Conditions: Cystic Fibrosis
Keywords: Cystic Fibrosis Creon Pancrelipase ABT-SLV-245 Exocrine Pancreatic Insufficiency (EPI)
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 36
Healthy volunteers: no

Brief summary:
Part 1 is a study to demonstrate that Creon (pancrelipase) delayed release (DR) capsules manufactured with a modernized process (MP) is non-inferior to currently marketed pancrelipase DR capsules in participants with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF), as measured by coefficient of fat absorption (CFA). Part 2 is a study to demonstrate that Creon (pancrelipase) manufactured with an alternate active pharmaceutical ingredient site (AAPIS) is non-inferior to currently marketed active control (Creon®) in participants with EPI due to CF, as measured by CFA. Safety is evaluated in each part.

Detailed description:

Arms:
arm 1: After receiving open-label currently marketed Creon delayed release (Creon DR) capsules during a pre-randomization period, participants receive double-blind Creon DR capsules manufactured by modernized process pellets (Creon MP) in treatment period 1, followed by double-blind Creon DR capsules in treatment period 2. Participants also receive open-label currently marketed Creon DR for an interval of up to 28 days between periods 1 and 2, and during a 30-day follow-up period after period 2. arm 2: After receiving open-label currently marketed Creon DR capsules during a pre-randomization period, participants receive double-blind Creon DR capsules in treatment period 1, followed by double-blind Creon MP in treatment period 2. Participants also receive open-label currently marketed Creon DR for an interval of up to 28 days between periods 1 and 2, and during a 30-day follow-up period after period 2. arm 3: After receiving open-label currently marketed Creon DR capsules during a pre-randomization period, participants receive double-blind Creon DR capsules manufactured at an alternate active pharmaceutical ingredient site (Creon AAPIS) in treatment period 1, followed by double-blind Creon DR capsules in treatment period 2. Participants also receive open-label currently marketed Creon DR for an interval of up to 28 days between periods 1 and 2, and during a 30-day follow-up period after period 2. arm 4: After receiving open-label currently marketed Creon DR capsules during a pre-randomization period, participants receive double-blind Creon DR capsules in treatment period 1, followed by double-blind Creon AAPIS in treatment period 2. Participants also receive open-label currently marketed Creon DR for an interval of up to 28 days between periods 1 and 2, and during a 30-day follow-up period after period 2.

Interventions: intervention 1: Pancrelipase intervention 2: Pancrelipase
Intervention descriptions: intervention 1: Delayed release capsules intervention 2: Delayed release capsules

Protocol document:
Prot_000.pdf: 


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M16-111 Protocol Amendment 7
EudraCT 2017-000578-12
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date 
Original
19 May 2017
Administrative Change 1
03 August 2017
Amendment 1
29 June 2018
Amendment 2
10 December 2018
Amendment 3
27 February 2019
Administrative Change 2
15 May 2019
Amendment 4
10 October 2019
Administrative Change 3
21 January 2020
Administrative Change 4
21 February 2020
Amendment 5
04 June 2020
Administrative Change 5
29 June 2020
Amendment 6
26 January 2021
The purpose of this amendment is to:
●
Updated throughout the protocol that General Medicine at AbbVie has 
changed to Specialty Development
Rationale:  To update the name of the Therapeutic Area for Creon studies.
●
Update Section 5.1, Overall Study Design and Plan:  Description:  Updated the 
target number of screened subjects to 30, enrolled subjects to 20 and evaluable 
subjects to 18 for Part 2. 
Rationale: To align with the updates from the Sample Size Determination in 
Section 8.2.2
●
Update Section 5.1, Overall Study Design and Plan:  Description:  Added 
language to clarify that open label study drug is given to subjects during the 
follow up period. 
Rationale: To add clarity
 


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EudraCT 2017-000578-12
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●
Update Section 5.5.1, Treatments Administered:  Description:  Added 
language to clarify that open label study drug is given to subjects during the 
follow up period. 
Rationale: To add clarity
●
Update Section 8.1.2, Primary and Secondary Endpoint Analyses: Added 
reference to the Statistical Analysis Plan (SAP) description of estimand 
attributes and supplementary analyses of primary endpoint.
Rationale: To add awareness
●
Update Section 8.2.2, Samples Size Determination:  Description:  Updated the 
target number of screened subjects to 30, enrolled subjects to 20 and evaluable 
subjects to 18 for Part 2, based on revised assumptions.
Rationale:  To update sample size determination for Part 2 based on revised 
assumptions (e.g., within-subject standard deviation of treatment difference) 
based on the results from the Part 1 Blinded Sample Size Re-estimation 
(BSSR).
●
Update Section 8.2.3, Blinded Sample Size Re-Estimation (BSSR):  
Description:  Updated initial planned sample size and revised within-subject 
standard deviation assumption for Part 2.  Provided rationale for revised 
assumption.
Rationale:  To align with updates from the Sample Size Determination in 
Section 8.2.2.
 


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M16-111 Protocol Amendment 7
EudraCT 2017-000578-12
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M16-111
Name of Study Drug:  Pancrelipase.
Phase of Development:  4 
Name of Active Ingredient:  
Pancrelipase
Date of Protocol Synopsis:  15 September 2021
Protocol Title:  
A Phase 4 Study to Compare US Marketed Creon® Drug Product with Drug Product Manufactured with 
a Modernized Process at an Alternate Manufacturing Site and with Drug Product manufactured with the 
Approved Manufacturing Process at an Alternate Active Pharmaceutical Ingredient Site, in Subjects with 
EPI due to Cystic Fibrosis
Objectives:  
The objective of Part 1 is to demonstrate non-inferiority of pancrelipase Delayed Release (DR) capsules 
Modernized Process (MP) 24,000 USP Units (lipase) drug product compared to the active control 
(pancrelipase DR capsules 24,000 USP Units (lipase) currently marketed in the US as Creon®) in 
subjects with Exocrine Pancreatic Insufficiency (EPI) due to Cystic Fibrosis (CF), as measured by 
Coefficient of Fat Absorption (CFA).
The objective of Part 2 is to demonstrate non-inferiority of delayed-release capsules of pancrelipase 
manufactured with the Approved Manufacturing Process at an Alternate Active Pharmaceutical 
Ingredient Site (AAPIS) 24,000 USP Units (lipase) compared to the active control (Creon®) in subjects 
with EPI due to CF, as measured by CFA.
Investigators:
Multi-center
Study Site(s):
Approximately 16 sites
Study Population:
Subjects aged 12 years or older with CF and EPI.
Number of Subjects to be Enrolled:
Part 1:  22 evaluable subjects (Approximately 26 subjects randomized)
Part 2:  18 evaluable subjects (Approximately 20 subjects randomized)
Subjects will participate in either part 1, part 2 or may choose to participate in both.
 


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Methodology:  
After eligibility is confirmed, the subject will be enrolled to one of the two Study Parts. For each Part, 
eligible subjects will be randomized into one of the two treatment sequences, as shown in the study 
schematic. Randomization for Part 1 and Part 2 are independent. After the completion of the 
participation in the Part they were originally enrolled to, the subjects may be offered the opportunity to 
participate in the other Part. This participation is optional. If the subject agrees to participate in the 
other Part, the subject will be kept on open label Creon® while eligibility to that Part is confirmed and 
the subject can initiate the next confinement period. Subjects who participate in the other Part of the 
study will be re-randomized in that Part.
Part 1 is designed to test pancrelipase DR MP for non-inferiority compared to an active control (Creon®) 
in a DB, randomized, active controlled, two-period, two-sequence crossover design in subjects 12 years 
or older with EPI due to CF, as measured by CFA.  Safety will also be assessed.
Part 2 is designed to test pancrelipase DR AAPIS for non-inferiority compared to an active control 
(Creon®) in a DB, randomized, active controlled, two-period, two-sequence crossover design in subjects 
of 12 years or older with EPI due to CF, as measured by CFA.  Safety will also be assessed.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:  
1.
Subject is 12 years or older at the time of informed consent/assent form signature.
2.
Subject has a documented diagnosis of CF previously confirmed by:
a.
a sweat chloride test ≥ 60 mmol/L, and/or 
b.
documented CF-causing CFTR mutations and clinical features of CF.*
3.
Diagnosis of moderate to severe EPI, as determined by Fecal Elastase 1 (FE-1) < 15 µg/g at 
screening.
4.
Subject has EPI that is currently clinically controlled (no clinically overt steatorrhea or diarrhea) 
under treatment with a commercially available Pancreatic Enzyme Replacement Therapy (PERT), 
on an individually established dose regimen for more than 3 months prior to Screening, with a daily 
dose not exceeding 4,000 LU/g fat/day or 10,000 LU/kg/day.
5.
Subject is available for two (if participating in one of the parts) or four (if participating in both parts) 
hospitalization/confinement periods of 6 to 8 days each during the expected study window.
6.
Subject is able to consume a diet with 100 g fat/day, a minimum of 1 g/kg of protein/day and normal 
to low fiber content.
 


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:  
1.
BMI percentile for age less than 10% in patients less than 18 years of age.
2.
Subject has a history of any of the following gastrointestinal disorders:
a.
acute pancreatitis within 6 months prior to SV1 or 
b.
chronic pancreatitis, or
c.
fibrosing colonopathy, or
d.
distal intestinal obstruction syndrome (DIOS) within 6 months prior to SV1, or
e.
C. difficile infection within 6 months prior to SV1, or
f.
celiac disease, or
g.
gastric bypass or partial/total gastrectomy, or
h.
Crohn's disease or other inflammatory bowel disease, or 
i.
small bowel surgery (other than minor resection due to meconium ileus without resultant 
malabsorption syndrome), or
j.
any type of malignancy involving the digestive tract in the last 5 years.
3.
Subject has a history of any clinically significant endocrine, respiratory (except mild asthma or CF-
related lung disease), neurological, cardiac, renal, hepatic (including Hepatitis B or C), hematologic 
or psychiatric disease or disorder, or any other uncontrolled medical illness which might limit 
participation in or completion of the study.
4.
Subject requires concomitant treatment with any medication not allowed by the protocol or a 
prohibited medication is expected to be needed during the study.
5.
Subject is currently receiving nutritional supplementation via tube feeding (nasogastric, 
gastrostomy, jejunostomy).
6.
Subject has clinically significant (as per Investigator's judgment) abnormalities in clinical chemistry, 
hematology, or urinalysis (excluding findings that are associated with CF) such as aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) levels ≥ 3 times the upper limit of 
normal values, or clinically significant (investigator opinion) elevation of uric acid.
Investigational Product(s):
For Part 1:

Pancrelipase DR capsules MP 24,000 USP Units (lipase)

