<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/NCT04498650</url>
  </required_header>
  <id_info>
    <org_study_id>PBD-01180</org_study_id>
    <secondary_id>2019-003532-23</secondary_id>
    <nct_id>NCT04498650</nct_id>
  </id_info>
  <brief_title>A Study to Evaluate Safety and Tolerability of Different Doses and Efficacy of PQ912 in Subjects With MCI and Mild AD</brief_title>
  <acronym>VIVIAD</acronym>
  <official_title>A Phase 2b Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel Group Dose Finding, Safety, Tolerability and Efficacy Study of PQ912 in Subjects With MCI and Mild Dementia Due to Alzheimer's Disease.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vivoryon Therapeutics N.V.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Nordic Bioscience A/S</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Amsterdam UMC, location VUmc</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Vivoryon Therapeutics N.V.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a phase 2B multicenter, randomized, double-blind, placebo-controlled, parallel group&#xD;
      dose finding study to evaluate the safety, tolerability and efficacy of PQ912, an inhibitor&#xD;
      of the glutaminyl cyclase enzyme, in 250 subjects with mild cognitive impairment and mild&#xD;
      dementia due to Alzheimer 's Disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In the parallel group dose finding part of the study the first 90 subjects will be randomized&#xD;
      1:1:1 between PQ912 300 mg BID, 600 mg BID, and placebo. When the 90th patient has completed&#xD;
      the week 24 treatment visit, the DSMB will decide on the dose of PQ912 to be continued. The&#xD;
      decision is based on safety findings only, no efficacy data will be considered. After the&#xD;
      DSMB has reached a decision on the dose to be continued, all subjects randomized to receive&#xD;
      PQ912 will be reallocated to this dose (1:1). The duration of Subjects participation in the&#xD;
      study is either 48, 60, 72, 84 or 96 weeks of treatment (depending on time of randomization).&#xD;
      Subjects recruited early into the study will be kept on treatment for 96 weeks or until the&#xD;
      regular, scheduled study visit which is closest to the scheduled week 48 visit of the last&#xD;
      subject recruited in the study, whichever comes first.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 6, 2020</start_date>
  <completion_date type="Anticipated">March 2024</completion_date>
  <primary_completion_date type="Anticipated">January 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Primary safety: The proportion of participants who experience any Adverse Event (AE), Serious Adverse Event (SAE), Adverse Event of Interest (AE-I)</measure>
    <time_frame>48 weeks</time_frame>
    <description>The safety analysis will include the number of subjects with, and the number of any AE, any SAE (both overall and related), AEs leading to discontinuation of treatment, AEs leading to temporary treatment interruption, treatment compliance, the number of subjects with AEs of interest as defined above, the severity, duration and outcome of AEs</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Primary efficacy: within-participant linear change with time of the combinded z-score for cognition compared between active arm and placebo.</measure>
    <time_frame>48 weeks and EoT (96 weeks at maximum)</time_frame>
    <description>The within-participant change over time in cognition measured by the combined z-score of the Detection test, Identification test and the 'One Back' test (attention and working memory domains) of the Neurological Test Battery</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Secondary efficacy: The within-participant linear change from baseline to week 48 in quantitative EEG (global relative theta wave power), compared between active and placebo.</measure>
    <time_frame>48 weeks at minimum or until EoT (96 weeks at maximum)</time_frame>
    <description>Using a quantitative EEG the within-participant change from baseline to week 48 of the global relative theta wave power (4-8 Hz) will serve as a primary efficacy outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Secondary efficacy: The within-participant linear change with time in overall cognition as measured by the CogState Brief Battery (CBB) Z-score compared between active arm and placebo</measure>
    <time_frame>48 weeks and EoT (96 weeks at maximum)</time_frame>
