Safety and Tolerability of Soy Fiber in the Elderly: A Dose Escalation Study
Phase: NA
Conditions: Safety Issues, Tolerance
Sponsor: Pennington Biomedical Research Center

Protocol Title: Safety and Tolerability of Soy Fiber in the Elderly: A Dose Escalation Study
PI Name: Candida Rebello, PhD, RD
Sub-Investigator: John Kirwan, PhD
Sub-Investigator: Jeffrey Keller, PhD
Medical Investigator: Frank Greenway, MD
Protocol Version Date: March 4, 2022
 
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Abstract
Background
Apathy, defined as the absence or lack of motivation and emotional detachment, is a clinical 
feature of depression. Depressive symptoms and insulin resistance are conditions that are 
interdependent. We hypothesize that increasing insulin sensitivity in apathetic insulin resistant 
individuals will reduce apathy. Our preliminary studies show that a low glycemic index (GI) diet 
and exercise (D+E) intervention for seven days and 12 weeks increases insulin sensitivity in 
older adults with obesity. The key feature of a low GI diet is its high dietary fiber (DF) content. In 
preparation for an efficacy trial, we will conduct a dose escalation trial in the elderly with obesity 
and determine the maximum tolerated dose of a novel DF from whole young soy pods (soy) 
delivered in soft foods.
Design and Method
Aim
Determine the maximum tolerated dose of dietary fiber from soy in elderly subjects with obesity 
and measure fecal short chain fatty acids (SCFA) as a biomarker of compliance.
Hypothesis
Since this is a dose finding study there is no hypothesis for the maximum tolerated dose; 
however, fecal SCFA will increase with the dose.
Study Design
We propose to conduct a dose escalation trial. We will test the tolerability to 10 g, 20 g, and 30 
g of soy containing 4 g, 8 g, and 12 g of DF respectively. At each dose, eight subjects will 
incorporate the foods into their usual diet for one week. We will evaluate tolerability to each 
dose and measure fecal SCFA as a biomarker of compliance. Subjects who satisfy the eligibility 
criteria and express willingness to consume the study foods will be enrolled. 
At baseline, weight and vital signs will be measured. Subjects will provide a stool sample 
collected within the last 48 hours and frozen in containers provided for the purpose. Part of the 
fecal samples will be archived for future analysis. The study dietitian will interview each subject 
in order to assess the subject’s current intake. Based on this information, subjects will be 
counseled on incorporating the study foods in their diet with the appropriate fluid intake. 
Subjects will receive the study foods containing 4g DF/10g soy/day for one week and complete 
a tolerability questionnaire.
Subjects will consume the soft foods containing soy along with their regular diet for one week, 
and will be advised to return all used and unused containers at the end of the week. Compliance 
will be assessed from an interview with the subject and an evaluation of used and unused 
containers returned by subjects. Pre-intervention tests and measures will be repeated, and 
adverse events will be recorded. If a dose is tolerated, subjects will receive the next escalated 
dose for one week (8 g DF/20 g soy/day or 12 g DF/30 g soy/day). At the end of each subject’s 
participation in the study, a fasting blood sample will be drawn for evaluation of CBC, and blood 
chemistry panel as safety markers.
The results of the present study will guide the design and implementation of a clinical trial to 
determine the effect of a low GI D+E program on insulin sensitivity and apathy in elderly 
subjects with obesity and insulin resistance. These results will be significant, in that they will 
potentially provide a cost-effective intervention that will substantially improve the health and 
quality of life for the growing number of elderly individuals with obesity who have developed 
insulin resistance and apathy.
 
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DESCRIPTION AND RATIONALE
The US population is expected to be comprised of approximately 24% older adults (> 65 years) 
by 2050.1 More than 35% of US adults over 60 years of age are obese and nearly half of older 
adults are insulin resistant.2 Depressive symptoms, which have an incidence of 6.8 per 100 
person-years in the elderly (> 70 years),3 and insulin resistance are conditions that are 
interdependent;4,5 yet, the effect of 
improving insulin sensitivity on 
depressive symptoms such as apathy 
has not been investigated.
Apathy. Apathy is a motivation 
disorder that results in diminished goal directed behavior, lack of concern about one’s health, 
and emotional indifference.6 Apathy occurs in more than 
30% of individuals with major depression and is most 
prevalent in depressed older adults.7,8 The prevalence of 
apathy in the absence of clinical depression in cognitively-
intact older adults (Geriatric Depression Scale [GDS] endorsed apathy items ≥ 2) ranges from 
14% to 26%.9,10 Impaired glucose metabolism is associated with depressive symptoms, 
particularly in the elderly11-15 (Figure 1). The biological link between depression and insulin 
resistance appears to be an overactive dysregulated hypothalamic-pituitary-adrenal (HPA) axis. 
The resulting hypercortisolemia promotes obesity and insulin resistance.11,16 Since insulin 
resistance and depressive symptoms are interdependent,4,5 improving insulin sensitivity has 
therapeutic potential in the treatment of apathy. The presence of apathy predicts chronicity of 
depression, poor response of depressive symptoms to treatment, and it is associated with 
disability that transcends the rest of the depressive syndrome.7,17-19 Apathy is a source of 
significant burden on the caregiver and current interventions lack the precision needed to 
address apathy and its underlying mechanisms.20  Identifying distinct pathways for intervention 
will guide the course of treatment and facilitate customized interventions for a pressing, unmet, 
aging need. 
Exercise and Insulin Resistance. The literature supports the benefits of exercise on insulin 
sensitivity in the overweight and obese elderly.21-24 Different doses of aerobic exercise ranging 
from 90 minutes/week to 300 minutes/week have been shown to improve insulin sensitivity. 
Adherence to the exercise prescription varies across the studies and the dose that would most 
likely foster compliance with a regimen, and yet be effective, remains unclear. The appropriate 
exercise regimen for older insulin resistant individuals that will be of relevance in real-world 
clinical practice settings constitutes a significant gap in the literature. Further, the effects of 
exercise on apathy are unexplored; but, evidence lends support to the usefulness of exercise in 
treating depression and preventing its onset.25-27 
Diet and Insulin Resistance. Some food sources of carbohydrates have a lower potential to 
raise blood glucose concentrations than other carbohydrate-rich food sources. This potential of 
individual foods, is measured by the glycemic index (GI), which provides a numerical value to 
represent the effect of the food on blood glucose concentrations.28,29 In a tightly controlled study, 
a low GI diet and exercise (D+E) based lifestyle intervention for 12 weeks improved insulin 
sensitivity in obese insulin resistant older adults.30 Supplementing the high GI diet with dietary 
fiber (DF) produced similar results.30 The key feature of the low GI diet is its high DF content. 
Another randomized controlled trial (RCT) showed that a low GI diet that included legumes high 
in soluble DF reduced glycosylated hemoglobin (HbA1C) in subjects with type 2 diabetes, but the 
improvements in glycemia did not differ from a regular diet high in insoluble wheat DF.31 Thus, 
the DF content of a low GI diet appears to be an important mediator of its effects on glucose 
metabolism. 
Figure 1. Relationship between 
insulin resistance and apathy
 
