<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/NCT01690962</url>
  </required_header>
  <id_info>
    <org_study_id>PCRM DN-1</org_study_id>
    <nct_id>NCT01690962</nct_id>
  </id_info>
  <brief_title>A Nutritional Intervention for Diabetic Neuropathy</brief_title>
  <official_title>A Nutritional Intervention for Diabetic Neuropathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Physicians Committee for Responsible Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Physicians Committee for Responsible Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to assess whether, in individuals with diabetic neuropathy, a&#xD;
      low-fat, vegan diet in combination with a vitamin B12 supplement improves pain, sensation and&#xD;
      other subjective symptoms, more effectively than a vitamin B12 supplement with no diet&#xD;
      changes. The principal measure is pain as measured by the following assessment tools:&#xD;
      Michigan Neuropathy Screening Instrument, Norfolk Quality of Life Questionnaire, Neuropathy&#xD;
      Impairment Score - Lower Limbs, Neuropathy Total Symptom Score, Neuropathy Pain Scale, McGill&#xD;
      Pain Questionnaire and Global Impression Scale. The study duration is 20 weeks.&#xD;
&#xD;
      This study also examines the effects of a low-fat, vegan diet on mood, using the Center for&#xD;
      Epidemiologic Studies Depression Scale-Revised, and the Beck Depression Inventory.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The following determinations will be made at baseline, mid-point, and end of each 20-week&#xD;
      study period, as well as at one-year follow up:&#xD;
&#xD;
      General status, symptoms, and medication accounting. Participants will be asked to report&#xD;
      changes in their health and medication use.&#xD;
&#xD;
      Disease Activity. The following assessments will be used to measure pain and changes in&#xD;
      sensory perception related to diabetic neuropathy:&#xD;
&#xD;
        -  Michigan Neuropathy Screening Instrument. The MNSI questionnaire consists of 15&#xD;
           questions followed by a single 8-point clinical examination involving inspection of the&#xD;
           foot, assessment of ankle reflexes, and semi-quantitative determination of vibration&#xD;
           perception.&#xD;
&#xD;
        -  Norfolk Quality of Life Questionnaire Norfolk QOL-DN is a 47-item questionnaire&#xD;
           developed by the Eastern Virginia Medical School, Norfolk, VA, for assessing subjects'&#xD;
           perception of the effects of diabetes and diabetic neuropathy. It consists of 28 items&#xD;
           pertaining specifically to to small fiber, large fiber and autonomic nerve function&#xD;
           symptoms, and activities of daily living (ADL).&#xD;
&#xD;
        -  Neuropathy Impairment Score for Lower Limbs (NIS-LL) The NIS-LL is the lower limb&#xD;
           component of the full Neuropathy Impairment Score (NIS) and has 3 domains including:&#xD;
           muscle weakness, reflexes, and sensation. The maximum score is 88 points. Based on&#xD;
           experience with and data collected from these clinical trials, the Peripheral Nerve&#xD;
           Society considers a 2 point change on the NIS-LL to correspond to a meaningful change in&#xD;
           clinical status.&#xD;
&#xD;
        -  Neuropathy Total Symptoms Score (NTSS-6) Neuropathy total symptom score-6 (NTSS-6) is a&#xD;
           neuropathy sensory symptom scale that is designed to evaluate the frequency and&#xD;
           intensity of individual neuropathy sensory symptoms identified frequently by patients&#xD;
           with DPN. A total of six questions are synthesized to identify and quantify the specific&#xD;
           positive and negative symptoms associated with sensory deficits in patients.&#xD;
&#xD;
        -  Neuropathy Pain Scale In order to assess and differentiate qualities of pain, Galer and&#xD;
           Jensen developed the Neuropathic Pain Scale (NPS) in 1997. The NPS is composed of 10&#xD;
           items that assess two global pain domains including pain intensity and unpleasantness,&#xD;
           and six pain qualities, including sharp, hot, dull, cold, sensitive, and itchy pain, in&#xD;
           two dimensions (internal and cutaneous).&#xD;
&#xD;
        -  McGill Pain Questionnaire The McGill Pain Questionnaire (MPQ) is used to specify&#xD;
           subjective pain experience using sensory, affective and evaluative word descriptors. The&#xD;
           short form of the McGill Pain Questionnaire (SF-MPQ) contains 11 questions referring to&#xD;
           the sensory dimension of the pain experience and four related to the affective&#xD;
           dimension.&#xD;
&#xD;
        -  Global Impression Scale Global impression scale (GIS) is also termed global rating of&#xD;
           change scales (GRC) and was developed to assess patients' overall improvement or&#xD;
           deterioration in a clinical setting, and has been frequently used in musculoskeletal and&#xD;
