Clinical trial NCT05069597
Conditions: Cystic Fibrosis Chronic Pancreatitis
Keywords: Cystic Fibrosis Chronic Pancreatitis Exocrine Pancreatic Insufficiency Creon Pancrelipase
Sponsor: AbbVie
Start date: 2021-10-14; Completion date: 2023-08-28
Enrollment: 30 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
Exocrine pancreatic insufficiency (EPI) is a condition that is caused by the inadequate pancreatic enzymes 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. This study will assess clinical symptoms when participants with CF or CP are treated with Creon with alternate source of active drug.

Creon is an approved drug for the treatment of EPI. This study is subject-blinded which means participants will not know the source of the study drug they are given. Approximately 30 adult participants with CF or CP will be enrolled at approximately 15 sites across the Unites States.

Participants will receive oral capsules of CREON for 113 days and will be followed for 30 days.

Participants will attend regular visits during the study at a hospital or clinic or via telemedicine. The effect of the treatment will be checked by medical assessments, checking for side effects and completing questionnaires.

Detailed description:

Arms: arm 1: Participants will receive Creon-ABT daily for 28 days. arm 2: Participants will receive Creon-AAPIS daily for 85 days.
Interventions: intervention 1: CREON
Intervention descriptions: intervention 1: Capsule; Oral

Protocol documents:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
6
2.1
BACKGROUND AND RATIONALE
6
2.2
BENEFITS AND RISKS TO SUBJECTS
6
3
OBJECTIVES AND ENDPOINTS
7
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
7
3.2
PHARMACODYNAMIC ENDPOINTS
7
3.3
SAFETY ENDPOINTS
7
4
INVESTIGATIONAL PLAN
7
4.1
OVERALL STUDY DESIGN AND PLAN
7
4.2
DISCUSSION OF STUDY DESIGN
9
5
STUDY ACTIVITIES
10
5.1
ELIGIBILITY CRITERIA
10
5.2
CONTINUATION CRITERIA
13
5.3
CONTRACEPTION RECOMMENDATIONS
14
5.4
PROHIBITED MEDICATIONS AND THERAPY
15
5.5
PRIOR AND CONCOMITANT THERAPY
16
5.6
PRIOR AND POST TREATMENT PERT THERAPY
16
5.7
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
16
5.8
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
17
5.9
STUDY DRUG
17
5.10 DRUG ASSIGNMENT
20
5.11 PROTOCOL DEVIATIONS
20
5.12 DATA MONITORING COMMITTEE
20
6
SAFETY CONSIDERATIONS
21
6.1
COMPLAINTS AND ADVERSE EVENTS
21
6.2
MANAGEMENT OF COVID-19 INFECTION
24
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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
24
7.1
STATISTICAL AND ANALYTICAL PLANS
24
7.2
DEFINITION FOR ANALYSIS POPULATIONS
24
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE STUDY ENDPOINTS
25
7.4
STATISTICAL ANALYSES FOR PHARMACODYNAMIC ENDPOINTS
25
7.5
STATISTICAL ANALYSES FOR SAFETY
25
7.6
OVERALL TYPE I ERROR CONTROL
26
7.7
SAMPLE SIZE DETERMINATION
26
8
ETHICS
26
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
26
8.2
ETHICAL CONDUCT OF THE STUDY
26
8.3
SUBJECT CONFIDENTIALITY
27
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
27
10 DATA QUALITY ASSURANCE
27
11 COMPLETION OF THE STUDY
27
12 REFERENCES
27
LIST OF TABLES
TABLE 1.
STUDY DRUG INFORMATION
19
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
8
LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
29
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
31
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
32
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APPENDIX D.
ACTIVITY SCHEDULE
33
APPENDIX E.
OPERATIONS MANUAL
35
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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, delivery or activity of pancreatic 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. There are approximately 190,000 patients in the United States 
(US) managing their EPI with pancreatic enzyme replacement therapy (PERT).1
Pancreatic enzyme replacement therapy is the cornerstone of EPI treatment.  Without PERT, patients 
may suffer from maldigestion and malabsorption and associated consequences, such as weight loss, 
malnutrition and sarcopenia.2-4  Pancrelipase delayed-release (DR) capsules is a PERT currently approved 
and marketed in the US by AbbVie as Creon® for the treatment of EPI due to CF, CP, pancreatectomy or 
other conditions.5 Currently approved and marketed Creon is manufactured using active pharmaceutical 
ingredient (API) produced at 
.
In order to protect Creon's supply chain through site and geographic diversity, AbbVie invested in new 
equipment and manufacturing site expansion to replicate the manufacturing process for pancrelipase 
DR API at an alternate site 
, in order 
to produce Creon using SPL API (CREON-SPL).  This study is being conducted to evaluate the clinical 
symptoms of EPI in subjects treated with the Creon manufactured with SPL API (CREON-SPL).
Information on CREON-ABT and CREON-SPL can be found in Section 5.9.  Further information on 
pancrelipase DR currently marketed as Creon® in the US can be found in the US Product Information 
(USPI).5
2.2 Benefits and Risks to Subjects
All subjects enrolled in this study will receive treatment for EPI during the study.  This is the primary 
benefit to subjects for this study.
The safety and efficacy of Creon has been well described in subjects with EPI.  The safety data describe a 
well-tolerated regimen, and the use of Creon is supported by a favorable benefit-risk profile.  Risks of 
study participation include those currently listed in the USPI for Creon,5 and are not expected to be 
different for CREON-SPL.
For further details, please see the current Creon Investigator's Brochure and the current product insert.5
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3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
This is a descriptive, exploratory study.
The objective of this study is to evaluate the clinical symptoms of EPI in subjects treated with 
CREON-SPL.  No clinical hypothesis is being tested.
3.2 Pharmacodynamic Endpoints

Total Symptom Score (TSS) as defined in the Pancreatic Exocrine Insufficiency Questionnaire 
(PEI-Q) at Days 1, 8, 15, 29 and 85.

Abdominal Symptom Domain Score (ASDS) as defined in PEI-Q at Days 1, 8, 15, 29 and 85.