Creon® [pancrelipase DR 24,000 USP Units (lipase)]
For Part 2:

Pancrelipase AAPIS 24,000 USP Units (lipase) 

Creon® [pancrelipase DR 24,000 USP Units (lipase)]
Dose(s):
The study drug total daily dose, calculated based on the maximum dose 
of 4,000 LU/g of fat/day, as recommended in the current US Creon®
capsules 24,000 USP units label, will be administered orally, divided 
proportionally based on three meals and two snacks.
Mode of Administration:
Oral
 


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Criteria for Evaluation:
Pharmacodynamics:
The primary pharmacodynamic variable will be the CFA which measures fat absorption.  Secondary 
pharmacodynamic variables will include the Coefficient of Nitrogen Analysis Absorption (CNA) 
(measuring protein absorption), stool fat content, and stool weight.  Additional exploratory variables will 
include stool frequency and consistency, diarrhea, abdominal pain, bloating and flatulence.
Safety:
The safety variables include:

Clinically significant physical examination findings and laboratory values

Proportion of subjects reporting treatment-emergent adverse events (TEAEs).
Statistical Methods:
Pharmacodynamics:
The primary pharmacodynamic variable will be the CFA.  The primary pharmacodynamic variable will 
be analyzed in all subjects who complete the 2 crossover treatment periods in the corresponding study 
Part.  The CFA measured at the end of each cross-over period will be analyzed using a mixed effects 
model including sequence, period and treatment group as fixed effects and subjects within sequence as a 
random effect.  From this model, the mean CFA difference between two treatment groups will be 
estimated, along with a two-sided 99% confidence interval (CI) that will be compared with a non-
inferiority margin of 12%.
The secondary pharmacodynamic variables will be the CNA, stool fat, and stool weight.  These variables 
will also be analyzed separately using a mixed effects model including sequence, period and treatment 
group as fixed effects and subjects within sequence as a random effect.  All comparisons for all 
secondary pharmacodynamic variables between the treatment groups will be descriptive.
Safety:
Safety analyses will be carried out using the safety population.  The safety population includes all 
subjects who received at least one dose of study drug at any time during the study.  Treatment-emergent 
AEs and SAEs, including pre- and post-treatment SAEs, will be summarized and reported.
Pharmacodynamic and safety analyses will be performed separately for Part 1 and Part 2.
*
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): S4-14.
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.
 


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
API
Active pharmaceutical ingredient
AAPIS
Delayed-release capsules of pancrelipase manufactured with the approved 
manufacturing process at an Alternate Active Pharmaceutical Ingredient Site
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BMI
Body Mass Index
CF
Cystic Fibrosis
CFA
Coefficient of Fat Absorption
CI
Confidence Interval
CNA
Coefficient of Nitrogen Absorption
Cork
AbbVie Fournier Laboratories, County Cork, Ireland
DB
Double-Blind
DIOS
Distal Intestinal Obstruction Syndrome
DR
Delayed-Release
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EPI
Exocrine Pancreatic Insufficiency
EudraCT
European Clinical Trials database
EU
European Union
FDA
US Food and Drug Administration
FD&C
US Food, Drug and Cosmetics
FE-1
Fecal Elastase-1
GCP
Good Clinical Practice
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
LU
Lipase Units
 


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MedDRA
Medical Dictionary for Regulatory Activities
MP
Modernized process uniform coated pellets manufactured in the large-scale suite
PERT
Pancreatic Enzyme Replacement Therapy
RSI
Reference Safety Information
SAE
Serious Adverse Events
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Drug Reaction
TA
Therapeutic Area
TEAE
Treatment Emergent Adverse Events
USPI
US Product Information
 


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Definition of Terms
Screening Period
Variable duration up to 35 days while confirming eligibility 
criteria.  During this period subjects will receive open label 
Creon® (Pancrelipase) 24,000 USP units (lipase) with every 
meal and snack until eligibility is confirmed and subject can 
be randomized.
Part 1 DB Treatment Periods 1 and 2
Periods during which subjects are taking study drug Creon®
(pancrelipase) Delayed Release capsules 24,000 USP Units 
(lipase) or pancrelipase Delayed Release capsules MP 
24,000 USP Units (lipase) every day at the time of 
meals/snacks.
Part 1 DB Treatment Period 1 starts at Visit 2 and ends at 
Visit 3 and is separated by an interval of up to 28 days from 
DB Treatment Period 2, which starts at Visit 4 and ends at 
Visit 5.
Part 2 DB Treatment Periods 1 and 2
Periods during which subjects are taking study drug Creon®
(pancrelipase) Delayed Release capsules 24,000 USP Units 
(lipase) or pancrelipase DR capsules manufactured with an 
Alternate Active Pharmaceutical Ingredient Site (AAPIS) 
24,000 USP Units (lipase) every day at the time of 
meals/snacks.
Part 2, DB Treatment Period 1 starts at Visit 2 and ends at 
Visit 3 and is separated by an interval of up to 28 days from 
DB Treatment Period 2, which starts at Visit 4 and ends at 
Visit 5.
Post-Treatment Follow-up Period for 
subjects participating in only one study 
Part (Part 1 or Part 2)
Interval between the last dose of study drug (Visit 5) and the 
safety follow-up telephone contact (Visit 6).  During this 
period subjects will receive open label Creon® (Pancrelipase) 
24,000 USP units (lipase).
 


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Post-Treatment Follow-up Periods for 
subjects participating in both study 
Parts (Part 1 and Part 2)
Interval between the last dose of study drug (Visit 5) of the 
study Part the subject was originally assigned to and Visit 6 of 
that Part, or Visit 1 of the next study Part, whichever comes 
first.  This period is variable in duration, and can last up to 30 
days.  During this period, subjects will receive open label 
Creon® (Pancrelipase) 24,000 USP units (lipase).  If visit 1 of 
the next Part does not occur within 30 days of the last dose of 
study drug (Visit 5) of the previous part, the subject will not 
receive any additional open label Creon® (Pancrelipase) 
24,000 USP units (lipase) past the provided for the first 30 
days, and the subject will need to be re-consented and 
rescreened for the next study part.
Once the subject has completed Visit 5 of the next study Part, 
the follow up period of that next Part is the interval between 
the last dose of study drug (Visit 5) and the safety follow-up 
telephone contact (Visit 6) and is 30 days.  During this period 
subjects will receive open label Creon® (Pancrelipase) 
24,000 USP units (lipase).
 


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................4
1.3
List of Abbreviations and Definition of Terms..........................................8
2.0
Table of Contents...................................................................12
3.0
Introduction ...........................................................................16
3.1
Differences Statement..............................................................................17
3.2
Benefits and Risks....................................................................................17
4.0
Study Objective......................................................................18
5.0
Investigational Plan...............................................................18
5.1
Overall Study Design and Plan:  Description ..........................................18
5.2
Selection of Study Population..................................................................27
5.2.1
Inclusion Criteria .....................................................................................28
5.2.2
Exclusion Criteria ....................................................................................30
5.2.3
Prior and Concomitant Therapy...............................................................32
5.2.3.1
Prior and Inter Treatment Interval PERT Therapy ..................................32
5.2.3.2
Concomitant Therapy...............................................................................32
5.2.3.3
Prohibited Therapy...................................................................................34
5.2.4
Contraception Recommendations and Pregnancy Testing.......................35
5.3
Pharmacodynamic and Safety Assessments/Variables............................36
5.3.1
Pharmacodynamic and Safety Measurements Assessed and Flow 
Chart.........................................................................................................36
5.3.1.1
Study Procedures .....................................................................................36
5.3.2
Drug Concentration Measurements .........................................................49
5.3.3
Pharmacodynamic Variables....................................................................49
5.3.3.1
Primary Variable......................................................................................49
5.3.3.2
Secondary Variables ................................................................................49
5.3.3.3
Additional Exploratory Variables ............................................................50
5.3.4
Safety Variables.......................................................................................50
5.4
Removal of Subjects from Therapy or Assessment.................................50
5.4.1
Discontinuation of Individual Subjects....................................................51
 


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5.4.2
Discontinuation of Entire Study...............................................................53
5.5
Treatments................................................................................................53
5.5.1
Treatments Administered.........................................................................53
5.5.2
Identity of Investigational Products.........................................................55
5.5.2.1
Packaging and Labeling...........................................................................59
5.5.2.2
Storage and Disposition of Study Drugs..................................................59
5.5.2.3
Preparation of Dosage Form ....................................................................60
5.5.3
Method of Assigning Subjects to Treatment Groups...............................60
5.5.4
Selection and Timing of Dose for Each Subject......................................61
5.5.5
Blinding....................................................................................................61
5.5.5.1
Blinding of Data for Independent Data Monitoring Committee 
(IDMC) ....................................................................................................62
5.5.6
Treatment Compliance.............................................................................62
5.5.7
Drug Accountability.................................................................................63
5.6
Discussion and Justification of Study Design..........................................64
5.6.1
Discussion of Study Design and Choice of Control Groups....................64
5.6.2
Appropriateness of Measurements...........................................................65
5.6.3
Suitability of Subject Population .............................................................65
5.6.4
Selection of Doses in the Study ...............................................................66
5.6.5
Assessments for COVID-19 Infection.....................................................66
6.0
Complaints .............................................................................67
6.1
Medical Complaints.................................................................................67
6.1.1
Definitions................................................................................................68
6.1.1.1
Adverse Event..........................................................................................68
6.1.1.2
Serious Adverse Events ...........................................................................69
6.1.2
Adverse Event Severity............................................................................70
6.1.3
Relationship to Study Drug......................................................................70
6.1.4
Adverse Event Collection Period.............................................................71
6.1.5
Adverse Event Reporting.........................................................................72
6.1.6
Pregnancy.................................................................................................74
6.1.7
Management of COVID-19 Infection......................................................74
6.2
Product Complaint ...................................................................................75
6.2.1
Definition .................................................................................................75
 


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6.2.2
Reporting..................................................................................................75
7.0
Protocol Deviations................................................................76
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................77
8.1
Statistical and Analytical Plans................................................................77
8.1.1
Definition for Analysis Populations.........................................................77
8.1.2
Primary and Secondary Endpoint Analyses.............................................78
8.1.3
Safety Analysis ........................................................................................79
8.2
Determination of Sample Size .................................................................79
8.2.1
Non-inferiority Margin Justification........................................................79
8.2.2
Sample Size Determination......................................................................80
8.2.3
Blinded Sample Size Re-Estimation (BSSR) ..........................................81
8.3
Study Data Reporting...............................................................................82
8.4
Randomization Methods ..........................................................................82
9.0
Ethics.......................................................................................83
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) .............................................................................................83
9.2
Ethical Conduct of the Study...................................................................84
9.3
Subject Information and Consent.............................................................84
10.0
Source Documents and Case Report Form 
Completion .............................................................................85
10.1
Source Documents ...................................................................................85
10.2
Case Report Forms...................................................................................85
11.0
Data Quality Assurance ........................................................87
12.0
Use of Information.................................................................89
13.0
Completion of the Study .......................................................90
14.0
Investigator's Agreement......................................................91
15.0
Reference List ........................................................................92
List of Tables
Table 1.
Clinical Laboratory Tests.........................................................................41
Table 2.
Identity of Investigational Product...........................................................56
 


