Conditions: Exocrine Pancreatic Insufficiency (EPI)
Keywords: Exocrine Pancreatic Insufficiency (EPI) Pancreatic Cancer Creon Pancrelipase
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
This is a study in participants with Exocrine Pancreatic Insufficiency (EPI) due to pancreatic cancer. This study will include resected participants who are post pancreatic cancer surgery, and an additional cohort in non-resected participants.

Detailed description:

Arms:
arm 1: Resected participants (surgery to remove pancreatic cancer) will first be given low dose pancrelipase. Low dose is defined as 12,000 USP units (lipase) with meals and 6000 U with snacks. At Weeks 1, 5, or 9, participants will be evaluated, and those who meet criteria for dose increase will be given high dose pancrelipase. High dose is defined as 72,000 U with meals and 36,000 U with snacks. All participants will receive placebo as needed to keep the number of pills the same in each group and for blinding. arm 2: Resected participants (surgery to remove pancreatic cancer) will receive and continue on high dose pancrelipase throughout the study. High dose is defined as 72,000 USP units (lipase) with meals and 36,000 U with snacks. All participants will receive placebo as needed to keep the number of pills the same in each group and for blinding. arm 3: Non-resected participants (those who did not have surgery to remove pancreatic cancer) will receive high dose pancrelipase throughout the study in an open-label cohort. High dose is defined as 72,000 USP units (lipase) with meals and 36,000 U with snacks.

Interventions: intervention 1: Pancrelipase intervention 2: Placebo
Intervention descriptions: intervention 1: Pancrelipase is administered orally as capsules with a meal or snack intervention 2: Placebo is administered orally as capsules with a meal or snack

Protocol document:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
8
2.1
BACKGROUND AND RATIONALE
8
2.2
BENEFITS AND RISKS TO PATIENTS
8
3
STUDY OBJECTIVES AND ENDPOINTS
9
3.1
OBJECTIVES
9
3.2
PRIMARY ENDPOINT
9
3.3
SECONDARY ENDPOINTS
10
3.4
ADDITIONAL ENDPOINTS
10
3.5
SAFETY ENDPOINTS
11
4
INVESTIGATIONAL PLAN
11
4.1
OVERALL STUDY DESIGN AND PLAN
11
4.2
DISCUSSION OF STUDY DESIGN
13
5
STUDY ACTIVITIES
14
5.1
ELIGIBILITY CRITERIA
14
5.2
CONTRACEPTION
16
5.3
PROHIBITED MEDICATIONS AND THERAPY
17
5.4
PRIOR AND CONCOMITANT THERAPY
17
5.5
WITHDRAWAL OF STUDY DRUG AND/OR DISCONTINUATION OF STUDY
18
5.6
STUDY DRUG
19
5.7
RANDOMIZATION/DRUG ASSIGNMENT
24
5.8
PROTOCOL DEVIATIONS
25
5.9
ADDITIONAL SUPPLIES
25
6
SAFETY CONSIDERATIONS
25
6.1
COMPLAINTS AND ADVERSE EVENTS
25
6.2
PRODUCT COMPLAINT
28
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
28
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7.1
STATISTICAL AND ANALYTICAL PLANS
28
7.2
DEFINITION FOR ANALYSIS POPULATIONS
28
7.3
STATISTICAL ANALYSES FOR EFFICACY
29
7.4
STATISTICAL ANALYSES FOR SAFETY
29
8
ETHICS
29
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
29
8.2
ETHICAL CONDUCT OF THE STUDY
30
8.3
SUBJECT CONFIDENTIALITY
30
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
30
10 DATA QUALITY ASSURANCE
30
11 COMPLETION OF THE STUDY
30
12 REFERENCES
30
LIST OF TABLES
TABLE 1.
DESCRIPTION OF STUDY DRUG
19
TABLE 2.
DESCRIPTION OF INVESTIGATIONAL PRODUCT
21
TABLE 3.
MASKING OF DOSES
22
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
12
FIGURE 2.
CARD DIAGRAM OF DOSING REGIMEN
23
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
32
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
34
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
35
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APPENDIX D.
ACTIVITY SCHEDULE
36
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
38
APPENDIX F.
OPERATIONS MANUAL
40
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Exocrine pancreatic insufficiency (EPI) is a debilitating condition that is caused by the inadequate 
secretion of pancreatic fluid containing digestive enzymes and bicarbonate needed for normal digestion 
and is commonly associated with a wide range of chronic diseases, including cystic fibrosis (CF), chronic 
pancreatitis (CP), and pancreatic cancer.
Evidence suggests that pancreatic enzyme replacement therapy (PERT) with pancrelipase is an 
acceptable approach for the treatment of patients with EPI and associated symptoms due to pancreatic 
adenocarcinoma, and PERT therapy may also improve nutrition, tolerance to chemotherapy, and quality 
of life in these patients.1,2  Current treatment guidelines for management of pancreatic cancer 
recommend that pancrelipase should be used in patients with EPI, but additional information on dosing 
would be helpful.
Previous studies suggest that pancrelipase doses of 72,000 USP units (Lipase) per meal and
36,000 USP units (Lipase) per snack per day have a significant effect on decreasing stool fat and 
improving EPI symptoms.3,4  The treatment duration of 5 days was selected as the minimum duration 
needed to detect potential differences in stool fat from Baseline (Day 1).  Electronic diary entries of the 
EPI symptoms and food intake prior to each study visit will be used.
2.2 Benefits and Risks to Patients
EPI can be a serious and debilitating condition.  Patients with EPI due to CF, CP, or pancreatectomy (PY) 
represent the major patient groups currently treated with pancrelipase and are the most studied 
populations in terms of maldigestion.  The majority of information regarding the clinical 
symptomatology of the disease, the degree of enzyme supplementation, and the therapeutic 
perspectives are based upon our understanding of EPI in these diseases.
Pancrelipase was shown to be effective in the treatment of EPI as demonstrated in both placebo-
controlled and long-term studies.3-7  Coefficient of fat absorption (CFA) values—a measure of fat 
absorption—exceeding 80% were achieved and maintained in patients receiving pancrelipase, 
representing a highly significant difference from placebo in double-blind trials.  In addition to a 
significant increase in CFA, a significant increase in the coefficient of nitrogen absorption (CNA)—a 
measure of protein absorption—was also observed, while the average stool frequency was lower 
compared to placebo.3-7
The short-term efficacy of CREON was evaluated in three Phase 3 studies conducted in 103 patients with 
EPI.  Two studies were conducted in 49 patients with EPI due to CF; one study was conducted in 
54 patients with EPI due to chronic pancreatitis or pancreatectomy.8
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Fibrosing colonopathy (FC) is a complication that has been reported in patients with CF taking high doses 
of PERT (≥ 10,000 USP Units [Lipase]/kg/day).9
Potential risks, as described in the United States prescribing information (USPI) are as follows:

To avoid irritation of oral mucosa, do not chew CREON or retain in the mouth.

Exercise caution when prescribing CREON to patients with gout, renal impairment, or 
hyperuricemia.

There is theoretical risk of viral transmission with all pancreatic enzyme products including 
CREON.

Exercise caution when administering pancrelipase to a patient with a known allergy to proteins 
of porcine origin.

Adverse reactions occurring in at least 2 cystic fibrosis patients (greater than or equal to 4%) 
receiving CREON during clinical trials are vomiting, dizziness, and cough.

Adverse reactions that occurred in at least 1 chronic pancreatitis or pancreatectomy patient 
(greater than or equal to 4%) receiving CREON during clinical trials are hyperglycemia, 
hypoglycemia, abdominal pain, abnormal feces, flatulence, frequent bowel movements, and 
nasopharyngitis.
Overall, EPI, if untreated, may have serious adverse health consequences.  No alternative treatments are 
available.  When assessing the relation of the demonstrated efficacy of pancrelipase in several disease 
states associated with EPI, compared to the potential consequences of not treating EPI, the benefits of 
pancrelipase treatment outweigh the risks.
For further details, please see findings from completed studies, including safety data, in the CREON® 
(pancrelipase) United States Prescribing Information (USPI).8
3 STUDY OBJECTIVES AND ENDPOINTS
3.1 Objectives
Evaluate the effects of CREON® (pancrelipase) on stool fat and EPI symptoms in subjects with resected 
pancreatic cancer receiving 2 dosing regimens, and one dosing regimen in non-resected pancreatic 
cancer subjects.
3.2 Primary Endpoint
Resected Pancreatic Cancer Subjects
The primary endpoint is change in stool fat from Baseline (Day 1) to Week 1 (Day 8) for each dose cohort
in Resected Subjects.  Stool fat is collected during the 48 hours prior to the Day 1 and Week 1 visits.
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3.5 Safety Endpoints
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign 
measurements, and clinical laboratory testing (hematology, chemistry, and urinalysis) as a measure of 
safety and tolerability for the entire study duration.
The primary safety endpoint is AEs reported during study participation or the 30-day safety follow-up 
period.  There are no adverse events of special interest (AESI) for pancrelipase in this study population.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
The schematic of the study is shown in Figure 1.  Details regarding study procedures are available in the 
Operations Manual.
See Section 5 for information regarding eligibility criteria.
This is a Phase 4, randomized, double-blind, parallel design study with 2 dose cohorts in resected 
subjects, and an open-label single dose cohort in non-resected subjects with EPI due to pancreatic 
cancer.
Resected subjects are defined as subjects who had a surgery to remove the pancreatic cancer.
Non-resected subjects are defined as unresectable, resectable, and borderline resectable or pancreatic 
cancer subjects who did not have a pancreatectomy of the cancer and do not plan to undergo such a 
surgery during study participation.
At Day 1, eligible resected subjects will be randomized in 1:1 ratio to one of following dose cohorts, and 
will remain on blinded therapy throughout the study:
1.
Low dose (regimen of 12,000 USP units (Lipase) with meals/6,000 USP units (Lipase) with snacks)
2.
High dose (regimen of 72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with 
snacks)
At Weeks 1, 5, or 9, subjects who meet dose modification criteria maintained by the IRT will be titrated 
once to the following regimen in a blinded fashion:

Subjects receiving the lower dose will escalate to pancrelipase 
72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with snacks.

Subjects receiving the high dose will continue receiving the high dose throughout the study.  In 
order to maintain the blind of the study, subjects in the high dose group will also receive a 
matching placebo and will not exceed the maximum dose per the USPI.8
Non-resected subjects in the open-label cohort will receive pancrelipase at a dose of 72,000 USP units 
(Lipase) with meals/36,000 USP units (Lipase) with snacks during the entire duration of the study.
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No interim analyses are currently planned.  Study sites and resected subjects in the double-blind cohorts 
will remain blinded for the treatment period of the study.
In support of the primary endpoints, it is critical for subjects to stop PERT a week prior to Day 1 and to 
initiate stool collection 48 hours prior to Day 1 and Week 1 visits. 
Figure 1.
Study Schematic
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4.2 Discussion of Study Design
Choice of Control Group
Placebo use in the study is for blinding purposes.  No placebo control will be used in this study because 
pancrelipase is an approved treatment and standard of care for EPI.  The cohort receiving 12,000 USP 
units (Lipase) with meals/6,000 USP units (lipase) with snacks will be the control group in this study.  The 
double-blind period compares 2 doses of pancrelipase in eligible resected subjects with EPI due to 
pancreatic cancer, who will be randomly assigned to treatment with pancrelipase at 72,000 USP units 
(Lipase) with meals/36,000 USP units (Lipase) with snacks, or treatment with pancrelipase at 12,000 USP 
units (Lipase) with meals/6,000 USP units (Lipase) with snacks.
The uncontrolled cohort of non-resected subjects will receive treatment with pancrelipase at 
72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with snacks.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All efficacy 
measurements in this study are standard for assessing disease activity in subjects with EPI.  All clinical 
and laboratory procedures in this study are standard and generally accepted.
Using stool fat to evaluate the efficacy of PERT is a well-established method for the measurement of EPI.
The EPI Symptom Questionnaire is a disease-specific tool that has been particularly developed to 
measure changes in gastrointestinal symptoms experienced by patients who have EPI.  This is a 12-item 
patient-reported outcome (PRO) tool that assesses EPI symptoms over the past seven days.
The Bristol Stool Chart will be utilized to describe stool consistency.
The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients.  
The questionnaire is composed of 5 domains (physical, role, social, emotional, and cognitive functioning) 
and 9 single items (pain, fatigue, financial impact, appetite loss, nausea/vomiting, diarrhea, constipation, 
sleep disturbance, and quality of life).  The tool has been validated in a cancer population.
EORTC QLQ-PAN26 is the pancreatic cancer module and is intended for patients at all disease stages 
undergoing surgical resection, palliative surgical intervention, endoscopic palliation, or palliative 
chemotherapy.  The tool comprises 26 questions assessing pain, dietary changes, jaundice, altered 
bowel habit, emotional problems related to pancreatic cancer, and other symptoms (cachexia, 
indigestion, flatulence, dry mouth, taste changes).  The tool has been validated in a pancreatic cancer 
population.
Suitability of Subject Population
This study will include resected and non-resected pancreatic cancer patients.2
Selection of Doses in the Study
A starting dose of 12,000 USP units (Lipase) with meals, although lower than 500 USP units (Lipase)/kg 
with meals, may be appropriate in the immediate postoperative period for patients not yet eating a diet 
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with a normal fat content.  The high-dose cohort of 72,000 USP units (Lipase) with meals/36,000 USP 
units (Lipase) with snacks is a safe and efficacious dose as reported in the literature and the Food and 
Drug Administration (FDA)-approved prescribing information (USPI) and does not exceed the maximum 
described in the USPI.8
Visit Window
Expecting that a few of the subjects might miss the target visit dates specified in the protocol, the 
windows below are defined around the target visit dates.  However, it is recommended that the subject 
should comply with the protocol timeline as best as they can.
Target Visit Week
Window
Week 1
+ 2 days 
Week 5
± 4 days 
Week 9
± 4 days 
Week 13
± 4 days 
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study.  Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects must voluntarily sign and date an informed consent, approved by an independent 
ethics committee (IEC)/institutional review board (IRB), before the initiation of any Screening or 
study-specific procedures.
Demographic and Laboratory Assessments
2. Adult male or female, must be at least 21 years of age at Screening.
3. Subject must be able to tolerate solid food and be able to consume a balanced diet
4. Subject must have FE-1 ≤ 150 µg/g stool at Screening.  FE-1 test can be repeated by subjects if 
needed; no washout period is required in this case.
5. A positive* Sudan stain for subjects without history of fat malabsorption [fat malabsorption 
defined as clinical steatorrhea, or measured stool fat greater than 7 g/day, or positive stool 
results by Sudan stain] within 1 week of Screening.
*Positive stool results are defined as increased level of neutral OR total fats (normal ranges are 
< 60 droplets/HPF and < 100 droplets/HPF, respectively).
Subject is able to follow study procedures as specified in the protocol and instructed by the site 
personnel.
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6. Subject must be willing and able to collect stool samples at home.
7. Subject must not be participating in another clinical study.
8. Resected subjects only:  Must be sufficiently recovered from surgery (investigator opinion)
Disease Activity
9. Subject has been diagnosed with pancreatic cancer with biopsy and/or radiography, with a life 
expectancy of at least 5 months at Screening Visit.
10. Subject's pancreatic cancer must involve the head and/or neck of the pancreas.
11. Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 
to 2 or Karnofsky performance status (PS) > 60%.
12. Subject must have stable organ and marrow function as defined below:

Absolute neutrophil count (ANC) > 500/µL;

Platelets > 50,000/µL;

Total bilirubin ≤ 4 × upper limit of normal (ULN);
Subject History
13. Subject must NOT have neuroendocrine pancreatic cancer.
14. Subject must NOT have a history of fibrosing colonopathy
15. Subject must NOT have any other malignancy within 1 year of Screening.
16. No diagnosis/history of renal impairment, hyperuricemia, or uncontrolled gout, including 
those with a recent acute flare within 60 days of Screening that would make the subject an 
unsuitable candidate to receive study drug.
17. Subject must NOT have other significant organ or bone marrow abnormality within 60 days 
of Screening.
Contraception
18. A negative urine pregnancy test for all female subjects (except postmenopausal and 
permanently surgically sterile) at Baseline before the first dose of study drug.  If urine pregnancy 
test is positive, withhold dosing and perform a serum pregnancy test.  Pregnant subjects must 
not be enrolled into the study.
19. If female, subject must be either postmenopausal OR permanently surgically sterile OR for 
women of childbearing potential practicing at least 1 protocol-specified method of birth 
control, that is effective from Screening through at least 30 days after the last dose of study 
drug.
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20. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the 
study from Screening, for approximately 30 days after the last dose of study drug.
Concomitant Medications/Surgery
21. Subjects who are receiving PERT at the time of Screening and who require a Sudan stain test 
are willing to be off PERT for a minimum of 48 hours prior to an initial or a repeated Sudan stain 
specimen collection.  Sudan stain test can be repeated by subjects if needed.  A washout-out 
period of 48 hours will be required if test is repeated.
22. It is critical that subject not consume PERT within 1 week prior to Day 1 [starting at Day –7].
23. Subject must be able to safely discontinue octreotide after signing the informed consent 
form (ICF) and must be able to safely be off octreotide during study participation.
24. Non-resected subjects (unresectable, resectable, and borderline resectable) must not plan 
to undergo a pancreatectomy during study participation.
25. Subject must be willing and able to consume daily supplements and document daily food 
intake at home.
5.2 Contraception
Contraception Requirements for Females
Postmenopausal is defined as:

Age > 55 years with no menses for 12 or more months without an alternative medical cause.

Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause 
AND follicle-stimulating hormone (FSH) level > 40 IU/L.
If female, subject must be either post-menopausal or permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy, or hysterectomy).  If the female subject is a woman of 
childbearing potential (WOCBP), she must practice at least one of the following methods of birth control 
throughout the study and for 30 days after the last study drug dose is given.

Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal) associated with inhibition of ovulation initiated at least 1 month before study 
Baseline Day 1.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 1 month before study Baseline Day 1.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Vasectomized sexual partner(s) (the vasectomized partner(s) provided the vasectomized partner 
has received medical assessment of the surgical success and is the sole sexual partner of the 
trial participant).
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
True abstinence:  Refraining from heterosexual intercourse when this is in line with the 
preferred and usual lifestyle of the subject (periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable).

Male or female condom with or without spermicide.

Cap, diaphragm, or sponge with spermicide.

A combination of male condom with cap, diaphragm, or sponge with spermicide (double barrier 
method).
Contraception Requirements for Males
Male subjects who are sexually active with a woman of childbearing potential are not required to use 
condoms during the study.
5.3 Prohibited Medications and Therapy
In addition to the medications listed in the eligibility criteria, use of non-CREON® pancreatic enzyme 
supplementation or over-the-counter supplements that contain lipase, protease, and amylase as active 
ingredients, other than the study drug, is prohibited during the treatment period until the last dose of 
study drug.
Subjects in Screening, who are washing out of PERT, may resume PERT after collecting Stool specimen
for Sudan stain test until 1 week prior to Day 1.
For resected subjects:  Subjects must not have started chemotherapy or radiation therapy from the time 
of the resection until after Week 1 of the study.  However, neoadjuvant therapy prior to the resection is 
allowed.
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving at the time of screening or receives during the study 
must be recorded through the Follow-up Visit and any unscheduled visits.
All chemotherapy (neoadjuvant/adjuvant therapy) drugs used during the study will be recorded and 
must include all drugs, doses, and date ranges of administration.  Any changes in planned chemotherapy 
should be recorded.
No drug interactions have been identified for pancrelipase.  No formal interaction studies have been 
conducted with pancrelipase.8
Subjects must be able to safely discontinue any prohibited medications as described in the eligibility 
criteria.  Subjects must be consented for the study before discontinuing any prohibited medications for 
the purpose of meeting study eligibility.
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Required and Rescue Concomitant Medications/Therapy
Not applicable.
5.5 Withdrawal of Study Drug and/or Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from study drug administration and/or the study at 
any time for reasons including, but not limited to, the following:

The subject requests to be withdrawn from the study.

The subject becomes pregnant while on study drug.    

The investigator believes it is in the best interest of the subject, for any reason, including:

Clinically significant abnormal laboratory results or AEs, which rule out continuation of the 
study drug, as determined by the investigator.

Eligibility criteria violation noted after the subject started study drug, if continuation of the 
study drug administration would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

Subject is significantly noncompliant with study procedures which would put the subject at risk 
for continued participation in the trial.
To minimize missing data, subjects who prematurely discontinue study drug treatment should continue 
to be followed for all regularly scheduled visits.  Subjects should be advised on the continued scientific 
importance of their data even if they discontinue treatment with study drug early.
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation.  The information will be recorded on the 
appropriate electronic case report form (eCRF) page.  If the subject has not had a study visit 30 days 
after study drug has been discontinued, a 30-day follow-up phone call after the last dose of study drug 
will be completed to ensure all treatment-emergent AEs/serious AEs (SAEs) have been resolved.
However, study procedures should not interfere with the initiation of any new treatments or 
therapeutic modalities that the investigator considers necessary to treat the subject's condition.  
Following discontinuation of study drug, the subject will be treated in accordance with the investigator's 
best clinical judgment, irrespective of whether or not the subject decides to continue to participate in 
the study.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the final status of the subject.  At a minimum, 2 telephone calls must be made, and 
1 certified letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site.  The investigator may 
also stop the study at his or her site if he or she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
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Withdrawal from Study Drug Treatment
In the event that a subject withdraws or is prematurely discontinued from study drug treatment, the 
subject should complete the Premature Discontinuation Visit as soon as possible (preferably within 
7 days of last dose of study drug) and undergo certain study procedures (discontinuation visit will be 
added).  These procedures should not interfere with the initiation of any new treatments or therapeutic 
modalities the investigator feels are necessary to treat the subject's condition.
Withdrawal from Study
If a subject prematurely discontinues study participation, the procedures outlined for the premature 
discontinuation (PD) visit should be completed as soon as possible, preferably within 1 week, unless the 
reason for the premature discontinuation is withdrawal of consent.
5.6 Study Drug
AbbVie will provide pancrelipase as capsules.  Pancrelipase will be taken orally with each meal and snack 
beginning at Baseline (Day 1).  The study drug should be taken with food.  Capsules should be swallowed 
whole.  If subjects forget to take their pancrelipase dose at their regularly scheduled dosing time, they 
should take the next dose at the next scheduled dosing time.  A description of study drug is provided in 
Table 1.
Table 1.
Description of Study Drug
Investigational 
Product
Manufacturer
Mode of 
Administration
Dosage Form
Strength
Pancrelipase
AbbVie
Oral
Delayed-Release 
Capsule
6,000 USP units 
(Lipase),
12,000 USP units 
(Lipase), 36,000 USP 
units (Lipase)
Matching placebo 
for purpose of 
blinding dose 
cohorts
AbbVie
Oral
Capsule
Not applicable
The non-investigational nutritional supplements, Ensure Plus® or Glucerna Hunger Shake® (for subjects 
with diabetes mellitus), are commercially available (standard of care) to be supplied by RX Card and 
should be consumed with each snack (Ensure Plus® 2 to 3 daily or Glucerna Hunger Shake® 3 to 4 daily).  
This service will deliver monthly supplies of nutritional supplements directly to the subject's home for 
the duration of their treatment.  Subjects will be provided access to the service at least 1 week prior to 
randomization as part of screening activities to have nutritional supplements available for consumption 
starting 7 days prior to randomization.
Pancrelipase will be packaged in bottles and blister cards with quantities sufficient to accommodate 
study design.  Subjects in the blinded portion of the study will receive cartons containing blister cards for 
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both meals and snacks.  This is to maintain the blind and to make it clear which capsules are to be taken 
with each meal and snack.
Subjects in the open-label portion will receive pancrelipase in bottles since blinding is not needed for 
this portion of the study.  These subjects will receive 2 capsules of pancrelipase 36,000 USP units 
(Lipase) (72,000 USP units [Lipase] with meals) and 1 capsule (36,000 USP units [Lipase] with snacks) 
during the entire duration of the study.  These subjects will not receive placebo capsules and will not be 
titrated per protocol.
Each kit (bottle, blister card, and carton) will be labeled per local requirements and this label must 
remain affixed to the kit.  Upon receipt, study drug should be stored as specified on the label and kept in 
a secure location.  Each label will contain a unique kit number.  This kit number is assigned to a subject 
via interactive response technology (IRT) and encodes the appropriate study drug to be dispensed at the 
subject's corresponding study visit.  All blank spaces on the label will be completed by the site staff 
before dispensing to subjects.  Study drug will only be used for the conduct of this study.
A description of investigational product is provided in Table 2.  All AbbVie personnel with direct 
oversight of the conduct and management of the trial (with the exception of AbbVie Drug Supply 
Management Team), the investigator, study site personnel, and the subject will remain blinded to each 
subject's treatment throughout the study.  To maintain the blind, the pancrelipase capsules and placebo 
capsules provided for the study will be identical in appearance.  The IRT will provide access to unblinded 
subject treatment information in the case of a medical emergency.
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Figure 2.
Card Diagram of Dosing Regimen
PBO = placebo
Note:
Diagrams are not to scale and are only meant as a visual representation.  Actual cards may differ in color and size.
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5.7 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the Screening Visit.  Subjects 
may rescreen once.  For subjects who rescreen, the Screening number assigned by the IRT at the initial 
Screening visit should continue to be used.  For subjects who do not meet the study selection criteria, 
the site personnel must contact the IRT system and identify the subject as a screen failure.   
The IRT will assign a randomization number that will encode the subject's dose cohort assignment 
according to the randomization schedule generated by the statistics department at AbbVie.
Eligible resected subjects will be randomized to 1 of the 2 dose cohorts in a 1:1 ratio on Day 1 as 
indicated in Section 4.1.
For resected subjects, all AbbVie personnel with direct oversight of the conduct and management of the 
trial (with the exception of AbbVie Drug Supply Management Team), the investigator, study site 
personnel, and the subject will remain blinded to each subject's randomized treatment throughout the 
study.  To maintain the blind, the pancrelipase capsules and placebo capsules provided for the study will 
be identical in appearance.  The IRT will provide access to un-blinded subject treatment information in 
the case of a medical emergency.
Eligible non-resected subjects will enter the open-label cohort to receive pancrelipase at a dose of 
72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with snacks during the entire duration of 
the study.
Dose Modification
Resected subjects
The dose for resected subjects in the low dose cohort (12,000 USP units (Lipase) with meals/6,000 USP 
units (Lipase) with snacks) may be modified to the high dose (72,000 USP units (Lipase) with 
meals/36,000 USP units (Lipase) with snacks) at Weeks 1, 5, or 9 and maintained at the high dose for the 
rest of the study.
Only one dose modification will be permitted at Weeks 1, 5, or 9.  For subjects who have experienced 
dose escalation, they will remain on the high dose level for the rest of the treatment duration, even if 
they continue to meet the dose escalation criteria in the subsequent visit(s).  No further dose escalation 
is provided.
Dose modification criteria will be documented in the IRT specifications and implemented by IRT based 
upon responses to the selected questions from the EPI Symptom Questionnaire.
Non-resected subjects 
Non-resected subjects in the open-label cohort will continue to receive pancrelipase at a dose of 
72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with snacks during the study; there will 
be no dose modification.
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Proton pump inhibitor (PPI) Therapy
An addition of proton pump inhibitor (PPI) therapy can be considered if all below criteria are met:

Subjects continue to have symptoms of fat malabsorption and if the investigator deems clinically 
appropriate.

