MC1267, A Randomized, Blinded Pilot Placebo-Controlled Trial With Oral Serum Bovine Immunoglobulin (SBI) to Assess Quality of Life and the Faster Post-Operative Recovery of Gynecological Cancer Patients
Phase: PHASE2
Conditions: Female Reproductive Cancer
Sponsor: Mayo Clinic

 
 
 
 
 
MC1267 / 12-009448 
 
 
A Randomized, Blinded Phase II Placebo-Controlled Trial With 
Oral Serum Bovine Immunoglobulin (SBI) to Assess Quality of 
Life and the Faster Post-Operative Recovery of Gynecological 
Cancer Patients 
 
 
NCT01867606 
 
 
Document Date: 05/07/2015 

MC1267 
Protocol Version Date: May 7, 2015 
 
Mayo Clinic Cancer Center 
 
MC1267, A Randomized, Blinded Pilot Placebo-Controlled Trial with Oral Serum Bovine 
Immunoglobulin (SBI) to Assess Quality of Life and the Faster Post-Operative Recovery of 
Gynecological Cancer Patients 
 
 
 
Study Chairs: 
Aminah Jatoi MD and Carrie Langstraat MD 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
507/284-2511 
507/284-5280 (FAX) 
 
 
Study Cochairs: 
Jamie Bakkum-Gamez MD 
 
 
Sean Dowdy MD 
 
 
Megan Grudem RN CNP 
 
 
Andrea Mariani MD 
 
 
Casey Swanson PA 
 
 
Statistician: 
Nathan R. Foster MS 
 
  
 
 
Agent Availability Commercial Agents:  None 
Agent Company Supplied:   Oral Serum Bovine Immunoglobulin (SBI) 
 
 
Document History 
(Effective Date) 
Activation 
10/4/2013 
Mayo Addendum 2 
10/4/2013 
Mayo Addendum 3 
10/4/2013 
MCCC Addendum 4 11/26/2013 
MCCC Addendum 5 8/25/2014 
MCCC Addendum 6 Pending approvals 
 
 

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Protocol Version Date:  May 7, 2015 
Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
intervention 
delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
Cristina Zabel, Quality Assurance Specialist 
Phone: (507) 284-4565 
E-mail: zabel.cristina@mayo.edu  
Forms completion and submission 
Jean Jensen, Clinical Research Coordinator 
Phone: (507) 538-1115 
Email: jensen.jean@mayo.edu  
 
Protocol document, consent form, 
regulatory issues 
Lynn M Flickinger, Research Protocol Specialist  
Phone: 507/538-7034 
Email: flickinger.lynn@mayo.edu 
 
Adverse Events (AdEERS, Non-AER, 
AML/MDS) 
Patricia G. McNamara, SAE C 
Phone:  (507) 266-3028 
E-mail:  mcnamara.patricia@mayo.edu 
  
*No waivers of eligibility per NCI  

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Table of Contents 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ........................................................................................................................................... 10 
3.0 
Patient Eligibility ........................................................................................................................ 11 
4.0 
Test Schedule .............................................................................................................................. 12 
5.0 
Stratification Factors ................................................................................................................... 13 
6.0  
Registration/Randomization Procedures ..................................................................................... 13 
7.0 
Protocol Intervention................................................................................................................... 15 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 16 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 16 
10.0 
Adverse Event (AE) Reporting and Monitoring ......................................................................... 16 
11.0 
Intervention Evaluation: None .................................................................................................... 22 
12.0 
Descriptive Factors: None ........................................................................................................... 22 
13.0 
Follow–up Decision at Evaluation of Participants ...................................................................... 22 
14.0 
Body Fluid Biospecimens ........................................................................................................... 23 
15.0 
Product Information .................................................................................................................... 25 
16.0  
Statistical Considerations and Methodology ............................................................................... 27 
17.0  
Pathology Considerations/Tissue Biospecimens: None .............................................................. 31 
18.0 
Records and Data Collection Procedures .................................................................................... 32 
19.0  
Budget ......................................................................................................................................... 33 
20.0 
References ................................................................................................................................... 34 
Appendix Ia BASELINE PATIENT INFORMATION SHEET ................................................................ 36 
Appendix Ib DURING Intervention PATIENT INFORMATION SHEET ................................................ 37 
Appendix II Postoperative Quality of Life Questionnaire .......................................................................... 38 
Appendix III UNISCALE – Patient Form .................................................................................................. 41 
Appendix IV SYMPTOM DISTRESS SCALE (SDS) ............................................................................... 42 
Appendix V Compliance Questionnaire ..................................................................................................... 44 
Appendix VI Nurse/CRA Phone Worksheet .............................................................................................. 45 
Appendix VII Entera Health Clarification Letter ........................................................................................ 47 
.

MC1267 
 
MCCC Addendum 6 
 
Protocol Version Date:  May 7, 2015 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle Length = 28 days (4 weeks) 
 
 
Generic name:    Serum-Derived Bovine Immunoglobulin 
Protein Isolate 
Brand name(s): SBI, EnteraGamTM 
Mayo Abbreviation: SBI  
Availability: Entera Health Inc 
Generic name: Placebo 
Brand name(s): Placebo 
Mayo Abbreviation: PLACEB 
Availability: Entera Health Inc 
Randomization 
Oral serum bovine 
immunoglobulin by mouth twice 
daily for 12 weeks (3 cycles) 
Crossover to Observation to 
obtain QOL assessment if study 
treatment does not begin or 
patient discontinues treatment 
early, and patient agrees to 
complete questionnaires 
Oral placebo 
by mouth twice daily 
for 12 weeks (3 cycles) Crossover 
to Observation to obtain QOL 
assessment if study treatment does 
not begin or patient discontinues 
treatment early, and patient agrees 
to complete questionnaires 
 
Off Study 
Unacceptable adverse events or 
patient refusal at any time → Off 
Study 
 
Observation (4 weeks post-intervention) 

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1.0 
Background 
 
1.1 
Ovarian cancer is an aggressive malignancy that results in over 15,000 deaths per year in 
the United States [1]. Most patients diagnosed with this cancer die from it. Nonetheless, 
the fact that approximately 25% of patients with even stage IIIC -- that is, large (> 2cm) 
peritoneal metastases that extend beyond the pelvis and the most commonly diagnosed 
stage of ovarian cancer -- can be cured underscores the need to maximize the efficacy of 
the therapeutic approaches that are recognized as contributing to this small chance of cure 
[1].  
 
1.2 
Capitalizing on Therapeutic Modalities with Demonstrated Efficacy:  Aggressive 
Surgery.  Although novel therapeutic interventions continue to emerge, the medical 
literature clearly demonstrates the importance of thoroughly capitalizing on therapeutic 
modalities that have already demonstrated an essential therapeutic role.  For example, a 
large body of literature shows that the definition of “optimal debulking” of tumor 
dramatically improves overall survival, and the definition of this term has evolved over 
time to the benefit of patients with ovarian cancer [2].  Previously, residual nodules of 1 
cm or less in size defined an optimal debulking surgery, but now this definition has been 
further refined as yielding “no gross residual tumor.”  Indeed, Chi and others have 
illustrated the importance of operating to achieve “no gross residual tumor.” Examining 
465 patients, these investigators assessed various prognostic factors, most relevantly, the 
extent of postoperative residual disease [2].  In multivariate analyses, hazard survival 
ratios (95% confidence intervals) increased significantly based on postoperative 
assessment of extent of residual disease:  no gross residual disease (reference);  </= 1 cm 
of gross residual disease yielded a hazard ratio of 2.07 (1.23, 3.46);  and > 1 cm gross 
residual disease yielded a hazard ratio 3.70 (2.27, 6.04).  These investigators concluded 
that the goal of any surgery for ovarian cancer should be “no gross residual disease” and, 
in the absence of this outcome, surgical cytoreduction to the greatest extent possible 
should be undertaken.  Such conclusions are relevant because they underscore the 
observation that highly aggressive surgeries that include enterotomies, resections of large 
portions of bowel, and manipulation of the bowel are not only commonplace but also 
highly justified in the state-of-the-art treatment of ovarian cancer.   
 
Indeed, the aggressiveness of these surgeries has yielded grade 3 or worse complication 
rates, which include death, in the range of 15-22%, as reported from high-volume 
medical centers [3,4].  Such notable complication rates underscore the need to evaluate 
strategies not only to lessen postoperative complications but also to improve long-term 
survival by means of exploring interventions to enhance postoperative recovery and 
thereby enable the prompt administration of chemotherapy. 
 
1.3 
Capitalizing on Therapeutic Modalities with Demonstrated Efficacy:  The Timely 
Administration of Post-Operative Chemotherapy.  Mahner and others recently 
demonstrated that timely administration of postoperative chemotherapy to patients with 
ovarian cancer improves outcomes [5].  These investigators examined individual patient 
data from 3326 ovarian cancer patients who had participated in 3 prospective phase III 
trials.  Within this large cohort, the median time to chemotherapy was 19 days (range 1, 
56 days), but starting chemotherapy sooner appeared to confer a survival advantage.  
Among patients who had had an optimal debulking surgery, a longer time to 
chemotherapy initiation was associated with a poorer survival (per week delay hazard 
ratio=1.87; 95% confidence interval 1.005, 1.176; p=0.038).  Indeed, a one week delay in 

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chemotherapy yielded an 8.7% increase in mortality in patients who had received an 
optimal debulking surgery.  These data point to the importance of the timely 
administration of chemotherapy in patients who have undergone an optimal debulking 
surgery for ovarian cancer. 
 
The above data become even more compelling when one considers preclinical data on 
surgery, the timing of chemotherapy, and tumor growth.  Fisher and others used a murine 
mammary tumor model to assess mitotic activity within tumors [6].  Assessing mitotic 
activity at various time points with respect to surgery, these investigators observed that an 
increase in mitotic activity and tumor growth occurred during the first 3-4 days after 
surgery and that the administration of cyclophosphamide the day of surgery was more 
advantageous in suppressing tumor growth.  In addition, Gunduz and others showed that 
tumor growth within residual malignant disease gained momentum to an extent that did 
not seem to occur in the absence of surgery, thus also suggesting that prompt 
administration of chemotherapy post-operatively is advantageous [7].  Taken together, 
such data provide preclinical justification to bolster further the conclusions from Mahner 
and others that the early administration of chemotherapy after optimal surgical debulking 
for ovarian cancer leads to more favorable clinical outcomes. 
 