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Table 3.
Study Power for Non-Inferiority in Primary Endpoint of CFA...............81
List of Figures
Figure 1.
Study Schematic.......................................................................................19
Figure 2.
Adverse Event Collection for each Study Part.........................................72
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ............................................93
Appendix B.
List of Protocol Signatories......................................................................95
Appendix C.
Study Activities........................................................................................96
 


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3.0
Introduction
Pancreatic enzyme replacement therapy (PERT) is the cornerstone of nutritional 
management of exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF), 
chronic pancreatitis (CP), partial or complete pancreatectomy (PY) or other conditions.  
Without pancreatic enzyme replacement, the patients may suffer from severe symptoms of 
maldigestion and malabsorption.
PERT is critical to achieve optimal growth in patients with EPI due to CF and resulting 
maldigestion.  In patients with CF, abnormally thick mucus blocks the pancreatic duct in 
the pancreas.  The pancreatic digestive enzymes from acinar cells and bicarbonate from 
ductal cells are not secreted into the intestine, thus preventing the normal digestion of 
starch, fat and protein.  This results in steatorrhea, abdominal pain, flatulence, changes in 
bowel habits and often, failure to thrive.
Pancrelipase Delayed-Release (DR) capsules is a PERT currently marketed in United 
States as Creon® for the treatment of EPI due to CF, CP, PY and other conditions.  
AbbVie has modernized the current drug product process for manufacturing the enteric 
coated drug product into uniform coated pancrelipase pellets at a new manufacturing site 
in Cork, Ireland.  Part 1 of this study is being conducted to determine whether the 
modernized process (MP) uniform coated pellets formulation from the large-scale suite 
[pancrelipase DR capsules MP 24,000 USP Units (lipase)] manufactured at the Cork 
facility results in similar clinical pharmacodynamics and safety as the current US 
marketed Creon®, and is thus appropriate to be administered for the same indication and 
patient populations as Creon®.
In order to protect CREON's supply chain through site and geographic diversity, AbbVie 
invested in new equipment and facility expansion to duplicate the approved Abbott 
Neustadt Active Pharmaceutical Ingredient (API) process used to manufacture Creon® 
currently marketed in the US, to manufacture pancrelipase DR capsules at an Alternate
Active Pharmaceutical Ingredient Site (AAPIS) in Waunakee, Wisconsin (Scientific 
Protein Laboratories, SPL).  The approved source countries of the starting material for the 
 


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manufacture of pancrelipase is the same for both manufacturing sites.  Part 2 of this study 
is being conducted to determine whether AAPIS 24,000 USP Units (lipase) results in 
similar clinical pharmacodynamics and safety as the current US marketed Creon®, and is 
thus appropriate to be administered for the same indication and patient populations as 
Creon®.
Information on Creon®, the MP formulation and the AAPIS formulation can be found in 
Section 5.5.2.  Further information on pancrelipase DR currently marketed as Creon® in 
the US can be found in the US Product Information (USPI).
The dose of study drug selected in each Part of this study is based on ~4,000 lipase units 
(LU) per gram fat/day, corresponding to the maximum dose of Creon® in CF patients as 
per current US label, and according to the upper limit of the US Cystic Fibrosis 
Consensus Committee.1,2  Each subject will consume a predetermined study diet that 
contains 100 g fat/day and a minimum of 1 g/kg protein/day, under the supervision of a 
registered dietitian.  The study drug dose will be individualized to this diet for each 
subject.
3.1
Differences Statement
Unlike typical efficacy and safety studies previously conducted with Creon®, which 
demonstrated superiority to placebo, this study aims to determine whether the drug 
products tested in each Part [pancrelipase DR capsules MP 24,000 USP Units (lipase) for 
Part 1 or pancrelipase AAPIS 24,000 USP Units (lipase) for Part 2] are non-inferior to the 
current US marketed drug product (Creon®) as measured by the coefficient of fat 
absorption (CFA).
3.2
Benefits and Risks
All subjects randomized in this study will receive treatment for EPI during the study at a 
safe and effective dose.  This is the primary benefit to subjects for this study.  Risks of 
study participation include those currently listed in the USPI for Creon®, and are not 
 


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expected to be different for the pancrelipase DR capsules MP 24,000 USP Units (lipase) 
or Pancrelipase AAPIS 24,000 USP Units (lipase) drug products.
4.0
Study Objective
The objective of Part 1 is to demonstrate non-inferiority of pancrelipase DR capsules MP 
24,000 USP Units (lipase) drug product compared to the active control [pancrelipase DR 
capsules 24,000 USP Units (lipase) currently marketed in the US as Creon®] in subjects 
with EPI due to CF, as measured by CFA.
The objective of Part 2 is to demonstrate non-inferiority of delayed-release capsules of 
pancrelipase AAPIS 24,000 USP Units (lipase) compared to an active control 
[pancrelipase DR capsules 24,000 USP Units (lipase) currently marketed in the US as 
Creon®] in subjects with EPI due to CF, as measured by CFA.
Safety will also be evaluated.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
For study Part 1, the target number of evaluable subjects is 22, with a screening of 
approximately 36 subjects and enrollment/randomization of approximately 26 subjects to 
meet scientific and regulatory objectives without enrolling an undue number of subjects, 
in alignment with ethical considerations.  Therefore, if the target number of evaluable 
subjects in Part 1 (22) has completed the study, there is a possibility that additional 
subjects in screening will not be enrolled in that Part.  
For study Part 2, the target number of evaluable subjects is 18, with a screening of 
approximately 30 subjects and enrollment/randomization of approximately 20 subjects to 
meet scientific and regulatory objectives without enrolling an undue number of subjects, 
in alignment with ethical considerations.  Therefore, if the target number of evaluable 
subjects in Part 2 (18) has completed the study, there is a possibility that additional 
subjects in screening will not be enrolled in that Part.  
 


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The study will be conducted in the US.  See Figure 1.
Figure 1.
Study Schematic
OL = Open Label DB; = Double-Blind; R = Randomization
Pancrelipase DR MP = Pancrelipase Delayed Release Modernized Process capsules 24,000 USP Units (lipase); 
Pancrelipase AAPIS = delayed-release capsules of pancrelipase manufactured at an Alternate Active Pharmaceutical 
Ingredient Site; Creon® (pancrelipase) = Us approved and marketed Creon® (pancrelipase) Delayed Release capsules 
24,000 USP Units (lipase)
*
Subjects who participate in both Part 1 and Part 2 may not need to repeat screening.
**
For subjects who participate in both Part 1 and Part 2, the follow up period of the first Part will end at Visit 6 of the 
current Part or the day before Visit 1 of the next study Part, whichever comes first.
Note:
First blue dye marker administered bedtime of study confinement Day 2 and stools collection starts once 
subject passes first blue dye marker. Second blue dye marker administered on study confinement Day 5 and 
stool collection continues until the appearance of the next blue dyed stool and stool collection will then stop.
Enrollment in the DB Treatment Period of study Part 1 will continue until at least 
22 subjects are evaluable for the analysis of coefficient of fat absorption (CFA).
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


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Enrollment in the DB Treatment Period of study Part 2 will continue until at least 
18 subjects are evaluable for the analysis of coefficient of fat absorption (CFA).
After eligibility is confirmed, the subject will be enrolled to one of the two Study Parts.  
For each Part, eligible subjects will be randomized into one of the two treatment 
sequences, as shown in the study schematic. Randomization for Part 1 and Part 2 are 
independent.  After the completion of the participation in the Part they were originally 
enrolled, the subject may be offered to participate in the other Part.  This participation is 
optional.  If the subject agrees to participate in the other Part and has completed consent to 
do so, the subject will be kept on OL Creon®, for a period of up to 30 days, while 
eligibility to that Part is confirmed and the subject can initiate the next confinement 
period.  If visit 1 of the next Part does not occur within 30 days of the last dose of study 
drug (Visit 5) of the previous part, the subject will not receive any additional open label 
Creon® (Pancrelipase) 24,000 USP units (lipase) past the amount provided for the first 30 
days, and the subject will need to be re-consented/rescreened for the next study part.  
Subjects who participate in the other Part of the study will be re-randomized in that Part.
Subjects who have already completed Part 1 at the time of implementation of this 
amendment will need to re-consent and rescreen (except for FE-1) for participation in 
Part 2.
Pharmacodynamic and safety analyses will be performed separately for Part 1 and Part 2.
An external data monitoring committee (DMC) composed of persons independent of 
AbbVie and with relevant expertise in their field will review unblinded 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 will be prepared outside of the protocol and will describe the 
roles and responsibilities of the DMC members, frequency of data reviews, relevant safety 
data to be assessed, and expectations for blinded communications.
 


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Methodology:
Part 1 is designed to test pancrelipase DR MP for non-inferiority compared to Creon® in a 
DB, randomized, active-controlled, two-period, two-sequence crossover design in subjects 
of 12 years or older with EPI due to CF, as measured by CFA.  Safety will also be 
assessed.
Part 2 is designed to test pancrelipase AAPIS for non-inferiority compared to Creon® in a 
DB, randomized, active-controlled, two-period, two-sequence crossover design in subjects 
of 12 years or older with EPI due to CF, as measured by CFA.  Safety will also be 
assessed.
Pancrelipase DR 24,000 USP Units (Lipase) capsules, commercially available in US as 
Creon®, will be administered as double-blind drug as the active control for the study and 
will be administered as open-label drug at the screening visit and will be taken by the 
subject until the subject randomizes into the study.  Open-label Creon® will also be given 
during the interval between treatment Periods 1 and 2 of each Part and during the follow-
up period.
Screening Period (35 Days Maximum)
At the Screening Visit (Visit 1) and during the screening period, subjects will be evaluated 
for eligibility to enter the DB Treatment Period.  Written informed consent will be signed 
before any study-related procedures are performed.  Written consent will need to be 
signed by a parent and/or guardian for minor subjects.  Written assent for minor study 
participants will also need to be signed where indicated by local requirements.
A stool sample for FE-1 testing will be obtained during the screening period to check for 
subject eligibility.  A pre-screening consent may also be obtained from the subject prior to 
the screening visit so a stool sample can be collected and brought to the study site at the 
Screening Visit.  If a sample cannot be provided at the Screening Visit, the subject will be 
given a FE-1 testing kit and will be given instructions to return the sample during the 
screening period as soon as possible.
 


