<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/NCT04472624</url>
  </required_header>
  <id_info>
    <org_study_id>20-1040</org_study_id>
    <nct_id>NCT04472624</nct_id>
  </id_info>
  <brief_title>Short Term Induction of Ketosis in PKD</brief_title>
  <acronym>RESET-PKD</acronym>
  <official_title>Short Term Induction of Ketosis in PKD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Cologne</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Cologne</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>
      Recently, it has been shown that ketose-inducing dietary interventions slow disease&#xD;
      progression in animal models of polycystic kidney disease (PKD), even when the state of&#xD;
      ketosis is only induced for a short period of time. The present study aims to investigate the&#xD;
      effects of short term ketosis on total kidney volume (TKV) (and other parameters) in 10&#xD;
      ADPKD-patients with rapidly progressive disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Recently, dietary models inducing ketosis have been shown to inhibit disease progression in&#xD;
      animal models of PKD. Those beneficial dietary models included time-restricted feeding (TRF)&#xD;
      without caloric reduction, ad libitum administered ketogenic diet (KD) and acute short-term&#xD;
      fasting in mouse, rat and feline models of PKD.&#xD;
&#xD;
      In a PKD rat model, TRF without caloric reduction resulted in a strong inhibition of mTOR&#xD;
      signaling, proliferation and fibrosis in the affected kidneys. The adminstration of an ad&#xD;
      libitum fed KD led to similar results. In rat, mouse and feline models of PKD, acute fasting&#xD;
      led to a significant reduction of cyst volume. Therefore, cystic cells seem to be&#xD;
      metabolically inflexible and exhibit an altered metabolism characterized by increased&#xD;
      glycolysis and, amongst others, defective fatty acid oxidation, similar to the Warburg effect&#xD;
      in cancer. (Torres, Kruger et al. 2019)&#xD;
&#xD;
      While those beneficial observations were made in mouse, rat and feline models of PKD, the&#xD;
      effects of a ketogenic diet in human ADPKD patients have not been investigated yet, even&#xD;
      though the adminstration of ketogenic diets is used as a treatment for epilepsy in children&#xD;
      since the 1920s and fasting is one of the oldest medical procedures.&#xD;
&#xD;
      Therefore, the aim of the present study is to investigate the effects of a short-period&#xD;
      ketonic state in 10 ADPKD patients with fast progressive disease.&#xD;
&#xD;
      10 ADPKD-patients (aged 18-60 years, CKD G 1-3a) will be enrolled after giving informed&#xD;
      consent. These 10 subjects will go through four trial-related visits. During these visits,&#xD;
      physical examinations will be performed, blood will be drawn, urine will be collected and&#xD;
      ketone body measurements in breath, blood and urine will be carried out. Each study visit&#xD;
      includes an abdominal MRI-scan. Between visit 1 and visit 2, patients will eat their regular&#xD;
      carbohydrate-rich diet. After visit 2, a ketonic state will be induced in those patients.&#xD;
      Patients can choose whether the ketonic state will be induced by acute fasting for 72 hours&#xD;
      (under sufficient water consumption and salt substitution) or by eating a KD for 14 days.&#xD;
      Study visit 3 will take place within 72 hours after finishing the dietary intervention. After&#xD;
      study visit 3, patients will restart eating their regular diet. Study visit 4 will provide&#xD;
      follow-up data 3-6 weeks after the dietary intervention.&#xD;
&#xD;
      After study completion, the relative difference of TKV measured by MRI-based volumetry of the&#xD;
      kidneys immediately before and immediately after the ketonic state, will be compared to TKV&#xD;
      growth/decline while eating a regular carbohydrate-rich diet.&#xD;
&#xD;
      In general, patients are counselled in our outpatient department as part of &quot;The German&#xD;
      AD(H)PKD Registry&quot; (more than 700 patients enrolled). As from those patients, clinical data,&#xD;
      laboratory data and imaging studies are present, identification and recruitment of patients&#xD;
      with fast rapidly progressing disease will be facilitated. Also, the investigators are&#xD;
      closely liaised with the German self-help group PKDCure (PKD Familiaere Zystennieren e.V.),&#xD;
      which is dedicated to ADPKD-linked research. This will facilitate recruitment of patients&#xD;
      even more.&#xD;
&#xD;
      Data obtained from the study visits will be collected. The parameters listed below constitute&#xD;
      the core data set, additional parameters can be included if considered essential.&#xD;
&#xD;
      Registered patients will be provided with diaries for the documentation of feeling of hunger,&#xD;
      problems and discomforts as well as acetoacetate concentrations in breath. Patients are also&#xD;
      provided with a portable breath-analyzer to measure acetoacetate concentrations in breath in&#xD;