Admittedly, not all data provide a consistent message on the importance of the timing of 
the administration of chemotherapy in postoperative ovarian cancer patients.  In an earlier 
review from Larsen and Blaakaer, this issue was discussed in detail in the context of a 
systematic analysis of seven previously-published studies [8].  Although two of the 
studies included in this review also suggested that prompt administration of 
chemotherapy led to improved outcomes, the other five reported no significant 
differences in outcomes -- neither in a positive nor negative direction -- with the prompt 
administration of chemotherapy.  Many factors might account for the negative neutral 
findings in these 5 studies, including 1) retrospective bias, or the plausible possibility that 
patients with worse prognostic factors may have started chemotherapy sooner, thus 
balancing out these negative prognostic factors but not improving clinical outcomes;  2)  
small sample sizes but with the larger studies in this analysis suggesting in either 
univariate or sub-analyses that timely chemotherapy administration may in fact be 
clinically advantageous with improved survival;  and 3)  relatively small variability in 
chemotherapy timing in general which again suggests that a much larger sample size 
might be necessary to detect subtle clinical benefits with early administration of 
chemotherapy.  Despite the above, the recent, robust data from Mahner and others, the 
other two supporting studies referenced by Larsen and Blaakaer, the fact that plausible 
explanations can be invoked to account for the neutral negative findings observed in the 
five previous studies, an absolute lack of negative studies that show clear clinical 
detriment with the early administration of postoperative chemotherapy in retrospective 
studies, and preclinical studies which also advocate for the early administration of 
chemotherapy --  all indicate a need to investigate ways to treat ovarian cancer patients 
promptly in a postoperative setting and justify proceeding with the current proposal. 
 
1.4 
Oral Serum Bovine Immunoglobulin (SBI):  A Review of Preclinical and Clinical 
Findings.  Serum-derived bovine immunoglobulin protein isolate is an orally 
administered prescription medical food containing a proprietary formulation of 
immunoglobulins (> 50% IgG) and other serum proteins.  The term medical food, as 
defined in Section 5(b) of the Orphan Drug Act (21USC.360ee(b) (3) is “a food which is 
formulated to be consumed or administered enterally under the supervision of a physician 
and which is intended for the specific dietary management of a…. condition for which 

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distinctive nutritional requirements based on recognized scientific principles, are 
established by medical evaluation.”  Serum-derived bovine immunoglobulin protein 
isolate is intended for the nutritional management of a patient who, because of 
therapeutic or chronic medical needs, has limited or impaired capacity to ingest, digest, 
absorb, or metabolize ordinary foodstuffs or certain nutrients, the dietary management of 
which cannot be achieved by the modification of the normal diet alone.  Serum-derived 
bovine immunoglobulin has self-affirmed generally recognized as safe (GRAS) status 
with no objections from the US Food and Drug Administration (FDA). 
 
A large portion of SBI consists of immunoglobulins, primarily IgG and to a lesser extent 
IgM as well as other proteins and amino acids.  SBI is derived from manufacturing 
processes for bovine serum albumin (BSA), making it a valuable but easily accessible 
byproduct.  Previous studies show that SBI resists part of the digestive process and that 
some of active IgG remains present in the gastrointestinal tract.  This combination of 
immunoglobulins and other proteins are thought to lead to the immunomodulatory effects 
of SBI and are thought to lead to maintenance of the intestine as a barrier and attenuation 
of malabsorption after an inflammatory assault to the gastrointestinal tract.  Indeed, when 
taken together, previous studies show that oral ingestion of SBI improves the absorption 
of nutrients, reduces intestinal permeability, and decreases overall infection rates.  The 
most striking clinical evidence in support of the above entails the administration of SBI to 
weanling farm animals with the observation of increased dietary intake and greater 
weight gain compared to control animals [9-11].  The published literature is replete with 
observations that show animals maintain their weight during the weaning process and 
continue to thrive as a result of SBI supplementation. 
 
Although studied on a far smaller scale in humans, SBI has nonetheless been studied 
clinically, and these early clinical studies outline a need to further study SBI within other 
medical conditions. At least 5 previous clinical studies demonstrate the complete safety 
of SBI in both children and adults with even some early evidence of clinical improvement 
in various medical conditions.  First, Lembecke and others focused on 10 male children, 
ages 9 to 25 months, with severe malnutrition.  These children were supplemented with 
SBI over a 7-day period during their nutritional recovery [12]. With SBI 
supplementation, they manifested a drop in fecal wet and dry weight, an observation that 
might suggest greater absorption of fat and energy perhaps as a result of this 
supplementation.  Although no major differences over time were seen in these children’s 
growth patterns, importantly, this intervention did not result in any adverse events.  
Second, Begin and others conducted a randomized trial in children less than 1 year of age 
from an impoverished region of Guatemala.  Children were randomly assigned to 4 
different nutritional supplements, two of which included SBI [13].  One hundred seven of 
these children received SBI.  Although this 8-month intervention did not improve growth 
patterns or morbidity as had been hoped, absolutely no adverse events related to SBI 
were observed.  In a third study, Earnest and others evaluated 52 adults, both men and 
women, with hypercholesterolemia to test the hypothesis that milk proteins such as SBI 
might have a salutary effect on cholesterol [14].  In this randomized, double-blind, 
placebo-controlled trial, SBI did result in a statistically significant reduction in LDL 
cholesterol over 6 weeks with no similar changes in the placebo group.  Once again, no 
adverse events occurred with the use of SBI.  Fourth, in a small 8-patient study of AIDS 
patients who were suffering from HIV enteropathy, supplementation with SBI over 8 
weeks at a dose of 2.5 grams orally BID yielded a drop in the frequency of bowel 
movements from 5.7 per day to 2 per day (unpublished date, personal communication 
from Gerald Klein, M.D., from Entera Health).  Patients also reported an improvement in 

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gastrointestinal-related quality of life that occurred concomitantly with supplementation.  
As anticipated, this intervention was again well-tolerated. 
 
Finally, a 51-patient unpublished study focused on irritable bowel disease, randomly 
assigning patients to SBI 10 grams per day versus SBI 5 grams per day versus placebo 
(unpublished date, personal communication from Gerald Klein, M.D., from Entera 
Health).  Patients assigned to the 10 g/day SBI supplement reported a drop in the number 
of days of symptoms, including abdominal pain (P=.008), flatulence (P=.003); bloating 
(P=.044); loose stools (P=.011), and urgency of defecation (P=.050), although 
statistically significant differences between groups were not detected.  At the same time, 
this dose of SBI was considered safe with no adverse events. These findings suggest a 
role for further SBI for its potential salutary bowel effects and for testing the 10 gram 
dose in the proposed postoperative study with a schedule of 5 grams twice a day. 
 
Taken together these 5 studies provide the following two conclusions:  1)  SBI is well-
tolerated, with no previously-reported adverse events, even among children, 
malnourished patients, AIDS patients, and patients with irritable bowel disease, all of 
whom would be considered highly vulnerable to severe adverse events with the 
administration of an unsafe intervention and 2)  these very preliminary studies indicate 
that in some circumstances, such as severely malnourished children, in AIDS patients 
with HIV enteropathy, and in patients with inflammatory bowel disease, SBI might 
confer a favorable effect on bowel integrity that appears in turn to translate into less 
diarrhea and fewer other gastrointestinal symptoms.  In view of the fact that these very 
preliminary clinical data are consistent with multiple similar observations in animals, a 
strong argument can be made for further studying SBI in postoperative gynecological 
cancer patients who undergo major, extensive surgeries and could conceivably benefit 
from a swifter recovery to enable them to receive potentially curative chemotherapy in a 
more timely manner.  Hence, in the current proposal/protocol, we test the hypothesis that 
SBI improves postoperative recovery to a greater extent than placebo. 
 
1.5 
Translational Component:  In effect, we hypothesize here that SBI, as a medical food, 
will enhance postoperative recovery.  However, to date, no biomarker or set of 
biomarkers have been demonstrated to serve as accurate predictors or correlates of 
convalescence.  As a result, this laboratory-based exploratory portion of this 
proposal/protocol will examine well-accepted inflammatory biomarkers and proteins that 
have previously been characterized within the gut microbiome in an effort to assess 
candidate biomarkers that might be suggestive of successful convalescence in a 
postoperative setting.  This approach is pragmatic and logical, in view of the fact that the 
surgeries conducted in ovarian cancer patients often entail a great deal of manipulation 
and sometimes resection of the bowel.  Hence, we propose to measure neopterin, soluble 
CD14, fatty acid binding protein, zonulin, a variety of inflammatory cytokines, and other 
such markers outlined in section 14.21 with the goal of identifying candidate biomarkers 
that might be utilized in a larger study that focuses further on testing SBI to enhance 
convalescence in a postoperative setting in ovarian cancer patients [14a,14b,14c,14d, 
14e]. This study will include a serial assessment at baseline, at a mid-time point, and at 
the end of the intervention. A complete listing of candidate markers appear in section 
14.21 of this protocol.  
 
1.6 
Consideration of Alternative Study Designs.  In view of the fact that this proposal tests a 
convalescent strategy that is novel and as yet has not received widespread attention, the 
investigators have considered a variety of alternative study designs, as outlined below: 

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1) A variety of other “nutritional boosters” have been touted, so why focus on SBI?  
Importantly, in addition to the scientific justification and prior clinical data described 
above, SBI’s manufacturing processes have been carefully monitored via quality 
assurance protocols for consistency, reliability, and safety.  Based in Iowa, Entera 
Health, Inc is providing SBI for this trial;  this product is manufactured by Proliant 
Biologicals, Boone, Iowa, USA in accordance with Good Manufacturing Practice 
(GMP) and FDA guidelines for medical good ingredients (21 CFR Part 110).  Entera 
Health is the largest manufacturer of bovine serum albumin (BSA), as used in 
research laboratories worldwide, and contributes protein products to major 
pharmaceutical companies throughout the United States to enable these other 
companies to proceed with the manufacturing and distributing of a variety of FDA-
approved agents. This degree of experience, demonstration of safety, and product 
awareness has enabled Entera Health, Inc to acquire for SBI “generally recognized as 
safe” (GRAS) FDA status that allows for the prompt testing of this agent in a variety 
of clinical settings without the need for an IND application. 
 