Subjects are not already receiving PPI therapy.
5.8 Protocol Deviations
The investigator is responsible for complying with all protocol requirements, written instructions, and 
applicable laws regarding protocol deviations.  AbbVie does not allow protocol waivers or 
intentional/prospective deviations from the protocol except when necessary to eliminate an immediate 
hazard to study subjects.  If a protocol deviation occurs (or is identified), after the subject has been 
enrolled, the investigator is responsible for notifying the IEC/IRB, regulatory authorities (as applicable),
and AbbVie (See Operations Manual Section 1).
5.9 Additional Supplies
AbbVie will provide stool collection kits, subject electronic diary (eDiary) for food intake and other 
subject data.  Subjects will be requested to record stool data, on paper in the event the data will not be 
collected in the eDiary.
Sites will be provided with electronic patient-reported outcomes (ePRO) instruments for collection of 
EORTC QLQ-C30, QLQ-PAN26, and EPI symptom data.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE, therefore, can be any unfavorable and unintended sign (including a clinically 
significant laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.  Any worsening of a pre-existing condition or illness is considered an AE.
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Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations," which must be reported whether or not associated with an AE.
There are no adverse events of special interest (AESI) for pancrelipase in this study population.  The 
investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout the study.  All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been 
pre planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
If an AE meets any of the following criteria, it is to be reported to AbbVie clinical pharmacovigilance or 
clinical research organization (CRO) (as appropriate) as a serious AE (SAE) within 24 hours after the site 
becomes aware of the SAE (refer to Section 4.3 of the Operations Manual for reporting details and 
contact information):
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not been 
taken.  This does not include an event that would have been fatal if it 
had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay.  This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
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Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, threat of loss of life, 
hospitalization, prolongation of hospitalization, congenital anomaly, 
or persistent or significant disability/incapacity).  Additionally, any 
elective or spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All AEs reported from the time of study drug administration until 30 days after discontinuation of study
drug administration will be collected, whether solicited or spontaneously reported by the subject.  In 
addition, SAEs and protocol-related nonserious AEs will be collected from the time the subject signs the 
study-specific informed consent.
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting for 
the Investigational Medicinal Product (IMP) in accordance with global and local guidelines.
Adverse Event Severity and Relationship to Study Drug
The investigators will rate the severity of each AE as mild, moderate, or severe.  
The investigator will use the following definitions to rate the severity of each AE:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the subject's 
usual activities.
Severe
The adverse event causes considerable interference with the subject's usual 
activities and may be incapacitating or life threatening.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable Possibility – After consideration of factors including timing of the event, biologic plausibility, 
clinical judgment, and potential alternative causes, there is sufficient evidence (information) to suggest 
a causal relationship.
No Reasonable Possibility – After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is insufficient evidence 
(information) to suggest a causal relationship.
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Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 working day after 
the site becomes aware of the pregnancy.  If a pregnancy occurs in a study subject, information 
regarding the pregnancy and the outcome will be collected.
Pregnancy in a study subject is not considered an AE. Subjects who become pregnant during the study 
must be discontinued (Section 5.5).  The medical outcome for either the mother or infant meeting any 
serious criteria, including an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
6.2 Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product, this may include but is not limited to damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device not working properly, 
or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 1 business day after the study site becomes aware of the event.  Product complaints occurring 
during the study will be followed up to a satisfactory conclusion.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully documented in the 
Statistical Analysis Plan (SAP).  The SAP will be finalized before the final database lock.  The statistical 
analyses will be performed using SAS (SAS Institute Inc., Cary, North Carolina, USA).
7.2 Definition for Analysis Populations
The full analysis set (FAS) includes all randomized subjects who received at least 1 dose of study drug.  
The FAS will be used for all efficacy and Baseline analyses.  Subjects will be grouped according to 
treatment as randomized.  Additional analysis population(s) may be used for the efficacy analysis.  
Details are provided in the SAP.
The safety analysis set consists of all subjects who received at least 1 dose of study drug.  For the safety 
analysis set, subjects are assigned to a dose cohort based on the treatment actually received, regardless 
of the treatment randomized.
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7.3 Statistical Analyses for Efficacy
Primary Analysis
The primary efficacy endpoint is the change in stool fat from Baseline (Day 1) to Week 1.  Within each 
dose cohort, a paired t-test will be performed to test the null hypothesis that the mean stool fat change 
is equal to zero.  For comparison between dose cohorts, the change from Baseline will be analyzed using 
an analysis of covariance model including treatment as a fixed effect and Baseline stool fat as the 
covariate.
Details on the primary and other efficacy analyses are provided in the SAP.
Sample Size Estimation
Resected subjects:  72 subjects total (36 subjects per dose group).  After adjusting a dropout rate of 
16%, the study will have 60 evaluable subjects for the evaluation of stool fat at Week 1.  This sample size 
will have an approximately 99% power to detect a 20 gram stool fat reduction in mean stool fat from 
Baseline in each dose group assuming that the standard deviation for the change is 25 g or 
approximately 94% power to detect a 10 g stool fat reduction in mean stool fat from baseline assuming 
that the SD for the change is 15 g.3,10  The type I error rate is 0.05 (2-sided).
In addition, the study will have an approximately 86% power to detect a difference of 20 g between 
2 dose groups in mean stool fat change from Baseline, assuming the same standard deviation of 25 g for 
both dose groups.  The power will drop to 63% if the difference is 15 g.
Non-resected subjects:  Up to 20 subjects.
7.4 Statistical Analyses for Safety
Analysis of safety will include AEs, clinical laboratory values, and vital sign results.  Details on the safety 
analyses are provided in the SAP.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form(s) will be IEC/IRB-approved.
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8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation (ICH) guidelines, applicable regulations and guidelines governing clinical study 
conduct, and the ethical principles that have their origin in the Declaration of Helsinki.  Responsibilities 
of the investigator are specified in Appendix B.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted and data are generated, documented, and reported 
in compliance with the protocol, ICH GCP, and applicable regulatory requirements.
11
COMPLETION OF THE STUDY
The end-of-study is defined as the time of the last subject last visit.
12
REFERENCES
1.
D'Haese JG, Ceyhan GO, Demir IE, et al.  Pancreatic enzyme replacement therapy in patients 
with exocrine pancreatic insufficiency due to chronic pancreatitis:  a 1-year disease 
management study on symptom control and quality of life.  Pancreas.  2014;43(6):834-41.
2.
Seiler CM, Izbicki J, Varga-Szabó L, et al.  Randomised clinical trial:  a 1-week, double-blind, 
placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (CREON 25000 MMS) 
for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label 
extension.  Aliment Pharmacol Ther.  2013;37(7):691-702.
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3.
Whitcomb DC, Lehman GA, Vasileva G, et al.  Pancrelipase delayed-release capsules (CREON) for 
exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery:  a double-
blind randomized trial.  Am J Gastroenterol.  2010;105(10):2276-86.
4.
Gubergrits N, Malecka-Panas E, Lehman GA, et al.  A 6-month, open-label clinical trial of 
pancrelipase delayed-release capsules (CREON) in patients with exocrine pancreatic insufficiency 
due to chronic pancreatitis or pancreatic surgery.  Aliment Pharmacol Ther.  
2011;33(10):1152-61.
5.
Graff GR, McNamara J, Royall J, et al.  Safety and tolerability of a new formulation of 
pancrelipase delayed-release capsules (CREON) in children under seven years of age with 
exocrine pancreatic insufficiency due to cystic fibrosis:  an open-label, multicentre, single-
treatment-arm study.  Clin Drug Investig.  2010;30(6):351-64.
6.
Graff GR, Maguiness K, McNamara J, et al.  Efficacy and tolerability of a new formulation of 
pancrelipase delayed-release capsules in children aged 7 to 11 years with exocrine pancreatic 
insufficiency and cystic fibrosis:  a multicenter, randomized, double-blind, placebo-controlled, 
two-period crossover, superiority study.  Clin Ther.  2010;32(1):89-103.
7.
Trapnell BC, Maguiness K, Graff GR, et al.  Efficacy and safety of CREON 24,000 in subjects with 
exocrine pancreatic insufficiency due to cystic fibrosis.  J Cyst Fibros.  2009;8(6):370-7.
8.
CREON (pancrelipase) delayed-release capsules [US prescribing information].  North Chicago, IL; 
AbbVie Inc., 2015.
9.
FitzSimmons SC, Burkhart GA, Borowitz D, et al.  High-dose pancreatic-enzyme supplements and 
fibrosing colonopathy in children with cystic fibrosis.  N Engl J Med.  1997;336(18):1283-9.
10. Ramesh H, Reddy N, Bhatia S, et al.  A 51-week, open-label clinical trial in India to assess the 
efficacy and safety of pancreatin 40000 enteric-coated minimicrospheres in patients with 
pancreatic exocrine insufficiency due to chronic pancreatitis.  Pancreatology.  2013;13(2):133-9.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
Adverse event
ANC
Absolute neutrophil count
BMI
Body mass index
CF
Cystic fibrosis
CFA
Coefficient of fat absorption
CNA
Coefficient of nitrogen absorption
CP
Chronic pancreatitis
CRO
Clinical research organization
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
eDiary
Electronic diary
EORTC
European Organisation for Research and Treatment of Cancer
EPI
Exocrine pancreatic insufficiency
ePRO
Electronic patient-reported outcomes
FAS
Full analysis set
FC
Fibrosing colonopathy
FDA
Food and Drug Administration
FE-1
Fecal elastase-1
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
ICH
International Council on Harmonisation
IEC
Independent ethics committee
IMP
Investigational medicinal product
IRB
Institutional review board
IRT
Interactive response technology
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
LP
Lipase 
PD
Premature discontinuation
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PERT
Pancreatic enzyme replacement therapy
PPI
Proton pump inhibitor
PRO
Patient-reported outcome
PS
Performance status
PY
Pancreatectomy
QLQ
Quality of life questionnaire
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SUSAR
Suspected Unexpected Serious Adverse Reactions
ULN
Upper limit of normal
US
United States
USP
United States Pharmacopeia
USPI
United States prescribing information
WOCBP
Women of childbearing potential
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M16-142:  CREON® (pancrelipase) therapy for subjects with exocrine pancreatic insufficiency 
(EPI) due to pancreatic cancer:  A double-blind, randomized, parallel design with 2 dose cohorts of 
pancrelipase in resected pancreatic cancer subjects and an open-label single dose cohort in 
non-resected pancreatic cancer subjects
Protocol Date:  22 November 2019
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
(ICH) Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site 
location.  In signing the Investigator Agreement, the investigator is agreeing to the following:
11. Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate independent ethics committee (IEC)/institutional review board 
(IRB), except when necessary to protect the subject from immediate harm.
12. Personally conducting or supervising the described investigation(s).
13. Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
14. Reporting complaints that occur in the course of the investigation(s) to AbbVie.
15. Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
16. Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
17. Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
18. Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
19. Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
20. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Director
Medical Writing
Therapeutic Area Physician
General Medicine and Virology
Executive Medical Director
General Medicine and Virology
Medical Director
General Medicine and Virology
Statistics Therapeutic Area Head
Data and Statistical Sciences
Senior Research Statistician, Statistics
Data and Statistical Sciences
Study Project Manager
Clinical Program Development
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions
Protocol
Date
Version 1.0
03 August 2018
Version 2.0
27 November 2018
Administrative Change 1
12 March 2019
The purpose of this version is to correct minor clerical errors for consistency throughout the protocol in 
addition to the following:
1.
Secondary Endpoints
Reclassified exploratory endpoints for the resected subjects as secondary endpoints (Section 2 and 
Section 3.3).
Rationale:  Since the majority of subjects in the trial are likely to have resection after PC, the sample size 
is likely to be large enough to get good estimates for these endpoints.
2.
Exploratory Endpoints
Removed exploratory endpoints:

Difference between 2 dose cohorts in change from Baseline in stool frequency at Week 1

Change in stool frequency from Baseline to Weeks 5, 9, and 13

Change in health care resource utilization (HCRU) from Baseline to Weeks 1, 5, 9, and 13

Change in EPI symptoms (as assessed by the EPI Symptom Questionnaire) from Baseline to 
Weeks 1, 5, 9, and 13

Changes in quality of life (QoL) (EORTC QLQ-C30 and QLQ-PAN26) from Baseline to Weeks 1, 5, 
9, and 13.

Chemotherapy tolerability

Change from Baseline to Weeks 1, 5, 9, and 13 for the following measurements: 

Body weight, and body mass index (BMI)
Rationale:  The endpoints in the first 2 bullets are included as secondary endpoints and HCRU endpoints 
were removed as they are no longer of interest.  The remainder of previous exploratory endpoints were 
removed or relocated to secondary endpoints.
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3.
Eligibility Criteria
Revised the eligibility criteria (Section 5.1) as follows:  Added FE-1 test repeat by subjects, if needed.  
Added the criticality of stopping PERT the week prior to Day 1.  Eliminated the exclusion of full 
pancreatectomy subjects from the eligibility criteria.  Allowed exposure to octreotide prior to consenting 
as long as subjects are safely able to discontinue it after consenting.  Prohibited diagnosis/history of 
renal impairment, hyperuricemia, or uncontrolled gout, including those with a recent acute flare within 
60 days of Screening that would make the subject an unsuitable candidate to receive study drug.
Rationale:  To more clearly define the subject population in the study.
4.
Prohibited Medications and Therapy
Added the sentence "Subjects in Screening who are washing out of PERT may resume PERT after 
collecting stool specimen for Sudan stain until 1 week prior to Day 1" (Section 5.3).
Rationale:  To alleviate any potential patient discomfort due to lack of PERT at Screening until Day (–)7.   
5.
Activity Schedule
Appendix D. ACTIVITY SCHEDULE
Added FSH testing at Screening.  Added specific timing for collection of stool-related parameters.
Rationale: Changes were made to ensure FSH is collected at Screening to verify postmenopausal status.
6.
Changes in the Operations Manual
Changes were made to the operations manual to reflect changes made to the protocol.
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STUDY M16-142  |  Version 3.0 
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX F. OPERATIONS MANUAL
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
1 CONTACTS
Sponsor/
Emergency 
Contact
 MD
AbbVie 
Development
1 N. Waukegan Road
North Chicago, IL 60064
Email:
EMERGENCY 24-hour Number:
+1 973-784-6402
Office:
Mobile:
Fax:
Safety 
Concerns
Therapeutic Area Safety Team
Dept. R48S, Bldg. AP31-1
1 North Waukegan Road 
North Chicago, IL 60064
Phone:
+1 847-935-7577
Email:
GPRD_SafetyManagement_Hormones@Abbvie.com
Serious 
adverse 
event (SAE) 
Reporting 
outside of 
RAVE
Email:
PPDINDPharmacovigilance@abbvie.com
Fax:
+1 847-938-0660
Protocol 
Deviations
Study Project Manager
1 North Waukegan Rd.
North Chicago, IL 60064
Phone:
Fax:
Email:
Certified 
Clinical Lab
Covance CLS
8211 SciCor Dr
Indianapolis, IN 46214
Phone:
+1 317-273-7872
Fax:
+1 317-616-4572
Additional 
Sample Lab
Covance CLS
8211, SciCor Dr.
Indianapolis, IN 46214
Phone:
+1 317-273-7872
Fax:
+1 317-616-4572
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
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TABLE OF CONTENTS
1
CONTACTS
2
2
INVESTIGATION PLAN
5
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
5
3
STUDY PROCEDURES
10
3.1
SUBJECT INFORMATION AND INFORMED CONSENT
10
3.2
MEDICAL HISTORY
10
3.3
DRUG AND ALCOHOL SCREEN
10
3.4
ADVERSE EVENT ASSESSMENT
11
3.5
PATIENT-REPORTED OUTCOMES
11
3.6
PHARMACOKINETIC SAMPLING
12
3.7
BIOMARKER AND/OR ADDITIONAL LABORATORY TESTS SAMPLING
12
3.8
12-LEAD ELECTROCARDIOGRAM
12
3.9
HEIGHT, WEIGHT, HIP, AND WAIST CIRCUMFERENCE
12
3.10 VITAL SIGNS
13
3.11 PHYSICAL EXAMINATION
13
3.12 DISPENSE STUDY DRUG
13
3.13 CLINICAL LABORATORY TESTS
14
3.14 STOOL FAT
16
4
SAFETY MANUAL
16
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
16
4.2
RECORDING DATA AND ANALYSES OF SAFETY FINDINGS
17
4.3
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
17
5
COUNTRY-SPECIFIC REQUIREMENTS
18
5.1
SAMPLE RETENTION REQUIREMENTS
18
5.2
SUSAR REPORTING
18
6
STUDY DRUG
19
6.1
TREATMENTS ADMINISTERED
19
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
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6.2
PACKAGING AND LABELING
20
6.3
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
21
6.4
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
22
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
23
APPENDIX B.
EORTC QLQ-C30
24
APPENDIX C.
EORTC QLQ-PAN26
26
APPENDIX D.
EPI SYMPTOM QUESTIONNAIRE
28
APPENDIX E.
BRISTOL STOOL CHART
32
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
  TREATMENT 
AND ASSOCIATED 
ACTIVITIES

Order nutritional supplement 
(Ensure Plus® or Glucerna 
Hunger Shake®) prescription at 
least 2 weeks prior to 
randomizationd,e

Instruct subjects to nutritional 
supplement consumption 1 week 
prior to Day 1:  Ensure Plus® 2 –
3 daily or Glucerna Hunger 
Shake® 3 – 4 daily

Subjects on pancreatic enzyme 
replacement therapy (PERT), 
must discontinue PERT a week 
prior to Day 1
NOTES:
a.
Subject must be consented prior to discontinuing any prohibited medications or 
conducting any other study activity.
b.
Only prescribed medication is allowed.
c.
Collected daily, by the subject, for 1 week prior to Day 1.  Stool Consistency and 
Frequency and Diarrhea may need to be recorded on paper in the event the data will 
not be collected in ePRO.
d.
The RX Card service will deliver monthly supplies of nutritional supplements directly 
to the subject's home for the duration of their treatment.  Subjects will be provided 
access to the service at least 1 week prior to randomization as part of Screening 
(pre-randomization) activities to have nutritional supplements available for 
consumption starting 7 days prior to randomization.  Similarly, with the monthly 
delivery during study participation, subjects will be provided access to the service at 
least 1 week prior to use.  The site will be responsible for nutritional supplement re-
ordering for subjects throughout the study (prior to randomization, at Week 1, and 
Week 5).
e.
Subjects will be required to start updating data in their electronic patient-reported 
outcomes (ePRO) device a week prior to randomization.
f.
The site will complete dipstick urinalysis at all required visits.  Specified abnormal 
macroscopic urinalyses defined as leukocytes, nitrite, protein, ketones, or blood 
greater than negative or glucose greater than normal will be followed up with a 
microscopic analysis at the central laboratory.
g.
Positive stool results are defined as increased level of neutral OR total fats (normal 
ranges are < 60 droplets/HPF and < 100 droplets/HPF, respectively).
h.
This will be provided to subjects by the site personnel.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
3 STUDY PROCEDURES
3.1 Subject Information and Informed Consent
The investigator or his or her representative will explain the nature of the study to the subject and 
answer all questions regarding this study.  Before any study-related Screening procedures are 
performed on the subject or any medications are discontinued by the subject in order to participate in 
this study, the informed consent statement must be reviewed, signed, and dated by the subject, the 
person who administered the informed consent, and any other signatories according to local 
requirements.  A copy of the signed informed consent will be given to the subject and the original will be 
placed in the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained before any study-related procedures and 
that the subject received a signed copy.
Information regarding benefits for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in the study can be found in 
the informed consent form.
3.2 Medical History
A complete medical history including history of tobacco, alcohol, and drug use will be taken at 
Screening.  The subject's medical history can be updated at each visit as appropriate.
3.3 Drug and Alcohol Screen
Subjects should have no history of clinically significant (per investigator's judgment) drug or alcohol 
abuse within the last 6 months.
Urine specimens will be tested at the Screening visit for the presence of drugs of abuse.  The panel for 
drugs of abuse will minimally include the drugs listed below.  Any positive result must be assessed for 
clinical significance.  These analyses will be performed by the certified central laboratory chosen for the 
study.  Prescribed medication will be allowed.

