Conditions: Pancreatic Insufficiency Pancreatic Cancer Pancreatic Enzyme Abnormality
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 16
Healthy volunteers: no

Brief summary:
Does pancreas enzyme replacement (PERT) decrease weight loss and improve quality of life in patients with unresectable pancreatic cancer?

Detailed description:
Randomized, double-blind clinical trial aiming to assess the impact of pancreas enzyme replacement therapy in weight loss and quality of life.

Prevalence of pancreatic exocrine insufficiency (PEI) will be determined with fecal elastase-1 test (FE1) in patients with unresectable pancreatic cancer, without evidence of pancreatic duct (PD) or common bile duct (CBD) obstruction based on MRI or / and endoscopic ultrasound (EUS).

Patients with PEI (FE1 \<200) receive Pertzye or placebo in a cross-over fashion, each for 4 weeks.

Body weight, body mass index (BMI), body composition (Bioimpedance), are measured at the time of diagnosis of PEI and at 4 and 10 weeks of cross-over treatment. Baseline measurement of Vitamin D-25, Vitamin A, iron (ferritin, total iron binding capacity (TIBC), iron), Vitamin B12,Tissue transglutaminase IgA (tTG) with total Immunoglobulin A (IgA).

Quality of Life (pain, diarrhea, weight, bloating, etc.) assessed at 0,4,10 weeks with the Functional Assessment of Cancer Therapy for patients with liver, bile duct and pancreas cancer (FACT-Hep) for physical, social, emotional, and functional quality of life.

Arms:
arm 1: Placebo oral capsule: 3 capsules taken with or after meals, and 2 capsules taken with or after snacks during 4 weeks in first intervention period, and Pancrelipase 3 capsules are taken with or after meals (4800 lipase units) and 2 capsules with or after snacks (3200 lipase units) during 4 weeks in second intervention period (after 2 week washout period). arm 2: Pancrelipase 3 capsules are taken with or after meals (4800 lipase units) and 2 capsules with or after snacks (3200 lipase units) during 4 weeks in first intervention period, and Placebo oral capsule: 3 capsules taken with or after meals, and 2 capsules taken with or after snacks during 4 weeks in second intervention period (after 2 week washout period).

Interventions: intervention 1: Pancrelipase intervention 2: Placebo Oral Capsule
Intervention descriptions: intervention 1: Lipase 16,000 United States Pharmacopoeia (USP) units, protease 57,500 USP units, and amylase 60,500 USP units intervention 2: Placebo Oral Capsule

Protocol document:
Prot_SAP_000.pdf: 
 
Pancreatic Enzyme Replacement 
Therapy for treatment of Exocrine 
Pancreatic Insufficiency in Patients with 
Unresectable Pancreatic Cancer 
 
NCT02985801 
 
 
May 15, 2018 


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IRB Minimal Risk Protocol Template 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Study Information 
 
Principal Investigator:    Massimo Raimondo, M.D. 
 
 
 
 
 
 
 
 
Study Title:  Pancreatic Enzyme Replacement Therapy for treatment of Exocrine Pancreatic Insufficiency in 
Patients with Unresectable Pancreatic Cancer 
Protocol version number and date:  version 5, 5/15/2018  
Purpose 
 
Hypothesis:  
Pancreas enzyme replacement therapy (PERT) decreases weight loss and improves quality of life in patients 
with unresectable pancreatic cancer. 
 
Aims, purpose, or objectives: 
1. Assess prevalence of pancreatic exocrine insufficiency (PEI) with fecal elastase-1 test (FE1) in patients with 
unresectable pancreatic cancer, without evidence of pancreatic duct (PD) or common bile duct (CBD) 
obstruction based on MRI or / and EUS. 
 
2. Patients with PEI (FE1 <200) receive Pertzye or placebo in a cross-over fashion, each for 4 weeks. 3 
capsules are taken with or after meals and 2 capsules with or after snacks (approximating 500 lipase 
units/kg/meal). 
 
Note: If this study establishes a human specimen repository (biobank) for research 
purposes, do not use this template. Use the Mayo Clinic Human Specimen Repository 
Protocol Template found on the IRB home page under Forms and Procedures at 
http://intranet.mayo.edu/charlie/irb/ 
 
First-time Use: Use this template to describe your study for a new IRB submission. 
1. Complete the questions that apply to your study. 
2. Save an electronic copy of this protocol for future revisions.    
3. When completing your IRBe application, you will be asked to upload this template to the protocol 
section. 
Modification:  To modify this template after your study has been approved: 
1. Open your study in IRBe. Click on the study ‘Documents’ tab and select the most recent version of the 
protocol. Save it to your files. 
2. Open the saved document and activate “Track Changes”.  
3. Revise the protocol template to reflect the modification points , save the template to your files 
4. Create an IRBe Modification for the study and upload the revised protocol template. 