This latter point merits further explanation.  Numerous discussions with staff from 
Proliant Biologicals, including the Chief Medical Office, Dr. Gerry Klein, and 
members of the Mayo Clinic regulatory community, have provided direction to the 
study team, indicating that a submission to the FDA for an IND is not necessary (See 
Appendix VII).  These discussions have highlighted the following three points.  First, 
evidence of GRAS status 
(http://www.accessdata.fda.gov/scripts/fcn/gras_notices/GRN000169.pdf) has been 
provided.  Again, this product is food-based and “generally recognized as safe,” thus 
providing some reassurance of safe administration.  Second, Proliant Biologicals 
personnel have pointed out that, as per 21 CFR Part 105.3, this company is not 
attempting to palliate a disease state. Rather the focus of the current study is 
postoperative convalescence.  This complete lack of focus on a disease state again 
makes an IND unnecessary.  Third, this protocol attempts to enhance convalescence 
after surgery with the use of this food product, as per Title 21, Part 105, section (a), 
(1), (i), with no associated drug claim.  .  SBI is not a drug but rather a nutritional 
agent.  In the absence of a drug claim, that the testing of SBI does not require an 
IND. 
 
2) Quality-of-life assessment appears to be a very “soft” outcome.  Why not focus on 
another endpoint, such as time-to-chemotherapy administration itself?  We point out 
that the Symptom Distress Scale and the Postoperative Quality of Life questionnaires 
have been validated and used for many years to measure quality of life [15].  Such 
questionnaires have also been used in many settings, including cancer settings and 
after other major illness, such as post-myocardial infarction.  These instruments ask 
relevant questions related to bowel function, pain, fatigue, and other symptoms that 
are all highly germane to oncologists as they decide whether to begin chemotherapy 
in postoperative cancer patients.  As most oncologists will acknowledge, specific 
criteria for starting chemotherapy are not well-defined, but it is of paramount 
importance to assess the symptoms above in conjunction with general postoperative 
healing in making a decision on when to start postoperative chemotherapy.  
Moreover, it should be noted that the instruments above are brief and enable a 
patient-reported, paper-based formatting that provides for a highly practical approach 
to symptom assessment.  We point out that we had carefully considered evaluating 
time-to-chemotherapy administration as the primary endpoint for this study, but the 

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fact that this endpoint can be artifactually modified as a result of return appointment 
availability and other scheduling issues suggest that patient-reported quality of life is 
a more clinically accurate and meaningful primary endpoint for the current 
proposal/protocol. 
 
3) This study does not focus specifically on ovarian cancer patients, yet the underlying 
premise is that reduction of time-to-chemotherapy administration is important 
specifically in the management of ovarian cancer patients.  Why the discrepancy?  
The primary driving force for including all patients with gynecological surgeries is to 
complete this study quickly and consider future development strategies promptly. 
Given the fact that other gynecological surgeries also involve major operations and 
given that a quality of life outcome would be relevant to these patients as well, we 
decided to embark on a more encompassing study design that includes a wide-range 
of patients with difference gynecological cancer types.  Were a larger study to be 
planned, then a more narrow focus on ovarian cancer patients would be called for. 
 
4) What if SBI supplementation does not improve quality of life? A great deal of effort 
will have gone towards a negative neutral study.  If our hypothesis proves incorrect 
and we observe no improvement in postoperative recovery, as suggested by improved 
quality of life scores, in the SBI versus placebo arm, we will nonetheless have 
acquired prospective quality of  life data (based on pooling data in both arms in 
ovarian cancer patients) that will position us well to proceed with other future 
interventions to test ways to decrease the time-to-chemotherapy administration in 
postoperative ovarian cancer patients. 
 
 
2.0 
Goals 
 
2.1 
Primary Efficacy 
 
2.11 
To compare the time-to-quality of life (QOL) improvement from baseline in 
postoperative gynecological cancer patients who are receiving oral SBI vs. 
placebo. 
 
2.2 
Secondary Efficacy 
 
2.21 
To compare the surgical complication rates between oral SBI vs. placebo up to 1 
month post-surgery (safety endpoint). 
 
2.22 
To compare the QOL, as derived from the previously-validated Symptom 
Distress Scale, the PQL (Postoperative Quality of Life questionnaire), and the 
uniscale (overall QOL item) between patients receiving oral SBI vs. placebo. 
 
2.23 
To compare the grade 2 or worse adverse event rates for patients receiving oral 
SBI vs. placebo.  
 
2.24 
To characterize the adverse event profile of oral SBI in postoperative 
gynecological cancer patients (safety endpoint). 
 
2.25 
To compare supplement adherence between patients receiving oral SBI vs. 
placebo. 
 

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2.3 
Correlative Research 
 
2.31 
To explore whether candidate biomarkers are modified with SBI versus placebo. 
 
2.32 
As part of ongoing research, to bank leftover blood samples for future studies. 
 
2.33 
To explore quality of life during postoperative recovery after gynecologic 
surgery, regardless of whether or not patients take the study intervention/placebo 
or discontinue intervention/placebo early. 
 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria 
 
3.11 
Age ≥ 18 years. 
 
3.12 
Diagnosis of gynecological cancer of any type or strong suspicion for cancer. 
 
3.13 
Patients must have begun postoperative oral intake of food prior to registration. 
 
3.14 
Open laparotomy or laparoscopic surgery undertaken with cancer therapeutic 
intent (not a subsequent surgery to manage a postoperative complication) that 
had occurred ≤7 days prior to registration and that entailed more than a simple 
hysterectomy. 
 
3.15 
The following laboratory values obtained ≤21days prior to registration.  
• 
Creatinine ≤ 1.5 x the upper limit of normal (ULN) 
• 
Absolute neutrophil count ≥ 1500/mm3 
• 
Platelet count  ≥ 100,000/mm3   
 
3.16 
Ability to complete questionnaire(s) by themselves or with assistance. 
 
3.17 
Provide informed written consent. 
 
3.18   Negative (serum) pregnancy test done ≤7 days prior to randomization, for women 
of childbearing potential only. 
 
3.19 
Willing to provide mandatory baseline blood samples for correlative research 
purposes (see Section 6.12 and 14.0). 
 
3.2 
Exclusion Criteria  
 
3.21 
Symptomatic and/or untreated brain metastases. 
 
3.22 
Ongoing parenteral nutrition (receiving intravenous nutrition support at the time 
of enrollment).  Note: patients may be receiving maintenance IV fluids.  
 
3.23 
Current enrollment in any other trial that entails the concurrent administration of 
any other agent designed to enhance postoperative recovery. 
 
3.24 
Allergy to beef. 
 

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4.0 
Test Schedule 
 
Active Monitoring Phase 
 
Tests and procedures 
≤21 days prior to 
randomization 
Day 1 of Cycle 
2 and 3 (+/- 3 
days) 
Weekly from 
registration for 
12 weeks total 
At the end of 
intervention (+/- 
3 days) 
Observation/crossover 
(ends after 16 weeks 
of total study 
participation) 
Patient assessment (includes 
weight**) 
X 
 
 
 
 
Adverse event assessment 
X 
X** 
 
X** 
X** 
Pregnancy test1(Serum)  
X 
 
 
 
 
Hematology group  
 
HgB 
 
WBC 
 
PLT 
 
ANC 
X 
 
 
 
 
Chemistry group  
 
Creatinine 
X 
 
 
 
 
Patient Questionnaire 
Booklets2, (Appendix 2-5) 
X 
 
X 
X 
X 
Blood specimens (see 
Section 14.0)3,R 
X 
X* 
 
 
 
1. For women of childbearing potential only.  Must be done ≤7 days prior to registration. 
2. Patient questionnaire booklets must be used; copies are not acceptable for this submission. Patients are required to fill out the questionnaires at 
baseline, and weekly for the duration of study participation, (16 weeks total, includes patients who never started therapy). 
3. Blood specimens will be collected and submitted at baseline. Kits are required. Baseline blood specimen is to be collected after consent 
and prior to patient receiving study agent. 
R Research funded (see Section 19.0) 
*These blood draws are optional but strongly recommended. 
** If patient cannot return, this assessment can be done by phone by the study coordinator (includes patient reported weight). However, 
study questionnaires must be mailed back.   
 

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5.0 
Stratification Factors  
5.1 
Patient age: ≥ 65 years vs. < 65 years 
5.2 
Splenectomy and/or rectosigmoid resection:  yes vs. no 
5.3 
Optimally debulked cancer (complete nodal and omental removal, as appropriate, with 
<1 cm of residual tumor, if appropriate): yes vs. no 
5.4 
Cancer type:  ovarian vs. endometrial vs. other 
5.5 
Open laparotomy vs. laparoscopic surgery 
 
6.0  
Registration/Randomization Procedures 
6.1 
Registration Procedures 
 
6.11 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration/randomization application. The registration/ 
randomization application is available 24 hours a day, 7 days a week. Back up 
and/or system support contact information is available on the Web site. If unable 
to access the Web site, call the MCCC Registration Office at (507) 284-2753 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
 
The instructions for the registration/randomization application are available on 
the MCCC web page (http://hsrwww.mayo.edu/ccs/training) and detail the 
process for completing and confirming patient registration.  Prior to initiation of 
the protocol intervention, this process must be completed in its entirety and a 
MCCC subject ID number must be available as noted in the instructions.  It is the 
responsibility of the individual registering the patient to confirm the process has 
been successfully completed prior to release of the study agent.  Patient 
registration via the registration/randomization application can be confirmed in 
any of the following ways: 
• 
Contact the MCCC Registration Office (507) 284-2753.  If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
 
6.12 
A mandatory baseline correlative research component is part of this study, the 
patient will be automatically registered onto this component (see Sections 3.19 
and 14.1). 
 
An optional correlative research component is part of this study, there will be an 
option to select if the patient is to be registered onto this component (see Section 
14.0) 
 
• 
Patient has/has not given permission to give his/her blood sample(s) for 
research testing for Cycles 2 and 3 

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6.13 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients. 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
(fax: 507-284-0885).  If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
 
6.14 
Prior to accepting the registration, the registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
 
6.15 
Intervention on this protocol must commence at Mayo Clinic Rochester, under 
the supervision of a medical oncologist.  
 
6.16 
Intervention cannot begin prior to registration and must begin ≤ 7 days after 
registration. 
 
6.17 
Pre-intervention tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.18 
All required baseline symptoms (see Section 10.6) must be documented and 
graded. 
 
6.19a 
Study agent is available on site 
 
6.19b Blood draw kit is available on site.  
 
6.19c 
Patient questionnaire booklet is available on site; copies are not acceptable for 
this submission.  
 
