<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/NCT04449926</url>
  </required_header>
  <id_info>
    <org_study_id>BCG-PANDA 01</org_study_id>
    <nct_id>NCT04449926</nct_id>
  </id_info>
  <brief_title>BCG and Plasma Amyloid in Non-Demented Adults</brief_title>
  <official_title>BCG and Plasma Amyloid in Non-Demented Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mindful Diagnostics and Therapeutics, LLC</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Mindful Diagnostics and Therapeutics, LLC</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      BCG vaccination, the most widely used vaccination in the world, is used to reduce risk of&#xD;
      tuberculosis infection; it is used for other mycobacterial infections as well, benefiting&#xD;
      leprosy and Buruli ulcer. BCG has &quot;heterologous&quot; effects that aids in an array of&#xD;
      non-mycobacterial and viral infections as well as bladder cancer. It is the heterologous&#xD;
      effect, sometimes called the &quot;off-target&quot; effect that may offer benefit in Alzheimer's&#xD;
      disease. Population studies and studies of adults receiving BCG show a lessened risk of&#xD;
      Alzheimer's disease. The study will see if BCG vaccination will alter a plasma test for&#xD;
      amyloid, a biomarker for cerebral amyloid.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Alzheimer's disease (AD) is commonly regarded as Alzheimer's dementia. It is now understood&#xD;
      that changes in the brain that result in late-onset AD dementia start years or even decades&#xD;
      prior to clinical dementia. Biomarkers aid in diagnosing AD however, currently approved&#xD;
      biomarkers have drawbacks as they are invasive and expensive. The two most commonly used&#xD;
      biomarkers are amyloid PET scan and spinal tap for amyloid and tau. A new plasma amyloid test&#xD;
      has received &quot;Breakthrough Device Designation&quot; from the US-FDA. As an investigational tool,&#xD;
      this blood test for amyloid peptides 42/40 levels accurately predicts brain amyloidosis in&#xD;
      cognitively normal individuals. In the past 100 years, four billion doses of BCG vaccination&#xD;
      have been given for tuberculosis prevention. A favorable effect with BCG for non-tuberculous&#xD;
      mycobacteria is also recognized in cervical lymphadeniits, leprosy and Buruli's ulcer.&#xD;
      Recently, BCG has found favorable use in autoimmune diseases type 1 diabetes (T1D) and&#xD;
      multiple sclerosis (MS); moreover, a protective role by BCG for Alzheimer's disease has been&#xD;
      described. Adult exposure to BCG lessened the risk of AD by four-fold. This is an&#xD;
      interventional pilot study to test 50 non-demented adults measuring their plasma amyloid&#xD;
      42/40 level prior to BCG prime/boost followed with the same plasma amyloid testing 9 months&#xD;
      after vaccination. Sub-clinical CMV infection is felt to drive immune senescence and increase&#xD;
      the risk of AD; we will test for CMV antibodies and we will measure lymphocyte phenotype&#xD;
      prior to BCG and at study end to look for an immune-modulating effect on this indicator of&#xD;
      immunosenescence.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 9, 2020</start_date>
  <completion_date type="Actual">December 5, 2021</completion_date>
  <primary_completion_date type="Actual">December 4, 2021</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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Plasma Amyloid</measure>
    <time_frame>9 months</time_frame>
    <description>Level of Plasma Peptides 42/40 pre-BCG vaccination are compared with levels nine months post vaccination</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Immune Risk Profile</measure>
    <time_frame>nine months</time_frame>
    <description>T-cell phenotype: CD4:CD8 ratios are measured pre-BCG vaccination and nine months post vaccination.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">49</enrollment>
