xml: <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/NCT06022068</url>
    </required_header>
    <id_info>
      <org_study_id>2023-00611-01</org_study_id>
      <nct_id>NCT06022068</nct_id>
    </id_info>
    <brief_title>Evaluating Rapamycin Treatment in Alzheimer's Disease Using Positron Emission Tomography</brief_title>
    <acronym>ERAP</acronym>
    <official_title>Evaluating Rapamycin Treatment in Alzheimer's Disease Using Positron Emission Tomography (ERAP)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Karolinska Institutet</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Karolinska University Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Karolinska Institutet</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 single-center, uncontrolled pilot study aims to evaluate the efficacy, safety, and&#xD;
        tolerability of six months of intermittently dosed oral rapamycin (sirolimus) in subjects&#xD;
        with early-stage Alzheimer's disease.&#xD;
  &#xD;
        Fifteen participants will be recruited. Following a set of baseline measurements, all&#xD;
        participants will receive a weekly oral dose of 7 mg rapamycin for six months. Participants&#xD;
        will be continuously monitored for safety and side effects. At the termination of the&#xD;
        treatment, follow-up measurements will be taken.&#xD;
  &#xD;
        The primary endpoint will be change in cerebral glucose metabolism, measured using 18F&#xD;
        labeled fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET).&#xD;
  &#xD;
        In addition to the registered outcome measures this pilot trial will explore the feasibility&#xD;
        of acquiring data on the effect of sirolimus treatment on age-related tissue changes in the&#xD;
        body using a variety of imaging modalities, such as bone mineral density assessed using&#xD;
        quantitative computed tomography, retinal structures assessed using optical coherence&#xD;
        tomography, periodontal tissue assessed using MRI and FDG-PET, cardiac function assessed&#xD;
        using MRI, vessel wall in large arteries using MRI and [18F]FDG PET.&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Enrolling by invitation</overall_status>
    <start_date type="Actual">September 1, 2023</start_date>
    <completion_date type="Anticipated">January 31, 2025</completion_date>
    <primary_completion_date type="Anticipated">January 31, 2025</primary_completion_date>
    <phase>Phase 1/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>Change in cerebral glucose metabolism</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>Cerebral glucose uptake measured through [18F]FDG positron emission tomography</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Incidence of Treatment-Emergent Adverse Events</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>Safety and tolerability of intermittent sirolimus treatment</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Cerebrospinal fluid (CSF) concentration of amyloid beta 42</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>CSF biomarker for Alzheimers disease</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in CSF concentration of phosphorylated tau</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>CSF biomarker for Alzheimers disease</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in CSF concentration of total tau</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>CSF biomarker for Alzheimers disease</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in cerebral blood flow</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>Cerebral blood flow measured with MRI using arterial spin labeling</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Area under the concentration versus time curve (AUC) of sirolimus</measure>
      <time_frame>Tested at one occasion between baseline to six months</time_frame>
      <description>Whole blood measurements of sirolimus concentration.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Peak Plasma Concentration (Cmax) of sirolimus</measure>
      <time_frame>Tested at one occasion between baseline to six months</time_frame>
      <description>Whole blood measurements of sirolimus concentration.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Trough Plasma Concentration (Cmin) of sirolimus</measure>
      <time_frame>Tested at one occasion between baseline to six months</time_frame>
      <description>Whole blood measurements of sirolimus concentration.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in Montreal Cognitive Assessment (MoCA) rating</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>Cognition assessed using the MoCA rating scale (0-30 points, higher scores indicating better cognitive performance)</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Change in composite z-score of neuropsychological tests</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>Cognition assessed with a composite score of the following tests: Rey Auditory Verbal Learning Test; Rey-Osterrieth Complex Figure; Hagman test; Trail Making Test A + B; Wechsler Adult Intelligence Scale (subtest to assess processing speed/attention). A composite score will be calculated using z-score approach..</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in concentration of neurofilament light in CSF</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>Neuronal damage assessed using concentraion of neurofilament light in CSF.</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in quotient of albumin concentration in serum and CSF</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>Blood-brain barrier integrity assessed using quotient of concentration albumin in serum and CSF</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in hand-grip strength</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>Measured using a hand-grip dynamometer</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in chair stand test</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>Number of completed chair stands in 30 seconds</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in walking speed</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>Timed 10-metre dual task walking test</description>