6.19d At the time of randomization, the following will be verified: 
• 
Patient has/has not given permission for his/her blood sample(s) to be stored 
and used in future research of ovarian cancer at Mayo Clinic. 
• 
Patient has/has not given permission for his/her blood sample(s) to be stored 
and used in future research at Mayo Clinic to learn about, prevent, or treat 
any other health problems 
• 
Patient has/has not given Mayo Clinic permission to give his/her blood 
sample(s) to outside institutions 
 

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6.2 
Randomization Procedures 
 
6.21 
The factors defined in Section 5.0 will be used as stratification factors. 
 
6.22  
After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
intervention groups using the Pocock and Simon dynamic allocation procedure 
which balances the marginal distributions of the stratification factors between the 
intervention groups [16]. 
• 
Oral Serum Bovine Immunoglobulin (SBI)  
• 
Placebo 
 
6.3 
Procedures for Double-Blinding the Intervention Assignment 
 
6.31 
After the intervention assignment has been ascertained by the 
registration/randomization application, the patient’s study medication code 
number will be displayed on the confirmation of registration screen. 
 
6.32 
The data manager/nurse/pharmacist at the patient’s institution must contact the 
MCCC Registration Office for a code number when additional study product is 
needed for the patient. 
 
6.33 
The number of the intervention bottle/packet assigned to the patient will be 
recorded on the dosing form. 
 
6.34 
MCCC Registration Office personnel will monitor the supply of coded 
bottles/packets at each participating institution and will arrange for the oncology 
pharmacist to send further supplies to the participating institutions as needed. 
 
7.0 
Protocol Intervention 
7.1 
Dosing Intervention Schedule** 
 
Agent 
Dose 
Route 
Day 
Retreat 
Serum bovine 
immunoglobulin 
or placebo 
packets 
5 grams (1-packet) 
per each dose* 
PO 
Twice a day for 12 
weeks (3 cycles) 
Every 4 weeks 
*total dose is 10 grams per day   
** Patients must begin taking agent/placebo within 7 days of registration (exceptions can be made if delays occur 
related to shipping agent/placebo and should be documented in the patient study record). 
 
7.2 
Patients can be instructed in administration techniques and granted intervention 
independence with nursing staff approval. 
 
7.3 
Patients will be instructed to add the contents of one packet (5 grams) to a cup and 
dissolve the powder with approximately one-half cup (4 fl. ounces, or 120 mL) of water.  
The patient will stir to mix and drink the contents.  The patient will take one dose twice a 
day, in the morning and evening, with or without food. 
 

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7.4 
Breaking Codes in Double–Blinded Studies-The intervention code may not be broken 
except for emergencies.   
 
In the event of an emergency, call the MCCC Registration Office at (507) 284–2753 to 
break the code on Monday through Friday, 8:00 a.m. to 4:30 p.m. Central Time.  If the 
code must be broken after hours, assume the patient was assigned to active treatment and 
treat accordingly.  Place a call to the MCCC Registration Office and leave a message 
informing them of the need to un-blind a patient.  Provide your contact information so 
that MCCC Registration Office personnel can return the call the next business day. 
 
8.0 
Dosage Modification Based on Adverse Events  
 
There are no dose modifications in this trial. If the patient experiences a grade 1 or worse adverse 
event that is thought to be related to the study intervention, the patient should discontinue the 
intervention and proceed to the 4 week post intervention observation.  
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors 
should follow published guidelines of the American Society of Clinical Oncology 
2006 Update of Recommendations for the Use of White Blood Cell Growth Factors: 
An Evidence-Based Clinical Practice Guideline J Clin Oncol 24(19): 3187-3205, 
2006.  
 
9.3 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
intervention administration until 30 days after the final dose will be recorded in the 
medical records. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)     
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 

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and if the adverse event is related to the medical intervention or procedure (see 
Section 10.3).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4).  Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.52 
and 18.0). 
 
10.12 Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).  Grade is an essential element of the Guidelines and, in 
general, relates to severity for the purposes of regulatory reporting to NCI. 
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same 
as serious AE which is defined in the table in Section 10.4. 
 
10.2 
Expected vs. Unexpected 
 
• 
The determination of whether an AE is expected is based on the agent-
specific information provided in Section 15.0 of this protocol. 
 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of this protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is 
neither identified in nature, severity, or frequency of risk in the information 
provided for IRB review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, the 
following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical intervention suggest there is evidence to indicate a causal 
relationship between the agent and the adverse event.  
 

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10.4  
Expedited Reporting Requirements for Commercial Agent(s) ONLY: 
 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-IND/IDE trial 
within 30 Days of the Last Administration of a Commercial Agent 1, 2  
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥24 hrs 
Not required 
7 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in section 
10.41 of the protocol.  
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via MedWatch within 24 hours of 
learning of the AE, followed by a complete expedited report within 3 calendar days of the initial 24-
hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
Effective Date:  May 5, 2011 
 
Additional Instructions: 
1. An increased incidence of an expected adverse event (AE) is based on the patients treated 
for this study at their site. A list of known/expected AEs is reported in the package insert 
or the literature, including AEs resulting from an agent overdose. 
 
2. Mayo Clinic Cancer Center (MCCC) Institutions:  Use FDA Medwatch (Form 3500A) 
available in forms packet for Investigational agents or commercial/investigational agents 
on the same arm. Submit to Entera Health, Inc. within 24 hours of notification to: 
CANCERCROSAFETYIN@mayo.edu and dave.mathews@enterahealth.com.* 
 
*Note:  FDA Submission will not occur due to GRAS status of SBI - See Appendix VII 
 
 

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Event Type 
REPORTING PROCEDURE 
Other Grade 4 or 5 Events 
and/or Any Hospitalizations 
During Treatment Not 
Otherwise Warranting an 
Expedited Report 
Complete a Notification Form: Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form electronically via 
the MCCC Remote Data Entry System or paper form within 
5 working days of the date the clinical research associate 
(CRA) is aware of the event(s) necessitating the form. 
If an expedited written report has been submitted, this form 
does not need to be submitted. 
 
10.41 Special Situations for Expedited Reporting 
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events 
 
An expedited report may not be required for specific Grade 1, 2 and 3 Serious 
Adverse Events where the AE is EXPECTED. Any protocol specific reporting 
procedures MUST BE SPECIFIED BELOW and will supersede the standard 
Expedited Adverse Event Reporting Requirements:  
System Organ Class (SOC) 
Adverse event/Symptoms 
CTCAE Grade at which 
the event will not be 
expeditedly reported. 
Blood and lymphatic system 
disorders 
Hemoglobin decreased 
≤Grade 2 
Lymphocyte count decreased 
≤Grade 2 
Investigations 
Neutrophil count decreased 
≤Grade 2 
Platelet count decreased 
≤Grade 2 
White blood cell decreased 
≤Grade 2 
 
Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 
 
10.5 
Other Required Reporting 
 
10.51 Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
abnormities or birth defects, must be reported immediately to the study team. 
 

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10.52 Death 
 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention requires expedited reporting within 
24-hours to the study team. 
 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention requires 
expedited reporting within 24-hours to the study team. 
 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal:  A disorder characterized by cessation of life during the 
first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be attributed to a CTCAE 
term associated with Grade 5. 
 
• 
Sudden death NOS:  A sudden (defined as instant or within one hour of 
the onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with a disease process) 
should be submitted. 
 
10.53 Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
• 
All secondary malignancies that occur  during the study require reporting 
to the study team.  Three options are available to describe the event: 
 
o 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o 
Myelodysplastic syndrome (MDS) 
 
o 
Treatment-related secondary malignancy 
 

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• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting mechanisms 
outlined in each protocol. 
 
10.54  Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy). Second 
malignancies require ONLY routine reporting. 
 
10.6 
Required Routine Reporting 
 
Adverse events to be graded at each evaluation and preintervention symptoms/conditions 
to be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the 
table below: 
System Organ Class (SOC)  
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Gastrointestinal disorders 
Abdominal pain 
X 
X 
 
Bloating 
X 
X 
 
Diarrhea 
 
X 
 
Baseline number of stools per day 
X 
 
 
Flatulence 
X 
X 
 
Nausea 
X 
X 
 
Vomiting 
X 
X 
General disorders and administration site 
conditions 
Fatigue 
X 
X 
Infections and infestations 
Wound infection 
X 
X 
Injury, poisoning and procedural complication Wound complication 
X 
X 
 
Wound dehiscence 
X 
X 
 
10.61 Submit via appropriate MCCC Case Report Forms (i.e., paper or  electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6 
 
10.611 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
intervention or procedure. 
 
10.612 Grade 3 and 4 AEs regardless of attribution to the study intervention or 
procedure. 
 
10.613 Grade 5 AEs (Deaths) 
 
10.6131 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
intervention or procedure. 
 
10.6132 
Any death more than 30 days after the patient’s last study 
intervention or procedure that is felt to be at least possibly 
intervention related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 

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11.0 
Intervention Evaluation: None 
 
12.0 
Descriptive Factors: None 
 
13.0 
Follow–up Decision at Evaluation of Participants  
13.1 
Participants will receive 3 cycles of therapy (12 weeks) with oral SBI or placebo, 
followed by a 4 week observation visit. No additional follow-up is required for these 
patients beyond the 4 week observation time point. 
 
13.2 
Participants who go off the intervention early for unacceptable adverse events or patient 
refusal of further treatment will go to the observation phase. Patients can continue in the 
observation phase for total of 16 weeks of study participation.  
 
13.3 
Participants where post-operative problems occur, study treatment cannot begin, and 
participant agrees to complete questionnaires will crossover to QOL assessment only. 
These participants will be followed per the test schedule (Section 4.0). 
 
 13.4 
A participant is deemed ineligible if after registration, it is determined that at the time of 
registration, the participant did not satisfy each and every eligibility criteria for study 
entry. The patient will go directly off study. 
• 
If the participant received therapy, all data up until the point of confirmation 
of ineligibility must be submitted. 
• 
If the participant never received therapy, on-study material must be 
submitted. 
 
13.5 
A participant is deemed a major violation, if protocol requirements regarding intervention 
in cycle 1 of the initial intervention are severely violated that evaluability for primary end 
point is questionable.  All data up until the point of confirmation of a major violation 
must be submitted.  The patient may continue therapy off-protocol at the discretion of the 
physician as long as there are no safety concerns, and the patient was properly registered. 
 
