Dietary Soy Isoflavones In Chronic Pancreatitis
Phase: NA
Conditions: Chronic Pancreatitis
Sponsor: Ohio State University

Dietary Soy Isoflavones in Chronic Pancreatitis 
 
 
 
 
NCT: 02577640 
Date of original document: 12/5/2013 
 
Research Plan. Study Design/ Overview.  (See Figure 1: Flow Diagram, Appendix) 
Specific Aim 1:  To evaluate the compliance and tolerability of soy bread in patients with 
chronic pancreatitis enrolled in a Phase I dose escalation clinical trial.  A single group, open-
labeled dose escalation study of soy bread intervention will be conducted in patients with chronic 
pancreatitis. We hypothesize that the soy bread formulation will be well-tolerated with high 
compliance in CP patients. This study will be guided by dosing from prior clinical experience with 
this soy bread in patients with prostate cancer.  The use of bread as a food-based delivery vehicle 
is advantageous as compared to administration of a supplement as it provides the opportunity for 
delivery of multiple complex bioactive agents in an appropriate matrix. This is the first study 
designed to determine the Grade 1 and 2 toxicities, (Dose Limiting Toxicities (DLTs), compliance 
and tolerability of soy bread in human chronic pancreatitis. Once the Maximum Tolerated Dose 
(MTD) or target dose is reached, 10 subjects will undergo a 4 week verification study [Section b, 
below] to confirm tolerance and safety.  Overall, this small clinical trial will provide the necessary 
clinical data required to move this intervention forward in the setting of a future placebo controlled 
trial for patients with CP.  In addition, it will provide us with valuable biologic material to assess 
changes in inflammatory biomarkers relevant to CP and to facilitate future study of individual 
differences in soy isoflavone metabolism within this patient population. 
a. Dose Escalation Phase. (n=15-25 CP subjects)  This dose escalation study of soy isoflavones 
will enroll chronic pancreatitis patients from a single academic medical center in Columbus, Ohio.  
All participants will be informed about the study and potential risks and required to provide written 
informed consent prior to undergoing study-related procedures. Here a traditional 3+3 design will 
be used to determine the compliance, tolerability and dose limiting toxicities in this unique patient 
population. [Table 1: Dose Escalation; Appendix] Dose escalation with soy bread will be continued 
until dose-limiting toxicities are observed in >33% of the participants or the daily target dose of 4 
slices of bread [132 mg soy isoflavone] is reached.   [Table 2: Toxicity Grades; see Appendix].   
Subject Enrollment. Successive cohorts of patients (3 patients / cohort) will be started on a fixed 
dose of 33 mg isoflavones (IF) for this study [1 slice of soy bread; 33 mg isoflavones/85 gram 
slice] for 1 week.  CP patients will be accrued in cohorts of 3 and dose escalation will be increased 
by 1 slice of bread in each successive cohort based on a modified Fibonacci sequence:  50% [2 
slices; 66 mg IF], 33% [3 slices; 99 mg IF], 25% [4 slices; 132 mg IF] in which dose increments 
become gradually lowered until the target of 4 slices of bread or a MTD is determined.  Subjects 
will be enrolled in the study for 7 days and will be seen in the clinic on Day 0 and Day 7.  After 
enrollment (Day 0) subjects will start a legume free diet through the completion of their enrollment 
(Day 7).  
An estimated 15-25 CP patients will be needed for this initial dose escalation phase. 
 
Monitoring. Subjects will be monitored for toxicities defined based on type(s), grade(s) and 
duration (s) of symptoms using a daily diary that will be reviewed by study staff before and after 
each dose escalation. Toxicities will be graded using the Common Toxicity Criteria Version 3.0 
(CTC 3.0).  If the CTC 3.0 did not apply to an adverse event, it will be graded as mild, moderate 
or severe.  DLT will be defined as any CTC 3.0 Grade 3 or 4 adverse event determined to be 
related to the soy bread. Our prior experience in prostate cancer patients indicates Grade 1-2 GI 
discomfort as primary adverse events following bread consumption. 