Bowel Movement Symptom Score (BMSS) as defined in PEI-Q at Days 1, 8, 15, 29 and 85.
3.3 Safety Endpoints
Safety evaluations include monitoring of treatment-emergent adverse events (TEAEs).
A TEAE compatible with the clinical symptoms of EPI will be considered an adverse event of special 
interest (AESI) for this study and will be summarized separately.
4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 4, prospective, single-arm, single-blinded study (subject will not be aware of the order in 
which study drugs are dispensed).  Approximately 30 subjects will be enrolled.
Female subjects of childbearing potential who have a positive pregnancy test during Screening, are not 
eligible to rescreen. Subjects who fail screening due to other reasons can be rescreened once.  In the 
event of rescreening, only prior disqualifying criterion/criteria will need to be repeated.
This study will consist of 4 periods as follows:
Screening Period:  Subjects have up to 14 days following the Screening Visit to confirm eligibility and 
enroll into the study at the Run-In Visit (RIV).  If all eligibility criteria can be verified during the Screening 
Visit, the RIV can occur on the same day as the Screening Visit, and the subject can be enrolled in the 
study and be dispensed Creon-ABT. If full eligibility cannot be confirmed at the Screening Visit, the 
subject will schedule the RIV on a separate date.
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Run-in Period:
At the RIV, after eligibility is confirmed, the subject will be dispensed blinded Creon 24,000 lipase units 
(LU) manufactured with Abbott API (CREON-ABT) to be used for the duration of the Run-in Period (28 
days) at the same stable individual dose of Creon he/she was on before Screening.  This assures that the 
Day 1 assessment reflects the symptoms on stable CREON-ABT use.
Treatment Period:  Subjects who complete the Run-in Period will be assessed for the continuation 
criteria at Day 1.  Only subjects who meet all continuation criteria will be dispensed additional study 
drug.  Blinded CREON-ABT study drug from the Run-In Period will be returned, and the subject will be 
dispensed blinded Creon 24,000 LU manufactured with SPL API (CREON-SPL) to use at the same stable 
individual dose per LU of Creon he/she was on before Screening and during the Run-in Period.  This 
assures that the treatment assessments after Day 1 reflect the symptoms on CREON-SPL.  Symptoms 
will be assessed at Day 1 and over both short- (Day 8) and long-term (Days 15, 29, and 85).  Study 
procedures, including assessment of EPI symptoms and adverse events (AEs), will be conducted at each 
visit.
Post-Treatment Period:  Subjects who complete or prematurely discontinue the Treatment Period will 
be followed for 30 days, through a safety follow-up telephone contact, to assess symptoms and to verify 
the subject's well-being.
The schematic of the study is shown in Figure 1.  Further details regarding study procedures are located 
in the Operations Manual.
See Section 5.1 for information regarding eligibility criteria.
See Section 5.2 for information regarding the continuation criteria.
Figure 1.
Study Schematic
CREON-ABT = Creon using active pharmaceutical ingredient produced at 
; CREON-SPL = Creon using 
active pharmaceutical ingredient produced 
; PT = post treatment; SCR = Screening; SB = single-
blinded; RIV = Run-in Visit
*
If all eligibility criteria can be confirmed at the SCR Visit, RIV can occur at the same day as the SCR Visit. 
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Study completion for each subject is defined as the date of the follow-up telephone contact or the 
premature study discontinuation visit, whichever comes later.  The maximum duration of study 
participation is approximately 157 days for each subject.
4.2 Discussion of Study Design
A single-arm, single-blind, prospective, longitudinal design is considered appropriate to evaluate 
symptoms, as the assessments being performed are reported by the subject (patient reported outcome 
[PRO]).  The 7-day recall period of the PEI-Q instrument assures that the measurement obtained at Day 
1 reflects the symptoms under CREON-ABT, i.e., before the switch to CREON-SPL.  Providing CREON-ABT
for 28 days before Day 1, assures the stability of the effect of CREON-ABT at the time it is assessed at 
Day 1.  Because of the subjective nature of symptom assessment, the subjects will be blinded to which 
study drug they are receiving at each point in the study.  The investigators will know the sequence of 
assignment of study drug but must not inform the subject of this assignment.
Additionally, a study with a simple design (e.g., utilizing telemedicine visits, avoiding confinement 
period, diet standardization or stool collection) was chosen to facilitate study execution during the 
current SARS-CoV-2 epidemic, in alignment with the study objective.  The number of in-person visits was 
minimized to essential visits where labs are collected, or study drug is dispensed/reconciled.  Most study 
visits will be conducted remotely via a telemedicine visit or a phone call.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All 
pharmacodynamic and safety-related measurements in this study are standard for assessing disease 
activity in subjects with CF or CP.  All clinical and laboratory procedures in this study are standard and 
generally accepted.
The pharmacodynamic assessments will be conducted using an EPI-specific PRO measure – the PEI-Q.  
The PEI-Q is an 18-item PRO measure designed to assess EPI symptoms and associated impact.6,7  The 
PEI-Q has demonstrated good content validity, reliability, and psychometric properties via the conduct 
of qualitative concept elicitation, cognitive debriefing interviews and quantitative psychometric 
evaluation studies in EPI patients due to CF and CP.6,7
Suitability of Subject Population
Male and female subjects with EPI and CF or CP who meet all of the eligibility criteria at the RIV will be 
eligible to enroll into the study.  Subjects who meet the continuation criteria at Day 1 will be allowed to 
initiate the Treatment Period of the study.  The instrument that will be used to assess EPI symptoms 
(PEI-Q) was developed in a population of CF and CP patients.  As subjects are required to be clinically 
controlled in their current PERT regimen, and subjects with a TSS ≥ 1.8 are most likely poorly clinically 
controlled, those subjects will be excluded.
Selection of Doses in the Study
This study does not select a specific dose of pancrelipase. The individualized dose that the subject is 
using before and during Screening will be maintained throughout the Run-in and Treatment Periods, as 
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specified in the eligibility criteria (see Section 5.1).  The subject's total daily dose should not exceed the 
approved dose of 4,000 LU/g fat/day or 10,000 LU/kg/day.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be enrolled 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 form (ICF), approved by an 
independent ethics committee (IEC)/institutional review board (IRB), prior to the initiation of 
any screening or study-specific procedures. The use of Legally Authorized Representatives 
(LARs) is prohibited for this protocol.
Demographic
2. Adult male or female, at least 18 years old at the time of ICF signature.
3. Are willing and able to comply with all procedures required in this protocol.
4. Subject must be able to read, and must be willing and capable to use the electronic patient 
reported outcome (ePRO) device and the platform needed for remote assessment and 
telemedicine visits.
Disease/Condition Activity
5. Subject has a previous diagnosis of Cystic Fibrosis (CF) or Chronic Pancreatitis (CP).

A diagnosis of CF is defined by:

sweat chloride test result ≥ 60 mmol/L, and/or

documented CF-causing CFTR mutations and clinical features of CF.8,9

A diagnosis of CP is defined by presence of definite or probable evidence of CP in a patient 
with history and physical examination suspicious for CP, as described in the 2014 APA 
Practice Guidelines in CP.10
6. Subject has a previous diagnosis of EPI that is currently clinically controlled (no clinically overt 
steatorrhea or diarrhea) with a Creon dosing regimen for more than 3 months prior to 
Screening.
7. Subject has a Total Symptom Score (TSS) < 1.8 on PEI-Q at Screening.
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Subject History
8. Subject is on an individualized, stable (no change in the prescribed total daily dose in LU for at 
least 3 months before Screening) dose regimen of commercially available Creon that includes 
the use of the 24,000 LU capsule strength (up to a maximum of sixteen 24,000 LU capsules per 
day). The subject's total daily dose should not exceed 4,000 LU/g fat/day or 10,000 LU/kg/day.
9. Subject does not have any medical history of any type of malignancy involving the digestive 
tract in the last 5 years, nor any of the following medical conditions: 
At any time prior to Screening:

fibrosing colonopathy

celiac disease

bariatric surgery or partial/total gastrectomy

inflammatory bowel disease

irritable bowel syndrome

lactose intolerance not controlled with diet

previous bowel surgery (other than minor resection that does not result in 
malabsorption syndromes)

any other clinically significant disease or medical condition that may interfere with the 
EPI symptom assessment, as per the investigator's judgment
Within 6 months prior to or during screening:

distal intestinal obstruction syndrome episode

Clostridioides (Clostridium) difficile infection

Small intestine bacterial overgrowth

acute pancreatitis
10. Subjects must not have a diagnosis/history of renal impairment, hyperuricemia, or 
uncontrolled gout, including those with a recent acute gout flare within 60 days of Screening 
that would make the subject an unsuitable candidate to receive study drug in the investigator's 
opinion.
11. Subjects must not have any history of an allergic reaction or significant sensitivity to pork, or 
constituents of Creon (and its excipients) and/or other products in the same class.
12. Subject did not have a recent history, in the 7 days prior to or at the RIV, of uncontrolled 
diabetes mellitus or any acute illness.
13. Subject should not have any signs or symptoms associated with COVID-19 infection during 
Screening or at the RIV.
Contraception
14. If female, subject must be either:
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
postmenopausal, defined as either:

female with age > 55 years with no menses for 12 or more months, without an 
alternative medical cause.

female with age ≤ 55 years with no menses for 24 or more months without an 
alternative medical cause
OR

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy) or premenopausal female with permanent sterility (non-surgical permanent 
infertility due to Mullerian agenesis, androgen insensitivity, or gonadal dysgenesis; 
investigator discretion should be applied to determining study entry for these individuals)
OR

For females of childbearing potential, practicing at least one protocol-specified method of 
birth control, as specified in Section 5.3, that is effective from study Screening through at 
least 7 days after the last dose of study drug.
15. Females of child-bearing potential must have a negative urine pregnancy test at Screening 
and at the RIV (prior to the first dose of study drug). 
16. Female subjects should not be pregnant, or breastfeeding, or considering becoming 
pregnant or donating eggs during the study or for approximately 7 days after the last dose of 
study drug.
Concomitant Medications
17. Subject did not initiate new antibiotic therapy (except for inhaled antibiotics) within 10 days 
prior to the RIV.
18. Subject has not used narcotic medications for at least 3 months prior to Screening.
19. Subject should not require, or should be able to safely discontinue, the medications or 
supplements listed below prior to the RIV throughout the end of the treatment period.

