<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/NCT03769883</url>
  </required_header>
  <id_info>
    <org_study_id>H-18038298</org_study_id>
    <nct_id>NCT03769883</nct_id>
  </id_info>
  <brief_title>The Effects of Different Doses of Exercise on Pancreatic β-cell Function in Patients With Newly Diagnosed Type 2 Diabetes</brief_title>
  <acronym>DOSE-EX</acronym>
  <official_title>The Effects of Different Doses of Exercise on Pancreatic ß-cell Function in Patients With Newly Diagnosed Type 2 Diabetes (DOSE-EX): A Randomized Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mathias Ried-Larsen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rigshospitalet, Denmark</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 project will provide an exercise-based lifestyle intervention with the potential to&#xD;
      reduce complications for patients with short standing type 2 diabetes (T2D). While exercise&#xD;
      is widely accepted as a component of T2D management, little is known about the additive&#xD;
      effect of exercise when combined with a diet on T2D pathophysiology and mechanisms believed&#xD;
      to lead to micro- and macrovascular complications. Moreover, the necessary dose of exercise&#xD;
      to revert the progression of T2D and the related complications has not been investigated. A&#xD;
      large-scale randomized controlled trial (RCT) will be essential to document the effectiveness&#xD;
      on reducing the risk of T2D complications. However, prior to conducting a large-scale RCT, we&#xD;
      need to specify the exercise dose that efficiently compliments the diet.&#xD;
&#xD;
      In a 4-armed randomized, clinical trial (N=80 T2D patients, T2D duration &lt; than 7 years) we&#xD;
      aim to investigate 1) the potential additive role of exercise on pancreatic β-cell function&#xD;
      in patients with T2D when combined with a diet, 2) the causal relationship between&#xD;
      lifestyle-induced reductions in glycaemic variability, oxidative stress and low-grade&#xD;
      inflammation and, 3) the role of exercise in rescuing dysregulated muscle progenitor cells.&#xD;
      The participants will be randomly allocated to either a) control, b) diet, c) diet and&#xD;
      exercise 3 times/week or d) diet and exercise 6 times/week for 16 weeks. Prior to, during and&#xD;
      following the interventions, all participants will undergo extensive testing.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A 4-armed, 16-week, parallel-group, assessor-blinded, randomized, clinical trial.&#xD;
      Participants will be randomly allocated (1:1:1:1), stratified by sex&#xD;
&#xD;
      Interventions:&#xD;
&#xD;
      The lifestyle interventions will consist of two main components; 1) increased physical&#xD;
      activity and structured exercise and/or 2) a dietary intervention aiming at a weight loss.&#xD;
      Whereas there will be no differences in the dietary intervention between the lifestyle&#xD;
      groups, the volume of physical activity and structured exercise will vary according to the&#xD;
      frequencies of the structured exercise sessions.&#xD;
&#xD;
      The study groups are prescribed:&#xD;
&#xD;
        1. Control group (CON): No intervention&#xD;
&#xD;
        2. Dietary control (DCON): Dietary intervention (see below)&#xD;
&#xD;
        3. Moderate Exercise Dose (MED): Two aerobic training sessions per week of 45-60 min&#xD;
           duration and one session per week with combined aerobic (30-35 min) and resistance (30&#xD;
           min) training and a dietary intervention (described below)&#xD;
&#xD;
        4. High Exercise Dose (HED): Four aerobic training sessions per week of 45-60 min duration&#xD;
           and two sessions per week with combined aerobic (30-35 min) and resistance (30 min)&#xD;
           training and a dietary intervention (described below)&#xD;
&#xD;
      Detailed description of the intervention components. Exercise: The training protocol will be&#xD;
      adapted based on a previous study where the T2D participants were prescribed 6 weekly&#xD;
      sessions of aerobic training alone or combined aerobic and resistance training (averaging&#xD;
      360-420 min of exercise per week). As previous analyses suggest that there may be an inverse&#xD;
      dose-response relationship between reductions in HbA1c and aerobic exercise volume, this&#xD;
      parameter will be used to adapt the training protocol. As the effect of exercise on HbA1c is&#xD;
      closer related to the number of training sessions rather than intensity15, we will reduce the&#xD;
      number of sessions by 50%, to three sessions/week in the moderate exercise dose group and&#xD;
      maintain the original session frequency in the high dose exercise group (six&#xD;
      sessions/week).Training will be supervised and monitored to ensure intensity and compliance.&#xD;
&#xD;
      Dietary intervention and intended weight loss (DCON, MED and HED: The dietary intervention&#xD;
      will be based on the recommendations from the American Diabetes Association (ADA) with&#xD;
      increased focus on macronutrient quality. The macronutrient distributions are in line with&#xD;
      the current guidelines from the national Diabetes Association and Canadian guidelines, where&#xD;
      individualization in macronutrient distribution should lie within the range of 45-60 energy%&#xD;
      carbohydrate, 15-20 energy% protein and 20-35 energy% fat. Thus, the dietary intervention&#xD;
      emphasis will be on low glycemic index and low glycemic load in shape of non-processed foods&#xD;