Dietary Soy Isoflavones in Chronic Pancreatitis 
 
 
 
 
If no DLTs are observed for 1 week after administration of soy bread, a new cohort will be enrolled 
at the next planned dose level.  If DLTs are observed in one participant in the cohort, another 
three participants will be treated with the same dose level. The maximum tolerated dose (MTD) 
will be defined as one dose level below the dose in which DLTs were observed in >33% of the 
participants who are at least 80% adherent to the soy bread intervention, as evidenced by the 
number of empty packets received.  In other words if DLTs are observed in a least 2 of 3 
participants, the MTD will be determined to be the dose administered to the previous cohort.  
Similarly, in a cohort of 6 participants, 3 of the 6 participants would have to experience DLTs to 
determine the MTD. 
 
Data collection. Subjects will be seen in clinic on Day 0 and at the end of the study on Day 7.  A 
physical exam, vital signs, a blood draw to assess complete blood count with differential, 
cytokines, and comprehensive metabolic profile, and a urinalysis, will be completed at both of 
these visits. Blood and Urine will be collected and stored at -80C to complete batch testing.  Urine 
isoflavones and their metabolites will also be analyzed from the urine collected at enrollment.   
Subjects will be given a container to collect a urine sample starting at 24 hours prior to Day 7 (Day 
6) and ending with the urine collected the morning of their Day 7 clinic visit.  The subject will bring 
the sample with them to their visit for urine isoflavones analysis.   
Symptoms, toxicity, compliance, and acceptance of the soy bread will be assessed before and 
after each dose escalation and maintained in a secure case report form.  Soy bread tolerability, a 
diet record, and consumer acceptance will be measured throughout the subject’s enrollment via 
a booklet and maintained in a secure case report form. 
 
Dietary compliance: Adherence to the soy bread diet and legume restriction will be measured 
using daily diary entries (see DEG phase I SMc Appendix) as well as a count of empty packets 
returned. Additionally, isoflavones in the urine will be used to verify the subject’s self-reported 
compliance. A detailed list of foods to avoid for the legume restricted (peas, beans, soy, sprouts, 
and foods made with these items as well as peanut butter limited to 1 tablespoon/week) diet will 
be provided. We have developed a checklist of the most common food sources of isoflavone-rich 
foods based on the USDA Isoflavone Database (release 2.0, September 2008) which will be 
included in the daily dairy. Subjects will be instructed on the proper storage, handling, and 
consumption of the soy bread slices (see Soy Bread Instruction Appendix).  
 
Three day diet record: Subjects will be instructed by the research team with detailed 
instructions of how to approximate food quantities and record all foods and beverages 
consumed for three days during a given week. The three days will be assigned by the study 
coordinator (typically two weekdays and one weekend day). Each participant will be provided 
with an instruction booklet (see DEG phase I SMc Appendix) and examples of data collection.  
When subjects return for their visit, the study coordinator will review the three day diet record 
with the participant to ensure thoroughness and resolve any ambiguities.  Subjects enrolled in 
this group will complete this one time over 3 days during their enrollment.  The dietary records 
will be used to assess compliance to the legume restricted diet and analyzed using the Nutrition 
Data System for Research (NDS-R; University of Minnesota, Minneapolis, MN).  
 
Soy bread tolerability and consumer acceptance: Soy bread tolerability and consumer 
acceptance will be measured using the sensory evaluation questionnaire and visual analogue 
scale to determine satiety.  This will be completed at least once a day.   
 

Dietary Soy Isoflavones in Chronic Pancreatitis 
 
 
 
 
b. MTD Verification Phase (n= up to 10). After the Phase I study has been completed, an 
additional 10 chronic pancreatitis patients will then be treated at the best tolerated dose for 4 
weeks to further verify safety and toxicity.   
  