    <description>he within-participant linear change with time in overall cognition as measured by the CBB (CogState Detection, Identification, One Card Learning and One Back test) -Z-score</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Exploratory efficacy - The within-participants change from baseline in a set of representative functional network topology EEG measures compared between active arms and placebo.</measure>
    <time_frame>48 weeks</time_frame>
    <description>Evaluation of brain functional network activity and connectivity will be performed using quantitative EEG measurements, as described by (Briels et al. 2020; Poil et al. 2013; Scheltens et al. 2018) Global relative power in the delta (0.5 - 4 Hz), alpha (8 -13 Hz) and beta (13 - 30Hz) frequency bands&#xD;
Global posterior dominant peak frequency&#xD;
Amplitude Envelope Correlation (AEC) in the 4- 13 Hz band Functional network topology measures such as centrality, modularity, minimum spanning tree.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">259</enrollment>
  <condition>Early Alzheimers Disease</condition>
  <condition>Mild Cognitive Impairment Due to AD</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>300 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose in weeks 1 and 2: 50 mg once daily (evening) Dose in weeks 3 and 4: 50 mg BID Dose in weeks 5-8: 150 mg BID Dose in weeks 9-24: 300 mg BID</description>
  </arm_group>
  <arm_group>
    <arm_group_label>600 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose in weeks 1 and 2: 50 mg once daily (evening) Dose in weeks 3 and 4: 50 mg BID Dose in weeks 5-8: 150 mg BID Dose in weeks 9-12: 300 mg BID Dose in weeks 12-24: 600 mg BID</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PQ912</intervention_name>
    <description>PQ912 50 mg tablets and 150 mg tablets</description>
    <arm_group_label>300 mg</arm_group_label>
    <arm_group_label>600 mg</arm_group_label>
    <other_name>varoglutamstat</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo tablets to mimic PQ912 50 mg and 150 mg tablets</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Main Inclusion Criteria:&#xD;
&#xD;
          -  Positive CSF AD biomarker signature according to the AA-NIA criteria&#xD;
&#xD;
          -  Clinical syndrome of MCI or mild dementia according to the AA-NIA Research Framework&#xD;
&#xD;
          -  A cognitive impairment in the WAIS IV Coding Test of at least 0.5 standard deviation&#xD;
             below the normative data&#xD;
&#xD;
          -  Adequate visual and auditory abilities to perform the cognitive and functional&#xD;
             assessments in the opinion of the investigator&#xD;
&#xD;
          -  Meeting the completion and performance criteria for the CogState NTB&#xD;
&#xD;
          -  Outpatient with study partner capable of accompanying the subject on all applicable&#xD;
             clinic visits&#xD;
&#xD;
        Main Exclusion Criteria:&#xD;
&#xD;
          -  Significant neurological or psychiatric disorders, other than AD, that may affect&#xD;
             cognition.&#xD;
&#xD;
          -  Atypical clinical presentations of MCI due to AD or mild dementia due to AD, such as&#xD;
             the visual variant of AD (including posterior cortical atrophy), frontal variant or&#xD;
             the language variant (including logopenic aphasia).&#xD;
&#xD;
          -  Moderate and severe dementia with a Mini-Mental State Examination score (MMSE) below&#xD;
             20.&#xD;
&#xD;
          -  Current presence of a clinically important major psychiatric disorder (e.g. major&#xD;
             depressive disorder) as defined by DSM-5 criteria, or symptom(s) (e.g. hallucinations)&#xD;
             that could affect the subject's ability to complete the study.&#xD;
&#xD;
          -  History of clinically evident stroke.&#xD;
&#xD;
          -  History of seizures within the last two years prior to the screening visit.&#xD;
&#xD;
          -  Myocardial infarction within the last six months prior to screening.&#xD;
&#xD;
          -  History of uncontrolled hypertension (in the opinion of the investigator) within six&#xD;
             months prior to screening.&#xD;
&#xD;
          -  Contraindication to lumbar puncture and MRI&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Everard Vijverberg, Dr</last_name>
    <role>Study Chair</role>
    <affiliation>VUmc Alzheimer Centre</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sanos Clinics</name>
      <address>
        <city>Ganderup</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sanos Clinics</name>
      <address>
        <city>Herlev</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sanos Clinics</name>
      <address>