Opiates

Barbiturates

Amphetamines

Cocaine

Benzodiazepines
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
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
Alcohol

Phencyclidine

Propoxyphene

Methadone
3.4 Adverse Event Assessment
Please refer to Section 4.2.
3.5 Patient-Reported Outcomes
Subjects will complete the self-administered patient-reported outcome (PRO) instruments (when 
allowed per local regulatory guidelines).  Subjects should be instructed to follow the instructions 
provided with the instrument and to provide the best possible response to each item.  Site personnel 
shall not provide interpretation or assistance to subjects other than encouragement to complete the 
tasks.  Subjects who are functionally unable to read any of the instruments may have site personnel read 
the questionnaire to them.  Site personnel will encourage completion of the instrument at all specified 
visits and will ensure that a response is entered for all items.
The PRO instruments to evaluate quality of life are the European Organisation for Research and 
Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 (Appendix B) and EORTC QLQ-
PAN26 (Appendix C).
The PRO instrument should be completed before drug administration on Day 1, Weeks 1, 5, and 9, as 
well as Week 13/premature discontinuation (PD) and before any discussion of adverse events or any 
review of laboratory findings.
EPI symptoms (using EPI Symptom Questionnaire) will be assessed at visits indicated in Section 2.1.  The 
subject should complete the questionnaire before site personnel perform any clinical assessments and 
before any interaction with site personnel occurs to avoid biasing the subject's response.  Site personnel 
will administer the EPI Symptom Questionnaire (Appendix D) to subjects.
Food intake, stool frequency, stool consistency and incidences of diarrhea will be collected by subjects 
daily for a week prior to the following visits; Day 1, Weeks 1, 5, 9, and 13.  For stool consistency, subjects 
will select the image from the Bristol Stool Chart that represents the most frequent or average stool 
consistency during a past 24-hour period. 
Study drug intake will be recorded daily, by subjects using the ePRO device, during the treatment period, 
starting on Day 1 through Week 13.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
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3.6 Pharmacokinetic Sampling
Not applicable.
3.7 Biomarker and/or Additional Laboratory Tests Sampling
A blood sample will be collected on Day 1, as well as Weeks 5, 9, and 13/premature discontinuation visit 
from each subject for a biomarker analysis.
The central laboratory, AbbVie, or its designee will provide specific instructions for preparation and 
storage of archive samples.
Specimen will be collected at Day 1, Weeks 5, 9, and 13/premature-discontinuation for potential 
nutritional analysis.
3.8 12-Lead Electrocardiogram
A 12-lead electrocardiogram (ECG) will be performed at the designated study visits as specified in 
Section 2.1.  The ECG should be performed before blood collection.
An appropriately trained physician at the site ("local reader") will evaluate the ECGs.  The local reader 
from the site will sign and date all ECG tracings and will provide his/her global interpretation as a written 
comment on the tracing using the following categories:

Normal ECG

Abnormal ECG – not clinically significant

Abnormal ECG – clinically significant
Only the local reader's evaluation of the ECG will be collected and documented in the subject's source 
folder.  The automatic machine reading (i.e., machine-generated measurements and interpretation that 
are automatically printed on the ECG tracing) will not be collected.
3.9 Height, Weight, Hip, and Waist Circumference
Height will be measured at Day 1 only.  Hip and waist circumference should be measured at Screening, 
(however, if missed, it can be recorded at the Day 1 visit), Day 1, Week 1, 5, 9, and 13/PD Visits and as 
specified in Section 2.1.  Body weight will be measured at scheduled visits as specified in Section 2.1.  
The subject will wear lightweight clothing and no shoes during weighing.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
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Hip and waist circumference will be measured while subject is wearing light clothing and stands with 
feet shoulder width apart and back straight.  To measure waist circumference, locate the top of the hip 
bone and align the bottom edge of the measuring tape with the top of the hip bone.  Wrap the tape 
measure all the way around the waist.  Have the subject take 2 normal breaths and on the exhale of the 
second breath tighten the tape measure.  Take the measure of the waist to the nearest 0.5 centimeter 
(1/4 inch).
To measure hip circumference, place the measuring tape around the maximum circumference of the 
buttocks.  The reading of the measurement should be taken at the end of gentle exhaling.  The 
measuring tape should be held firmly, ensuring its horizontal position.  Verify that the tape is horizontal 
all around the waist.  The tape should be loose enough to allow the observer to place 1 finger between 
the tape and the subject's body.
3.10 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure, pulse rate, and body temperature will 
be obtained at visits as specified in Section 2.1.  Blood pressure and pulse rate should be measured after 
the subject has been sitting for at least 3 minutes.
3.11 Physical Examination
A symptom-directed physical examination will be performed at the designated study visits as specified in 
Section 2.1.  The physical examination performed on Day 1 will serve as the Baseline physical 
examination for the entire study.  Any significant physical examination findings after the first dose will 
be recorded as adverse events.  All findings, whether related to an adverse event or part of each 
subject's medical history, will be captured on the appropriate electronic case report form (CRF) page.
At any time, a symptom-directed physical examination can be performed as the investigator deems 
necessary.
3.12 Dispense Study Drug
Study drug will be dispensed to subjects beginning at Baseline (Day 1) and as specified in Section 2.1.  
The first dose of study drug will be administered after all other Baseline (Day 1) procedures are 
completed.  At the visits specified in Section 2.1, the site personnel will review the dosing diary, review 
returned study drug kits, and empty study drug packaging to verify compliance.
Study drug (i.e., pancrelipase) capsules to be taken orally should be dosed together and taken with food.  
Subjects will also be requested to start taking nutritional supplements 7 days prior to randomization.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
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3.13 Clinical Laboratory Tests
The Baseline laboratory test results for clinical assessment for a particular test will be defined as the last 
measurement before the initial dose of study drug unless otherwise specified in the Statistical Analysis 
Plan.
A certified laboratory will be utilized to process and provide results for the clinical laboratory tests.  
Laboratory reference ranges will be obtained before the initiation of the study.
The central laboratory will provide instructions regarding the collection, processing, and shipping of 
these samples and send them to the following certified laboratory addresses:
Covance CLS
8211 SciCor Dr.
Indianapolis, IN 46214
If a laboratory test value is outside the reference range and the investigator considers the laboratory 
result to be clinically significant, the investigator will:

Repeat the test to verify the out-of-range value;

Follow the out-of-range value to a satisfactory clinical resolution; or

Discontinue the subject from the study or require the subject to receive treatment; in this case, 
the laboratory result will be recorded as an adverse event.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
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Clinical Laboratory Tests
Hematology
Clinical Chemistry
Other Tests
Hematocrit
Hemoglobin
Red blood cell (RBC) count
Red cell distribution width (RDW)
RBC morphology and mean 
corpuscular volume (MCV)
White blood cell (WBC) count
Neutrophils
Bands 
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not
   acceptable)
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Pre-albumin
Albumin
Alanine transaminase (ALT) 
Aspartate transaminase (AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Bicarbonate/CO2
Chloride
Follicle-stimulating hormone (FSH)
FSH (-70)
SERUM BETA human chorionic 
gonadotropin (hCG)
B-hCG, Qualitative
B-hCG, Quantitative
Serum albumin and prealbumin
Potential nutritional biomarkers
Fecal elastase- 1 
Sudan Stain 
Stool Fat
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Pregnancy Tests (Urine and Serum)
A qualitative urine pregnancy test will be performed at Screening, Day 1, Weeks 1, 5, 9 and Week 13 for 
all women of childbearing potential (WOCBP) subjects.
Determination of postmenopausal status will be made during the Screening period.
A pregnant or breastfeeding female will not be eligible for participation or continuation in this study.
Urine pregnancy tests will be performed at visits indicated in Section 2.1.
Sites will receive supplies from the central lab to run urine pregnancy test.
If the urine pregnancy test (which is performed at the site) is negative, begin or continue dosing.  If urine 
pregnancy test is positive, withhold dosing and perform a serum pregnancy test. Pregnant subjects 
must discontinue from the study.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
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Urinalysis
The site will complete dipstick urinalysis at all required visits.  Sites will receive supplies from the central 
lab to run dipstick urinalysis.  Specified abnormal macroscopic urinalyses defined as leukocytes, nitrite, 
protein, ketones, or blood greater than negative or glucose greater than normal will be followed up with 
a microscopic analysis at the central laboratory.
3.14 Stool Fat
Stool fat sample will be collected at visits indicated in Section 2.1.
It is critical that all stool samples will be collected 48 hours prior to Day 1 and 48 hours prior to Day 8 
(Week 1 visit).
See central laboratory manual and sites' instructions for additional details regarding stool collection.
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All serious adverse events (SAEs) as well as protocol-related nonserious adverse events will be collected 
from the time the subject signed the study-specific informed consent until study drug administration.  
From the time of study drug administration until 30 days after discontinuation of study treatment, all 
adverse events, and SAEs will be collected whether solicited or spontaneously reported by the subject.
After 30 days following completion of study treatment and throughout the Post-Treatment Period, all 
spontaneously reported SAEs will be collected (nonserious AEs will not be collected).
There are no adverse events of special interest (AESI) for pancrelipase in this study population.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
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6 STUDY DRUG
6.1 Treatments Administered
The study drug (pancrelipase) will be dispensed in the form of capsules at the visits listed in Section 2.1.  
Subjects will be instructed to take study drugs daily with each meal or snack.
AbbVie will provide pancrelipase as capsules to be taken as a combination of 6,000, 12,000, and 
36,000 USP units (Lipase).
Pancrelipase will be taken orally daily with each meal or snack from Day 1 through Week 13.  Subjects in 
the blinded cohorts will take 3 capsules with each meal and 2 capsules with each snack.  Subjects in the 
open-label cohort will take 2 capsules with each meal and 1 capsule with each snack.
Study drug must not be dispensed without contacting the interactive response technology (IRT) system.  
Study drug may only be dispensed to subjects enrolled in the study through the IRT system.  At the end 
of the Treatment Period or at the Premature Discontinuation (PD) visit, the site will contact the IRT 
system to provide visit date information and study drug return information for each kit.
At Day 1 eligible resected subjects will be randomized in 1:1 ratio to one of following dose cohorts, and 
will remain on blinded therapy throughout the study:

Low-dose (Regimen of 12,000 USP units (Lipase) with meals/6,000 USP units (Lipase) with 
snacks)

High-dose (Regimen of 72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with 
snacks)
At Week 1, 5, or 9, resected subjects who meet the "Dose Modification Criteria" specified below will be 
titrated once to the following regimen in a blinded fashion:

Subjects in the low dose cohort will escalate to the high dose (72,000/36,000 USP units [Lipase] 
regimen).

Subjects in the high dose cohort will continue on the high dose (72,000/36,000 USP units 
[Lipase] regimen).
Non-resected (unresectable, resectable, and borderline resectable) subjects will receive pancrelipase 
delayed-release capsules administered daily with every meal and snack.  Subjects will participate in the 
study for up to approximately 177 days (Screening up to 56 days, double-blind, and/or open-label 
treatment up to 91 days, and up to a 30-day safety follow-up period).
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
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Dose Modification
Resected subjects
Resected subjects in the low dose cohort (12,000 USP units [Lipase] with meals/6,000 USP units [Lipase] 
with snacks) may modify to receive the high dose (72,000 USP units [Lipase] with meals/36,000 USP 
units [Lipase] with snacks) at Week 1, 5, or 9 and maintain it throughout the study.  Resected subjects in 
the high dose cohort (72,000 USP units [Lipase] with meals/36,000 USP units [Lipase] with snacks) will 
remain on the high dose at Week 1, 5, or 9.
Only one dose modification will be permitted at Week 1, 5, or 9.  For subjects who have experienced 
dose escalation, they will remain on the high dose level for the rest of the treatment duration, even if 
they continue to meet the dose escalation criteria in the subsequent visit(s).  No further dose escalation 
is provided.
Dose modification criteria will be documented in the EDC or IRT specifications and implemented by IRT 
based upon responses to the selected questions from the EPI Symptom Questionnaire.
Non-resected subjects (unresectable, resectable, and borderline resectable subjects) in the open-label 
cohort will continue to receive pancrelipase at a dose of 72,000 USP units (Lipase) with 
meals/36,000 USP units (Lipase) with snacks during the study.
For subjects who continue to have fat malabsorption, addition of proton pump inhibitor (PPI) therapy 
can be considered, if clinically appropriate and subjects are not receiving PPI therapy.
All subjects who receive at least 1 dose of study drug and meet the discontinuation criteria will be 
discontinued from treatment.
The non-investigational nutritional supplements are commercially available Ensure Plus® and Glucerna 
Hunger Shake® (standard of care) to be supplied by RX Card.  This service will deliver approximately 
monthly supplies of nutritional supplements directly to the subject's home for the duration of their 
treatment.  Subjects will be provided access to the service at least 1 week prior to randomization as part 
of pre-randomization activities to have nutritional supplements available for consumption starting 
7 days prior to randomization.
6.2 Packaging and Labeling
Blinded pancrelipase and matching placebo will be supplied in blister cards.  Open-label pancrelipase 
will be supplied in bottles.
Each bottle and blister card will be labeled as required per country requirements.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The labels must remain affixed to the kit.  Upon receipt, study drug should be stored as specified on the 
label and kept in a secure location.  Each kit will contain a unique kit number.  This kit number is 
assigned to a subject via IRT and encodes the appropriate study drug to be dispensed at the subject's 
corresponding study visit.  All blank spaces on the label will be completed by the site staff before 
dispensing to subjects.
Storage and Disposition of Study Drug
Pancrelipase must be stored at controlled room temperature (15° to 25°C/59° to 77°F) and protected 
from moisture.  The pancrelipase material must not be frozen.  The investigational products are for 
investigational use only and are to be used only within the context of this study.  The study drug 
supplied for this study must be maintained under adequate security and stored under the conditions 
specified on the label until dispensed for subject use or destroyed on site as appropriate.
Nutritional supplements must be stored according to the conditions specified in the package insert.  
Storage conditions are within the subjects' responsibilities and AbbVie should not be involved with 
monitoring the temperature of the nutritional supplements.  Any instance including, but not limited to, 
temperature excursions or damaged supplies, should be reported to the manufacturer of the product as 
specified in the product insert.  Instances involving incorrect shipments or missing shipments should be 
reported to Rx Card, the company that handles distribution of the supplies.  Extra supplies remaining 
after the completion of dosing should be handled by the subject.
6.3 Method of Assigning Subjects to Treatment Groups
This is a randomized, double-blind, 2-cohort dose-response study in subjects with EPI due to pancreatic 
cancer that has been resected.  Eligible resected subjects will be randomized to one of the following 
dosing cohorts in a 1:1 ratio to receive 1 of 2 doses (12,000 USP units [Lipase] with meals/6,000 USP 
units [Lipase] with snacks), 72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with snacks.
Non-resected (unresectable, resectable, and borderline resectable) subjects in the open-label cohort will 
receive pancrelipase at a dose of 72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with 
snacks during the entire duration of the study.
All subjects will be assigned a unique identification number by the IRT at the Screening Visit.  For 
subjects who rescreen, the Screening number assigned by the IRT at the initial Screening visit should be 
used.  For resected subjects, the IRT will assign a randomization number that will encode the subject's 
dose cohort assignment according to the randomization schedule generated by the statistics 
department at AbbVie.
Subjects who are enrolled will retain their subject number assigned at the Screening visit throughout the 
study.  Upon receipt of study drug, the site will acknowledge receipt in the IRT system.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Contact information and user guidelines for IRT use will be provided to each site.
6.4 Selection and Timing of Dose for Each Subject
All capsules of pancrelipase will be dosed at the time of snack or meal.  All subjects should take all doses 
of study medications with food around the same time each day.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
BMI
Body mass index
CBC
Complete blood count
eDiary
Electronic diary
ECG
Electrocardiogram
EDC
Electronic data capture
EORTC
European Organisation for Research and Treatment of Cancer
EORTC QLQ-C30
EORTC Quality of Life Questionnaire–C30
EPI
Exocrine pancreatic insufficiency
ER
Emergency room
FSH
Follicle-stimulating hormone
hCG
Human chorionic gonadotropin
IRT
Interactive response technology
MedDRA
Medical Dictionary for Regulatory Activities
MCV
Mean corpuscular volume
PD
Premature discontinuation
PPI
Proton pump inhibitor
PRO
Patient-reported outcome
PT
Preferred term
QLQ
Quality of life questionnaire
RDW
Red cell distribution width 
SAE
Serious adverse event
SOC
System organ class
SUSAR
Suspected Unexpected Serious Adverse Reaction
UA
Urinalysis
USP
United States Pharmacopeia
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
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APPENDIX B. EORTC QLQ-C30
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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p. 26 of 32
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX C. EORTC QLQ-PAN26
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
APPENDIX D. EPI SYMPTOM QUESTIONNAIRE
Exocrine Pancreatic Insufficiency (EPI) Symptom Questionnaire
Instructions:  These questions ask about symptoms you may have had during the past 7 days.  
Please answer all questions by selecting the one option that best describes your experience.
1.
Rate your abdominal pain during the past 7 days.
None
Mild
Moderate
Severe 
Very Severe
2.
Rate your bloating (feeling like you need to loosen your clothes) during the past 7 days.
None
Mild
Moderate
Severe
Very Severe
3.
Rate your nausea during the past 7 days.
None
Mild
Moderate
Severe
Very Severe
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
4.
Rate your vomiting during the past 7 days.
None
Mild
Moderate
Severe
Very Severe
5.
Rate your gas (flatulence) during the past 7 days
None
Mild
Moderate
Severe
Very Severe
6.
Rate your constipation during the past 7 days.
None
Mild
Moderate
Severe
Very Severe
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
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7.
Rate your foul smelling stools during the past 7 days. 
None
Mild
Moderate
Severe
Very Severe
8.
Rate your greasy or fatty stools during the past 7 days. 
None
Mild
Moderate
Severe
Very Severe
9.
Rate your abdominal cramps during the past 7 days. 
None
Mild
Moderate
Severe
Very Severe
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
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10.
Rate your diarrhea during the past 7 days.
None
Mild
Moderate
Severe
Very Severe
11.
Rate your lack of appetite during the past 7 days.
None
Mild
Moderate
Severe
Very Severe
12.
Rate your tiredness during the past 7 days.
None
Mild
Moderate
Severe
Very Severe
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M16-142 Version 3.0
CONFIDENTIAL INFORMATION
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APPENDIX E. BRISTOL STOOL CHART
Page 72 of 74
 
