<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02997982</url>
  </required_header>
  <id_info>
    <org_study_id>UmU-2016-390-31M</org_study_id>
    <secondary_id>2016-002317-22</secondary_id>
    <nct_id>NCT02997982</nct_id>
  </id_info>
  <brief_title>Feasibility and Effects of Valaciclovir Treatment in Persons With Early Alzheimer's Disease</brief_title>
  <acronym>VALZ-Pilot</acronym>
  <official_title>Feasibility and Effects on Markers in Spinal Fluid in Persons With Early Alzheimer's Disease When Treated With Valaciclovir - Open Fas II Pilot Study (VALZ-Pilot)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hugo Lovheim</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Umeå University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study investigates the effects of Valaciclovir treatment to individuals with Alzheimer's&#xD;
      disease or Mild Cognitive Impairment of Alzheimer's Disease Type. It is an open pilot trial&#xD;
      where 36 participants will receive 4 weeks of Valaciclovir treatment. Participants will be&#xD;
      investigated using different measures before and after the treatment period.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study investigates the effects of valaciclovir treatment to individuals with Alzheimer's&#xD;
      disease (AD) or Mild Cognitive Impairment of Alzheimer's Disease Type. It is an open pilot&#xD;
      trial where 36 participants will receive 4 weeks of oral valaciclovir treatment. To find 36&#xD;
      persons fulfilling inclusion criteria, up to 120 persons will be screened. Important&#xD;
      inclusion criteria are Herpes Simplex Virus (HSV) Immunoglobulin G (IgG)-positivity (HSV&#xD;
      carriage), Apolipoprotein E allele 4 carriage and sufficient kidney function (estimated&#xD;
      glomerular filtration rate above 30 ml/min). All participants must give their informed&#xD;
      consent to participation.&#xD;
&#xD;
      The valaciclovir dose will be 500 mg three times daily the first week and 1000 mg three times&#xD;
      daily week 2-4.&#xD;
&#xD;
      Participants will be investigated using different measures before and after the treatment&#xD;
      period: Mini Mental State Examination to assess cognitive function, Cerebrospinal fluid&#xD;
      biomarkers of Alzheimer's disease and [18F]-FHBG-PET/CT&#xD;
      (9-[4-[18F]fluoro-3-(hydroxymethyl)butyl]guanine positron emission tomography/computed&#xD;
      tomography)) to possibly indicate active HSV infection within the central nervous system.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 2016</start_date>
  <completion_date type="Actual">March 4, 2020</completion_date>
  <primary_completion_date type="Actual">March 4, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cerebrospinal fluid (CSF) Total Tau</measure>
    <time_frame>Baseline and treatment day 28</time_frame>
    <description>Change in CSF Total Tau between samples taken before and after drug treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cerebrospinal fluid (CSF) Neurofilament light chain (NFL)</measure>
    <time_frame>Baseline and treatment day 28</time_frame>
    <description>Change in CSF NFL between samples taken before and after drug treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebrospinal fluid (CSF) phosphorylated Tau (p-Tau)</measure>
    <time_frame>Baseline and treatment day 28</time_frame>
    <description>Change in CSF p-Tau between samples taken before and after drug treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebrospinal fluid (CSF) Amyloid beta 1-42</measure>
    <time_frame>Baseline and treatment day 28</time_frame>
    <description>Change in Amyloid beta 1-42 between samples taken before and after drug treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PET/CT: [18F]-FHBG accumulation within the central nervous system (CNS)</measure>
    <time_frame>One week before drug treatment start</time_frame>
    <description>Can [18F]-FHBG-PET/CT detect replicating HSV infection within the CNS?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PET/CT: Location of [18F]-FHBG accumulation</measure>
    <time_frame>One week before drug treatment start</time_frame>
    <description>Do [18F]-FHBG accumulation locate to brain areas affected in AD?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PET/CT: [18F]-FHBG accumulation</measure>
    <time_frame>One week before and one week after drug treatment</time_frame>
