<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/NCT03818568</url>
  </required_header>
  <id_info>
    <org_study_id>2015-785-038</org_study_id>
    <nct_id>NCT03818568</nct_id>
  </id_info>
  <brief_title>Supplemented Low Protein Diet and Progression of CKD</brief_title>
  <official_title>Restriction of Proteins in the Diet and Supplementation With Ketoanalogues to Prevent Disease Progression in Patients With Stage 4 Chronic Kidney Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Coordinación de Investigación en Salud, Mexico</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fresenius Kabi</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Coordinación de Investigación en Salud, Mexico</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>
      Investigators intend to analyze diets restricted in protein and supplemented with&#xD;
      ketoanalogues of essential amino acids, to slow the progress of renal damage and improve&#xD;
      nutritional status in diabetic patients over 60 years with stage 4 chronic kidney disease.&#xD;
&#xD;
      Evey 2 months, evaluations were performed of renal function (creatinine clearance, serum&#xD;
      cysteine, proteinuria) and nutritional status (subjective global evaluation,dominant had&#xD;
      pressure strength, body composition by bioelectric impedance, serum transferrin, serum&#xD;
      prealbumin and serum aminogram) for a follow-up period of 2 years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Design. A multicenter, controlled, randomized, open label clinical trial was performed in&#xD;
      patients with T2DM in CKD stage 3b-4 (GFR &lt;44 to &gt;15 mL/min/1.73 m2) treated in hospitals of&#xD;
      the Mexican Social Security Institute. The follow-up period was at least 1 year from the&#xD;
      inclusion of the last patient. The study was conducted in accordance with the provisions of&#xD;
      the Declarations of Helsinki and Tokyo with the amendments in Venice (1983). The protocol was&#xD;
      approved by the National Research and Ethics Committee and by the Research Committees of all&#xD;
      participating hospitals and was registered in National Clinical Trials (NCT03818568).&#xD;
&#xD;
      Patients. Inclusion criteria: Adult patients with T2DM (&gt;18 years) of either sex, with stage&#xD;
      3b-4 of CKD. All patients gave their signed informed consent at the time of recruitment.&#xD;
      Exclusion criteria: Previous treatment with KA, kidney transplantation, cancer, HIV-AIDS, or&#xD;
      seropositive for hepatitis B or C, patients receiving immunosuppressors, with hypercalcemia,&#xD;
      intolerance to KA or disorders of amino acid metabolism. Patients who lost social security&#xD;
      during the study, changed address or treating physician were also excluded.&#xD;
&#xD;
      Sample size. Sample size calculation was made on the basis of two independent groups with&#xD;
      unequal variances, α=0.05, β=0.20, and assuming a difference of 4.0 mL/min/yr between groups&#xD;
      in reduction of eGFR, lower in LPD+KA. Calculation was made with sample size software. A&#xD;
      minimum of 51 per group was obtained.&#xD;
&#xD;
      Intervention. Diet design. Energy: 35 kcals/kg of ideal body weight in patients with normal&#xD;
      BMI; 30 kcals/kg of ideal body weight in overweight patients (BMI&gt;25 kg/m2) and 40 kcals/kg&#xD;
      of ideal weight in underweight patients (BMI&lt;25 kg/m2). Lipids accounted for 35% of the total&#xD;
      energy intake (2/3 from polyunsaturated fatty acids). Carbohydrate intake was set at 55-60%&#xD;
      of the total energy intake, with &gt;70% of complex carbohydrates. The fiber content was 20-25 g&#xD;
      per day. The dietary recommendation for sodium chloride was ~5 g daily and potassium 50-60&#xD;
      mEq/day. Phosphate intake was set at 800-1000 mg per day.&#xD;
&#xD;
      Both groups were prescribed with PrI of 0.6 g/kg/day, preferably plant-based. Patients in&#xD;
      LPD+KA group received KA (Ketosteril® (Fresenius Kabi, Deutschland GMBH, BadHomburg, Germany)&#xD;
      according to the manufacturer's recommendations (1 tablet/5 kg of body weight divided into 3&#xD;
      doses). All other treatments were provided according to institutional guidelines and&#xD;
      prescribed by and according to the criteria of the treating physicians.&#xD;
&#xD;
      Randomization. Patients were centrally randomized 1:1 using an electronic system of random&#xD;
      numbers generator.&#xD;
&#xD;
      Outcomes. The primary outcome was: the rate of decline in kidney function (Δ eGFR/year).&#xD;
      Secondary outcomes included: start of dialysis, impairment of nutritional status, adverse&#xD;
      events, hospitalizations, and mortality.&#xD;
&#xD;
      Follow-up. Patients were followed-up with scheduled visits every two months, for clinical and&#xD;
      biochemical evaluation. Blood samples were obtained after an overnight fast, serum and plasma&#xD;
      were separated and kept in frozen aliquots (-70 °C) until assay. The 24 h urine volumes were&#xD;
      recorded and frozen aliquots stored (-70 °C) until assay. In total blood, hemoglobin,&#xD;
      hematocrit, and glycated hemoglobin were measured, and in plasma/serum: glucose, urea,&#xD;
      creatinine, albumin, total proteins, triglycerides, total cholesterol, HDL cholesterol,&#xD;
      calcium, phosphorus, C-reactive protein. In 24-hour urine: urea and creatinine. Serum&#xD;
      Cystatin-C was measured at baseline and months 6, 9 and 12.&#xD;
&#xD;
      Measurements of biochemical parameters were performed on automated equipment using routine&#xD;
      techniques. High sensitivity C-reactive protein and Cystatin-C were measured by&#xD;
      immunoturbidimetry (Diazyme's Cystatin C Assay. Poway, CA, USA). The protein nitrogen&#xD;
      appearance normalized by body weight (nPNA) was calculated with the Maroni formula, GFR was&#xD;
      calculated using formulas based on sCr (eCKDCr), and serum Cystatin C (eGFRCysC).&#xD;
&#xD;
      Nutritional evaluations. The patients were evaluated by Nephrology Nutritionists. Nutritional&#xD;
      status was monitored by body weight, body mass index, subjective global assessment, body&#xD;
      composition analyzed by electrical bioimpedance, and biochemical parameters. As a functional&#xD;
      index, the hand grip force was measured with a dynamometer. Treatment adherence was monitored&#xD;
      by the 24-hour food intake questionnaire and/or the 3-day food intake diary, nPNA was also&#xD;
      used. In the intervention group, adherence to the use of KA was evaluated by counting tablets&#xD;
      and packaging at each visit.&#xD;
&#xD;
      Statistical analysis. Data are presented as means and standard deviations or standard errors&#xD;
