<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/NCT03814694</url>
  </required_header>
  <id_info>
    <org_study_id>CUTDM-HYPO</org_study_id>
    <nct_id>NCT03814694</nct_id>
  </id_info>
  <brief_title>Cut Down on Carbohydrate Usage in the Diet of Type 2 Diabetes. The Hypo-energetic Study</brief_title>
  <acronym>CutDM-Hypo</acronym>
  <official_title>Cut Down on Carbohydrate Usage in the Diet of Type 2 Diabetes; Mechanisms of Effective Therapy of Diabetes by Selective Choice of Macronutrients. The Hypo-energetic Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bispebjerg Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Copenhagen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Aarhus</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Danish Dairy Research Foundation, Denmark</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Arla Foods</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Bispebjerg Hospital</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>
      Scientific evidence for the dietary treatment of type 2 diabetes (T2D) is insufficient, which&#xD;
      is why the investigators aim to reform dietary recommendation to the overweight or obese&#xD;
      patient with type 2 diabetes. This clinical study will examine the effect of a highly&#xD;
      controlled hypo-energetic carbohydrate-reduced high-protein (CRHP) diet intervention under&#xD;
      caloric restriction-induced body weight loss as a treatment modality in T2D. The&#xD;
      investigators hypothesize that this intervention compared to the conventional diabetes (CD)&#xD;
      diet with similar loss in body weight improves metabolic control and cardiovascular risk&#xD;
      profile in T2D by:&#xD;
&#xD;
        -  Reducing diurnal and postprandial glycaemia, thereby facilitating a significant&#xD;
           reduction in HbA1c&#xD;
&#xD;
        -  Reducing ectopic lipid deposits in liver, muscle and pancreas&#xD;
&#xD;
        -  Improving lipid profile towards a less atherogenic profile&#xD;
&#xD;
        -  Improving metabolic actions of insulin, through increased sensitivity and β-cell&#xD;
           function&#xD;
&#xD;
        -  Reducing diurnal blood pressure with no adverse effect on heart rate variability&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The present study will be performed as a 6-week randomized fully controlled feeding study,&#xD;
      which will address the effect of the hypo-energetic CRHP diet compared with the&#xD;
      hypo-energetic CD diet with the macronutrient composition currently recommended to patients&#xD;
      with T2D combined with a caloric restriction-induced 5-7% body weight loss on T2D. The study&#xD;
      includes n=80 T2D patients.&#xD;
&#xD;
      Measurements include fasting blood samples every 2 weeks during the 6 weeks of the study.&#xD;
      Additionally, larger measurement programs will be undertaken at baseline and after 6 weeks,&#xD;
      including MRi/s for liver, pancreas and muscle fat content and visceral and subcutaneous&#xD;
      adipose tissue; DXA scans for body composition; oral glucose tolerance tests (OGTT);&#xD;
      continuous glucose monitoring (CGM); diurnal blood pressure and holter recording.&#xD;
      Questionnaires of health-related quality of life, level of physical activity and satiety by&#xD;
      visual analogue scale will be performed at baseline and week 6 as well as fecal and diurnal&#xD;
      urine sampling.&#xD;
&#xD;
      To ensure a similar body weight loss between intervention groups as well as participants,&#xD;
      aimed at 5-7%, caloric intake during the 6 weeks of the study will be hypo-energetic adjusted&#xD;
      for each participant according to estimated daily total energy expenditure (TEE). A&#xD;
      calculation requiring sex, age, weight and height will be performed to estimate resting&#xD;
      energy expenditure (REE), which multiplied with the participant's physical activity level&#xD;
      (PAL) will estimate TEE, and thus with an initial caloric deficit of 5% determine the caloric&#xD;
      content in the hypo-energetic diet for each participant. Additionally, participants will be&#xD;
      weighed twice a week and caloric content adjusted accordingly to ensure a controlled body&#xD;
      weight loss.&#xD;
&#xD;
      It is important to recognize that the CRHP diet and the CD diet principally do not differ in&#xD;
      the quality of carbohydrate and protein. Thus, this study is unable to address a potential&#xD;
      benefit of changes in quality of carbohydrate; however, both diet interventions exhibit a&#xD;
      relatively low glycemic index of maximum 55.&#xD;
&#xD;
      Until week 6 diets will be prepared and distributed from the research kitchen of the&#xD;
      Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen,&#xD;
      Denmark, to optimize compliance and adherence to the prescribed diet. Following this period&#xD;
      and again after approximately 3 months participants will be invited to group sessions with&#xD;
      dietician guidance on how to sustain their body weight loss and continue with their assigned&#xD;
      diet. A follow-up visit at week 30 will include a blood sample, a spot urine sample and body&#xD;
      weight measurement.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 29, 2019</start_date>
  <completion_date type="Actual">December 30, 2020</completion_date>
