<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/NCT03232112</url>
  </required_header>
  <id_info>
    <org_study_id>EXALT study</org_study_id>
    <nct_id>NCT03232112</nct_id>
  </id_info>
  <brief_title>Does Treatment With GLP-1 Reduce Alcohol Intake in Patients With Alcohol Dependence?</brief_title>
  <acronym>EXALT</acronym>
  <official_title>Does Glucagon-like Peptide (GLP-1) Receptor Agonist Stimulation Reduce Alcohol Intake in Patients With Alcohol Dependence?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Anders Fink-Jensen, MD, DMSci</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Novavì outpatient clinics, Copenhagen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Neurobiology Research Unit, Rigshospitalet, Copenhagen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Section of Biostatistics University of Copenhagen, Copenhagen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Psychiatric Centre Rigshospitalet</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study is a double-blinded, randomized, placebo-controlled, 26-weeks clinical trial. The&#xD;
      objective of the trial is to investigate the effects of the GLP-1 receptor agonist Bydureon®&#xD;
      (exenatide) vs. placebo on alcohol intake in patients with a diagnosis of alcohol dependence.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Number of patients and target population:&#xD;
&#xD;
      144 patients with a diagnosis of alcohol dependence and 25 healthy participants (described&#xD;
      later).&#xD;
&#xD;
      The patients included in the trial will be treated for 26 weeks with once-weekly subcutaneous&#xD;
      injection of Bydureon® (exenatide) 2 mg or placebo. The medication will be provided as a&#xD;
      supplement to a standard, psychosocial alcohol treatment program. There will be a long-term&#xD;
      follow up 26 weeks after end of participation in the trial&#xD;
&#xD;
      Recruitment of the patients:&#xD;
&#xD;
      The patients will be recruited from the out-patient treatment clinics &quot;Novavì ambulatorierne&quot;&#xD;
      in suburbs of Copenhagen. All patients will receive psychosocial alcohol treatment based on&#xD;
      psycho educative elements, motivational interviewing and cognitive behavioural treatment.&#xD;
      Skilled staff members administer the treatment.&#xD;
&#xD;
      The recruitment procedure starts when the patients contact Novavì ambulatorierne. The first&#xD;
      contact is often without any appointment - i.e. as &quot;drop-in&quot;. At this point the patients will&#xD;
      be met by a healthcare provider at his/her local Novavì ambulatorie. The healthcare provider&#xD;
      will be a nurse or a doctor. The patient will be treated in accordance to the Novavì&#xD;
      guidelines, i.e. start of abstinence treatment and a plan will be agreed on. At this point,&#xD;
      the health personal will also ask if the patient could be interested in our project.&#xD;
      Information regarding the project will also be available on the web page of Novavì. If he/she&#xD;
      is interested and the patient fits the inclusion criteria the patient will be handed written&#xD;
      information about the trial, and an information meeting will be set up a few days later. The&#xD;
      patient will be informed about his/her right to bring a friend or adviser.&#xD;
&#xD;
      Pre-treatment evaluation/screening:&#xD;
&#xD;
      Before screening, all patients will be provided with oral and written information about the&#xD;
      trial, including the most common adverse events, and the procedures involved in the study.&#xD;
      All patients will be fully in-formed, verbally and in writing, of their rights and&#xD;
      responsibilities while participating in the trial. Screening examinations will only be&#xD;
      performed after the patient has agreed to participate and has signed and dated the informed&#xD;
      consent form.&#xD;
&#xD;
      Screening:&#xD;
&#xD;
      At screening examinations, the patient will be asked about his/her alcohol intake the&#xD;
      previous 30 days. The information will be recorded via TLFB (Time Line Follow Back) method.&#xD;
      The patient will be asked questions about his/her lifetime alcohol consumption, previous&#xD;
      treatment and general information about psychosocial factors, i.e. education level,&#xD;
      employment and marital status.&#xD;
&#xD;
      In addition, Alcohol Users Identification Test (AUDIT) score, the Clinical Institute&#xD;
      Withdrawal Assessment of Alcohol Scale Revised (CIWA-Ar), The Drug User Identification Test&#xD;
      (DUDIT) score, Major Depression Inventory (MDI) score (related to the SPECT results), Penn&#xD;
      alcohol craving scale (PACS), smoking status (Fagerströms test), height, weight, waist&#xD;
      circumference, blood pressure and pulse will be registered. In order to evaluate psychosocial&#xD;
      status a general assessment including questionnaires regarding health (SF-36), Symptom&#xD;