      between study visits. Study diaries are collected on Visit 4.&#xD;
&#xD;
      Data capture will be performed at each study visit after enrollment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 1, 2020</start_date>
  <completion_date type="Actual">July 1, 2021</completion_date>
  <primary_completion_date type="Actual">July 1, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Relative difference of TKV immediately before and after the ketonic state</measure>
    <time_frame>Visit 2: 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2</time_frame>
    <description>MRI-based kidney volumetry at study visit 2 and study visit 3</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative difference of TKV</measure>
    <time_frame>Baseline visit (V1) and final study visit (V4) after at maximum 95 days</time_frame>
    <description>assessed by MRI-based volumetry at all study visits</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative difference of height-adjusted total kidney volume (htTKV)</measure>
    <time_frame>Baseline visit (V1) and final study visit (V4) after at maximum 95 days</time_frame>
    <description>assessed by MRI-based volumetry at all study visits</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative difference of total liver volume (TLV)</measure>
    <time_frame>Baseline visit (V1) and final study visit (V4) after at maximum 95 days</time_frame>
    <description>assessed by MRI-based volumetry at all study visits</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative difference of cystic burden of kidneys and liver</measure>
    <time_frame>Baseline visit (V1) and final study visit (V4) after at maximum 95 days</time_frame>
    <description>assessed by MRI at all study visits</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of Renal Function Panel</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement of creatinine, urea and uric acid in blood and urine samples (measurement unit mg/dl)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of electrolytes and minerals</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement of electrolyte and minerals (sodium, natrium, potassium, magnesium, chloride, phosphate) in blood (measurement unit mmol/L) and urine samples (measurement unit mmol/24h)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of albumin</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement in blood and urine samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of glucose</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement in blood and urine samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of Hepatic Function Panel</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement of Alanine aminotransferase(ALT), Aspartate Aminotransferase (ASP), Alkaline Phosphatase (ALP), gamma-glutamyl transferase (GGT) and Lactate Dehydrogenase (LD) in blood samples (measurement unit U/L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of bilirubin</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of lipid panel</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement of high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol, triglycerides and lipoprotein(a) in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of inflammatory parameters</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement of c-reactive protein (CRP) and high sensitivity c-reactive protein (hsCRP) in blood samples ( measurement unit mg/L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change in blood count</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement of white blood cells, red blood cells, platelets in blood samples (measurement unit 10^9/L )</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of hemoglobin</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of hematokrit</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement in blood samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of betahydroxybutyrate level</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement of betahydroxybutyrate level in blood samples for determination of ketosis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change in blood gas analysis</measure>
    <time_frame>Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Measurement with blood gas analyzer for determination of ketosis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Analysis of the ketonic state with betahydroxybutyrate level</measure>
    <time_frame>Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Betahydroxybutyrate measurement from blood samples of the fingertip by patients at home</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Analysis of the ketonic state with ketonuria</measure>
    <time_frame>Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Ketonuria measured with urine stix by patients at home</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Analysis of the ketonic state with acetoacetate in breath</measure>
    <time_frame>Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days</time_frame>
    <description>determination of acetoacetate in breath by patients at home</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of height</measure>