      and as percentages or frequencies according variable characteristics. Differences between&#xD;
      groups were analyzed with Chi2 test, or Student´s t test. For calculation of decline of GFR&#xD;
      during follow-up, only actual eGFR data were considered, and two-way analyses of variance&#xD;
      used. For analysis of the effect of concomitant medication, differences in slopes of&#xD;
      regression lines of eGFR over time among users and non-users of specific medication were&#xD;
      used. Differences in distribution of adverse events was analyzed with Chi2 and&#xD;
      Kolmogorov-Smirnov test. All statistical calculations were made with wSPSS v19 package.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 1, 2017</start_date>
  <completion_date type="Actual">February 1, 2021</completion_date>
  <primary_completion_date type="Actual">January 31, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Design. A multicenter, controlled, randomized, open label clinical trial. Group were: Low Protein Diet (LPD) and LPD Supplemented with Ketoanalogs (LPD+KA). The follow-up period was 1 year.&#xD;
Inclusion criteria: Adult patients with Type 2 Diabetes Mellitus, either sex, in stage 3b-4 of CKD. Exclusion criteria: Previous treatment with KA, kidney transplantation, cancer, HIV-AIDS, hepatitis B or C, patients receiving immunosuppressors, hypercalcemia, intolerance to KA or disorders of amino acid metabolism.&#xD;
Intervention. In both groups diet composition was the same: Energy, 35 kcals/kg, Lipids 35% and, Carbohydrate 55-60% of the total energy intake, fiber 20-25 g, NaCl ~5 g, K 50-60, Phosphate 800-1000 mg. Protein intake was 0.6 g/kg/day.&#xD;
Patients in LPD+KA received KA (1 tablet/5 kg/day). Each tablet contains: Keto-analogs of Isoleucine, Leucine, Phenylalanine, and Valine; hydroxyl analog of Methionine, and aminoacids Lysine, Threonine, Tryptophan, Histidine, and Tyrosine.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>glomerular filtration</measure>
    <time_frame>2 years</time_frame>
    <description>Speed of reduction in glomerular filtration measured by cysteine C clearance and the need for dialysis glomerular filtration &lt;15 mL/min/1.73 m2)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Comorbidities</measure>
    <time_frame>2 years</time_frame>
    <description>measure of frequency and number of comorbidities</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospitalizations</measure>
    <time_frame>2 years</time_frame>
    <description>measure of number and length of hospitalizations</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>2 years</time_frame>
    <description>measure of incidence of mortality</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">149</enrollment>
  <condition>Stage 4 Chronic Kidney Disease</condition>
  <arm_group>
    <arm_group_label>ketoanalogues of essential amino acids</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive conventional treatment according to the institution's clinical guidelines, with moderate restriction of proteins 0.6 g protein/kg/day, as recommended to slow renal damage progression), plus ketoanalogues in the established dosage (1 tablet/5 kg weight divided into 3 doses per day).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will receive conventional treatment according to the institution's clinical guidelines, with moderate restriction of proteins 0.6 g protein/kg/day, as recommended to slow renal damage progression).</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>ketoanalogues of essential amino acids</intervention_name>
    <description>Patients will receive conventional treatment according to the institution's clinical guidelines, with moderate restriction of proteins 0.6 g protein/kg/day, as recommended to slow renal damage progression), plus ketoanalogues in the established dosage (1 tablet/5 kg weight divided into 3 doses per day).</description>
    <arm_group_label>Control</arm_group_label>
    <arm_group_label>ketoanalogues of essential amino acids</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with diabetic nephropathy in stage 4 chronic kidney disease&#xD;
&#xD;
          -  Patients in pre-dialysis&#xD;
&#xD;
          -  Patients with signed informed consent forms.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have received Ketosteril previously&#xD;
&#xD;
          -  Patients participating in other intervention studies&#xD;
&#xD;
          -  Pregnant women&#xD;
&#xD;
          -  Patients with background of renal transplant&#xD;
&#xD;
          -  Patients with cancer, HIV, seropositive for hepatitis B or C or receiving&#xD;
             immunosuppressors, hypercalcemia&#xD;
&#xD;
          -  Intolerance of Ketosteril ingredients&#xD;
&#xD;
          -  Hereditary disorders in amino acid metabolism&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ramon Paniagua, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Instituto Mexicano del Seguro Social</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Unidad de Investigación Médica en Enfermedades Nefrológicas, Instituto Mexicano del Seguro Social</name>
      <address>
        <city>Mexico City</city>
        <state>DF</state>
        <zip>06722</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Unidad de Investigacion Medica en Enfermedades Nefrologicas, Hospital de Especialidades Centro Medico Nacional Siglo XXI</name>
      <address>
        <city>Mexico City</city>
        <zip>06720</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Mexico</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>June 7, 2018</study_first_submitted>
  <study_first_submitted_qc>January 24, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 28, 2019</study_first_posted>
  <last_update_submitted>August 6, 2021</last_update_submitted>
  <last_update_submitted_qc>August 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 12, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Coordinación de Investigación en Salud, Mexico</investigator_affiliation>
    <investigator_full_name>Jose Ramon Paniagua Sierra</investigator_full_name>
    <investigator_title>Chief investigator</investigator_title>
  </responsible_party>
  <keyword>chronic kidney disease</keyword>
  <keyword>ketoanalogue</keyword>
  <keyword>diabetes</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Renal Insufficiency, Chronic</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/NCT03818568
org study id: 2015-785-038
nct id: NCT03818568
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Investigators intend to analyze diets restricted in protein and supplemented with
      ketoanalogues of essential amino acids, to slow the progress of renal damage and improve
      nutritional status in diabetic patients over 60 years with stage 4 chronic kidney disease.

