<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/NCT03810378</url>
  </required_header>
  <id_info>
    <org_study_id>49218</org_study_id>
    <nct_id>NCT03810378</nct_id>
  </id_info>
  <brief_title>Contrasting Ketogenic and Mediterranean Diets in Individuals With Type 2 Diabetes and Prediabetes: The Keto-Med Trial</brief_title>
  <official_title>Contrasting Ketogenic and Mediterranean Diets in Individuals With Type 2 Diabetes and Prediabetes: The Keto-Med Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Stanford University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of this study is to compare two metabolically distinct diets, WFKD vs Med-Plus,&#xD;
      in order to examine the potential benefits, and unintended consequences, of going beyond a&#xD;
      focus on maximally avoiding added sugars and refined grains, to also avoiding legumes,&#xD;
      fruits, and whole grains.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The proposed randomized clinical trial will investigate differential population-specific&#xD;
      effects of two low-carbohydrate (low-carb) diet patterns, addressing a gap in the evidence&#xD;
      base in this area that will lead to 1) improved treatment strategies for common adverse&#xD;
      clinical conditions, 2) improved health for these individuals, and 3) long-term decreases in&#xD;
      health care costs. This impactful research will advance the field of personalized and&#xD;
      precision medicine.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 5, 2019</start_date>
  <completion_date type="Actual">December 6, 2020</completion_date>
  <primary_completion_date type="Actual">December 4, 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>Crossover Assignment</intervention_model>
    <intervention_model_description>40 adults will be randomized in cross-over design to a Ketogenic or Mediterranean diet for 12 weeks each (no washout) with a 1 month follow-up at the end of the second phase.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Hemoglobin A1c (HbA1c)</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Change from baseline in HbA1c at 12 weeks of each phase</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Microbiota composition</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Change from baseline in alpha diversity at 12 weeks of each phase. We will be using number of observed sequence variants (&quot;species&quot;) determined by standard 16S rRNA amplicon sequencing (V3-V5 region followed by DADA2 to define error-corrected sequence variants) as our primary metric of alpha diversity. Higher alpha diversity is better. The units are the # of sequence variants.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Microbiota function</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Change from baseline in composite of short-chain fatty acids (SCFA) concentration (ug/g stool: acetate + propionate + butyrate) at 12 weeks of each phase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LDL Cholesterol</measure>
    <time_frame>Baseline and12 weeks</time_frame>
    <description>Change from baseline in LDL cholesterol at 12 weeks of each phase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HDL Cholesterol</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Change from baseline in HDL cholesterol at 12 weeks of each phase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Triglycerides</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Change from baseline in triglycerides at 12 weeks of each phase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting insulin</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Change from baseline in fasting insulin at 12 weeks of each phase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pressure</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Change from baseline in blood pressure at 12 weeks of each phase.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Satisfaction with WFKD and Med-Plus diets</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Average satisfaction level with meals at 12 weeks of each phase (WFKD compared to Med-Plus phase) using a 5-point Likert scale (1=not at all satisfied; 2=slightly satisfied; 3=moderately satisfied; 4=very satisfied; 5=extremely satisfied).</description>
  </other_outcome>
  <other_outcome>