    <description>Change in [18F]-FHBG accumulation after, as compared to before, drug treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mini Mental State Examination - Swedish Revision (MMSE-SR)</measure>
    <time_frame>Baseline and treatment day 28</time_frame>
    <description>Change in MMSE-SR scores from baseline to after drug treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebrospinal fluid (CSF) acyclovir concentration</measure>
    <time_frame>Treatment day 28</time_frame>
    <description>Cerebrospinal fluid (CSF) acyclovir concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebrospinal fluid (CSF) 9-carboxymethoxymethylguanine (CMMG) concentration</measure>
    <time_frame>Treatment day 28</time_frame>
    <description>Concentration of CMMG, main acyclovir metabolite</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum acyclovir concentration</measure>
    <time_frame>Treatment day 28</time_frame>
    <description>Serum acyclovir concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum 9-carboxymethoxymethylguanine (CMMG) concentration</measure>
    <time_frame>Treatment day 28</time_frame>
    <description>Concentration of CMMG, main acyclovir metabolite</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion completing the [18F]-FHBG-PET/CT investigations</measure>
    <time_frame>For the investigations one week before and one week after drug treatment</time_frame>
    <description>Is [18F]-FHBG-PET/CT a feasible examination among persons with Alzheimer's disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion completing the 28 days treatment with valaciclovir at specified doses</measure>
    <time_frame>Treatment day 28</time_frame>
    <description>Feasibility of valaciclovir treatment as measured by the number of participants completing the full treatment period at the specified dose</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>Alzheimer Disease</condition>
  <condition>Mild Cognitive Impairment</condition>
  <condition>Herpes Simplex</condition>
  <arm_group>
    <arm_group_label>Valaciclovir treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Valaciclovir 500Mg Tablet</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Valaciclovir 500Mg Tablet</intervention_name>
    <description>Valaciclovir treatment (oral, 500 mg tablets). First week: 500 mg three times daily, second to fourth week: 1000 mg three times daily.</description>
    <arm_group_label>Valaciclovir treatment</arm_group_label>
    <other_name>Valtrex (R)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Man or women, age ≥ 65 years&#xD;
&#xD;
          -  Ability to take a stand and to make and to sign an informed consent to participate in&#xD;
             the study. This implies that a person with MMSE (Mini Mental State Examination) &lt; 18&#xD;
             will probably not be included.&#xD;
&#xD;
          -  Diagnosed with Alzheimer's disease or mild cognitive impairment due to Alzheimer's&#xD;
             disease. At least one brain imaging examination should have been done (CT, MR, SPECT&#xD;
             or PET/CT) and at least one objective finding should support the diagnosis beyond&#xD;
             specific medical history. Reduced perfusion or reduced metabolism bilaterally&#xD;
             temporally, hippocampal atrophy or pathological markers for Alzheimer's disease in&#xD;
             cerebrospinal fluid is such findings. Persons with vascular brain disorders e.g.&#xD;
             severe white matter changes or previous brain infarction will not be included but&#xD;
             those with white matter changes considered normal for their age can be included.&#xD;
&#xD;
          -  Positive for anti-HSV (Herpes Simplex Virus) Immunoglobulin G (IgG) in plasma, i.e.&#xD;
             carrier of HSV.&#xD;
&#xD;
          -  Hetero or Homozygote for allele 4 of gene Apolipoprotein E.&#xD;
&#xD;
          -  Stable over all medication including medication for Alzheimer's disease (rivastigmine,&#xD;
             galantamin, donepezil or memantin) for at least one month.&#xD;
&#xD;
          -  No known allergy or oversensitivity against valaciclovir or aciclovir.&#xD;
&#xD;
          -  Ability to independently or by support from relative or other caretaker comply to&#xD;
             study drug.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Renal insufficiency with estimated GFR (Glomerular Filtration Rate) ≤ 30 ml/min/1.73m2&#xD;
&#xD;