           chronic pain trials.&#xD;
&#xD;
      Height. Height will be measured at baseline (only) with participants standing barefoot with&#xD;
      their backs to a wall-mounted stadiometer and heels against the wall, recorded to the nearest&#xD;
      0.5 cm.&#xD;
&#xD;
      Body weight. With participants wearing light, indoor clothing but without shoes, body weight&#xD;
      will be measured to the nearest 0.1 kg, using a digital scale.&#xD;
&#xD;
      Blood pressure. A digital blood pressure monitor and a cuff of a size appropriate to the&#xD;
      participant's arm will be used. The cuff size for each participant will be recorded for&#xD;
      consistency of use at each visit. Participants will be asked to remove all clothing that&#xD;
      covers the location of cuff placement and then rest in a seated position for 5 minutes with&#xD;
      legs uncrossed, without talking or reading. The back and arm will be supported such that the&#xD;
      middle of the cuff on the upper arm is at the level of the right atrium (the mid-point of the&#xD;
      sternum). Three measurements will be taken at 1-minute intervals. The first measurement will&#xD;
      be disregarded, and the mean of the remaining 2 measurements will be calculated.&#xD;
&#xD;
      Serum cholesterol and triacylglycerol concentrations will be measured using the Olympus&#xD;
      Cholesterol Reagent on Olympus Chemistry Analyzers. HDL-cholesterol will be measured directly&#xD;
      using the HDL-C plus 3rd generation test with the Roche direct HDL-cholesterol assay.Low&#xD;
      density lipoprotein cholesterol (LDL-C) concentration will be estimated using the Friedewald&#xD;
      equation. Plasma triglyceride levels will be measured using Olympus Chemistry analyzers from&#xD;
      Quest Diagnostics.&#xD;
&#xD;
      Comprehensive Metabolic Panel. These values will be evaluated at baseline, 20 weeks, and&#xD;
      one-year follow-up.&#xD;
&#xD;
      Hemoglobin A1c. Hemoglobin A1c will be measured in whole blood using the COBAS INTEGRA on&#xD;
      Roche clinical chemistry analyzers.&#xD;
&#xD;
      Glucose. Plasma glucose will be measured using an Olympus Chemistry Analyzer from Quest&#xD;
      Diagnostics, Baltimore, MD, USA.&#xD;
&#xD;
      Urinary albumin and creatinine will be assessed on spot urine samples. Samples for the&#xD;
      albumin assay will be tested using the K-Assay High-Sensitive Microalbumin assay from Quest&#xD;
      Diagnostics.&#xD;
&#xD;
      Apolipoprotein E (APOE): Participants who consent to this aspect of the study will be&#xD;
      genotyped for the ε2, ε3, and ε4 alleles. A sample of approximately 5 ml of the participant's&#xD;
      blood is required and will be drawn simultaneously with the 20-week health assessment labs.&#xD;
      Individuals with diabetes are at greatly increased risk of developing Alzheimer's disease,&#xD;
      and some studies have suggested that the effect of saturated fat intake on Alzheimer's risk&#xD;
      may be most evident in (or even limited to) carriers of the APOEε4 allele. The ApoE protein&#xD;
      produced by the APOE gene is a major plasma apolipoprotein and the primary cholesterol&#xD;
      carrier in the brain [62]. As a group, these individuals have higher plasma LDL&#xD;
      concentrations, compared with APOEε3 homozygotes [63] Moreover, APOE status may influence the&#xD;
      relationship between dietary intake and plasma lipid concentrations [63]. APOE determination&#xD;
      may provide useful information as to who benefits from dietary changes that aim to modify&#xD;
      plasma lipid concentrations, with implications for subsequent risk of cardiovascular disease&#xD;
      and Alzheimer's disease. The blood test will be drawn once, at the 20-week health assessment&#xD;
      only. This test will be optional. If participants decide not to do the test, it will not&#xD;
      affect their status in the study. The blood samples that are collected will be used for APOE&#xD;
      allele testing for this study only. All samples will be destroyed after analysis and no part&#xD;
      of the specimen will be retained per policy of Quest Diagnostics.&#xD;
&#xD;
      Genotyping for Taq1 A and Taq1B polymorphisms. Participants who consent to this aspect of the&#xD;
      study will be genotyped for the A1 and B1 alleles, using the PCR method [64] A sample of&#xD;
      approximately 5 ml of the participant's blood is required and will be drawn simultaneously&#xD;
      with the 20-week health assessment labs. Studies suggest that the A1 allele of the Taq1A&#xD;
      polymorphism (rs1800497), located ≈10 kb downstream of the D2 dopamine receptor (DRD2) gene,&#xD;
      may influence dietary behavior and response to treatment. Individuals with the A1 allele&#xD;
      generally have a lower-than-normal complement of dopamine receptors (DRD2) in the human&#xD;
      brain, and are more likely than others to engage in smoking, substance abuse, and compulsive&#xD;