    <measure>Adherence to diet protocols</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Adherence to diet protocols 12 weeks of each phase in subjects with Diabetes compared to subjects with prediabetes, according to 3-day food records.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">61</enrollment>
  <condition>Diabetes Mellitus, Type 2</condition>
  <condition>PreDiabetes</condition>
  <arm_group>
    <arm_group_label>Mediterranean Diet (Med-Plus)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will follow a Mediterranean-type diet (Med-Plus) for 12 weeks. This diet will maximize the intake of vegetables, legumes, fruits and nuts, whole intact grains/cereals and fish; and minimize the intake of meat, poultry, and dairy. It will exclude added sugars and refined grains.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Well-Formulated Ketogenic Diet (WFKD)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will follow a Well-Formulated Ketogenic Diet (WFKD) for 12 weeks. This diet will maximize the intake of non-processed beef, pork, and poultry (preferably organic/grass-fed), fish, heavy cream, low-lactose, high-fat cheeses, animal fats, oils (avocado, coconut, or other nut oils), non-starchy (above ground) vegetables and limited amounts of some fruits (berries). It will exclude legumes, grains, sugars, starchy (below ground) vegetables, most fruits, and polyunsaturated oils (soy, sunflower, peanut, cottonseed, canola, etc.). It will aim for an intake of 20 g of carbohydrates/day at start, with the goal to have no more than 50 grams/day to maintain ketosis.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Mediterranean Diet (Med-Plus)</intervention_name>
    <description>Participants will follow the Med-Plus diet for 12 weeks, then switch to the alternate diet for another 12 weeks (no washout period).</description>
    <arm_group_label>Mediterranean Diet (Med-Plus)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Well-Formulated Ketogenic Diet (WFKD)</intervention_name>
    <description>Participants will follow the WFKD diet for 12 weeks, then switch to the alternate diet for another 12 weeks (no washout period).</description>
    <arm_group_label>Well-Formulated Ketogenic Diet (WFKD)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18&#xD;
&#xD;
          -  Diagnosed with type 2 diabetes mellitus, OR prediabetes (defined as HbA1c &lt;/= 5.7% OR&#xD;
             Fasting Glucose of &gt;100 mg/dL)&#xD;
&#xD;
        Identify exclusion criteria.&#xD;
&#xD;
          -  Weight &lt; 110 lb&#xD;
&#xD;
          -  BMI &gt; 40&#xD;
&#xD;
          -  LDL-C &gt;190 mg/dL&#xD;
&#xD;
          -  Blood pressure: SBP &gt; 160 mmHg OR DBP: &gt; 90 mmHg&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Weight &lt; 110 lb&#xD;
&#xD;
          -  BMI ≥ 40&#xD;
&#xD;
          -  LDL-C &gt;190 mg/dL&#xD;
&#xD;
          -  Systolic blood pressure (SBP) &gt; 160 mmHg OR Diastolic blood pressure (DBP) &gt; 90 mmHg&#xD;
&#xD;
          -  Diagnosed with type 1 diabetes or history of ketoacidosis&#xD;
&#xD;
          -  Uncontrolled and untreated diabetes (by discretion of study physician)&#xD;
&#xD;
          -  Active cardiovascular disease (in past year with myocardial infarction, coronary stent&#xD;
             or bypass surgery)&#xD;
&#xD;
          -  Kidney disease (eGFR less than 50 mL/min per 1.73 m2)&#xD;
&#xD;
          -  Liver disease (liver transaminase higher than 3 times the normal range for the&#xD;
             laboratory)&#xD;
&#xD;
          -  Symptomatic gallstones&#xD;
&#xD;
          -  History of bariatric surgery&#xD;
&#xD;
          -  Anemia&#xD;
&#xD;
          -  Taking any of the following medications in past 3 months: SGLT-2 inhibitors, GLP-1&#xD;
             receptor agonist, Insulin, Amylin analog, Alpha-glucosidase inhibitor, Dopamine&#xD;
             agonist, Bile acid sequestrant.&#xD;
&#xD;
          -  Taking any medications for weight loss&#xD;
&#xD;
          -  History of active cancer in the past 3 years except for squamous or basal cell&#xD;
             carcinomas of the skin that have been medically managed by local excision&#xD;
&#xD;
          -  Unstable dietary history as defined by major changes in diet during the previous&#xD;
             month, where the subject has eliminated or significantly increased a major food group&#xD;
             in the diet.&#xD;
&#xD;
          -  Recent history of chronic excessive alcohol consumption defined as more than five&#xD;