      and will aim at reducing saturated fat intake &lt;7 energy%.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">December 12, 2018</start_date>
  <completion_date type="Anticipated">August 2021</completion_date>
  <primary_completion_date type="Anticipated">August 2021</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>Single (Outcomes Assessor)</masking>
    <masking_description>Upon completion of the study and prior to breaking the allocation code, a data-collection form is generated by a statistician and the principal investigator. The data-analyst breaks the allocation code and labels the participants according to the assigned treatment and analyzes the outcomes. Following the analyses, group allocation will be concealed in all data outputs and the N per group and present the data to the writing committee in a blinded fashion. Then the writing committee will provide their blinded interpretations.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Pancreatic beta-cell function (Per protocol)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>The change in the late-phase disposition index (DI) during the final 30 minutes of hyperglycemic phase of the hyperglycemic clamp.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pancreatic beta-cell function (Intention to treat)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>As for per protocol</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucagon like peptide 1 sensitivity (c-peptide)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Glucagon like peptide 1 stimulated C-peptide secretion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucagon like peptide 1 sensitivity (glucagon)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Glucagon like peptide 1 stimulated glucagon secretion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucagon like peptide 1 sensitivity (insulin)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Glucagon like peptide 1 stimulated insulin secretion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arginine sensitivity (insulin)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Arginine stimulated insulin secretion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arginine sensitivity (c-peptide)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Arginine stimulated C-peptide secretion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arginine sensitivity (glucagon)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Arginine stimulated glucagon secretion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Early phase disposition index (c-peptide)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in 1st phase C-peptide secretion defined as the peak concentration during the initial 10 minutes of the hyperglycaemic clamp</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Early phase disposition index (insulin)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in 1st phase insulin secretion defined as the peak concentration during the initial 10 minutes of the hyperglycaemic clamp</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucose clearance</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Rate of glucose clearance (stable isotope infusion) during steady state hyperglycemia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucose appearance</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Rate of glucose appearance (stable isotope infusion) during steady state hyperglycemia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Insulin sensitivity</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in mean Glucose infusion rate over last 30 min of clamp phase/(mean insulin×glucose</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean amplitude of glycemic excursions</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Mean amplitude of glycemic excursions (MAGE - calculated based on min 3 days sensor glucose profiles)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Coefficient of glucose variation</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Coefficient of variation defined as (mean glucose/the standard deviation (SD)) of min 3 days sensor glucose profiles</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean glucose levels</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in the mean glucose levels (calculated based on min 3 days sensor glucose profiles)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time in hyperglycemia</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in time in hyperglycaemia (calculated based on min 3 days sensor glucose profiles)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time in hypoglycemia</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in time in hypoglycaemia from min 3 days sensor glucose profiles</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pancreatic fat</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Pancreatic fat</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hepatic fat</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Hepatic fat</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visceral fat</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in visceral fat</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total fat mass</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Total fat mass</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total fat free mass</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Total fat free mass</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total lean body mass</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Total lean body mass</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Android fat mass</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in Android fat mass</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gynoid fat mass</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in gynoid fat mass</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body weight</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in body weight</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body mass index</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in body mass index</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systemic oxidative stress (RNA)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)</time_frame>