      gambling [65]. The prevalence of A1 and B1 alleles of the DRD2 gene is strongly associated&#xD;
      with severe alcoholism [66]. Further, the A1 allele is also common among obese individuals&#xD;
      [67]. We identified this allele in approximately half of individuals with type 2 diabetes&#xD;
      participating in a research study [68]. The possibility that genetic factors may influence&#xD;
      dietary behavior may mean that extended support is essential for facilitating dietary&#xD;
      transitions among many, if not all, individuals with diabetes. In group settings, support can&#xD;
      be engaging and cost effective. The blood test will be drawn once, at the 20-week health&#xD;
      assessment only. This test will be optional. If participants decide not to do the test, it&#xD;
      will not affect their status in the study. The blood samples that are collected will be used&#xD;
      for TaqA1 allele testing for this study only. All samples will be destroyed after analysis&#xD;
      and no part of the specimen will be retained per policy of The Biological Samples Processing&#xD;
      Core Facility (BSPC) at the University of California, Los Angeles (UCLA).&#xD;
&#xD;
      Skin biopsy. A single skin biopsy (3 millimeters in diameter and 4 millimeters in depth) will&#xD;
      be removed from one of three sites on the leg at baseline and 20 week health assessment, as&#xD;
      well as at one year follow up. The epidermal nerve fiber density test is the only objective&#xD;
      test currently available for assessing small fiber neuropathy. A physician or experienced&#xD;
      health care professional will clean the skin with alcohol pads and anaesthetize the skin by&#xD;
      administering 2% lidocaine with epinephrine. The biopsy will be performed using a 3mm&#xD;
      disposable, circular punch. The biopsies will be immediately placed in a fixative container,&#xD;
      and then placed into a cooler with an ice pack. The samples will then be shipped for&#xD;
      analysis.&#xD;
&#xD;
      2-day dietary record: A 2-day dietary record will be used to assess macro- and micronutrient&#xD;
      intakes. Participants will be given the option to complete a manual or online version&#xD;
      (online: http://riskfactor.cancer.gov/tools/instruments/asa24/) for collecting and&#xD;
      calculating diet and nutrient intake. Participants will need Internet access if they choose&#xD;
      to do an online version. If necessary, digitized records will be analyzed using Nutrition&#xD;
      Data Systems for Research software (University of Minnesota), by a registered dietitian&#xD;
      certified by the Nutrition Coordinating Center.&#xD;
&#xD;
      24-Hour Multi-Pass Dietary Recalls. At weeks 3 and 12, a registered dietitian will make&#xD;
      unannounced telephone calls to each participant to administer a 24-hour diet recall, using a&#xD;
      multi-pass approach (Nutrition Coordinating Center, University of Minnesota, Minneapolis,&#xD;
      MN). These recalls will not be subjected to statistical analysis, but will allow the&#xD;
      investigators to check for poor adherence. The ASA-24 is a software tool developed by&#xD;
      National Cancer Institute. It enables automated and self-administered 24-hour dietary&#xD;
      recalls. The format and design of ASA-24 are based on a modified version of the&#xD;
      interviewer-administered Automated Multiple Pass Method (AMPM) 24-hour recall developed by&#xD;
      the U.S. Department of Agriculture. Participants will be provided a user name, password, and&#xD;
      link to the ASA-24 online diet recall Web site.&#xD;
&#xD;
      The Eating Inventory is a highly reliable 51-item questionnaire providing quantitative&#xD;
      measures of dietary restraint, disinhibition, and hunger. It will serve as a gauge of ease in&#xD;
      adapting to the intervention diet.&#xD;
&#xD;
      The International Physical Activity Questionnaire short form assesses recent physical&#xD;
      activity patterns. The method is highly reliable; an assessment of test-retest repeatability&#xD;
      produced a correlation of 0.8.&#xD;
&#xD;
      The Clinical Epidemiologic Studies Depression Scale-Revised (CESD-R) assesses mood. The CES-D&#xD;
      is a 20-item self-report measure designed originally for use among the general population. It&#xD;
      measures the frequency with which participants have experienced a specific symptom within the&#xD;
      preceding week, using a four-point rating scale.&#xD;
&#xD;
      The Beck Depression Inventory II (BDI-II) assesses mood. It is the most widely used&#xD;
      instrument for detecting depression. The questions on the BDI-II are in alignment with DSM-IV&#xD;
      criteria. Each item is a list of four statements arranged in increasing severity about a&#xD;
      particular symptom of depression.&#xD;
&#xD;
      Overall quality of life will be assessed using the SF-36, which is a brief health survey with&#xD;