  <condition>Alzheimer Disease, Late Onset</condition>
  <arm_group>
    <arm_group_label>BCG Vaccinated</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Experimental: BCG Group FDA-approved BCG Tice strain, procured from Merck, will be used. The vaccine will be reconstituted according to the package insert. In brief, a vial containing ~1x10^8 CFU of lyophilized BCG will be reconstituted in 50 mL of saline. A single dose will consist of 0.1 mL (~2x10^5 CFU) will be administered by slow intradermal injection using a 25 gauge/ 0.5 mm syringe in the deltoid area. A follow up &quot;booster&quot; dose will be given one month after the initial dose.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Bacillus of Calmette and Guerin (BCG)</intervention_name>
    <description>Prime and boost vaccination</description>
    <arm_group_label>BCG Vaccinated</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  BCG naive&#xD;
&#xD;
          -  Ability to read, understand and sign consent form&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known allergy to (components of) the BCG vaccine or serious adverse events to prior&#xD;
             vaccine administration&#xD;
&#xD;
          -  Known active or latent Mycobacterium tuberculosis or with another mycobacterial&#xD;
             species. A history of - or a suspicion of M. tuberculosis infection.&#xD;
&#xD;
          -  Fever (&gt;38 C) within the past 24 hours.&#xD;
&#xD;
          -  Suspicion of active viral or bacterial infection.&#xD;
&#xD;
          -  Vaccination in the past 4 weeks or expected vaccination during the study period,&#xD;
             independent of the type of vaccination.&#xD;
&#xD;
          -  Severely immunocompromised subjects. This exclusion category comprises: a) subjects&#xD;
             with known infection by the human immunodeficiency virus (HIV-1); b) neutropenic&#xD;
             subjects with less than 500 neutrophils/mm3; c) subjects with solid organ&#xD;
             transplantation; d) subjects with bone marrow transplantation; e) subjects under&#xD;
             chemotherapy; f) subjects with primary immunodeficiency; g) severe lymphopenia with&#xD;
             less than 400 lymphocytes/mm3; h) treatment with any anti-cytokine therapies. i)&#xD;
             treatment with oral or intravenous steroids defined as daily doses of 10mg prednisone&#xD;
             or equivalent for longer than 3 months, or probable use of oral or intravenous&#xD;
             steroids in the following four weeks.&#xD;
&#xD;
          -  Active solid or non-solid malignancy or lymphoma within the prior two years.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Coad T Dow, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mindful Diagnostics and Therapeutics</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mindful Diagnostics and Therapeutics</name>
      <address>
        <city>Eau Claire</city>
        <state>Wisconsin</state>
        <zip>54701-3016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Schindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Li Y, Gordon BA, Holtzman DM, Morris JC, Benzinger TLS, Xiong C, Fagan AM, Bateman RJ. High-precision plasma beta-amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019 Oct 22;93(17):e1647-e1659. doi: 10.1212/WNL.0000000000008081. Epub 2019 Aug 1.</citation>
    <PMID>31371569</PMID>
  </reference>
  <reference>
    <citation>Gofrit ON, Klein BY, Cohen IR, Ben-Hur T, Greenblatt CL, Bercovier H. Bacillus Calmette-Guerin (BCG) therapy lowers the incidence of Alzheimer's disease in bladder cancer patients. PLoS One. 2019 Nov 7;14(11):e0224433. doi: 10.1371/journal.pone.0224433. eCollection 2019.</citation>
    <PMID>31697701</PMID>
  </reference>
  <reference>
    <citation>Gofrit ON, Bercovier H, Klein BY, Cohen IR, Ben-Hur T, Greenblatt CL. Can immunization with Bacillus Calmette-Guerin (BCG) protect against Alzheimer's disease? Med Hypotheses. 2019 Feb;123:95-97. doi: 10.1016/j.mehy.2019.01.007. Epub 2019 Jan 11.</citation>
    <PMID>30696606</PMID>