13.6 
A participant is deemed a cancel/withdrawal if he/she is removed from the study for any 
reason before any study intervention is given or participant does not agree to crossover to 
QOL assessment only. On-study material and the End of Active Intervention/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 

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14.0 
Body Fluid Biospecimens 
 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be collected for this Protocol 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection Tube 
(color of tube 
top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Baseline 
Day 1 of 
Cycle 2 
and 3 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions for 
Storage 
/Shipping 
Correlative Studies 
Mandatory 
Blood 
2 purple top 
tubes 
Volume of 
7cc 
X 
 
Yes 
Frozen at -80 
centigrade, 
Shipped frozen 
Correlative Studies* 
Optional 
Blood 
2 purple top 
tubes 
Volume of 
7cc 
 
X 
Yes 
Frozen at -80 
centigrade, 
Shipped frozen 
 
*If the patient does not participate in the optional blood draws, it does not cause the patient to be ineligible; however, the collection of the 
blood is strongly recommended. 
 

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14.2 
Collection and Processing  
 
14.21 Correlative Research  
 
 
This protocol will check the following laboratory-based translational 
studies from the blood at baseline and at the time of completion of the 
intervention: 
 
1. Biomarkers to explore convalescence will be examined. Biomarkers 
associated with bacterial translocation, enterocyte damage and 
intestinal epithelial barrier function will be measured with and 
without lipopolysaccharide (LPS) stimulation in vitro.  LPS binding 
protein (LBP), bactericidal/permeability increasing protein (BPI), 
soluble CD14 (sCD14),16s rDNA, intestinal fatty acid binding 
protein (I-FABP) and zonulin in plasma will be measured in this 
manner. 
 
2. We will also measure plasma CRP and d dimer.  Commercially 
available enzyme-linked immunosorbent assays will be used 
according to the manufacturer’s instructions for measuring for 
inflammation-coagulation parameters. 
 
3. Plasma cytokines involved in the pro-inflammatory cascade will be 
assessed.  These cytokines include TNF-α, IFN-γ, IL 1, IL 6, IL 10, 
as well as neopterin.  Standard enzyme-linked immunosorbent assay 
kits will be used according to manufacturer’s recommendations. 
 
 
For the translational component of this study, patients will have blood 
drawn at the time points specified in section 4.0.   
 
Blood will be drawn in 2 purple top tubes capable of holding a blood 
volume of 7cc.  Each tube will be spun down, and the plasma will be 
stored at -80 degrees centrigrade. 
 
Frozen plasma will be batched and sent to EnterHealth at the end of the 
study (see below for shipping details.) ELISA kits will be used to assay 
all the proteins.  
 
14.3 
Shipping and Handling 
 
14.31 Kits will be used for this study. 
 
14.311 Kits will be supplied by the Biospecimen Accessioning and Processing 
Shared Resource (BAP).  
 
14.312 The kit contains supplies and instructions for collecting, processing and 
shipping specimens. 
 
14.313 Participating institutions may obtain kits by faxing the Supply Order 
Form to the number listed on the form.  Because we are charged for all 

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outgoing kits, a small, but sufficient, supply of the specimen collection 
kits should be ordered prior to patient entry.  Supply Order Forms must 
be filled in completely and legibly for quick processing. 
 
14.314 Kits will be sent via Fed Ex Ground at no additional cost to the 
participating institutions.  Allow at least two weeks to receive the kits. 
 
14.315 Kits will not be sent via rush delivery service unless the participating 
institution provides their own Fed Ex account number or alternate 
billing number for express mail.  Cost for rush delivery of kits will not be 
covered by the study. 
 
14.316 All specimens must be collected and shipped Monday – Thursday 
ONLY. 
 
14.32 Shipping Specimens 
 
14.321 Samples will be shipped on dry ice via FEDEX at the end of the study to 
the following address: 
 
ATTENTION:  Eric Weaver PhD 
Chief Scientific Officer 
Entera Health 
2425 SE Oak Tree CT 
Ankeny, Iowa 50021-7102 
Phone: 515-289-7662 
 
15.0 
Product Information 
 
15.1 
Serum-Derived Bovine Immunoglobulin Protein Isolate (SBI, EnteraGamTM) or 
matching placebo 
 
15.11 Background: Serum-derived bovine immunoglobulin protein isolate is an orally 
administered prescription medical food containing a proprietary formulation of 
bovine immunoglobulin (> 50% IgG) and other serum proteins.  The product is 
manufactured in accordance with Good Manufacturing Practices and FDA 
guidelines for medical food ingredients.   
It is indicated for the nutritional management of a patient with enteropathy who, 
because of therapeutic or chronic medical needs, has limited or impaired capacity 
to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients. 
Serum-derived bovine immunoglobulin protein isolate must be non-digestible 
and able to reach the gastrointestinal tract to benefit an immunocompromised or 
otherwise dysfunctional GI mucosa. In humans, SBI is used as a passive, 
immunity-enhancing nutrient to augment traditional medications. Clinical studies 
have provided evidence that SBI lowers total and LDL cholesterol in patients 
with mild hypercholesterolemia, reduces symptoms of gastroenteropathy in IBS-
D and HIV+ patients, increases GI absorption, and decreases GI permeability. 
 

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15.12 Formulation: Serum-derived bovine immunoglobulin protein isolate is a light-
colored powder composed of finely ground flakes of immunoglobulin and other 
serum proteins (ie, transferrin, albumin, alpha and beta proteins).  Serum-derived 
bovine immunoglobulin protein isolate is supplied in individual packets 
containing 5 grams of SBI and the following ingredients: dextrose, orange 
(natural and artificial flavors) and coloring (Yellow #6). 
Matching placebo packets will be supplied and will appear identical to SBI with 
respect to volume, appearance, and taste. The ingredients of the placebo will 
include dextrose, orange (natural and artificial flavors) and coloring (Yellow #6). 
 
15.13 Preparation and storage:  Blinded investigational product (SBI or 
matching placebo) will be packaged in kits containing 5 grams of SBI per 
each packet or as matching placebo packets.  An investigational product 
kit with a unique ID number will contain 14 packets (7 days of required 
product) and 4 extra packets (18 packets total) to accommodate the 
flexibility with return visits.  
Packets are to be stored at 20-25°C (68-77°F), with excursions permitted 
between 15-30°C (59-86°F). 
 
15.14 Administration:  SBI is administered orally or enterally.  Each patient will be 
instructed to add the contents of one packet (5 grams) to a cup and dissolve the 
powder with approximately on-half cup (4 fl. ounces or 120 mL) of water.  The 
patient will stir to mix and drink the contents.  The patient will take one dose 
twice a day, in the morning and the evening, with or without food.  Foods such as 
applesauce or pudding may be used instead of liquid to blend the product if the 
patient desires.   
 
15.15 Potential Agent Interactions:  No significant interactions of SBI with 
commonly prescribed medications have been observed.   
 
15.16 Known potential toxicities:  Study subjects with known beef allergies or 
allergies to other components of SBI should not take SBI.   
As with any ingested food or product, subjects who develop a hypersensitivity or 
food intolerance to SBI should discontinue its use. 
Subjects who are pregnant or breastfeeding should not take SBI, as there are no 
data regarding the effects. 
Serum-derived bovine immunoglobulin has self-affirmed generally recognized as 
safe (GRAS) status, with no objections from the FDA, and is demonstrated to be 
safe and well tolerated in pediatric and adult patients.  SBI is marketed in 
Mexico, the Czech Republic, Japan, Egypt, and the United States.  More than 
100,000 kg of SBI in various dosages have been ingested by the general 
population since 2001.  No serious adverse events have been reported to the 
manufacturer or the FDA. 
Literature reports indicate AEs include worsening or reoccurrence of diarrhea, 
constipation, and worsening neuropathy.  Increased urination, stomach cramps, 
fatigue, headache, sore throat, softened stools, and nausea have also been 
reported. 

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15.18 Agent procurement: 
Serum-derived bovine immunoglobulin protein isolate and matching placebo will 
be manufactured by Proliant Biologicals, Boone, Iowa in accordance with Good 
Manufacturing Practice (GMP) and FDA guidelines for medical good ingredients 
(21 CFR Part 110) and will be provided by Entera Health Inc. 
 
15.19 Nursing Guidelines:  
 
15.191 Due to the early investigational nature of this medical food, not all side 
effects can be known at this time. Assess for side effects  and monitor 
patients closely. 
 
15.192 Patients with beef allergy or intolerance should not take SBI. 
 
15.193 GI adverse events may occur. Treat symptomatically and monitor for 
effectiveness. 
 
15.194 Warn of possibility of neuropathy. Instruct patients to report any 
development or increase in neuropathy to the study team. 
 
15.195 Headache may occur. Treat symptomatically and monitor for 
effectiveness. 
 
16.0  
Statistical Considerations and Methodology  
16.1 
Overview  
 
This randomized study is pilot in nature insofar as its main goal is to provide preliminary 
data to put in place the groundwork for a much larger, definitive study.  The primary aim 
of the current study is to compare the time-to-quality of life (QOL) improvement from 
baseline in postoperative gynecological cancer patients who are receiving oral SBI vs. 
placebo.  If this trial can provide preliminary evidence that oral SBI significantly 
improves the time-to-QOL improvement as compared to placebo, further study would be 
warranted to determine whether the administration of oral SBI shortens the time-to-
chemotherapy administration post-operatively in ovarian cancer patients.  In addition to 
time-to-QOL improvement, this trial will also compare adverse event rates, complication 
rates, QOL from validated QOL tools, and intervention compliance between patients 
receiving oral SBI vs. placebo.  
 
16.11 Primary Endpoint and Statistical Design:  To compare the time-to-QOL 
improvement from baseline in postoperative gynecological cancer patients who 
are receiving oral SBI vs. placebo. 
 