             1.5-ounce servings of 80 proof distilled spirits, five 12-ounce servings of beer or&#xD;
             five 5-ounce servings of wine per day; or &gt; 14 drinks/week.&#xD;
&#xD;
          -  Women: Pregnant currently or planning to become pregnant during the course of the&#xD;
             study, and/or breastfeeding&#xD;
&#xD;
          -  Regular/frequent use of smoking or chewing tobacco, e-cigarettes, cigars or other&#xD;
             nicotine-containing products&#xD;
&#xD;
          -  Regular use of prescription opiate pain medication&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Christopher Gardner, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://med.stanford.edu/nutrition/research/completed-studies/KETOMEDstudy.html</url>
    <description>Study description and summary of results</description>
  </link>
  <reference>
    <citation>Gardner CD, Landry MJ, Perelman D, Petlura C, Durand LR, Aronica L, Crimarco A, Cunanan KM, Chang A, Dant CC, Robinson JL, Kim SH. Effect of a ketogenic diet versus Mediterranean diet on glycated hemoglobin in individuals with prediabetes and type 2 diabetes mellitus: The interventional Keto-Med randomized crossover trial. Am J Clin Nutr. 2022 Sep 2;116(3):640-652. doi: 10.1093/ajcn/nqac154. Erratum In: Am J Clin Nutr. 2022 Dec 19;116(6):1904.</citation>
    <PMID>35641199</PMID>
  </reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>January 9, 2019</study_first_submitted>
  <study_first_submitted_qc>January 17, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 18, 2019</study_first_posted>
  <last_update_submitted>February 18, 2023</last_update_submitted>
  <last_update_submitted_qc>February 18, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Christopher Gardner</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Ketogenic diet</keyword>
  <keyword>Mediterranean diet</keyword>
  <keyword>Diabetes</keyword>
  <keyword>Prediabetes</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>
    <mesh_term>Prediabetic State</mesh_term>
    <mesh_term>Glucose Intolerance</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 18, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/78/NCT03810378/SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03810378
org study id: 49218
nct id: NCT03810378
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The objective of this study is to compare two metabolically distinct diets, WFKD vs Med-Plus,
      in order to examine the potential benefits, and unintended consequences, of going beyond a
      focus on maximally avoiding added sugars and refined grains, to also avoiding legumes,
      fruits, and whole grains.
The proposed randomized clinical trial will investigate differential population-specific
      effects of two low-carbohydrate (low-carb) diet patterns, addressing a gap in the evidence
      base in this area that will lead to 1) improved treatment strategies for common adverse
      clinical conditions, 2) improved health for these individuals, and 3) long-term decreases in
      health care costs. This impactful research will advance the field of personalized and
      precision medicine.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: 40 adults will be randomized in cross-over design to a Ketogenic or Mediterranean diet for 12 weeks each (no washout) with a 1 month follow-up at the end of the second phase.
primary purpose: Prevention
masking: Double (Investigator, Outcomes Assessor)
measure: Hemoglobin A1c (HbA1c)
time frame: Baseline and 12 weeks
description: Change from baseline in HbA1c at 12 weeks of each phase
measure: Microbiota composition
time frame: Baseline and 12 weeks
description: Change from baseline in alpha diversity at 12 weeks of each phase. We will be using number of observed sequence variants ("species") determined by standard 16S rRNA amplicon sequencing (V3-V5 region followed by DADA2 to define error-corrected sequence variants) as our primary metric of alpha diversity. Higher alpha diversity is better. The units are the # of sequence variants.
measure: Microbiota function
time frame: Baseline and 12 weeks
description: Change from baseline in composite of short-chain fatty acids (SCFA) concentration (ug/g stool: acetate + propionate + butyrate) at 12 weeks of each phase.
measure: LDL Cholesterol
time frame: Baseline and12 weeks
description: Change from baseline in LDL cholesterol at 12 weeks of each phase.