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After completing the Screening Visit, while waiting on FE-1 results to confirm eligibility, 
subjects will receive open label Creon® at their usual pre-study PERT dose (lipase units) 
to be taken during the screening period.  Subjects who decide to participate in both Study 
Parts and have been consented to do so and it has been ≤ 30 days since the subject 
completed Visit 5 of the previous Part will not need to repeat all screening procedures for 
the second study Part.  Eligibility should be re-confirmed at the start of the next study 
Part; however, subjects do not need to repeat the FE-1 or serum pregnancy (if applicable) 
tests.  Urine pregnancy tests still need to be performed as per Appendix C.  Subjects who 
participate in both Parts can complete the Screening Visit (Visit 1) to re-confirm 
eligibility and Visit 2 on the same day.
Subjects who decide to participate in both Study Parts and have been consented to do so 
and it has been > 30 days since the subject completed Visit 5 of the previous Part will 
need to repeat screening procedures (except FE-1, which does not need to be repeated) 
and should complete the Screening Visit as a separate visit.
Site to discuss/consult with AbbVie in regards to the planned confinement location in the 
study prior to screening their first subject or if there is any change in confinement location 
during the study.
Rescreening
Subjects who have FE-1 > 15 µg/g at Screening or female subjects of childbearing 
potential who have a positive serum pregnancy test at screening are not eligible to 
rescreen or retest.  Subjects who screen-failed for other reasons may be re-screened (only 
once per study part) within 6 months of when they were originally screened. Subjects 
must sign a new ICF and be rescreened for all eligibility criteria (except for an eligible 
FE-1 value, which does not need to be repeated), not just those that were exclusionary.  
The investigators are encouraged to consult with the AbbVie TA MD when considering 
rescreening subjects.
 


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For subjects do not meet the study eligibility criteria upon retest/rescreen, the site 
personnel must contact the Interactive Response System (IRT) and identify the subject as 
a screen failure.
Subjects who screen-fail due to COVID-19 infection (as per Inclusion Criteria 10 and 
Exclusion Criteria 12, Section 5.2.1) may only rescreen if the following criteria are met:

If the subject had symptomatic infection:  At least 2 consecutive negative 
COVID-19 tests, ≥ 24 hours apart after at least 7 days have passed since 
recovery, defined as resolution of fever without use of antipyretics and
improvement in respiratory symptoms (e.g., cough, shortness of breath).

If the subject had asymptomatic infection:  At least two negative COVID-19 
tests in a row, ≥24 hours apart after at least 7 days have passed since prior 
positive test result.
Please see Section 5.3.1.1 for directions on retesting/rescreening after a positive 
COVID-19 test.
Re-screened subjects will sign a new ICF and all Screening Visit procedures (except 
FE-1) have to be repeated.
Double-Blind Treatment Period for Study Part 1 and/or Study Part 2
Once study eligibility has been confirmed, subjects will be enrolled into the DB 
Treatment Period of either Part 1 or Part 2. After they complete the Part they were 
initially enrolled in, the subject may elect to participate in the other Part.
DB Treatment Period 1 (Visit 2 to Visit 3)
Eligible subjects will be admitted to the clinical site or designated confinement location, 
in the morning (prior to breakfast) of Visit 2 or in the evening (after dinner) on the 
previous day and will be hospitalized/confined at the clinical site or designated 
confinement location for approximately 6 to 8 days, depending on each subject's 
gastrointestinal motility.
 


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At Visit 2 (DB Treatment Period 1 Day 1), subjects will be allocated into Study Part 1 or 
Part 2 and randomized in a 1:1 ratio to 1 of the 2 treatment sequence arms within their 
study Part, as shown below:
Part 1:
Sequence Arm
Treatment Period 1
Treatment Period 2
A
Pancrelipase DR capsules MP
Creon® (Pancrelipase) DR
B
Creon® (Pancrelipase) DR capsules
Pancrelipase DR capsules MP
DR = Delayed release; MP = Modernized Process uniform coated pellets, large scale
Part 2:
Sequence Arm
Treatment Period 1
Treatment Period 2
C
Pancrelipase DR capsules AAPIS
Creon® (Pancrelipase) DR capsules
D
Creon® (Pancrelipase) DR capsules
Pancrelipase DR capsules AAPIS
AAPIS = Delayed-release capsules of pancrelipase manufactured at an Alternate Active Pharmaceutical Ingredient Site; 
DR = Delayed release
Before any study drug administration on DB Treatment Period 2 Day 1 (Visit 4), the 
subject's weight will be confirmed to be 40 kg or more.  Then subjects will stop their open 
label Creon® treatment and will receive DB treatment with study drug and an 
individualized diet with 100 grams daily fat content, a minimum of 1 g/kg of daily protein 
and normal to low fiber content for 6 – 8 days.  They will consume the specified diet with 
pre-specified fat and protein content during all DB treatment periods, although the actual 
foods consumed may differ.  Each subject's diet for the two treatment periods of each 
study Part (if applicable) will be created at the same time by a site-based dietitian using 
ABVDiet, (see Section 5.3.1.1 Diet Plan Design) after an interview with the subject, and 
reviewed and approved by a central dietitian, prior to Visit 2.
During the hospitalization/confinement, dietary surveillance and stool collection will be 
accurately performed to allow for the evaluation of CFA and CNA.  Subjects must adhere 
to the individualized study meal plan.  Therefore, no food or drink outside of the 
 


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prescribed diet will be allowed.  Site personnel will encourage subjects to eat all of the 
food served at each meal or snack.
The stool collection period will be demarcated with a stool marker consisting of 
2 capsules of 250 mg of food dye (coloring according to FDA Food, Drug and Cosmetics 
– FD&C Blue No. 2/European E132). 
After the last food intake on hospitalization/confinement Day 2 (bedtime), the first blue 
dye marker (2 capsules) will be administered orally, and food intake recording will begin 
with hospitalization/confinement Day 3 breakfast.  After subjects pass the first blue dye 
marker, all bowel movements (excluding the first blue dyed stool) will be collected. 
After the last food intake on hospitalization/confinement Day 5 (bedtime), the second blue 
dye marker (2 capsules) will be administered, and dietary recording will be stopped 
(Day 5 last food intake will be included in the dietary recording).  Stool collection will 
continue until the appearance of the next blue dyed stool.  The last collected stool will be 
the first blue dyed stool after the second blue dye marker administration.  Depending on 
each subject's gastrointestinal motility, the stool collection period may be longer than 
72 hours.  
Subject will stop DB treatment and will be discharged from the clinical site or designated 
confinement location, (or begin preparation for DB Treatment Period 2) after the first blue 
dyed stool following the second dye administration is collected (Visit 3).  This could be 
hospitalization/confinement Day 6, 7 or 8, depending on each subject's gastrointestinal 
motility.  
If subject chooses to leave the clinical site or designated confinement location after DB 
Treatment Period 1, subject will re-start his/her usual diet and will be given a supply of 
open label Creon® at the dose of open label Creon® they received for the screening period 
to be taken during this period, until returning to the clinical site or designated confinement 
location, for DB Treatment Period 2.  The interval between DB Treatment Period 1 and 
DB Treatment Period 2 will last up to a maximum of 28 days:  In exceptional 
 


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circumstances, such as impact by COVID-19-related activities, this period may be 
extended upon specific consultation with the sponsor.  If the subject elects to continue 
directly into DB Treatment Period 2, and site capacity allows, Visit 4 will be the day 
following Visit 3.
DB Treatment Period 2 (Visit 4 to Visit 5)
Subject will again be hospitalized/confined (or continue to be hospitalized/confined) at the 
clinical site or designated confinement location, for approximately 6 to 8 days, starting in 
the morning (prior to breakfast) of Visit 4 or in the evening (after dinner) on the previous 
day. 
Before any study drug administration on DB Treatment Period 2 Day 1 (Visit 4), subject's 
weight will be confirmed to be 40 kg or more.  Then subjects will stop current open label 
Creon® (if receiving it) and will receive DB study drug and an individualized diet with 
100 grams daily fat content, a minimum of 1 g/kg of daily protein and normal to low fiber 
content for 6 - 8 days.  Each subject's diet for the two treatment periods will be created at 
the same time by a site-based dietitian using ABVDiet, after an interview with the subject, 
and reviewed and approved by a central dietitian, prior to Visit 2.  Dietary surveillance 
and stool collection will be performed as during DB Treatment Period 1.  
Subjects will stop DB treatment and will be discharged from the clinical site or designated 
confinement location, after the first blue dyed stool following the second dye 
administration is collected (Visit 5).  This could occur at hospitalization/confinement 
Day 6, 7 or 8, depending on each subject's gastrointestinal motility.  
Subjects who withdraw during any Part of the study will immediately enter the Post-
Treatment Follow-Up Period, and will undergo early discontinuation activities as 
specified in Appendix C, Visit 5.
After completing the Part to which the subject was originally enrolled, the subjects may 
be given the opportunity to participate in the other Study Part.  If the subject agrees to 
participate in the other study Part, he/she will re-start his/her usual diet and will be given a 
 


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supply of open label Creon®, at the dose they received during the screening period, to be 
taken during this period of up to 30 days, while eligibility for the other Part is re-assessed.  
The subject will then return to the clinical site or designated confinement location for 
randomization into the other Study Part.  If visit 1 of the next Part does not occur within 
30 days of the last dose of study drug (Visit 5) of the previous part, the subject will not 
receive any additional open label Creon® (Pancrelipase) 24,000 USP units (lipase) past 
the amount provided for the first 30 days, and the subject will need to be re-
consented/rescreened for the next study part.
Post-Treatment Follow-Up Period (Visit 5 to Visit 6)
During the follow-up period for both study parts, subjects will be given at Visit 5 a supply 
of open label Creon® at the dose they received during the screening period to be taken 
during this period, along with their usual diet.
A safety follow-up telephone contact (Visit 6) will be performed 30 days after discharge 
upon completion of DB Treatment Period 2 (or following study withdrawal) to verify the 
subject's well-being and to assess for AEs and changes in concomitant medication use. If 
a subject is participating in both study Parts and they are starting the second study Part 
≤30 days following completion of DB Treatment Period 2 of the previous Part, Visit 6 
can be completed on the same day as the start of the next study Part.
Study completion for each subject is defined as the date of the follow-up telephone 
contact (Visit 6) for the last Part the subject participated in.  The maximum duration of 
study participation is approximately 109 days for each subject participating in one study 
Part only and approximately 183 days for each subject participating in both study parts.
5.2
Selection of Study Population
Male and female subjects aged 12 years or older, who meet all of the inclusion criteria and 
none of the exclusion criteria, will be eligible for enrollment into the DB Treatment 
Periods of the study.  
 