      36 questions. The SF-36 provides psychometrically-based physical and mental health summary&#xD;
      measures. The SF-36 is a general measure that has been administered across various age&#xD;
      groups, disease spectra, and treatment regimens. Items on the SF-36 are scored on a scale of&#xD;
      0-100, with a higher score indicating better health-related quality of life.&#xD;
&#xD;
      Medications. Participants in both groups will be asked to keep their medications constant and&#xD;
      to add no new nutritional supplements to their current medication regimen, except as&#xD;
      recommended by their personal physicians.&#xD;
&#xD;
      The interventions for the diet and supplement group and supplement-only group are described&#xD;
      below:&#xD;
&#xD;
        -  The diet and supplement group will be asked to follow a low-fat, vegan diet and take a&#xD;
           daily vitamin B12 supplement of 1000mcg of methylcobalamin for 20 weeks. According to&#xD;
           the American Dietetic Association, vegan and vegetarian diets meet all nutritional&#xD;
           requirements when appropriately planned.The diet consists of whole grains, vegetables,&#xD;
           legumes, and fruits, with no restriction on energy intake. Animal products, added oils,&#xD;
           and sugars will be excluded. In choosing grain products and starchy vegetables (e.g.,&#xD;
           bread, potatoes), participants will be encouraged to select those retaining their&#xD;
           natural fiber and having a glycemic index &lt;70, using tables standardized to a value of&#xD;
           100 for glucose. No meals will be provided. Participants will handle their own food&#xD;
           preparation and purchases, with guidance from the research team.&#xD;
&#xD;
        -  Participants will be provided with a commercially available supplement containing&#xD;
           vitamin B12 and asked to take it daily during the study. Should they wish to continue&#xD;
           the diet thereafter, they will be counseled to use any standard multivitamin or other&#xD;
           reliable source of vitamin B12.&#xD;
&#xD;
        -  The supplement-only group will follow an unrestricted diet, but will be given the&#xD;
           identical vitamin B12 supplement of 1000mcg of methylcobalamin as the diet group.&#xD;
&#xD;
      Before randomization, participants will be told that they will either be assigned to a diet&#xD;
      and supplement intervention group or a supplement-only group.&#xD;
&#xD;
      For both groups, alcoholic beverages will be limited to one per day for women, and two for&#xD;
      men.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">February 2014</completion_date>
  <primary_completion_date type="Actual">February 2014</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>Supportive Care</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pain</measure>
    <time_frame>20 weeks</time_frame>
    <description>Pain will be measured follow the baseline and 20 week score using n the following assessment tools:&#xD;
Michigan Neuropathy Screening Instrument&#xD;
Norfolk Quality of Life Questionnaire&#xD;
Neuropathy Impairment Score - Lower Limbs&#xD;
Neuropathy Total Symptom Score 6&#xD;
Neuropathy Pain Scale&#xD;
McGill Pain Questionnaire&#xD;
Global Impression Scale</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Sensation</measure>
    <time_frame>20 weeks</time_frame>
    <description>Sensation will be measured follow the baseline and 20 week score using the following assessment tools:&#xD;
Michigan Neuropathy Screening Instrument&#xD;
Norfolk Quality of Life Questionnaire&#xD;
Neuropathy Impairment Score - Lower Limbs&#xD;
Neuropathy Total Symptom Score 6</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Disease activity</measure>
    <time_frame>20 weeks</time_frame>
    <description>Disease activity will be measured by change in small fiber density of lower limbs as measured by skin biospy done at baseline and 20 weeks.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Glycemic control</measure>
    <time_frame>20 weeks</time_frame>
    <description>Glycemic control will be measured by change in hemoglobin A1c percentage points at baseline and 20 weeks.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mood</measure>
    <time_frame>20 weeks</time_frame>
    <description>Mood will be measured by change in score using the following assessment tools at baseline and 20 weeks:&#xD;
Beck Depression Inventory&#xD;
Center for Epidemiologic Studies Depression Scale Revised</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Quality of life</measure>
    <time_frame>20 weeks</time_frame>
    <description>Quality of Life will be measured by change in score using the following assessment tools at baseline and 20 weeks:&#xD;
Norfolk Quality of Life Questionnaire&#xD;
MOS SF-36 Questionnaire</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Acceptability of vegan diet</measure>
    <time_frame>20 weeks</time_frame>
