<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/NCT03791203</url>
  </required_header>
  <id_info>
    <org_study_id>304/PPSP/61313173</org_study_id>
    <nct_id>NCT03791203</nct_id>
  </id_info>
  <brief_title>Effectiveness and Adherence of Modified Alternate-day Calorie Restriction (MACR) in Non-Alcoholic Fatty Liver Disease</brief_title>
  <official_title>A Randomized Controlled Trial on the Effectiveness and Adherence of Modified Alternate-day Calorie Restriction (MACR) in Improving Activity of Non-Alcoholic Fatty Liver Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universiti Sains Malaysia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Universiti Sains Malaysia</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>
      There is no effective therapy for non-alcoholic fatty liver disease (NAFLD), although&#xD;
      intensive calorie restriction is typically recommended but dietary adherence is an issue.&#xD;
      Currently, there are no studies had been focusing the effect of Modified Alternate Day&#xD;
      Calorie Restriction in NAFLD patient focusing on changes in liver steatosis and fibrosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Disease activity and progression of non-alcoholic fatty liver disease (NAFLD) to&#xD;
      non-alcoholic steatohepatitis (NASH) and cirrhosis can be highly variable, where 2-3% will&#xD;
      eventually progress to end-stage liver diseases. With the rising prevalence of metabolic&#xD;
      syndrome and obesity, NAFLD has become the most frequent form of chronic liver disease in the&#xD;
      West but also in Asia.&#xD;
&#xD;
      There are good evidence that weight loss is effective in improving liver histology in NAFLD,&#xD;
      for example, 31 obese patients with NASH was randomised into intensive lifestyle changes over&#xD;
      48 weeks versus structured basic education only, and the intensive lifestyle group showed&#xD;
      significant improvements in steatosis, necrosis, and inflammation. Intense calorie&#xD;
      restriction is the recommended form of dietary strategy for management of NAFLD. Even though&#xD;
      such intense dietary strategy has proven to be effective, some patients find it difficult to&#xD;
      adhere and maintain.&#xD;
&#xD;
      On the other hand, intermittent fasting achieves more consistent weight loss by improving&#xD;
      adherence, as intermittent fasting only requires calorie restriction every other day compared&#xD;
      to conventional form of daily calorie restriction. Alternate day calorie restriction can be&#xD;
      divided into two components, a 'feed day' and a 'fast day' where food is consumed ad libitum&#xD;
      for 24 hours period alternating with either complete or partial (modified) calorie&#xD;
      restriction for the next 24 hours. MACR, the dietary strategy employed in the investigator's&#xD;
      study, restricts 70% of an individual's daily requirement of calorie per day. There are other&#xD;
      forms of intermittent fasting, for example, 2-4 days of ad libitum feeding alternating with&#xD;
      2-4 days of calorie restriction.&#xD;
&#xD;
      Currently, there are no approved pharmacological therapies for NAFLD, and many guidelines&#xD;
      advocate recommendation with a focus on controlling risk factors and lifestyle interventions&#xD;
      that include dietary and physical activities. No specific NAFLD trials have evaluated the&#xD;
      effectiveness of modified form of intermittent fasting in the control of NAFLD activity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 1, 2015</start_date>
  <completion_date type="Actual">October 1, 2017</completion_date>
  <primary_completion_date type="Actual">July 31, 2017</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>
    <intervention_model_description>Participants who fulfilled the selection criteria were randomly assigned to the modified alternate-day calorie restriction (MACR) group or the control group after a 2 week run-in period. During the 2 weeks, participants were required to keep their body weight stable by maintaining their usual eating habits and their daily activities. Randomization was performed using a random number generator with recruitment aimed for three MACR participants for every control participant by principal investigator.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>Participants were blinded after assignment to interventions or control group.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change from baseline shear wave elastography (SWE) at 8 weeks</measure>
    <time_frame>Change from baseline at 8-week</time_frame>
    <description>Through the intercostal approach, SWE measurements were performed in the right liver lobe, at the supine position with the right arm in maximal abduction. The sonographer, assisted by an ultrasonic time-motion image, located a liver portion of at least 6 cm thick, free of large vascular structures. Once the measurement area had been located, the sonographer pressed the probe button to start an acquisition. Patients were asked to hold their breath for about five seconds, while the stiffness of the region of interest was measured and 10 measurements were made for each patient and the median average value of those measurements was recorded in kilopascals (kPa: metric).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from baseline liver steatosis at 8 weeks</measure>
    <time_frame>Change from baseline at 8-week</time_frame>
    <description>Ultra-sonographic measurements including liver steatosis and shear wave elastography (SWE) were performed with the SuperSonic Imagine's Aixplorer® Ultrasound machine (Super Sonic Image, Aix-en Provence, France). All measurements were performed by a single sonographer where the inter-observer agreement level with another experienced sonographer was 85%.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of high-density lipoprotein (HDL)</measure>
    <time_frame>Change from baseline at 8-week</time_frame>
    <description>Blood samples (8-10 hours of fasting blood samples) were collected from participants at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of low-density lipoprotein (LDL)</measure>
    <time_frame>Change from baseline at 8-week</time_frame>
