<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/NCT04442620</url>
  </required_header>
  <id_info>
    <org_study_id>201630.10</org_study_id>
    <nct_id>NCT04442620</nct_id>
  </id_info>
  <brief_title>Prevention and Reversion of NAFLD in Obese Patients With Metabolic Syndrome by Mediterranean Diet and Physical Activity</brief_title>
  <acronym>FLIPAN</acronym>
  <official_title>Prevention and Reversion of Non-Alcoholic Fatty Liver Disease in Obese Patients With Metabolic Syndrome by Mediterranean Diet and Physical Activity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of the Balearic Islands</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fundació La Marató de TV3</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of the Balearic Islands</source>
  <oversight_info>
    <has_dmc>No</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 prospective randomized trial evaluates the role of customized dietary and physical&#xD;
      activity intervention on the progression of Non-Alcoholic Fatty Liver Disease (NAFLD) in&#xD;
      patients with obesity and presenting at least three of the main Metabolic Syndrome traits.&#xD;
&#xD;
      The project proposes a personalized nutritional intervention based on a Mediterranean&#xD;
      customized diet which introduces plenty of antioxidant and anti-inflammatory bioactive&#xD;
      components, coupled with physical activity promotion to prevent and reverse NAFLD among obese&#xD;
      patients with metabolic syndrome. This will be compared with two more dietary strategies&#xD;
      including a Mediterranean Diet intervention with seven meals a day and the conventional&#xD;
      dietary approach proposed by the American Association for the Study of Liver Diseases&#xD;
      (AASLD).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      There is currently no licensed pharmacological treatment for reversing Non-Alcoholic Fatty&#xD;
      Liver Disease (NAFLD), this is why nutritional and lifestyle strategies are pivotal to&#xD;
      ameliorate risk factors and prevent disease progression. Weight loss achieved by a weight&#xD;
      loss diet and exercise is certainly the principal treatment for the amelioration of fatty&#xD;
      liver, nevertheless quality of diet composition could also play a crucial role. Since&#xD;
      oxidative stress and inflammation have been cited among the mechanisms involved in NAFLD,&#xD;
      foods containing antioxidant and anti-inflammatory bioactive components should be considered&#xD;
      when designing a nutritionally sound diet. The Mediterranean Diet, naturally rich in&#xD;
      antioxidants and antinflammatory foods, together with personalised physical activity could&#xD;
      have a variety of positive health effects, including the slowing down of degenerative&#xD;
      diseases such as liver steatosis.&#xD;
&#xD;
      The present study aims to compare and evaluate the efficacy of three interventions on the&#xD;
      pathophysiological mechanisms that may affect changes in liver fat deposits and progression&#xD;
      of NAFLD in patients with obesity and presenting at least three of the main Metabolic&#xD;
      Syndrome traits.&#xD;
&#xD;
      The first intervention group receives a caloric restricted Mediterranean Diet coupled with&#xD;
      physical activity (delivered through guided gym classes); the second group receives a caloric&#xD;
      restricted Mediterranean Diet distributed over 7 meals and advise to walk 10.000 steps a day;&#xD;
      the third group receives the conventional diet proposed by the American Association for the&#xD;
      Study of Liver Diseases (AASLD) and advise to walk 10.000 steps a day.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">October 26, 2017</start_date>
  <completion_date type="Anticipated">December 1, 2021</completion_date>
  <primary_completion_date type="Actual">November 29, 2019</primary_completion_date>
  <phase>N/A</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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in liver steatosis</measure>
    <time_frame>At baseline, 6, 12 and 24 months</time_frame>
    <description>The primary outcome is to measure the change of liver steatosis (expressed as percentage of liver steatosis) after applying a different intervention to each group (PA-MD; HMF-MD; or CD) of participants with metabolic syndrome.&#xD;
It will be measured (at baseline, and after 6, 12 and 24 months of intervention) by means of a 1.5-T Magnetic Resonance Imaging (MRI) (Signa Explorer 1.5T, General Electric Healthcare, Chicago, Illinois., U.S.A) by using a 12-channel phased-array coil.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in liver fibrosis</measure>
    <time_frame>At baseline, 6, 12 and 24 months</time_frame>
    <description>The secondary otucome is to measure the changes of liver fibrosis (expressed as percentage of liver fibrosis) after applying a different intervention to each group (PA-MD; HMF-MD; or CD) of participants with metabolic syndrome.&#xD;
It will be measured (at baseline, and after 6, 12 and 24 months of intervention) by using Shear Wave Measurement (SWM) (Hitachi Ltd, Japan) and the echograph Arietta V70 (Hitachi Medical System Europe Holding AG, Steinhausen, Switzerland).</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">150</enrollment>