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Dietary Fiber in Soybean. The whole pods of young soybean (edamame) provide 
approximately four times the DF in an equivalent amount of the green soybean.32 A high-DF diet 
prevents the stress related rise in cortisol.33,34,35,36 The majority of the clinical and epidemiologic 
evidence supports the anti-depressive effects of diets high in soybeans.37  Observational studies 
in Asian populations showed an association between soybean consumption and reduced 
incidence of type 2 diabetes and cardiovascular disease.38-40 A meta-analysis of nine RCTs 
determined that consumption of whole soy products, reduced hyperglycemia.41 Including 
soybean in a Western diet in the amounts consumed in Asian cultures poses a challenge. 
However, milled to a flour the whole pods of young soybean (soy) taste like other legume flours, 
and contain far more DF. Moreover, soy contains DF, protein, isoflavones, and phytochemicals 
in their original proportions. In rodents, soy increases fecal fat and glucose excretion, and the 
synthesis of short chain fatty acids (SCFA).42 Therefore, we hypothesize that soy will potentiate 
the effects of a low GI diet on insulin sensitivity. 
Summary. Depressive symptoms, which are common in the elderly (> 70 years), and insulin 
resistance are conditions that predispose to each other. Therefore, improving insulin sensitivity 
may be beneficial in reducing depressive symptoms in the obese elderly. Apathy, being a 
common depressive symptom in the elderly and among individuals with diabetes, represents a 
particularly attractive therapeutic target for interventions designed to improve glucose 
metabolism. A low glycemic index (GI) diet and exercise (D+E) intervention increases insulin 
sensitivity in obese older adults. To maintain the benefits of a low GI diet in the elderly, foods 
must be DF-dense, yet soft and tasty. The effect of whole pods of young soybean (soy) on 
insulin sensitivity has never been explored in humans. In preparation for conducting an efficacy 
trial of the effect of soy on insulin sensitivity, we will first conduct a dose escalation study in an 
elderly population to determine the maximum dose of fiber from soy that wil be tolerated.
HYPOTHESIS AND SPECIFIC AIMS
Edamame or green soybean in the pod has approximately four times more dietary fiber than 
soybean without the pod. The whole soy pod (soy), rich in phytonutrients, increases fecal fat 
and glucose excretion and the synthesis of short chain fatty acids in mice. The majority of the 
clinical and epidemiologic evidence supports the anti-depressive effects of diets high in 
soybeans. In previous controlled feeding and exercise studies, we found that a low GI D+E for 
one week (n = 32) or 12 weeks (n = 22) increases insulin sensitivity in older adults with obesity. 
These data form the basis of a proposal to test the hypothesis that insulin sensitivity mediates 
apathy in depression. No study to date has empirically tested this hypothesis. The success of 
the efficacy trial depends on a determination of the optimal dose of dietary fiber from soy that 
will be tolerated by the elderly. Therefore, the present study will determine the maximum 
tolerated dose of dietary fiber from soy. The results will inform the development of a randomized 
controlled trial (RCT) to test the efficacy of a low GI D+E program (with and without soy) to 
increase insulin sensitivity and reduce apathy in the elderly.
Aim. Determine the maximum tolerated dose of dietary fiber from soy in elderly subjects with 
obesity. This aim requires a dose escalation trial in the elderly with obesity. We will test the 
tolerability to soft foods including 10 g, 20 g, and 30 g of soy containing 4 g, 8 g, and 12 g of 
dietary fiber, respectively. At each dose, eight subjects will consume the foods for one week. 
We will evaluate tolerability to each dose and measure fecal short chain fatty acids as a 
biomarker of compliance with the intervention.
Hypothesis: Since this is a dose finding study there is no hypothesis for the maximum tolerated 
dose; however, fecal short chain fatty acids will increase with the dose.
 