    <description>Acceptability of vegan diet will be measured by change in score at baseline and 20 weeks using the Eating Inventory questionnaire.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Diabetic Neuropathy</condition>
  <arm_group>
    <arm_group_label>Vegan diet and vitamin B12 supplement</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The diet/supplement group will be asked to follow a low-fat, vegan diet for 20 weeks, and take a vitamin B12 supplement daily.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vitamin B12 supplement</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The supplement group will be asked to take a daily vitamin B12 supplement, and to make no changes to their current diet.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Vegan diet and vitamin B12 supplement</intervention_name>
    <description>A low-fat, vegan diet (no meat, fish, eggs or dairy products) and a vitamin B12 supplement in the form of 2000mcg of methylcobalamin</description>
    <arm_group_label>Vegan diet and vitamin B12 supplement</arm_group_label>
    <other_name>Vegan diet</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Vitamin B12 supplement</intervention_name>
    <description>A daily vitamin B12 supplement in the form of 2000mcg of methylcobalamin</description>
    <arm_group_label>Vitamin B12 supplement</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men and women age 18 - 65 years old&#xD;
&#xD;
          -  A diagnosis of type 2 diabetes&#xD;
&#xD;
          -  A diagnosis of diabetic neuropathy for at least 6 months or symptoms of diabetic&#xD;
             neuropathy for at least 6 months&#xD;
&#xD;
          -  Score of greater than 2 on the Michigan Neuropathy Screening Instrument&#xD;
&#xD;
          -  Score of greater than 6on the Norfolk Quality of Life Questionnaire&#xD;
&#xD;
          -  Score of greater than 2 on the Neuropathy Impairment Score for Lower Limbs (NIS-LL)&#xD;
&#xD;
          -  Score of greater than 1 on the Neuropathy Total Symptom Score 6 (NTSS-6)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Vitamin B12 deficiency&#xD;
&#xD;
          -  Alcohol consumption of more than 2 drinks per day or the equivalent, episodic&#xD;
             increased drinking (e.g., more than 2 drinks per day on weekends), or a history of&#xD;
             alcohol abuse or dependency followed by any current use&#xD;
&#xD;
          -  Use of recreational drugs in the past 6 months (past drug use, if fully recovered, is&#xD;
             not a criteria for exclusion)&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Unstable medical or psychiatric illness&#xD;
&#xD;
          -  Likely to be disruptive in group sessions (as determined by research staff)&#xD;
&#xD;
          -  Already following a low-fat, vegan diet&#xD;
&#xD;
          -  Lack of English fluency&#xD;
&#xD;
          -  Inability to maintain current medication regimen&#xD;
&#xD;
          -  Inability or unwillingness to participate in all components of the study&#xD;
&#xD;
          -  Sensitivity to lidocaine or epinephrine (or their preservatives)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Neal Barnard, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Physicians Committee for Responsible Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Physicians Committee for Responsible Medicine</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2014</verification_date>
  <study_first_submitted>September 17, 2012</study_first_submitted>
  <study_first_submitted_qc>September 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 24, 2012</study_first_posted>
  <last_update_submitted>September 2, 2014</last_update_submitted>
  <last_update_submitted_qc>September 2, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 4, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>diabetic neuropathy, diet, vegan, vegetarian</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Peripheral Nervous System Diseases</mesh_term>
    <mesh_term>Diabetic Neuropathies</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamins</mesh_term>
    <mesh_term>Hydroxocobalamin</mesh_term>
    <mesh_term>Vitamin B 12</mesh_term>
    <mesh_term>Vitamin B Complex</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01690962
org study id: PCRM DN-1
nct id: NCT01690962
lead sponsor: 
has dmc: Yes
The purpose of this study is to assess whether, in individuals with diabetic neuropathy, a
      low-fat, vegan diet in combination with a vitamin B12 supplement improves pain, sensation and
      other subjective symptoms, more effectively than a vitamin B12 supplement with no diet
      changes. The principal measure is pain as measured by the following assessment tools:
      Michigan Neuropathy Screening Instrument, Norfolk Quality of Life Questionnaire, Neuropathy
      Impairment Score - Lower Limbs, Neuropathy Total Symptom Score, Neuropathy Pain Scale, McGill
      Pain Questionnaire and Global Impression Scale. The study duration is 20 weeks.