    <time_frame>Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Determination of height</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of weight</measure>
    <time_frame>Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Determination of weight</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute and relative change of waist circumference</measure>
    <time_frame>Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Determination of waist circumference</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relative change of calorimetry</measure>
    <time_frame>Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Could be determined instead of anthropometric parameters</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Bioimpedance</measure>
    <time_frame>Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days</time_frame>
    <description>Bioimpedance measurements on each visit</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feeling of hunger, discomforts and problems</measure>
    <time_frame>In between baseline visit (V1) and final study visit (V4) after at maximum 95 days</time_frame>
    <description>measured and documented at home in a study dietary in between study visits</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acetoacetate-concentrations</measure>
    <time_frame>In between baseline visit (V1) and final study visit (V4) after at maximum 95 days</time_frame>
    <description>measured and documented at home in a study dietary in between study visits</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Changes of renal functional panel in 24-h-urine</measure>
    <time_frame>Baseline and during 14 days of ketogenic diet or 3 days fasting</time_frame>
    <description>Urin samples will be collected before and during the dietary intervention for the determination of creatinine, uric acid and urea (measurement unit mg/24h)</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes of electrolytes and minerals in 24-h-urine</measure>
    <time_frame>Baseline and during 14 days of ketogenic diet or 3 days fasting</time_frame>
    <description>Urin samples will be collected before and during the dietary intervention for the determination of sodium, natrium, potassium, magnesium, chloride, phosphate (measurement unit mmol/24h )</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes of glucose in 24-h-urine</measure>
    <time_frame>Baseline and during 14 days of ketogenic diet or 3 days fasting</time_frame>
    <description>Urin samples will be collected before and during the dietary intervention</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes of albumin in 24-h-urine</measure>
    <time_frame>Baseline and during 14 days of ketogenic diet or 3 days fasting</time_frame>
    <description>Urin samples will be collected before and during the dietary intervention</description>
  </other_outcome>
  <other_outcome>
    <measure>Analysis of stool samples</measure>
    <time_frame>Baseline and during 14 days of ketogenic diet or 3 days fasting</time_frame>
    <description>Stool samples will be collected before and during the dietary intervention and analysed</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes of renal functional panel in spot urine</measure>
    <time_frame>Baseline and during 14 days of ketogenic diet or 3 days fasting</time_frame>
    <description>Urin samples will be collected before and during the dietary intervention for the determination of creatinine, uric acid and urea (measurement unit g/24h)</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes of electrolytes and minerals in spot urine</measure>
    <time_frame>Baseline and during 14 days of ketogenic diet or 3 days fasting</time_frame>
    <description>Urin samples will be collected before and during the dietary intervention for the determination of sodium, natrium, potassium, magnesium, chloride, phosphate (measurement unit mmol/24h)</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes of albumin in spot urine</measure>
    <time_frame>Baseline and during 14 days of ketogenic diet or 3 days fasting</time_frame>
    <description>Urin samples will be collected before and during the dietary intervention</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes of glucose in spot urine</measure>
    <time_frame>Baseline and during 14 days of ketogenic diet or 3 days fasting</time_frame>
    <description>Urin samples will be collected before and during the dietary intervention</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in urinary doubly refractile lipid bodies</measure>
    <time_frame>Baseline and during 14 days of ketogenic diet or 3 days fasting</time_frame>
    <description>Urin samples will be collected before and during the dietary intervention</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>ADPKD</condition>
  <arm_group>
    <arm_group_label>Fasting arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be fasting during 72 hours</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Diet arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be using ketogenic diet for 14 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Fasting</intervention_name>