      checklist (SCL-92) and Screen for Cognitive Impairment in Psychiatry (SCIP) - test will be&#xD;
      performed.The patients will also be asked questions regarding somatic symptoms, i.e.&#xD;
      GI-symptoms, in order to obtain baseline information. In addition, other medications than&#xD;
      Bydureon® will be registered.&#xD;
&#xD;
      Different safety blood samples and a urine test will be collected. A blood sample and a urine&#xD;
      sample will be saved for an investigational biobank and a biobank for future research.&#xD;
&#xD;
      Weekly visits:&#xD;
&#xD;
      The patient will meet every week to get his/her weekly injection by the un-blinded nurse. The&#xD;
      nurse will collect a weekly alcohol diary and hand them a new one, for the following week.&#xD;
&#xD;
      Examinations during and in the end of the trial:&#xD;
&#xD;
      At week 4, 12 and 20, parts of the baseline examinations - including blood samples - will be&#xD;
      conducted. The alcohol diaries collected in relation to the weekly injection-visits will be&#xD;
      used as template for the 30 day TLFB at the examinations, i.e. the examiner will fill out the&#xD;
      TLFB based on the diaries and in close collaboration with the patient. At week 26, the final&#xD;
      examination will take place repeating all the baseline examinations.&#xD;
&#xD;
      Long-term follow up 26 weeks after end of participation in the trial:&#xD;
&#xD;
      All participants completing the final week 26 examination, will be contacted after six&#xD;
      months, and invited to a follow up meeting . TLFB, PACS, AUDIT and Fagerstrøms questionnaire&#xD;
      will be repeated. A new questionnaire, which gives us a better characteristic of the&#xD;
      patient's alcohol history, &quot;Alco-life&quot; will be registered. A single blood test, (PEth) will&#xD;
      be collected.&#xD;
&#xD;
      Study of the possible neuro molecular and -anatomical underpinnings:&#xD;
&#xD;
      In addition to the clinical outcome parameters, the investigators will explore the neuro&#xD;
      molecular and -anatomical underpinnings of potential therapeutic effects of Bydureon® in two&#xD;
      subgroups of patients who are treated with either Bydureon® or placebo. In order to study&#xD;
      this,two different brain scans will be performed: Single-photon emission computed tomography&#xD;
      (SPECT)-scan (sixty) and functional Magnetic Resonance Imaging (fMRI)-scan (seventy-five&#xD;
      patients) at baseline and after 26 weeks of treatment. The patients will be included&#xD;
      continuously until the aimed number (i.e. sixty and seventy-five patients for each scan type,&#xD;
      respectively) have completed base line scan. The patients will be asked to undergo both scan&#xD;
      types (except from the last fifteen patients out of the seventy-five patients included for&#xD;
      scans, who will only undergo fMRI scan) as the information from both scans will be paired&#xD;
      during evaluation. When baseline scans are performed, the patients start the treatment they&#xD;
      were randomized for at inclusion.&#xD;
&#xD;
      The SPECT-scan:&#xD;
&#xD;
      Studies have lately reported on a GLP-1-induced upregulation of the rat dopamine transporter&#xD;
      activity in vitro. In the present study, the investigators want to investigate whereas GLP-1&#xD;
      receptor stimulation induces changes in the striatal dopamine transporter availability in&#xD;
      humans. The investigators will conduct the SPECT brain scan with the dopamine transporter&#xD;
      ligand 123I-2-b-carbomethoxy-3b-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ([123I]-FP-CIT)&#xD;
      (DaTSCAN, Amersham Health). The SPECT scans will be conducted at the Neurobiology Research&#xD;
      Unit, Rigshospitalet.&#xD;
&#xD;
      The fMRI-scan:&#xD;
&#xD;
      The fMRI-scan measures brain blood flow, which reflects activity in different areas of the&#xD;
      brain. We will test two different paradigms: 1) Alcohol cue sensitivity. Sixty&#xD;
      alcohol-related and 45 neutral stimuli are presented using a block design. Following each&#xD;
      block, the patients rate the intensity of their alcohol craving on a visual analogue scale&#xD;
      ranging from 0 (no craving) to 100 (extremely extensive craving). 2) Spatial working memory.&#xD;
      Spatial working memory is assessed using 2-back and 0-back variants of the N-back task for&#xD;
      the active working memory and control conditions.&#xD;
&#xD;
      Study-schedule for the 25 healthy fMRI-participants:&#xD;
&#xD;
      To have comparable standard data in the fMRI alcohol related paradigm, 25 healthy&#xD;
      participants with no record of alcohol dependence will be recruited. The participants will be&#xD;
      matched with gender and age of the patients and have to fulfil the exclusion-criteria.&#xD;
&#xD;