    <description>Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of triglycerides (TG)</measure>
    <time_frame>Change from baseline at 8-week</time_frame>
    <description>Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of total cholesterol (TC)</measure>
    <time_frame>Change from baseline at 8-week</time_frame>
    <description>Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of fasting blood sugar (FBS)</measure>
    <time_frame>Change from baseline at 8-week</time_frame>
    <description>Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of alanine aminotransferase (ALT)</measure>
    <time_frame>Change from baseline at 8-week</time_frame>
    <description>Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in U/L.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of aspartate aminotransferase (AST)</measure>
    <time_frame>Change from baseline at 8-week</time_frame>
    <description>Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in U/L.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Dietary plan adherence</measure>
    <time_frame>At 8-week</time_frame>
    <description>Adherence data were assessed each week as percentage of adherence</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">43</enrollment>
  <condition>Non-Alcoholic Fatty Liver Disease</condition>
  <arm_group>
    <arm_group_label>Calorie restriction (MACR)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants restricted 70% of their energy needs over 24 hours on a calorie restriction day alternate with a feeding day for the next 24 hours, where they were allowed eating (ad libitum). The calorie restriction and feeding days begun at 9 am each day, and on the calorie restriction day, meals were consumed between 2 pm and 8 pm to ensure that they underwent the same duration of calorie restriction. On each calorie restriction day, they were allowed energy-free beverages and sugar-free gum and encouraged to drink plenty of water. Diet plans were self-selected using detailed individualized food portion lists, meal plans, and recipes. Participants received phone calls from the investigator and four 2-weekly appointments with a dietitian. Adverse experiences were assessed every 2 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Participants in the control group continued their usual habitual diet for 8 weeks. No specific dietary advice or educations were provided throughout the entire trial.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Calorie restriction (MACR)</intervention_name>
    <description>This was a randomized, single-blind controlled trial with modified alternate-day calorie restriction (MACR) as the active intervention and normal habitual diet as control at Hospital University of Sains Malaysia.</description>
    <arm_group_label>Calorie restriction (MACR)</arm_group_label>
    <other_name>Modified Alternate-day Calorie Restriction (MACR)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Have elevated ALT or AST level (ALT &gt;41 or AST&gt;34 IU/L)&#xD;
&#xD;
          -  No evidence of other forms of liver diseases&#xD;
&#xD;
          -  For those with diabetes mellitus and dyslipidaemia, they must be on a stable therapy&#xD;
             for at least 6 months prior to study enrolment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Significant alcohol consumption (&gt; 1 standard drink per day)&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Involvement in an active weight loss program or taking weight loss medications&#xD;
&#xD;
          -  Substance abuse and significant psychiatric problems.&#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>Yeong Yeh Lee, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universiti Sains Malaysia</affiliation>
  </overall_official>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 16, 2018</study_first_submitted>
  <study_first_submitted_qc>December 29, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">January 2, 2019</study_first_posted>
  <last_update_submitted>December 29, 2018</last_update_submitted>
  <last_update_submitted_qc>December 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 2, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Universiti Sains Malaysia</investigator_affiliation>
    <investigator_full_name>Muhammad Izzad Bin Johari</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Non-alcoholic fatty liver disease</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>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 10, 2015</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/03/NCT03791203/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 10, 2015</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/03/NCT03791203/ICF_001.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/NCT03791203
org study id: 304/PPSP/61313173
nct id: NCT03791203
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
There is no effective therapy for non-alcoholic fatty liver disease (NAFLD), although
      intensive calorie restriction is typically recommended but dietary adherence is an issue.
      Currently, there are no studies had been focusing the effect of Modified Alternate Day
      Calorie Restriction in NAFLD patient focusing on changes in liver steatosis and fibrosis.
Disease activity and progression of non-alcoholic fatty liver disease (NAFLD) to
      non-alcoholic steatohepatitis (NASH) and cirrhosis can be highly variable, where 2-3% will
      eventually progress to end-stage liver diseases. With the rising prevalence of metabolic
      syndrome and obesity, NAFLD has become the most frequent form of chronic liver disease in the
      West but also in Asia.

      There are good evidence that weight loss is effective in improving liver histology in NAFLD,
      for example, 31 obese patients with NASH was randomised into intensive lifestyle changes over
      48 weeks versus structured basic education only, and the intensive lifestyle group showed
      significant improvements in steatosis, necrosis, and inflammation. Intense calorie
      restriction is the recommended form of dietary strategy for management of NAFLD. Even though
      such intense dietary strategy has proven to be effective, some patients find it difficult to
      adhere and maintain.