  
  
  
  
 
 
 
 
 
 
 
 
 
    
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 

SAP_001.pdf: 
CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
1
Statistical Analysis Plan for Study M16-142
Creon® (pancrelipase) therapy for subjects with 
Exocrine Pancreatic Insufficiency (EPI) due to 
pancreatic cancer:  A double-blind, randomized, 
parallel design with 2 dose cohorts of pancrelipase 
in resected pancreatic cancer subjects and an open-
label single dose cohort in non-resected pancreatic 
cancer subjects
Date:  13 December 2020
Version 1.0
 
NCT03859869


CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
2
Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives, Hypotheses, and Estimands ....................................................5
2.2
Study Design Overview .............................................................................6
2.3
Treatment Assignment and Blinding .........................................................9
2.4
Sample Size Determination........................................................................9
2.5
Dose Modification ...................................................................................10
3.0
Endpoints................................................................................11
3.1
Primary Endpoint(s).................................................................................11
3.2
Secondary Endpoint(s).............................................................................12
3.3
Additional Endpoint(s).............................................................................12
3.4
Safety Endpoint(s) ...................................................................................15
4.0
Analysis Populations .............................................................15
4.1
Analysis Treatment Groups .....................................................................16
4.2
Analysis Treatment Groups for Various Analyses ..................................18
5.0
Subject Disposition................................................................20
6.0
Study Drug Duration and Compliance................................21
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................21
7.1
Demographics and Baseline and Disease Characteristics........................22
7.2
Medical History .......................................................................................22
7.3
Prior and Concomitant Medications ........................................................23
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints..............................24
9.0
Efficacy Analyses...................................................................24
9.1
General Considerations............................................................................24
9.2
Handling of Missing Data........................................................................25
9.2.1
Adjustment for Missing Stool Fat Samples in Stool Fat per Day............25
9.2.2
Missing EPI Symptoms Score .................................................................26
9.2.3
Missing Stool Frequency .........................................................................26
9.2.4
Missing Stool Consistency.......................................................................27
 


CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
3
9.2.5
Missing QoL Score (EORTC QLQ-C30 and QLQ-PAN26)...................28
9.3
Primary Efficacy Endpoint(s) and Analyses............................................28
9.3.1
Primary Efficacy Endpoint(s) ..................................................................28
9.3.2
Main Analysis of Primary Efficacy Endpoint (s) ....................................28
9.3.2.1
Criteria for Evaluable Stool Fat Sample ..................................................29
9.3.3
Supplementary Analyses of the Primary Efficacy Endpoint(s) ...............30
9.4
Secondary and Additional Efficacy Analyses..........................................30
9.4.1
Stool Fat...................................................................................................30
9.4.2
Stool Frequency .......................................................................................31
9.4.3
Stool Consistency.....................................................................................32
9.4.4
EPI Symptom Score.................................................................................33
9.4.5
QoL (EORTC QLQ-C30 Score and QLQ-PAN26 Score).......................34
9.4.6
Chemotherapy Tolerability ......................................................................35
9.4.7
BMI, Body Weight...................................................................................35
9.4.8
Serum Albumin, Pre-Albumin.................................................................36
9.4.9
Exploratory Analysis for Dietary Intake..................................................36
9.5
Efficacy Subgroup Analyses....................................................................36
10.0
Safety Analyses ......................................................................36
10.1
General Considerations............................................................................36
10.2
Adverse Events ........................................................................................37
10.2.1
Treatment-Emergent Adverse Events ......................................................37
10.2.1.1
Incidence Rate of TEAE in the First Week of Study Treatment .............38
10.2.1.2
Exposure-Adjusted Incidence Rate (EAIR) for TEAE During the 
Entire Treatment Period...........................................................................39
10.2.1.3
Incidence Rate of TEAE Leading to Study Drug Discontinuation 
During the Entire Treatment Period.........................................................40
10.2.2
Listing of AEs..........................................................................................40
10.3
Analysis of Laboratory Data....................................................................41
10.4
Analysis of Vital Signs and Weights .......................................................43
11.0
Interim Analyses....................................................................43
12.0
Overall Type-I Error Control ..............................................44
13.0
Version History......................................................................44
14.0
References...............................................................................44
 


CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
4
List of Tables
Table 1.
Analysis Population and Analysis Treatment Groups for Various 
Analyses...................................................................................................18
Table 2.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint...................................................................................................29
Table 3.
Characterization of Bristol Stool Chart for Analysis...............................33
Table 4.
Laboratory Variable and Corresponding Statistical Analyses .................42
Table 5.
SAP Version History Summary...............................................................44
Table 6.
Scoring the QLQ-C30..............................................................................48
Table 7.
Scoring the QLQ-PAN-26 .......................................................................49
List of Figures
Figure 1.
Study Schematic.........................................................................................8
List of Appendices
Appendix A.
Protocol Deviations..................................................................................45
Appendix B.
Quality of Life (QoL) (EORTC QLQ-C30 and QLQ PAN 26)...............46
Appendix C.
Missing Data Imputation of Quality of Life (QoL) (EORTC QLQ-
C30 and QLQ PAN 26.............................................................................50
Appendix D.
Questions from the EPI Questionnaire Considered for Dose 
Modification.............................................................................................51
 


CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
5
1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for CREON or 
ABT-SLV245 Study M16-142 titled "Creon® (pancrelipase) therapy for subjects with 
exocrine pancreatic insufficiency (EPI) due to pancreatic cancer:  A double-blind, 
randomized, parallel design with 2 dose cohorts of pancrelipase in resected pancreatic 
cancer subjects and an open-label single dose cohort in non-resected pancreatic cancer 
subjects".
Study M16-142 examines the effects of Creon in subjects with resected pancreatic cancer 
receiving 2 dosing cohorts, and one dosing cohort in non-resected pancreatic cancer 
subjects.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
This SAP includes changes to analyses described in the protocol version 3.0 dated 
22 November 2019.  Details are outlined in Section 12.0.
2.0
Study Design and Objectives
2.1
Objectives, Hypotheses, and Estimands
The objective of this study is to evaluate the effects of Creon® (pancrelipase) on stool fat 
and EPI symptoms in subjects with resected pancreatic cancer receiving 2 dosing cohorts, 
and one dosing cohort in non-resected pancreatic cancer subjects.
The hypothesis for the primary objective of a significant change in stool fat from Baseline 
to Week 1 will be tested at 2-sided 5% α-level for each dose cohort in the resected 
pancreatic cancer population and for the non-resected population as well.
 


CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
6
For each subject, the average stool fat per day ( grams/day) from the stools collected in 
last 48 hours prior to the baseline visit and prior to the Week 1 visit will be calculated and 
the difference between those 2 visits will be calculated.
The estimand corresponding to the primary objective is:
Mean change in stool fat from baseline to Week 1 will be calculated in subjects treated 
with either high dose of CREON (72,000 USP units (Lipase) with meals/36,000 USP 
units (Lipase) with snacks) or low dose of CREON (12,000 USP units (Lipase) with 
meals/6,000 USP units (Lipase) with snacks) in the Evaluable Analysis Set for stool fat in 
the Resected Pancreatic Cancer regimen. Subjects who do not have an evaluable stool 
sample (described in Section 9.2.3) at both Baseline and Week 1 will be excluded from 
the analysis.
2.2
Study Design Overview
This is a Phase 4, randomized, double-blind, parallel design study with 2 dose cohorts in 
resected subjects, and an open-label single dose cohort in non-resected subjects with EPI 
due to pancreatic cancer.
Resected subjects are defined as subjects who had surgery to remove the pancreatic 
cancer.
Non-resected subjects are defined as unresectable, resectable, and borderline resectable or 
pancreatic cancer subjects who did not have a pancreatectomy due to cancer and do not 
plan to undergo such a surgery during study participation.
At Day 1, eligible resected subjects will be randomized in 1:1 ratio to one of following 
dose cohorts, and will remain on blinded therapy for 13 weeks:
1.
Low dose (cohort of 12,000 USP units (Lipase) with meals/6,000 USP units 
(Lipase) with snacks)
 


CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
7
2.
High dose (cohort of 72,000 USP units (Lipase) with meals/36,000 USP units 
(Lipase) with snacks)
At Weeks 1, 5, or 9, subjects who meet dose modification criteria described in Section 2.4
will be titrated once by the IRT to the following dose cohorts in a blinded fashion:
●
Subjects receiving the lower dose will escalate to pancrelipase 72,000 USP 
units (Lipase) with meals/36,000 USP units (Lipase) with snacks.
●
Subjects receiving the high dose will continue receiving the high dose 
throughout the study. In order to maintain the blind of the study, subjects in 
the high dose cohort will also receive a matching placebo and will not exceed 
the maximum dose per the USPI.
Non-resected subjects in the open-label dose cohort will receive pancrelipase at a dose of 
72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with snacks during the 
entire duration of the study.
No interim analyses are currently planned. Study sites and resected subjects in the 
double-blind cohorts will remain blinded for the treatment period of the study.
In support of the primary endpoints, it is critical for subjects, who were on PERT before 
the start of the study, to stop PERT a week prior to Day 1 and to initiate stool collection 
48 hours prior to Day 1 and Week 1 visits. The schematic of the study is shown in 
Figure 1.
The schematic of the study is shown in Figure 1.
 


CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
8
Figure 1.
Study Schematic
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 


CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
9
2.3
Treatment Assignment and Blinding
Eligible resected subjects will be randomized in 1:1 ratio to one of following dose cohorts, 
and will remain on blinded therapy throughout the study treatment period (13 weeks):
1.
Low dose (cohort of 12,000 USP units (Lipase) with meals/6,000 USP units 
(Lipase) with snacks) (n = 36)
2.
High dose (cohort of 72,000 USP units (Lipase) with meals/36,000 USP units 
(Lipase) with snacks) (n = 36)
Subjects in the non-resected population will receive open-label Creon (cohort of 
72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with snacks) for 
13 weeks (n = 20).
The randomization is central with no stratification.
2.4
Sample Size Determination
Resected Subjects: 72 subjects total will be enrolled (36 subjects per dose cohort). After 
adjusting for a dropout rate of 16%, the study will have 60 evaluable subjects for the 
evaluation of stool fat at Week 1. This sample size will have an approximately 99% 
power to detect a 20 g stool fat reduction in mean stool fat from Baseline in each dose 
cohort assuming that the standard deviation for the change is 25 g or approximately 94% 
power to detect a 10 g stool fat reduction in mean stool fat from baseline assuming that 
the SD for the change is 15 g. The type I error rate is 0.05 (2-sided).
In addition, the study will have an approximately 86% power to detect a difference of 20 g 
between 2 dose cohorts in mean stool fat change from Baseline, assuming the same 
standard deviation of 25 g for both dose cohorts. The power will drop to 63% if the 
difference is 15 g.
Non-Resected Subjects: Up to 20 subjects will be enrolled. This is an exploratory 
cohort and no formal statistical tests are planned for this cohort.
 


CREON (ABT-SLV-245)
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Version 1.0 – 13 December 2020
10
2.5
Dose Modification
Dose modifications will be determined by a "dispensation score" calculated in EDC based 
on the responses to Questions 7, 8 and 10 from the EPI Symptom Questionnaire 
(Appendix D). The "dispensation score" will be then entered in IRT by the sites. 
Whether the subject needs dose modification will be determined by the "dispensation 
score" and IRT will then dispense the corresponding drug accordingly. The process will 
keep the site staff and the subjects blinded on whether the subject will be dose modified or 
not. The dose modification process including the details of the IRT dispensation score 
derivations are documented in the Study M16-142 Documentation of Key Decision dated 
09 February 2020.  The general dose modification rules are described as below.
Calculation of Total Score for Dose Modification:
The score for dose modification will be calculated by assigning the following values to 
each one of the responses to Questions 7, 8, and 10 in the EPI symptom questionnaire:  
none = 0, mild = 1, moderate = 2, severe = 3, very severe = 4.  The total score for dose 
modification will be calculated as the sum of the responses to Questions 7, 8, and 10 
within each visit. If none of the three questions are answered, the score will be noted as 
NULL.
The criteria for dose modification are described below:
a.
If current score = NULL, then maintain dose.
b. If the previous score is NULL and the score for the current visit is available, 
then replace the previous score with the last available visit score as the previous 
score and follow the dose escalation criteria d) e) or f).
c.
If the Baseline visit score and all other visit scores prior to the present visit are 
NULL but the present visit score is available, then maintain dose.
d. If current score <= 2, then maintain dose.
e.
If current score > 2 and there is less than 30% improvement from the previous 
score, i.e., current score > (0.7 × previous score), then increase dose.
 


CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
11
f.
If current score > 2 and there is 30% or more improvement from the previous 
score i.e., current score <= (0.7 × previous score), then maintain dose.
The subjects, site staffs and Abbvie site monitors will be blinded to the detailed dose 
modification criteria as well as the subject's dose medication status.
Resected Subjects
The dose for resected subjects in the low dose cohort (12,000 USP units (Lipase) with 
meals/6,000 USP units (Lipase) with snacks) will be modified to the high dose 
(72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with snacks) at 
Week 1, 5, or 9 if the dose modification criteria defined above are met. Subjects 
randomized to the high dose cohort are not dose modified.
Only one dose modification will be permitted throughout the study. For subjects who 
have already experienced dose escalation, they will remain on the high dose level for the 
rest of the treatment duration, even if they continue to meet the dose escalation criteria in 
the subsequent visit(s). No further dose escalation is allowed.
Non-Resected Subjects
Non-resected subjects in the open-label population will continue to receive pancrelipase at 
a dose of 72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with snacks 
during the study; there will be no dose modification.
3.0
Endpoints
3.1
Primary Endpoint(s)
Resected Pancreatic Cancer Subjects
The primary endpoint is change in stool fat from Baseline (Day 1) to Week 1 (Day 8). 
Stool fat is collected during the 48 hours prior to the Day 1 and Week 1 visits.
 


CREON (ABT-SLV-245)
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12
3.2
Secondary Endpoint(s)
Resected Pancreatic Cancer Subjects
●
Change from Baseline to Week 1 in average daily stool frequency. The 
average daily stool frequency is calculated from the last 3 days prior to each of 
Baseline and Week 1 visit.
●
Change from Baseline to Week 1 in stool consistency, based on the proportion 
of days having watery stool consistency in the last 7 days prior to each of 
Baseline and Week 1 visit.
●
Change from Baseline to Week 1 in the total EPI Symptoms Score.
3.3
Additional Endpoint(s)
Resected Pancreatic Cancer Subjects
●
Average daily stool frequency for 7 days prior to each of Weeks 5, 9 and 13 
visits compared to Baseline visit.
●
Stool consistency in the 7 days prior to each of Weeks 5, 9 and 13 visits 
compared to Baseline visit.
●
Total EPI Symptom Score at Weeks 5, 9 and 13 visits compared to Baseline 
visit.
●
The scaled total score for each scale/item as described below of Quality of life 
(QoL) (European Organisation for Research and Treatment of Cancer 
[EORTC] Quality of Life Questionnaire [QLQ]-C30 and QLQ PAN26) at 
Weeks 1, 5, 9, and 13 visits compared to Baseline visit.
QLQ-C30:
○
Global health status/QoL.
○
Functional scales (Physical functioning, Role functioning, Emotional 
functioning, Cognitive functioning, Social functioning).
○
Symptom scales/items (Fatigue, Nausea and vomiting, Pain, Dyspnoea, 
Insomnia, Appetite loss, Constipation, Diarrhoea, Financial difficulties).
 