Final Analysis: 
The primary goal of this trial is to compare the oral SBI arm (experimental) to 
the placebo arm (standard), where the alternative hypothesis is that the 
experimental arm has a shorter time to QOL improvement from baseline as 
compared to the standard arm.  For this primary endpoint, the total score of the 
14-item Postoperative Quality of Life (PQL) tool [15] will be used, where the 
total score could range from 0 to 140 (0 being the worst and 140 being the best).  
These scores will be converted to the percentage scale, where a score of 140 will 

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be converted to 100 and a score of 0 will remain as 0.  This QOL will be 
measured weekly for the entire 12 week length of the study and at the end of the 
intervention.  QOL improvement will be defined as at least a 10 point increase in 
the QOL score from baseline, on the percentage scale.  This 10 point change 
represents a clinically meaningful improvement in QOL based on work done by 
Jeff Sloan [17].  The date at which the QOL score is first known to increase by at 
least 10 from baseline (on the 100 point scale), will be considered the event date 
for the purpose of analysis.  Patients without at least a 10 point increase in QOL 
from baseline, will be censored on their last QOL evaluation date up to a 
maximum of 12 weeks.  We will enter a total of 70 evaluable patients (35 per 
arm) using a 1:1 randomization scheme.  The primary analysis will be a 
comparison of oral SBI vs. placebo using a two-sided log-rank test between the 2 
Kaplan-Meier curves [18].  This analysis will take place after an approximate 16 
month accrual period, and after 66  total events across both arms combined 
(which should happen after about 12 weeks of follow-up in all evaluable 
patients).  Additionally, we assume a constant accrual rate over the course of the 
study, and that no patients will drop-out of the study, since historically the lost to 
follow-up rate is <1%.  To determine the appropriate sample size of 35 evaluable 
patients per arm, we assumed exponential survival and that the median time-to-
QOL improvement is around 3 weeks in the oral SBI arm and 6 weeks in the 
placebo arm (HR=2).    This hazard ratio is based on our institution’s data which 
shows that patients often begin postoperative chemotherapy 6 weeks after 
surgery.  These assumptions yield 80% power to detect a significant difference 
between the arms using a 2-sided log-rank test at alpha=0.05.  All patients who 
meet the eligibility criteria, sign the consent form, and are randomized, will be 
considered evaluable for this endpoint.  All eligible patients will be followed a 
maximum of 12 weeks.  If the 2-sided log-rank test p-value is < 0.05 showing 
significantly shortened time-to-QOL improvement in the oral SBI arm as 
compared to placebo, further study will be warranted.  Of course, any final 
decisions will be based on all primary and secondary endpoints.   
 
16.2 
Sample Size:  The study design to be utilized is fully described in Section 16.11 (see 
above).  There will be 35 evaluable patients randomized to each arm of this study.  
We anticipate accruing an additional 15 patients to each arm to account for ineligibility, 
cancellation, major intervention violation, or other reasons.  Therefore, maximum accrual 
is  100 patients (50 per arm).   
 
16.3 
Accrual Time and Study Duration:  The anticipated accrual rate is approximately 4-5 
patients per month.  Therefore, the accrual period for this randomized Pilot study is 
expected to be around 24 months.  The final analysis can begin approximately 28 months 
after the trial begins, i.e., as soon as the last patient registered has been observed for 4 
months. 
 
16.4 
Other Considerations: Adverse events as well as scientific discoveries or changes in 
standard care will be taken into account in any decision to terminate the study. 
 

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16.5 
Data & Safety Monitoring: 
 
16.51 The principal investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing.  The trial is monitored continually by the study team 
who are notified of every grade 4 and 5 event in real time.  The Mayo Clinic 
Cancer Center (MCCC) Data Safety Monitoring Board (DSMB) is responsible 
for reviewing accrual and safety data for this trial at least twice a year, based on 
reports provided by the MCCC Statistical Office.   
 
16.52 Adverse Event Stopping Rules:  The stopping rules specified below are based on 
the knowledge available at study development.  We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the 
intervention(s) under investigation.  The study team may choose to suspend 
accrual because of unexpected adverse event profiles that have not crossed the 
specified rule below.  CTCAE v4.0 will be used to determine grading for these 
stopping rules. 
 
We expect about 10% of patients to experience grade 3 or worse adverse events 
(at least possibly related to the study intervention).  In addition, we expect less 
than 1% of patients to experience a Grade 5 adverse event, at least possibly 
related to the study intervention. Accrual will be temporarily suspended to this 
study if at any time we observe adverse events that satisfy any of the following 
within each arm separately (i.e. if any of the following occur in arm A or arm B, 
we will suspend accrual to the trial): 
 
• 
If at any time 4 or more in the first 20 treated patients (or 20% or more 
after the first 20) experience a Grade 3 or worse adverse event (possibly, 
probably, or definitely related to the intervention).  
• 
If at any time, 1 patient experiences a grade 5 adverse event (possibly, 
probably, or definitely related to the intervention).  
  
We note that we will review all Grade 5 adverse events on a case-by-case basis 
as well (regardless of attribution), and may suspend accrual after just one  
Grade 5 event, if we feel it is necessary for patient safety. 
 
16.6 
Definitions and Analyses of Secondary Endpoints:  All these endpoints will be assessed 
individually and will also be compared between the 2 arms.  Monthly phone calls may be 
used to collect the secondary endpoint information for each patient, including adverse 
events, surgical complications, and other data (e.g. patient reported weight, intervention 
compliance, etc.).  We will be assessing, reporting on, and potentially analyzing all the 
data collected from these monthly telephone calls.   
 
16.61  Adverse Events:  All eligible patients who have intitiated therapy will be 
considered evaluable for adverse event analyses.  The maximum grade for each 
type of adverse event will be recorded for each patient up to 16 weeks post-
randomization (12 weeks of intervention + 1 month post-intervention observation 
timepoint), and frequency tables will be reviewed to determine adverse event 

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patterns.  The overall adverse event rates for grade 2 or higher adverse events, 
will be compared using Chi-Square or Fisher’s Exact tests.  In addition, the 
surgical complication rates (up to 1 month post-surgery) will also be compared 
between the 2 arms using Chi-Square or Fisher’s Exact tests.  
 
16.62   Intervention Compliance:  Intervention compliance will be assessed using the 
Compliance Questionnaire in Appendix V.  The frequency and percentage for 
each Compliance Questionnaire category will be summarized descriptively by 
cycle and by intervention arm.  In addition, cycle by cycle compliance data will 
be compared between the 2 arms using a Chi-square test.   
 
16.63 Quality of Life:  QOL will be measured with 3 QOL tools.  For the primary 
endpoint, the total score from the 14-item Postoperative Quality of Life (PQL) 
tool [15] (Appendix II) will be used (16.11).  As a secondary analysis, all 14 of 
the individual items from the PQL tool (Appendix II), along with the 4 additional 
items after the PQL questions (Appendix II) will be analyzed and compared 
between the 2 intervention arms.  In addition, the time-to-QOL improvement will 
be compared between the 2 arms for any increase (> 0) from baseline for the total 
score from the PQL tool.  This will be done descriptively, and using a Kaplan-
Meier analysis [18], where any increase in the QOL from baseline will represent 
an event.  QOL will also be measured using the Uniscale (Appendix III), and the 
previously-validated Symptom Distress Scale (SDS; Appendix IV).  These QOL 
tools will measure QOL at baseline, every week up to 12 weeks post-
randomization, and at the end of intervention.  Differences between post-
randomization and baseline QOL scores will be analyzed and compared between 
the 2 arms using a Wilcoxon Rank-sum test.  Also, other graphical and statistical 
methods will be used to compare the QOL and time-to-QOL improvement 
between the 2 arms.  As an exploratory analysis, we will also collect QOL data 
on patients who  do not start intervention/placebo or discontinue 
intervention/placebo early and are willing to be followed per the test schedule 
(Section 4).  This analysis will be descriptive in nature to see if these patients 
have a poorer QOL than patients who stay on study. 
 
16.64 Translational Component:  The hypothesis is that oral SBI will improve 
postoperative recovery.  However, we know of no biomarkers indicative of 
postoperative recovery.  Hence in an exploratory manner, we will measure a host 
of candidate biomarkers.  This study will include serial assessment at baseline, at 
a mid-way timepoint, and at the end of the intervention intervention.  The 
differences between biomarker values over time will be compared between the 2 
intervention arms using a Wilcoxon Rank-sum test.  In addition, other graphical 
and statistical methods will be used to compare the data over time between oral 
SBI and placebo.  All these analyses will be considered hypothesis-generating. 
 
16.7 
Inclusion of Women and Minorities 
 
16.71   This study will be available to all eligible patients, regardless of race, or ethnic 
origin. 
 
16.72   There is no information currently available regarding differential effects of this 
regimen in subsets  defined by race, or ethnicity, and there is no reason to expect 
such differences to exist.  Therefore, although the planned analysis will, as 

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always, look for differences in intervention effect based on racial groupings, the 
sample size is not increased in order to provide additional power for subset 
analyses. 
 
16.73 The geographical region served by the Mayo Clinic has a population which 
includes approximately 5% minorities.  We expect about 5% of patients will be 
classified as minorities by race and all will be women.  Expected sizes of racial 
subsets are shown in the following table: 
Accrual Estimates by Ethnicity/Race 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
• 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 
17.0  
Pathology Considerations/Tissue Biospecimens: None 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
0 
0 
0 
Not Hispanic or Latino 
100 
0 
0 
100 
Ethnic Category: Total of all subjects 
100 
0 
0 
100 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
2 
0 
0 
2 
Black or African American 
3 
0 
0 
3 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
95 
0 
0 
95 
Racial Category: Total of all subjects 
100 
0 
0 
100 

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18.0 
Records and Data Collection Procedures   
18.1 
Submission Timetable 
 
18.11 Initial Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study Form 
≤2 weeks after registration 
Baseline Adverse Event Form 
Research Blood Submission Form - Baseline 
(see Section 14.0) 
End of Active Intervention/Cancel 
Notification Form 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
Patient Questionnaire - Baseline Booklet 
≤2 weeks after registration - Patient questionnaire booklet 
must be used; copies are not acceptable for this submission. 
Patient Questionnaire Booklet Compliance 
Form 
≤2 weeks after registration - This form must be completed 
only if the Patient Questionnaire – Baseline booklet contains 
absolutely NO patient provided assessment information. 
 
18.12 Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during the 
intervention period 
At end of intervention 
Observation/Crossover 
Nurse/CRA Evaluation/Intervention 
Form 
X 
X 
 
Nurse/CRA Observation Form (4 
weeks after completion of intervention 
 
 
X 
Adverse Event Form 
X 
X 
X* 
Research Blood Submission Form 
X (see Section 14.0) 
 
 
Patient Questionnaire  
X1 
X1 
X 
Patient Questionnaire Booklet 
Compliance Form 
 
X2 
 
X2 
 
End of Active Intervention/Cancel 
Notification Form 
 
X 
 
Notification Form – Grade 4 or 5 Non-
AER Reportable 
Events/Hospitalization Form 
At each occurrence 
(see Section 10.0) 
 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
 
* If the patient does not start therapy, adverse events will not be collected. 
1. Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
2.This form must be completed only if the Patient Questionnaire contains absolutely NO patient provided 
assessment information. 
 