      This study also examines the effects of a low-fat, vegan diet on mood, using the Center for
      Epidemiologic Studies Depression Scale-Revised, and the Beck Depression Inventory.
The following determinations will be made at baseline, mid-point, and end of each 20-week
      study period, as well as at one-year follow up:

      General status, symptoms, and medication accounting. Participants will be asked to report
      changes in their health and medication use.

      Disease Activity. The following assessments will be used to measure pain and changes in
      sensory perception related to diabetic neuropathy:

        -  Michigan Neuropathy Screening Instrument. The MNSI questionnaire consists of 15
           questions followed by a single 8-point clinical examination involving inspection of the
           foot, assessment of ankle reflexes, and semi-quantitative determination of vibration
           perception.

        -  Norfolk Quality of Life Questionnaire Norfolk QOL-DN is a 47-item questionnaire
           developed by the Eastern Virginia Medical School, Norfolk, VA, for assessing subjects'
           perception of the effects of diabetes and diabetic neuropathy. It consists of 28 items
           pertaining specifically to to small fiber, large fiber and autonomic nerve function
           symptoms, and activities of daily living (ADL).

        -  Neuropathy Impairment Score for Lower Limbs (NIS-LL) The NIS-LL is the lower limb
           component of the full Neuropathy Impairment Score (NIS) and has 3 domains including:
           muscle weakness, reflexes, and sensation. The maximum score is 88 points. Based on
           experience with and data collected from these clinical trials, the Peripheral Nerve
           Society considers a 2 point change on the NIS-LL to correspond to a meaningful change in
           clinical status.

        -  Neuropathy Total Symptoms Score (NTSS-6) Neuropathy total symptom score-6 (NTSS-6) is a
           neuropathy sensory symptom scale that is designed to evaluate the frequency and
           intensity of individual neuropathy sensory symptoms identified frequently by patients
           with DPN. A total of six questions are synthesized to identify and quantify the specific
           positive and negative symptoms associated with sensory deficits in patients.

        -  Neuropathy Pain Scale In order to assess and differentiate qualities of pain, Galer and
           Jensen developed the Neuropathic Pain Scale (NPS) in 1997. The NPS is composed of 10
           items that assess two global pain domains including pain intensity and unpleasantness,
           and six pain qualities, including sharp, hot, dull, cold, sensitive, and itchy pain, in
           two dimensions (internal and cutaneous).

        -  McGill Pain Questionnaire The McGill Pain Questionnaire (MPQ) is used to specify
           subjective pain experience using sensory, affective and evaluative word descriptors. The
           short form of the McGill Pain Questionnaire (SF-MPQ) contains 11 questions referring to
           the sensory dimension of the pain experience and four related to the affective
           dimension.

        -  Global Impression Scale Global impression scale (GIS) is also termed global rating of
           change scales (GRC) and was developed to assess patients' overall improvement or
           deterioration in a clinical setting, and has been frequently used in musculoskeletal and
           chronic pain trials.

      Height. Height will be measured at baseline (only) with participants standing barefoot with
      their backs to a wall-mounted stadiometer and heels against the wall, recorded to the nearest
      0.5 cm.

      Body weight. With participants wearing light, indoor clothing but without shoes, body weight
      will be measured to the nearest 0.1 kg, using a digital scale.

      Blood pressure. A digital blood pressure monitor and a cuff of a size appropriate to the
      participant's arm will be used. The cuff size for each participant will be recorded for
      consistency of use at each visit. Participants will be asked to remove all clothing that
      covers the location of cuff placement and then rest in a seated position for 5 minutes with
      legs uncrossed, without talking or reading. The back and arm will be supported such that the
      middle of the cuff on the upper arm is at the level of the right atrium (the mid-point of the
      sternum). Three measurements will be taken at 1-minute intervals. The first measurement will
      be disregarded, and the mean of the remaining 2 measurements will be calculated.

      Serum cholesterol and triacylglycerol concentrations will be measured using the Olympus
      Cholesterol Reagent on Olympus Chemistry Analyzers. HDL-cholesterol will be measured directly
      using the HDL-C plus 3rd generation test with the Roche direct HDL-cholesterol assay.Low
      density lipoprotein cholesterol (LDL-C) concentration will be estimated using the Friedewald
      equation. Plasma triglyceride levels will be measured using Olympus Chemistry analyzers from
      Quest Diagnostics.

      Comprehensive Metabolic Panel. These values will be evaluated at baseline, 20 weeks, and
      one-year follow-up.

      Hemoglobin A1c. Hemoglobin A1c will be measured in whole blood using the COBAS INTEGRA on
      Roche clinical chemistry analyzers.

      Glucose. Plasma glucose will be measured using an Olympus Chemistry Analyzer from Quest
      Diagnostics, Baltimore, MD, USA.

      Urinary albumin and creatinine will be assessed on spot urine samples. Samples for the
      albumin assay will be tested using the K-Assay High-Sensitive Microalbumin assay from Quest
      Diagnostics.

      Apolipoprotein E (APOE): Participants who consent to this aspect of the study will be
      genotyped for the ε2, ε3, and ε4 alleles. A sample of approximately 5 ml of the participant's
      blood is required and will be drawn simultaneously with the 20-week health assessment labs.
      Individuals with diabetes are at greatly increased risk of developing Alzheimer's disease,
      and some studies have suggested that the effect of saturated fat intake on Alzheimer's risk
      may be most evident in (or even limited to) carriers of the APOEε4 allele. The ApoE protein
      produced by the APOE gene is a major plasma apolipoprotein and the primary cholesterol
      carrier in the brain [62]. As a group, these individuals have higher plasma LDL
      concentrations, compared with APOEε3 homozygotes [63] Moreover, APOE status may influence the
      relationship between dietary intake and plasma lipid concentrations [63]. APOE determination
      may provide useful information as to who benefits from dietary changes that aim to modify
      plasma lipid concentrations, with implications for subsequent risk of cardiovascular disease
      and Alzheimer's disease. The blood test will be drawn once, at the 20-week health assessment
      only. This test will be optional. If participants decide not to do the test, it will not
      affect their status in the study. The blood samples that are collected will be used for APOE
      allele testing for this study only. All samples will be destroyed after analysis and no part
      of the specimen will be retained per policy of Quest Diagnostics.