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3. Body weight, body mass index (BMI), body composition (Bodystat Bioimpedance), are measured at the 
time of diagnosis of PEI and at 4 and 8 weeks of cross-over treatment. Baseline measurement of Vitamin D-
25, Vitamin A, iron (ferritin, TIBC, iron), Vitamin B12,Tissue transglutaminase IgA (tTG) with total 
Immunoglobulin A (IgA) 
 
4. Quality of Life (pain, diarrhea, weight, bloating, etc.) assessed at 0,4,8 weeks with  
a.  
b. Functional Assessment (FACT-Hep) for  physical, social, emotional, and functional QOL 2 
 
 
Background  
Pancreatic exocrine insufficiency (PEI) is a known complication of pancreatic cancer. Several mechanisms of 
PEI have been described in context of pancreatic cancer, including pancreatic atrophy secondary to tumor 
induced pancreatic duct obstruction and pancreatic fibrosis, both leading to PEI in patients with unresectable 
pancreatic cancer.3 
Although the majority of patients with pancreatic cancer are inoperable at the time of diagnosis, only few 
authors addressed PEI in this patient cohort. Small studies with 8 to 12 patients detected PEI in 75% to 100%. 
The  prevalence of PEI tended to be higher in setting of significant pancreatic duct obstruction.4,5 The largest 
cohort study included 194 patients with advanced pancreatic cancer which was defined as metastatic or 
unresectable due to local invasion. 50% of study participants had PEI.6 As a next step, Sikkens et al 
prospectively assessed the progression of PEI in 32 patients with unresectable cancer of the pancreatic head 
region. Based on FE1 testing, 67% of patients had PEI at the time of pancreatic cancer diagnosis and 89% at 2 
months follow up (median).7 
Despite a high prevalence of PEI in patients with unresectable pancreatic cancer, clinical symptoms like 
steatorrhea are not uniformly present. In fact, 2 hallmark studies, including one with 12 and one with 194 
patients, found no statistically significant correlation between the dyspepsia, number of bowel movements on 
the one hand and the presence of fat malabsorption on the other hand in patients with unresectable pancreatic 
cancer. Only 16.7% of patients with very severe PEI had clinically evident steatorrhea, whereas 5.2% of 
patients had subjective steatorrhea without PEI.5,6 Weight loss is another well-known complication of pancreatic 
cancer. Perez et al. who found a significant correlation between fat-protein malabsorption and weight loss in 
non-surgical patients with pancreatic cancer however not between diminished caloric consumption and weight 
loss.5 
As of now, multiple studies showed improved fat absorption with pH-sensitive microsphere formulation in 
comparison to conventional pancreatic enzyme preparations or placebo in chronic pancreatitis patients with 
PEI.8-14 However, only few studies addressed the utility of PERT for patients with inoperable pancreatic cancer, 
including a randomized study by Bruno et al. with 21 patients with unresectable pancreatic cancer and 
pancreatic duct obstruction. Patients randomized into PERT for 4 weeks had reduced weight loss compared with 
patients who were treated with placebo.15 A retrospective study by Domínguez-Muñoz et al. included 76 
patients with inoperable pancreatic cancer. Patients who received PERT (Creon®) had a longer median survival 
than patients with palliative therapy alone.16 Of note, PEI was not formally assessed in either of those studies. 
Based on these limited results current pancreatic cancer guidelines recommend PERT for patients with 
unresectable pancreatic cancer, in the realm of palliative therapy.17 However the efficacy of PERT in patients 
with unresectable pancreatic cancer was never proven in a randomized controlled trial. 
A further concern is the adverse drug reaction profile of PERT. In adult population no severe side effects of 
PERT are documented. Hyperuricosuria and especially colonic fibrosis are the most feared severe adverse drug 
reaction (ADR) of long term PERT, however they were reported only in children with cystic fibrosis.18,19, 20,21 


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However dyspepsia, heartburn and bloating are well described mild ADR of PERT. In this context, several 
randomized controlled trials revealed a higher incidence of bloating and abdominal pain in patients who 
received PERT for PEI for mostly benign pancreatic conditions.21,22,23,24 The impact of ADR on the quality of 
life was never assessed in a randomized controlled fashion in patients with unresectable pancreatic cancer.  
Finally, the high costs of PERT, which range up to $2000 a month, emphasis the importance to clarify the 
pros and cons of PERT for patients with unresectable pancreatic cancer, to avoid unnecessary and costly 
treatments. 
 