  <primary_completion_date type="Actual">July 22, 2020</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in glycated hemoglobin (HbA1c) during 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>The change in HbA1c will be assessed during 6 weeks of fully provisioned hypo-energetic CRHP diet compared with hypo-energetic CD diet, while achieving concurrent body weight loss of 5-7 percent in both groups. Levels of HbA1c will be measured at baseline, week 2, 4, 5 and 6. HbA1c will be expressed in mmol/mol.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in hepatic fat content after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Hepatic fat content will be assessed by magnetic resonance spectroscopy (MRs) at baseline and week 6.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in fasting plasma triglycerides during 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Levels of triglycerides will be measured from fasting at baseline, week 2, 4, 5 and 6. Triglycerides will be expressed in mmol/L.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in fat content subcutaneously, viscerally and ectopically in pancreas and skeletal muscle after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Subcutaneous, visceral and ectopic fat in pancreas and skeletal muscle will be assessed by magnetic resonance imaging/spectroscopy (MRi/s) at baseline and week 6.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in lean body mass (LBM) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>LBM will be assessed by dual-energy X-ray absorptiometry (DXA) at baseline and week 6. Changes will be expressed in kilograms (kg).</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in fat mass (FM) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>FM will be assessed by dual-energy X-ray absorptiometry (DXA) at baseline and week 6. Changes will be expressed in kilograms (kg).</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in diurnal blood pressure (DBP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>DBP will be assessed over 24 hours by a blood pressure monitor (Ontrak 90227 from Spacelabs Healthcare) at baseline and week 6. DBP will be expressed in mmHg.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in heart rate variability (HRV) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>HRV will be assessed by 48-hour Holter-monitoring (Faros 360 from Bittium) at baseline and week 6.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in diurnal glycemia after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Glycemia will be assessed using 7-day continuous glucose monitoring (CGM) (FreeStyle Libre Pro from Abbott) at baseline and week 6.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in glycemic variability after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Glycemic variability will be assessed using 7-day continuous glucose monitoring (CGM) (FreeStyle Libre Pro from Abbott) at baseline and week 6.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in insulin sensitivity after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Insulin sensitivity will be assessed based on a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6 and expressed by the Matsuda Index.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in beta-cell function after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Beta-cell function will be assessed based on a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6 and expressed by the Insulinogenic Index and Disposition Index.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in Homeostasis Model Assessment (HOMA) of insulin resistance and beta-cell function after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>HOMA will be performed at baseline and week 6 and expressed by HOMA-IR and HOMA-beta.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in lipid profile after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Lipid profile, including lipoproteins will be assessed from fasting at baseline and week 6.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in glucose after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Glucose will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Glucose will be expressed in mmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in insulin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Insulin will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Insulin will be expressed in pmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in C-peptide after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>C-peptide will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. C-peptide will be expressed in pmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in non-esterified fatty acids (NEFA) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>NEFA metabolism will be assessed using the minimal model technique based on an oral glucose tolerance test (OGTT) at baseline and week 6. NEFA will be expressed in micromol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in triglycerides after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Triglycerides will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Triglycerides will be expressed in mmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in glucagon after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Glucagon will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Glucagon will be expressed in pmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in glucagon-like-peptide-1 (GLP-1) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>GLP-1 will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. GLP-1 will be expressed in pmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in glucose-dependent insulinotropic polypeptide (GIP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>GIP will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. GIP will be expressed in pmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in peptide YY (PYY) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>PYY will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. PYY will be expressed in pmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in ghrelin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Ghrelin will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Ghrelin will be expressed in pmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in cholecystokinin (CCK) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>CCK will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. CCK will be expressed in pmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in gastrin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Gastrin will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Gastrin will be expressed in pmol/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in growth hormone (GH) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>GH will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. GH will be expressed in ng/mL.