      Genotyping for Taq1 A and Taq1B polymorphisms. Participants who consent to this aspect of the
      study will be genotyped for the A1 and B1 alleles, using the PCR method [64] A sample of
      approximately 5 ml of the participant's blood is required and will be drawn simultaneously
      with the 20-week health assessment labs. Studies suggest that the A1 allele of the Taq1A
      polymorphism (rs1800497), located ≈10 kb downstream of the D2 dopamine receptor (DRD2) gene,
      may influence dietary behavior and response to treatment. Individuals with the A1 allele
      generally have a lower-than-normal complement of dopamine receptors (DRD2) in the human
      brain, and are more likely than others to engage in smoking, substance abuse, and compulsive
      gambling [65]. The prevalence of A1 and B1 alleles of the DRD2 gene is strongly associated
      with severe alcoholism [66]. Further, the A1 allele is also common among obese individuals
      [67]. We identified this allele in approximately half of individuals with type 2 diabetes
      participating in a research study [68]. The possibility that genetic factors may influence
      dietary behavior may mean that extended support is essential for facilitating dietary
      transitions among many, if not all, individuals with diabetes. In group settings, support can
      be engaging and cost effective. The blood test will be drawn once, at the 20-week health
      assessment only. This test will be optional. If participants decide not to do the test, it
      will not affect their status in the study. The blood samples that are collected will be used
      for TaqA1 allele testing for this study only. All samples will be destroyed after analysis
      and no part of the specimen will be retained per policy of The Biological Samples Processing
      Core Facility (BSPC) at the University of California, Los Angeles (UCLA).

      Skin biopsy. A single skin biopsy (3 millimeters in diameter and 4 millimeters in depth) will
      be removed from one of three sites on the leg at baseline and 20 week health assessment, as
      well as at one year follow up. The epidermal nerve fiber density test is the only objective
      test currently available for assessing small fiber neuropathy. A physician or experienced
      health care professional will clean the skin with alcohol pads and anaesthetize the skin by
      administering 2% lidocaine with epinephrine. The biopsy will be performed using a 3mm
      disposable, circular punch. The biopsies will be immediately placed in a fixative container,
      and then placed into a cooler with an ice pack. The samples will then be shipped for
      analysis.

      2-day dietary record: A 2-day dietary record will be used to assess macro- and micronutrient
      intakes. Participants will be given the option to complete a manual or online version
      (online: http://riskfactor.cancer.gov/tools/instruments/asa24/) for collecting and
      calculating diet and nutrient intake. Participants will need Internet access if they choose
      to do an online version. If necessary, digitized records will be analyzed using Nutrition
      Data Systems for Research software (University of Minnesota), by a registered dietitian
      certified by the Nutrition Coordinating Center.

      24-Hour Multi-Pass Dietary Recalls. At weeks 3 and 12, a registered dietitian will make
      unannounced telephone calls to each participant to administer a 24-hour diet recall, using a
      multi-pass approach (Nutrition Coordinating Center, University of Minnesota, Minneapolis,
      MN). These recalls will not be subjected to statistical analysis, but will allow the
      investigators to check for poor adherence. The ASA-24 is a software tool developed by
      National Cancer Institute. It enables automated and self-administered 24-hour dietary
      recalls. The format and design of ASA-24 are based on a modified version of the
      interviewer-administered Automated Multiple Pass Method (AMPM) 24-hour recall developed by
      the U.S. Department of Agriculture. Participants will be provided a user name, password, and
      link to the ASA-24 online diet recall Web site.

      The Eating Inventory is a highly reliable 51-item questionnaire providing quantitative
      measures of dietary restraint, disinhibition, and hunger. It will serve as a gauge of ease in
      adapting to the intervention diet.

      The International Physical Activity Questionnaire short form assesses recent physical
      activity patterns. The method is highly reliable; an assessment of test-retest repeatability
      produced a correlation of 0.8.

      The Clinical Epidemiologic Studies Depression Scale-Revised (CESD-R) assesses mood. The CES-D
      is a 20-item self-report measure designed originally for use among the general population. It
      measures the frequency with which participants have experienced a specific symptom within the
      preceding week, using a four-point rating scale.

      The Beck Depression Inventory II (BDI-II) assesses mood. It is the most widely used
      instrument for detecting depression. The questions on the BDI-II are in alignment with DSM-IV
      criteria. Each item is a list of four statements arranged in increasing severity about a
      particular symptom of depression.