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19.0  
Budget 
 
19.1 
Costs charged to patient:  routine clinical care 
 
19.2 
Tests to be research funded: Research samples. 
 
19.3 
Other budget concerns: None 
 

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20.0 
References 
 
1.  Aletti GD, Gallenberg MM, Cliby WA, Jatoi A, Hartmann LC.  Current management of strategies for 
ovarian cancer.  Mayo Clin Proc 2007;  82:751-70, 2007. 
 
2.  Chi DS, Eisenhauer EL, Zivanovic O, et al.  Improved progression-free and overall survival in 
advanced ovarian cancer as a result of a change in surgical paradigm.  Gynecological Cancer 2009;  
114:26-31. 
 
3.  Chi DS, Zivanovic O, Levinson KL, et al.  The incidence of major complications after the performance 
of extensive upper abdominal surgical procedures during primary cytoreduction of advanced ovarian, 
tubal, and peritoneal carcinomas.  Gynecological Cancer  2010;  119:38-41. 
 
4.  Magtibay PM, Adams PB, Silverman MB, et al.  Splenectomy as part of cytoreductive surgery in 
ovarian cancer.  Gynecologic Oncology 2006;  102:  369-374. 
 
5.  Mahner S, Eulenburg C, Staehle A, et al.  Prognostic impact of the time interval between surgery and 
chemotherapy in advanced ovarian cancer:  analysis of prospective randomized phase III trials.  Eur J 
Cancer 2012, August 23rd. 
 
6.  Fisher B, Gunduz N, Saffer EA.  Influence of the interval between primary tumor removal and 
chemotherapy on kinetics and growth of metastases.  Cancer Research 1983; 43:1488-1492. 
 
7.  Gunduz N, Fisher B, Saffer EA.  Effect of surgical removal on the growth and kinetics of residual 
tumor.  Cancer Res 1979;  39:3861-3865. 
 
8.  Larsen E, Blaakaer J.  Epithelial ovarian cancer:  does the time interval between primary surgery and 
postoperative chemotherapy have any prognostic importance?  Acta Obstetricia et Gynecologica 2009;  
88:373-377. 
 
9.  Jiang R, Chang X, Stoll B, et al.  Dietary plasma protein reduces small intestinal growth and lamina 
propria cell density in early weaned pigs.  J Nutr 2000;  130:21-26. 
 
10.  Peace RM, Campbell J, Polo J, et al.  Spray-dried porcine plasma influences intestinal barrier 
function, inflammation, and diarrhea in weaned pigs.  J Nutr 2011; May 25th. 
 
11.  Perez-bosque A, Miro L, Maijo M, et al.  Dietary supplementation with bovine immunoglobulins 
ameliorates colitis in mdr1a-/mice (submitted) 
 
12.  Lembcke JL, Peerson JM, Brown KH.  Acceptability, safety, and digestibility of spray-dried bovine 
serum added to diets of recovering malnourished children. J Pediatri Gastroenterol Nutr 1997;  25:381-4. 
 
13.  Begin F, Santizo MC, Peerson JM, Torun B, Brown KH.  Effects of bovine serum concentrate, with 
or without supplemental micronutrients, on the growth, morbidity, and micronutrient status of young 
children in a low-income, peri-urban Guatemalan community. Eur J Clin Nutr 2008;  62:39-50. 
 
14.  Earnest C, Jordan A, Safir M, et al.  Cholesterol-lowering effects of bovine serum immunoglobulin in 
participants with mild hypercholesterolemia.  Am J Clin Nutr 2005;  81:792-8. 
 
14a.  Fasano A.  Intestinal permeability and its regulation by zonulin:  diagnostic and therapeutic 
implications.  Clin Gastoenterol Hepatol 2012;  1096-100. 
14b.  Kralisch S. Fasshauer M.  Adipocyte fatty acid binding protein:  a novel adipokine involved in the  

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pathogenesis of metabolic and vascular disease?  Diabetologia 2013;  56: 10-21. 
 
14c.  Gosalbes MJ, Abellan JJ, Durban A, et al.  Metagenomics of human microbiome:  beyond 16s 
rDNA.  Clin Microbiol Infect 2012;  18 Suppl 4:47-9. 
 
14d.  Reiner AP, Lange EM, Jenny NS, et al.  Soluble CD14:  genomewide association analysis and 
relationship to cardiovascular risk and mortality in older adults.  Aterioscler Thromb Vasc Biol 2013;  
33:158-64. 
 
14e.  Husain N, Tokoro K, Popov JM, et al.  Neopterin concentration as an index of disease activity in 
Crohn’s disease and ulcerative colitis.  J Clin Gastroenterol 2013;  47:246-51. 
 
15.  Delaney CP, Lindsetmo RO, O’Brien-Ermlich B, et al.  Validation of a novel postoperative quality of 
life scoring system.  Am J Surg 2009;  197:382-5. 
 
16. Pocock SJ, Simon R.  Sequential Treatment Assignment with Balancing for Prognostic Factors in the 
Controlled Clinical Trial. Biometrics 31(1):103-115, 1975 Mar. 
 
17. Sloan JA. Assessing the minimally clinically significant difference: scientific considerations, 
challenges and solutions. COPD 2005;2: 57–62. 
 
18. Kaplan E, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 53:457-
481, 1958. 
 
 

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Appendix Ia BASELINE PATIENT INFORMATION SHEET 
Patient Completed Baseline Quality of Life Booklet 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains questions 
about your symptoms.   
 
These forms sometimes ask repeatedly for very similar information.  This is done 
intentionally in order to get a clear understanding of your condition.  Please answer all of 
the questions, even if they sound similar to a question you have already answered.   
 
1. This booklet contains the following questionnaires:  
 
a.   Postoperative Quality of Life (PQL) Questionnaire 
 
b.   UNISCALE 
 
c.   Symptom Distress Scale (SDS) 
 
2. These questionnaires are to be filled out at baseline.   
 
3. Please complete the booklet and return it to your nurse or doctor before you start the 
study intervention.   
 
4.  It is very important that you return the booklet to us.   
 
 
 
Thank you for taking the time to help us. 
 
 

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Appendix Ib DURING Intervention PATIENT INFORMATION SHEET 
Patient Completed Quality of Life Booklet (during therapy/observation/crossover) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains questions 
about your symptoms.   
 
These forms sometimes ask repeatedly for very similar information.  This is done 
intentionally in order to get a clear understanding of your condition.  Please answer all of 
the questions, even if they sound similar to a question you have already answered.   
 
1. This booklet contains the following questionnaires:  
 
a.   Postoperative Quality of Life (PQL) Questionnaire 
 
b.   UNISCALE 
 
c.   Symptom Distress Scale (SDS) 
 
d. Compliance Questionnaire 
 
 
2. These questionnaires are to be filled out weekly for a total of 16 weeks; within the 12 
weeks of Intervention/Observation/Crossover. 
 
 
3. Please complete the booklet at the appropriate times and return it to your nurse or doctor 
on a monthly basis and then at the end of your study intervention.   
 
 
4.  It is very important that you return the booklet to us, whether you finish the study or not.   
 
 
 
Thank you for taking the time to help us. 

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Appendix II Postoperative Quality of Life Questionnaire 
 
Name and  
Patient number ____________________________ Date_________________  
 
The following questions are designed to gauge your current quality of life. Circle the 
answer that best indicates how you feel.  
 
1. Quality of Life    
(0 = worst; 10 = best)  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
2. Quality of Health  
(0 = worst; 10 = best)  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
3. Level of Energy  
(0 = worst; 10 = best)  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
4. Pain at Rest  
No Pain  
 
 
 
 
 
 
 
Worst pain  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
5. Pain at Current Maximum Level of Activity  
No Pain  
 
 
 
 
 
 
 
Worst pain  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
6. Severity of Nausea or Vomiting  
No nausea or vomiting  
 
 
 
   
 
Worst nausea  
 
 
 
 
 
 
 
 
 
or vomiting 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
7. Fatigue  
No Fatigue  
 
 
 
 
 
 
 
Worst fatigue  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
8. How close is your bowel function to normal?  
(0 = most abnormal; 10 = normal)  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
9. How close are you to overall normal functioning for you? (0 = most abnormal; 10 = normal)  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
10. How close are you to your normal ability to get around the house? (0 = most abnormal; 10 = 
normal)  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
11. How close are you to your usual level of leisure activity? (0 = most abnormal; 10 = normal)  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 

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12. At what level is your sexual activity compared with normal? (0 = most abnormal; 10 = normal)  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
 
13. What is your current level of happiness: (0=sad; 10=happy)  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
14. What is your satisfaction with your overall level of medical care, including and since any 
surgery? (0=dissatisfied; 10=100%satisfied)  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
 
 
 
Additional Questions related to Quality of Life Post-surgery 
 
1.   Level of sleepiness 
 
Totally alert    
 
 
 
 
 
 
Very sleepy 
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
10 
 
 
2.  How many times per day on average did you experience nausea or vomiting? 
 
Never  
1-2 times  
3-5 times  
 
> 5 times 
 
 
3.  How many times per day on average did you have a bowel movement 
 
None          1 time             2-3 times                   3-5 times               > 5 times  
 
 
 

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4.  What picture represents the typical bowel movement you had over the past 7 days. 
 Please place an “X” over the appropriate picture.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix III UNISCALE – Patient Form 
 
 
 
Patient Name:  ____________________________ 
Date:  _________________________ 
 
Patient Number:  __________________________ 
 
 
Directions:  Please circle the number (0-10) best reflecting your response to the following question 
that describes your feelings during the past week, including today. 
 