        <city>Vejle</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Charité - Universitätsmedizin Berlin</name>
      <address>
        <city>Berlin</city>
        <zip>10450</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Schleswig-Holstein (UKSH), Klinik für Neurologie</name>
      <address>
        <city>Kiel</city>
        <zip>24105</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Magdeburg / Institut für Kognitive Neurologie und Demenzforschung</name>
      <address>
        <city>Magdeburg</city>
        <zip>39120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut für Studien zur Psychischen Gesundheit (ISPG)</name>
      <address>
        <city>Mannheim</city>
        <zip>68165</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum rechts der Isar der TU München / Klinik für Psychiatrie und Psychotherapie</name>
      <address>
        <city>München</city>
        <zip>81675</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Münster / Klinik für Allgemeine Neurologie</name>
      <address>
        <city>Münster</city>
        <zip>48149</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinik für Neurologie Universitätsklinikum Ulm</name>
      <address>
        <city>Ulm</city>
        <zip>89081</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brain Research Center</name>
      <address>
        <city>Amsterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brain Research Center</name>
      <address>
        <city>Den Bosch</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brain Research Center Zwolle</name>
      <address>
        <city>Zwolle</city>
        <zip>8025</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Podlaskie Centrum</name>
      <address>
        <city>Białystok</city>
        <zip>15-756</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>SOMED CR</name>
      <address>
        <city>Warsaw</city>
        <zip>01-737</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>SOMED CR</name>
      <address>
        <city>Łódź</city>
        <zip>90-368</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinika Psychiatrii Wieku Podeszłego i Zaburzeń Psychotycznych Uniwersytetu Medycznego w Łodzi</name>
      <address>
        <city>Łódź</city>
        <zip>92-216</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology (Memory Unit) - Hospital de la Santa Creu i Sant Pau</name>
      <address>
        <city>Barcelona</city>
        <zip>08025</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fundació ACE</name>
      <address>
        <city>Barcelona</city>
        <zip>08028</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cae Oroitu</name>
      <address>
        <city>Getxo</city>
        <zip>48993</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Unidad de Neurociencias. Hospital Victoria Eugenia</name>
      <address>
        <city>Seville</city>
        <zip>41009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
    <country>Germany</country>
    <country>Netherlands</country>
    <country>Poland</country>
    <country>Spain</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>July 21, 2020</study_first_submitted>
  <study_first_submitted_qc>August 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 4, 2020</study_first_posted>
  <last_update_submitted>September 14, 2023</last_update_submitted>
  <last_update_submitted_qc>September 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</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/NCT04498650
org study id: PBD-01180
secondary id: 2019-003532-23
nct id: NCT04498650
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a phase 2B multicenter, randomized, double-blind, placebo-controlled, parallel group
      dose finding study to evaluate the safety, tolerability and efficacy of PQ912, an inhibitor
      of the glutaminyl cyclase enzyme, in 250 subjects with mild cognitive impairment and mild
      dementia due to Alzheimer 's Disease.
In the parallel group dose finding part of the study the first 90 subjects will be randomized
      1:1:1 between PQ912 300 mg BID, 600 mg BID, and placebo. When the 90th patient has completed
      the week 24 treatment visit, the DSMB will decide on the dose of PQ912 to be continued. The
      decision is based on safety findings only, no efficacy data will be considered. After the
      DSMB has reached a decision on the dose to be continued, all subjects randomized to receive
      PQ912 will be reallocated to this dose (1:1). The duration of Subjects participation in the
      study is either 48, 60, 72, 84 or 96 weeks of treatment (depending on time of randomization).
