Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01953757 |
| Other study ID # |
PCRM DN-2 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
September 26, 2013 |
| Last updated |
April 24, 2015 |
| Start date |
September 2013 |
| Est. completion date |
March 2015 |
Study information
| Verified date |
April 2015 |
| Source |
Physicians Committee for Responsible Medicine |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Institutional Review Board |
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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).
All participants will undergo assessment of peripheral autonomic neuropathy via SUDOSCAN
testing. SUDOSCAN is an FDA cleared device to assess Galvanic Skin Response (Sudoscan has
510(k) clearance, which is a premarketing submission made to FDA to demonstrate that the
device to be marketed is as safe and effective, that is, substantially equivalent (SE), to a
legally marketed device that is not subject to premarket approval). Previous work has shown
that galvanic skin response is a promising, sensitive, simple tool for detecting diabetic
neuropathy, because the production of perspiration depends on the presence of functional
small nerve fibers. One study of 83 diabetic patients and 210 healthy controls showed that
the Sudoscan measurement showed a sensitivity of 78% and a specificity of 92%, which is as
good as or better than clinical evaluation methods.48 In addition, test-retest reliability
is very high, especially for the feet.49 A study of 167 type 1 and type 2 diabetics showed
that galvanic skin response improved after 1 year of intense insulin therapy.49 This method
is appropriate for inclusion in this study because it is a non-invasive, objective way to
assess neurological function. Participants will place both palms and soles on large area
stainless-steel electrodes and stand still for the 3-minute scan. A low voltage (<4V) is
applied incrementally to the electrodes, generating a current (around 0.2mA) proportional to
the chloride ions in the sweat glands of the palms and soles. The electrochemical skin
conductance measured in microSiemens for each foot and each hand will be recorded by the
SUDOSCAN.
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.