      Evey 2 months, evaluations were performed of renal function (creatinine clearance, serum
      cysteine, proteinuria) and nutritional status (subjective global evaluation,dominant had
      pressure strength, body composition by bioelectric impedance, serum transferrin, serum
      prealbumin and serum aminogram) for a follow-up period of 2 years.
Design. A multicenter, controlled, randomized, open label clinical trial was performed in
      patients with T2DM in CKD stage 3b-4 (GFR <44 to >15 mL/min/1.73 m2) treated in hospitals of
      the Mexican Social Security Institute. The follow-up period was at least 1 year from the
      inclusion of the last patient. The study was conducted in accordance with the provisions of
      the Declarations of Helsinki and Tokyo with the amendments in Venice (1983). The protocol was
      approved by the National Research and Ethics Committee and by the Research Committees of all
      participating hospitals and was registered in National Clinical Trials (NCT03818568).

      Patients. Inclusion criteria: Adult patients with T2DM (>18 years) of either sex, with stage
      3b-4 of CKD. All patients gave their signed informed consent at the time of recruitment.
      Exclusion criteria: Previous treatment with KA, kidney transplantation, cancer, HIV-AIDS, or
      seropositive for hepatitis B or C, patients receiving immunosuppressors, with hypercalcemia,
      intolerance to KA or disorders of amino acid metabolism. Patients who lost social security
      during the study, changed address or treating physician were also excluded.