    <description>Change in 8-oxo-guanosine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systemic oxidative stress (DNA)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)</time_frame>
    <description>Change in 8-oxo-deoxoguonase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Advanced glycation end-products (AGE)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)</time_frame>
    <description>Change in AGE</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The circulating receptor for advanced glycation end-products (sRAGE)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)</time_frame>
    <description>Change in sRAGE</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of low-grade inflammation</measure>
    <time_frame>From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)</time_frame>
    <description>Change in inflammatory markers (e.g. high sensitive C-reactive protein, interferon-ϒ, interleukin-10, interleukin-8, interleukin-6, interleukin-1, TNFα)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glycated haemoglobin type 1AC (HbA1c)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)</time_frame>
    <description>Change in HbA1c</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total cholesterol</measure>
    <time_frame>From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)</time_frame>
    <description>Change in total cholesterol</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total triglyceride</measure>
    <time_frame>From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)</time_frame>
    <description>Change in total triglyceride</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Low density lipoprotein (LDL)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)</time_frame>
    <description>Change in LDL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>High density lipoprotein (HDL)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)</time_frame>
    <description>Change in HDL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systolic blood pressure</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change systolic blood pressures</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diastolic blood pressure</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change diastolic blood pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucose tolerance</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change incremental and total area under the curve (glucose, c-peptide, insulin) during a mixed meal tolerance test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gastric emptying (AUC)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in the AUC (paracetamol) during a mixed meal tolerance test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gastric emptying (Rate of appearance)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in rate of appearance of paracetamol during a mixed meal tolerance test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical fitness (VO2max)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in physical fitness (VO2) during a progressive maximal bicycle ergometer test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Muscular 1 repetition max (strength)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in 1 repetition max</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total physical activity</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in objectively measured physical activity (counts per minute)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Moderate and vigorous physical activity (MVPA)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in time spend on MVPA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sedentary time (SED)</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in time spend on SED</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical well being</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in physical well being (Based on the physical dimension score from short-form 36, range 0-100)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mental well being</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in mental well being (Based on the mental dimension score from Short-form 36) (range 0-100)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Satiety</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in self-reported satiety (VAS) during a mixed meal tolerance test (range 0-10)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Muscular metabolic function</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in metabolic function (Based on muscle biopsies in a subset of participants, N=16-32))</description>
  </other_outcome>
  <other_outcome>
    <measure>Fat tissue metabolic function</measure>
    <time_frame>From baseline (0 weeks) to follow-up (16 weeks)</time_frame>