    <description>Acute fasting for 72 hours</description>
    <arm_group_label>Fasting arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Ketogenic diet</intervention_name>
    <description>Intake of a ketogenic diet for 14 days</description>
    <arm_group_label>Diet arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and female ADPKD-patients (diagnosed by genetics / typical MRI / ultrasound)&#xD;
&#xD;
          -  With evidence of fast progression, at least one of the following criteria&#xD;
&#xD;
               1. Mayo Class 1C-1E&#xD;
&#xD;
               2. Truncating PKD1-mutation&#xD;
&#xD;
               3. Hypertension &lt; 35 years&#xD;
&#xD;
               4. Urological complications &lt; 35 years&#xD;
&#xD;
               5. ≥ 1 first class or second class family member with need of renal replacement&#xD;
                  therapy &lt; 60 years&#xD;
&#xD;
               6. eGFR loss &gt; 2,5 ml/min/1,73m2 per year&#xD;
&#xD;
               7. PROPKD-Score &gt; 6&#xD;
&#xD;
          -  Age ≥ 18 and ≤ 60 years&#xD;
&#xD;
          -  CKD stage 1-3a according to eGFR&#xD;
&#xD;
          -  Signed written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Currently under tolvaptan&#xD;
&#xD;
          -  BMI &lt; 18 or &gt; 35&#xD;
&#xD;
          -  Diabetes mellitus (Type I, Type II, MODY, LADA)&#xD;
&#xD;
          -  Active alcoholism&#xD;
&#xD;
          -  Vegan or vegetarian lifestyle&#xD;
&#xD;
          -  Inability to sign or understand written informed consent&#xD;
&#xD;
          -  Anamnestically known circumstances which forbid the induction of a ketonic state by&#xD;
             ketogenic diet or acute fasting (Liver damage (AST/ALT &gt; 3x upper limit of normal,&#xD;
             alkaline phosphatase &gt; 6x upper limit of normal , Bilirubin ≥ 3 mg/dl), Diabetes&#xD;
             mellitus, Pyruvate carboxylase deficiency, defects of gluconeogenesis, defects of&#xD;
             ketolysis / ketogenesis, hyperinsulinism, defects of fatty acid oxidation )&#xD;
&#xD;
          -  Allergies or food intolerance against components of a ketogenic diet&#xD;
&#xD;
          -  Eating disorders (Anorexia nervosa / Bulimia)&#xD;
&#xD;
          -  Participation in a weight loss program (e.g. Optifast) or intake of medication to&#xD;
             promote weight loss within the last six months&#xD;
&#xD;
          -  Ketogenic Diet &gt; 1 month within the last 12 months&#xD;
&#xD;
          -  Chronic renal replacement therapy&#xD;
&#xD;
          -  Previous history of kidney transplantation&#xD;
&#xD;
          -  Uncontrolled local or systemic infection (according to clinical assessment)&#xD;
&#xD;
          -  Simultaneous participation in other interventional studies&#xD;
&#xD;
          -  Pregnant or breastfeeding women&#xD;
&#xD;
          -  Persons who are dependent of or employed by the study investigators&#xD;
&#xD;
          -  Contraindications against MRI examinations (stents, pacemakers or other metal inserts,&#xD;
             claustrophobia)&#xD;
&#xD;
          -  Persons living in an establishment by court order or official instructions&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Roman-Ulrich Müller, Prof.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department II of Internal Medicine, University of Cologne</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department II of Internal Medicine, University Hospital Cologne</name>
      <address>
        <city>Cologne</city>
        <zip>50937</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <reference>
    <citation>Torres JA, Kruger SL, Broderick C, Amarlkhagva T, Agrawal S, Dodam JR, Mrug M, Lyons LA, Weimbs T. Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease. Cell Metab. 2019 Dec 3;30(6):1007-1023.e5. doi: 10.1016/j.cmet.2019.09.012. Epub 2019 Oct 17.</citation>
    <PMID>31631001</PMID>
  </reference>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>June 9, 2020</study_first_submitted>
  <study_first_submitted_qc>July 13, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 15, 2020</study_first_posted>
  <last_update_submitted>September 13, 2021</last_update_submitted>
  <last_update_submitted_qc>September 13, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Cologne</investigator_affiliation>
    <investigator_full_name>Roman Müller</investigator_full_name>
    <investigator_title>Department II of Internal Medicine</investigator_title>
  </responsible_party>
  <keyword>ADPKD</keyword>
  <keyword>dietary intervention</keyword>
  <keyword>ketosis</keyword>
  <keyword>fasting</keyword>
  <keyword>ketogenic diet</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT04472624
org study id: 20-1040
nct id: NCT04472624
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Recently, it has been shown that ketose-inducing dietary interventions slow disease
      progression in animal models of polycystic kidney disease (PKD), even when the state of
      ketosis is only induced for a short period of time. The present study aims to investigate the
      effects of short term ketosis on total kidney volume (TKV) (and other parameters) in 10
      ADPKD-patients with rapidly progressive disease.