Subject Information – charts, records, images, or specimens are considered ‘subjects’ 
 
Target accrual is the proposed number of subjects to be included in your study at your site. “Subjects” may 
include Mayo Clinic charts, records, or specimens, and/or charts, records, or specimens received at Mayo 
Clinic from external sources for collaborating analysis by the investigator under this IRB application:    
 
Target accrual: 
30 completed patients 
 
Subject population:   
 
Inclusion Criteria:  
• Patients 18- 100years 
• Underlying pancreatic adenocarcinoma, unresectable (local invasion or distant metastasis) 
• On established chemotherapy regimen for pancreas cancer, which will be continued over the time of 
study 
• Fecal elastase-1 test (FE1) less than 200 mcg pancreatic elastase/g stool 
 
Exclusion Criteria:   
• Common bile duct obstruction resulting in obstructive jaundice 
• Celiac disease 
• Crohn’s disease 
• Benign pancreatic conditions 
• Bowel obstruction 
• Surgically altered bowel anatomy 
 
 
 Yes   
  No   Will a Certificate of Confidentiality (COC) be obtained from NIH?  If yes, 
Who is obtaining the COC: Mayo Clinic investigator, study sponsor, other:  
Explain why a COC is needed:   
Study Design  
 
Methods: 
Patients with unresectable pancreatic adenocarcinoma (local invasion or distant metastasis) receive pancreatic 
enzyme replacement therapy (PERT) by the oncology team as presumed standard of care. Patients will be 
offered to participate in study, which lasts 10 weeks. 


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Pancreatic enzyme insufficiency (PEI) will be detected by (fecal elastase-1) FE1 testing. Patients with FE1 less 
than 200 mcg pancreatic elastase/g stool are eligible for study. Patients will be randomized into first placebo or 
first treatment group (cross over study) by enclosed envelope. 
Patients will received either Pertzye (Pancrelipase) 500 lipase units/kg/meal or placebo, each for 4 weeks. 
Dosing will be 3 capsules 3 times a day with or after meals and 2 capsules with or after snacks. No treatment 
will be administered at weeks 5 and 6 to assure adequate washout. Pertzye or placebo will be given for another 
4 weeks (week 7 - 10) in a cross-over fashion. 
Body weight, body mass index (BMI), body composition (Tanita, TBF-310GS, Bodystat Bioimpedance), 
FACT-Hep quality of life assessment will be measured at randomization and at last day of treatment or placebo 
(week 4 and 10). 
 
 
Resources: 
Patients will be recruited in oncology or gastroenterology clinic by oncology fellow or gastroenterology fellow 
in the setting of their regular clinical work. 
Pertzye and placebo will be sponsored by pharmaceutical company.   
 
 
Check all that apply. If none apply, leave blank: 
 
  This is a multisite study involving Mayo Clinic and non-Mayo Clinic sites.  
When checked, describe the research procedures/activities being conducted only at Mayo Clinic: 
 
  Mayo Clinic staff will be engaged in research activity at a non-Mayo Clinic site.  When checked, provide 
the location and a detailed description of the Mayo Clinic research staff involvement. 
 
 
  This study is to establish and/or maintain an ongoing database or registry for research purposes only. 
 
 The research involves contact or interaction with subjects, for example, surveys, questionnaires, observation, 
blood draw. 
 
  The study involves photographing, audiotaping or videotaping subjects (and guests).  
 
 
 
Review of Chart, Images, Specimens 
Provide the date range for collection of data and/or specimens that will be included in your research dataset.   
Check all that apply: 
 
  This study involves only data and/or specimens that exist at the time this application is submitted to the IRB 
(IRB submission date). No data or specimens will be collected beyond this date.  
 
 


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x  This study involves only data and/or specimens that will be collected after submission to the IRB. 
 
  The study involves data and/or specimens that exist at the time of submission to the IRB and data and/or 
specimens that will be collected after submission to the IRB, for example a study that includes collection of 
existing data and prospective collection of specimens. 
 