    <description>Change in metabolic function (Based on muscle biopsies in a subset of participants, N=16-32)</description>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Type 2 Diabetes Mellitus</condition>
  <condition>Type2 Diabetes</condition>
  <condition>Diabetes Mellitus, Type 2</condition>
  <condition>Type2 Diabetes Mellitus</condition>
  <arm_group>
    <arm_group_label>Dietary control (DCON)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The macro-nutrient distributions are in line with the current guidelines from the national Diabetes Association and Canadian guidelines, where individualization in macronutrient distribution should lie within the range of 45-60E% carbohydrate, 15-20E% protein and 20-35E% fat. The dietary plan will aim at reducing saturated fat intake &lt;7E% aiming at a caloric deficit of 500 kilo calories/day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Moderate Exercise Dose (MED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Two aerobic training sessions per week of 45-60 min duration and one session per week with combined aerobic (30-35 min) and resistance (30 min) training and a dietary intervention (as above)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High Exercise Dose (HED)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Four aerobic training sessions per week of 45-60 min duration and two sessions per week with combined aerobic (30-35 min) and resistance (30 min) training and a dietary intervention (as above)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>No intervention</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Exercise and diet</intervention_name>
    <description>The participants will undergo diet or combined diet and exercise. The exercise will be provided at different volumes</description>
    <arm_group_label>High Exercise Dose (HED)</arm_group_label>
    <arm_group_label>Moderate Exercise Dose (MED)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Diet</intervention_name>
    <description>Dietary intervention</description>
    <arm_group_label>Dietary control (DCON)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Diagnosed with diabetes type 2 and/or HbA1c ≥ 48 mmol/mol if no treatment with&#xD;
        anti-diabetic medication and/or use of antidiabetic medication&#xD;
&#xD;
        Caucasian&#xD;
&#xD;
        No diagnose of Type 1 diabetes, mature onset diabetes of the young, Latent autoimmune&#xD;
        diabetes of adults&#xD;
&#xD;
        T2D 0-6 years of duration&#xD;
&#xD;
        No treatment with insulin&#xD;
&#xD;
        Body Mass Index (BMI) &gt;27 kg/m2 and &lt;40 kg/m2&#xD;
&#xD;
        No known or signs of intermediate or severe microvascular complications to diabetes&#xD;
        (retino-, neuro- or nephropathy)&#xD;
&#xD;
        No known cancer&#xD;
&#xD;
        No Known lung disease&#xD;
&#xD;
        No known cardiovascular disease&#xD;
&#xD;
        No known thyroid disease&#xD;
&#xD;
        No known liver disease&#xD;
&#xD;
        No known autoimmune disease&#xD;
&#xD;
        No other endocrine disorder causing obesity&#xD;
&#xD;
        No current treatment with anti-obesity medication&#xD;
&#xD;
        No current treatment with anti-inflammatory medication&#xD;
&#xD;
        No weight loss of &gt; 5kg within the last 6 months&#xD;
&#xD;
        No diagnose of depression or treatment with anti-depressive medication, ongoing or within&#xD;
        the last three months before enrolment&#xD;
&#xD;
        No diagnose of psychiatric disorder or treatment with anti-psychotic medication&#xD;
&#xD;
        No history of suicidal behavior or ideations within the last three months before enrolment&#xD;
&#xD;
        No previous surgical treatment for obesity (excluding liposuction &gt; 1 year prior to&#xD;
        enrolment)&#xD;
&#xD;
        Not pregnant/considering pregnancy&#xD;
&#xD;
        No functional impairments that prevents the performance of intensive exercise&#xD;
&#xD;
        Accept of medical regulation by the U-TURN endocrinologist&#xD;
&#xD;
        Inactivity, defined as &lt; 1,5 hours of structured physical activity pr. week at moderate&#xD;
        intensity and cycling &lt; 30 minutes/5 km pr. day at moderate intensity (moderate intensity =&#xD;
        out of breath but able to speak)&#xD;
&#xD;
        No participation in other research intervention studies&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        HbA1c: &gt;=75 mmol/mol with no glucose lowering medications&#xD;
&#xD;
        HbA1c: &gt;=64 mmol/mol with mono glucose lowering therapy (if compliant with the&#xD;
        prescription)&#xD;
&#xD;
        HbA1c: &gt;=57 mmol/mol with &gt;=dual glucose lowering therapy (if compliant with the&#xD;
        prescription)&#xD;
&#xD;
        estimated glomerular filtration rate&lt;60 mL/min&#xD;
&#xD;
        Protein or glucose in the urine at pre-screening&#xD;
&#xD;
        No biochemical sign of other major diseases&#xD;
&#xD;
        Presence of circulating glutamate-decarboxylase anti body (GAD) 65&#xD;
&#xD;
        Objective findings that contraindicates participation in intensive exercise&#xD;
&#xD;
        Anamnestic findings that contraindicates participation in the study&#xD;
&#xD;
        Unable to allocate the needed time to fulfill the intervention&#xD;
&#xD;
        Language barrier, mental incapacity, unwillingness or inability to understand and be able&#xD;
        to complete the interventions&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mathias Ried-Larsen, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centre for Physical Activity Research, Righospitalet</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Inge Holm</last_name>