Subject Enrollment: Subject enrollment will begin 14 days prior to the start of eating the soy 
bread.  Total enrollment time for this group is 6 weeks.  During the first two weeks of enrollment 
subjects will undergo a legume-free washout period and will be asked to refrain from eating 
legumes during this time.  Subjects will continue the legume free diet until they complete the study 
(total of 6 weeks).   Subjects enrolled in this phase will be asked to stop any multivitamins that 
they are taking and all will be asked to start a multivitamin with a mineral supplement (MVI) each 
day.  This multivitamin with mineral supplement will be provided to the subjects enrolled in this 
phase for consistency. 
  
Data Collection: Data and bio-specimen collection will be obtained at enrollment, when they start 
eating the soy bread and then weekly through the end of the study.  Subjects will be seen in clinic 
at enrollment (Day -14), when they start eating the soy bread (Day 0), Week 1, Week 2, Week 3, 
and at the end of the study on Week 4.  A physical exam and vital signs will be completed at each 
of these visits. A blood draw for complete blood count with differential, cytokines testing, 
comprehensive metabolic profile will be completed at Day 0 and Week 4.  A urinalysis will be 
completed weekly starting with Week 0 and ending with Week 4. 
Subjects will be given a container at Day -14 to collect a urine sample starting at 24 hours prior 
to Day 0 and ending with the urine collected the morning of the Day 0 visit.  The subject will bring 
the sample with them to their Week 0 visit.  They will also be given a container at Week 3 visit to 
collect a urine sample starting at 24 hours prior to their last study visit (Week 4 visit) and ending 
with the urine collected the morning of the Week 4 visit. Urine isoflavones and their metabolites 
will be analyzed with this urine collection. 
 
Dietary adherence: Adherence and tolerability to the soy bread diet and legume restriction will 
be measured using daily diary entries, sensory evaluation questionnaire, and visual analogue 
scale measuring the subject’s satiety (see MTD Phase II SMc Appendix) as well as count of empty 
packets returned. Additionally, isoflavones and their metabolites in the urine will be used to verify 
the subject’s self-reported adherence. A detailed list of foods to avoid for the legume restricted 
(peas, beans, soy, sprouts, and foods made with these items as well as peanut butter limited to 
1 tablespoon/week) diet will be provided. We have developed a checklist of the most common 
food sources of isoflavone-rich foods based on the USDA Isoflavone Database (release 2.0, 
September 2008) which will be included in the daily dairy, Appendix. Subjects will be instructed 
on the proper storage, handling, and consumption of the soy bread slices, Appendix.  
 
Three day diet record Subjects will be instructed by the research team with detailed 
instructions of how to approximate food quantities and record all foods and beverages 
consumed for three days during a given week. The three days will be integrated into the 
booklets (see MTD Phase II SMc Appendix) provided. Each participant will be given written 
instructions and examples of diet record data collection.  When subjects return for their visit, the 
study coordinator will review the three day diet record with the participant to ensure 
thoroughness and resolve any ambiguities.  Two 3 day diet records will be administered in the 
MTD phase, once between enrollment (Day -14) and Day 0 and once between Week 3 and 
Week 4. The dietary records will be used to assess compliance to the legume restricted diet and 
analyzed using the Nutrition Data System for Research (NDS-R; University of Minnesota, 
Minneapolis, MN).  
 

Dietary Soy Isoflavones in Chronic Pancreatitis 
 
 
 
 
Soy bread tolerability and consumer acceptance: Soy bread tolerability and consumer 
acceptance will be measured using the sensory evaluation questionnaire and visual analogue 
scale to determine satiety.  This will be completed at least once a day while subjects are eating 
the bread.   
 