Recently, dietary models inducing ketosis have been shown to inhibit disease progression in
      animal models of PKD. Those beneficial dietary models included time-restricted feeding (TRF)
      without caloric reduction, ad libitum administered ketogenic diet (KD) and acute short-term
      fasting in mouse, rat and feline models of PKD.

      In a PKD rat model, TRF without caloric reduction resulted in a strong inhibition of mTOR
      signaling, proliferation and fibrosis in the affected kidneys. The adminstration of an ad
      libitum fed KD led to similar results. In rat, mouse and feline models of PKD, acute fasting
      led to a significant reduction of cyst volume. Therefore, cystic cells seem to be
      metabolically inflexible and exhibit an altered metabolism characterized by increased
      glycolysis and, amongst others, defective fatty acid oxidation, similar to the Warburg effect
      in cancer. (Torres, Kruger et al. 2019)

      While those beneficial observations were made in mouse, rat and feline models of PKD, the
      effects of a ketogenic diet in human ADPKD patients have not been investigated yet, even
      though the adminstration of ketogenic diets is used as a treatment for epilepsy in children
      since the 1920s and fasting is one of the oldest medical procedures.

      Therefore, the aim of the present study is to investigate the effects of a short-period
      ketonic state in 10 ADPKD patients with fast progressive disease.

      10 ADPKD-patients (aged 18-60 years, CKD G 1-3a) will be enrolled after giving informed
      consent. These 10 subjects will go through four trial-related visits. During these visits,
      physical examinations will be performed, blood will be drawn, urine will be collected and
      ketone body measurements in breath, blood and urine will be carried out. Each study visit
      includes an abdominal MRI-scan. Between visit 1 and visit 2, patients will eat their regular
      carbohydrate-rich diet. After visit 2, a ketonic state will be induced in those patients.
      Patients can choose whether the ketonic state will be induced by acute fasting for 72 hours
      (under sufficient water consumption and salt substitution) or by eating a KD for 14 days.
      Study visit 3 will take place within 72 hours after finishing the dietary intervention. After
      study visit 3, patients will restart eating their regular diet. Study visit 4 will provide
      follow-up data 3-6 weeks after the dietary intervention.

      After study completion, the relative difference of TKV measured by MRI-based volumetry of the
      kidneys immediately before and immediately after the ketonic state, will be compared to TKV
      growth/decline while eating a regular carbohydrate-rich diet.

      In general, patients are counselled in our outpatient department as part of "The German
      AD(H)PKD Registry" (more than 700 patients enrolled). As from those patients, clinical data,
      laboratory data and imaging studies are present, identification and recruitment of patients
      with fast rapidly progressing disease will be facilitated. Also, the investigators are
      closely liaised with the German self-help group PKDCure (PKD Familiaere Zystennieren e.V.),
      which is dedicated to ADPKD-linked research. This will facilitate recruitment of patients
      even more.

      Data obtained from the study visits will be collected. The parameters listed below constitute
      the core data set, additional parameters can be included if considered essential.

      Registered patients will be provided with diaries for the documentation of feeling of hunger,
      problems and discomforts as well as acetoacetate concentrations in breath. Patients are also
      provided with a portable breath-analyzer to measure acetoacetate concentrations in breath in
      between study visits. Study diaries are collected on Visit 4.