CREON (ABT-SLV-245)
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QLQ-PAN26:
○
Pancreatic Pain.
○
Digestive symptoms (Gastrointestinal).
○
Hepatic (Jaundice).
○
Altered bowel habit.
○
Poor body image.
○
Satisfaction with health care.
○
Sexuality (Sexual dissatisfaction).
●
Body weight and body mass index (BMI) at Weeks 1, 5, 9 and 13 visits 
compared to Baseline visit.
●
Chemotherapy tolerability (as defined in Section 9.4.6).
○
Difference in expected or planned chemotherapy from the last scheduled 
visit (Yes / No / Not Applicable, no chemotherapy planned) at Week 1, 5,
9 and 13 visits.
○
Proportion of expected or planned chemotherapy due to chemotherapy 
tolerability.
○
Proportion of different types of changes due to chemotherapy tolerability 
(entire regimen permanently discontinued / one or multiple agents 
permanently discontinued / dose held / dose interrupted / dose reduced / 
change in treatment administration schedule).
○
Diagnosis of changes due to chemotherapy tolerability (Adverse events / 
Medical history).
●
Serum albumin and pre-albumin level at Weeks 1, 5, 9 and 13 compared to 
Baseline.
Non-Resected Pancreatic Cancer Subjects
●
Change in stool fat from Baseline (Day 1) to Week 1 (Day 8).
●
Change from Baseline to Week 1, 5, 9 and 13 in average daily stool frequency. 
The average daily stool frequency is calculated from the last 7 days prior to 
each of Baseline and Weeks 1, 5, 9, and 13 visits.
 


CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
14
●
Change from Baseline to Week 1, 5, 9, and 13 in stool consistency, based on 
the proportion of days having watery stool consistency in the last 7 days prior 
to each of Baseline and Week 1 visit.
●
Change in the total EPI Symptoms Score from Baseline to Weeks 1, 5, 9, 
and 13.
●
Change in scaled total score for each domain as described below of QoL 
(EORTC QLQ-C30 and QLQ-PAN26) from Baseline to Weeks 1, 5, 9, and 13.
QLQ-C30:
○
Global health status/QoL.
○
Functional scales (Physical functioning, Role functioning, Emotional 
functioning, Cognitive functioning, Social functioning).
○
Symptom scales/items (Fatigue, Nausea and vomiting, Pain, Dyspnoea, 
Insomnia, Appetite loss, Constipation, Diarrhoea, Financial difficulties).
QLQ-PAN26:
○
Pancreatic Pain.
○
Digestive symptoms (Gastrointestinal).
○
Hepatic (Jaundice).
○
Altered bowel habit.
○
Poor body image.
○
Satisfaction with health care.
○
Sexuality (Sexual dissatisfaction).
●
Chemotherapy tolerability (as defined in Section 9.4.6).
○
Difference in expected or planned Chemotherapy from the last scheduled 
visit (Yes / No / Not Applicable, no chemotherapy planned) at Week 1,5,9 
and 13 visits.
○
Proportion of expected or planned Chemotherapy due to chemotherapy 
tolerability.
○
Proportion of different types of changes due to chemotherapy tolerability 
(entire regimen permanently discontinued / one or multiple agents 
permanently discontinued / dose held / dose interrupted / dose reduced / 
change in treatment administration schedule).
 


CREON (ABT-SLV-245)
M16-142 – Statistical Analysis Plan
Version 1.0 – 13 December 2020
15
○
Diagnosis of changes due to chemotherapy tolerability (Adverse events / 
Medical history).
●
Change in the following measurements from Baseline to Weeks 1, 5, 9, 
and 13: Body weight, and BMI.
●
Change in the following measurements from Baseline to Week 5, 9, and 13 for 
serum albumin and serum pre-albumin level.
3.4
Safety Endpoint(s)
Safety endpoints will be based on evaluations including adverse events (AE) monitoring, 
physical examinations, vital sign measurements, and clinical laboratory testing 
(hematology, chemistry, and urinalysis).  This information will be copied from the 
protocol.
4.0
Analysis Populations
The following population sets will be used for the analyses.
1.
Intention to Treat (ITT)
The Intention to Treat (ITT) Set consists of all randomized subjects in the resected 
regimen and all enrolled subjects in the non-resected regimen. Subjects will be analyzed 
as randomized or enrolled. This population will be used to summarize subject disposition 
only.
The randomized treatment group in the resected regimen consists of the following groups:
a.
High Dose: Subjects randomized to Creon 72,000 dose cohort (72,000 USP 
units (Lipase) with meals/36,000 USP units (Lipase) with snacks)
b. Low Dose: Subjects randomized to Creon 12,000 dose cohort (12,000 USP 
units (Lipase) with meals/6,000 USP units (Lipase) with snacks)
 


CREON (ABT-SLV-245)
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Version 1.0 – 13 December 2020
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The treatment group in the non-resected regimen consists of all the subjects enrolled. All 
the subjects in this group will be receiving the High Dose of Creon 72,000 dose cohort 
(72,000 USP units (Lipase) with meals/36,000 USP units (Lipase) with snacks).
2.
Full Analysis Set (FAS)
Resected and Non-Resected Subjects
The Full Analysis Set (FAS) includes all randomized or enrolled subjects who received at 
least one dose of study drug in the resected or the non-resected regimens, respectively. 
FAS will be used to summarize baseline characteristics unless it is specified otherwise.
3.
Evaluable Analysis Set for Stool Fat Analysis (EAS-SF)
Resected and Non-Resected Subjects
The Evaluable Analysis Set for Stool Fat Analysis includes subjects from the FAS who 
have evaluable stool fat (see Section 9.3.2.1) at both Baseline and Week 1 visits.
4.
Supplementary Analysis Set for Stool Fat Analysis (EAS-SF-SUPP)
The Supplementary Analysis Set for the Stool Fat Analysis includes subjects from the 
FAS in the resected regimen who have 100% stool sample collected for the 48 hour 
collection period at both Baseline (Day 1) and Week 1 visits (see Section 9.2.1).
5.
Safety Analysis Set (Safety)
Resected and Non-Resected Subjects
The Safety Analysis Set will include all randomized/enrolled subjects who received at 
least one dose of study drug.
4.1
Analysis Treatment Groups
The following analysis treatment groups will be used in different analyses:
 


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1.
Analysis Treatment Group Per Day 1 Dispensing (ATG-Day 1, Resected and 
Non-Resected Regimen): These treatment groups will be determined by the 
actual study drug the subjects were dispensed at Day 1 visit.
a.
High Dose Group: Subjects who were dispensed the high dose (72,000 USP 
units (Lipase) with meals/36,000 USP units (Lipase) with snacks) at the Day 1 
visit.
b. Low Dose Group: Subjects who were dispensed the low dose (12,000 USP 
units (Lipase) with meals/6,000 USP units (Lipase) with snacks) at the Day 1 
visit.
2.
Analysis Treatment Group Per All Dispensing (ATG-All Dispensing, Resected 
regimen only): The following treatment groups will be determined by the actual 
study drug the subjects were dispensed throughout the study.
a.
High Dose: Subjects who were dispensed the high dose (72,000 USP units 
(Lipase) with meals/36,000 USP units (Lipase) with snacks) at the Day 1 visit.
b. Low Dose: Subjects who were dispensed the low dose (12,000 USP units 
(Lipase) with meals/6,000 USP units (Lipase) with snacks) at the Day 1visit.
c.
All low Dose: Subjects who were dispensed the low dose (12,000 USP units 
(Lipase) with meals/6,000 USP units (Lipase) with snacks) at all visits.
d. Any High Dose: Subjects who was dispensed the high dose (72,000 USP units 
(Lipase) with meals/36,000 USP units (Lipase) with snacks) at any of the visits.
3.
Analysis Treatment Group - Dynamic (ATG-Dynamic) per visit (Week 1, 
Week 5, Week 9, Week 13, Resected regimen only): These treatment group will 
be defined based on study drug dispensed to the subjects at the prior visit. For 
example, the dynamic treatment group at Week 1 visit would be based on the study 
drug dispensed to the subjects at Day 1 visit, which can be identified after 
unblinding by the kit number that had been dispensed to the subjects at Day 1 visit.
 


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a.
High Dose Group: Subjects who was dispensed the high dose (72,000 USP 
units (Lipase) with meals/36,000 USP units (Lipase) with snacks) at the prior 
visit.
b. Low Dose Group: Subjects who was dispensed the low dose (12,000 USP 
units (Lipase) with meals/6,000 USP units (Lipase) with snacks) at the prior 
visit.
4.2
Analysis Treatment Groups for Various Analyses
Table 1.
Analysis Population and Analysis Treatment Groups for Various 
Analyses
Analysis
Analysis 
Set
Resected
Non-
Resected
(All High 
Dose)
Analysis 
Treatment 
Groups
Treat Group 
Category
Analysis 
Treatment 
Groups
Disposition
ITT
As 
randomized
High Dose, Low 
Dose, Overall
As enrolled
Baseline Characteristics, Medical 
History, Prior and Concomitant 
Medications
FAS
ATG-Day 1
High Dose, Low 
Dose, Overall
ATG-
Day 1
Drug Exposure
Safety
ATG-All 
Dispensing
High Dose, Low
Dose, All Low
Dose, Any High
Dose, Overall
ATG-
Day 1
 


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Table 1.
SA Analysis Treatment Groups for Various Analyses P Version 
Summary History (Continued)
Analysis
Analysis 
Set
Resected
Non-
Resected
(All High 
Dose)
Analysis 
Treatment 
Groups
Treat Group 
Category
Analysis 
Treatment 
Groups
Drug Compliance (week 1)
Safety
ATG-Day 1
High Dose, Low 
Dose, Overall
ATG-
Day 1
Efficacy
Primary
stool fat 
(Week 1 within 
group)
EAS-SF,
EAS-SF-
SUPP
ATG-Day 1
High Dose, Low 
Dose
ATG-
Day 1
Secondary
stool fat 
(Week 1 
between group)
EAS-SF,
EAS-SF-
SUPP
ATG-Day 1
High Dose, Low 
Dose
NA
Stool 
Frequency/Stool 
Consistency/EPI 
Symptom 
Week 1
FAS
ATG-Day 1
High Dose, Low 
Dose
ATG-
Day 1
Additional
Stool 
Frequency/Stool 
Consistency by 
visit
FAS
ATG-
Dynamic
High Dose, Low 
Dose, Overall
ATG-
Day 1
PRO by visit 
(EPI/PAN 
26/C30)
FAS
ATG-
Dynamic
High Dose, Low 
Dose, Overall
ATG-
Day 1
BMI/Weight by 
visit
FAS
ATG-All 
Dispensing
High Dose, Low
Dose, All Low
Dose, Any High
Dose, Overall
ATG-
Day 1
 


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Table 1.
SA Analysis Treatment Groups for Various Analyses P Version 
Summary History (Continued)
Analysis
Analysis 
Set
Resected
Non-
Resected
(All High 
Dose)
Analysis 
Treatment 
Groups
Treat Group 
Category
Analysis 
Treatment 
Groups
Efficacy
Additional
Albumin and 
pre-albumin by 
visit
FAS
ATG-All 
Dispensing
High Dose, Low
Dose, All Low
Dose, Any High
Dose, Overall
ATG-
Day 1
Chemotherapy 
tolerability by 
visit
FAS
ATG-All 
Dispensing
High Dose, Low
Dose, All Low
Dose, Any High
Dose, Overall
ATG-
Day 1
Safety
AE/SAE in 
Week 1
Safety
ATG-Day 1
High Dose, Low 
Dose, Overall
ATG-
Day 1
AE/SAE 
analyses (entire 
treatment 
period)
Safety
ATG-
Dynamic
High Dose, Low 
Dose, Overall
NA
All other 
AE/SAE 
analysis
Safety
ATG-All 
Dispensing
High Dose, Low
Dose, All Low
Dose, Any High
Dose
ATG-
Day 1
Lab / Vital 
Signs
Safety
ATG-All 
Dispensing
High Dose, Low
Dose, All Low
Dose, Any High
Dose
ATG-
Day 1
5.0
Subject Disposition
The total number of subjects who were screened, randomized or enrolled, and treated will 
be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for high or low dose cohort at 
 


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randomization in the resected regimen and for subjects enrolled in the non-resected 
regimen:
●
Subjects randomized or enrolled in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed protocol-specified treatment;
●
Subjects who completed the study;
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason);
●
Subjects who prematurely discontinued study (all reasons and primary reason).
6.0
Study Drug Duration and Compliance
The overall treatment duration (irrespective of whether the subjects are receiving high 
dose or low dose of the study drug) will be summarized. Duration of treatment is defined 
for each subject as (last dose date – first dose date + 1). Duration of treatment will be 
summarized using the number of subjects treated, mean, standard deviation, median, 
minimum and maximum. In addition, the number and percentage of subjects in each 
treatment duration interval (< 1 Week, 1 to < 5 weeks, 5 to < 9 weeks, 9 to < 13 weeks, 
≥13 weeks) will be summarized.
The number of capsules taken per day for the first week of treatment will be summarized 
for all subjects in the Safety Analysis Set. The number of meals and snacks per day 
reported in the dosing diary for the first week of treatment will also be tabulated.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the FAS population.  Categorical 
variables will be summarized with the number and percentage of subjects; percentages 
will be calculated based on the number of non-missing observations.  Continuous 
 


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variables will be summarized with descriptive statistics (number of non-missing 
observations, mean and standard deviation, median, minimum and maximum).
7.1
Demographics and Baseline and Disease Characteristics
Continuous demographic variables include baseline age, weight, height, body mass index 
(BMI), hip and waist circumference, and Fecal elastase-1 (FE-1).  Categorical 
demographic variables include sex, ethnicity, race, weight (< 60 or ≥ 60 kg), BMI (< 25 or 
≥ 25 kg/m2), tobacco user (current, former, never, unknown), alcohol user (current, 
former, never, unknown) and ECOG performance status.
Cancer history data will also be summarized categorically according to their histologic 
type, overall staging at the initial diagnosis, overall staging at study entry, anatomical 
location of the cancer involvement in the pancreas (head, neck, body, tail or multiple), the 
presence of metastatic disease at study entry (Yes or No), completion of neo-adjuvant 
chemotherapy or neo-adjuvant radiotherapy (Yes or No), history of resection of their 
primary pancreatic cancer (Yes/No).
Pancreatic Cancer resection history will also be summarized according to what procedure 
they went through (pancreaticoduodenectomy, polyrus preserving whipple, distal 
pancreatectomy, total pancreatectomy, or other).
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall by high or low dose cohort as the study drug is dispensed to the 
subjects at randomization (Day 1) in the resected population and for subjects enrolled in 
the non-resected populations.  The system organ class (SOC) will be presented in 
alphabetical order, and the preferred terms will be presented in alphabetical order within 
 


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each SOC.  Subjects reporting more than one condition/diagnosis will be counted only 
once in each row (SOC or preferred term).
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name. The number 
and percentage of medications will be summarized per subject for both prior and 
concomitant medications.
A prior medication and procedure are defined as any medication and procedure performed 
prior to the date of the first dose of study drug. This includes medications and procedures 
with a start date before the first study drug administration date. In cases where 
incomplete or missing medication and procedure dates are collected, a conservative 
approach will be taken and it will be counted as a prior medication and procedure. Prior 
radiation therapies will be summarized according to the relative location category 
(primary, regional, distant, unknown and multiple).
A concomitant medication is defined as any medication that started prior to the date of the 
first dose of study drug and continued to be taken after the first dose of study drug or any 
medication that started on or after the date of the first dose of study drug, but not after the 
date of the last dose of study drug.
In the situation where an incomplete or missing medication date is collected, a 
conservative approach will be taken and it will be counted as a concomitant medication 
unless there is evidence that the medication was not taken before the study drug treatment 
(e.g., an end date before study drug start date).
A concomitant procedure is defined as any procedure that started prior to the date of the 
first dose of study drug and continued after the first dose of study drug or any procedure 
that started on or after the date of the first dose of study drug, but not after the date of the 
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In the situation where an incomplete or missing procedure date is collected, a conservative 
approach will be taken and it will be counted as a concomitant procedure unless there is 
evidence that the procedure was performed before the study drug treatment (e.g., an end 
date before study drug start date). A procedure will be considered a concomitant 
procedure where one of the following three cases occurs (1) the start date is missing and 
the end date is either after or on the first study drug dose date; (2) the start date is prior to 
or on the last dose of study drug and the end date is missing; (3) both the start date and the 
end date are missing.
Note that a medication or a procedure can be considered both a prior and concomitant 
medication or procedure if it started prior to the first dose of study drug and continued 
after the first dose of study drug.
Prior procedures (excluding pancreatic resection), concomitant procedures and study 
cancer concomitant radiation therapies will be listed by subjects numbers.
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints
The primary efficacy endpoint of change in stool fat from Baseline to Week 1 (defined in 
Section 3.1) will be analyzed based on the EAS-SF and EAS-SF-SUPP population and the 
following methods will be used to address potential intercurrent events:
●
Subjects with missing or incomplete (not evaluable) stool fat sample at either 
Baseline or Week 1 will be excluded from the analysis.
9.0
Efficacy Analyses
9.1
General Considerations
The primary efficacy analyses will be conducted in the EAS-SF and EAS-SF-SUPP for 
the supplementary analysis of the stool fat.  All other efficacy analyses will be conducted 
 