Sensory testing of soy breads will be used to assess the acceptance and physical 
characteristics of the soy bread and will be conducted during the first day of soy bread 
consumption. The information gained will be used to assess the effects of soy bread consumer 
acceptance (liking) to soy bread. In our previous studies, acceptance of the soy bread was 
excellent surrogate measures of adherence. Overall acceptance of the soy bread will be 
conducted using a nine point hedonic scale (1=dislike extremely to 9=like extremely) whereas a 
five point Just About Right (JAR) scale (1=much too little to 5=much too much) will be used to 
optimize the soy bread formulation for future trials with this cohort, Appendix. Descriptive 
analysis will be used to characterize the organoleptic qualities (saltiness, sweetness, beaniness, 
hardness, and brown color) of the soy bread. A horizontal line scale (6 inch) ranging from 1 to 
10 will be used to measure the intensity of each attribute. At the last clinic appointment (week 4) 
general consumer questions regarding the soy bread will be collected. 
 
The satiety scale will determine the subjects hunger levels after they eat the bread.  Measures 
of satiety (perceived fullness or lack of hunger) will be conducted using visual analogue scale 
(VAS) adapted from Hill and Blundell (1983)41 and will be used to examine the impact of satiety 
on soy bread compliance. Subjects will be asked to rate their satiety (hunger, fullness, 
satisfaction, and thoughts of food) as well rate their nausea, thirst, and energy. VAS will be 
completed prior to the first slice of soy bread consumed and immediately after bread 
consumption, 240 minutes after consumption of the soy bread as well as before going to bed.   
 
Isoflavone Metabolism and Adherence to Soy Bread Intervention Patients with pancreatitis 
may have altered metabolism which can cause significant changes in glycated hemoglobin. 
HbA1c and is often times closely monitored in these patients. Advanced glycation end products 
as well as individual differences in activity, nutritional status, and smoking have shown to affect 
isoflavone metabolism and expression of novel isoflavone metabolites42 43. For these reasons, 
subjects most recent HbA1c will be recorded.  This HbA1c may be completed prior to enrollment 
in the study or after as their standard medical treatment for Chronic Pancreatitis. Furthermore, 
factors such as activity level, nutritional status, and smoking affect the absorption and metabolism 
of isoflavones within and among individuals and over time their biological activity44. Therefore a 
standardized vitamin will be provided to participants in the MTD phase of the study as well daily 
activity and daily exposure to smoking will be monitored.  
  
 
Specific Aim 2:  To determine the effect of soy bread intervention on pro-inflammatory 
cytokine expression in serum and urine from patients with chronic pancreatitis. Cytokine 
and lipid biomarkers relevant to inflammation will be assessed at baseline and following soy bread 
intervention in patients’ serum and urine. We hypothesize that dietary soy will be associated with 
reduced levels of key pro-inflammatory cytokines that drive the pathogenesis of CP including IL-6, 
CRP, IL-1β and TNF-α, among others 
Blood sampling.  At enrollment, patients will present for a blood draw at the Outpatient Clinic. In 
addition to standard-of-care blood work ordered by the physician, a phlebotomist will collect 
another 30 ml (1 ounce) into sodium-heparin Vacutainer tubes (Fisher) and a clean catch urine 
sample for our study. Blood and urine will be immediately processed, and stored at -80°C for 
analyses. The same procedure will be used on 1 subsequent visit at the end of study, for a total 

Dietary Soy Isoflavones in Chronic Pancreatitis 
 
 
 
 
of two blood draws to monitor changes in cytokine profile over time.  Cytokine biomarkers will be 
assessed at [1] Baseline and [2] upon completion of the study. 
 