Pennington Biomedical IRB FWA 00006218
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STUDY TIMELINE
This is a dose escalation trial. We expect to complete the study within four months. Each eligible 
subject’s participation in the study will be approximately four weeks. Primary analyses are 
expected to be completed within a month of the study completion.
STUDY ENDPOINTS
Eligible subjects will consume each dose of soy for one week. They will report any adverse 
events and complete a tolerability questionnaire. Our primary aim is to determine the maximum 
tolerated dose. The secondary outcome will be the change in fecal SCFA with each escalating 
dose.
RESEARCH DESIGN AND METHODS
To determine an acceptable dose of DF, we will conduct a dose escalation trial in eight elderly 
subjects with obesity and test the tolerability to soft foods containing 4 g, 8 g, and 12 g of 
DF/day from soy for one week at each dose. The soy contains approximately 39% DF.42 
Therefore, subjects will consume soft foods containing 10 g, 20 g, and 30 g of soy/day to 
provide the required DF doses and the phytonutrients in soy. This clinical trial is patterned 
according to the National Cancer Institute’s (NCI’s) recommendation for dose escalation to 
determine toxicity to a drug.43 We are testing a food, and we know that relatively large doses of 
DF are tolerated if daily intake is divided into small portions throughout the day.44 However, we 
will evaluate tolerability to DF from soy, and measure fecal SCFA as a biomarker of compliance 
with the intervention. The maximum recommended starting dose (MRSD) for DF may be 
estimated at 4 g which added to average DF intake in the US of approximately 17g45 is not in 
excess of the recommended adequate intake of 25 - 38  g/day.46 The dose escalation scheme 
recommended for first-in-human trials is rapid dose escalation initially (MRSD x 2) until the 
estimated desirable dose (8 g) is reached and then at a more cautious escalation (e.g. MRSD x 
1.5).47 Subjects will consume soft foods containing 4 g/day of DF from soy for one week, then 
proceed to 8 g/day for one week, followed by 12 g/day for one week, incorporated into their 
usual diet. 
Adverse events will be recorded as they occur and collated for each week. Fecal SCFA and 
gastrointestinal (GI) symptoms will be evaluated at the end of each week (Figure 2).
 
Study Subjects
This study will enroll 10 healthy adult male and female subjects. Subjects will be enrolled on the 
basis of the following eligibility criteria:
Inclusion Criteria
•
Adult (70 - 85 years).
•
Body mass index between 30 and 40 kg/m2.
•
No evidence of diabetes (fasting blood sugar <126 mg/dL).
•
No evidence of dementia (MMSE score > 25).
Figure 2. Study schema 
 
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•
No evidence of depression (Geriatric Depression Scale-15 [GDS-15] < 6.
•
Are weight stable (< 3 kg weight change in the past three months).
Exclusion Criteria
Subjects will not be eligible for participation if they meet one or more of the following exclusion 
criteria:
•
Have type 1 or type 2 diabetes.
•
Had diagnosis of cancer (within the last five years).
•
Report advanced disease of any major organs.
•
Report clinically significant gastrointestinal malabsorption syndromes such as chronic 
diarrhea, or celiac disease.
•
Have serum triglyceride concentrations > 400 mg/dl.
•
Clinically significant abnormal laboratory markers (as determined by the medical 
investigator).
•
Subjects with anticipated surgery during the study period. 
•
Subjects with a reported history of substance abuse or alcoholism or significant 
psychiatric disorder that would interfere with the ability to complete the study. 
•
Subjects who are current smokers or have smoked within the previous three months. 
Smoking is not permitted during the study. 
•
Subjects who are unable to provide a baseline blood or fecal sample or if they have any 
condition that impedes testing of the study hypothesis or makes it unsafe to consume 
the food being tested in the study (determined by the investigative team).
•
Women on hormone replacement therapy unless weight has been stable over the last 
six months.
Recruitment. Subjects will be recruited through the use of printed material, targeted solicitation 
through the Pennington Biomedical Research Center (PBRC) email listserv and social media. 
Participants will complete an online screening and will be contacted by a PBRC recruiter for a 
brief telephone interview to assess eligibility criteria, prior to being scheduled for a clinic visit. 
Participation will also be solicited with the help of the LA CATS Center community advisory 
board. Subject eligibility criteria will be evaluated at a single screening visit. The screening visit 
will occur in the outpatient clinic, in the morning following confirmation of an overnight (at least 
ten hours) fast. Subjects who provide informed consent will proceed with the tests and 
measurements of the screening visit. Subjects who satisfy the eligibility criteria will be enrolled 
in the study. The schedule of assessments in provided in Table 1.
CLINIC VISITS
Subjects will complete one screening visit. There will be four study visits unless a participant 
is intolerant to a dose and cannot be advanced to the next higher dose. 
Screening Visit (2 hours)
Subjects will report to Pennington Biomedical in the morning following an overnight fast (except 
for water) that began no later than 10 hours prior to the study appointment. The screening visit 
includes explanation of the study purpose, procedures, and signing of the informed consent. If 
the participant agrees to participate by signing a consent form, the following tests and 
measurements will be performed:
•
Self-report of personal and family medical history.
•
Blood draw for CBC/Chemistry 15 panel. 
•
Height, weight, vital signs (blood pressure, pulse, and temperature).  
•
Concomitant medication use.
 
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•
Questionnaires (GDS-15 and MMSE).
Eligible subjects will be contacted by a coordinator to schedule the baseline visit. Subjects will 
collect a stool collection kit from the coordinator before the baseline visit. 
Baseline (1 hour)
Subjects will report to the clinic for the visit. The following tests and measurements will be 
performed:
•
Collection of fecal sample.
•
Measurement of weight and vital signs.
•
Recording of medications.
•
Dispensation of study foods.
•
Nutrition counseling.
•
Completion of tolerability questionnaire.
•
Dispensation of stool collection kit.
Visit 1 (Week 1, 1 hour)
Assessment of adverse events, completion of the tolerability questionnaire, and nutrition 
counseling will be completed by phone on the day prior to the visit to avoid unnecessary food 
preparations in the event that the participant does not tolerate the dose. Subjects will report to 
the clinic for the visit and the following tests and measurements will be performed:
•
Collection of fecal sample.
•
Measurement of weight and vital signs.
•
Recording of changes in medications.
•
Dispensation of study foods.
•
Assessment of compliance by metabolic kitchen staff.
Procedure
Screening 1
Baseline
Visit 1
Visit 2
Visit 3
PBRC Outpatient Unit 
Infromed Consent
x
Height
x
Weight, and Vital Signs
x
x
x
x
x
Chemistry 15 Panel/CBC
x
x*
Medical History Questionnaire
x
MMSE and GDS-15
x
Adverse Events**
x
x
x
Medications
x
x
x
x
x
Tolerability Questionnaire**
x
x
x
x
Food Dispensation
x
x
x
Nutrition Counseling**
x
x
x
Compliance with Study Foods
x
x
x
Fecal Sample (SCFA)***
x
x
x
x
Fecal Sample (Archives)
x
x
x
x
* Or at a prior visit if the dose is not tolerated
** By phone call on day prior to the study visit.
***Measured at Scioto Biosciences
Table 1. Schedule of Assessments for Dose Response Study
 