      Data capture will be performed at each study visit after enrollment.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: None (Open Label)
measure: Relative difference of TKV immediately before and after the ketonic state
time frame: Visit 2: 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2
description: MRI-based kidney volumetry at study visit 2 and study visit 3
measure: Absolute and relative difference of TKV
time frame: Baseline visit (V1) and final study visit (V4) after at maximum 95 days
description: assessed by MRI-based volumetry at all study visits
measure: Absolute and relative difference of height-adjusted total kidney volume (htTKV)
time frame: Baseline visit (V1) and final study visit (V4) after at maximum 95 days
description: assessed by MRI-based volumetry at all study visits
measure: Absolute and relative difference of total liver volume (TLV)
time frame: Baseline visit (V1) and final study visit (V4) after at maximum 95 days
description: assessed by MRI-based volumetry at all study visits
measure: Absolute and relative difference of cystic burden of kidneys and liver
time frame: Baseline visit (V1) and final study visit (V4) after at maximum 95 days
description: assessed by MRI at all study visits
measure: Absolute and relative change of Renal Function Panel
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement of creatinine, urea and uric acid in blood and urine samples (measurement unit mg/dl)
measure: Absolute and relative change of electrolytes and minerals
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement of electrolyte and minerals (sodium, natrium, potassium, magnesium, chloride, phosphate) in blood (measurement unit mmol/L) and urine samples (measurement unit mmol/24h)
measure: Absolute and relative change of albumin
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement in blood and urine samples
measure: Absolute and relative change of glucose
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement in blood and urine samples
measure: Absolute and relative change of Hepatic Function Panel
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement of Alanine aminotransferase(ALT), Aspartate Aminotransferase (ASP), Alkaline Phosphatase (ALP), gamma-glutamyl transferase (GGT) and Lactate Dehydrogenase (LD) in blood samples (measurement unit U/L)
measure: Absolute and relative change of bilirubin
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement in blood samples
measure: Absolute and relative change of lipid panel
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement of high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol, triglycerides and lipoprotein(a) in blood samples
measure: Absolute and relative change of inflammatory parameters
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement of c-reactive protein (CRP) and high sensitivity c-reactive protein (hsCRP) in blood samples ( measurement unit mg/L)
measure: Absolute and relative change in blood count
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement of white blood cells, red blood cells, platelets in blood samples (measurement unit 10^9/L )
measure: Absolute and relative change of hemoglobin
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement in blood samples
measure: Absolute and relative change of hematokrit
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement in blood samples
measure: Absolute and relative change of betahydroxybutyrate level
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement of betahydroxybutyrate level in blood samples for determination of ketosis
measure: Absolute and relative change in blood gas analysis
time frame: Baseline visit (V1), study visit 2 (V2): 2-4 Weeks after enrolment; Visit 3: 3 - 21 days after Visit 2, and final study visit (V4) after at maximum 95 days
description: Measurement with blood gas analyzer for determination of ketosis
measure: Analysis of the ketonic state with betahydroxybutyrate level
time frame: Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days
description: Betahydroxybutyrate measurement from blood samples of the fingertip by patients at home
measure: Analysis of the ketonic state with ketonuria
time frame: Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days
description: Ketonuria measured with urine stix by patients at home
measure: Analysis of the ketonic state with acetoacetate in breath
time frame: Baseline visit (V1), during 14 days of ketogenic diet or 3 days fasting and final study visit (V4) after at maximum 95 days
description: determination of acetoacetate in breath by patients at home
measure: Absolute and relative change of height
time frame: Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days
description: Determination of height
measure: Absolute and relative change of weight
time frame: Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days