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in insulin-like growth factor-1 (IGF-1) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>IGF-1 will be measured from fasting at baseline and week 6. IGF-1 will be expressed in ng/mL.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in insulin-like growth factor-binding protein 1 (IGFBP-1) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>IGFBP-1 will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. IGFBP-1 will be expressed in ng/mL.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in leptin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Leptin will be measured from fasting at baseline and week 6. Leptin will be expressed in ng/mL.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in adiponectin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Adiponectin will be measured from fasting at baseline and week 6. Adiponectin will be expressed in microg/mL.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in tumor necrosis factor alpha (TNF-alpha) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>TNF-alpha will be measured from fasting at baseline and week 6 and expressed in pg/mL.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in interleukin-6 (IL-6) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>IL-6 will be measured from fasting at baseline and week 6 and expressed in pg/mL.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in high-sensitive C-reactive protein (hsCRP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>hsCRP will be measured from fasting at baseline and week 6 and expressed in mg/L.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in renal function assessed from eGFR and diurnal excretion of albumin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>eGFR and diurnal excretion of albumin will be assessed at baseline and week 6.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in urinary excretion of urea and glucose after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Urinary excretion of urea and glucose will be assessed at baseline and week 6.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in urinary oxidative DNA and RNA modifications after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Urinary oxidative DNA and RNA modifications will be assessed at baseline and week 6.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in subjective satiety after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>Subjective satiety will be assessed by a self-reported visual analog scale (VAS) questionnaire with four questions regarding experienced satiety (range 0-100 mm) integrated into one composite satiety score at baseline and week 6.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in health-related quality of life (HRQoL) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.</measure>
    <time_frame>6 weeks</time_frame>
    <description>HRQoL will be assessed using a self-reported 36-item Short-Form (SF-36) health survey with 36 questions regarding different domains of HRQoL (each scoring from 0-100 points) at baseline and week 6. HRQoL will be reported as composite scores; a physical and mental component summary (PCS/MCS) score.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">72</enrollment>
  <condition>Diabetes Mellitus, Type 2</condition>
  <condition>Overweight and Obesity</condition>
  <arm_group>
    <arm_group_label>CRHP Diet</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Hypo-energetic carbohydrate-reduced high-protein (CRHP) dietary intervention with a controlled 5-7% loss in body weight.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CD Diet</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Hypo-energetic conventional diabetes (CD) dietary intervention with a controlled 5-7% loss in body weight.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>CRHP Diet</intervention_name>
    <description>Dietary macronutrient composition of 30 E% from carbohydrate, 30 E% from protein and 40 E% from fat</description>
    <arm_group_label>CRHP Diet</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>CD Diet</intervention_name>
    <description>Dietary macronutrient composition of 50 E% from carbohydrate, 17 E% from protein and 33 E% from fat</description>
    <arm_group_label>CD Diet</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Type 2 diabetes with HbA1c between 48 mmol/mol and 97 mmol/mol with or without&#xD;
             metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors&#xD;
&#xD;
          -  Overweight or obesity with BMI ≥ 25 kg/m2 and desired weight loss&#xD;
&#xD;
          -  Non-smokers for &gt; 1 year&#xD;
&#xD;
          -  Willingness to abstain from alcohol for 6 weeks&#xD;
&#xD;
          -  Hemoglobin &gt; 7 mmol/L for men and &gt; 6 mmol/L for women&#xD;
&#xD;
          -  Estimated glomerular filtration rate (eGFR) &gt; 30 mL/min/1.73 m2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Critical illness as evaluated by the principal investigator&#xD;