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Each Investigator will employ his/her clinical judgment in conjunction with protocol 
specified inclusion/exclusion criteria to determine if subject meets eligibility.  Questions 
should be directed to the AbbVie Therapeutic Area (TA) MD listed on the Title Page and 
in Section 6.1.5 if further clarification is required.
5.2.1
Inclusion Criteria
A subject will be eligible for randomization if he/she meets ALL of the following criteria:
1.
Subject has voluntarily signed and dated an informed consent form (ICF) 
approved by an Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB), prior to any study specific procedures.  For subjects aged less than 18 
years, the subject has provided voluntary assent and the subject's legal 
representative has voluntarily signed and dated an ICF, approved by an IEC/IRB, 
prior to screening and all study related procedures.  If indicated by local 
requirements, written assent will also need to be signed.
2.
Subject is 12 years or older at the time of informed consent/assent form signature.
3.
Subject has a documented diagnosis of CF previously confirmed by:
a.
a sweat chloride test ≥ 60 mmol/L, and/or 
b. documented CF-causing CFTR mutations and clinical features of CF.3,4
4.
Diagnosis of moderate to severe EPI, as determined by Fecal Elastase 1 (FE-1) 
< 15 µg/g at screening.
5.
Subject has EPI that is currently clinically controlled (no clinically overt 
steatorrhea or diarrhea) under treatment with a commercially available PERT, on 
an individually established dose regimen for more than 3 months prior to 
Screening, with a daily dose not exceeding 4,000 LU/g fat/day or 
10,000 LU/kg/day. 
6.
Subject is available for two (if participating in one of the Parts) or four (if 
participating in both Parts) hospitalization/confinement periods of 6 to 8 days 
each.
 


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7.
Subject is able to consume a diet with 100 g of fat/day, a minimum of 1 g/kg of 
protein/day and normal to low fiber content.
8.
If female, subject must be either postmenopausal, defined as:
●
Age > 55 years with no menses for 12 or more months without an alternative 
medical cause.
●
Age ≤ 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L.
OR
●
Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
OR
●
For females of childbearing potential, practicing at least one protocol specified 
method of birth control (Section 5.2.4).
9.
Females of childbearing potential must have a negative serum pregnancy test 
result at Screening, and a negative urine pregnancy test at Study Day 1 of Visit 2.
Females of non-childbearing potential (either postmenopausal or permanently 
surgically sterile as defined in Section 5.2.4) at Screening do not require 
pregnancy testing.
10.
Subjects must have a negative viral test (e.g., PCR, antigen) for COVID-19 done 
within 7 days before V2.
11.
At Screening (Visit 1) and Visit 2, before dosing, subject weight is 40 Kg or more.
Rationale for Inclusion Criteria:
1
In accordance with harmonised Good Clinical Practices (GCP)
2 – 7
To select the adequate subject population with appropriate disease 
severity for the evaluation of the study drug
8, 9, 10
For the safety of the study subjects
 


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5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets ANY of the following 
criteria:
1.
BMI percentile for age less than 10% in patients less than 18 years of age.
2.
Subject has a history of any of the following gastrointestinal disorders:
a.
acute pancreatitis within 6 months prior to SV1, or 
b. chronic pancreatitis, or
c.
fibrosing colonopathy, or
d. distal intestinal obstruction syndrome (DIOS) within 6 months prior to SV1, or
e.
C. difficile infection within 6 months prior to SV1, or
f.
celiac disease, or
g. gastric bypass or partial/total gastrectomy, or
h. Crohn's disease or other inflammatory bowel disease, or 
i.
small bowel surgery (other than minor resection due to meconium ileus without 
resultant malabsorption syndrome), or
j.
any type of malignancy involving the digestive tract in the last 5 years.
3.
Subject has a history of any clinically significant endocrine, respiratory (except 
mild asthma or CF-related lung disease), neurological, cardiac, renal, hepatic 
(including Hepatitis B or C), hematologic or psychiatric disease or disorder, or any 
other uncontrolled medical illness which might limit participation in or completion 
of the study.
4.
Subject requires concomitant treatment with any medication not allowed by the 
protocol or a prohibited medication is expected to be needed during the study.
5.
Subject is currently receiving nutritional supplementation via tube feeding 
(nasogastric, gastrostomy, jejunostomy).
 


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6.
Subject has clinically significant (as per Investigator's judgment) abnormalities in 
clinical chemistry, hematology, or urinalysis (excluding findings that are 
associated with CF) such as aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) levels ≥ 3 times the upper limit of normal values, or 
clinically significant (investigator opinion) elevation of uric acid.
7.
Subject is currently participating in any other interventional clinical study or has 
taken any experimental drug (other than for this study) within 30 days prior to 
Screening.
8.
Subject has a known hypersensitivity and/or contraindication to pancrelipase (also 
named pancreatin) of any source or inactive ingredients (excipients) of study 
drugs, or to Federal Food, Drug, and Cosmetic (FD & C) Blue No. 2/European 
E132 dye marker.
9.
Subject has experienced problems or lack of efficacy with prior Creon® treatment.
10.
Female subject who is pregnant, breastfeeding or is considering becoming 
pregnant during the study or for approximately 7 days after the last dose of study 
drug.
11.
Subject presents any other factor/condition which, in the opinion of the 
investigator, would pose a significant risk for the subject, invalidate the informed 
consent process or interfere with the ability of the subject to comply with study
requirements or interfere otherwise with the conduct of the study. 
12.
Subject has signs or symptoms associated with COVID-19 infection at V2.
Rationale for Exclusion Criteria:
1, 2, 3, 4, 8, 9, 10, 
11, 12
To ensure safety of the subjects throughout the study
3, 5, 6, 7
To avoid bias for the evaluation of non-inferiority by concomitant 
diseases or conditions
8
To avoid bias for the evaluation of non-inferiority by previous use
 


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5.2.3
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 along with the specific reason for use 
(e.g., bronchodilators for CF-related lung disease, vitamin supplements for CF-related 
hypovitaminosis), date(s) of administration including start and end dates, and dosage 
information including dose, route and frequency.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapy(ies).
5.2.3.1
Prior and Inter Treatment Interval PERT Therapy
The daily dose of PERT taken prior to the Screening Visit will be recorded in the eCRF.
The daily dose of Open Label Creon® taken during the Screening Period (Visit 1 to Visit 
2) will be recorded in the eCRF.
The daily dose of Open Label Creon® taken during the interval between Visit 3 and 
Visit 4 will be recorded in the eCRF.
The daily dose of Open Label Creon® taken during the Follow up Period (Visit 5 to 
Visit 6) will be recorded in the eCRF.
5.2.3.2
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) taken by the subject during their study participation 
(from signing the ICF [Visit 1] through follow-up call [Visit 6]) is to be recorded on the 
Concomitant Medication form of the eCRF, except for the study drug(s).  Subjects who 
are taking concomitant medications should have corresponding entries in the Medical 
History and/or Adverse Event forms of the eCRF to document the need for the 
 


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medications.  Reason for use for concomitant medications should be as specific as 
possible, e.g., bronchodilators used for chronic bronchitis or bronchiectasis, not CF.
Any intake of enzyme preparations in addition or in substitution to the study drug, starting
at screening (Visit 1) and throughout the completion of both DB Treatment Periods (of all 
the Parts the subject agrees to participate in), is not allowed and will lead to the exclusion 
of the subject from the study.
The following concomitant medications or nutritional supplements CAN BE GIVEN
during the Screening Period, the study drug treatment periods and the interval between 
study Parts (if applicable) under specified circumstances:
●
Concomitant medications influencing duodenal pH 
○
H2-receptor antagonists
○
Antacids containing only bicarbonate (examples:  Alka Seltzer, Alkaligen, 
Bicarbonato de Sosa TM, Bicarbonato Sod Agadrian, Bicarbonato Sod 
Cinfa, Bicarbonato Sod Grifols, Bicarbonato Sod Serra, Bicarbonato Sod 
Viviar, Bicarbonato Sodico Braun, Bicarbonato Sodico Mein, Hospal, 
Justegas, Natrium bicarbonicum Polpharma, Natrium-Hydrogen-
Carbonicum Pharmamagist, Natrium-Hydrogen-Carbonicum 
Pharmamagist 8.4%, Natrium-Hydrogenkarbonat Braun, sodium 
bicarbonate, Venofusin Bicarb Sodico)
○
Sucralfate
○
Proton-pump-inhibitors
○
Prostaglandins
○
Somatostatin
○
Anticholinergic agents. 
●
Drugs acting on gastric emptying (e.g., metoclopramide or erythromycin).
●
Prebiotic or probiotic drugs.
●
Immunosuppressive steroids (local or systemic).
●
Osmotic laxatives (e.g., Miralax).
 


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●
Flax seeds or chia seeds taken for nutritional supplementation or bowel 
regularity.
The specified circumstances are:
●
The medication is commercially available and is prescribed according to the 
recommended dose range. 
●
The medication has been taken by the subject for more than 4 weeks before 
start of the study in the prescribed dose and is planned to be kept at a stable 
dose during the conduct of the study.
●
Any nutritional supplements are accounted for in the subject Diet Plan.
5.2.3.3
Prohibited Therapy
Medications prohibited during the DB Treatment Periods are:
●
fat or protein containing nutritional supplements (e.g., Ensure, Glucerna, 
protein shakes), unless they are accounted for in the study Diet Plan, 
●
narcotic analgesics, 
●
antidiarrheals, antispasmodics, non-osmotic laxatives, 
●
antacids containing aluminum (US)/aluminium (EU), magnesium or calcium 
carbonate, 
●
oral fiber supplements (e.g., Psyllium plantago, Metamucil),
●
immunosuppressive drugs (not including steroids).
●
Tube feeding
The use of prohibited therapies during the DB Treatment Periods will lead to the 
exclusion of the subject from the study.
Note: These medications are NOT prohibited during the Screening Period, during the 
interval between Treatment Periods 1 and 2 or during the interval between Parts (if 
applicable), if the subjects leave the clinical site or designated confinement location.
 


