparing first and second measurement day 1 and day 28.
    End point values
    Study site A and B Administrative group for single arm study
    Number of subjects analysed
    33
    1
    Units: units
    33
    1
    Statistical analysis title
    Statistical differences between two measurements
    Statistical analysis description
    Diffrence in NFL before and after treatment with Valaciclovir. Each individual is it´s own control.
    Comparison groups
    Study site A and B v Administrative group for single arm study
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.52 [3]
    Method
    t-test, 2-sided
    Confidence interval
    Notes
    [3] - NFL before and after (mean +- SD): 1768.8 ± 680.4 och 1816.3 ± 702.4 pg/mL

    Primary: Safety

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    End point title
    Safety [4]
    End point description
    Is treatment with Valaciklovir 1500 mg/day or 3000 mg/day safe and tolerated in elderly patients with Alzheimer's disease and is [18F]-FHBG-PET/CT a safe examination in patients with Alzheimer's disease? Fourteen AEs in 11 participants and two SAEs in one participant were reported. Ten AEs and no SAE in six participants (18.2% of all) were considered to be related to the valacyclovir intervention (fatigue, headache [n = 2 each]; thirst, nausea, loose stools, mild depressive symptoms, mild tremor, polyuria [n = 1 each]). One AE (panic attack) related to the [18F]FHBG PET/CT intervention occurred.” The serum creatinine did not change significantly during the intervention, but seven participants experienced temporary creatinine increases > 10%; all of these participants’ creatinine levels had normalized at the time of subsequent medical records reviews.”
    End point type
    Primary
    End point timeframe
    Evaluates at v 2, v3, v4, v5 and v6, there will also be two telephone calls between v 3 and v4 where adverse events will be recorded.
    Notes
    [4] - 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: This is a one armed study with only one group to analyse.
    End point values
    Study site A and B Administrative group for single arm study
    Number of subjects analysed
    33
    1
    Units: units
        number (not applicable)
    33
    1
    No statistical analyses for this end point

    Secondary: Can[18F]- FHBG-PET/CT be used to show replicating HSV in the brain at early Alzheimer's disease.

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    End point title
    Can[18F]- FHBG-PET/CT be used to show replicating HSV in the brain at early Alzheimer's disease.
    End point description
    Secondary objectives, concerning a subgroup were to evaluate if [18F]- FHBG-PET/CT can be used to show replicating HSV in the brain at early Alzheimer's disease.
    End point type
    Secondary
    End point timeframe
    Before start with study drug and after 28 days of treatment.
    End point values
    [18F]-FHBG-PET/CT
    Number of subjects analysed
    9
    Units: units
        number (not applicable)
    9
    No statistical analyses for this end point

    Secondary: Evaluate biomarkers in CSF and MMSE-SR before and after treatment with Valaciklovir

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    End point title
    Evaluate biomarkers in CSF and MMSE-SR before and after treatment with Valaciklovir
    End point description
    Secondary objectives were also to evaluate biomarkers in CSF and MMSE-SR before and after treatment with Valaciklovir and to evaluate the concentration of Aciklovir and the breakdown product CMMG in plasma and CSF when treating elderly persons with Alzheimer's disease.
    End point type
    Secondary
    End point timeframe
    Before start with study drug and after 28 days of treatment.
    End point values
    Study site A and B
    Number of subjects analysed
    33
    Units: units
    33
    No statistical analyses for this end point

    Secondary: To investigate if [18F]-FHBG is accumulated in the areas of the brain that are affected in early Alzheimer's disease and if [18F]-FHBG-PET/CT can be used to demonstrate the effect of Valaciklovir

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    End point title
    To investigate if [18F]-FHBG is accumulated in the areas of the brain that are affected in early Alzheimer's disease and if [18F]-FHBG-PET/CT can be used to demonstrate the effect of Valaciklovir
    End point description
    Another secondary objective, concerning a subgroup (study site A), is to investigate if [18F]-FHBG is accumulated in the areas of the brain that are affected in early Alzheimer's disease and if [18F]-FHBG-PET/CT can be used to demonstrate the effect of Valaciklovir and identify individuals that have an extra good effect by the treatment.
    End point type
    Secondary
    End point timeframe
    Before start with study drug and after 28 days of treatment.
    End point values
    [18F]-FHBG-PET/CT
    Number of subjects analysed
    9
    Units: units
        number (not applicable)
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of first dose study treatment (both Valaciklovir and [18F]-FHBG) until 30 days after last dose study drug.
    Adverse event reporting additional description
    Known complications of the underlying disease (Alzheimer's) are not considered complications and will not be reported as AE and SAE.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    All patients signed informed concent
    Reporting group description
    Deviating laboratory findings (ex clinical, haematological and urine specimens) or other abnormal findings assessed by the investigator to be clinically significant will be recorded as AE or SAE if they meet the definition of an AE or SAE and occur within the following AE reporting time frames: All AEs are registered from the time when the study participant receives the first dose of study medicine ([18F] FHBG) site type A and Valtrex at site, until 30 days after the end of treatment with Valtrex; or 30 days after the second PET / CT scan.

    Serious adverse events
    All patients signed informed concent
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 33 (3.03%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcus
    alternative dictionary used: CTCAE 5.0
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    All patients signed informed concent
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 33 (33.33%)
    Nervous system disorders
    Paresthesia leg
    Additional description: Numbness weakness in leg after lumbar puncture
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Tremor mild
    alternative dictionary used: CTCAE 5.0
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Loose stools
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Psychiatric disorders
    Panic attack
    Additional description: related to the [18F]FHBG PET/CT intervention
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Mild depressive mood
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Back pain
    Additional description: Back pain after lumbar puncture
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Thirst
    alternative dictionary used: CTCAE 5.0
         subjects affected / exposed
    1 / 33 (3.03%)
         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
    24 Jul 2018
    All outcome measures related to the [18F] -FHBG-PET / CT examinations have been changed to secondary outcome measures. Minimum number who will undergo the study according to protocol, study site A has been specified for at least 14 study participants. The amendment also inculdes change in the number of study sites with the addition of a study site at Skellefteå Hospital and the University Hospital in Uppsala. Due to the availability of performing [18F]-FHBG-PET/CT examinations, the study is carried out at the two new study sites according to a somewhat simplified procedure with only three visits, according to the revised protocol.

    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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