&#xD;
          -  Systemic corticosteroid treatment, e.g. prednisolone&#xD;
&#xD;
          -  Reported or journalized severe food allergy or intolerance&#xD;
&#xD;
          -  Reported or journalized severe gut disease e.g. Crohn's disease, Coeliac disease etc.&#xD;
&#xD;
          -  Reported or journalized alcohol dependence syndrome&#xD;
&#xD;
          -  Injectable diabetes medication, including insulin and GLP-1 analogues&#xD;
&#xD;
          -  Sulfonylureas (SUs) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, unless&#xD;
             discontinuation is possible, in which case a 2-month wash-out is mandatory&#xD;
&#xD;
          -  Repeated fasting plasma glucose &gt; 13.3 mmol/L&#xD;
&#xD;
          -  Urine albumin / creatinine ratio &gt; 300 mg/g&#xD;
&#xD;
          -  Lactation, pregnancy or planning of pregnancy during the study&#xD;
&#xD;
          -  Inability, physically or mentally, to comply with the procedures required by the study&#xD;
             protocol, as evaluated by the principal investigator&#xD;
&#xD;
          -  Presently participating in other clinical trials&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Steen B Haugaard, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dept. of Endocrinology, Copenhagen University Hospital Bispebjerg</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Bispebjerg Hospital</name>
      <address>
        <city>Copenhagen</city>
        <state>Copenhagen NV</state>
        <zip>2400</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>January 8, 2019</study_first_submitted>
  <study_first_submitted_qc>January 20, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 24, 2019</study_first_posted>
  <last_update_submitted>January 26, 2021</last_update_submitted>
  <last_update_submitted_qc>January 26, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 27, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Bispebjerg Hospital</investigator_affiliation>
    <investigator_full_name>Mads N Thomsen</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Weight Loss</keyword>
  <keyword>Diet, Carbohydrate-Restricted</keyword>
  <keyword>Diet, High-Protein</keyword>
  <keyword>Insulin Resistance</keyword>
  <keyword>Non-alcoholic Fatty Liver Disease</keyword>
  <keyword>Metabolic Syndrome</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Overweight</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Individual participant data (IPD) may be shared by request to the corresponding author in accordance with the Danish Data Protection Agency.</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/NCT03814694
org study id: CUTDM-HYPO
nct id: NCT03814694
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Scientific evidence for the dietary treatment of type 2 diabetes (T2D) is insufficient, which
      is why the investigators aim to reform dietary recommendation to the overweight or obese
      patient with type 2 diabetes. This clinical study will examine the effect of a highly
      controlled hypo-energetic carbohydrate-reduced high-protein (CRHP) diet intervention under
      caloric restriction-induced body weight loss as a treatment modality in T2D. The
      investigators hypothesize that this intervention compared to the conventional diabetes (CD)
      diet with similar loss in body weight improves metabolic control and cardiovascular risk
      profile in T2D by:

        -  Reducing diurnal and postprandial glycaemia, thereby facilitating a significant
           reduction in HbA1c

        -  Reducing ectopic lipid deposits in liver, muscle and pancreas

        -  Improving lipid profile towards a less atherogenic profile

        -  Improving metabolic actions of insulin, through increased sensitivity and β-cell
           function

        -  Reducing diurnal blood pressure with no adverse effect on heart rate variability
The present study will be performed as a 6-week randomized fully controlled feeding study,
      which will address the effect of the hypo-energetic CRHP diet compared with the
      hypo-energetic CD diet with the macronutrient composition currently recommended to patients
      with T2D combined with a caloric restriction-induced 5-7% body weight loss on T2D. The study
      includes n=80 T2D patients.

      Measurements include fasting blood samples every 2 weeks during the 6 weeks of the study.
      Additionally, larger measurement programs will be undertaken at baseline and after 6 weeks,
      including MRi/s for liver, pancreas and muscle fat content and visceral and subcutaneous
      adipose tissue; DXA scans for body composition; oral glucose tolerance tests (OGTT);
      continuous glucose monitoring (CGM); diurnal blood pressure and holter recording.
      Questionnaires of health-related quality of life, level of physical activity and satiety by
      visual analogue scale will be performed at baseline and week 6 as well as fecal and diurnal
      urine sampling.

      To ensure a similar body weight loss between intervention groups as well as participants,
      aimed at 5-7%, caloric intake during the 6 weeks of the study will be hypo-energetic adjusted
      for each participant according to estimated daily total energy expenditure (TEE). A
      calculation requiring sex, age, weight and height will be performed to estimate resting
      energy expenditure (REE), which multiplied with the participant's physical activity level
      (PAL) will estimate TEE, and thus with an initial caloric deficit of 5% determine the caloric
      content in the hypo-energetic diet for each participant. Additionally, participants will be
      weighed twice a week and caloric content adjusted accordingly to ensure a controlled body
      weight loss.