    <phone>+45 35 45 76 41</phone>
    <email>inge.holm@regionh.dk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Bente K Pedersen, Dr Med</last_name>
    <phone>+45 35 45 76 41</phone>
    <email>inge.holm@regionh.dk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Center for Physical Activity Research, Copenhagen University Hospital</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mathias Ried-larsen, PhD</last_name>
      <phone>0045 35 45 06 99</phone>
      <email>mathias.ried-larsen@regionh.dk</email>
    </contact>
    <contact_backup>
      <last_name>Inge Holm</last_name>
      <phone>0045 35 45 76 21</phone>
      <email>inge.holm@regionh.dk</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>November 22, 2018</study_first_submitted>
  <study_first_submitted_qc>December 5, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 10, 2018</study_first_posted>
  <last_update_submitted>December 12, 2018</last_update_submitted>
  <last_update_submitted_qc>December 12, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 13, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Mathias Ried-Larsen</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <keyword>Exercise</keyword>
  <keyword>Physical Activity</keyword>
  <keyword>Type 2 diabetes</keyword>
  <keyword>Pancreatic beta-cell function</keyword>
  <keyword>Insulin sensitivity</keyword>
  <keyword>Dose finding</keyword>
  <keyword>lifestyle</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>If the data can be fully anonymized the data can be shared.</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/NCT03769883
org study id: H-18038298
nct id: NCT03769883
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This project will provide an exercise-based lifestyle intervention with the potential to
      reduce complications for patients with short standing type 2 diabetes (T2D). While exercise
      is widely accepted as a component of T2D management, little is known about the additive
      effect of exercise when combined with a diet on T2D pathophysiology and mechanisms believed
      to lead to micro- and macrovascular complications. Moreover, the necessary dose of exercise
      to revert the progression of T2D and the related complications has not been investigated. A
      large-scale randomized controlled trial (RCT) will be essential to document the effectiveness
      on reducing the risk of T2D complications. However, prior to conducting a large-scale RCT, we
      need to specify the exercise dose that efficiently compliments the diet.

      In a 4-armed randomized, clinical trial (N=80 T2D patients, T2D duration < than 7 years) we
      aim to investigate 1) the potential additive role of exercise on pancreatic β-cell function
      in patients with T2D when combined with a diet, 2) the causal relationship between
      lifestyle-induced reductions in glycaemic variability, oxidative stress and low-grade
      inflammation and, 3) the role of exercise in rescuing dysregulated muscle progenitor cells.
      The participants will be randomly allocated to either a) control, b) diet, c) diet and
      exercise 3 times/week or d) diet and exercise 6 times/week for 16 weeks. Prior to, during and
      following the interventions, all participants will undergo extensive testing.
A 4-armed, 16-week, parallel-group, assessor-blinded, randomized, clinical trial.
      Participants will be randomly allocated (1:1:1:1), stratified by sex

      Interventions:

      The lifestyle interventions will consist of two main components; 1) increased physical
      activity and structured exercise and/or 2) a dietary intervention aiming at a weight loss.
      Whereas there will be no differences in the dietary intervention between the lifestyle
      groups, the volume of physical activity and structured exercise will vary according to the
      frequencies of the structured exercise sessions.

      The study groups are prescribed:

        1. Control group (CON): No intervention

        2. Dietary control (DCON): Dietary intervention (see below)

        3. Moderate Exercise Dose (MED): Two aerobic training sessions per week of 45-60 min
           duration and one session per week with combined aerobic (30-35 min) and resistance (30
           min) training and a dietary intervention (described below)

        4. High Exercise Dose (HED): Four aerobic training sessions per week of 45-60 min duration
           and two sessions per week with combined aerobic (30-35 min) and resistance (30 min)
           training and a dietary intervention (described below)

      Detailed description of the intervention components. Exercise: The training protocol will be
      adapted based on a previous study where the T2D participants were prescribed 6 weekly
      sessions of aerobic training alone or combined aerobic and resistance training (averaging
      360-420 min of exercise per week). As previous analyses suggest that there may be an inverse
      dose-response relationship between reductions in HbA1c and aerobic exercise volume, this
      parameter will be used to adapt the training protocol. As the effect of exercise on HbA1c is
      closer related to the number of training sessions rather than intensity15, we will reduce the
      number of sessions by 50%, to three sessions/week in the moderate exercise dose group and
      maintain the original session frequency in the high dose exercise group (six
      sessions/week).Training will be supervised and monitored to ensure intensity and compliance.