 
 
How would you describe your overall Quality of Life? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad 
as it 
can be 
 
 
 
 
 
 
 
 
 
As 
good 
as it 
can be 
 

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Appendix IV SYMPTOM DISTRESS SCALE (SDS) 
 
Each of the following sections lists 5 different statements.  Think about what each statement says, and 
then place a circle around the one statement that most closely indicates how you have been feeling during 
the past 7 days.  Please circle one statement for each section. 
Appetite 
1. 
I have my normal appetite 
 
2. 
My appetite is usually, but not always, pretty good 
 
3.  
I don’t really enjoy my food like I used to  
 
4.  
I have to force myself to eat my food 
 
5.  
I cannot stand the thought of food 
 
Insomnia 
1. 
I sleep as well as I always have 
 
2. 
I have occasional spells of sleeplessness 
 
3.  
I frequently have trouble getting to sleep and staying asleep 
 
4. 
I have difficulty sleeping almost every night. 
 
5. 
It is almost impossible for me to get a decent night’s sleep 
 
Pain (a): 
1. 
 I almost never have pain 
 
2. 
 I have pain once in a while 
 
3. 
 I frequently have pain-several times a week 
 
4. 
 I am usually in some degree of pain 
 
5. 
 I am in some degree of pain almost constantly 
 
Pain (b) 
1.  
When I do have pain, it is very mild 
 
2.  
When I do have pain, it is mildly distressing 
 
3. 
The pain I do have is usually fairly intense 
 
4.  
The pain I have is usually very intense 
 
5.  
The pain I have is almost unbearable 
 
Fatigue 
1. 
I am usually not tired at all 
 
2. 
I am occasionally rather tired 
 
3. 
There are frequently periods when I am quite tired 
 
4. 
I am usually very tired 
 
5. 
Most of the time, I feel exhausted 
 
Bowel 
1. 
I have my normal bowel pattern 
 
2. 
My bowel pattern occasionally causes me some discomfort 
 
3.  
I frequently have discomfort from my present bowel pattern 
 
4. 
I am usually in discomfort because of my present bowel pattern 
 
5.  
My present bowel pattern has changed drastically from what was 
 
 
normal for me. 
 
 
Concentration 
1. 
I have my normal ability to concentrate 
 
2.  
I occasionally have trouble concentrating 
 
3. 
I often have trouble concentrating 
 
4.  
I usually have at least some difficulty concentrating 
 
5. 
I just can’t seem to concentrate at all 
 
 

MC1267 
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MCCC Addendum 6 
Protocol Version Date:  May 7, 2015 
 
Appearance:  
1.  
My appearance has basically not changed 
 
2.  
My appearance has gotten a little worse 
 
3.  
My appearance is definitely worse than it used to be, but I am  
 
 
not greatly concerned about it 
 
4. 
My appearance is definitely worse than it used to be, and I am  
 
 
concerned about it 
 
5. 
My appearance has changed drastically from what it was 
 
Breathing:  
1.  
I usually breathe normally 
 
2. 
I occasionally have trouble breathing 
 
3. 
I often have trouble breathing 
 
4. 
I can hardly ever breathe as easily as I want 
 
5. 
I almost always have severe trouble with my breathing 
 
Outlook:  
1. 
I am not fearful or worried 
 
2. 
I am a little worried about things 
 
3. 
I am quite worried, but unafraid 
 
4. 
I am worried and a little frightened about things 
 
5. 
I am worried and scared about things 
 
Cough:  
1. 
I seldom cough 
 
2. 
I have an occasional cough 
 
3. 
I often cough 
 
4. 
I often cough, and occasionally have severe coughing spells 
 
5. 
I often have persistent and severe coughing spells 
 
Nausea (a) 
1. 
I seldom feel any nausea at all 
 
2.  
I am nauseous once in awhile 
 
3. 
I am often nauseous 
 
4. 
I am usually nauseous 
 
5. 
I suffer from nausea almost continually 
 
Nausea (b) 
1.  
When I do have nausea, it is very mild 
 
2.  
When I do have nausea, it is mildly distressing 
 
3.  
When I do have nausea, I feel pretty sick 
 
4. 
When I do have nausea, I feel very sick 
 
5.   
When I do have nausea, I am as sick as I could possibly be 
 
Depression 
1. 
 I seldom feel sad and depressed 
 
2. 
 I am sad and depressed once in a while 
 
3. 
 I am often sad and depressed 
 
4. 
 I am usually sad and depressed 
 
5. 
 I am sad and depressed almost all the time 
 

MC1267 
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MCCC Addendum 6 
Protocol Version Date:  May 7, 2015 
Appendix V Compliance Questionnaire 
 
 
Please answer the question below about how often you took your study treatment during the past 
cycle.   
Check only one box that reflects your response.   
 
 
Over the past week, I took my study supplement: 
 
□ Always or almost always  
 
□ Usually  
 
□ Occasionally  
 
□ Rarely  
 
□ Never or almost never  
 
 
 
Patient reported weight: ___ ___ ___.____   Unit of measure: (check one) ___ lbs.   ___ kg 
 
 

M C 1 2 6 7  
4 5  
M C C C A d de n d u m 6  
Pr ot oc ol Versi o n Date:  Ma y 7, 2 0 1 5  
A p pe n di x VI  N urse/ C R A P h o ne W or ks heet  
 
P h o ne C o ntact G ui de  
N O T E: T his s h o ul d ser ve o nl y as a g ui de t o c ollect i nf or mati o n w hile o n t he p h o ne wit h t he patie nt a n d 
d oes n ot re place a n y data f or ms w hic h are re q uire d t o be fille d o ut. D o n ot fill o ut a n d s u b mit t his f or m, 
rat her s u b mit t he data f or ms usi n g t he R D E s yste m.  
 
1. Call patie nt o n da y 2 of c ycle 1 t o rei nf orce dail y q uesti o n naire c o m pleti o n a n d a ns wer a n y q uesti o ns 
t he y ma y ha ve. If da y 2 falls o n a wee ke n d or h oli da y, y o u ma y call t he patie nt o n t he ne xt b usi ness da y. .  
 
2. Call patie nt o n da y 2 of c ycle 2 a n d da y 2 of c ycle 3 t o assess c o m plia nce a n d a ns wer q uesti o ns bel o w. 
N ote: p h o ne calls are o nl y re q uire d f or patie nts n ot ret ur ni n g t o t he accr ui n g i nstit uti o n f or m o nt hl y 
t hera p y/assess me nt. Patie nts ret ur ni n g t o t he accr ui n g i nstit uti o n f or m o nt hl y t hera p y s h o ul d be see n a n d 
assesse d i n pers o n. Patie nts n ot ret ur ni n g t o t he accr ui n g i nstit uti o n f or t hera p y s h o ul d be assesse d via 
p h o ne.  
 
1.  Ite ms t o d oc u me nt i ncl u de:  
 
 Date of p h o ne call.  
 
 St u d y c ycle.  
 
 C o m plia nce: Has t he partici pa nt c o m plete d t he q uesti o n naire b o o klet eac h wee k (al wa ys, us uall y, 
rarel y, ne ver)? If n ot al wa ys, d oc u me nt reas o n(s) a n d rei nf orce wee kl y b o o klet c o m pleti o n. If ne ver, 
d oc u me nt reas o n( s) i n t he Patie nt Q uesti o n naire B o o klet C o m plia nce F or m a n d rei nf orce wee kl y b o o klet 
c o m pleti o n. 
  
 Si de effects  
 
A b d o mi nal pai n  
Bl oati n g  
Diarr hea  
Baseli ne n u m ber of st o ols per da y  
Flat ule nce  
Na usea  
V o miti n g  
Fati g ue  
W o u n d i nfecti o n  
W o u n d c o m plicati o n  
W o u n d de hisce nce  
 
 Has t he patie nt bee n ta ki n g t he a ge nt  ( Al wa ys or al m ost al wa ys; Us uall y; Occasi o nall y; Rarel y; Ne ver 
or al m ost ne ver) ?  
 
4. Rei nf orce c o m plia nce wit h b o o klet a n d re mi n d partici pa nt t o ret ur n b o o klet t o st u d y staff at t heir ne xt 
a p p oi nt me nt or i n t he e n vel o pe pr o vi de d  at t he e n d of eac h 4 wee ks .  
 
5. Rei nf orce c o m pleti o n of q uesti o n naires. N O T E: if patie nt deci des t o st o p st u d y earl y, as k t he m t o fill 
o ut t he q uesti o n naires at t he e n d of t he b o o klet a n d ret ur n i n t he e n vel o pe pr o vi de d.  
 

M C 1 2 6 7  
4 6  
M C C C A d de n d u m 6  
Pr ot oc ol Versi o n Date:  Ma y 7, 2 0 1 5  
 
7. Ite ms t o d oc u me nt i ncl u de:  
 Date of p h o ne call.  
 St u d y c ycle.  
 Patie nt re p orte d wei g ht.  (l bs/ k g) 
 Has ca ncer t hera p y starte d ( yes/ n o).  If yes, c he m o/ R T/ h or m o nal/ ot her, s pecif y -List start date of eac h.  
 C o m plia nce q uesti o n naire  
 

MC1267 
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MCCC Addendum 6 
Protocol Version Date:  May 7, 2015 
Appendix VII Entera Health Clarification Letter 
 
 
To whom it may concern: 
 
Please find enclosed for review Protocol ….. 
 
Serum-derived bovine immunoglobulin protein isolate (SBI) is an orally administered 
prescription medical food containing a proprietary formulation of bovine immunoglobulins and 
proteins.  The term medical food, as defined in Section 5(b) of the Orphan Drug Act (21 U.S.C. 
360ee (b) (3)) is "a food which is formulated to be consumed or administered enterally under the 
supervision of a physician and which is intended for the specific dietary management of a 
disease or condition for which distinctive nutritional requirements, based on recognized scientific 
principles, are established by medical evaluation."  
 
Serum-derived bovine immunoglobulin protein isolate is intended for the nutritional 
management of a patient with enteropathy who, because of therapeutic or chronic medical needs, 
has limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or 
certain nutrients, the dietary management of which cannot be achieved by the modification of the 
normal diet alone. Serum-derived bovine immunoglobulin has self-affirmed generally recognized 
as safe (GRAS) status with no objections from the US Food and Drug Administration (FDA), 
and is demonstrated to be safe and well-tolerated in pediatric and adult patients. 
 
Medical foods are regulated by the US Food and Drug Administration under the Food Drug and 
Cosmetic Act regulations 21 CFR 101.9(j) (8), however, medical foods do not undergo 
premarket review or approval by FDA since they do not meet the definition of the term drug in 
section 201(g)(1) of the FD&C Act includes, among other things, “articles intended for use in the 
diagnosis, cure, mitigation, treatment, or prevention of disease . . .” and “articles (other than 
food) intended to affect the structure or any function of the body of man or other animals.” In 
addition, substances designated as GRAS for use in food are not approved as drug products since 
they are not intended to evaluate the product's ability to diagnose, cure, mitigate, treat, or prevent 
disease; therefore an IND under part 312 is not required.