  Data and/or specimens used in this study are collected under another IRB protocol. When checked, provide 
the IRB number(s) from which the research material will be obtained. When appropriate, check the box below 
to attest that subjects have provided consent for future use of their data and/or specimens, as described in this 
protocol.  
 
 
IRB Number/s - Data Only:  _____________________________________________ 
 
IRB Number/s - Specimens Only: _________________________________________ 
 
IRB Number/s - Data and Specimens:  _____________________________________ 
 
Note:  When subjects provided consent for use of their data and/or specimens, as described in this protocol. 
 
  Other data sources will be utilized in this study, e.g. receiving data/specimens from an external party. When 
checked, provide all data sources: 
 
 
 
Data Confidentiality, HIPAA Subject Identifiers 
 
Review the list of subject identifiers below and, if applicable, check the box next to each subject identifier being 
recorded at the time you are collecting/abstracting data/specimens for use in this study. 
 
Subject Identifiers:  Individually identifiable information, including demographic data, that identifies the 
individual or for which there is reasonable basis to believe it can be used to identify the individual.  NOTE: 
Identifiers apply to subjects enrolled in your study and to the subject’s relatives, household members, 
employers, etc. 
 
Internal refers to subject identifiers that will be included in the dataset maintained by the study team. 
External refers to subject identifiers that will be shared with persons outside of the immediate study team, for 
example, sent to an external collaborator or shared with a national registry.  
 
 
SUBJECT IDENTIFIERS 
Check all that apply 
INTERNAL 
IDENTIFIER 
EXTERNAL 
IDENTIFIER 
Name 
x 
 
Social Security number 
 
 
Medical record/patient registration number, lab accession, specimen or 
radiologic image number 
x 
 


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Study number, subject ID, or any other unique identifying number, 
characteristic or code that can be used to link the identity of the subject to the 
data 
x 
 
Dates: All elements of dates [month, day, and year] directly related to an 
individual. Their birth date, date of death, date of diagnosis, etc.   
Note: Recording a year only is not a unique identifier.  
x 
 
Medical device identifiers and serial numbers 
 
 
Biometric identifiers, including finger and voice prints, full face photographic 
images and any comparable images 
 
 
Web Universal Resource Locators (URLs), Internet Protocol (IP) address 
numbers, email address 
 
 
Street address, city, county, precinct, zip code, and their equivalent geocodes 
 
 
Phone or fax numbers 
 
 
Account, member, certificate or professional license numbers, health 
beneficiary numbers 
 
 
Vehicle identifiers and serial numbers, including license plate numbers 
 
 
If None of the above identifiers will be recorded or maintained in the 
dataset and/or sent outside of the study team, please check “None”. 
 None 
 None 
 


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Statistical Information 
 
Statistical Considerations 
 
Data Analysis Plan and Power Statement:   
Statistical significance will be calculated with pair t-test. 
According to Bruno et al and Dominguez-Munoz et al a 5% weight difference between the treatment groups is 
expected within 4 weeks. Standard deviation is expected to be less than 5% based on the cross over fashion. 
Assuming a patient drop out of 30%, a minimum of 13 patients need to be included in the trial to detect a 
statistically significant difference, with a power of 80% and alpha error of 5%. Eventually, we target to include 
30 patients to assure adequate power, given the statistical limitations of previously reviewed studies. 
 
 
 
Endpoints 
    
 
Primary:  
 
       
 
 
1. Weight change 
 
Secondary:  
1. Quality of life (QOL) 
2. Change in body composition 
 


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References 
 
1. 
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Gastrointestinal Quality of Life Index: development, validation and application of a new instrument. The 
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2. 
Heffernan N, Cella D, Webster K, Odom L, Martone M, Passik S, Bookbinder M, Fong Y, Jarnagin W, 
Blumgart L. Measuring health-related quality of life in patients with hepatobiliary cancers: the 
functional assessment of cancer therapy-hepatobiliary questionnaire. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2002;20:2229-39. 
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Ghaneh P, Neoptolemos JP. Exocrine pancreatic function following pancreatectomy. Annals of the New 
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DiMagno EP, Malagelada JR, Go VL. The relationships between pancreatic ductal obstruction and 
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Perez MM, Newcomer AD, Moertel CG, Go VL, Dimagno EP. Assessment of weight loss, food intake, 
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Partelli S, Frulloni L, Minniti C, Bassi C, Barugola G, D'Onofrio M, Crippa S, Falconi M. Faecal 
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Graham DY. An enteric-coated pancreatic enzyme preparation that works. Digestive diseases and 
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