      Subjects recruited early into the study will be kept on treatment for 96 weeks or until the
      regular, scheduled study visit which is closest to the scheduled week 48 visit of the last
      subject recruited in the study, whichever comes first.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Primary safety: The proportion of participants who experience any Adverse Event (AE), Serious Adverse Event (SAE), Adverse Event of Interest (AE-I)
time frame: 48 weeks
description: The safety analysis will include the number of subjects with, and the number of any AE, any SAE (both overall and related), AEs leading to discontinuation of treatment, AEs leading to temporary treatment interruption, treatment compliance, the number of subjects with AEs of interest as defined above, the severity, duration and outcome of AEs
measure: Primary efficacy: within-participant linear change with time of the combinded z-score for cognition compared between active arm and placebo.
time frame: 48 weeks and EoT (96 weeks at maximum)
description: The within-participant change over time in cognition measured by the combined z-score of the Detection test, Identification test and the 'One Back' test (attention and working memory domains) of the Neurological Test Battery
measure: Secondary efficacy: The within-participant linear change from baseline to week 48 in quantitative EEG (global relative theta wave power), compared between active and placebo.
time frame: 48 weeks at minimum or until EoT (96 weeks at maximum)
description: Using a quantitative EEG the within-participant change from baseline to week 48 of the global relative theta wave power (4-8 Hz) will serve as a primary efficacy outcome.
measure: Secondary efficacy: The within-participant linear change with time in overall cognition as measured by the CogState Brief Battery (CBB) Z-score compared between active arm and placebo
time frame: 48 weeks and EoT (96 weeks at maximum)
description: he within-participant linear change with time in overall cognition as measured by the CBB (CogState Detection, Identification, One Card Learning and One Back test) -Z-score
measure: Exploratory efficacy - The within-participants change from baseline in a set of representative functional network topology EEG measures compared between active arms and placebo.
time frame: 48 weeks
description: Evaluation of brain functional network activity and connectivity will be performed using quantitative EEG measurements, as described by (Briels et al. 2020; Poil et al. 2013; Scheltens et al. 2018) Global relative power in the delta (0.5 - 4 Hz), alpha (8 -13 Hz) and beta (13 - 30Hz) frequency bands
Global posterior dominant peak frequency
Amplitude Envelope Correlation (AEC) in the 4- 13 Hz band Functional network topology measures such as centrality, modularity, minimum spanning tree.
arm group label: Placebo
arm group type: Placebo Comparator
arm group label: 300 mg
arm group type: Experimental
description: Dose in weeks 1 and 2: 50 mg once daily (evening) Dose in weeks 3 and 4: 50 mg BID Dose in weeks 5-8: 150 mg BID Dose in weeks 9-24: 300 mg BID
arm group label: 600 mg
arm group type: Experimental
description: Dose in weeks 1 and 2: 50 mg once daily (evening) Dose in weeks 3 and 4: 50 mg BID Dose in weeks 5-8: 150 mg BID Dose in weeks 9-12: 300 mg BID Dose in weeks 12-24: 600 mg BID
intervention type: Drug
intervention name: PQ912
description: PQ912 50 mg tablets and 150 mg tablets
arm group label: 300 mg
arm group label: 600 mg
other name: varoglutamstat
intervention type: Drug
intervention name: Placebo
description: Placebo tablets to mimic PQ912 50 mg and 150 mg tablets
arm group label: Placebo
criteria: 
gender: All
minimum age: 50 Years
maximum age: 80 Years
healthy volunteers: No
last name: Everard Vijverberg, Dr
role: Study Chair
affiliation: VUmc Alzheimer Centre
facility: 
facility: 
facility: 
facility: 
facility: 
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facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
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facility: 
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facility: 
country: Denmark
country: Germany
country: Netherlands
country: Poland
country: Spain
responsible party type: Sponsor
mesh term: Alzheimer Disease
mesh term: Cognitive Dysfunction
sharing ipd: Yes