      Sample size. Sample size calculation was made on the basis of two independent groups with
      unequal variances, α=0.05, β=0.20, and assuming a difference of 4.0 mL/min/yr between groups
      in reduction of eGFR, lower in LPD+KA. Calculation was made with sample size software. A
      minimum of 51 per group was obtained.

      Intervention. Diet design. Energy: 35 kcals/kg of ideal body weight in patients with normal
      BMI; 30 kcals/kg of ideal body weight in overweight patients (BMI>25 kg/m2) and 40 kcals/kg
      of ideal weight in underweight patients (BMI<25 kg/m2). Lipids accounted for 35% of the total
      energy intake (2/3 from polyunsaturated fatty acids). Carbohydrate intake was set at 55-60%
      of the total energy intake, with >70% of complex carbohydrates. The fiber content was 20-25 g
      per day. The dietary recommendation for sodium chloride was ~5 g daily and potassium 50-60
      mEq/day. Phosphate intake was set at 800-1000 mg per day.

      Both groups were prescribed with PrI of 0.6 g/kg/day, preferably plant-based. Patients in
      LPD+KA group received KA (Ketosteril® (Fresenius Kabi, Deutschland GMBH, BadHomburg, Germany)
      according to the manufacturer's recommendations (1 tablet/5 kg of body weight divided into 3
      doses). All other treatments were provided according to institutional guidelines and
      prescribed by and according to the criteria of the treating physicians.

      Randomization. Patients were centrally randomized 1:1 using an electronic system of random
      numbers generator.

      Outcomes. The primary outcome was: the rate of decline in kidney function (Δ eGFR/year).
      Secondary outcomes included: start of dialysis, impairment of nutritional status, adverse
      events, hospitalizations, and mortality.

      Follow-up. Patients were followed-up with scheduled visits every two months, for clinical and
      biochemical evaluation. Blood samples were obtained after an overnight fast, serum and plasma
      were separated and kept in frozen aliquots (-70 °C) until assay. The 24 h urine volumes were
      recorded and frozen aliquots stored (-70 °C) until assay. In total blood, hemoglobin,
      hematocrit, and glycated hemoglobin were measured, and in plasma/serum: glucose, urea,
      creatinine, albumin, total proteins, triglycerides, total cholesterol, HDL cholesterol,
      calcium, phosphorus, C-reactive protein. In 24-hour urine: urea and creatinine. Serum
      Cystatin-C was measured at baseline and months 6, 9 and 12.

      Measurements of biochemical parameters were performed on automated equipment using routine
      techniques. High sensitivity C-reactive protein and Cystatin-C were measured by
      immunoturbidimetry (Diazyme's Cystatin C Assay. Poway, CA, USA). The protein nitrogen
      appearance normalized by body weight (nPNA) was calculated with the Maroni formula, GFR was
      calculated using formulas based on sCr (eCKDCr), and serum Cystatin C (eGFRCysC).