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•
Dispensation of stool collection kit.
A blood draw for CBC/Chemistry panel will be performed if participants are not being advanced 
to the next dose. Participants will be advised to report after a ten hour fast.
Visit 2 (Week 2, 1 hour)
Assessment of adverse events, completion of the tolerability questionnaire, and nutrition 
counseling will be completed by phone on the day prior to the visit. Subjects will report to the 
clinic for the visit and the following tests and measurements will be performed:
•
Collection of fecal sample.
•
Measurement of weight and vital signs.
•
Recording of changes in medications.
•
Dispensation of study foods.
•
Assessment of compliance by metabolic kitchen staff.
•
Dispensation of stool collection kit.
A blood draw for CBC/Chemistry panel will be performed if participants are not being advanced 
to the next dose. Participants will be advised to report after a ten hour fast.
Visit 3 (Week 3, 1 hour)
Assessment of adverse events and completion of the tolerability questionnaire will be completed 
by phone on the day prior to the visit. Subjects will report to the clinic in the morning following an 
overnight fast (except for water) that began no later than 10 hours prior to the study 
appointment and the following tests and measurements will be performed:
•
Collection of fecal sample.
•
Measurement of weight and vital signs.
•
Recording of changes in medications.
•
Blood draw for CBC/Chemistry 15 panel. 
•
Assessment of compliance by metabolic kitchen staff.
STUDY PROCEDURES
Whole soy pods (soy). The plants will be grown under carefully monitored conditions at the 
LSU Agricultural Center and harvested at reproductive stage six or when the green pods contain 
soybeans that fill the pods. The whole pods will be processed at the United States Department 
of Agriculture (USDA, New Orleans, LA), Food Processing and Sensory Quality Research Unit, 
where scientists work with foods for research purposes. Slicing the pods into thin cross-sections 
injures plant cells and activates the synthesis of an anti-microbial compound (glyceollin) 
synthesized by the plant de novo in response to stress. Glyceollins have been shown to improve 
insulin sensitivity and cognition.48-52 The sliced pods will be lyophilized and milled. Nutrient 
analysis, will be performed at Eurofins Food Chemistry Testing (Madison, WI) using methods of 
analysis of the Association of Official Analytical Chemists.53
Food Development. The soy will be incorporated in foods and prepared by the PBRC 
metabolic kitchen. The PBRC metabolic kitchen is staffed with research dietitians who have a 
primary responsibility to develop foods for research purposes, plan diets, and execute their 
delivery. In addition, the applicant is a registered dietitian with experience in food development 
across cuisines and cultures. 
Nutrition Counseling. Subjects will be counseled by the study dietitian who will interview the 
subject in order to assess the subject’s current intake. Based on this information, subjects will 
be counseled on incorporating the test foods in their diet. We expect that subjects will 
experience GI symptoms from increased DF intake, but from the applicant’s practice as a 
 
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registered dietitian and evidence in the literature we know that these symptoms resolve.54 To 
enhance compliance with the protocol, subjects will receive counseling on managing GI 
symptoms.
Food Tolerability. Subjects will complete a version of the GI symptoms questionnaire designed 
as a validated assessment for dyspepsia,55 and modified to make it specific by only including 
the symptoms that may be experienced with high DF intake. The scale is ranked as none, mild, 
moderate, and severe for each of four GI symptoms (bloating, abdominal rumbling, flatulence, 
and abdominal pain). Additionally, subjects will report their stool frequency ranging from 0 to 9+, 
and stool consistency based on the Bristol Stool scale.56  
Blood and Fecal Assessments. Chemistry 15 panel and CBC, measurements will be 
performed according to standard PBRC procedures for blood draws and the relevant 
measurement. The total amount of blood that will be drawn across the study is approximately 20 
ml. Homogenized fecal samples will be analyzed for SCFA as previously described.42,57  
MMSE. A cut-off score of 25 on the MMSE administered at screening will be used to exclude 
subjects with dementia.58
GDS-15. The Geriatric Depression Scale is validated for evaluating symptoms of apathy and 
depression,59,60 and will be used as a screening tool. A score > 6 on the GDS-15 has been 
shown to effectively screen for depression.61 
SAMPLE SIZE AND ANALYSIS 
The primary objective of the study is to determine the maximum tolerated dose of DF. Six 
subjects at each dose are sufficient to detect tolerability.43,62,63 However, we will enroll 10 
subjects to test each dose of DF from soy. Dose safety will be investigated by compiling by 
treatment (e.g. 4 g dose, 8 g dose, 12 g dose) a list of adverse events such as frequency of 
headaches, nausea, vomiting. For GI symptoms the scale is ranked as none (no symptoms), 
mild, moderate, and severe for each of four GI symptoms and the assessment of intensity is 
provided in the data safety monitoring plan. Moderate and severe ratings will be considered 
intolerance to the dose. Stool frequency of one to three/day, or three times/per week is 
considered regular. Therefore, stool frequency of less than one and more than nine over a 72 
hour period will be a consideration for determining intolerance. Stool consistency of Type three 
to five on the Bristol Stool Scale is considered normal.64 Any other rating will be considered in 
the determination of intolerance. To be considered intolerance, subjects must rate stool 
frequency and consistency as being of moderate to severe intensity.
 According to the NCI convention for dose limiting toxicity to a drug, 1) if two out of three (66%) 
subjects are intolerant to the dose, the next lower dose is the maximum dose tested; and 2) if 
one out of three (33%) are intolerant to a dose, then that dose is considered the maximum 
tolerated dose. Therefore for a food, 1) if five out of eight (63%) are intolerant, we will adopt the 
next lower dose; and 2) if three out of eight (37%) are intolerant to a dose, then that dose will be 
taken as the maximum tolerated dose. 
A mixed effect linear model will be used to estimate changes in the fecal SCFA while accounting 
for subject correlation across time using all available data. The outcome will be within subject 
changes over time.
DATA SAFETY MONITORING 
The National Institute on Aging-approved data safety monitoring plan and appointment of the 
safety officer is provided in the Appendix.
 