Anti-diarrheal and antispasmodic drugs

Stimulant or lubricant laxatives

Antacids containing aluminum, magnesium, or calcium

Fiber supplements (e.g., psyllium, calcium polycarbophil)

Immunosuppressive drugs (not including steroids)

Any pancreatic enzyme preparations other than the study drug (except for any other Creon 
strength, besides the 24,000 LU strength, that the subject was taking as part of their stable 
regimen before study, which must be continued along with the 24,000 LU study drug)

Nutritional supplementation via tube feeding (nasogastric, gastrostomy, jejunostomy)
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20. If the medications below are used, the subject should be able to safely keep the same stable 
dose used at the RIV throughout the end of the treatment period.  If not used, the investigator
should not be planning to initiate these drugs from the RIV throughout the end of the treatment 
period:

proton pump inhibitors, H2-blockers

Antacids containing bicarbonate only

Cholestyramine, sucralfate 

Prokinetics (e.g., domperidone, bromopride, metoclopramide, sulpiride)

Prostaglandins, Somatostatin

Prebiotics or probiotic drugs or supplements

Immunosuppressive steroids (local or systemic)

Osmotic laxatives

Oral iron supplementation
21. Subject must not have been treated with any investigational drug within 30 days or 
5 half-lives of the drug (whichever is longer) prior to the RIV, or be currently enrolled in another 
clinical study, or have been previously enrolled in this study.
5.2 Continuation Criteria
At the Day 1 visit, the subject will be assessed for the following continuation criteria and will only be 
able to initiate the Treatment Period at Day 1 (i.e., start CREON-SPL) if the following criteria are met:

Subject continues to be willing and capable to use the ePRO device and the platform needed for 
remote assessment and telemedicine visits throughout the rest of the study.

Subject has a TSS on PEI-Q < 1.8 at Day 1.

Subject has not been identified as non-compliant with study drug administration, as per the 
investigator's assessment.

Subject did not have a recent history, starting within 7 days prior to or at Day 1, of uncontrolled 
diabetes mellitus or any acute illness.

Subject does not have any signs or symptoms associated with COVID-19 infection at Day 1.

Females of child-bearing potential have a negative urine pregnancy test at Day 1, prior to the 
initiation of CREON-SPL.

Subject did not initiate new antibiotic therapy (except for inhaled antibiotics) within 10 days 
prior to Day 1.

Subject does not have any other clinically significant disease or medical condition that may 
interfere with the EPI symptom assessment, as per the investigator's judgment.
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5.3 Contraception Recommendations
Contraception Requirements for Females
Female subjects should not be pregnant, breastfeeding or considering becoming pregnant during the 
study or for approximately 7 days after the last dose of study drug.
Subjects must follow the following contraceptive guidelines as specified:
Females, Non-Childbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of non-childbearing potential due to meeting any of the following criteria:
1.
Premenopausal female with permanent sterility or permanent infertility due to one of the 
following:

Permanent surgical sterility due to a hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy

Non-surgical permanent infertility due to Mullerian agenesis, androgen insensitivity, or 
gonadal dysgenesis; investigator discretion should be applied to determining study entry 
for these individuals.
2.
Postmenopausal female

Age > 55 years with no menses for 12 or more months without an alternative medical 
cause.

Age ≤ 55 years with no menses for 24 or more months without an alternative medical 
cause
Females, of Childbearing Potential
Females of childbearing potential must avoid pregnancy while taking study drug(s) and for at 
least 7 days after the last dose of study drug.  Females of childbearing potential must commit to 
one of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral, intravaginal, 
transdermal, injectable) associated with inhibition of ovulation-initiated at least 30 days 
prior to Screening.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to Screening.

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action, initiated at least 30 days prior to Screening.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram 
confirms success of the procedure).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).
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
Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject).

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).

Practice true abstinence, defined as:  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).
Contraception Requirements for Males
Male subjects are not required to use contraception methods during the study.
5.4 Prohibited Medications and Therapy
The following medications/therapies are prohibited from the RIV to the end of the Treatment Period:

Anti-diarrheal and antispasmodic drugs

Stimulant or lubricant laxatives

Antacids containing aluminum, magnesium, or calcium

Fiber supplements (e.g., psyllium, calcium polycarbophil)

Immunosuppressive drugs (not including steroids)

Nutritional supplementation via tube feeding (nasogastric, gastrostomy, jejunostomy)

Any pancreatic enzyme preparations other than the study drug (except for any other Creon 
strength, besides the 24,000 LU strength, that the subject was taking as part of their stable 
regimen before study, which must be continued along with the 24,000 LU study drug)
The following medications/therapies are prohibited from 30 days or 5 half-lives of the drug (whichever is 
longer) prior to the RIV, until the end of the study:

Any investigational drugs
Narcotic analgesics can be used only if necessary for management of an AE, such as acute pain 
management.
Subjects must be consented for the study prior to discontinuing any prohibited medications for the 
purpose of meeting study eligibility.
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5.5 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.
Any questions regarding concomitant or prior therapy should be raised to the Sponsor Medical contact.
5.6 Prior and Post Treatment PERT Therapy
The total daily dose of Creon® taken prior to the RIV will be recorded in the electronic case report form 
(eCRF).
The total daily dose of Creon® taken during the Post-Treatment 30-day Period will be recorded in the 
eCRF.
5.7 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:  

The subject requests to be withdrawn from the study.

Any intake of pancreatic enzyme preparations in addition or substitution to the study drug 
during the study.

When continuation of the study drug would place the subject at risk, as determined by the 
Investigator.

Subjects who become pregnant during the study. 

Subject is significantly noncompliant with study procedures, which would put the subject at risk 
for continued participation in the study.