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in the FAS population, considering different groups for different analysis as tabulated in 
Table 2 in Section 4.2. All tests will be 2-sided at an alpha level of 0.05.
The Primary Analysis and other analyses will be performed after all subjects in the 
resected and non-resected population have completed the study and the database has been 
locked.  This will be the only and final analysis for the primary and secondary efficacy 
endpoints as well as all other efficacy endpoints in the study.
"Baseline" refers to the last non-missing observation before the first administration of 
study drug or randomization if no study drug is given, unless otherwise specified in the 
individual analysis section.
9.2
Handling of Missing Data
Missing data will be imputed using the following methods for the efficacy analyses.
9.2.1
Adjustment for Missing Stool Fat Samples in Stool Fat per 
Day
The stool fat (g) will be reported for each subject per 24 hours period for 2 consecutive 
24-hour collection periods (total 48-hour period) separately, prior to both Baseline 
(Day 1) visit and Week 1 (Day 8) visit. The average daily stool fat (g/day) at both 
Baseline and Week 1 visit will be calculated from these two reported 24-hour stool fat for 
each subject.
Step 1: The two reported 24-hour stool fat value will be assessed to  see whether they are 
evaluable values at both Baseline and Week 1 based on the stool frequency and number of 
stool sample missed to be collected for the corresponding 24-hour period, following the 
rules in Section 9.3.2.1.
Step 2: If the reported 24-hour stool fat value is deemed to be evaluable but there are 
missing stools in that 24-hour collection period, the adjusted 24-hour stool fat will be 
calculated as following:
 


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 = 
 ∗100
where,
x : Calculated adjusted stool fat for a 24 hour period 
p : Percentage of stool sample collected in a 24 hour period
y : Laboratory reported 24-hour stool fat from the stool samples collected in a 24 hour 
period 
If a subject has evaluable 24-hour stool fat value for both days for a visit, then the stool fat 
for that visit will be determined based on the average of the two evaluable value (with 
adjustment if needed as described in Step 2 above). If subject has only one evaluable 
24-hour stool fat value for a visit, then the stool fat for that visit will be determined based 
on that evaluable value (with adjustment if needed as described in Step 2 above). If both 
24-hour stool fat values for that visit are not evaluable, then subject is considered having 
no evaluable stool fat data for that visit with no imputation.
9.2.2
Missing EPI Symptoms Score
The EPI Symptoms Questionnaire data will be used to compute the EPI Symptom score. 
Each of the 12 questions is scored as described in Dose modification, Section 2.5. The 
missing answers to any of the 12 questions of the EPI questionnaire will not be possible 
unless the subject did not complete the EPI questionnaire at all. The questionnaire can be 
submitted only when all the questions in the questionnaire have been answered. No 
questions can be skipped before submitting. Missing EPI questionnaire will not be 
imputed.
9.2.3
Missing Stool Frequency
Daily stool frequency will be collected from Day –7 through Day –1, Day 1 through 
Day 7 and for 7 days prior to each subsequent visit. For the stool frequency analysis, the 
mean frequency for 3 days prior to each visit (for example, Day –3, –2, –1 will be 
 


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considered for Baseline, and Day 5, 6, 7 for Week 1) is considered. If stool frequency 
data for any of the 3 days prior to each visit is not available, then the missing value is 
estimated using the following criteria.
●
If data for none or only 1 day is available for a visit, then the mean stool 
frequency for the visit will be considered as missing.
●
If data for 2 days of the 3 required days are available, then the mean stool 
frequency for the visit will be calculated based on the data from the 2 available 
days.
For the supplementary analysis of the stool frequency, the mean stool frequency for each 
week is considered. If stool frequency data for all 7 days in a week is not available, then 
the missing value is estimated using the following criteria.
●
If data for 50% or less i.e., three or less days are available for each week, then 
the mean stool frequency for the week will be considered missing for the 
analysis.
●
If data for more than 50% i.e., 4 or more days are available, then the stool 
frequency for the missing days will be imputed using the mean value of the 
available data. Finally, the mean stool frequency for the week will be 
calculated.
9.2.4
Missing Stool Consistency
Daily stool consistency will be collected once daily from Day –7 through Day –1, Day 1 
through Day 7 and for 7 days prior to each subsequent visit. For the stool consistency 
analysis, the proportion of watery stool consistency among the 7 days prior to each visit 
(for example, Day –7 to –1 will be considered for Baseline, and Day 1 to Day 7 for 
Week 1) is considered. For example, among the 7 days for a visit if 6 of those days have 
watery consistency, then the proportion of days with watery stool consistency will be 6/7. 
If stool consistency data for any of the seven days prior to each visit is not available, then 
the proportion of days with watery stool consistency will be estimated using the following 
criteria.
 


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●
If data for 50% or less i.e., 3 or less days are available for each week, then the 
mean stool consistency for the week will be considered missing for the 
analysis.
●
If data for more than 50% i.e., 4 or more days are available, then the 
proportion of days with watery stool consistency will be determined based on 
the available data. For example, if 5 days data is available for a visit and 3 of 
those days have watery consistency, then the proportion of days with watery 
stool consistency will be 3/5.
9.2.5
Missing QoL Score (EORTC QLQ-C30 and QLQ-PAN26)
Refer to the score manual for the EORTC QLQ-C30 for imputing missing items 
(Appendix B).
9.3
Primary Efficacy Endpoint(s) and Analyses
9.3.1
Primary Efficacy Endpoint(s)
Resected Pancreatic Cancer Subjects
The primary endpoint is change in stool fat from Baseline (Day 1) to Week 1 (Day 8) for 
each dose cohort. Stool fat is collected during the 48 hours prior to the Day 1 (Day –2 
and Day –1) and Week 1 (Day 6 and Day 7) visits.
9.3.2
Main Analysis of Primary Efficacy Endpoint (s)
The stool fat (g) for each subject for the 48 period prior both Baseline (Day 1) visit and 
Week 1 (Day 8) visit will be calculated according to Section 9.2.1. The change in stool 
fat from Baseline to Week 1 will be analyzed using an analysis of covariance (ANCOVA) 
model including treatment as a fixed effect and Baseline stool fat as the covariate. The 
least square mean estimates for change in stool fat along with its two-sided 95% CI will 
be provided for each treatment group. The hypothesis testing for a difference from 
baseline to Week 1 in stool fat will be tested at 2-sided 5% α-level for each treatment 
group in EAS-SF separately.
 




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both Baseline and Week 1 visit will be calculated from these two reported 24-hour stool 
fat for each subject. If the stool collection for a 24-hour period is evaluable with missing 
stool samples, then the total stool fat for that period will be adjusted following the 
imputation rule in Section 9.2.1. The average daily stool fat (g/day) at both Baseline and 
Week 1 visit will be calculated from the adjusted stool fat values for the analysis.
If the data on the "total bowel movements" and the "bowel movements not collected" is 
missing on any of the 4 days, then the stool fat will be regarded as missing for that day.
9.3.3
Supplementary Analyses of the Primary Efficacy 
Endpoint(s)
A supplementary analysis will be performed for the primary efficacy endpoint on the 
subjects included in the EAS-SF-SUPP (subjects with 100% stool sample collected for the 
48 hour collection period at both Baseline (Day 1) and Week 1 visits) using the ATG-
Day 1 group (High Dose and Low Dose) for the resected population. The change in stool 
fat from Baseline to Week 1 for each treatment group will be analyzed using the 
ANCOVA model described in Section 9.3.2.
9.4
Secondary and Additional Efficacy Analyses
9.4.1
Stool Fat
Resected Subjects
For comparison between dose cohorts for change in stool fat from Baseline to Week 1, the 
ANCOVA model including treatment as fixed effect and baseline stool fat as the covariate 
as described for the primary analysis will be used. The least square mean estimate of the 
difference between two treatment groups in change from baseline in stool fat will be 
provided along with the 95% CI and P value. The analysis will be performed using the 
EAS-SF and EAS-SF-SUPP set for the resected population only.
 


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Non-Resected Subjects
The change in stool fat from Baseline to Week 1 will be analyzed using an analysis of 
covariance (ANCOVA) model including Baseline stool fat as the covariate. The least 
square mean estimates for change in stool fat along with its two-sided 95% CI will be 
provided. The null hypothesis of no change in mean stool fat from Baseline to Week 1 
will be tested at 2- sided 5% α – level in EAS-SF.
9.4.2
Stool Frequency
Stool frequency is collected each day for 7 days prior to each visit during the study period. 
For the analysis, the average number of stool frequency per day is considered for the last 3 
days prior to each visit (Day –3 to Day –1 for Baseline and Day 5 to Day 7 for Week 1 
visit). The average stool frequency per day for a visit is defined as total number of stools 
in the last 3 days divided by 3 for that visit.
The analyses will be performed using the population and treatment groups as described in 
Table 1 in Section 4.2.
●
For analysis of change in stool frequency from Baseline to Week 1, both 
within dose cohort and for comparison between dose cohorts (resected regimen 
only), an ANCOVA model including treatment as a fixed effect (resected 
population only) and Baseline stool frequency as the covariate will be used. 
Day –3, Day –2 and Day –1 would be considered for Baseline and Day 5, 
Day 6 and Day 7 would be considered for Week 1 visit.
●
Descriptive summary statistics will be provided for change in stool frequency 
from Baseline to Week 1, 5, 9 and 13. For the summary, the average stool 
frequency per day for the Baseline and Week 1 is defined as total number of 
stool frequency in the last 3 days divided by 3 for that visit for comparison to 
Week 1. However, the average stool frequency per day for the Baseline and 
Week 5, 9 and 13 is defined as total number of stool frequency in the last 
7 days divided by 7 for that visit for comparison to all other post-baseline 
visits.
 


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●
Descriptive statistics per day for stool frequency are presented specifying the 
mean, standard deviation, median, minimum and maximum of stool frequency 
for 7 days prior to Baseline and Week 1.
Sensitivity Analysis for Stool Frequency:
●
For the sensitivity analysis, the average number of stool frequency per day is 
considered for the last 7 days prior to each visit. The average stool frequency 
per day for a visit is defined as total number of stool frequency in the last 
7 days divided by 7 for that visit. Day –7 to Day –1 would be considered for 
Baseline and Day 1 to Day 7 would be considered for Week 1 visit.
●
The 7-day mean will be analyzed similar to the primary analysis of the stool 
frequency using an ANCOVA model including treatment as a fixed effect 
(resected population only) and Baseline stool frequency as the covariate. 
Summary statistics and comparing the change in stool frequency from Baseline 
to Week 1 will also be summarized.
9.4.3
Stool Consistency
Stool consistency will be collected once a day for 7 days prior to each visit using the 
Bristol Stool Chart and will be characterized based on the typology below for the analysis. 
The proportion of days with watery consistency during 7-day period prior to each visit 
will be calculated at each visit for each subject. The analyses will be performed using the 
population and treatment groups as described in Table 1 in Section 4.2.
●
A Wilcoxon paired signed rank test will be performed for comparison of the 
proportion of days with watery stool consistency of Week 1 to that at Baseline 
within each dose cohort in the resected population. Similar test will be 
performed in the non-resected population as well.
●
For comparison of change in the proportion of days with watery stool 
consistency from Baseline to Week 1 between two dose cohorts will be 
assessed through the non-parametric Wilcoxon Rank-Sum test in the resected 
population.
 


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●
Descriptive statistics will be provided for proportion of days with watery stool 
consistency at Week 1 (Day 8), 5, 9 and 13 as well as change from Baseline 
for each visit in both the resected and non-resected population.
●
The number and percentages of subjects with 7 different types of stool 
consistency reported and 2 different types of characterization of stool 
consistency as described in Table 3 will be summarized per day for 7 days 
prior to Baseline (Day 1) and 7 days prior to Week 1 (Day 8) visit for the 
non-resected population and for each analysis treatment group in the resected 
population.
Table 3.
Characterization of Bristol Stool Chart for Analysis
Stool Type (Score)
Characterization
Type 1 (1), Type 2 (2), Type 3 (3), Type 4 (4), Type 5 (5)
Hard/Normal
Type 6 (6), Type 7 (7)
Watery
9.4.4
EPI Symptom Score
EPI symptom score for the efficacy analysis will be calculated at each visit as the total 
score for the responses to all the 12 questions in the EPI Symptoms Questionnaire. The 
response score will range from 0 to 4 for each question (0 corresponding to None to 4 
corresponding to Very Severe). Therefore, the total score will range from 0 to 48.
The analyses will be performed using the population and treatment groups as described in 
Table 1 in Section 4.2.
●
Change in EPI Symptom Score from baseline to Week 1 will be analyzed 
similarly to the stool frequency analyses using an ANCOVA model including 
treatment as a fixed effect (resected population only) and Baseline EPI 
Symptom score as the covariate for both within dose cohort and for 
comparison between dose cohorts (resected population only).
●
Similar analyses will also be provided for the subset of questions (Question 7, 
8 and 10) used for dose modification criteria (resected population only).
 


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●
Descriptive summary statistics will be provided for change in EPI Symptom 
score from Baseline to Week 1, 5, 9 and 13 in both the resected and non-
resected population.
●
Descriptive statistics per day for EPI Symptom score are presented specifying 
the mean, standard deviation, median, minimum and maximum of stool 
frequency for 7 days prior to Baseline (Day 1) and Week 1 (Day 8).
9.4.5
QoL (EORTC QLQ-C30 Score and QLQ-PAN26 Score)
The score calculations are described in Appendix B. The total scaled score for each 
domain in both the Questionnaires will range from 0 to 100. The analyses will be 
performed using the population and treatment groups as described in Table 1 in 
Section 4.2.
QLQ-C30:
There are 3 scales/domains described in the QLQ-C30 questionnaire. The global health 
status/QoL scale, functional scale (Physical functioning, Role functioning, Emotional 
functioning, Cognitive functioning, Social functioning), and symptom scale/items 
(Fatigue, Nausea and vomiting, Pain, Dyspnoea, Insomnia, Appetite loss, Constipation, 
Diarrhoea, Financial difficulties) will be analyzed separately.
●
Descriptive statistics will be provided for each scaled score and change from 
baseline for each visit.
QLQ-PAN-26:
There are several domains described in the QLQ-PAN-26 questionnaire. The score in the 
Pancreatic pain, Digestive symptoms (Gastrointestinal), Hepatic (Jaundice), Altered 
bowel habit, Poor body image, Satisfaction with the Health Care and Sexuality (Sexual 
dissatisfaction) domains will be analyzed.
Similar analyses as QLQ-C30 will be performed.
 


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9.4.6
Chemotherapy Tolerability
The following analysis for chemotherapy tolerability will be provided using descriptive 
statistics for each visit:
●
Number and percentage of subjects with change in expected/planned 
chemotherapy from the last scheduled visit (Yes / No / Not Applicable, no 
chemotherapy planned)
●
For change in expected/planned chemotherapy = yes, the number and percent 
of subjects that had this change due to chemotherapy tolerability (Yes / No)
●
For both change in expected/planned chemotherapy = yes and change in 
chemotherapy due to tolerability = yes, number and percent of subjects with 
each type of changes due to chemotherapy tolerability (entire regiment 
permanently discontinued / one or multiple agents permanently discontinued / 
dose held / dose interrupted / dose reduced / change in treatment 
administration schedule)
●
For both change in expected/planned chemotherapy = yes and change in 
chemotherapy due to tolerability=yes, number and percent of subjects with 
changes due to Adverse events or Medical history.
●
The analyses will be performed in both the resected and non-resected 
population using the population and treatment groups as described in Table 1
in Section 4.2.
9.4.7
BMI, Body Weight
The change from baseline to each visit in body weight, BMI, hip and waist circumference, 
will be summarized from Baseline (Day 1) to each post baseline visit using descriptive 
statistics.
The number and percentage of subjects who had more than 10% (≥10%) reduction in 
their body weight and for subjects who had more than 10% ( ≥10% ) increment in their 
body weight for each visit will also be summarized.
Body Mass Index (BMI) is calculated as follows at each visit:
 


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BMI (kg/m2) = Body Weight (kg) / Body Height2 (m2):
The analyses will be performed in both the resected and non-resected population using the 
population and treatment groups as described in Table 1 in Section 4.2.
9.4.8
Serum Albumin, Pre-Albumin
The analyses will be performed in both the resected and non-resected population using the 
population and treatment groups as described in Table 1 in Section 4.2.
For all the laboratory parameters of serum albumin and pre-albumin, the change from 
baseline to each of the post baseline visit (Week 5, 9 and 13), and from baseline to the 
final post-baseline values will be summarized using descriptive statistics.
9.4.9
Exploratory Analysis for Dietary Intake
The fat intake data will be summarized using descriptive statistics including the average 
fat intake per day (gram/day) by week and by treatment group. The fat intake data for 
each subject will be included in a listing as well. Similar descriptive summary and 
listings will also be developed for protein, carbohydrate and calorie intake data.
Additional exploratory analyses may be performed.
9.5
Efficacy Subgroup Analyses
There is no subgroup analysis planned.
10.0
Safety Analyses
10.1
General Considerations
The analyses will be performed in both the resected and non-resected population using the 
population and treatment groups as described in Table 1 in Section 4.2.
 