      Dietary intervention and intended weight loss (DCON, MED and HED: The dietary intervention
      will be based on the recommendations from the American Diabetes Association (ADA) with
      increased focus on macronutrient quality. The macronutrient distributions are in line with
      the current guidelines from the national Diabetes Association and Canadian guidelines, where
      individualization in macronutrient distribution should lie within the range of 45-60 energy%
      carbohydrate, 15-20 energy% protein and 20-35 energy% fat. Thus, the dietary intervention
      emphasis will be on low glycemic index and low glycemic load in shape of non-processed foods
      and will aim at reducing saturated fat intake <7 energy%.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
masking description: Upon completion of the study and prior to breaking the allocation code, a data-collection form is generated by a statistician and the principal investigator. The data-analyst breaks the allocation code and labels the participants according to the assigned treatment and analyzes the outcomes. Following the analyses, group allocation will be concealed in all data outputs and the N per group and present the data to the writing committee in a blinded fashion. Then the writing committee will provide their blinded interpretations.
measure: Pancreatic beta-cell function (Per protocol)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: The change in the late-phase disposition index (DI) during the final 30 minutes of hyperglycemic phase of the hyperglycemic clamp.
measure: Pancreatic beta-cell function (Intention to treat)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: As for per protocol
measure: Glucagon like peptide 1 sensitivity (c-peptide)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Glucagon like peptide 1 stimulated C-peptide secretion
measure: Glucagon like peptide 1 sensitivity (glucagon)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Glucagon like peptide 1 stimulated glucagon secretion
measure: Glucagon like peptide 1 sensitivity (insulin)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Glucagon like peptide 1 stimulated insulin secretion
measure: Arginine sensitivity (insulin)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Arginine stimulated insulin secretion
measure: Arginine sensitivity (c-peptide)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Arginine stimulated C-peptide secretion
measure: Arginine sensitivity (glucagon)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Arginine stimulated glucagon secretion
measure: Early phase disposition index (c-peptide)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in 1st phase C-peptide secretion defined as the peak concentration during the initial 10 minutes of the hyperglycaemic clamp
measure: Early phase disposition index (insulin)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in 1st phase insulin secretion defined as the peak concentration during the initial 10 minutes of the hyperglycaemic clamp
measure: Glucose clearance
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Rate of glucose clearance (stable isotope infusion) during steady state hyperglycemia
measure: Glucose appearance
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Rate of glucose appearance (stable isotope infusion) during steady state hyperglycemia
measure: Insulin sensitivity
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in mean Glucose infusion rate over last 30 min of clamp phase/(mean insulin×glucose
measure: Mean amplitude of glycemic excursions
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Mean amplitude of glycemic excursions (MAGE - calculated based on min 3 days sensor glucose profiles)
measure: Coefficient of glucose variation
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Coefficient of variation defined as (mean glucose/the standard deviation (SD)) of min 3 days sensor glucose profiles
measure: Mean glucose levels
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in the mean glucose levels (calculated based on min 3 days sensor glucose profiles)
measure: Time in hyperglycemia
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in time in hyperglycaemia (calculated based on min 3 days sensor glucose profiles)
measure: Time in hypoglycemia
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in time in hypoglycaemia from min 3 days sensor glucose profiles
measure: Pancreatic fat
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Pancreatic fat
measure: Hepatic fat
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Hepatic fat
measure: Visceral fat
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in visceral fat
measure: Total fat mass
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Total fat mass
measure: Total fat free mass
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Total fat free mass
measure: Total lean body mass
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Total lean body mass
measure: Android fat mass
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in Android fat mass
measure: Gynoid fat mass
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in gynoid fat mass
measure: Body weight
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in body weight
measure: Body mass index
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in body mass index
measure: Systemic oxidative stress (RNA)
time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
description: Change in 8-oxo-guanosine
measure: Systemic oxidative stress (DNA)
time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
description: Change in 8-oxo-deoxoguonase
measure: Advanced glycation end-products (AGE)