Subject does not meet all continuation criteria at Day 1.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  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/her site if he/she has safety concerns.  If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
COVID-19 Pandemic-Related Acceptable Protocol Modification
During the COVID 19 pandemic, it may be necessary to employ mitigation strategies to enable the 
investigator to ensure subject safety and continuity of care.  Refer to Section 2 and Section 3.1 of the 
Operations Manual in Appendix E.
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5.8 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
To minimize missing data for study assessments, subjects who prematurely discontinue study drug 
treatment should continue to be followed for all regularly scheduled visits, unless subjects have decided 
to discontinue the study participation entirely (withdrawal of informed consent).  Subjects should be 
advised on the continued scientific importance of their data even if they discontinue treatment with 
study drug early.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation Visit (PD Visit) should be completed as soon as 
possible, preferably within 2 weeks.  In addition, if subject is willing, a 30-day follow-up phone call after 
the last dose of study drug may be completed to ensure all treatment-emergent AEs/serious adverse 
events (SAEs) have been resolved.
5.9 Study Drug 
Study drug will only be shipped to clinical sites that have provided the sponsor (or an authorized 
representative) with all required study documents, including Independent ethics 
committee/institutional review board (IEC/IRB) approval, and have signed a clinical study agreement.
Study drug capsules (CREON-ABT or CREON-SPL) will be taken orally with each meal and snack (as per 
patient's usual practice) with enough fluids to swallow the capsules completely.  Capsules must be 
swallowed whole (capsules must not be crushed, chewed, or opened).  Subjects will maintain 
throughout the study the same stable individual dose per LU of Creon they were on before initiating 
Screening.
If the Screening Visit and the RIV do not occur on the same day, subjects will continue their existing 
stable dose of commercial Creon until the RIV.
At the RIV, eligible subjects will be dispensed blinded Creon 24,000 LU manufactured with Abbott API 
(CREON-ABT) for the Run-in Period. At the RIV, and for the duration of the study, eligible subjects will 
stop using the commercial Creon 24,000 LU capsules they were taking before the RIV and begin taking 
the same corresponding number of capsules at meals and snacks (maintaining the same daily dosing as 
prescribed by their doctor), using the 24,000 LU capsules dispensed as study drug.  If the subject is using 
more than one strength of commercial Creon capsules, the subject will keep taking the commercial 
Creon capsules of any other strength besides the 24,000 LU strength at the same previous dose and will 
switch the 24,000 LU capsules from the commercial Creon they were using before Screening to the 
24,000 LU capsules dispensed as study drug.
At Day 1, subjects will return all the bottles dispensed at the RIV.  Subjects who meet all continuation 
criteria at Day 1 will be dispensed blinded Creon 24,000 LU manufactured with SPL API (CREON-SPL) for 
the Treatment Period at the same dose used during the Run-in Period.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The subjects will be blinded to the type of study drug they will be receiving; therefore, site personnel 
MUST NOT inform the subject whether they are receiving CREON-ABT or CREON-SPL at each 
dispensation visit, in order to maintain the single-blind of the study.
If a subject forgets to take their study drug dose at their regularly scheduled dosing time, they should 
take the next dose at the next snack or meal. Information on the study drugs is provided in Table 1.  
AbbVie-provided study drug must not be substituted.  Direct-from-patient shipping at Day 85/PD Visit is 
also described in the Operations Manual (Appendix E).
The subject will be instructed to return all drug containers (even if empty) to the study site personnel at 
the completion of the Run-in and Treatment Periods.  The study site personnel will document study drug 
usage.
Pancrelipase (CREON-ABT or CREON-SPL) will be packaged in bottles with quantities sufficient to 
accommodate the study design. Each kit 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 kit 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.  Site staff will complete all blank spaces on the label before 
dispensing to subjects.  Study drug will only be used for the conduct of this study. 
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STUDY M21-432  |  Version 1.0 
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Digital Health Tools Accountability
The investigator or his/her representative will verify that the digital health tools (e.g., PRO devices) are 
received intact and in the correct amounts.  A proof of receipt or similar document will be kept in the 
site files as a record of what was received.
In addition, sites will maintain records of traceability, accountability, and return including but not limited 
to date received/dispensed/returned, subject number, and the identification of the person 
dispensing/returning the digital health tools.
5.10 Drug Assignment
This is a single-arm study, and all eligible subjects will receive both study drugs (CREON-ABT during the 
Run-in Period; CREON-SPL during the study Treatment Period).  However, to blind subjects to the 
sequence of study drugs, the IRT system will be used to allocate drug.
All subjects will be assigned a unique subject identification number by the IRT at the Screening Visit.  For 
subjects who rescreen, the subject number assigned by the IRT at the initial Screening Visit should be 
used.
AbbVie personnel, the investigator, study site personnel, and anyone with access to the full protocol, 
will be unblinded to the sequence of study drug assignment. Only subjects will remain blinded to their 
treatments throughout the study.  To maintain the subject blind, the CREON-SPL and CREON-ABT
capsules provided for the study will be identical in appearance. The investigator, study site personnel 
must not inform the subject of the order they will receive the 2 study drugs. The subject should remain 
blinded even if the subject experiences an AE.
5.11 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying independent ethics committee (IEC)/independent review 
board (IRB), regulatory authorities (as applicable), and AbbVie.
5.12 Data Monitoring Committee
The external, independent data monitoring committee (DMC) will review unblinded safety data during 
the study.  The DMC Charter for Study M21-432 will include, but is not limited to, the following:  the 
frequency and scope of data reviews, the suggested relevant data to be included in the review, the DMC 
responsibilities, and the DMC members and their credentials.
Since this is a single-arm, single-blinded study and the sponsor is unblinded, the sponsor will be 
responsible for performing the DMC analyses described in the DMC Charter as well as any additional 
analyses requested by the DMC.
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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.
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 damage or not 
working properly, or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event.  Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
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 can therefore be any unfavorable and unintended sign (including an abnormal 
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.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not. Any worsening of a pre-existing condition or illness is 
considered an AE.  Worsening in severity of a reported AE should be reported as a new AE.  Laboratory 
abnormalities and changes in vital signs are considered to be AEs only if they result in discontinuation 
from the study, necessitate therapeutic medical intervention, and/or if the investigator considers them 
to be AEs.
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/or the surgery/procedure has 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
All AEs reported from the time of first 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, study procedure-related serious and nonserious AEs will be collected from the time the 
subject signs the study-specific informed consent.
Adverse events will be monitored throughout the study to identify any of special interest for this study.
Adverse Events of Special Interest
The following TEAEs compatible with clinical symptoms of EPI will be considered AESI for this study:

Diarrhea 

Abdominal pain

Abdominal bloating

Flatulence

Steatorrhea
Patients with signs and symptoms suggestive of worsening EPI should be evaluated and treated as 
clinically indicated by the investigator.
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 to Creon 
24,000 LU dispensed as CREON-ABT or CREON-SPL.
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 to Creon 
24,000 LU dispensed as CREON-ABT or CREON-SPL.
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STUDY M21-432  |  Version 1.0 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study must be 
discontinued (Section 5.7).  If a pregnancy occurs in a study subject, information regarding the 
pregnancy and the outcome will be collected.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
6.2 Management of COVID-19 Infection
Clinical management of confirmed or suspected COVID-19 infection during the study will be handled by 
the investigator according to treatment guidelines and local standard of care.
For suspected COVID-19 infection, prompt and comprehensive evaluation should be performed to 
confirm COVID-19 infection or exclude other causes (e.g., influenza).  For negative COVID-19 results, the 
investigator should consider re-testing based on clinical suspicion (exposures, clinical findings).
All cases of suspected or confirmed COVID-19 infection must be discussed with the Sponsor/Emergency 
Medical Contact regarding additional COVID-19 testing, alternative etiologies and/or study visit 
disposition (including but not limited to the possibility of screen fail due to an expiring screening 
window, premature discontinuations, etc.).
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be focused on high level description of the 
statistical analyses.  Complete and specific details of the statistical analysis will be described in the 
Statistical Analysis Plan (SAP).
The planned analyses will be conducted after all subjects have completed the study or prematurely 
discontinued from the study.
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all enrolled subjects who received at least 1 dose of study drug of 
CREON-SPL.  The FAS will be used for the summary of subject disposition and baseline characteristics.
A Per-Protocol (PP) Population includes all enrolled subjects who received at least 1 dose of study drug 
of CREON-SPL, had Day 1 (baseline) PEI-Q scores collected, and had at least one post-baseline PEI-Q 
scores collected during the Treatment Period (Days 8, 15, 29, and 85).  The pharmacodynamic endpoints 
will be analyzed in the PP Population.
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STUDY M21-432  |  Version 1.0 
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The Safety Analysis Set for CREON-ABT (SAS-CREON-ABT) consists of all subjects who received at least 1 
dose of CREON-ABT study drug during the Run-in Period. The Safety Analysis Set for CREON-SPL (SAS-
CREON-SPL) consists of all subjects who received at least 1 dose of CREON-SPL study drug.
7.3 Handling Potential Intercurrent Events for the Study Endpoints
The pharmacodynamic endpoints (TSS, ASDS and BMSS) will be analyzed based on the PP population 
and the following potential intercurrent events will be addressed:

Subjects who did not receive any dose of study drug CREON-SPL will be excluded from the PP 
population.