description: Determination of weight
measure: Absolute and relative change of waist circumference
time frame: Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days
description: Determination of waist circumference
measure: Relative change of calorimetry
time frame: Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days
description: Could be determined instead of anthropometric parameters
measure: Changes in Bioimpedance
time frame: Baseline visit (V1), V2 (2-4 Weeks after enrolment); Visit 3 (3 - 21 days after Visit 2 ) and final study visit (V4) after at maximum 95 days
description: Bioimpedance measurements on each visit
measure: Feeling of hunger, discomforts and problems
time frame: In between baseline visit (V1) and final study visit (V4) after at maximum 95 days
description: measured and documented at home in a study dietary in between study visits
measure: Acetoacetate-concentrations
time frame: In between baseline visit (V1) and final study visit (V4) after at maximum 95 days
description: measured and documented at home in a study dietary in between study visits
measure: Changes of renal functional panel in 24-h-urine
time frame: Baseline and during 14 days of ketogenic diet or 3 days fasting
description: Urin samples will be collected before and during the dietary intervention for the determination of creatinine, uric acid and urea (measurement unit mg/24h)
measure: Changes of electrolytes and minerals in 24-h-urine
time frame: Baseline and during 14 days of ketogenic diet or 3 days fasting
description: Urin samples will be collected before and during the dietary intervention for the determination of sodium, natrium, potassium, magnesium, chloride, phosphate (measurement unit mmol/24h )
measure: Changes of glucose in 24-h-urine
time frame: Baseline and during 14 days of ketogenic diet or 3 days fasting
description: Urin samples will be collected before and during the dietary intervention
measure: Changes of albumin in 24-h-urine
time frame: Baseline and during 14 days of ketogenic diet or 3 days fasting
description: Urin samples will be collected before and during the dietary intervention
measure: Analysis of stool samples
time frame: Baseline and during 14 days of ketogenic diet or 3 days fasting
description: Stool samples will be collected before and during the dietary intervention and analysed
measure: Changes of renal functional panel in spot urine
time frame: Baseline and during 14 days of ketogenic diet or 3 days fasting
description: Urin samples will be collected before and during the dietary intervention for the determination of creatinine, uric acid and urea (measurement unit g/24h)
measure: Changes of electrolytes and minerals in spot urine
time frame: Baseline and during 14 days of ketogenic diet or 3 days fasting
description: Urin samples will be collected before and during the dietary intervention for the determination of sodium, natrium, potassium, magnesium, chloride, phosphate (measurement unit mmol/24h)
measure: Changes of albumin in spot urine
time frame: Baseline and during 14 days of ketogenic diet or 3 days fasting
description: Urin samples will be collected before and during the dietary intervention
measure: Changes of glucose in spot urine
time frame: Baseline and during 14 days of ketogenic diet or 3 days fasting
description: Urin samples will be collected before and during the dietary intervention
measure: Changes in urinary doubly refractile lipid bodies
time frame: Baseline and during 14 days of ketogenic diet or 3 days fasting
description: Urin samples will be collected before and during the dietary intervention
arm group label: Fasting arm
arm group type: Experimental
description: Participants will be fasting during 72 hours
arm group label: Diet arm
arm group type: Experimental
description: Participants will be using ketogenic diet for 14 days
intervention type: Other
intervention name: Fasting
description: Acute fasting for 72 hours
arm group label: Fasting arm
intervention type: Other
intervention name: Ketogenic diet
description: Intake of a ketogenic diet for 14 days
arm group label: Diet arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Roman-Ulrich Müller, Prof.
role: Principal Investigator
affiliation: Department II of Internal Medicine, University of Cologne
facility: 
country: Germany
citation: Torres JA, Kruger SL, Broderick C, Amarlkhagva T, Agrawal S, Dodam JR, Mrug M, Lyons LA, Weimbs T. Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease. Cell Metab. 2019 Dec 3;30(6):1007-1023.e5. doi: 10.1016/j.cmet.2019.09.012. Epub 2019 Oct 17.
PMID: 31631001
responsible party type: Principal Investigator
investigator affiliation: University of Cologne
investigator full name: Roman Müller
investigator title: Department II of Internal Medicine
mesh term: Ketosis
sharing ipd: No