  <condition>Non Alcoholic Fatty Liver Disease</condition>
  <arm_group>
    <arm_group_label>1st group: Physical Activity and Mediterranean Diet (PA-MD)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A first group of participants will be advised to reduce their caloric intake by 25-30% with a macronutrients distribution of 35-40% fat, 20% proteins, and 40-45% carbohydrates. Healthy fats (a maximum of 8-10% from saturated fats, &gt;20% from monounsaturated fats, &gt;10% from polyunsaturated fats and &lt;300 mg/day of cholesterol) and low glycaemic index foods rich in fibre (not less than 30-35g /day) are strongly advised, together with foods rich in antioxidants, namely fruits and vegetables. Such diet reflects the traditional Mediterranean Diet described in the PREDIMED (Primary Prevention of Cardiovascular Disease with a Mediterranean Diet)-Plus study.&#xD;
As for physical activity, patients the participants will be recommended a 35 minutes interval training session three times a week. Physical activity sessions of 35 minutes will consist of 5 minutes warm-up, 20 minutes interval training, and 10 minutes breathing and stretching.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2nd group: High Meal Frequency of Mediterranean Diet (HMF-MD)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A second group of participants will be advised to reduce their caloric intake by 25-30% with a macronutrients distribution of 30-35% fat, 25% proteins, and 40-45% carbohydrates. Healthy fats and low glycaemic index foods will be strongly advised, together with foods rich in antioxidants, namely fruits and vegetables. Participants will be advised to consume 7 meals a day, gradually reducing the caloric content at each main meal, and to walk 10.000 steps a day.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3rd group: Control diet (CD)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>A third group of participants will be advised to reduce their caloric intake by 25-30% with a macronutrients distribution of 30% fat, 15% proteins, and 55% carbohydrates, and maintain an adequate fibre (25g/day) and cholesterol (&lt;250mg/day) intake. Meal frequency will be of 3-5 meals a day. Moreover, the participants will be advised to walk 10.000 steps a day.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Physical activity and Mediterranean Diet (PA-MD)</intervention_name>
    <description>Physical Activity plus caloric restricted Mediterranean diet</description>
    <arm_group_label>1st group: Physical Activity and Mediterranean Diet (PA-MD)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>High meal frequency of Mediterranean Diet (HMF-MD)</intervention_name>
    <description>High meal frequency of unaltered Mediterranean diet</description>
    <arm_group_label>2nd group: High Meal Frequency of Mediterranean Diet (HMF-MD)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Control diet (CD)</intervention_name>
    <description>Control Diet</description>
    <arm_group_label>3rd group: Control diet (CD)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age between 40 and 60 years&#xD;
&#xD;
          -  Diagnosis of NAFLD by ultrasound&#xD;
&#xD;
          -  BMI ≥ 27 and &lt; 40 kg/m2&#xD;
&#xD;
          -  Meeting at least 3 of 5 criteria for the metabolic syndrome [as described in the&#xD;
             International Diabetes Federation consensus]: (1) BMI &gt;30kg/m² or increased waist&#xD;
             circumference: ≥ 94 cm in males; ≥ 80 cm in females; (2) Triglycerides (TG) levels ≥&#xD;
             150 mg/dL (1.7 mmol/L) or specific treatment; (3) Reduced HDL cholesterol: &lt; 40 mg/dL&#xD;
             (1.03 mmol/L) in males; &lt; 50 mg/dL (1.29 mmol/L) in females or specific treatment; (4)&#xD;
             Raised blood pressure: systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg or treatment of&#xD;
             previously diagnosed hypertension; (5) Raised fasting plasma glucose (FPG) ≥ 100 mg/dL&#xD;
             (5.6 mmol/L), or previously diagnosed type 2 diabetes&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability or unwillingness to give informed consent or communicate with staff study&#xD;
&#xD;
          -  Documented history of prior cardiovascular disease [angina; myocardial infarction;&#xD;
             coronary revascularization procedures; stroke (ischemic or hemorrhagic including&#xD;
             transient ischemic attacks); symptomatic peripheral artery disease that required&#xD;
             surgery or was diagnosed with vascular imaging techniques; ventricular arrhythmia;&#xD;
             uncontrolled atrial fibrillation; congestive heart failure (New York Heart Association&#xD;
             Class III or IV); hypertrophic myocardiopathy; and history of aortic aneurism &gt;=5.5cm&#xD;
             in diameter or aortic aneurism surgery]&#xD;
&#xD;
          -  Documented history of prior liver diseases (other than NAFLD)&#xD;
&#xD;
          -  Active cancer or a history of malignancy in the last 5 years&#xD;
&#xD;
          -  Low predicted probability to change food habits according to the Stages of Change&#xD;
             Model (Nigg, 1999)&#xD;
&#xD;
          -  Unwillingness or inability to adhere to the dietary and physical activity intervention&#xD;