Subjects who did not have baseline (Day 1) PEI-Q score data or did not have any post-baseline 
PEI-Q score data will be excluded from the PP population. 
Subjects who have missing PEI-Q data for the visit will be excluded from the analysis of that visit.
7.4 Statistical Analyses for Pharmacodynamic Endpoints
Summary and Analysis of the Pharmacodynamic Endpoints
Analyses of the pharmacodynamic endpoints will be conducted on the PP population.  Descriptive 
statistics (N, mean, standard deviation [SD], median, minimum, and maximum) will be used to 
summarize the TSS as well as the symptom score for each domain of abdominal symptoms and bowel 
movement symptoms from PEI-Q.  The summaries will be provided for the Screening Visit, Baseline Visit 
(Day 1), each Post-Baseline Visit (Days 8, 15, 29, 85), and the change from baseline for each.  Two-sided 
95% confidence interval based on t-distribution will also be provided for the mean estimate of each 
score at each visit, and the mean change from baseline for each post-baseline visit.
7.5 Statistical Analyses for Safety
Safety analyses will be provided based on safety analysis sets.  Number and proportion of subjects 
reporting a TEAE during the Run-in Period (CREON-ABT) and Treatment Period (CREON-SPL), will be 
summarized separately using SAS-CREON-ABT and SAS-CREON-SPL, respectively.  A TEAE compatible 
with the clinical symptoms of EPI (see Section 6.1) will be considered an AESI and will be summarized 
separately.  Details of the safety analyses will be provided in the SAP.
Adverse event will be coded using MedDRA. A -TEAE is defined as an AE with an onset date on or after 
the first dose of corresponding study drug and within 30 days after the last dose of study drug or 
initiation of the next study drug, whichever is earlier.  The number and percentage of subjects 
experiencing TEAEs will be tabulated using MedDRA system organ class (SOC) and preferred term (PT), 
as well as by severity and by relationship to the study drug as assessed by the investigator.  Summaries 
(i.e., number and percentages) of TEAEs, SAEs, deaths, AEs leading to discontinuation, and AESIs will be 
provided.
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7.6 Overall Type I Error Control
Not applicable for this study as the study will provide descriptive statistics with no hypothesis testing.
7.7 Sample Size Determination
Approximately 30 subjects will be enrolled at the RIV.  The sample size is calculated based on the 
descriptive statistics for the TSS based on PEI-Q.  No formal statistical hypothesis testing is planned.  
Assuming a dropout rate of 20% after the RIV, the number of evaluable subjects will be around 24 for 
the analysis of pharmacodynamic endpoints.
Based on Johnson CD, et al,6 the average TSS from PEI-Q was estimated to be 1.4 (SD = 0.7) for CP and CF 
subjects with EPI symptoms.  Assuming the covariance between the TSS at baseline and post-baseline 
after switching to CREON-SPL to be 0.365, the SD for the change of the TSS between baseline and post-
baseline is estimated to be 0.5.  A sample size of 24 evaluable subjects will provide a precision of ± 0.2 in 
terms of half-length of the 95% confidence interval for the estimate of change in TSS based on PEI-Q.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, ICF, recruitment materials, and all subject materials will be submitted to the IEC/IRB for 
review and approval.  Approval of both the protocol and the ICF 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.
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.
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, conflict/combat) 
occurs leading to difficulties in performing protocol-specified procedures, AbbVie may engage with 
study site personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity of care.  This 
may include alternative methods for assessments (e.g., phone contacts or virtual site visits), alternative 
locations for data collection (e.g., use of a local lab instead of a central lab), and shipping investigational 
product and/or supplies direct to subjects to ensure continuity of treatment where allowed.  In all cases, 
these alternative measures must be allowed by local regulations and permitted by IRB/IEC. Investigators 
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
should notify AbbVie if any urgent safety measures are taken to protect the subjects against any 
immediate hazard.
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). During the COVID-19 pandemic, remote monitoring of data may be employed if allowed 
by the local regulatory authority, IRB/IEC, and the study site.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be 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 date of the last subject's last visit.
12
REFERENCES
1.
AbbVie. Data on file. 2019.
2.
Fieker A, Philpott J, Armand M. Enzyme replacement therapy for pancreatic insufficiency: present 
and future. Clin Exp Gastroenterol. 2011;4:55-73.
3.
Shintakuya R, Uemura K, Murakami Y, et al. Sarcopenia is closely associated with pancreatic exocrine 
insufficiency in patients with pancreatic disease. Pancreatology. 2017;17(1):70-5.
4.
Lindkvist B. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol. 
2013;19(42):7258-66.
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CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
5.
CREON® (pancrelipase) [prescribing information]. North Chicago, IL; AbbVie Inc., 2020.
6.
Johnson CD, Williamson N, Janssen-van Solingen G, et al. Psychometric evaluation of a patient-
reported outcome measure in pancreatic exocrine insufficiency (PEI). Pancreatology. 
2019;19(1):182-90.
7.
Johnson CD, Arbuckle R, Bonner N, et al. Qualitative Assessment of the Symptoms and Impact of 
Pancreatic Exocrine Insufficiency (PEI) to Inform the Development of a Patient-Reported Outcome 
(PRO) Instrument. Patient. 2017;10(5):615-28.
8.
Farrell PM, Rosenstein BJ, White TB, et al. Guidelines for diagnosis of cystic fibrosis in newborns 
through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr. 2008;153(2):S4-S14.
9.
Smyth AR, Bell SC, Bojcin S, et al. European Cystic Fibrosis Society Standards of Care: Best Practice 
guidelines. J Cyst Fibros. 2014;13 Suppl 1:S23-42.
10. Conwell DL, Lee LS, Yadav D, et al. American Pancreatic Association Practice Guidelines in Chronic 
Pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014;43(8):1143-62.
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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
ABT
AE
adverse event
AESI
adverse event of special interest
API
active pharmaceutical ingredient, synonym: drug substance
ASDS
Abdominal Symptom Domain Score
BMSS
Bowel Movement Symptom Score
CBC
complete blood count
CF
cystic fibrosis
CP
chronic pancreatitis
CRF
case report form
DFP
direct from patient
DMC
Data Monitoring Committee
DR
delayed-release
eCRF
electronic case report form
EDC
electronic data capture
EPI
Exocrine Pancreatic Insufficiency
ePRO
electronic patient reported outcome (device)
FAS
full analysis set
GCP
Good Clinical Practice
HRQoL
health-related quality of life
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
independent ethics committee
IMP
Investigational Medicinal Product
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
LARs
Legally Authorized Representatives
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LU
lipase units
MedDRA
Medical Dictionary for Regulatory Activities
PD
premature discontinuation (visit)
PEI-Q
Pancreatic Exocrine Insufficiency Questionnaire
PERT
pancreatic enzyme replacement therapy
PP
per-protocol
PRO
patient reported outcome
PT
preferred term
RIV
Run-in Visit
SAE
serious adverse event
SAP
statistical analysis plan
SAS-CREON-ABT
safety analysis set for CREON-ABT
SAS-CREON-SPL
safety analysis set for CREON-SPL
SD
standard deviation
SOC
system organ class
SPL
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
TSS
Total Symptom Score
US
United States
USP
United States Pharmacopoeia
USPI
US Product Information
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STUDY M21-432  |  Version 1.0 
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M21-432:  A Phase 4 Study to Assess Symptoms of Exocrine Pancreatic Insufficiency in Subjects 
with Cystic Fibrosis or Chronic Pancreatitis Treated with Creon® (Pancrelipase) with an Alternate Source 
of Active Pharmaceutical Ingredient
Protocol Date:  19 May 2021
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (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:
1.
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 Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
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.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
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).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
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.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
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.
10. 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
Study Project Manager
Clinical Program Development
Principal Medical Writer 
Medical Writing
Medical Director
General Medicine and Virology
Statistics Therapeutic Area Head
Statistics
Director, Statistics
Statistics
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SAP_001.pdf: 
CREON or ABT-SLV-245 
M21-432 – Statistical Analysis Plan 
Version 2.0 – 20 July 2023
1 
Statistical Analysis Plan for Study M21-432 
Exocrine Pancreatic Insufficiency (EPI): Phase 4 
Study of Symptoms of EPI in Subjects Treated with 
CREON® (Pancrelipase) with an Alternate Source of 
Active Pharmaceutical Ingredient 
Date:  20 July 2023 
Version 2.0 
NCT05069597


CREON or ABT-SLV-245 
M21-432 – Statistical Analysis Plan 
Version 2.0 – 20 July 2023
2 
Table of Contents 
1.0
Introduction ............................................................................. 4
2.0
Study Design and Objectives .................................................. 4
2.1
Objectives, Hypotheses, and Estimands ....................................................4
2.2
Study Design Overview .............................................................................5
2.3
Treatment Assignment and Blinding .........................................................6
2.4
Sample Size Determination ........................................................................7
3.0
Endpoints ..................................................................................7
3.1
Pharmacodynamic Endpoint(s) ..................................................................7
3.2
Safety Endpoint(s) .....................................................................................7
4.0
Analysis Populations ...............................................................8
5.0
Subject Disposition ..................................................................8
6.0
Study Drug Duration and Compliance ..................................9
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications .................... 10
7.1
Demographics and Baseline Characteristics ............................................10
7.2
Medical History .......................................................................................10
7.3
Prior and Concomitant Medications ........................................................11
8.0
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary endpoints ..............................12
9.0
Pharmacodynamic Endpoint Analyses ................................ 13
9.1
General Considerations ............................................................................13
9.2
Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q) Domain 
Scores .......................................................................................................13
9.2.1
Abdominal Symptoms Domain Score (ASDS) ........................................13
9.2.2
Bowel Movement Symptoms Score (BMSS) .......................................... 14
9.2.3
Total Symptom Score (TSS) ....................................................................14
9.3
Handling of Missing Data in PEI-Q .........................................................14
9.4
Pharmacodynamic Endpoints and Analyses ............................................14
9.4.1
Pharmacodynamic Endpoints................................................................... 14
9.4.2
Main Analysis of Pharmacodynamic Endpoints ......................................15
10.0
Safety Analyses ......................................................................15