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10.2
Adverse Events
Per the study protocol, all AEs (non-serious and serious) reported from the time of study 
drug administration until 30 days post discontinuation of study drug administration will be 
collected. In addition, SAEs will be collected from the time the subject signed the study-
specific informed consent.
All AEs and SAEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Organ Classes (SOCs) and preferred terms (PTs), Version 21.0 or higher. 
Specific adverse events will be counted once for each subject for calculating percentages, 
unless stated otherwise.  In addition, if the same adverse event occurs multiple times 
within a subject, the highest severity and level of relationship to investigational product 
will be reported.
10.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs (TEAE) is defined as AEs that first occur or worsen on or after 
the first dose of study treatment in until the last study drug treatment. Pancrelipase acts 
locally in the gastrointestinal tract and is not absorbed in the body thus the effect of the 
study drug will disappear right after the drug discontinuation. Therefore, the AEs 
occurring after the study drug treatment period is not considered to be TEAE. Events 
where the onset date is the same as the study drug start date are assumed to be treatment-
emergent. If an incomplete onset date was collected for an AE, the AE will be assumed to 
be treatment-emergent unless there is evidence that confirms that the AE was not 
treatment-emergent (e.g., the AE end date was prior to the date of the first dose of study 
drug).
Three main analyses for TEAE will be provided:
●
Incidence rate of TEAE in the first week of study treatment
●
Exposure-adjusted incidence rate for TEAE during the entire treatment period
●
Incidence rate of TEAE leading to study drug discontinuation
 


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10.2.1.1
Incidence Rate of TEAE in the First Week of Study 
Treatment
Number and percent of subjects experiencing TEAEs will be summarized for the 
first week of study treatment (Day 1 to Week 1 visit, inclusive), for resected population 
and non-resected population. Specifically, TEAEs will be summarized by treatment 
group as described below:
1.
An overview of the number and percentage of subjects with TEAEs in the 
first week
2.
A summary of the number and percentage of subjects with TEAEs in descending 
order of overall incidence frequency by MedDRA PT in the first week
3.
A summary of the number and percentage of subjects with TEAEs by primary 
MedDRA SOC and PT in the first week
4.
A summary of the number and percentage of subjects with serious TEAEs in 
descending order of overall incidence frequency by MedDRA PT in the first week
5.
A summary of the number and percentage of subjects with serious TEAEs by 
primary MedDRA SOC and PT TEAEs in the first week
6.
A summary of the number and percentage of subjects with TEAEs leading to 
discontinuation of study drug by primary MedDRA SOC and PT in the first week
7.
A summary of the number and percentage of subjects with drug-related (i.e., with 
reasonable possibility to be related to study drug) TEAEs by primary MedDRA 
SOC and PT in the first week
8.
A summary of the number and percentage of subjects with TEAEs by primary 
MedDRA SOC, PT and maximum severity in the first week
 


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10.2.1.2
Exposure-Adjusted Incidence Rate (EAIR) for TEAE During 
the Entire Treatment Period
Dose escalation is allowed for subjects in resected population who meet dose escalation 
criteria on or after Week 1 visit. To adjust for potentially different exposure times 
between treatment groups, exposure-adjusted incidence rates will be provided based on 
ATG-Dynamic treatment group for resected population, and for Creon high dose cohort 
for non-resected population.
The exposure-adjusted incidence rate (EAIR) for a treatment group is defined as the 
number of subjects with a particular TEAE under that treatment group divided by the total 
exposure-time to that treatment group among subjects who had received that treatment.  
More specifically,
 = 

=  ∑

,
where, 
i = high dose, low dose;
j = 1, number of subjects who received treatment i,
 : the number of subjects with the event when subject is under treatment i,
 :  subject j's total exposure under treatment i, and
Ti : the total exposure time for treatment i.
For subjects in resected population, to determine whether subject has the event under 
treatment i, ATG-dynamic group will be used. Namely, the treatment group will be 
determined based on the drug dispensed at prior study visit before the event occur. To 
calculate the total exposure time under treatment i for a subject, the drug dispensed at 
each dispensing visit will be considered, the total exposure time under high dose and/or 
 


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low dose will be calculated for each subject.  E.g., if a subject has Day 1 dispensing = low 
dose, and Week 1 and subsequent visits dispensing = high dose, then for this subject:
●
Low dose exposure time for this subject = date of Week 1 visit – date of Day
●
High dose exposure time for this subject = last date of study drug – date of 
Week 1 visit +1.
Specifically, EAIR for TEAE during the entire treatment period will be summarized by
treatment group as described below:
1.
EAIR of TEAEs in descending order of overall incidence frequency by MedDRA 
PT in the entire treatment period
2.
EAIR of serious TEAEs in descending order of overall incidence frequency by 
MedDRA PT in the entire treatment period
3.
EAIR with drug-related (i.e., with reasonable possibility to be related to study 
drug) TEAEs by primary MedDRA SOC and PT
4.
EAIR with drug-related (i.e., with reasonable possibility to be related to study 
drug) serious TEAEs by primary MedDRA SOC and PT
10.2.1.3
Incidence Rate of TEAE Leading to Study Drug 
Discontinuation During the Entire Treatment Period
A summary of the number and percentage of subjects with TEAEs leading to 
discontinuation of study drug by primary MedDRA SOC and PT will be provided by 
treatment group (ATG-All dispensing) for resected population, and for high dose cohort in 
non-resected populations.
10.2.2
Listing of AEs
The following additional listings will be prepared. Both ATG-Day 1 treatment group and 
ATG-Dynamic treatment group prior to AE start date will be included in the listing.
 


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●
List of all TEAEs by resection cohort, ATG-Day 1 treatment group and subject 
ID
●
Listing of all serious TEAEs by resection cohort, ATG-Day 1 treatment group 
and subject ID
●
Listing of all TEAEs that led to discontinuation of study drug by resection 
cohort, ATG-Day 1 treatment group and subject ID
●
Listing of all fatal TEAEs
●
Listing of all AEs in the safety follow-up period, by resection cohort, ATG-
Day 1 treatment group and subject ID 
●
Listing of all deaths by resection cohort, ATG-Day 1 treatment group and 
subject ID
●
List of subject numbers associated with each PT for all AEs assessed by the 
investigator as having a reasonable possibility of being related to study drug by 
resection cohort, ATG-Day 1 treatment group.
10.3
Analysis of Laboratory Data
Laboratory test variables as well as their statistical analysis methods including 
hematology, chemistry, urinalysis, and additional test variables are specified in Table 4. 
The analyses will be performed in both the resected and non-resected population using the 
population and treatment groups as described in Table 1 in Section 4.2.
 


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Table 4.
Laboratory Variable and Corresponding Statistical Analyses
Laboratory Test Variables
Hematology
Hematocrit
Hemoglobin
Red blood cell (RBC) count
White blood cell (WBC) count
Neutrophils
Bands 
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not acceptable)
Urinalysis
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Clinical Chemistry
Blood urea nitrogen (BUN)
Creatinine
Total bilirubin
Pre-albumin
Albumin
Alanine transaminase (ALT) 
Aspartate transaminase (AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
 


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Table 4.
Laboratory Variable and Corresponding Statistical Analyses
(Continued)
Laboratory Test Variables
Clinical Chemistry (continued)
Inorganic phosphorus
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Bicarbonate/CO2
Chloride
Other Tests
Nutritional Biomarkers
For all the laboratory parameters, the mean change from baseline to Week 13 visit (the 
final post-baseline) will be summarized with descriptive statistics.
Where it is applicable to categorize a laboratory assessment by Normal, High, or Low 
according to the normal range provided by the central laboratory, changes in laboratory 
parameters will be tabulated using shift tables categorized as low, normal, or high based 
on the normal ranges of the laboratory used for each sample.  A shift table from baseline 
to the minimum and maximum value during treatment will be created by the analysis 
treatment groups described above.
10.4
Analysis of Vital Signs and Weights
The mean change from baseline to Week 13/EOT visit in vital signs, will be summarized 
for both resected and non-resected population. Vital sign variables include systolic blood 
pressure (SBP), diastolic blood pressure (DBP), pulse rate, body temperature. 
11.0
Interim Analyses
No Interim analysis is planned.
 


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12.0
Overall Type-I Error Control
The primary endpoint will be tested for each treatment group (high dose, low dose) in 
resected population separately at 2-sided alpha level of 0.05. Multiplicity adjustment is 
not planned for the primary endpoint analysis, as well not planned for any secondary 
endpoint analysis, as this study is not intent for registrational purpose or drug label 
enhancement.
13.0
Version History
Table 5.
SAP Version History Summary
Version
Date
Summary
1.0
13 December 2020
Original version
14.0
References
1.
Christopher HN, Mukherjee S, Bridgewater J,et al.  Health-Related Quality of Life 
in SCALOP, a Randomized Phase 2 Trial Comparing Chemoradiation Therapy 
Regimens in Locally Advanced Pancreatic Cancer.  Int J Radit Oncol Biol Phy.
2015;93(4):810-18.
2.
MedDRA – Medical Dictionary for Regulated Activities. International Federation 
of Pharmaceutical Manufacturers Associations (IFPMA), c/o TRW, 
VAR1/8A/MSSO, 12011 Sunset Hills Road, Reston, VA 20190-3285, USA, 
Version 8.1.
3.
Kim MK, Kim SB, Ahn JH, et al.  Gemcitabine Single or Combination 
Chemotherapy in Post Anthracycline and Taxane Salvage Treatment of Metastatic 
Breast Cancer: Retrospective Analysis of 124 Patients.  Cancer Res Treat. 
2006;38(4):206-13.
4.
https://www.cancercareontario.ca/sites/ccocancercare/files/gemcitabine.pdf
 


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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not 
withdrawn.
●
Subject received wrong treatment or incorrect dose of study.
●
Subject took prohibited concomitant medication.
 


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Appendix B.
Quality of Life (QoL) (EORTC QLQ-C30 and QLQ PAN 26)
The QLQ-C30 is composed of both multi-item scales and single-item measures. These 
include five functional scales, three symptom scales, a global health status / QoL scale, 
and six single items. Each of the multi-item scales includes a different set of items - no 
item occurs in more than one scale. 
All of the scales and single-item measures range in score from 0 to 100. A high scale 
score represents a higher response level.
Thus, a high raw score for a functional scale represents a high / healthy level of 
functioning, a high score for the global health status / QoL represents a high QoL, but a 
high score for a symptom scale / item represents a high level of symptomatology / 
problems.
The principle for scoring these scales is the same in all cases:
●
To estimate the average of the items that contribute to the scale; this is the raw 
score.
●
To use a linear transformation to standardize the raw score, so that scores 
range from 0 to 100; a higher score represents a higher ("better") level of 
functioning, or a higher ("worse") level of symptoms.
In practical terms, if items I1, I2, In are included in a scale, the procedure is as follows.
Raw Score
We calculate the raw score as follows:
Raw Score = RS = (I1 + I2 + … + In)/n
Linear Transformation
Then linear transformation is applied to 0-100 to obtain the score S.
 


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Functional Scales: 
 =  −1
 ∗100
Symptom Scales / items:
 = 1 − −1
 ∗100
Global health status / QoL:
 =  −1
 ∗100
Range is the difference between the maximum possible value of RS and the minimum 
possible value. The QLQ-C30 has been designed so that all items in any scale take the 
same range of values. Therefore, the range of RS equals the range of the item values. 
Most items are scored 1 to 4, giving range = 3. The exceptions are the items contributing 
to the global health status / QoL, which are 7-point questions with range = 6.
 


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Table 6.
Scoring the QLQ-C30
Scale
Number 
of items
Item 
Range
Version 3.0 Item 
numbers
Global health status / QoL
Global health status / QoL
QL2
2
6
29,30
Functional Scales
Physical Functioning
PF2
5
3
1 to 5
Role Functioning
RF2
2
3
6,7
Emotional Functioning
EF
4
3
21 to 24
Cognitive Functioning
CF
2
3
20,25
Social Functioning
SF
2
3
26,27
Symptom Scales / items
Fatigue
FA
3
3
10,12,18
Nausea and vomiting
NV
2
3
14,15
Pain
PA
2
3
9,19
Dyspnoea
DY
1
3
8
Insomnia
SL
1
3
11
Appetite loss
AP
1
3
13
Constipation
CO
1
3
16
Diarrhea
DI
1
3
17
Financial Difficulties
FI
1
3
28
QLQ-PAN-26, the pancreatic cancer module, is designed for patients at all disease stages 
undergoing surgical resection, palliative surgical intervention, endoscopic palliation or 
palliative chemotherapy (Fitzsimmons et al., 1999a,b). The module comprises 26 
questions hypothesized as 17 scales and single items specifically related to pancreatic 
disease symptoms, treatment side-effects, and emotional issues. The scores for QLQ-
PAN-26 are calculated in the same way as QLQ-C30. 
Score after Linear transformation for each scale:
 =  −1
 ∗100
 


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where, RS is the Raw Score as described above.
A high score will represent a high level of disease symptoms/problems. The QLQ-PAN-
26 has been designed so that all items in any scale take the same range of values. 
Therefore, the range of RS equals the range of the item values. All items are scored 1 to 
4, giving range = 3. 
Table 7.
Scoring the QLQ-PAN-26
Scale
Number of 
items
Item Range
Item numbers
Pancreatic Pain
PP
4
3
31,33 to 35
Bloating
BO
1
3
32
Gastrointestinal
GA
2
3
36,37
Taste Loss
TL
1
3
38
Indigestion
IN
1
3
39
Flatulence
FL
1
3
40
Weight
WE
1
3
41
Weak Limbs
WL
1
3
42
Dry Mouth
DM
1
3
43
Jaundice
JA
2
3
44,45
Altered Bowel Habit
AB
2
3
46,47
Poor Body Image
PB
2
3
48,49
Side Effects of Treatment
SI
1
3
50
Future Health Concern
FH
1
3
51
Forward Planning limited
FP
1
3
52
Satisfaction with Health Care
SA
2
3
53,54
Sexual dissatisfaction
SX
2
3
55,56
 


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Appendix C.
Missing Data Imputation of Quality of Life (QoL) (EORTC QLQ-
C30 and QLQ PAN 26
If 50% or less are unanswered for each functioning, assume that the missing items have 
values equal to the average of those items which are present for that functioning. The 
missing items are simply ignored when making the calculations. For example, if a
functioning (ith functioning with scores Qij to the jth question) has range 4 and one of the 
item (Ii3) is missing. Then, following the rule, the raw score for that function will be 
calculated as:
Raw score () = ()) + )+ + ),)/3
Functioning Scale Score (S) = 1 − −1 
3
 ∗100
However, if more than 50% of the questions are unanswered, the score for that 
functioning will be left missing. The single item measures, if missing, cannot be imputed 
as well.
 


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Appendix D.
Questions from the EPI Questionnaire Considered for Dose 
Modification
Exocrine Pancreatic Insufficiency (EPI) Symptom Questionnaire
Instructions: These questions ask about symptoms you may have had during the past 7 
days. Please answer all questions by selecting the one option that best describes your 
experience.
1.
Rate your foul smelling stools during the past 7 days.
None
Mild
Moderate
Severe
Very Severe
2.
Rate your greasy or fatty stools during the past 7 days.
None
Mild
Moderate
Severe
Very Severe
3.
Rate your diarrhea during the past 7 days.
None
Mild
Moderate
 


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Severe
Very Severe