             over the entire period of the study&#xD;
&#xD;
          -  Failure to follow scheduled visits&#xD;
&#xD;
          -  Weight loss (&gt;5 kg) during 6 months prior to visit&#xD;
&#xD;
          -  Previous surgical procedures for weight loss or scheduled bariatric surgery within the&#xD;
             next 12 months&#xD;
&#xD;
          -  Use of weight loss medications during 6 months prior to visit&#xD;
&#xD;
          -  Previous history of bowel resection, inflammatory bowel disease&#xD;
&#xD;
          -  Obesity associated with endocrine disease (except treated hypothyroidism)&#xD;
&#xD;
          -  Allergy to Mediterranean diet foods or components&#xD;
&#xD;
          -  Severe psychiatric disorders (schizophrenia, bipolar disorder, eating disorders, or&#xD;
             depression with hospitalization within the last 6 months) or Beck Depression Inventory&#xD;
             score &gt; 30&#xD;
&#xD;
          -  Severe condition with less than 24 months life expectancy&#xD;
&#xD;
          -  Chronic abuse of drugs or alcohol (&gt;21 and &gt;14 units of alcohol a week for men and&#xD;
             women, respectively; 1 unit = 125 mL of wine)&#xD;
&#xD;
          -  Treatment with steroids&#xD;
&#xD;
          -  Pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Josep A Tur, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of the Balearic Islands</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of the Balearic Islands</name>
      <address>
        <city>Palma</city>
        <state>Balearic Islands</state>
        <zip>07122</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>January 28, 2020</study_first_submitted>
  <study_first_submitted_qc>June 19, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 22, 2020</study_first_posted>
  <last_update_submitted>June 19, 2020</last_update_submitted>
  <last_update_submitted_qc>June 19, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of the Balearic Islands</investigator_affiliation>
    <investigator_full_name>Josep1</investigator_full_name>
    <investigator_title>Professor of Physiology</investigator_title>
  </responsible_party>
  <keyword>Non Alcoholic Fatty Liver Disease</keyword>
  <keyword>Metabolic syndrome</keyword>
  <keyword>Mediterranean Diet</keyword>
  <keyword>Physical activity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Fatty Liver</mesh_term>
    <mesh_term>Non-alcoholic Fatty Liver Disease</mesh_term>
    <mesh_term>Metabolic Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There are restrictions on the availability of data for the FLIPAN trial, due to the signed consent agreements around data sharing, which only allow access to external researchers for studies following the project purposes. Requestors wishing to access the FLIPAN trial data used in this study can make a request to the FLIPAN trial. Steering Committee chair: pep.tur@uib.es. The request will then be passed to members of the FLIPAN Steering Committee for deliberation.</ipd_description>
  </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/NCT04442620
org study id: 201630.10
nct id: NCT04442620
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This prospective randomized trial evaluates the role of customized dietary and physical
      activity intervention on the progression of Non-Alcoholic Fatty Liver Disease (NAFLD) in
      patients with obesity and presenting at least three of the main Metabolic Syndrome traits.

      The project proposes a personalized nutritional intervention based on a Mediterranean
      customized diet which introduces plenty of antioxidant and anti-inflammatory bioactive
      components, coupled with physical activity promotion to prevent and reverse NAFLD among obese
      patients with metabolic syndrome. This will be compared with two more dietary strategies
      including a Mediterranean Diet intervention with seven meals a day and the conventional
      dietary approach proposed by the American Association for the Study of Liver Diseases
      (AASLD).
There is currently no licensed pharmacological treatment for reversing Non-Alcoholic Fatty
      Liver Disease (NAFLD), this is why nutritional and lifestyle strategies are pivotal to
      ameliorate risk factors and prevent disease progression. Weight loss achieved by a weight
      loss diet and exercise is certainly the principal treatment for the amelioration of fatty
      liver, nevertheless quality of diet composition could also play a crucial role. Since
      oxidative stress and inflammation have been cited among the mechanisms involved in NAFLD,
      foods containing antioxidant and anti-inflammatory bioactive components should be considered
      when designing a nutritionally sound diet. The Mediterranean Diet, naturally rich in
      antioxidants and antinflammatory foods, together with personalised physical activity could
      have a variety of positive health effects, including the slowing down of degenerative
      diseases such as liver steatosis.

      The present study aims to compare and evaluate the efficacy of three interventions on the
      pathophysiological mechanisms that may affect changes in liver fat deposits and progression
      of NAFLD in patients with obesity and presenting at least three of the main Metabolic
      Syndrome traits.