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DATA COLLECTION AND QUALITY ASSUARANCE
The only people who will know that these patients are research participants are members of the 
research team.  No information about them, or provided by them during the research, will be 
disclosed to others without their written permission, except if it is necessary to protect their 
rights or welfare (for example, in case of injury or emergency care), or if it is required by law.  
When the results of the research are published or discussed in conferences, no information will 
be included that would reveal the identity of these patients.  All data will be kept in locked files, 
and subjects will be identified by codes when the data gathered in this procedure is presented 
or published.  Authorized representatives of the National Institutes of Health may need to review 
records of individual participants.  As a result, they may see their name; but they are bound by 
rules of confidentiality not to reveal the patients’ identity to others. 
Privacy
The subjects will be interviewed in the privacy of an exam room and their records will be 
protected by a secure medical records area and a password-protected electronic database 
monitored by the Pennington Research Computing group. Subjects will be asked to sign a 
written consent after reading it, having it reviewed with them by the study staff and having all 
their questions answered.  The consent conversation will be conducted in the privacy of an 
exam room and the subject will be allowed to take the consent home to discuss their decision 
with their family or counselor, if desired. Study procedures will be conducted by trained staff in 
accordance with PBRC outpatient clinic standards of practice and with subjects’ informed 
consent. Confidential subject information including medical records and test results will be 
available only to persons authorized by the Pennington. Information collected from subjects will 
be the minimum amount of data necessary to accomplish the research purposes.
Data and Specimen Management
Study participants will be assigned unique subject identification (ID) numbers. Study subject ID 
numbers will be used on all data collection instruments, to include questionnaires, data 
collection forms, and computer records. The forms used for data collection and questionnaires 
such as the medical history questionnaire will be the standard forms used in PBRC studies. A 
master list linking the participants’ names and ID numbers will be kept in a password-protected 
computer file with access restricted to the PI and co-PI’s. Data collection forms will be kept 
secure, or password-protected if computerized, and under the control of the PI, co-PIs, and 
medical investigator. Only personnel assigned to the research study by the PI will have access 
to the data. Hard-copy data records will be stored for a minimum of 3 years.
The PBRC has a fully integrated, campus-wide, automated data management system. All data 
are entered into a central database using existing methodology that has been fully validated and 
undergoes continuous quality assurance by the PBRC Research Computing Core. All data are 
backed up daily, and the Research Computing Core at the PBRC oversees all data 
management. The research team has extensive experience using the procedures and methods 
required to conduct this study. Standard operating procedures in place throughout the units at 
Pennington Biomedical will be utilized for repeatable, valid data collection and quality.  
In accordance the standards of practice followed by the Clinical Chemistry core, blood samples 
will be stored frozen at PBRC until analysis can be completed. Fecal samples will be shipped to 
Scioto Biosciences, Indianapolis, IN for analysis. Packaging and shipping of biological samples 
will be overseen by the PI, shipped by the laboratory and will be completed in accordance with 
 
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International Air Transport Association regulations to ensure that viable biological samples 
reach their intended destination.  
WITHDRAWAL OF SUBJECTS
We will attempt to retain program participants once randomized for study completion through 
the end of study visit. It is our desire to analyze results on all participants who were enrolled in 
the study. In accordance with the declaration of Helsinki/Tokyo/Venice/Hong Kong, participants 
have the right to withdraw from the program at any time for any reason. The investigator also 
has the right to withdraw participants from the program treatments in the event of inter-current 
illness, adverse experience, treatment failure, protocol violation, or other reasons. Should a 
participant decide to withdraw from treatment, all efforts will be made to complete and report 
follow-up observations as thoroughly as possible. 
PAYMENT FOR PARTICIPATION 
At the completion of all study visits and procedures, participants will be paid $125 for the time 
spent in the clinic. If subjects’ participation in the study ends early, they will receive $25 for 
completion of each visit.This compensation is in line with all the other studies conducted at the 
Pennington Biomedical Research Center. 
EMERGENCY CARE AND COMPENSATION FOR RESEARCH-RELATED INJURY
No form of compensation for medical treatment is available from the Pennington Biomedical 
Research Center.  In the event of injury or medical illness resulting from the research 
procedures the research volunteer (from any group) will be referred to their physician/surgeon 
or a treatment facility.  The Pennington Biomedical Research Center is a research facility and 
provides medical treatment only as part of research protocols.  Should a volunteer require 
medical treatments, community physicians and hospitals must provide them to him/her.  
SHARING OF RESULTS WITH SUBJECTS 
The screening lab will be shared with the subjects on their first testing visit. At the end of the 
study, a manuscript will be prepared for submission to a peer-reviewed journal. A summary of 
the results will be posted on ClinicalTrials.gov which subjects may access. Since subjects are 
elderly, a written summary will be provided.
RESOURCES AVAILABLE 
The outpatient research units are well equipped and staffed to carry out the requirements of this 
study and appropriate standards of practice are in place to ensure appropriate research 
procedures.
ECONOMIC BURDEN TO SUBJECTS 
There are no costs for which the subjects will be responsible. 
CONSENT PROCESS 
Written informed consent will be obtained in the outpatient research clinic by the coordinators 
and one of the physicians will be available to answer questions if needed. A waiting period will 
be allowed, if desired by the participant. The coordinators and investigators will be available for 
questions throughout the study.
 