      Nutritional evaluations. The patients were evaluated by Nephrology Nutritionists. Nutritional
      status was monitored by body weight, body mass index, subjective global assessment, body
      composition analyzed by electrical bioimpedance, and biochemical parameters. As a functional
      index, the hand grip force was measured with a dynamometer. Treatment adherence was monitored
      by the 24-hour food intake questionnaire and/or the 3-day food intake diary, nPNA was also
      used. In the intervention group, adherence to the use of KA was evaluated by counting tablets
      and packaging at each visit.

      Statistical analysis. Data are presented as means and standard deviations or standard errors
      and as percentages or frequencies according variable characteristics. Differences between
      groups were analyzed with Chi2 test, or Student´s t test. For calculation of decline of GFR
      during follow-up, only actual eGFR data were considered, and two-way analyses of variance
      used. For analysis of the effect of concomitant medication, differences in slopes of
      regression lines of eGFR over time among users and non-users of specific medication were
      used. Differences in distribution of adverse events was analyzed with Chi2 and
      Kolmogorov-Smirnov test. All statistical calculations were made with wSPSS v19 package.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Design. A multicenter, controlled, randomized, open label clinical trial. Group were: Low Protein Diet (LPD) and LPD Supplemented with Ketoanalogs (LPD+KA). The follow-up period was 1 year.
Inclusion criteria: Adult patients with Type 2 Diabetes Mellitus, either sex, in stage 3b-4 of CKD. Exclusion criteria: Previous treatment with KA, kidney transplantation, cancer, HIV-AIDS, hepatitis B or C, patients receiving immunosuppressors, hypercalcemia, intolerance to KA or disorders of amino acid metabolism.
Intervention. In both groups diet composition was the same: Energy, 35 kcals/kg, Lipids 35% and, Carbohydrate 55-60% of the total energy intake, fiber 20-25 g, NaCl ~5 g, K 50-60, Phosphate 800-1000 mg. Protein intake was 0.6 g/kg/day.
Patients in LPD+KA received KA (1 tablet/5 kg/day). Each tablet contains: Keto-analogs of Isoleucine, Leucine, Phenylalanine, and Valine; hydroxyl analog of Methionine, and aminoacids Lysine, Threonine, Tryptophan, Histidine, and Tyrosine.
primary purpose: Prevention
masking: None (Open Label)
measure: glomerular filtration
time frame: 2 years
description: Speed of reduction in glomerular filtration measured by cysteine C clearance and the need for dialysis glomerular filtration <15 mL/min/1.73 m2)
measure: Comorbidities
time frame: 2 years
description: measure of frequency and number of comorbidities
measure: Hospitalizations
time frame: 2 years
description: measure of number and length of hospitalizations
measure: Mortality
time frame: 2 years
description: measure of incidence of mortality
arm group label: ketoanalogues of essential amino acids
arm group type: Experimental
description: Patients will receive conventional treatment according to the institution's clinical guidelines, with moderate restriction of proteins 0.6 g protein/kg/day, as recommended to slow renal damage progression), plus ketoanalogues in the established dosage (1 tablet/5 kg weight divided into 3 doses per day).
arm group label: Control
arm group type: Active Comparator
description: Patients will receive conventional treatment according to the institution's clinical guidelines, with moderate restriction of proteins 0.6 g protein/kg/day, as recommended to slow renal damage progression).
intervention type: Dietary Supplement
intervention name: ketoanalogues of essential amino acids
description: Patients will receive conventional treatment according to the institution's clinical guidelines, with moderate restriction of proteins 0.6 g protein/kg/day, as recommended to slow renal damage progression), plus ketoanalogues in the established dosage (1 tablet/5 kg weight divided into 3 doses per day).
arm group label: Control
arm group label: ketoanalogues of essential amino acids
criteria: 
gender: All
minimum age: 60 Years
maximum age: 80 Years
healthy volunteers: No
last name: Ramon Paniagua, MD, PhD
role: Study Director
affiliation: Instituto Mexicano del Seguro Social
facility: 
facility: 
country: Mexico
responsible party type: Principal Investigator
investigator affiliation: Coordinación de Investigación en Salud, Mexico
investigator full name: Jose Ramon Paniagua Sierra
investigator title: Chief investigator
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic
sharing ipd: No