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5.2.4
Contraception Recommendations and Pregnancy Testing 
If female, subject must be either postmenopausal or permanently surgically sterile (refer 
to inclusion criteria for definitions of both) OR a Women of Childbearing Potential, 
practicing at least one of the following methods of birth control, on Study Day 1 (or 
earlier) through at least 30 days after the last dose of study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to screening.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to 
screening.
●
Progestogen-only oral hormonal contraception, where inhibition of ovulation 
is not the primary mode of action, initiated at least 1 month prior to screening.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.
●
Vasectomized partner(s), provided that the vasectomized partner verbally 
confirms receipt of medical assessment of the surgical success, and is the sole 
sexual partner of the female of childbearing potential trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
Male or female condom with or without spermicide.
●
Cap, diaphragm or sponge with spermicide.
●
A combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier method).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].
●
Male subjects who are sexually active with a woman of childbearing potential 
are not required to use contraception methods during the study.
 


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5.3
Pharmacodynamic and Safety Assessments/Variables
The primary pharmacodynamic variable will be the CFA which measures fat absorption.  
Secondary pharmacodynamic variables will include the CNA (measuring protein 
absorption), stool fat content, stool weight.  Additional exploratory pharmacodynamic 
variables include assessment of EPI symptoms.
The safety variables assessed will include clinically significant physical examination 
findings, laboratory values and AE's.
5.3.1
Pharmacodynamic and Safety Measurements Assessed and 
Flow Chart
Study procedures, with the exception of treatment compliance monitoring (Section 5.5.6), 
collection of concomitant medication (Section 5.2.3.2) and AE information collection 
(Section 6.1), are listed in the following section of this protocol and are summarized in 
tabular format in Appendix C.
5.3.1.1
Study Procedures
Informed Consent
At the Screening Visit, signed informed consent (and subject's assent as applicable) will 
be obtained from the subject before beginning any study-specific procedure.  A pre-
screening consent may also be obtained from the subject prior to the screening visit so a 
stool sample can be collected and brought to the study site at the Screening Visit.  Details 
on how informed consent/assent will be obtained and documented are provided in 
Section 9.3.
Subjects who have signed informed consent/assent and do not complete the study-specific 
procedures during the Screening Period will be considered screen failures.  The reason(s) 
for screen failure will be documented in the source documents and will be captured in the 
eCRF.
 


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Medical History
A complete medical history, including documentation of any clinically significant medical 
conditions and medications (including history of tobacco, nicotine-containing products 
and alcohol use) will be collected during the Screening Visit of the first part the subject is 
participating in.  The Medical History form of the eCRF must contain all 
diseases/conditions for which the subject is taking concomitant medications.
For subjects who are participating in more than 1 study Part, the medical history will be 
reviewed at the screening visit for the next part the subject is participating in and updated 
for any new information available.
Pancreatic Enzyme Replacement Therapy (PERT)
Under the direction of their usual treating physician, at the screening visit subjects will 
start receiving open label Creon® at their usual established dose until all eligibility criteria 
are confirmed and the subject randomized, or until the subject is screen-failed.
For subjects who enter DB Treatment Period 2 directly from DB Treatment Period 1 
(without leaving the hospital/confinement site):  during the 24 h period until Treatment 
Period 2 can be started, subjects will be maintained at their usual diet and will be 
administered open label Creon® at the dose they received during the screening period.  
This daily dose of open label Creon® should be recorded in the eCRF.
For subjects who do not enter DB Treatment Period 2 directly from DB Treatment 
Period 1 (i.e., leave the hospital/confinement site):  if a subject chooses to leave the 
clinical site or designated confinement location after DB Treatment Period 1, the subject 
will re-start his/her usual diet and will be given a supply of Creon® at the dose they 
received for the screening period to be taken until returning to the clinical site or 
designated confinement location for DB Treatment Period 2.  The daily dose of open label 
Creon® will be recorded in the eCRF.
 


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Subjects participating in both Parts and who decide to enter the second study Part directly 
after the first Part will be given a supply of open label Creon® at the dose they received 
during the screening period to be taken during this time, along with their usual diet, for 
24 hours.  The dose of open label for these 24 hours should be recorded in the eCRF.
Subjects participating in both Parts and who choose to leave the clinical site or designated 
confinement area after completion of the Part they were originally enrolled will re-start 
his/her usual diet and will be given a supply of Creon® at the dose they received for the 
screening period to be taken until returning to the clinical site or designated confinement 
location, for DB Treatment Period 1 of the other study Part they are participating in.  The 
dose of open label Creon® will be recorded in the eCRF.
During the follow up period Subjects will be given a supply of open label Creon® at the 
dose they received during the screening period to be taken during this time, along with 
their usual diet.
Physical Examination
A physical examination will be performed at the Screening Visit after the ICF is signed.  
A physical examination update will be performed at Visit 2, Visit 3, Visit 4 (unless 
subject has directly entered DB Treatment Period 2 from DB Treatment Period 1, in 
which case the physical examination at Visit 3 will suffice for this requirement at Visit 4) 
and a complete final physical examination will be performed at Visit 5.  Subjects 
participating in both Parts and who decide to enter the second study Part directly after the 
first Part will not need a physical examination done at Visit 1 of the next study Part they 
are participating in, as long as it has been < 30 days between Visit 5 and Visit 1 of the 
next study part. The physical examination at Visit 5 of the previous study Part will 
suffice for this requirement at Visit 1 of the next study Part.
The physical examination at Visit 2 of each Part will serve as the baseline physical 
examination for that Part of the study.
 


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Height
Height will be measured at the Screening Visit only, with the subjects not wearing shoes.
Body Weight and BMI 
Body weight will be measured, with the subjects in light weight clothing without shoes, at 
the Screening Visit, on Day 1 of the 2 study drug treatment periods for each study Part 
and at Visit 3 and 5 preferably using the same calibrated weighing scale at all visits.  The 
body weight should be assessed in the morning prior to any food intake and to any blood 
sampling.
The body weight measured at Visit 2 of each Part will serve as the baseline measurement
for clinical assessment during DB Treatment Periods 1 and 2 for that study Part.
The BMI will be calculated as follows:  body weight (kg)/height2 (m).
Vital Signs
Vital sign determinations of sitting blood pressure, heart rate and body temperature will 
be obtained at the Screening Visit, Visit 2, Visit 3, Visit 4 and Visit 5 for each study Part.
The blood pressure and heart rate measurements should be taken prior to scheduled blood 
collections.  Body temperature measurements should be assessed using the same modality 
consistently throughout the study, e.g., oral, aural, axillary, etc., and the modality will be 
reported in the source documentation and eCRF.
The vital signs measurements prior to dosing on Visit 2 of each Part will serve as the 
baseline measurements for clinical assessment during DB Treatment Periods 1 and 2 for 
that study Part.
 


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Pregnancy Testing
For females of childbearing potential, a serum pregnancy test will be performed at the 
Screening Visit and a urine pregnancy test will be performed by designated study site 
personnel at Visit 2 and at Visit 4 (only if subject has not continued confinement from 
Visit 3), for each study Part.
Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile as defined in Section 5.2.4) at Screening do not require pregnancy testing.
Subjects with a positive pregnancy test at the Screening Visit or at Visit 2 or Visit 4 for 
either study Part may not continue participation in the study and must be discontinued.
Subjects who completed the study Part they were originally enrolled in and agree to 
participate in the other study Part and it has been ≤30 days since Visit 5 of the first Part 
they participated in will not need to repeat the serum pregnancy test, but will still need to 
perform the urine pregnancy test as required in Appendix C.
Clinical Laboratory Tests
Samples will be obtained for the laboratory tests listed in Table 1 at the Screening Visit 
and at Visit 2, Visit 3, Visit, 4 (except if ≤ 24 hours post Visit 3) and Visit 5 (ref to 
Appendix C) for each study Part.
Subjects participating in both Parts and who decide to enter the second study Part directly 
after the first Part will not need Clinical Laboratory tests done at Visit 1 of the next study 
Part they are participating in, as long as it has been < 30 days between Visit 5 and Visit 1 
of the next study part. The Clinical Laboratory tests done at Visit 5 of the previous study 
Part will suffice for this requirement at Visit 1 of the next study Part.
Blood draws will be performed after (or at least 30 minutes prior to) vital sign 
measurements during a visit. 
 


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The clinical chemistry should be preferably performed following a fast of a minimum of 
8 hours except at the Screening Visit which may be performed in the non-fasting state.  
Fasting conditions will be reported in the eCRF.
A central laboratory contracted by AbbVie will be utilized for the clinical laboratory tests.  
Instructions regarding the collection requirements, processing, and shipping of these 
samples will be provided by the central laboratory.  
Table 1.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not
acceptable)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Albumin
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acid
Cholesterol
Total protein
Glucose
Triglycerides
Bicarbonate/CO2
Chloride
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Other Tests
COVID-19
The laboratory results will be provided by the central laboratory to the investigative site 
where they will be reviewed, signed, and dated by the Investigator.  For any value outside 
of the reference range, the investigator will indicate on the report if the result is clinically 
significant (CS) or not clinically significant (NCS).  The Investigator will receive Sponsor 
defined laboratory alerts from the central lab.  The Investigator will review the laboratory 
alerts and assess clinical significance for potential AEs.
All screening laboratory results must be reviewed prior to Visit 2.
 