          -  Ongoing treatment with anticoagulants (Warfarin, low molecular heparin or other&#xD;
             anticoagulant agents). Antiplatelet agents in recommended dose are accepted (i.e.&#xD;
             Acetylsalicylic acid 75 mgx1)&#xD;
&#xD;
          -  Life expectancy &lt; 1 year due to other comorbidity&#xD;
&#xD;
          -  Ongoing severe somatic condition that might interfere with the patients participation&#xD;
             in the study (i.e. ongoing cancer treatment)&#xD;
&#xD;
          -  Ongoing illness that makes exams in a supine position impossible (i.e. severe heart&#xD;
             failure, severe back pain).&#xD;
&#xD;
          -  Dementia diagnosis other than Alzheimer's disease, including Vascular dementia.&#xD;
&#xD;
          -  Other known neurological/neurodegenerative disorder (i.e. brain tumor, MS (Multiple&#xD;
             sclerosis), ALS (amyotrophic lateral sclerosis))&#xD;
&#xD;
          -  Claustrophobia or other contraindication for doing a PET/CT scanning.&#xD;
&#xD;
          -  Depression or other psychiatric illness that requires treatment (i.e. severe psychosis&#xD;
             or other illness with equal grade of seriousness)&#xD;
&#xD;
          -  Dementia or cognitive dysfunction to such extent that an informed consent is&#xD;
             impossible to obtain, corresponding to about MMSE-SR (Mini Mental State&#xD;
             Examination-Swedish revision) &lt;18.&#xD;
&#xD;
          -  History of substance abuse (i.e. central nervous system stimulants or alcohol).&#xD;
             Nicotine use is accepted.&#xD;
&#xD;
          -  Not willing to participate in the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hugo Lövheim, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Umeå University, Umeå, Sweden</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Geriatric Centre, University Hospital in Umeå</name>
      <address>
        <city>Umeå</city>
        <state>Västerbotten</state>
        <zip>90185</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memory Clinic, Uppsala University Hospital</name>
      <address>
        <city>Uppsala</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>April 2020</verification_date>
  <study_first_submitted>December 6, 2016</study_first_submitted>
  <study_first_submitted_qc>December 15, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <last_update_submitted>April 1, 2020</last_update_submitted>
  <last_update_submitted_qc>April 1, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">April 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Umeå University</investigator_affiliation>
    <investigator_full_name>Hugo Lovheim</investigator_full_name>
    <investigator_title>Associate professor</investigator_title>
  </responsible_party>
  <keyword>Alzheimer's Disease</keyword>
  <keyword>Herpes Simplex Virus</keyword>
  <keyword>HSV</keyword>
  <keyword>Antiviral Drugs</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Herpes Simplex</mesh_term>
    <mesh_term>Alzheimer Disease</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Valacyclovir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02997982
org study id: UmU-2016-390-31M
secondary id: 2016-002317-22
nct id: NCT02997982
lead sponsor: 
has dmc: Yes
This study investigates the effects of Valaciclovir treatment to individuals with Alzheimer's
      disease or Mild Cognitive Impairment of Alzheimer's Disease Type. It is an open pilot trial
      where 36 participants will receive 4 weeks of Valaciclovir treatment. Participants will be
      investigated using different measures before and after the treatment period.
This study investigates the effects of valaciclovir treatment to individuals with Alzheimer's
      disease (AD) or Mild Cognitive Impairment of Alzheimer's Disease Type. It is an open pilot
      trial where 36 participants will receive 4 weeks of oral valaciclovir treatment. To find 36
      persons fulfilling inclusion criteria, up to 120 persons will be screened. Important
      inclusion criteria are Herpes Simplex Virus (HSV) Immunoglobulin G (IgG)-positivity (HSV
      carriage), Apolipoprotein E allele 4 carriage and sufficient kidney function (estimated
      glomerular filtration rate above 30 ml/min). All participants must give their informed
      consent to participation.

      The valaciclovir dose will be 500 mg three times daily the first week and 1000 mg three times
      daily week 2-4.