measure: HDL Cholesterol
time frame: Baseline and 12 weeks
description: Change from baseline in HDL cholesterol at 12 weeks of each phase.
measure: Triglycerides
time frame: Baseline and 12 weeks
description: Change from baseline in triglycerides at 12 weeks of each phase.
measure: Fasting insulin
time frame: Baseline and 12 weeks
description: Change from baseline in fasting insulin at 12 weeks of each phase.
measure: Blood pressure
time frame: Baseline and 12 weeks
description: Change from baseline in blood pressure at 12 weeks of each phase.
measure: Satisfaction with WFKD and Med-Plus diets
time frame: Baseline and 12 weeks
description: Average satisfaction level with meals at 12 weeks of each phase (WFKD compared to Med-Plus phase) using a 5-point Likert scale (1=not at all satisfied; 2=slightly satisfied; 3=moderately satisfied; 4=very satisfied; 5=extremely satisfied).
measure: Adherence to diet protocols
time frame: Baseline and 12 weeks
description: Adherence to diet protocols 12 weeks of each phase in subjects with Diabetes compared to subjects with prediabetes, according to 3-day food records.
arm group label: Mediterranean Diet (Med-Plus)
arm group type: Experimental
description: Participants will follow a Mediterranean-type diet (Med-Plus) for 12 weeks. This diet will maximize the intake of vegetables, legumes, fruits and nuts, whole intact grains/cereals and fish; and minimize the intake of meat, poultry, and dairy. It will exclude added sugars and refined grains.
arm group label: Well-Formulated Ketogenic Diet (WFKD)
arm group type: Experimental
description: Participants will follow a Well-Formulated Ketogenic Diet (WFKD) for 12 weeks. This diet will maximize the intake of non-processed beef, pork, and poultry (preferably organic/grass-fed), fish, heavy cream, low-lactose, high-fat cheeses, animal fats, oils (avocado, coconut, or other nut oils), non-starchy (above ground) vegetables and limited amounts of some fruits (berries). It will exclude legumes, grains, sugars, starchy (below ground) vegetables, most fruits, and polyunsaturated oils (soy, sunflower, peanut, cottonseed, canola, etc.). It will aim for an intake of 20 g of carbohydrates/day at start, with the goal to have no more than 50 grams/day to maintain ketosis.
intervention type: Behavioral
intervention name: Mediterranean Diet (Med-Plus)
description: Participants will follow the Med-Plus diet for 12 weeks, then switch to the alternate diet for another 12 weeks (no washout period).
arm group label: Mediterranean Diet (Med-Plus)
intervention type: Behavioral
intervention name: Well-Formulated Ketogenic Diet (WFKD)
description: Participants will follow the WFKD diet for 12 weeks, then switch to the alternate diet for another 12 weeks (no washout period).
arm group label: Well-Formulated Ketogenic Diet (WFKD)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Christopher Gardner, PhD
role: Principal Investigator
affiliation: Stanford University
facility: 
country: United States
url: https://med.stanford.edu/nutrition/research/completed-studies/KETOMEDstudy.html
description: Study description and summary of results
citation: Gardner CD, Landry MJ, Perelman D, Petlura C, Durand LR, Aronica L, Crimarco A, Cunanan KM, Chang A, Dant CC, Robinson JL, Kim SH. Effect of a ketogenic diet versus Mediterranean diet on glycated hemoglobin in individuals with prediabetes and type 2 diabetes mellitus: The interventional Keto-Med randomized crossover trial. Am J Clin Nutr. 2022 Sep 2;116(3):640-652. doi: 10.1093/ajcn/nqac154. Erratum In: Am J Clin Nutr. 2022 Dec 19;116(6):1904.
PMID: 35641199
responsible party type: Principal Investigator
investigator affiliation: Stanford University
investigator full name: Christopher Gardner
investigator title: Professor of Medicine
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Prediabetic State
mesh term: Glucose Intolerance
sharing ipd: No
provided document: 