      On the other hand, intermittent fasting achieves more consistent weight loss by improving
      adherence, as intermittent fasting only requires calorie restriction every other day compared
      to conventional form of daily calorie restriction. Alternate day calorie restriction can be
      divided into two components, a 'feed day' and a 'fast day' where food is consumed ad libitum
      for 24 hours period alternating with either complete or partial (modified) calorie
      restriction for the next 24 hours. MACR, the dietary strategy employed in the investigator's
      study, restricts 70% of an individual's daily requirement of calorie per day. There are other
      forms of intermittent fasting, for example, 2-4 days of ad libitum feeding alternating with
      2-4 days of calorie restriction.

      Currently, there are no approved pharmacological therapies for NAFLD, and many guidelines
      advocate recommendation with a focus on controlling risk factors and lifestyle interventions
      that include dietary and physical activities. No specific NAFLD trials have evaluated the
      effectiveness of modified form of intermittent fasting in the control of NAFLD activity.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Participants who fulfilled the selection criteria were randomly assigned to the modified alternate-day calorie restriction (MACR) group or the control group after a 2 week run-in period. During the 2 weeks, participants were required to keep their body weight stable by maintaining their usual eating habits and their daily activities. Randomization was performed using a random number generator with recruitment aimed for three MACR participants for every control participant by principal investigator.
primary purpose: Treatment
masking: Single (Participant)
masking description: Participants were blinded after assignment to interventions or control group.
measure: Change from baseline shear wave elastography (SWE) at 8 weeks
time frame: Change from baseline at 8-week
description: Through the intercostal approach, SWE measurements were performed in the right liver lobe, at the supine position with the right arm in maximal abduction. The sonographer, assisted by an ultrasonic time-motion image, located a liver portion of at least 6 cm thick, free of large vascular structures. Once the measurement area had been located, the sonographer pressed the probe button to start an acquisition. Patients were asked to hold their breath for about five seconds, while the stiffness of the region of interest was measured and 10 measurements were made for each patient and the median average value of those measurements was recorded in kilopascals (kPa: metric).
measure: Change from baseline liver steatosis at 8 weeks
time frame: Change from baseline at 8-week
description: Ultra-sonographic measurements including liver steatosis and shear wave elastography (SWE) were performed with the SuperSonic Imagine's Aixplorer® Ultrasound machine (Super Sonic Image, Aix-en Provence, France). All measurements were performed by a single sonographer where the inter-observer agreement level with another experienced sonographer was 85%.
measure: Concentration of high-density lipoprotein (HDL)
time frame: Change from baseline at 8-week
description: Blood samples (8-10 hours of fasting blood samples) were collected from participants at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L.
measure: Concentration of low-density lipoprotein (LDL)
time frame: Change from baseline at 8-week
description: Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L.
measure: Concentration of triglycerides (TG)
time frame: Change from baseline at 8-week
description: Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L.
measure: Concentration of total cholesterol (TC)
time frame: Change from baseline at 8-week
description: Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L.
measure: Concentration of fasting blood sugar (FBS)
time frame: Change from baseline at 8-week
description: Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in mmol/L.
measure: Concentration of alanine aminotransferase (ALT)
time frame: Change from baseline at 8-week
description: Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in U/L.
measure: Concentration of aspartate aminotransferase (AST)
time frame: Change from baseline at 8-week
description: Blood samples (8-10 hours of fasting blood samples) were collected at 8-10 am at baseline and 8-week post intervention for biochemical analysis. It was measured in U/L.
measure: Dietary plan adherence
time frame: At 8-week
description: Adherence data were assessed each week as percentage of adherence
arm group label: Calorie restriction (MACR)
arm group type: Experimental
description: Participants restricted 70% of their energy needs over 24 hours on a calorie restriction day alternate with a feeding day for the next 24 hours, where they were allowed eating (ad libitum). The calorie restriction and feeding days begun at 9 am each day, and on the calorie restriction day, meals were consumed between 2 pm and 8 pm to ensure that they underwent the same duration of calorie restriction. On each calorie restriction day, they were allowed energy-free beverages and sugar-free gum and encouraged to drink plenty of water. Diet plans were self-selected using detailed individualized food portion lists, meal plans, and recipes. Participants received phone calls from the investigator and four 2-weekly appointments with a dietitian. Adverse experiences were assessed every 2 weeks.
arm group label: Control group
arm group type: No Intervention
description: Participants in the control group continued their usual habitual diet for 8 weeks. No specific dietary advice or educations were provided throughout the entire trial.
intervention type: Behavioral
intervention name: Calorie restriction (MACR)
description: This was a randomized, single-blind controlled trial with modified alternate-day calorie restriction (MACR) as the active intervention and normal habitual diet as control at Hospital University of Sains Malaysia.
arm group label: Calorie restriction (MACR)
other name: Modified Alternate-day Calorie Restriction (MACR)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Yeong Yeh Lee, MD, PhD
role: Principal Investigator
affiliation: Universiti Sains Malaysia
responsible party type: Principal Investigator
investigator affiliation: Universiti Sains Malaysia
investigator full name: Muhammad Izzad Bin Johari
investigator title: Principal Investigator
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
sharing ipd: No
provided document: 
provided document: 