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APPENDIX
DATA & SAFETY MONITORING PLAN (DSMP)
 
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Candida Joan Rebello
Grant #: 5K99AG065419 - 02
Lifestyle intervention to reduce apathy in the elderly
Brief Description of Intervention:  To determine an acceptable dose of dietary fiber from 
soy, a dose escalation trial in eight older subjects with obesity will be conducted. The 
tolerability to soft foods containing approximately 4 g, 8 g, and 12 g/day of dietary fiber 
(depending on the nutrition analysis of the soy flour) from 10g, 20g, and 30g of soy flour for 
one week at each dose will be assessed, and the maximum tolerated dose will be determined. 
Brief Description of Project Design
•
Eight subjects will consume soft foods containing soy along with their regular diet for one 
week.
•
Compliance will be assessed from an interview with the subject and an evaluation of used 
and unused containers returned by subjects. 
•
Subjects will provide a stool sample for measurement of short chain fatty acids as an 
objective biomarker of compliance.
•
Subjects will complete a tolerability questionnaire at the end of each week. If a dose is 
tolerated, subjects will receive the next escalated dose for one week.
 
Stage of Behavioral Intervention Development Stage I
NIH Phase III Clinical Trial?   No.
Multiple Site Trial?   No.
List of Specific Aims 
•
Determine the maximum tolerated dose of dietary fiber from soy in elderly subjects with 
obesity and measure fecal short chain fatty acids (SCFA) as a biomarker of compliance.
 
Pennington Biomedical IRB FWA 00006218
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TABLE OF CONTENTS 
Page
1.0
1.0 PARTICPANTS SAFETY ........................................................................................1
1.1 Potential Risks and Benefits for Participants......................................................................1
1.2 Adverse Event and Serious Adverse Event Collection and Reporting...............................1
1.3 Protection Against Study Risks ..........................................................................................4
2.0
INTERIM ANALYSIS ....................................................................................................4
3.0
Data and Safety monitoring............................................................................................5
3.1 Frequency of Data and Safety Monitoring .........................................................................5
3.2 Data Analysis and Coordination.........................................................................................5
3.3 Content of Data and Safety Monitoring Report..................................................................5
3.4 DSMB Membership and Affiliation ...................................................................................5
3.5 Conflict of Interest for DSMB’s.........................................................................................5
3.6 Protection of Confidentiality ..............................................................................................6
3.7 DSMB Responsibilities ......................................................................................................6
 
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1.0
PARTICPANTS SAFETY
1.1 Potential Risks and Benefits for Participants
The study involves the following procedures which may pose a potential risk:
•
Blood Draws. There is the possibility of discomfort, pain, and bruising at the vein on the 
arm where the needle is inserted. There may also be a small risk of bleeding and a very 
small risk of infection at the site of the blood draw. Sterile technique and trained personnel 
minimize these risks.
•
Safety Assessments. Complete blood count (CBC), and chemistry 15 panel (glucose, 
creatinine, potassium, uric acid, albumin, calcium, magnesium, creatine phosphokinase, 
alanine aminotransferase, alkaline phosphatase, iron, cholesterol [total, high density 
lipoprotein, low density lipoprotein], and triglycerides) reports will be used to screen for 
eligibility prior to enrollment and will be used as a safety assessment following completion of 
each dose of dietary fiber during the study. The medical investigator will review the reports, 
and clinically significant changes in laboratory values will be investigated, and the subject 
will be referred for treatment, as appropriate.  
•
Whole soy pods. The soy being tested in the study is a food. The soybean will be grown at 
the Louisiana State University (LSU) Agricultural Center and milled to a flour at the United 
States Department of Agriculture (USDA, New Orleans, LA.) Food Processing and Sensory 
Quality Research Unit, where scientists work with foods for research purposes. This 
research examines an approach that mimics soybean consumption from parts of the world 
where its efficacy and health benefits are known.38-40 We expect that subjects will 
experience GI symptoms from increased dietary fiber intake, but from the applicant’s 
practice as a registered dietitian and evidence in the literature we know that these 
symptoms resolve.54 In the general population, supplementation with dietary fibers such as 
inulin and guar gum is well-tolerated at 15 g/day.44 Therefore, we expect that 
supplementation of the usual diet with 4 g, 8 g, and 12 g dietary fiber from soy will be 
tolerated by the elderly.
•
Study Foods. There is ordinarily no risk associated with the foods provided by the 
Pennington Metabolic kitchen. Additionally, subjects will be asked to inform staff about any 
food allergies or intolerances. A dietary questionnaire is routinely administered at the 
screening visit when the study involves a meal service. Research dietitians are responsible 
for managing the dietary component of specific study protocols. A continuous quality 
assurance program is followed to check food item weights, recipe procedures, packed meal 
and tray assembly, and food temperatures.  Documentation is  maintained for each study. 
All Metabolic Kitchen staff members receive training in food sanitation and in research diet 
preparation. 
•
Anthropometric Measurements and Vital Signs. The PBRC outpatient clinic staff are 
trained to perform these procedures in accordance with PBRC standards of practice. 
•
Fecal Samples. The clinical chemistry core staff will collect the fecal samples in accordance 
with standard operating practices. 
In addition to the potential risks listed above, participants may experience a previously unknown 
risk or side effect.
 