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10.1
General Considerations ............................................................................ 15
10.2
Adverse Events ........................................................................................ 15
10.2.1
Treatment-Emergent Adverse Events ...................................................... 16
10.2.2
Adverse Event Overview ......................................................................... 17
10.2.3
Treatment-Emergent Adverse Events by SOC and/or PT .......................17
10.2.4
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure ..................................................................................................18
10.2.5
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ...............................................................................19
10.2.6
Adverse Events of Special Interest ..........................................................19
10.3
Analysis of Laboratory Data ....................................................................19
10.4
Analysis of Vital Signs ............................................................................19
11.0
Interim Analysis .....................................................................19
11.1
Data Monitoring Committee ....................................................................20
12.0
Overall Type-I Error Control ..............................................20
13.0
Version History ......................................................................20
14.0
References ...............................................................................20
List of Tables 
Table 1.
PEI-Q Score Assignment .........................................................................14
Table 2.
SAP Version History Summary ...............................................................20
List of Figures 
Figure 1.
Study Schematic .........................................................................................6
Appendix A.
Protocol Deviations ..................................................................................21
Appendix B.
Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q) ......................23
List of Appendices 
Appendix A.
Protocol Deviations ..................................................................................21
Appendix B.
Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q) ...................... 23


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1.0 
Introduction 
This Statistical Analysis Plan (SAP) describes the statistical analyses for CREON or 
ABT-SLV245 Study M21-432 titled "Exocrine Pancreatic Insufficiency (EPI): Phase 4 
Study of Symptoms of EPI in Subjects Treated with CREON® (Pancrelipase) with an 
Alternate Source of Active Pharmaceutical Ingredient." 
Study M21-432 evaluates the clinical symptoms of EPI in subjects diagnosed with Cystic 
Fibrosis (CF) or Chronic Pancreatitis (CP) treated with CREON-SPL. 
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. 
2.0 
Study Design and Objectives 
2.1 
Objectives, Hypotheses, and Estimands 
The objective of this study is to evaluate the clinical symptoms of EPI in subjects 
diagnosed with Cystic Fibrosis (CF) or Chronic Pancreatitis (CP) treated with CREON-
SPL. 
This is a descriptive and exploratory study.  No formal statistical hypothesis is being 
tested.  The estimands corresponding to the study objective are the descriptive statistics 
for the difference in the pharmacodynamic endpoints (see Section 3.1) of CREON-SPL
between Baseline and each of the post-Baseline visit in the PP population (see 
Section 4.0).   
For each subject, the Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q) score is 
collected at Screening, Baseline (Day 1), Day 8, Day 15, Day 29 and Day 85.  The score 
for Abdominal Symptom Domain Score (ASDS) [A] and Bowel Movement Symptom 
Score (BMSS) [B] are averaged to get the Total Symptom Score (TSS) [T = (A+B)/2] at 


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each visit.  The difference between Baseline and each of the post-Baseline visit will be 
calculated. 
2.2 
Study Design Overview 
This is a Phase 4, prospective, single-arm, single-blinded study (subject will not be aware 
of the order in which study drugs are dispensed).  Approximately 30 subjects will be 
enrolled. 
This study will consist of 4 periods as follows: 
Screening Period: Subjects have up to 14 days following the Screening Visit to confirm 
eligibility and enroll into the study at the Run-in Visit (RIV).  If all eligibility criteria can 
be verified during the Screening Visit, the RIV can occur on the same day as the 
Screening Visit, and the subject can be enrolled in the study and be dispensed Creon-
ABT.  If full eligibility cannot be confirmed at the Screening Visit, the subject will 
schedule the RIV on a separate date. 
Run-in Period: At the RIV, after eligibility is confirmed, the subject will be dispensed 
blinded Creon 24,000 lipase units (LU) manufactured with Abbott API (CREON-ABT) 
to be used for the duration of the Run-in Period (28 days) at the same stable individual 
dose of Creon he/she was on before Screening.  This assures that the Day 1 assessment 
reflects the symptoms on stable CREON-ABT use. 
Treatment Period: Subjects who complete the Run-in Period will be assessed for the 
continuation criteria at Day 1.  Only subjects who meet all continuation criteria will be 
dispensed additional study drug.  Blinded CREON-ABT study drug from the Run-in 
Period will be returned, and the subject will be dispensed blinded Creon 24,000 LU 
manufactured with SPL API (CREON-SPL) to use at the same stable individual dose per 
LU of Creon he/she was on before Screening and during the Run-in Period.  This assures 
that the treatment assessments after Day 1 reflect the symptoms on CREON-SPL.  
Symptoms will be assessed at Day 1 and over both short- (Day 8) and long-term (Days 




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85 days.  The investigators will know the sequence of assignment of study drug but must 
not inform the subject of this assignment. 
2.4 
Sample Size Determination 
Approximately 30 subjects will be enrolled at the Run-in-Visit (RIV).  The sample size is 
calculated based on the descriptive statistics for the change in TSS based on PEI-Q.  No 
formal statistical hypothesis testing is planned.  Assuming a dropout rate of 20% after the 
RIV, the number of evaluable subjects will be around 24 for the analysis of 
pharmacodynamic endpoints. 
Based on Johnson CD, et al,1 the average TSS from PEI-Q was estimated to be 1.4 (SD = 
0.7) for CP and CF subjects with EPI symptoms.  Assuming the covariance between the 
TSS at Baseline and post-Baseline after switching to CREON-SPL to be 0.365, the SD 
for the change of the TSS between Baseline and post-Baseline is estimated to be 0.5.  A 
sample size of 24 evaluable subjects will provide a precision of ± 0.2 in terms of half-
length of the 95% confidence interval for the estimate of change in TSS based on PEI-Q. 
3.0 
Endpoints 
3.1 
Pharmacodynamic Endpoint(s) 
The pharmacodynamic endpoints include: 
●
Total Symptom Score (TSS) as defined in the Pancreatic Exocrine 
Insufficiency Questionnaire (PEI-Q) at Days 1, 8, 15, 29 and 85. 
●
Abdominal Symptom Domain Score (ASDS) as defined in PEI-Q at Days 1, 8, 
15, 29 and 85. 
●
Bowel Movement Symptom Score (BMSS) as defined in PEI-Q at Days 1, 8, 
15, 29 and 85. 
3.2 
Safety Endpoint(s) 
Safety evaluations include monitoring of treatment-emergent adverse events (TEAEs). 


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A TEAE compatible with the clinical symptoms of EPI will be considered an adverse 
event of special interest (AESI) for this study and will be summarized separately. 
4.0 
Analysis Populations 
The following population sets will be used for the analyses. 
Full Analysis Set (FAS): The FAS includes all enrolled subjects who received at least 1 
dose of study drug of CREON-SPL.  The FAS will be used for the summary of subject 
disposition, demographics, and Baseline characteristics. 
Per-Protocol (PP) Population: The PP Population includes all enrolled subjects who 
received at least 1 dose of study drug of CREON-SPL, had Day 1 (Baseline) PEI-Q 
scores collected, and had at least one post-Baseline PEI-Q scores collected during the 
Treatment Period (Days 8, 15, 29, and 85).  The pharmacodynamic endpoints will be 
analyzed in the PP Population. 
Safety Analysis Set for CREON-ABT (SAS-CREON-ABT): The SAS-CREON-ABT 
consists of all subjects who received at least 1 dose of CREON-ABT study drug during 
the Run-in Period.  
Safety Analysis Set for CREON-SPL (SAS-CREON-SPL): The SAS-CREON-SPL 
consists of all subjects who received at least 1 dose of CREON-SPL study drug during 
the Treatment Period. 
5.0 
Subject Disposition 
The number of subjects in each of the following categories will be summarized by 
investigator and overall, for the following group: 
●
Subjects who were screened; 
●
Subjects who took at least one dose of CREON-ABT; 
●
Subjects who prematurely discontinued study drug CREON-ABT; 
●
Subjects who completed protocol-specified Run-in-Period; 