      Day 1: The participants will have an interview about physical symptoms, diagnosis and current&#xD;
      medication. They will be asked to fill out the Alcohol Users Identification Test (AUDIT), the&#xD;
      Drug Users Identification Test (DUDIT), have a basic physical examination and a blood and a&#xD;
      urine test done.&#xD;
&#xD;
      Day 2: They will start with the Screen for Cognitive Impairment in Psychiatry (SCIP) test,&#xD;
      and afterwards have the fMRI scan done.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 7, 2017</start_date>
  <completion_date type="Actual">October 5, 2020</completion_date>
  <primary_completion_date type="Actual">March 15, 2020</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>
    <intervention_model_description>Double-blinded, randomized, placebo-controlled.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
    <masking_description>An un-blinded nurse will be responsible for carrying out the randomization of the patients in REDCap. When randomization is carried out, the nurse will ensure that the patient gets the treatment that he/she is allocated to. Patients, investigators, other care givers performing assessments and persons performing data analysis will remain blinded from the time of randomization until time of database unlock. In order to maintain the blinding of the patients, the nurse will prepare the injection in a separate room and the patients will be blindfolded as the injection is given.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Heavy drinking days</measure>
    <time_frame>30 days prior to baseline and 30 days prior to final follow up at 26 weeks</time_frame>
    <description>Percent reduction in alcohol consumption, defined as total number of heavy drinking days (as days with an excess intake of 60/48 grams of alcohol per day (men and women, respectively)) for the past 30 days. This will be registered via the Timeline-Follow-Back (TLFB) method.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Total alcohol consumption</measure>
    <time_frame>30 days prior to baseline and 30 days prior to final follow up at 26 weeks</time_frame>
    <description>Percent reduction in alcohol consumption, defined as &quot;x&quot; grams of alcohol for the past 30 days. This will be registered via the Timeline-Follow-Back (TLFB) method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Penn Alcohol Craving Scale (PACS) score</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Score for measuring alcohol craving</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alcohol Use Disorders Identification Test (AUDIT) score</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Screening for excessive drinking</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Drug Use Disorders Identification Test (DUDIT) score</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>A parallel instrument to the AUDIT for identification of individuals with drug-related problems</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Screen For Cognitive Impairment in Psychiatry (SCIP) test</measure>
    <time_frame>Baseline, 4 weeks and 26 weeks</time_frame>
    <description>The 20 minute test is a simple scale developed for screening cognitive deficits</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma-gamma-glutamyltransferase (GGT)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Liver parameter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma-alanine aminotransferase (ALAT)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Liver parameter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma-phosphatidylethanol (PEth)</measure>
    <time_frame>Baseline, 4, 12, 20 and 26 weeks</time_frame>
    <description>Biomarker for alcohol consumption</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood-mean cell volume</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Measure of the average volume of a red blood cell</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body weight</measure>
    <time_frame>Baseline, 4, 12, 20 and 26 weeks</time_frame>
    <description>Body weight in kilograms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pressure</measure>
    <time_frame>Baseline, 4, 12, 20 and 26 weeks</time_frame>
    <description>Systolic and diastolic blood pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulse</measure>
    <time_frame>Baseline, 4, 12, 20 and 26 weeks</time_frame>
    <description>Number of heartbeats pr. minute</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Waist circumference</measure>
    <time_frame>Baseline, 4, 12, 20 and 26 weeks</time_frame>
    <description>Widest abdominal circumference in centimeters</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma-glycemic control parameters</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>HbA1c, cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Kidney function</measure>
    <time_frame>Baseline and 26 weeks (eGFR also at week 12)</time_frame>