      The first intervention group receives a caloric restricted Mediterranean Diet coupled with
      physical activity (delivered through guided gym classes); the second group receives a caloric
      restricted Mediterranean Diet distributed over 7 meals and advise to walk 10.000 steps a day;
      the third group receives the conventional diet proposed by the American Association for the
      Study of Liver Diseases (AASLD) and advise to walk 10.000 steps a day.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Changes in liver steatosis
time frame: At baseline, 6, 12 and 24 months
description: The primary outcome is to measure the change of liver steatosis (expressed as percentage of liver steatosis) after applying a different intervention to each group (PA-MD; HMF-MD; or CD) of participants with metabolic syndrome.
It will be measured (at baseline, and after 6, 12 and 24 months of intervention) by means of a 1.5-T Magnetic Resonance Imaging (MRI) (Signa Explorer 1.5T, General Electric Healthcare, Chicago, Illinois., U.S.A) by using a 12-channel phased-array coil.
measure: Changes in liver fibrosis
time frame: At baseline, 6, 12 and 24 months
description: The secondary otucome is to measure the changes of liver fibrosis (expressed as percentage of liver fibrosis) after applying a different intervention to each group (PA-MD; HMF-MD; or CD) of participants with metabolic syndrome.
It will be measured (at baseline, and after 6, 12 and 24 months of intervention) by using Shear Wave Measurement (SWM) (Hitachi Ltd, Japan) and the echograph Arietta V70 (Hitachi Medical System Europe Holding AG, Steinhausen, Switzerland).
arm group label: 1st group: Physical Activity and Mediterranean Diet (PA-MD)
arm group type: Experimental
description: A first group of participants will be advised to reduce their caloric intake by 25-30% with a macronutrients distribution of 35-40% fat, 20% proteins, and 40-45% carbohydrates. Healthy fats (a maximum of 8-10% from saturated fats, >20% from monounsaturated fats, >10% from polyunsaturated fats and <300 mg/day of cholesterol) and low glycaemic index foods rich in fibre (not less than 30-35g /day) are strongly advised, together with foods rich in antioxidants, namely fruits and vegetables. Such diet reflects the traditional Mediterranean Diet described in the PREDIMED (Primary Prevention of Cardiovascular Disease with a Mediterranean Diet)-Plus study.
As for physical activity, patients the participants will be recommended a 35 minutes interval training session three times a week. Physical activity sessions of 35 minutes will consist of 5 minutes warm-up, 20 minutes interval training, and 10 minutes breathing and stretching.
arm group label: 2nd group: High Meal Frequency of Mediterranean Diet (HMF-MD)
arm group type: Experimental
description: A second group of participants will be advised to reduce their caloric intake by 25-30% with a macronutrients distribution of 30-35% fat, 25% proteins, and 40-45% carbohydrates. Healthy fats and low glycaemic index foods will be strongly advised, together with foods rich in antioxidants, namely fruits and vegetables. Participants will be advised to consume 7 meals a day, gradually reducing the caloric content at each main meal, and to walk 10.000 steps a day.
arm group label: 3rd group: Control diet (CD)
arm group type: Active Comparator
description: A third group of participants will be advised to reduce their caloric intake by 25-30% with a macronutrients distribution of 30% fat, 15% proteins, and 55% carbohydrates, and maintain an adequate fibre (25g/day) and cholesterol (<250mg/day) intake. Meal frequency will be of 3-5 meals a day. Moreover, the participants will be advised to walk 10.000 steps a day.
intervention type: Other
intervention name: Physical activity and Mediterranean Diet (PA-MD)
description: Physical Activity plus caloric restricted Mediterranean diet
arm group label: 1st group: Physical Activity and Mediterranean Diet (PA-MD)
intervention type: Other
intervention name: High meal frequency of Mediterranean Diet (HMF-MD)
description: High meal frequency of unaltered Mediterranean diet
arm group label: 2nd group: High Meal Frequency of Mediterranean Diet (HMF-MD)
intervention type: Other
intervention name: Control diet (CD)
description: Control Diet
arm group label: 3rd group: Control diet (CD)
criteria: 
gender: All
minimum age: 40 Years
maximum age: 60 Years
healthy volunteers: No
last name: Josep A Tur, PhD
role: Principal Investigator
affiliation: University of the Balearic Islands
facility: 
country: Spain
responsible party type: Principal Investigator
investigator affiliation: University of the Balearic Islands
investigator full name: Josep1
investigator title: Professor of Physiology
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
mesh term: Metabolic Syndrome
sharing ipd: No
ipd description: There are restrictions on the availability of data for the FLIPAN trial, due to the signed consent agreements around data sharing, which only allow access to external researchers for studies following the project purposes. Requestors wishing to access the FLIPAN trial data used in this study can make a request to the FLIPAN trial. Steering Committee chair: pep.tur@uib.es. The request will then be passed to members of the FLIPAN Steering Committee for deliberation.