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●
Subjects who failed the continuation criteria; 
●
Subjects who took at least one dose of CREON-SPL; 
●
Subjects who prematurely discontinued study drug CREON-SPL; 
●
Subjects who completed protocol-specified Treatment Period; 
●
Subjects who prematurely discontinued study  
●
Subjects who completed study (completed the Follow-Up period after the 
Treatment Period); 
●
Subjects in the PP Population. 
The number and percentage of subjects who prematurely discontinued CREON-ABT and 
CREON-SPL will be summarized by each primary reason.  The denominator will be SAS-
CREON-ABT and SAS-CREON-SPL, respectively.  Similar summaries will be provided 
for the premature discontinuation of study.  The denominator will be the total number of 
subjects who took at least one dose of CREON-ABT or CREON-SPL. 
The number and percentage of subjects who failed the continuation criteria will be 
summarized by each criterion.  The denominator will be the total number of subjects who 
completed CREON-ABT. 
6.0 
Study Drug Duration  
The overall treatment duration will be summarized separately for Run-in-Period and 
Treatment Period.  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.   
1.
Summary of Duration of treatment in Run-in Period using FAS and SAS-CREON-
ABT population separately.  In addition, the number and percentage of subjects in 
each treatment duration interval 1 to <8 days of treatment, 8 to <15 days of 
treatment and >=15 days treatment will be summarized. 
2.
Summary of Duration of treatment in the Treatment Period using FAS population.  
In addition, the number and percentage of subjects in each treatment duration 


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interval (, 1 to <8 days, 8 to < 15 days, 15 to < 29 days, 29 to < 85 days, ≥85 days) 
will be summarized. 
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 
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 Characteristics 
Continuous demographic variables include age, weight, height, body mass index (BMI), 
and TSS both at the start of the Run-in Period and at Baseline (Day 1), and prior Creon 
total daily dose.  Categorical demographic variables include sex (male, female), ethnicity 
(Hispanic or Latino, Not Hispanic or Latino), race (White, Black, American Indian/Alaska 
Native, native Hawaiian or Other Pacific Islander, Asian, Multi, or Other), study 
population (CF only, CP only, or CF and CP), weight (< 60 or ≥ 60 kg), BMI (< 25 or ≥ 
25 kg/m2), tobacco user (current, former, never, unknown), and alcohol user (current, 
former, never, unknown). 
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.  The system organ class (SOC) will be presented in alphabetical order, and 
the preferred terms will be presented in alphabetical order within each SOC.  Subjects 


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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 CREON-ABT.  This includes medications and 
procedures with a start date before the first dose of CREON-ABT.  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.   
A concomitant medication for CREON-ABT is defined as any medication that started 
prior to the date of the first dose of CREON-ABT and continued to be taken after the first 
dose of CREON-ABT or any medication that started on or after the date of the first dose 
of CREON-ABT, but not after the date of the last dose of CREON-ABT.  
A concomitant medication for CREON-SPL is defined as any medication that started prior 
to the date of the first dose of CREON-SPL and continued to be taken after the first dose 
of CREON-SPL or any medication that started on or after the date of the first dose of 
CREON-SPL, but not after the date of the last dose of CREON-SPL.  
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 during the study drug treatment 
(e.g., an end date before the first dose of study drug (CREON-ABT or CREON-SPL, 
where applicable).  
A concomitant procedure for CREON-ABT is defined as any procedure that started prior 
to the date of the first dose of CREON-ABT and continued after the first dose of CREON-


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ABT or any procedure that started on or after the date of the first dose of CREON-ABT, 
but not after the date of the last dose of CREON-ABT.  
A concomitant procedure for CREON-SPL is defined as any procedure that started prior 
to the date of the first dose of CREON-SPL and continued after the first dose of CREON-
SPL or any procedure that started on or after the date of the first dose of CREON-SPL, 
but not after the date of the last dose of CREON-SPL.  
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 the first dose of study drug (CREON-ABT or CREON-SPL, where 
applicable).   
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 (CREON-ABT or 
CREON-SPL, where applicable) and continued after the first dose of study drug. 
Prior procedures and concomitant procedures will be listed by subject numbers. 
8.0 
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary endpoints 
The pharmacodynamic endpoints (TSS, ASDS and BMSS) will be analyzed based on the 
PP population and the following potential intercurrent events will be addressed: 
●
Subjects who did not receive any dose of study drug CREON-SPL will be 
excluded from the PP population. 
●
Subjects who did not have Baseline (Day 1) PEI-Q score data or did not have 
any post-Baseline PEI-Q score data will be excluded from the PP population. 
Subjects who have missing PEI-Q data for a particular visit (besides Day 1) will be 
excluded from the analysis of that visit. 


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9.0 
Pharmacodynamic Endpoint Analyses 
9.1 
General Considerations 
All pharmacodynamic analyses will be conducted in the PP population. 
This is a descriptive and exploratory study.  No formal statistical hypothesis is being 
tested. 
All the analyses will be performed after all ongoing subjects have completed the 
Treatment Period and the database has been locked.  This will be the final analysis for the 
pharmacodynamic endpoints. 
"Baseline" refers to the last non-missing observation before the first administration of 
CREON-SPL, unless otherwise specified in the individual analysis section. 
9.2 
Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q) 
Domain Scores 
The Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q) is provided in Appendix C.  
It is comprised of three domains: abdominal symptoms, bowel movements, and impacts.  
Assessment of EPI symptoms will be done using abdominal symptoms domain, bowel 
movement symptoms domain, and the Total Symptom Score. 
9.2.1 
Abdominal Symptoms Domain Score (ASDS) 
The Abdominal Symptoms Domain (ASD) consists of 7 questions, each with 5 answer 
choices.  A score of 0 - 4 will be assigned to each answer as specified in the Table 1.  The 
Mean Abdominal Symptoms Domain Score (A) is the average of the total score.  The 
mean score for this domain can range from 0 to 4. 


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Table 1. 
PEI-Q Score Assignment 
ANSWER 
SCORE 
NO NOT AT ALL 
0 
YES, A LITTLE BIT 
1 
YES, SOME 
2 
YES, QUITE A BIT 
3 
YES, A LOT 
4 
9.2.2 
Bowel Movement Symptoms Score (BMSS) 
The Bowel Movement Symptoms (BMS) consists of 6 questions, each with 5 answer 
choices.  A score of 0 - 4 will be assigned as specified in the Table 1.  The Mean Bowel 
Movement Symptoms Score (B) is the average of the total score for this domain.  The 
mean score for this domain can range from 0 to 4. 
9.2.3 
Total Symptom Score (TSS) 
The Total Symptom Score will be calculated as the average of the Mean Abdominal 
Symptoms Domain Score (A) and Mean Bowel Movement Symptoms Score (B).  It can 
range from 0 to 4. 
9.3 
Handling of Missing Data in PEI-Q 
The PEI-Q data are designed to be collected when all questions are answered, so there 
will be no missing data.  Subjects who have missing PEI-Q data for a particular visit 
(besides Day 1) will be excluded from the analysis of that visit. 
9.4 
Pharmacodynamic Endpoints and Analyses 
9.4.1 
Pharmacodynamic Endpoints 
The pharmacodynamic endpoints include the TSS, ASDS and BMSS at Baseline (Day 1), 
each of the post-Baseline visits (Day 8, 15, 29 and 85) and change from Baseline to each 
of the post-Baseline visits. 