    </other_outcome>
    <other_outcome>
      <measure>Change in ratio of CSF concentration of amyloid beta 42 and 40</measure>
      <time_frame>From baseline to six months</time_frame>
      <description>CSF biomarker for Alzheimers disease</description>
    </other_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">15</enrollment>
    <condition>Alzheimer Disease</condition>
    <arm_group>
      <arm_group_label>Rapamycin</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Sirolimus tablets will be administered orally, 7 mg once per week during 26 weeks</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Sirolimus</intervention_name>
      <description>7 mg taken once per week during 26 weeks.</description>
      <arm_group_label>Rapamycin</arm_group_label>
      <other_name>Rapamycin</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Clinical diagnosis of mild cognitive impairment (MCI), or dementia of Alzheimer's type&#xD;
  &#xD;
            2. Amyloid positivity established with either amyloid positron emission tomography or&#xD;
               cerebrospinal fluid analysis.&#xD;
  &#xD;
            3. For subjects with dementia, the disease should be in an early stage, operationalized&#xD;
               as:&#xD;
  &#xD;
                 -  Stage 4 (Mild dementia) or lower, according to the National Institute on Aging -&#xD;
                    Alzheimer's Association 2018 clinical staging criteria, AND&#xD;
  &#xD;
                 -  Clinical Dementia Rating Scale (CDR) global score of 1 or lower, AND&#xD;
  &#xD;
                 -  Montreal Cognitive Assessment (MoCA) score of ≥ 18 OR Rey Auditory Verbal&#xD;
                    Learning Test (RAVLT) &gt;4 words after 30 minutes&#xD;
  &#xD;
            4. Capable of giving, and has the capacity to give informed consent&#xD;
  &#xD;
            5. Availability of a responsible study partner who can accompany the subject to all&#xD;
               planned visits&#xD;
  &#xD;
            6. Male or female between 50 and 80 years&#xD;
  &#xD;
            7. Normal or clinically acceptable medical history, physical examination, and vital signs&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. History of any major disease that may interfere with safe engagement in the&#xD;
               intervention (especially severe liver or kidney disease, or uncontrolled diabetes).&#xD;
  &#xD;
            2. Central nervous system infarct, infection, or focal lesions of clinical significance&#xD;
               on MRI scans.&#xD;
  &#xD;
            3. Fulfills any contraindication for the use of sirolimus as per the summary of product&#xD;
               characteristics, including but not restricted to:&#xD;
  &#xD;
                 -  Current or planned medication with a strong inhibitor of CYP3A4 or P-gp&#xD;
  &#xD;
                 -  Current or planned medication with a strong inducer of CYP3A4 or P-gp&#xD;
  &#xD;
                 -  Other current medications with known serious interaction risks with sirolimus&#xD;
  &#xD;
                 -  Known allergy or hypersensitivity to sirolimus&#xD;
  &#xD;
            4. Significant obesity&#xD;
  &#xD;
            5. Untreated and clinically significant hyperlipidemia&#xD;
  &#xD;
            6. Treatment with immunosuppressive medications within the last 90 days (topical and&#xD;
               nasal corticosteroids and inhaled corticosteroids for asthma are permitted), or&#xD;
               chemotherapeutic agents for malignancy within the last 3 years&#xD;
  &#xD;
            7. Major surgery within 3 months prior to the planned start of sirolimus treatment, OR&#xD;
               has major surgery planned during the period of the trial.&#xD;
  &#xD;
            8. Use of experimental medications for Alzheimer's or any other investigational&#xD;
               medication or device within 60 days. Participants who have been involved in a&#xD;
               monoclonal antibody study are excluded unless it is known that they were receiving&#xD;
               placebo in that trial&#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>Jonas Svensson, MD, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Karolinska Institutet</affiliation>
    </overall_official>
    <location>
      <facility>
        <name>Karolinska University Hospital Memory clinic</name>
        <address>
          <city>Solna</city>
          <state>Stockholm</state>
          <zip>171 64</zip>
          <country>Sweden</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Sweden</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>August 15, 2023</study_first_submitted>
    <study_first_submitted_qc>August 30, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 1, 2023</study_first_posted>
    <last_update_submitted>September 4, 2023</last_update_submitted>
    <last_update_submitted_qc>September 4, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 7, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Karolinska Institutet</investigator_affiliation>
      <investigator_full_name>Jonas Svensson</investigator_full_name>
      <investigator_title>MD</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Alzheimer Disease</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Sirolimus</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Undecided</sharing_ipd>
      <ipd_description>We aim to share pseudonymized individual participant data that underlie results in a publication in accordance with institutional regulations.</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06022068
  org study id: 2023-00611-01
  nct id: NCT06022068
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  This single-center, uncontrolled pilot study aims to evaluate the efficacy, safety, and
        tolerability of six months of intermittently dosed oral rapamycin (sirolimus) in subjects
        with early-stage Alzheimer's disease.