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Covid-19 Testing
COVID-19 tests will be performed locally prior to each confinement period to confirm 
whether or not the subject has known COVID-19 infection.  If a site does not have access 
to testing locally, or if the turn-around-time of the local test is greater that the central 
laboratory, the central laboratory can be used.  The site will also have the option to have 
the tests collected at the subject's home by a qualified home health nurse.
Initiation of Confinement Periods
Subjects must have a negative viral test (e.g., PCR, antigen) for COVID-19, from a test 
done within 7 days prior to each Confinement period (V2 and V4).  The test can be 
performed locally or via central laboratory, considering availability and whichever may 
provide faster turnaround time, as well as no signs or symptoms associated with COVID-
19 infection.
If a subject has confirmed or suspected COVID-19 infection between confinement 
periods, the subject can only enter the next confinement period if the following criteria are 
met prior to the next dose scheduled confinement:
For symptomatic subjects:
●
At least two consecutive COVID-19 tests, ≥ 24 hours apart after at least 7 days 
have passed since recovery, defined as resolution of fever without use of 
antipyretics and improvement in respiratory symptoms (e.g., cough, shortness 
of breath)
For asymptomatic subjects:
●
At least two negative COVID-19 tests in a row, ≥ 24 hours apart after at least 
7 days have passed since prior positive test results
Subjects who enter DB Treatment Period 2 less than 7 days at the end of DB Treatment 
Period 1 do not need to perform a COVID-19 test unless otherwise directed by the 
 


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investigator.  Subjects must have no signs or symptoms associated with COVID-19 
infection at Day 1 of DB Treatment Period 2.
Subjects participating in both study Parts do not need to perform a COVID-19 test to 
begin Treatment Period 1 of the other Part (unless directed by the investigator) if they:
●
do not leave the confinement location following completion of the Part they 
were originally enrolled into and decide to enter the other study Part directly 
following the original Part, or;
●
enter DB Treatment Period 1 of the other Part within 7 days after the end of 
DB Treatment Period 2 of the Part they were originally enrolled into.
Diet Plan Design
A prospective individualized diet plan that will meet the subject's calorie and protein 
requirements will be designed by a clinical site dietitian for the screening confinement 
period and each of the treatment periods in consultation with each subject before V2 and 
will include food items which the subject prefers so that compliance with the consumption 
requirements is met.
The diet plan must be designed ensuring:
●
a total protein intake of a minimum of 1 g/kg/day;
●
a normal to low fiber content;
●
a total daily fat intake of 100 grams.
The fat intake should be distributed proportionally across:
○
3 meals with 25 grams fat per meal (± 3 grams is acceptable, if needed), 
and
○
2 snacks with 12.5 grams fat per snack (± 2 grams is acceptable, if needed),
The subject's individualized diet plan will be implemented by the clinical site dietitian 
during each of the 2 treatment periods for each study Part (beginning at Visit 2 and 
 


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restarting at Visit 4, if subject is discharged between the two DB treatment periods), only 
after review and approval by the central dietitian.
The individualized diet plan should be similar for each of the two treatment periods for 
each study Part with the same daily amount of fat and protein, and the same fat 
distribution across meals and snacks.
A web-based dietary program (ABVDiet) has been developed by AbbVie to track 
nutrition information of foods and beverages, diet plans and subject food consumption.  
ABVDiet will be utilized by the site dietitians to design and implement the diet plan for 
each study subject prior to each confinement period.  ABVDiet is designed to send 
automatic email alerts to the designated individuals and to streamline diet plan approvals 
by the central dietitian, and will also record the amount of food not consumed during 
meals and snacks.  
Assignment of Subject Number and Randomization
The site will access the Interactive Response Technology (IRT) system at the Screening 
Visit to obtain a 4-digit subject number once the subject has signed the informed consent.  
Consecutive and unique subject numbers will be assigned.  The same 4-digit subject 
number will be used to identify the subject throughout Screening, DB Treatment Periods 1 
and 2 for all study Parts (if a subject is participating in both Parts) and the Post-Treatment 
Follow-Up Period.  If the subject is not enrolled into the study, the reason for screen 
failure will be documented in the eCRF and the site will access the IRT system to register 
the subject as a screen failure.
All inclusion/exclusion criteria must be reviewed prior to the hospitalization/confinement 
at Visit 2 for each study Part.  For subjects entering the DB treatment periods, subjects 
who meet all of the eligibility criteria will be enrolled to one of the study Parts and 
randomized to one of the 2 treatment sequence arms on Day 1 of DB Treatment Period 1 
(Visit 2) of the enrolled study Part by accessing the IRT system and providing the 4-digit 
subject number assigned at the Screening Visit (Visit 1).
 


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During the randomization contact at Visit 2 for each study Part the subject is being 
enrolled to, a 5-digit randomization number (only used within the system for treatment 
assignment) and a 6-digit study drug kit number will be assigned by the IRT system for 
DB Treatment Period 1 of the enrolled Part according to a randomization schedule 
generated by the statistics department at AbbVie (see Section 5.5.3).  At Visit 4, the site 
will access the IRT system to obtain the 6-digit study drug kit number allocated for DB 
Treatment Period 2 of that study Part.  Randomization for study Part 1 and Part 2 are 
independent.
In the event study drug becomes lost or damaged, or if additional drug is needed, the site 
can access the IRT system to obtain an unscheduled re-supply of study drug kit numbers 
to dispense.  Sites will also register the Post-Treatment Follow-Up Visit (Visit 6).
Diet Administration and Dietary Records
For each study Part the diet will be administered from each confinement period Day 1 
(Visit 2 and Visit 4) until the last stool has been collected (Visit 3 and Visit 5) during each 
of the 2 confinement periods (or 4 confinement periods for subjects participating in both 
Parts).  The subjects must be encouraged to eat all food provided and will not be allowed 
to eat anything in addition to the 3 meals and 2 snacks provided within the diet plan.  Fat 
or protein containing nutritional supplements (e.g., nutritional shakes, fish oil 
supplements, omega fatty acids) not included in the diet plan are not allowed to be taken.  
If the study diet does not provide sufficient food to prevent hunger, a third snack may be 
consumed by the subject and the sites will be provided with a list of examples of low-
calorie, low-fat foods that subjects may consume.  The calories and nutrients from these 
foods will not need to be included in the diet plan.  The fat content of this additional snack 
should be ≤ 2 grams/serving and the protein content should be ≤4 grams/serving.
During all study confinement periods, subjects will be actively monitored by site 
personnel for compliance with the diet consumption requirements.  Subjects must be 
encouraged and instructed to consume all food provided as per the planned diet during 
hospitalization/confinement with specific reference to Days 3, 4 and 5.
 


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ABVDiet is designed to calculate the consumed amounts of fat, protein and calories.  The 
proportion of food provided in the diet that is consumed each day on Day 3 (starting from 
first food intake), Day 4 and Day 5 (ending with last food intake) will be determined and 
recorded in ABVDiet by specifically assigned site personnel.  Non-consumed meals, 
snacks and any other deviations to the diet requirements will be determined and will be 
recorded similarly in ABVDiet.  The preferred method to quantify the amount of uneaten 
food is by weight or volume, as appropriate for the individual solid or liquid food, 
respectively.  Thus, food selections in meals/snacks should be of a type which can be 
easily measured.  The same calibrated food scale should be used for weighing the 
subjects' meals/uneaten food.  The total daily fat and protein intake will be determined 
from the quantity of food actually consumed and will be recorded in the eCRF.
In the event that not all food in the planned diet is consumed on Days 3, 4 and 5, non-
compliance will exist when either of the following occur:
●
the subject consumes less than 80% of the planned fat consumption, or
●
the difference in fat consumption in the two treatment periods is more than 
10% based on the lower amount consumed.
Human Fecal Elastase
A stool sample for fecal elastase testing will be collected as a pre-screening activity or 
during the screening period and will be evaluated in spot stool sample in a specialty lab 
contracted by AbbVie (monoclonal antibody test).  Instructions regarding the collection 
requirements, processing, and shipping of these samples will be provided by the central 
laboratory.  Results of Fecal Elastase will be electronically transferred from the central 
laboratory to the study database using validated software.
Stool Collection
Stool collection will be performed during each of the treatment periods (see Appendix C) 
for both study Parts.  In order to ensure accurate collection of stool samples corresponding 
 


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to a known food intake, each subject will be administered stool dye markers orally on 
two occasions, separated by 72 hours, in order to mark the beginning and end of the stool 
collection period.
AbbVie will supply stool dye markers (250 mg capsules of encapsulated FD&C Blue 
No. 2/E132) packaged in high density polyethylene (HDPE) bottles.  Each bottle will 
contain 50 capsules, will be labeled per local requirements and must be stored at 
controlled room temperature (15° to 25°C or 59° to 77°F).  
For each study Part the subjects will be hospitalized/confined on Day 1 of each treatment 
period (Visit 2 and Visit 4) until the stool collection is completed (Treatment Period 
Day 6, 7 or 8).  The stool dye markers will be administered as follows:
●
the 1st stool dye marker (2 capsules) will be administered after the last food 
intake on the hospitalization/confinement Day 2 (bedtime); subjects will not be 
allowed to eat anything after the stool dye marker intake until breakfast on the 
hospitalization/confinement Day 3;
○
If a subject does not excrete the first blue dyed stool by 
hospitalization/confinement Day 5 following the 1st stool dye marker 
intake on Day 2, the subject will not be administered the second stool dye 
marker and will be discontinued from the study.
●
the 2nd stool dye marker (2 capsules) will be administered after the last food 
intake on the hospitalization/confinement Day 5 (bedtime); subjects will not be 
allowed to eat anything after the stool dye marker intake until breakfast on the 
hospitalization/confinement Day 6.  
○
If a subject does not excrete the second blue dyed stool by 
hospitalization/confinement Day 8, following the 2nd stool dye marker 
intake on Day 5, the subject will be discontinued from the study. 
During the confinement periods, subjects will be actively monitored by site personnel for 
compliance with the stool collection requirements, including reporting stool excretion data 
in the stool collection log.
 


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The subjects will be given appropriate containers for stool collection.  Stool collection 
will begin after appearance of the first stool dye marker, excluding the 1st blue dyed stool, 
and end with the first stool sample containing the 2nd stool dye marker, including the blue 
dyed stool.  Each stool will be collected in a separate container.  Instructions regarding the 
collection, processing and shipping of the stool samples will be provided by the central 
laboratory.  
Food intake will be recorded by clinical site personnel on Day 3 (from first food intake), 
Day 4 and Day 5 (ending with last food intake).  Although the timing of the stool 
collection in this protocol is noted as being 72 hours, individual subjects may experience 
different durations depending on their intestinal transit time. 
Results of stool analyses during the DB Treatment Periods will be electronically 
transferred from the central laboratory to the study database using validated software.
The stools collected during the stool collection periods will be analyzed by a specialty lab 
contracted by AbbVie for the following:
●
Stool Weight.
Total stool weight will be determined from the net weight of the stool samples 
collected. 
●
Stool Fat Content.
Stools will be analyzed by a central laboratory for fat according to the method 
of Van de Kamer5 to allow for the CFA determination. 
●
Stool Nitrogen Content.
Stools will be analyzed by a central laboratory for nitrogen according to the 
Kjeldahl6 method to allow for the CNA determination.*
*
Stool nitrogen content will not be measured for the screening confinement period.
 