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Potential Benefits 
Constipation is a common problem in the elderly. With the increase in dietary fiber, participants 
may experience benefits in their bowel movements, and as a result, in their general well-being.
1.2 Adverse Event and Serious Adverse Event Collection and Reporting
Unanticipated Problem
An unanticipated problem is any incident, experience, or outcome that meets all of the following 
criteria: (1) unexpected, in terms of nature, severity, or frequency, given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the study 
population; (2) related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); (3) suggests that the research places 
participants or others at a greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized. Unanticipated problems include other 
incidents, experiences, and outcomes that are not adverse events.
Adverse Events
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. We define AE as any unfavorable and unintended 
sign (including a clinically significant abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of the study food. 
We will define a serious adverse event (SAE) as any untoward medical occurrence that results 
in death, is life threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity or in a congenital anomaly. 
Safety will be assessed by recording all adverse events. The study team will inquire regarding 
adverse events while minimizing the chance for bias when detecting AEs/SAEs. The study team 
will employ open-ended and non-leading verbal questioning of the subject as the preferred 
method to inquire about AE occurrence. For examples, appropriate questions include: “How are 
you feeling?”, “Have you had any (other) medical problems since your last visit/contact?”, or 
“Have you taken any new medicines since your last visit/contact?” It is the responsibility of the 
investigator to attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis will be documented as the AE/SAE and 
not the individual signs/symptoms. 
Assessment of Intensity. An assessment of intensity for each AE and SAE reported during the 
study will be provided by the investigator and the investigator will assign it to one of the 
following categories:
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.
 
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Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities.
Severe: An event that prevents normal everyday activities.
An AE that is assessed as severe will not be confused with an SAE and both AEs and SAEs 
can be assessed as severe. Severe Adverse Event is a category utilized for rating the intensity 
of an event.
Assessment of Causality. The investigator is obligated to assess the relationship between 
study treatment and the occurrence of each AE/SAE. A "reasonable possibility" is meant to 
convey that there are facts/evidence or arguments to suggest a causal relationship, rather than 
that a relationship cannot be ruled out. The investigator will use clinical judgment to determine 
the relationship. Alternative causes, such as concomitant therapy, other risk factors, and the 
temporal relationship of the event to the study treatment will be considered and investigated.
Events meeting the definition of an AE:
•
Any abnormal laboratory test results (clinical chemistry) or other safety assessments (e.g., 
vital signs measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study treatment administration even though it 
may have been present prior to the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment 
or a concomitant medication (overdose per se will not be reported as an AE/SAE).
Events that do not meet the definition of an AE:
•
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
that are associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the subject’s condition.
•
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to 
the procedure is an AE
•
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
AEs will be reported per IRB policies, and to the NIA on an annual basis. The reporting of AEs 
will follow the standards of practice as outlined by the Pennington Biomedical Research Center 
(PBRC) IRB in the ‘Unanticipated problems Involving risks to subjects or others’ policy. Once 
the investigator determines that an event meets the definition of an AE that must be reported, 
the investigator will not wait to receive additional information before notifying the responsible 
parties of the event and completing the appropriate forms. An assessment of causality at the 
time of the initial report will be provided. Email transmission of the AE data collection tool will be 
the preferred method to transmit this information followed by notification by telephone and/or 
 
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fax. A copy of the AE report will also be sent to the institution officials. New or updated 
information will be recorded in the originally completed data collection tool. 
We are testing tolerability to a dietary fiber at supplementation levels known to be tolerated. In 
some instances, increased intake of dietary fiber may result in gastrointestinal symptoms which 
resolve over time. Nevertheless, should an SAE occur, a summary will be reported to NIA 
Program Officer and to the Safety Officer quarterly, in accordance with NIA policies. When 
SAEs occur that are unexpected (i.e., have not been previously reported for the study’s 
intervention) and that are related to the intervention, they will be reported to NIA Program 
Officer and to the Safety Officer within 48 hours of study’s knowledge of the SAE. All deaths will 
be reported within 24 hours of study’s knowledge of death. The report of death will be submitted 
to NIA Program Officer and to the Safety Officer.
The investigators will abide by PBRC policy for ensuring prompt reporting to the IRB, NIA, and 
the Safety Officer, of any Unanticipated Problem involving risks to study participants or others 
(45 CFR 46.103(b)(5)). Accordingly, events meeting the definition of unanticipated problems will 
be reported within 48 hours, when possible, to avoid potential harm to subjects. PBRC 
Unanticipated Problems reporting procedures require completion and submission to the IRB of 
forms which include detailed information on the event and the actions that will be taken to 
prevent reoccurrence. Reports of Unanticipated Problems, as defined above, will be forwarded 
to OHRP using ohrp@osophs.dhhs.gov, within two weeks of the event.
Data Safety Monitoring Plan. For each AE, the seriousness, intensity, and relationship to 
study product will be assessed, documented, and supported by an entry in the subject’s medical 
records. During the study, each subject will be carefully monitored for any adverse events. After 
the initial AE/SAE report is completed and sent, the investigator is required to follow each 
subject at subsequent visits/contacts. As currently practiced, it is planned that all AEs and SAEs 
will be followed in clinic until: 1) resolution; 2) the condition stabilizes; 3) the event is otherwise 
explained; or 4) the subject is lost to follow-up.
1.3 Protection Against Study Risks
Informed Consent Process. 
The subjects will be interviewed in the privacy of an exam room and their records will be 
protected by a secure medical records area and a password-protected electronic database 
monitored by the Pennington Research Computing group. Subjects will be asked to sign a 
written consent after reading it, having it reviewed with them by the study staff and having all 
their questions answered.  The consent conversation will be conducted in the privacy of an 
exam room and the subject will be allowed to take the consent home to discuss their decision 
with their family or counselor, if desired. Written informed consent will be obtained in the 
outpatient research clinic by the coordinators and one of the physicians will be available to 
answer questions if needed. A waiting period will be allowed, if desired by the participant. The 
coordinators and investigators will be available for questions throughout the study.
Minimizing risks
Study procedures will be conducted by trained staff in accordance with PBRC outpatient clinic 
standards of practice and with subjects’ informed consent. Continuous monitoring by the PI 
and/or the medical investigator of the study and institution of a safety officer will minimize all 
potential risks and discomforts. Research participants will be immediately withdrawn from the 
 