  
        Fifteen participants will be recruited. Following a set of baseline measurements, all
        participants will receive a weekly oral dose of 7 mg rapamycin for six months. Participants
        will be continuously monitored for safety and side effects. At the termination of the
        treatment, follow-up measurements will be taken.
  
        The primary endpoint will be change in cerebral glucose metabolism, measured using 18F
        labeled fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET).
  
        In addition to the registered outcome measures this pilot trial will explore the feasibility
        of acquiring data on the effect of sirolimus treatment on age-related tissue changes in the
        body using a variety of imaging modalities, such as bone mineral density assessed using
        quantitative computed tomography, retinal structures assessed using optical coherence
        tomography, periodontal tissue assessed using MRI and FDG-PET, cardiac function assessed
        using MRI, vessel wall in large arteries using MRI and [18F]FDG PET.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Change in cerebral glucose metabolism
  time frame: From baseline to six months
  description: Cerebral glucose uptake measured through [18F]FDG positron emission tomography
  measure: Incidence of Treatment-Emergent Adverse Events
  time frame: From baseline to six months
  description: Safety and tolerability of intermittent sirolimus treatment
  measure: Change in Cerebrospinal fluid (CSF) concentration of amyloid beta 42
  time frame: From baseline to six months
  description: CSF biomarker for Alzheimers disease
  measure: Change in CSF concentration of phosphorylated tau
  time frame: From baseline to six months
  description: CSF biomarker for Alzheimers disease
  measure: Change in CSF concentration of total tau
  time frame: From baseline to six months
  description: CSF biomarker for Alzheimers disease
  measure: Change in cerebral blood flow
  time frame: From baseline to six months
  description: Cerebral blood flow measured with MRI using arterial spin labeling
  measure: Area under the concentration versus time curve (AUC) of sirolimus
  time frame: Tested at one occasion between baseline to six months
  description: Whole blood measurements of sirolimus concentration.
  measure: Peak Plasma Concentration (Cmax) of sirolimus
  time frame: Tested at one occasion between baseline to six months
  description: Whole blood measurements of sirolimus concentration.
  measure: Trough Plasma Concentration (Cmin) of sirolimus
  time frame: Tested at one occasion between baseline to six months
  description: Whole blood measurements of sirolimus concentration.
  measure: Change in Montreal Cognitive Assessment (MoCA) rating
  time frame: From baseline to six months
  description: Cognition assessed using the MoCA rating scale (0-30 points, higher scores indicating better cognitive performance)
  measure: Change in composite z-score of neuropsychological tests
  time frame: From baseline to six months
  description: Cognition assessed with a composite score of the following tests: Rey Auditory Verbal Learning Test; Rey-Osterrieth Complex Figure; Hagman test; Trail Making Test A + B; Wechsler Adult Intelligence Scale (subtest to assess processing speed/attention). A composite score will be calculated using z-score approach..
  measure: Change in concentration of neurofilament light in CSF
  time frame: From baseline to six months
  description: Neuronal damage assessed using concentraion of neurofilament light in CSF.
  measure: Change in quotient of albumin concentration in serum and CSF
  time frame: From baseline to six months
  description: Blood-brain barrier integrity assessed using quotient of concentration albumin in serum and CSF
  measure: Change in hand-grip strength
  time frame: From baseline to six months
  description: Measured using a hand-grip dynamometer
  measure: Change in chair stand test
  time frame: From baseline to six months
  description: Number of completed chair stands in 30 seconds
  measure: Change in walking speed
  time frame: From baseline to six months
  description: Timed 10-metre dual task walking test
  measure: Change in ratio of CSF concentration of amyloid beta 42 and 40
  time frame: From baseline to six months
  description: CSF biomarker for Alzheimers disease
  arm group label: Rapamycin
  arm group type: Experimental
  description: Sirolimus tablets will be administered orally, 7 mg once per week during 26 weeks
  intervention type: Drug
  intervention name: Sirolimus
  description: 7 mg taken once per week during 26 weeks.
  arm group label: Rapamycin
  other name: Rapamycin
  criteria: 
  gender: All
  minimum age: 50 Years
  maximum age: 80 Years
  healthy volunteers: No
  last name: Jonas Svensson, MD, PhD
  role: Principal Investigator
  affiliation: Karolinska Institutet
  facility: 
  country: Sweden
  responsible party type: Principal Investigator
  investigator affiliation: Karolinska Institutet
  investigator full name: Jonas Svensson
  investigator title: MD
  mesh term: Alzheimer Disease
  mesh term: Sirolimus
  sharing ipd: Undecided
  ipd description: We aim to share pseudonymized individual participant data that underlie results in a publication in accordance with institutional regulations.