Immune Biomarkers. Studies investigating the effect of dietary soy on immune parameters in 
patients with CP are non-existent. This trial will fill a critical gap in understanding how dietary soy 
affects key biomarkers of inflammation in CP patients. Blood from patients will be processed via 
centrifugation with ficoll-paque. Our primary objective will be to assess the change in three pro-
inflammatory cytokines (IL-6, CRP, IL-1β) known to be important in the pathogenesis of 
pancreatitis via a Luminex-based assay (Affymetrix). However, our high-throughput analytical 
platform will allow for an assessment of other factors that regulate inflammatory processes 
including: [1] inflammatory cell mobilization expansion: G-CSF, GM-CSF; [2] inflammatory cell 
trafficking: IP-10, MCP-1, M-CSF, MIG, RANTES, SDF-1; [3] Th1-type CD4+ T cell responses: 
IFN-γ, IL-1β, TNF-α;  [4] Th2 or Th17-type CD4+ T cell responses: IL-4, IL-6, IL-10, IL-17; [5] 
Other measureable factors relevant to inflammation as they relate to pancreatic carcinogenesis: 
IL-11, IL-13, TGFβ, PGE2, HMGB1. Sufficient volume of samples will also be available for 
validation by a second method in the event interesting trends are observed (i.e. ELISA). All 
samples will be analyzed in a batched manner to assess changes across the four individual time 
points per each patient. These data will provide us with a comprehensive understanding of how 
dietary soy alters the expression of soluble factors implicated in inflammatory processes.  
Lipid Biomarkers Pro-inflammatory markers from adipose (adiponectin, leptin, and resistin) and 
lipid metabolism (triglycerides, total cholesterol, LDL, HDL) will be collected for subjects enrolled 
in the MTD group at enrollment (Day 0) and at the end of study visit (Week 4), as they are related 
to pancreatitis and soy exposure.  This will be obtained from blood collected after a 12 hour fast. 
One serum separator (10 mL) will be collected for these analyses. Serum lipids (total cholesterol, 
HDL, LDL, triglycerides, adipokines, and leptin) will be batch analyzed by the CRC Core 
Laboratory using Dimension Xpand Clinical Chemistry analyzer or Immulite 1000 (Siemens 
Medical Diagnostics, Decatur, GA.).    
 
Conclusion. We have assembled a multi-disciplinary research team to assess compliance, 
toxicity and changes in pro-inflammatory cytokine expression from a soy based dietary bread 
product using a classic 3+3 dose escalation study design in subjects with chronic pancreatitis.  
This novel non-pharmacologic intervention has a high likelihood of being tolerable and safe in 
patients with chronic pancreatitis and in down-regulating the pro-inflammatory cytokine cascades 
that drives the pathobiology of this debilitating illness. 
 
 
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Dietary Soy Isoflavones in Chronic Pancreatitis 
 
 
 
 
 
 
 
 
 
 

Dietary Soy Isoflavones in Chronic Pancreatitis 
 
 
 
 
Budget – uploaded 
 
D. Other Support – uploaded 
E. IRB Approval Letter – pending submission 
F.  Conflict of Interest – uploaded 
G.  Curriculum Vitae – uploaded 
H. Supporting Letters - uploaded 
 
 
I.Appendix 
 
Figure 1: Study Flow Diagram 
 
a. 
Dose Escalation Phase [n=15-25] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
b. 
MTD  Verification Phase [n=10] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A. Start at 
dose level 1 
Treat cohort 1 wk 
(3 CP subjects) 
Number 
of DLTs 
No further 
escalation 
Recruit 3 more CP 
subjects 
Further 
DLTs? 
Stop 
B. Escalate dose  
Yes 
No 
<1 
2 or 3 
Start at MTD 
Treat cohort 4 wks 
(10 CP subjects) 
Monitor 
Toxicites 
No further 
escalation 

Dietary Soy Isoflavones in Chronic Pancreatitis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1:  Dose escalation will proceed within each cohort according to the following scheme.  
Dose-limiting toxicity (DLT) is defined below in Table 2. 
 
Number of Participants with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 participants at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest 
dose administered).  Three (3) additional participants 
will be entered at the next lowest dose level if only 3 
participants were treated previously at that dose. 
1 out of 3 
Enter at least 3 more participants at this dose level. 
 If 0 of these 3 participants experience DLT, proceed 
to the next dose level. 
 If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
participants will be entered at the next lowest dose level 
if only 3 participants were treated previously at that 
dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. At 
least 6 participants must be entered at the 
recommended phase 2 dose. 
 