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study upon evidence of any significant adverse event if the investigative team deems that the 
safety of the participant is in jeopardy.
2.0
INTERIM ANALYSIS
The primary objective of the study is to determine the maximum tolerated dose of dietary fiber. 
Dose safety will be investigated by compiling by treatment (e.g. 4 g dose, 8 g dose, 12 g dose) a 
list of adverse events such as frequency of headaches, nausea, vomiting. For GI symptoms the 
scale is ranked as none (no symptoms), mild, moderate, and severe for each of four GI 
symptoms and the assessment of intensity is provided in the section on adverse events. 
Moderate and severe ratings will be considered intolerance to the dose. Stool frequency of one 
to three/day, or three times/per week is considered regular. Therefore, stool frequency of less 
than one and more than nine over a 72-hour period will be a consideration for determining 
intolerance. Stool consistency of Type three to five on the Bristol Stool Scale is considered 
normal.64 Any other rating will be considered in the determination of intolerance. To be 
considered intolerance, subjects must rate stool frequency and consistency as being of 
moderate to severe intensity. If a dose is tolerated, subjects will receive the next escalated dose 
for one week.
Stopping Rules. The study foods will be stopped, and further dosing will be halted until un-
blinded safety information can be reviewed in the event that:
•
A death occurs.
•
Two or more subjects experience the same SAE following administration of study product.
•
Based on AEs, laboratory findings, or clinical findings the Investigator determines that 
review of pertinent safety information is required.  
Dosing may only resume if, after review of safety information, both the Investigator and IRB 
agree that it is safe to proceed. 
3.0
Data and Safety monitoring 
The Principal Investigator (PI) will be responsible for ensuring participants’ safety on a daily 
basis. The Safety Officer advises the NIA Program staff and Principal Investigator on participant 
safety, evaluates the progress of the study, reviews procedures for maintaining the 
confidentiality of data, the quality of data collection, management, and analyses. 
3.1 Frequency of Data and Safety Monitoring 
Safety reports are sent to the Safety Officer at least twice a year and will include an analysis of 
study progress, data and safety issues.  
3.2 Data Analysis and Coordination
The proposed safety officer is a physician in the PBRC Outpatient Clinic. The safety officer is 
independent of the study. The PI will discuss tolerability with the Safety Officer during the dose 
titration to determine whether the next escalation of dose is indicated. All of the data except raw 
data identifying individual participants will be made available to the Safety Officer and upon 
request to the Program Officer.  
At the end of the study, a manuscript will be prepared for submission to a peer-reviewed journal. 
A summary of the results will be posted on ClinicalTrials.gov which subjects may access. 
 
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3.3 Content of Data and Safety Monitoring Report 
The study team for this trial will prepare a written report for the Safety Officer. This report will 
summarize the current status of the study, including enrollment and toxicity information. All 
subjects in the study receive the study product and tolerability to the dose of dietary fiber is 
being assessed. Hence, there is no masking of data.  
3.4 Safety Officer and Affiliation  
The following individual has accepted the position of Safety Officer (pending NIA approval)
Raoul Manalac, M.D.
Assistant Professor, Pennington Biomedical Research Center
Dr. Manalac is trained and boarded in internal medicine with additional certifications in 
metabolic disease (Obesity Medicine, Clinical Lipidology) and acute inpatient medicine (Fellow 
of Hospital Medicine). Furthermore, he has a Master of Science in Clinical Trial Research and 
has served as Primary and Medical Investigators on numerous studies.  He is an active clinician 
in both the inpatient and outpatient realms giving him familiarity with the monitoring parameters 
and actions necessary to address abnormal findings.  
3.5 Conflict of Interest for Safety Officer
Dr. Manalac has no direct involvement with the study or conflict of interest with the investigators 
conducting the study. Dr. Manalac will sign a confidentiality agreement. He will be expected to 
follow the PBRC guidelines for disclosing conflicts of interest.
3.6 Protection of Confidentiality 
Participant identities will not be revealed to the Safety Officer. The only people who will know 
that these individuals are research participants are members of the research team. No 
information about them, or provided by them during the research, will be disclosed to others 
without their written permission, except if it is necessary to protect their rights or welfare (for 
example, in case of injury or emergency care), or if it is required by law. When the results of the 
research are published or discussed in conferences, no information will be included that would 
reveal the identity of these patients. 
3.7 Safety Officer Responsibilities
The responsibilities of the Safety Officer are to:
•
Review the entire IRB-approved study protocol with regard to participant safety, recruitment, 
intervention, data management, quality control and analysis and the informed consent 
document.
•
Recommend changes to the protocol and the informed consent form, when applicable.
•
Discuss with the PI and communicate the relevant data parameters and the format of the 
information to be regularly reported. 
•
Recommend participant recruitment be initiated after receipt of a satisfactory IRB-approved 
protocol. 
•
Review study data. These data can be related to safety, recruitment, retention, protocol 
adherence and trial operations.
•
Identify needs for additional data relevant to safety issues and request these data from the 
study investigators.
 
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•
Communicate with the PI and periodically review developing data on safety and endpoints.  
•
Consider the rationale for continuation of the study, with respect to progress of retention, 
protocol adherence, data management, safety issues, and outcome data and make a 
recommendation for or against the trial's continuation.
•
Review and make recommendations on proposed protocol changes, and/or new protocols 
proposed during the trial. 
•
Provide advice on issues regarding data discrepancies found by the data auditing system or 
other sources.
•
Review manuscripts of trial results if requested by the NIA Program Officer who may seek 
Safety Officer review of manuscripts reporting major outcomes prior to their submission for 
publication.
 
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