    <description>e-GFR, urine albumine/creatinine-ratio.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Short Form Health Survey (SF-36)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>36-item, patient-reported survey of patient health</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma amylase</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>Safety (i.e. pancreatic function)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Symptom Checklist (SCL-92)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>92-item, patient-reported survey of a broad range of psychological problems and symptoms of psychopathology.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Single-photon emission computed tomography (SPECT)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>In this study we want to investigate whereas GLP-1 receptor stimulation induces changes in the striatal dopamine transporter availability in humans.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>fMRI (functional magnetic resonance imaging)</measure>
    <time_frame>Baseline and 26 weeks</time_frame>
    <description>In this study we want to investigate whereas GLP-1 treatment modulate neural responses in reward processing regions including nucleus accumbens. Data from the 25 healthy participants will be used as comparable standard when analyzing the data.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">152</enrollment>
  <condition>Alcohol Dependence, in Remission</condition>
  <condition>Addiction, Alcohol</condition>
  <arm_group>
    <arm_group_label>Exenatide 2 MG Injection</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Bydureon® (exenatide) is supplied as powder and solvent for prolonged release injection (once-weekly). Bydureon® is delivered in a carton containing four pens. Each single-dose, dual-chamber pen contains 0.65 ml of diluent and 2 mg of exenatide, which are isolated until mixed by the person administering the drug. Needles are supplied with the pen.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>BD PosiFlush (saline)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>The placebo will be supplied for as pre-filled saline syringes (BD PosiFlush™, BD Worldwide) containing 3 ml each. Needles are bought separately.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Exenatide 2 MG Injection</intervention_name>
    <description>Subcutaneous injection once-weekly</description>
    <arm_group_label>Exenatide 2 MG Injection</arm_group_label>
    <other_name>Bydureon Pen, 2 Mg, Extended Release</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BD PosiFlush (saline)</intervention_name>
    <description>Subcutaneous injection once-weekly</description>
    <arm_group_label>BD PosiFlush (saline)</arm_group_label>
    <other_name>Saline</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Informed oral and written consent&#xD;
&#xD;
          -  Diagnosed with alcohol dependence according to the criteria of International&#xD;
             Classification of Diseases (ICD) 10, World Health Organization and DSM-5&#xD;
&#xD;
          -  Alcohol use disorder identification test (AUDIT) score &gt;15&#xD;
&#xD;
          -  Age 18 - 70 years&#xD;
&#xD;
          -  Heavy alcohol drinking defined as having alcohol consumption over 60 g of alcohol per&#xD;
             day (men) or 48 g of alcohol per day (women) for at least 5 days in the past 30 days&#xD;
             prior to inclusion measured by the TLFB method.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe psychiatric disease, defined as a diagnosis of schizophrenia, paranoid&#xD;
             psychosis, bipolar dis-order or mental retardation&#xD;
&#xD;
          -  A history of delirium tremens or alcohol withdrawal seizures&#xD;
&#xD;
          -  No serious withdrawal symptoms at inclusion (a score higher than 9 on the Clinical&#xD;
             Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar)) at baseline&#xD;
             examinations&#xD;
&#xD;
          -  Present or former neurological disease including traumatic brain injury&#xD;
&#xD;
          -  Present or former diagnosis of type 1 or type 2 diabetes or plasma Haemoglobin A1c&#xD;
             (HbA1c ) ≥48 moll/L at inclusion&#xD;
&#xD;
          -  Females of child bearing potential who are pregnant, breast-feeding or have intention&#xD;
             of becoming pregnant within the next 9 months (26 weeks plus three months after&#xD;
             discontinuation of Bydureon®) , or are not using contraceptives (during the whole&#xD;
             study period) considered as highly effective (combined (oestrogen and progestogen&#xD;
             containing) hormonal contraception associated with inhibition of ovulation (oral,&#xD;
             intravaginal, transdermal), progestogen-only hormonal contraception associated with&#xD;
             inhibition of ovulation (oral, injectable, implantable) intrauterine device - IUD,&#xD;
             IUS, bilateral tubal occlusion, vasectomised partner, sexual abstinence) (33)&#xD;