      It is important to recognize that the CRHP diet and the CD diet principally do not differ in
      the quality of carbohydrate and protein. Thus, this study is unable to address a potential
      benefit of changes in quality of carbohydrate; however, both diet interventions exhibit a
      relatively low glycemic index of maximum 55.

      Until week 6 diets will be prepared and distributed from the research kitchen of the
      Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen,
      Denmark, to optimize compliance and adherence to the prescribed diet. Following this period
      and again after approximately 3 months participants will be invited to group sessions with
      dietician guidance on how to sustain their body weight loss and continue with their assigned
      diet. A follow-up visit at week 30 will include a blood sample, a spot urine sample and body
      weight measurement.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in glycated hemoglobin (HbA1c) during 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: The change in HbA1c will be assessed during 6 weeks of fully provisioned hypo-energetic CRHP diet compared with hypo-energetic CD diet, while achieving concurrent body weight loss of 5-7 percent in both groups. Levels of HbA1c will be measured at baseline, week 2, 4, 5 and 6. HbA1c will be expressed in mmol/mol.
measure: Change in hepatic fat content after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Hepatic fat content will be assessed by magnetic resonance spectroscopy (MRs) at baseline and week 6.
measure: Change in fasting plasma triglycerides during 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Levels of triglycerides will be measured from fasting at baseline, week 2, 4, 5 and 6. Triglycerides will be expressed in mmol/L.
measure: Change in fat content subcutaneously, viscerally and ectopically in pancreas and skeletal muscle after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Subcutaneous, visceral and ectopic fat in pancreas and skeletal muscle will be assessed by magnetic resonance imaging/spectroscopy (MRi/s) at baseline and week 6.
measure: Change in lean body mass (LBM) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: LBM will be assessed by dual-energy X-ray absorptiometry (DXA) at baseline and week 6. Changes will be expressed in kilograms (kg).
measure: Change in fat mass (FM) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: FM will be assessed by dual-energy X-ray absorptiometry (DXA) at baseline and week 6. Changes will be expressed in kilograms (kg).
measure: Change in diurnal blood pressure (DBP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: DBP will be assessed over 24 hours by a blood pressure monitor (Ontrak 90227 from Spacelabs Healthcare) at baseline and week 6. DBP will be expressed in mmHg.
measure: Change in heart rate variability (HRV) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: HRV will be assessed by 48-hour Holter-monitoring (Faros 360 from Bittium) at baseline and week 6.
measure: Change in diurnal glycemia after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Glycemia will be assessed using 7-day continuous glucose monitoring (CGM) (FreeStyle Libre Pro from Abbott) at baseline and week 6.
measure: Change in glycemic variability after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Glycemic variability will be assessed using 7-day continuous glucose monitoring (CGM) (FreeStyle Libre Pro from Abbott) at baseline and week 6.
measure: Change in insulin sensitivity after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Insulin sensitivity will be assessed based on a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6 and expressed by the Matsuda Index.
measure: Change in beta-cell function after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Beta-cell function will be assessed based on a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6 and expressed by the Insulinogenic Index and Disposition Index.
measure: Change in Homeostasis Model Assessment (HOMA) of insulin resistance and beta-cell function after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: HOMA will be performed at baseline and week 6 and expressed by HOMA-IR and HOMA-beta.
measure: Change in lipid profile after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Lipid profile, including lipoproteins will be assessed from fasting at baseline and week 6.
measure: Change in glucose after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Glucose will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Glucose will be expressed in mmol/L.
measure: Change in insulin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Insulin will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Insulin will be expressed in pmol/L.
measure: Change in C-peptide after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: C-peptide will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. C-peptide will be expressed in pmol/L.
measure: Change in non-esterified fatty acids (NEFA) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: NEFA metabolism will be assessed using the minimal model technique based on an oral glucose tolerance test (OGTT) at baseline and week 6. NEFA will be expressed in micromol/L.
measure: Change in triglycerides after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Triglycerides will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Triglycerides will be expressed in mmol/L.
measure: Change in glucagon after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Glucagon will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Glucagon will be expressed in pmol/L.
measure: Change in glucagon-like-peptide-1 (GLP-1) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: GLP-1 will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. GLP-1 will be expressed in pmol/L.