 
 
 
 
 
 
 
 

Dietary Soy Isoflavones in Chronic Pancreatitis 
 
 
 
 
 
 
 
 
 
Table 2:  Definition of Toxicity Grades 
 
a. 
Dose Limiting Toxicity (DLT) – Appearance of side effects during treatment that are 
severe enough to prevent further increase in dosage or strength of treatment agent, or to 
prevent continuation of treatment at any dosage level.   
b. 
Grade – a numeric scale used to rate the severity of toxicity associated with a treatment. 
Each side effect is separately rated from "0" to "4." "0" = side effect not present. "1"= present but 
minor. "2"=present, moderate effect. "3"= present, with significant effect. "4" = potentially life 
threatening effect. G. "3" or "4" toxicity usually results in further treatment being delayed or 
stopped. If resumed, treatment may be at lower dosage or frequency. 
 
Table ___ 
Nausea, Vomiting, 
Diarrhea, 
Abdominal pain, 
Bloating 
Management/Next Dose for  
[Soy Bread] 
Management/Next Dose for  
[Soy Bread] 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
Hold* until < Grade 2.  Resume at 
one dose level lower, if indicated.** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Participants requiring a delay of > 1 week should go off protocol therapy. 
**Participants requiring > two dose reductions should go off protocol therapy. 
Recommended management:  Nausea / vomiting (antiemetics); diarrhea (loperamide); 
abdominal pain (acetaminophen, NSAID) 
 
For the purposes of this Phase I trial, side effects rated  >= 3, lasting > 1 week are considered 
dose limiting. Side effects will be managed with standard medications such as anti-diarrheals, 
antiemetics and non-narcotic analgesics. 
 
 
 
 
 
 
 
 
 
 

Dietary Soy Isoflavones in Chronic Pancreatitis 
 
 
 
 
Appendix A 
Inclusion criteria 
1. Diagnosis of chronic pancreatitis by fulfilling any one of the following three 
clinical scenarios (i.e., a or b or c): 
a. Presence of pancreatic calcifications - Pancreatic parenchymal or 
ductal calcifications (≥1) seen on abdominal imaging study 
b. Suggestive for chronic pancreatitis – fulfillment of any of the following 
3 criteria (i.e., i or ii or iii): 
i. EUS demonstrating lobular appearing pancreas (≥3 
continuous lobules) and ≥3 minor EUS criteria 
1. Minor EUS criteria (aka Rosemont criteria) include: lobular 
appearing pancreas (1-2 lobules), hyperechoic foci without 
shadowing, cysts, hyperechoic stranding, irregular main 
pancreatic duct contour, dilated side branches, main 
pancreatic duct dilation, or hyperechoic main pancreatic duct 
walls 
ii. EUS demonstrating ≥ 5 minor EUS criteria 
iii. Presence of ≥ 3 abnormal pancreatic duct side branches visualized 
on MRCP or ERCP (derived from Cambridge criteria for mild 
chronic pancreatitis) 
c. Indeterminate EUS findings for chronic pancreatitis with evidence 
of exocrine pancreatic insufficiency (EPI) (i.e., i + [ii or iii or iv or v]) 
i. Presence of 3-4 minor EUS criteria (listed above) 
ii. Abnormal fecal fat collection (>15g fat per day) 
iii. Abnormal endoscopic pancreas function test (i.e., maximum 
duodenal bicarbonate concentration <80 meq/L) 
iv. Decreased serum trypsin (<20 ng/mL) 
v. Decreased fecal elastase level (<200 microgram/gram stool) 
2. Age ≥18 years 
 
Exclusion criteria 
1. Inability to provide written consent 
2. Inability to comply with the study protocol 
3. Soy allergy 
4. Pancreatic cancer 
5. History of prior pancreatic surgery (this does not include endoscopic therapies) 
6. Comorbid diseases characterized by a chronic inflammatory state, including, but 
not limited to rheumatologic diseases, chronic kidney disease, extra-pancreatic 
malignancy (these conditions would confound the measurement of inflammatory 
mediators) 
7. Pregnancy (based on verbal history alone; the study intervention does not have 
known harmful effects to a mother or fetus, and therefore, pre-study pregnancy 
testing will not be mandated).