&#xD;
          -  Pregnancy (serum hCG &gt; 3 at inclusion) Impaired hepatic function (liver transaminases&#xD;
             &gt;3 times up-per normal limit)&#xD;
&#xD;
          -  Impaired renal function (eGFR &lt; 50 ml/min and/or microalbuminuria) Impaired pancreatic&#xD;
             function (any history of acute or chronic pancreatitis and/or amylase &gt; 2 times upper&#xD;
             limit)&#xD;
&#xD;
          -  S-triglycerides &gt; 10 mmol/l&#xD;
&#xD;
          -  Former medullary thyroid carcinoma (MTC) and/or family history with MTC and/or&#xD;
             Multiple Endo-crine Neoplasia syndrome type 2 (MEN 2)&#xD;
&#xD;
          -  Cardiac problems defined as decompensated heart failure (NYHA class III or IV),&#xD;
             unstable angina pectoris and/or myocardial infarction within the last 12 months&#xD;
&#xD;
          -  Uncontrolled hypertension (systolic blood pressure &gt;180 mmHg, diastolic blood pressure&#xD;
             &gt;110 mmHg)&#xD;
&#xD;
          -  Concomitant pharmacotherapy against alcohol dependence including disulfiram,&#xD;
             naltrexone, acamprosate and nalmefene or treatment with any of these compounds within&#xD;
             1 month prior to inclusion&#xD;
&#xD;
          -  Concomitant pharmacotherapy with dopamine active drugs, such as some types of&#xD;
             Attention Deficit Hyperactivity Disorder (ADHD) medication (methylphenidate)&#xD;
&#xD;
          -  Receiving any investigational drug within the last 3 months&#xD;
&#xD;
          -  Use of weight-lowering pharmacotherapy within the preceding 3 month&#xD;
&#xD;
          -  Any other active substance use defined as a DUDIT-score &gt; 6 (for men) &gt;2 (for women)&#xD;
             and fulfilling the criteria's for dependence of the substance according to the&#xD;
             criteria of International Classification of Diseases (ICD) 10 (except nicotine)&#xD;
&#xD;
          -  BMI &lt;18.5 kg/m2&#xD;
&#xD;
          -  Hypersensitivity to the active substance or to any of the excipients&#xD;
&#xD;
          -  Only for patients undergoing brain scans: Contraindications for undergoing an fMRI&#xD;
             scan (magnetic implants, pacemaker, claustrophobia etc.). Contraindications for&#xD;
             undergoing a SPECT-scan (allergy towards iodine, radiation exposure, excluding&#xD;
             background radiation but including diagnostic x-rays and other medical exposures,&#xD;
             exceeding 10 mSv in the last 12 months)&#xD;
&#xD;
          -  Unable to speak and/or understand Danish&#xD;
&#xD;
          -  Any condition that the investigator feels would interfere with trial participation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Signe W. Düring, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Novavi outpatient clinics, Copenhagen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Novavì ambulatorierne</name>
      <address>
        <city>Copenhagen</city>
        <state>Frederiksberg</state>
        <zip>2000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>July 20, 2017</study_first_submitted>
  <study_first_submitted_qc>July 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2017</study_first_posted>
  <last_update_submitted>June 3, 2021</last_update_submitted>
  <last_update_submitted_qc>June 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 4, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Psychiatric Centre Rigshospitalet</investigator_affiliation>
    <investigator_full_name>Anders Fink-Jensen, MD, DMSci</investigator_full_name>
    <investigator_title>Professor, MD, DMSci</investigator_title>
  </responsible_party>
  <keyword>Alcohol</keyword>
  <keyword>Addiction</keyword>
  <keyword>Glucagon Like Peptide-1</keyword>
  <keyword>GLP-1</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alcoholism</mesh_term>
    <mesh_term>Behavior, Addictive</mesh_term>
    <mesh_term>Alcohol Drinking</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Exenatide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>At the start and at the end of the study a blood sample (9ml) and a urine sample (7.2ml) will be stored in a biobank for future research. The patients will be asked to give a separate written consent. Using this biobank in the future will require a new approval from the Danish Data Protection Agency.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 26, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/12/NCT03232112/SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03232112
org study id: EXALT study
nct id: NCT03232112
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The study is a double-blinded, randomized, placebo-controlled, 26-weeks clinical trial. The
      objective of the trial is to investigate the effects of the GLP-1 receptor agonist Bydureon®
      (exenatide) vs. placebo on alcohol intake in patients with a diagnosis of alcohol dependence.
Number of patients and target population:

      144 patients with a diagnosis of alcohol dependence and 25 healthy participants (described
      later).

      The patients included in the trial will be treated for 26 weeks with once-weekly subcutaneous
      injection of Bydureon® (exenatide) 2 mg or placebo. The medication will be provided as a
      supplement to a standard, psychosocial alcohol treatment program. There will be a long-term
      follow up 26 weeks after end of participation in the trial

      Recruitment of the patients:

      The patients will be recruited from the out-patient treatment clinics "Novavì ambulatorierne"
      in suburbs of Copenhagen. All patients will receive psychosocial alcohol treatment based on
      psycho educative elements, motivational interviewing and cognitive behavioural treatment.
      Skilled staff members administer the treatment.

      The recruitment procedure starts when the patients contact Novavì ambulatorierne. The first
      contact is often without any appointment - i.e. as "drop-in". At this point the patients will
      be met by a healthcare provider at his/her local Novavì ambulatorie. The healthcare provider
      will be a nurse or a doctor. The patient will be treated in accordance to the Novavì
      guidelines, i.e. start of abstinence treatment and a plan will be agreed on. At this point,
      the health personal will also ask if the patient could be interested in our project.
      Information regarding the project will also be available on the web page of Novavì. If he/she
      is interested and the patient fits the inclusion criteria the patient will be handed written
      information about the trial, and an information meeting will be set up a few days later. The
      patient will be informed about his/her right to bring a friend or adviser.

      Pre-treatment evaluation/screening:

      Before screening, all patients will be provided with oral and written information about the
      trial, including the most common adverse events, and the procedures involved in the study.
      All patients will be fully in-formed, verbally and in writing, of their rights and
      responsibilities while participating in the trial. Screening examinations will only be
      performed after the patient has agreed to participate and has signed and dated the informed
      consent form.

      Screening:

      At screening examinations, the patient will be asked about his/her alcohol intake the
      previous 30 days. The information will be recorded via TLFB (Time Line Follow Back) method.
      The patient will be asked questions about his/her lifetime alcohol consumption, previous
      treatment and general information about psychosocial factors, i.e. education level,
      employment and marital status.

      In addition, Alcohol Users Identification Test (AUDIT) score, the Clinical Institute
      Withdrawal Assessment of Alcohol Scale Revised (CIWA-Ar), The Drug User Identification Test
      (DUDIT) score, Major Depression Inventory (MDI) score (related to the SPECT results), Penn
      alcohol craving scale (PACS), smoking status (Fagerströms test), height, weight, waist
      circumference, blood pressure and pulse will be registered. In order to evaluate psychosocial
      status a general assessment including questionnaires regarding health (SF-36), Symptom
      checklist (SCL-92) and Screen for Cognitive Impairment in Psychiatry (SCIP) - test will be
      performed.The patients will also be asked questions regarding somatic symptoms, i.e.
      GI-symptoms, in order to obtain baseline information. In addition, other medications than
      Bydureon® will be registered.

      Different safety blood samples and a urine test will be collected. A blood sample and a urine
      sample will be saved for an investigational biobank and a biobank for future research.

      Weekly visits:

      The patient will meet every week to get his/her weekly injection by the un-blinded nurse. The
      nurse will collect a weekly alcohol diary and hand them a new one, for the following week.

      Examinations during and in the end of the trial:

      At week 4, 12 and 20, parts of the baseline examinations - including blood samples - will be
      conducted. The alcohol diaries collected in relation to the weekly injection-visits will be
      used as template for the 30 day TLFB at the examinations, i.e. the examiner will fill out the
      TLFB based on the diaries and in close collaboration with the patient. At week 26, the final
      examination will take place repeating all the baseline examinations.

      Long-term follow up 26 weeks after end of participation in the trial:

      All participants completing the final week 26 examination, will be contacted after six
      months, and invited to a follow up meeting . TLFB, PACS, AUDIT and Fagerstrøms questionnaire
      will be repeated. A new questionnaire, which gives us a better characteristic of the
      patient's alcohol history, "Alco-life" will be registered. A single blood test, (PEth) will
      be collected.