      Participants will be investigated using different measures before and after the treatment
      period: Mini Mental State Examination to assess cognitive function, Cerebrospinal fluid
      biomarkers of Alzheimer's disease and [18F]-FHBG-PET/CT
      (9-[4-[18F]fluoro-3-(hydroxymethyl)butyl]guanine positron emission tomography/computed
      tomography)) to possibly indicate active HSV infection within the central nervous system.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Cerebrospinal fluid (CSF) Total Tau
time frame: Baseline and treatment day 28
description: Change in CSF Total Tau between samples taken before and after drug treatment
measure: Cerebrospinal fluid (CSF) Neurofilament light chain (NFL)
time frame: Baseline and treatment day 28
description: Change in CSF NFL between samples taken before and after drug treatment
measure: Cerebrospinal fluid (CSF) phosphorylated Tau (p-Tau)
time frame: Baseline and treatment day 28
description: Change in CSF p-Tau between samples taken before and after drug treatment
measure: Cerebrospinal fluid (CSF) Amyloid beta 1-42
time frame: Baseline and treatment day 28
description: Change in Amyloid beta 1-42 between samples taken before and after drug treatment
measure: PET/CT: [18F]-FHBG accumulation within the central nervous system (CNS)
time frame: One week before drug treatment start
description: Can [18F]-FHBG-PET/CT detect replicating HSV infection within the CNS?
measure: PET/CT: Location of [18F]-FHBG accumulation
time frame: One week before drug treatment start
description: Do [18F]-FHBG accumulation locate to brain areas affected in AD?
measure: PET/CT: [18F]-FHBG accumulation
time frame: One week before and one week after drug treatment
description: Change in [18F]-FHBG accumulation after, as compared to before, drug treatment
measure: Mini Mental State Examination - Swedish Revision (MMSE-SR)
time frame: Baseline and treatment day 28
description: Change in MMSE-SR scores from baseline to after drug treatment
measure: Cerebrospinal fluid (CSF) acyclovir concentration
time frame: Treatment day 28
description: Cerebrospinal fluid (CSF) acyclovir concentration
measure: Cerebrospinal fluid (CSF) 9-carboxymethoxymethylguanine (CMMG) concentration
time frame: Treatment day 28
description: Concentration of CMMG, main acyclovir metabolite
measure: Serum acyclovir concentration
time frame: Treatment day 28
description: Serum acyclovir concentration
measure: Serum 9-carboxymethoxymethylguanine (CMMG) concentration
time frame: Treatment day 28
description: Concentration of CMMG, main acyclovir metabolite
measure: Proportion completing the [18F]-FHBG-PET/CT investigations
time frame: For the investigations one week before and one week after drug treatment
description: Is [18F]-FHBG-PET/CT a feasible examination among persons with Alzheimer's disease
measure: Proportion completing the 28 days treatment with valaciclovir at specified doses
time frame: Treatment day 28
description: Feasibility of valaciclovir treatment as measured by the number of participants completing the full treatment period at the specified dose
arm group label: Valaciclovir treatment
arm group type: Experimental
description: Valaciclovir 500Mg Tablet
intervention type: Drug
intervention name: Valaciclovir 500Mg Tablet
description: Valaciclovir treatment (oral, 500 mg tablets). First week: 500 mg three times daily, second to fourth week: 1000 mg three times daily.
arm group label: Valaciclovir treatment
other name: Valtrex (R)
criteria: 
gender: All
minimum age: 65 Years
maximum age: N/A
healthy volunteers: No
last name: Hugo Lövheim, M.D., Ph.D.
role: Principal Investigator
affiliation: Umeå University, Umeå, Sweden
facility: 
facility: 
country: Sweden
responsible party type: Sponsor-Investigator
investigator affiliation: Umeå University
investigator full name: Hugo Lovheim
investigator title: Associate professor
mesh term: Herpes Simplex
mesh term: Alzheimer Disease
mesh term: Cognitive Dysfunction
mesh term: Valacyclovir
sharing ipd: No