      Overall quality of life will be assessed using the SF-36, which is a brief health survey with
      36 questions. The SF-36 provides psychometrically-based physical and mental health summary
      measures. The SF-36 is a general measure that has been administered across various age
      groups, disease spectra, and treatment regimens. Items on the SF-36 are scored on a scale of
      0-100, with a higher score indicating better health-related quality of life.

      Medications. Participants in both groups will be asked to keep their medications constant and
      to add no new nutritional supplements to their current medication regimen, except as
      recommended by their personal physicians.

      The interventions for the diet and supplement group and supplement-only group are described
      below:

        -  The diet and supplement group will be asked to follow a low-fat, vegan diet and take a
           daily vitamin B12 supplement of 1000mcg of methylcobalamin for 20 weeks. According to
           the American Dietetic Association, vegan and vegetarian diets meet all nutritional
           requirements when appropriately planned.The diet consists of whole grains, vegetables,
           legumes, and fruits, with no restriction on energy intake. Animal products, added oils,
           and sugars will be excluded. In choosing grain products and starchy vegetables (e.g.,
           bread, potatoes), participants will be encouraged to select those retaining their
           natural fiber and having a glycemic index <70, using tables standardized to a value of
           100 for glucose. No meals will be provided. Participants will handle their own food
           preparation and purchases, with guidance from the research team.

        -  Participants will be provided with a commercially available supplement containing
           vitamin B12 and asked to take it daily during the study. Should they wish to continue
           the diet thereafter, they will be counseled to use any standard multivitamin or other
           reliable source of vitamin B12.

        -  The supplement-only group will follow an unrestricted diet, but will be given the
           identical vitamin B12 supplement of 1000mcg of methylcobalamin as the diet group.

      Before randomization, participants will be told that they will either be assigned to a diet
      and supplement intervention group or a supplement-only group.

      For both groups, alcoholic beverages will be limited to one per day for women, and two for
      men.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Supportive Care
masking: None (Open Label)
measure: Pain
time frame: 20 weeks
description: Pain will be measured follow the baseline and 20 week score using n the following assessment tools:
Michigan Neuropathy Screening Instrument
Norfolk Quality of Life Questionnaire
Neuropathy Impairment Score - Lower Limbs
Neuropathy Total Symptom Score 6
Neuropathy Pain Scale
McGill Pain Questionnaire
Global Impression Scale
measure: Sensation
time frame: 20 weeks
description: Sensation will be measured follow the baseline and 20 week score using the following assessment tools:
Michigan Neuropathy Screening Instrument
Norfolk Quality of Life Questionnaire
Neuropathy Impairment Score - Lower Limbs
Neuropathy Total Symptom Score 6
measure: Disease activity
time frame: 20 weeks
description: Disease activity will be measured by change in small fiber density of lower limbs as measured by skin biospy done at baseline and 20 weeks.
measure: Glycemic control
time frame: 20 weeks
description: Glycemic control will be measured by change in hemoglobin A1c percentage points at baseline and 20 weeks.
measure: Mood
time frame: 20 weeks
description: Mood will be measured by change in score using the following assessment tools at baseline and 20 weeks:
Beck Depression Inventory
Center for Epidemiologic Studies Depression Scale Revised
measure: Quality of life
time frame: 20 weeks
description: Quality of Life will be measured by change in score using the following assessment tools at baseline and 20 weeks:
Norfolk Quality of Life Questionnaire
MOS SF-36 Questionnaire
measure: Acceptability of vegan diet
time frame: 20 weeks
description: Acceptability of vegan diet will be measured by change in score at baseline and 20 weeks using the Eating Inventory questionnaire.
arm group label: Vegan diet and vitamin B12 supplement
arm group type: Experimental
description: The diet/supplement group will be asked to follow a low-fat, vegan diet for 20 weeks, and take a vitamin B12 supplement daily.
arm group label: Vitamin B12 supplement
arm group type: Active Comparator
description: The supplement group will be asked to take a daily vitamin B12 supplement, and to make no changes to their current diet.
intervention type: Other
intervention name: Vegan diet and vitamin B12 supplement
description: A low-fat, vegan diet (no meat, fish, eggs or dairy products) and a vitamin B12 supplement in the form of 2000mcg of methylcobalamin
arm group label: Vegan diet and vitamin B12 supplement
other name: Vegan diet
intervention type: Dietary Supplement
intervention name: Vitamin B12 supplement
description: A daily vitamin B12 supplement in the form of 2000mcg of methylcobalamin
arm group label: Vitamin B12 supplement
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Neal Barnard, MD
role: Principal Investigator
affiliation: Physicians Committee for Responsible Medicine
facility: 
country: United States
responsible party type: Sponsor
mesh term: Peripheral Nervous System Diseases
mesh term: Diabetic Neuropathies
mesh term: Vitamins
mesh term: Hydroxocobalamin
mesh term: Vitamin B 12
mesh term: Vitamin B Complex