  </reference>
  <reference>
    <citation>Dow CT. Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Autoimmune Diseases. Microorganisms. 2020 Feb 5;8(2):212. doi: 10.3390/microorganisms8020212.</citation>
    <PMID>32033287</PMID>
  </reference>
  <reference>
    <citation>Lurain NS, Hanson BA, Martinson J, Leurgans SE, Landay AL, Bennett DA, Schneider JA. Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease. J Infect Dis. 2013 Aug 15;208(4):564-72. doi: 10.1093/infdis/jit210. Epub 2013 May 9.</citation>
    <PMID>23661800</PMID>
  </reference>
  <reference>
    <citation>Westman G, Berglund D, Widen J, Ingelsson M, Korsgren O, Lannfelt L, Sehlin D, Lidehall AK, Eriksson BM. Increased inflammatory response in cytomegalovirus seropositive patients with Alzheimer's disease. PLoS One. 2014 May 7;9(5):e96779. doi: 10.1371/journal.pone.0096779. eCollection 2014.</citation>
    <PMID>24804776</PMID>
  </reference>
  <reference>
    <citation>Luz Correa B, Ornaghi AP, Cerutti Muller G, Engroff P, Pestana Lopes R, Gomes da Silva Filho I, Bosch JA, Bonorino C, Bauer ME. The inverted CD4:CD8 ratio is associated with cytomegalovirus, poor cognitive and functional states in older adults. Neuroimmunomodulation. 2014;21(4):206-12. doi: 10.1159/000356827. Epub 2014 Feb 6.</citation>
    <PMID>24504177</PMID>
  </reference>
  <verification_date>December 2021</verification_date>
  <study_first_submitted>June 24, 2020</study_first_submitted>
  <study_first_submitted_qc>June 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 29, 2020</study_first_posted>
  <last_update_submitted>December 22, 2021</last_update_submitted>
  <last_update_submitted_qc>December 22, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">December 23, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Alzheimer's disease</keyword>
  <keyword>biomarker</keyword>
  <keyword>BCG</keyword>
  <keyword>plasma amyloid</keyword>
  <keyword>peptides 42/40</keyword>
  <keyword>heterologous effect</keyword>
  <keyword>immune risk profile</keyword>
  <keyword>CMV</keyword>
  <keyword>HHV5</keyword>
  <keyword>immunosenescence</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
    <mesh_term>Late Onset Disorders</mesh_term>
  </condition_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/NCT04449926
org study id: BCG-PANDA 01
nct id: NCT04449926
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
BCG vaccination, the most widely used vaccination in the world, is used to reduce risk of
      tuberculosis infection; it is used for other mycobacterial infections as well, benefiting
      leprosy and Buruli ulcer. BCG has "heterologous" effects that aids in an array of
      non-mycobacterial and viral infections as well as bladder cancer. It is the heterologous
      effect, sometimes called the "off-target" effect that may offer benefit in Alzheimer's
      disease. Population studies and studies of adults receiving BCG show a lessened risk of
      Alzheimer's disease. The study will see if BCG vaccination will alter a plasma test for
      amyloid, a biomarker for cerebral amyloid.
Alzheimer's disease (AD) is commonly regarded as Alzheimer's dementia. It is now understood
      that changes in the brain that result in late-onset AD dementia start years or even decades
      prior to clinical dementia. Biomarkers aid in diagnosing AD however, currently approved
      biomarkers have drawbacks as they are invasive and expensive. The two most commonly used
      biomarkers are amyloid PET scan and spinal tap for amyloid and tau. A new plasma amyloid test
      has received "Breakthrough Device Designation" from the US-FDA. As an investigational tool,
      this blood test for amyloid peptides 42/40 levels accurately predicts brain amyloidosis in
      cognitively normal individuals. In the past 100 years, four billion doses of BCG vaccination
      have been given for tuberculosis prevention. A favorable effect with BCG for non-tuberculous
      mycobacteria is also recognized in cervical lymphadeniits, leprosy and Buruli's ulcer.