      Study of the possible neuro molecular and -anatomical underpinnings:

      In addition to the clinical outcome parameters, the investigators will explore the neuro
      molecular and -anatomical underpinnings of potential therapeutic effects of Bydureon® in two
      subgroups of patients who are treated with either Bydureon® or placebo. In order to study
      this,two different brain scans will be performed: Single-photon emission computed tomography
      (SPECT)-scan (sixty) and functional Magnetic Resonance Imaging (fMRI)-scan (seventy-five
      patients) at baseline and after 26 weeks of treatment. The patients will be included
      continuously until the aimed number (i.e. sixty and seventy-five patients for each scan type,
      respectively) have completed base line scan. The patients will be asked to undergo both scan
      types (except from the last fifteen patients out of the seventy-five patients included for
      scans, who will only undergo fMRI scan) as the information from both scans will be paired
      during evaluation. When baseline scans are performed, the patients start the treatment they
      were randomized for at inclusion.

      The SPECT-scan:

      Studies have lately reported on a GLP-1-induced upregulation of the rat dopamine transporter
      activity in vitro. In the present study, the investigators want to investigate whereas GLP-1
      receptor stimulation induces changes in the striatal dopamine transporter availability in
      humans. The investigators will conduct the SPECT brain scan with the dopamine transporter
      ligand 123I-2-b-carbomethoxy-3b-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ([123I]-FP-CIT)
      (DaTSCAN, Amersham Health). The SPECT scans will be conducted at the Neurobiology Research
      Unit, Rigshospitalet.

      The fMRI-scan:

      The fMRI-scan measures brain blood flow, which reflects activity in different areas of the
      brain. We will test two different paradigms: 1) Alcohol cue sensitivity. Sixty
      alcohol-related and 45 neutral stimuli are presented using a block design. Following each
      block, the patients rate the intensity of their alcohol craving on a visual analogue scale
      ranging from 0 (no craving) to 100 (extremely extensive craving). 2) Spatial working memory.
      Spatial working memory is assessed using 2-back and 0-back variants of the N-back task for
      the active working memory and control conditions.

      Study-schedule for the 25 healthy fMRI-participants:

      To have comparable standard data in the fMRI alcohol related paradigm, 25 healthy
      participants with no record of alcohol dependence will be recruited. The participants will be
      matched with gender and age of the patients and have to fulfil the exclusion-criteria.

      Day 1: The participants will have an interview about physical symptoms, diagnosis and current
      medication. They will be asked to fill out the Alcohol Users Identification Test (AUDIT), the
      Drug Users Identification Test (DUDIT), have a basic physical examination and a blood and a
      urine test done.