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9.4.2 
Main Analysis of Pharmacodynamic Endpoints 
The pharmacodynamic endpoints will be analyzed in a descriptive manner.  Descriptive 
statistics (N, mean, standard deviation [SD], median, minimum, and maximum) will be 
used to summarize the TSS as well as the mean symptom score for each domain of 
abdominal symptoms and bowel movement symptoms from PEI-Q.  The summaries will 
be provided for the Baseline Visit (Day 1), each Post-Baseline Visit (Days 8, 15, 29, 85), 
and the mean change from Baseline to each post-Baseline visit.  Two-sided 95% 
confidence interval based on t-distribution will also be provided for the mean estimate of 
each score at each visit, and the mean change from Baseline for each post-Baseline visit. 
The same descriptive statistics will also be produced for the scores at the Screening Visit 
because change from Screening to Baseline will be used as the context for the main 
efficacy analysis. 
In addition, a sensitivity analysis for TSS, ASDS and BMSS will be provided by 
excluding subject 1401 as this subject may have been accidentally unblinded by the site 
during the Creon-SPL treatment period.  
10.0 
Safety Analyses 
10.1 
General Considerations 
Safety data will be summarized for the SAS-CREON-ABT and SAS-CREON-SPL 
population separately.  Safety summaries will be presented by treatment periods using the 
respective population groups. 
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 


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collected.  In addition, AEs related to study procedures (non-serious and serious) will be 
collected from the time the subject signed the study-specific informed consent.  
All Adverse events (AEs) and Serious Adverse events (SAEs) will be summarized and 
presented using primary MedDRA System Organ Classes (SOCs) and preferred terms 
(PTs) coded according to the version of the MedDRA coding dictionary used for the study 
at the time of database lock.  The actual version of the MedDRA coding dictionary used 
will be noted in the AE tables and in the clinical study report.  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) for the SAS-CREON-ABT are defined as any AE with 
the onset date on or after the first dose of the CREON-ABT until 30 days after the last 
dose of CREON-ABT or until the initiation of CREON-SPL, whichever is earlier.  
Similarly, TEAEs for SAS-CREON-SPL are defined as any AE with the onset date on or 
after the first dose of CREON-SPL until 30 days after the last dose of CREON-SPL.  In 
the cases that an AE happens in a day that a subject takes both CREON-ABT and 
CREON-SPL, such AE will be counted under CREON-SPL. This definition will be used 
for all summaries except the one additional AE overview summaries in Section 10.2.2.  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). 
All TEAEs will be summarized overall, as well as by primary MedDRA SOC and 
Preferred Term.  The SOCs will be presented in alphabetical order, and the PTs will be 
presented in alphabetical order within each SOC. 
The number and percentage of subjects experiencing TEAEs will be summarized. 


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10.2.2 
Adverse Event Overview 
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories for the 
SAS-CREON-ABT and SAS-CREON-SPL: 
●
Any TEAE 
●
TEAEs with a "reasonable possibility" of being related to study drug according 
to the investigator 
●
Severe TEAEs 
●
Serious TEAEs 
●
Serious TEAEs with a "reasonable possibility" of being related to study drug 
according to the investigator 
●
TEAEs leading to discontinuation of study drug 
●
TEAEs leading to death 
●
TEAEs of Special Interest 
●
TEAEs of Special Interest with a "reasonable possibility" of being related to 
study drug according to the investigator 
●
All deaths 
The same summaries will be repeated by restricting the analysis period of SAS-CREON-
ABT and SAS-CREON-SPL to 28 days after the first dose of CREON-ABT and CREON-
SPL, respectively.  For SAS-CREON-ABT, the analysis period will not include days on 
or after the first dose of SAS-CREON-SPL. 
The same summaries will also be repeated by using AE rates per 100 patient years of 
exposure, instead of number and percentage of AEs.  For this summary, the definitions of 
SAS-CREON-ABT and SAS-CREON-SPL in Section 10.2.1 will apply. 
10.2.3 
Treatment-Emergent Adverse Events by SOC and/or PT 
Treatment-emergent adverse events will be summarized by SOC and PT for the 
SAS-CREON-ABT and SAS-CREON-SPL; by maximum relationship to study drug as 


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assessed by the investigator (e.g., reasonable possibility or no reasonable possibility) and 
SOC and PT; by maximum severity and SOC and PT; and by subject number and SOC 
and PT.  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. 
If a subject has an AE with unknown severity or relationship to study drug, the subject 
will be counted in the severity/relationship level category of "unknown" even if the 
subject has another occurrence of the same AE with a known severity/relationship.  The 
only exception is if the subject has another occurrence of the same AE with the highest 
level of severity or a relationship assessment of "Reasonable possibility."  In this case, the 
subject will be counted under the most extreme severity/relationship category. 
In addition, treatment-emergent adverse events will be summarized by PT for the SAS-
CREON-ABT and SAS-CREON-SPL, sorted by decreasing frequency in SAS-CREON-
SPL  
10.2.4 
Treatment-Emergent Adverse Events per Patient-Years of 
Exposure 
Treatment-emergent adverse events will also be summarized by PT using AE rates per 
100 patient years for the SAS-CREON-ABT and SAS-CREON-SPL, sorted by decreasing 
rates in SAS-CREON-SPL.  AE rates per 100 patient-years of exposure are defined as the 
number of AEs divided by the total exposure in 100 patient-years.  Exposure period for 
CREON-ABT and CREON-SPL is the same as the reporting period for treatment-
emergent AE defined in Section 10.2.1.  Different occurrence of the same TEAE in a 
single subject will all be counted. 


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10.2.5 
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation 
SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and in listing format for SAS-CREON-ABT and SAS-
CREON-SPL. 
10.2.6 
Adverse Events of Special Interest 
Adverse events of special interest will be summarized by SOC and PT.  The following 
TEAEs compatible with clinical symptoms of EPI will be considered as Adverse Events 
of Special Interest (AESI)  for this study: 
●
Diarrhea 
●
Abdominal pain 
●
Abdominal bloating 
●
Flatulence 
●
Steatorrhea 
Detailed information about the search criteria is in Appendix B. 
Tabular listings of adverse events of special interest will be provided. 
10.3 
Analysis of Laboratory Data 
Laboratory data are not collected prospectively during the treatment period.  No 
laboratory analysis is planned. 
10.4 
Analysis of Vital Signs 
Vital sign data are not collected prospectively during the treatment period.  No vital sign 
analysis is planned. 
11.0 
Interim Analysis 
No formal interim analysis is planned. 


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11.1 
Data Monitoring Committee   
An external data monitoring committee (DMC) composed of persons independent of 
AbbVie and with relevant expertise in their field will review safety data from the ongoing 
study.  The primary responsibility of the DMC will be to protect the safety of the subjects 
participating in this study. 
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations. 
12.0 
Overall Type-I Error Control 
Since there are no efficacy analyses for early stopping planned for the DMC review, or 
formal statistical hypothesis testing, alpha spending is not applicable. 
There are pharmacodynamic endpoints analyzed descriptively.  Multiplicity adjustment is 
not planned for analyses. 
13.0 
Version History 
Table 2. 
SAP Version History Summary 
Version 
Date 
Summary 
1.0 
07 Dec 2021 
Original version 
2.0 
20 Jul 2023 
Major updates: 
1.
Section 9.4.2 - Sensitivity analysis for events of 
accidentally breaking blindness. 
2.
Section 10.2.1 - In the cases that an AE happens in a 
day that a subject takes both CREON-ABT and 
CREON-SPL, such AE will be counted under 
CREON-SPL.
14.0 
References 
1.
Johnson CD, Williamson N, Janssen-van Solingen G, et al.  Psychometric 
evaluation of a patient-reported outcome measure in pancreatic exocrine 
insufficiency (PEI).  Pancreatology.  2019;19(1):182-90. 


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Appendix A.
Protocol Deviations 
The number and percentage of subjects for each category in the collected data for protocol 
deviation will be summarized. 


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Appendix B.
Definition of Adverse Events of Special Interest 
Adverse Events of Special Interest (AESI) will be identified using the following search 
criteria: 
Adverse Event of Special 
Interest  
Preferred Terms 
Diarrhea 

Diarrhoea  

Diarrhoea haemorrhagic 

Diarrhoea infectious  

Defaecation urgency 

Frequent bowel movements  

Gastrointestinal hypermotility   

 Faecal volume increased 

Overflow diarrhoea 
Abdominal pain 

Abdominal discomfort 

Abdominal Pain  

Abdominal pain lower   

Abdominal pain upper   

Gastrointestinal pain 
Abdominal bloating 

Abdominal distension 

Gastrointestinal sounds abnormal 
Flatulence 

Flatulence 
Steatorrhea 

Faeces pale  

Faecal fat increased   

Faeces discoloured