time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
description: Change in AGE
measure: The circulating receptor for advanced glycation end-products (sRAGE)
time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
description: Change in sRAGE
measure: Markers of low-grade inflammation
time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
description: Change in inflammatory markers (e.g. high sensitive C-reactive protein, interferon-ϒ, interleukin-10, interleukin-8, interleukin-6, interleukin-1, TNFα)
measure: Glycated haemoglobin type 1AC (HbA1c)
time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
description: Change in HbA1c
measure: Total cholesterol
time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
description: Change in total cholesterol
measure: Total triglyceride
time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
description: Change in total triglyceride
measure: Low density lipoprotein (LDL)
time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
description: Change in LDL
measure: High density lipoprotein (HDL)
time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
description: Change in HDL
measure: Systolic blood pressure
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change systolic blood pressures
measure: Diastolic blood pressure
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change diastolic blood pressure
measure: Glucose tolerance
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change incremental and total area under the curve (glucose, c-peptide, insulin) during a mixed meal tolerance test
measure: Gastric emptying (AUC)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in the AUC (paracetamol) during a mixed meal tolerance test
measure: Gastric emptying (Rate of appearance)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in rate of appearance of paracetamol during a mixed meal tolerance test
measure: Physical fitness (VO2max)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in physical fitness (VO2) during a progressive maximal bicycle ergometer test
measure: Muscular 1 repetition max (strength)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in 1 repetition max
measure: Total physical activity
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in objectively measured physical activity (counts per minute)
measure: Moderate and vigorous physical activity (MVPA)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in time spend on MVPA
measure: Sedentary time (SED)
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in time spend on SED
measure: Physical well being
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in physical well being (Based on the physical dimension score from short-form 36, range 0-100)
measure: Mental well being
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in mental well being (Based on the mental dimension score from Short-form 36) (range 0-100)
measure: Satiety
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in self-reported satiety (VAS) during a mixed meal tolerance test (range 0-10)
measure: Muscular metabolic function
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in metabolic function (Based on muscle biopsies in a subset of participants, N=16-32))
measure: Fat tissue metabolic function
time frame: From baseline (0 weeks) to follow-up (16 weeks)
description: Change in metabolic function (Based on muscle biopsies in a subset of participants, N=16-32)
arm group label: Dietary control (DCON)
arm group type: Experimental
description: The macro-nutrient distributions are in line with the current guidelines from the national Diabetes Association and Canadian guidelines, where individualization in macronutrient distribution should lie within the range of 45-60E% carbohydrate, 15-20E% protein and 20-35E% fat. The dietary plan will aim at reducing saturated fat intake <7E% aiming at a caloric deficit of 500 kilo calories/day
arm group label: Moderate Exercise Dose (MED)
arm group type: Experimental
description: Two aerobic training sessions per week of 45-60 min duration and one session per week with combined aerobic (30-35 min) and resistance (30 min) training and a dietary intervention (as above)
arm group label: High Exercise Dose (HED)
arm group type: Experimental
description: Four aerobic training sessions per week of 45-60 min duration and two sessions per week with combined aerobic (30-35 min) and resistance (30 min) training and a dietary intervention (as above)
arm group label: Control
arm group type: No Intervention
description: No intervention
intervention type: Behavioral
intervention name: Exercise and diet
description: The participants will undergo diet or combined diet and exercise. The exercise will be provided at different volumes
arm group label: High Exercise Dose (HED)
arm group label: Moderate Exercise Dose (MED)
intervention type: Behavioral
intervention name: Diet
description: Dietary intervention
arm group label: Dietary control (DCON)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Mathias Ried-Larsen, PhD
role: Principal Investigator
affiliation: Centre for Physical Activity Research, Righospitalet
last name: Inge Holm
phone: +45 35 45 76 41
email: inge.holm@regionh.dk
last name: Bente K Pedersen, Dr Med
phone: +45 35 45 76 41
email: inge.holm@regionh.dk
facility: 
status: Recruiting
contact: 
contact backup: 
country: Denmark
responsible party type: Sponsor-Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Mathias Ried-Larsen
investigator title: Principal investigator
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
sharing ipd: Undecided
ipd description: If the data can be fully anonymized the data can be shared.