measure: Change in glucose-dependent insulinotropic polypeptide (GIP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: GIP will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. GIP will be expressed in pmol/L.
measure: Change in peptide YY (PYY) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: PYY will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. PYY will be expressed in pmol/L.
measure: Change in ghrelin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Ghrelin will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Ghrelin will be expressed in pmol/L.
measure: Change in cholecystokinin (CCK) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: CCK will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. CCK will be expressed in pmol/L.
measure: Change in gastrin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Gastrin will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. Gastrin will be expressed in pmol/L.
measure: Change in growth hormone (GH) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: GH will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. GH will be expressed in ng/mL.
measure: Change in insulin-like growth factor-1 (IGF-1) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: IGF-1 will be measured from fasting at baseline and week 6. IGF-1 will be expressed in ng/mL.
measure: Change in insulin-like growth factor-binding protein 1 (IGFBP-1) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: IGFBP-1 will be measured during a 4-hour oral glucose tolerance test (OGTT) at baseline and week 6. IGFBP-1 will be expressed in ng/mL.
measure: Change in leptin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Leptin will be measured from fasting at baseline and week 6. Leptin will be expressed in ng/mL.
measure: Change in adiponectin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Adiponectin will be measured from fasting at baseline and week 6. Adiponectin will be expressed in microg/mL.
measure: Change in tumor necrosis factor alpha (TNF-alpha) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: TNF-alpha will be measured from fasting at baseline and week 6 and expressed in pg/mL.
measure: Change in interleukin-6 (IL-6) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: IL-6 will be measured from fasting at baseline and week 6 and expressed in pg/mL.
measure: Change in high-sensitive C-reactive protein (hsCRP) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: hsCRP will be measured from fasting at baseline and week 6 and expressed in mg/L.
measure: Change in renal function assessed from eGFR and diurnal excretion of albumin after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: eGFR and diurnal excretion of albumin will be assessed at baseline and week 6.
measure: Change in urinary excretion of urea and glucose after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Urinary excretion of urea and glucose will be assessed at baseline and week 6.
measure: Change in urinary oxidative DNA and RNA modifications after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Urinary oxidative DNA and RNA modifications will be assessed at baseline and week 6.
measure: Change in subjective satiety after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: Subjective satiety will be assessed by a self-reported visual analog scale (VAS) questionnaire with four questions regarding experienced satiety (range 0-100 mm) integrated into one composite satiety score at baseline and week 6.
measure: Change in health-related quality of life (HRQoL) after 6 weeks of hypo-energetic CRHP diet compared with hypo-energetic CD diet.
time frame: 6 weeks
description: HRQoL will be assessed using a self-reported 36-item Short-Form (SF-36) health survey with 36 questions regarding different domains of HRQoL (each scoring from 0-100 points) at baseline and week 6. HRQoL will be reported as composite scores; a physical and mental component summary (PCS/MCS) score.
arm group label: CRHP Diet
arm group type: Experimental
description: Hypo-energetic carbohydrate-reduced high-protein (CRHP) dietary intervention with a controlled 5-7% loss in body weight.
arm group label: CD Diet
arm group type: Active Comparator
description: Hypo-energetic conventional diabetes (CD) dietary intervention with a controlled 5-7% loss in body weight.
intervention type: Dietary Supplement
intervention name: CRHP Diet
description: Dietary macronutrient composition of 30 E% from carbohydrate, 30 E% from protein and 40 E% from fat
arm group label: CRHP Diet
intervention type: Dietary Supplement
intervention name: CD Diet
description: Dietary macronutrient composition of 50 E% from carbohydrate, 17 E% from protein and 33 E% from fat
arm group label: CD Diet
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Steen B Haugaard, Professor
role: Principal Investigator
affiliation: Dept. of Endocrinology, Copenhagen University Hospital Bispebjerg
facility: 
country: Denmark
responsible party type: Principal Investigator
investigator affiliation: Bispebjerg Hospital
investigator full name: Mads N Thomsen
investigator title: Principal Investigator
mesh term: Diabetes Mellitus
mesh term: Overweight
mesh term: Diabetes Mellitus, Type 2
sharing ipd: No
ipd description: Individual participant data (IPD) may be shared by request to the corresponding author in accordance with the Danish Data Protection Agency.