      Day 2: They will start with the Screen for Cognitive Impairment in Psychiatry (SCIP) test,
      and afterwards have the fMRI scan done.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Double-blinded, randomized, placebo-controlled.
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
masking description: An un-blinded nurse will be responsible for carrying out the randomization of the patients in REDCap. When randomization is carried out, the nurse will ensure that the patient gets the treatment that he/she is allocated to. Patients, investigators, other care givers performing assessments and persons performing data analysis will remain blinded from the time of randomization until time of database unlock. In order to maintain the blinding of the patients, the nurse will prepare the injection in a separate room and the patients will be blindfolded as the injection is given.
measure: Heavy drinking days
time frame: 30 days prior to baseline and 30 days prior to final follow up at 26 weeks
description: Percent reduction in alcohol consumption, defined as total number of heavy drinking days (as days with an excess intake of 60/48 grams of alcohol per day (men and women, respectively)) for the past 30 days. This will be registered via the Timeline-Follow-Back (TLFB) method.
measure: Total alcohol consumption
time frame: 30 days prior to baseline and 30 days prior to final follow up at 26 weeks
description: Percent reduction in alcohol consumption, defined as "x" grams of alcohol for the past 30 days. This will be registered via the Timeline-Follow-Back (TLFB) method.
measure: Penn Alcohol Craving Scale (PACS) score
time frame: Baseline and 26 weeks
description: Score for measuring alcohol craving
measure: Alcohol Use Disorders Identification Test (AUDIT) score
time frame: Baseline and 26 weeks
description: Screening for excessive drinking
measure: Drug Use Disorders Identification Test (DUDIT) score
time frame: Baseline and 26 weeks
description: A parallel instrument to the AUDIT for identification of individuals with drug-related problems
measure: Screen For Cognitive Impairment in Psychiatry (SCIP) test
time frame: Baseline, 4 weeks and 26 weeks
description: The 20 minute test is a simple scale developed for screening cognitive deficits
measure: Plasma-gamma-glutamyltransferase (GGT)
time frame: Baseline and 26 weeks
description: Liver parameter
measure: Plasma-alanine aminotransferase (ALAT)
time frame: Baseline and 26 weeks
description: Liver parameter
measure: Plasma-phosphatidylethanol (PEth)
time frame: Baseline, 4, 12, 20 and 26 weeks
description: Biomarker for alcohol consumption
measure: Blood-mean cell volume
time frame: Baseline and 26 weeks
description: Measure of the average volume of a red blood cell
measure: Body weight
time frame: Baseline, 4, 12, 20 and 26 weeks
description: Body weight in kilograms
measure: Blood pressure
time frame: Baseline, 4, 12, 20 and 26 weeks
description: Systolic and diastolic blood pressure
measure: Pulse
time frame: Baseline, 4, 12, 20 and 26 weeks
description: Number of heartbeats pr. minute
measure: Waist circumference
time frame: Baseline, 4, 12, 20 and 26 weeks
description: Widest abdominal circumference in centimeters
measure: Plasma-glycemic control parameters
time frame: Baseline and 26 weeks
description: HbA1c, cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL).
measure: Kidney function
time frame: Baseline and 26 weeks (eGFR also at week 12)
description: e-GFR, urine albumine/creatinine-ratio.
measure: Short Form Health Survey (SF-36)
time frame: Baseline and 26 weeks
description: 36-item, patient-reported survey of patient health
measure: Plasma amylase
time frame: Baseline and 26 weeks
description: Safety (i.e. pancreatic function)
measure: Symptom Checklist (SCL-92)
time frame: Baseline and 26 weeks
description: 92-item, patient-reported survey of a broad range of psychological problems and symptoms of psychopathology.
measure: Single-photon emission computed tomography (SPECT)
time frame: Baseline and 26 weeks
description: In this study we want to investigate whereas GLP-1 receptor stimulation induces changes in the striatal dopamine transporter availability in humans.
measure: fMRI (functional magnetic resonance imaging)
time frame: Baseline and 26 weeks
description: In this study we want to investigate whereas GLP-1 treatment modulate neural responses in reward processing regions including nucleus accumbens. Data from the 25 healthy participants will be used as comparable standard when analyzing the data.
arm group label: Exenatide 2 MG Injection
arm group type: Active Comparator
description: Bydureon® (exenatide) is supplied as powder and solvent for prolonged release injection (once-weekly). Bydureon® is delivered in a carton containing four pens. Each single-dose, dual-chamber pen contains 0.65 ml of diluent and 2 mg of exenatide, which are isolated until mixed by the person administering the drug. Needles are supplied with the pen.
arm group label: BD PosiFlush (saline)
arm group type: Placebo Comparator
description: The placebo will be supplied for as pre-filled saline syringes (BD PosiFlush™, BD Worldwide) containing 3 ml each. Needles are bought separately.
intervention type: Drug
intervention name: Exenatide 2 MG Injection
description: Subcutaneous injection once-weekly
arm group label: Exenatide 2 MG Injection
other name: Bydureon Pen, 2 Mg, Extended Release
intervention type: Drug
intervention name: BD PosiFlush (saline)
description: Subcutaneous injection once-weekly
arm group label: BD PosiFlush (saline)
other name: Saline
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Signe W. Düring, MD
role: Principal Investigator
affiliation: The Novavi outpatient clinics, Copenhagen
facility: 
country: Denmark
responsible party type: Sponsor-Investigator
investigator affiliation: Psychiatric Centre Rigshospitalet
investigator full name: Anders Fink-Jensen, MD, DMSci
investigator title: Professor, MD, DMSci
mesh term: Alcoholism
mesh term: Behavior, Addictive
mesh term: Alcohol Drinking
mesh term: Exenatide
sharing ipd: Yes
ipd description: At the start and at the end of the study a blood sample (9ml) and a urine sample (7.2ml) will be stored in a biobank for future research. The patients will be asked to give a separate written consent. Using this biobank in the future will require a new approval from the Danish Data Protection Agency.
provided document: 