      Recently, BCG has found favorable use in autoimmune diseases type 1 diabetes (T1D) and
      multiple sclerosis (MS); moreover, a protective role by BCG for Alzheimer's disease has been
      described. Adult exposure to BCG lessened the risk of AD by four-fold. This is an
      interventional pilot study to test 50 non-demented adults measuring their plasma amyloid
      42/40 level prior to BCG prime/boost followed with the same plasma amyloid testing 9 months
      after vaccination. Sub-clinical CMV infection is felt to drive immune senescence and increase
      the risk of AD; we will test for CMV antibodies and we will measure lymphocyte phenotype
      prior to BCG and at study end to look for an immune-modulating effect on this indicator of
      immunosenescence.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Change in Plasma Amyloid
time frame: 9 months
description: Level of Plasma Peptides 42/40 pre-BCG vaccination are compared with levels nine months post vaccination
measure: Change in Immune Risk Profile
time frame: nine months
description: T-cell phenotype: CD4:CD8 ratios are measured pre-BCG vaccination and nine months post vaccination.
arm group label: BCG Vaccinated
arm group type: Experimental
description: Experimental: BCG Group FDA-approved BCG Tice strain, procured from Merck, will be used. The vaccine will be reconstituted according to the package insert. In brief, a vial containing ~1x10^8 CFU of lyophilized BCG will be reconstituted in 50 mL of saline. A single dose will consist of 0.1 mL (~2x10^5 CFU) will be administered by slow intradermal injection using a 25 gauge/ 0.5 mm syringe in the deltoid area. A follow up "booster" dose will be given one month after the initial dose.
intervention type: Biological
intervention name: Bacillus of Calmette and Guerin (BCG)
description: Prime and boost vaccination
arm group label: BCG Vaccinated
criteria: 
gender: All
minimum age: 50 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Coad T Dow, M.D.
role: Principal Investigator
affiliation: Mindful Diagnostics and Therapeutics
facility: 
country: United States
citation: Schindler SE, Bollinger JG, Ovod V, Mawuenyega KG, Li Y, Gordon BA, Holtzman DM, Morris JC, Benzinger TLS, Xiong C, Fagan AM, Bateman RJ. High-precision plasma beta-amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019 Oct 22;93(17):e1647-e1659. doi: 10.1212/WNL.0000000000008081. Epub 2019 Aug 1.
PMID: 31371569
citation: Gofrit ON, Klein BY, Cohen IR, Ben-Hur T, Greenblatt CL, Bercovier H. Bacillus Calmette-Guerin (BCG) therapy lowers the incidence of Alzheimer's disease in bladder cancer patients. PLoS One. 2019 Nov 7;14(11):e0224433. doi: 10.1371/journal.pone.0224433. eCollection 2019.
PMID: 31697701
citation: Gofrit ON, Bercovier H, Klein BY, Cohen IR, Ben-Hur T, Greenblatt CL. Can immunization with Bacillus Calmette-Guerin (BCG) protect against Alzheimer's disease? Med Hypotheses. 2019 Feb;123:95-97. doi: 10.1016/j.mehy.2019.01.007. Epub 2019 Jan 11.
PMID: 30696606
citation: Dow CT. Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Autoimmune Diseases. Microorganisms. 2020 Feb 5;8(2):212. doi: 10.3390/microorganisms8020212.
PMID: 32033287
citation: Lurain NS, Hanson BA, Martinson J, Leurgans SE, Landay AL, Bennett DA, Schneider JA. Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease. J Infect Dis. 2013 Aug 15;208(4):564-72. doi: 10.1093/infdis/jit210. Epub 2013 May 9.
PMID: 23661800
citation: Westman G, Berglund D, Widen J, Ingelsson M, Korsgren O, Lannfelt L, Sehlin D, Lidehall AK, Eriksson BM. Increased inflammatory response in cytomegalovirus seropositive patients with Alzheimer's disease. PLoS One. 2014 May 7;9(5):e96779. doi: 10.1371/journal.pone.0096779. eCollection 2014.
PMID: 24804776
citation: Luz Correa B, Ornaghi AP, Cerutti Muller G, Engroff P, Pestana Lopes R, Gomes da Silva Filho I, Bosch JA, Bonorino C, Bauer ME. The inverted CD4:CD8 ratio is associated with cytomegalovirus, poor cognitive and functional states in older adults. Neuroimmunomodulation. 2014;21(4):206-12. doi: 10.1159/000356827. Epub 2014 Feb 6.
PMID: 24504177
responsible party type: Sponsor
mesh term: Alzheimer Disease
mesh term: Late Onset Disorders
sharing ipd: No