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Patient EPI Symptom Diary
A paper EPI symptoms diary, which will collect information on stool frequency, stool 
consistency, diarrhea, abdominal pain, bloating and flatulence, will be provided to all 
subjects to complete on each day during each of the confinement periods.  The EPI 
symptom diary should be completed before the subject receives the first study drug dose, 
prior to breakfast on each day.  The clinical site personnel should remind subjects to 
complete the diary as instructed.
5.3.2
Drug Concentration Measurements
Since pancrelipase is not absorbed from the intestine, there will be no drug concentration 
measurements in this study.
5.3.3
Pharmacodynamic Variables
5.3.3.1
Primary Variable
The primary pharmacodynamic variable is the CFA measured at the end of each 
confinement period.
The CFA is calculated as 100•[fat intake – fat excretion]/fat intake.
Fat intake will be determined from fat content of food consumed.  Fat excretion will be 
determined from the fat content in the stool(s) collected between the two dye markers.
5.3.3.2
Secondary Variables
The secondary pharmacodynamic variables include:
●
CNA, measured at the end of each treatment period.
○
The CNA is calculated as 100•[nitrogen intake – nitrogen 
excretion]/nitrogen intake.
○
Nitrogen intake will be determined from protein content of food consumed.  
Based on the assumption that all proteins are polypeptide chains with a 
 


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mass containing 16% nitrogen on average, calculated protein intake is to be 
converted into nitrogen intake by multiplying the grams of protein ingested 
by 0.16.  Nitrogen excretion will be determined from the nitrogen content 
in the stool(s) collected between the two dye markers.
●
Stool fat.
●
Stool weight.
5.3.3.3
Additional Exploratory Variables
Additional exploratory pharmacodynamic variables include:
●
Stool frequency
●
Stool consistency
●
Diarrhea
●
Abdominal pain
●
Bloating
●
Flatulence
5.3.4
Safety Variables
The safety variables include: 
●
Clinically significant physical examination findings or laboratory values
●
Proportion of subjects reporting treatment-emergent adverse events (TEAEs).
5.4
Removal of Subjects from Therapy or Assessment
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator may discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason, including the occurrence of an AE or 
noncompliance with the protocol.  In the event that a subject withdraws or is discontinued 
 


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from the study, the primary reason for discontinuation and any other reason(s) for the 
discontinuation from the study will be recorded according to the following definitions:
●
AE:  discontinuation due to any AE with a corresponding entry reflected on the 
Adverse Events form in the eCRF.
●
Lack of pharmacodynamic effect:  subject fails to respond to the study drug at 
an acceptable level where the subject or the Investigator feels it is in the best 
interests of the subject to seek another treatment.
●
Lost to follow-up:  the subject fails to return to the study site for scheduled 
visits and does not respond to telephone or written attempts to contact.
●
Withdrew consent: subject decides to stop his/her participation in the study for 
any reason or is unable to complete the study as described in the clinical study 
protocol (e.g., subject is relocating to another location).
●
Other
5.4.1
Discontinuation of Individual Subjects
For each study Part, a subject may voluntarily withdraw or be withdrawn at any time for 
reasons including, but not limited to, the following:
●
The subject requests to be withdrawn from the study.
●
Any intake of enzyme preparations in addition or substitution to the study drug 
during the study.
●
The subject does not excrete the first blue dyed stool by 
hospitalization/confinement Day 5, following the 1st blue dye marker intake on 
Day 2.
●
The subject does not excrete the second blue dyed stool by 
hospitalization/confinement Day 8, following the 2nd blue dye marker intake 
on Day 5.
●
The subject does not consume study drug as specified in Treatment 
Compliance, Section 5.5.6.
●
The subject does not consume the study specific diet as specified in Diet 
Administration and Diet Records, Section 5.3.1.1.
 


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●
Introduction of prohibited therapies during any confinement period.
●
When continuation of the study drug would place the subject at risk as 
determined by the Investigator.
●
Subjects who become pregnant during the study must be discontinued 
(Section 5.3.1.1).
For subjects discontinued from one of the study Parts, the PI must assess if the reason for 
discontinuation does not preclude the subject from adhering to the procedures on the next 
study Part before offering the subject participation in the other Part.  Also, the PI is 
encouraged to consult with the AbbVie Therapeutic Area MD before enrolling the subject 
in the next Part.
Compliance with stool collection is also important, as missing even 1 stool collection can 
invalidate the results for the CFA endpoint.  Subjects will be considered compliant only if 
all specified stools (100%) of each confinement period are collected (see Section 5.3.1.1
for specifics of stool collection requirements).  Subjects who do not have 100% stool 
collection compliance during any confinement period will be excluded and will not be 
able to begin the subsequent confinement period within that Part.
In the event that a subject withdraws or is prematurely discontinued before completion of 
the DB Treatment Period 2 for the study Part they are participating in, he/she must have a 
final evaluation according to the procedures required at Visit 5 as well as a safety follow-
up call 30 days after the last study drug intake.  The investigator should schedule blood 
samples with the subject before premature withdrawal or within the week following the 
premature withdrawal.  The results of these evaluations and observations, and a clear 
reason for the subject's withdrawal, must be recorded in the eCRF. 
If a subject is discontinued from the study with an ongoing AE, the investigator will
attempt to follow up until a satisfactory resolution of the AE is achieved or the subject 
returns to a stable state medically, or the database is locked.
 


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5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or its Parts, or at any 
study site, for reasonable cause, provided that written notice is submitted in advance of 
the intended termination.  The investigator may also terminate the study at his/her site for 
reasonable cause, after providing written notice to AbbVie in advance of the intended 
termination to allow for transfer of care of enrolled subjects.  Advance notice is not 
required by either party if the study is stopped due to safety concerns.  If the investigator 
terminates the study at a site for safety reasons, the investigator must notify the AbbVie 
monitor immediately (within 24 hours), who will then notify the study team.  The AbbVie 
monitor will notify the site in writing of any instructions from the study team for study 
termination.  If AbbVie terminates the study for safety reasons, the AbbVie monitor will 
immediately notify the investigator by telephone and subsequently provide written 
instructions for study termination.
5.5
Treatments
Study drug will only be shipped to clinical sites which have provided the Sponsor (or an 
authorized representative) with all required study documents, including IEC/IRB 
approval, and have signed a clinical study agreement.
5.5.1
Treatments Administered
On completion of the screening visit the subject will be given a 30 day supply of open 
label Creon® at their usual pre-study daily dose (lipase units) of PERT to be taken until 
the subject comes back for Treatment Period 1 (if considered eligible).  In exceptional 
circumstances, such as impact by COVID-19-related activities, this period may be 
extended by an additional 30 days upon specific consultation with the sponsor.  Once 
results have been received and if it is deemed that a subject is not eligible, they will not 
receive any more open label Creon® and will be considered a screen failure.
For Part 1 of the study, study drug, consisting of Pancrelipase delayed release capsules 
MP 24,000 USP Units (Lipase) or Creon® (Pancrelipase) delayed release capsules 
 


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24,000 USP Units (Lipase) blinded capsules (same size, color and appearance), will be 
administered during DB Treatment Period 1 (Visit 2 to Visit 3) and DB Treatment 
Period 2 (Visit 4 to Visit 5) by the clinical site personnel at the time of each meal/snack as 
follows, depending on the treatment sequence arm the subject will be randomized to, as 
shown below:
Sequence Arm
Treatment Period 1
Treatment Period 2
A
Pancrelipase DR capsules MP
Creon® (Pancrelipase) DR capsules
B
Creon® (Pancrelipase) DR capsules 
Pancrelipase DR capsules MP
DR = Delayed release; MP = Modernized Process uniform coated pellets, large scale
For Part 2 of the study, study drug, consisting of Pancrelipase DR capsules AAPIS, 
24,000 USP Units (Lipase) or Creon® (Pancrelipase) delayed release capsules 24,000 USP 
Units (Lipase) blinded capsules (same size, color and appearance), will be administered 
during DB Treatment Period 1 (Visit 2 to Visit 3) and DB Treatment Period 2 (Visit 4 to 
Visit 5) by the clinical site personnel at the time of each meal/snack as follows, depending 
on the treatment sequence arm the subject will be randomized to, as shown below:
Sequence Arm
Treatment Period 1
Treatment Period 2
C
Pancrelipase DR capsules AAPIS
Creon® (Pancrelipase) DR capsules 
D
Creon® (Pancrelipase) DR capsules 
Pancrelipase DR capsules AAPIS
AAPIS = Delayed-release capsules of pancrelipase manufactured at an Alternate Active Pharmaceutical Ingredient Site; 
DR = Delayed release
For each study Part the 2 DB treatment periods will be separated by a maximum of 
28 days, unless the subject elects to directly enter DB Treatment Period 2 from DB 
Treatment Period 1.  In exceptional circumstances, such as impact by COVID-19-related 
activities, this period may be extended upon specific consultation with the sponsor.
At the end of DB Treatment Period 1 (between Visit 3 and Visit 4), the subjects will be 
given a 30 day supply of open label Creon® at the dose they received for the screening 
period to be taken during this period.  In exceptional circumstances, such as impact by 
COVID-19-related activities, this period may be extended by an additional 30 days upon 
 


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specific consultation with the sponsor.  If the subject elects to directly enter DB Treatment 
Period 2, the duration between Visit 3 and Visit 4 will be ≤ 24 hours.
During the follow up period for both study parts, subjects will be given, at Visit 5, a 
supply of open label Creon® at the dose they received during the screening period to be 
taken during this period, along with their usual diet.
The study drug total daily dose, calculated based on the maximum dose of 4,000 LU/g of 
fat/day, as recommended in the current Creon® (Pancrelipase) delayed release capsules 
24,000 USP Units (Lipase) label, will be administered orally, divided proportionally 
based on three meals and two snacks as follows:
Study diet 
g fat/day
# Capsules/ 
Meal
# Capsules/ 
Snack
Total # 
Capsules/Day
LU/Meal
LU/Snack
Total Daily 
Dose
100
4
2
16
96,000
48,000
384,000
For each of the treatment periods, the study drug intake will start on Treatment Period 
Day 1 at breakfast and will continue with each meal/snack until the last stool has been 
collected.  Individual subjects may experience different treatment durations due to the fact 
the stool collection period depends on their intestinal transit time. 
The study drug capsules must be swallowed intact (capsules must not be crushed, chewed 
or opened), and will be taken during the meal or snack (as per patient's usual practice), 
with enough fluids to swallow the capsules completely.
All scheduled doses must be taken.  Subjects must be encouraged and instructed to 
consume all food provided as per the individualized diet during 
hospitalization/confinement.
5.5.2
Identity of Investigational Products
Information about the study drug formulations used in this study is presented in Table 2.
 


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Table 2.
Identity of Investigational Product
Study Part(s)
Part 1
Part 1
Part 2
Part 2
Parts 1 and 2
Parts 1 and 2
Investigational Product 
Name
DB Creon®
(Pancrelipase 
orange/orange 
capsules)
DB Pancrelipase 
MP
DB Creon®
(pancrelipase 
clear/orange 
capsules)
DB Pancrelipase 
AAPIS
FD&C Blue No. 2 
(E132)
OL Creon®
(Pancrelipase)
API 
Manufacturing site
Abbott Neustadt, 
Germany
Abbott Neustadt, 
Germany
Abbott Neustadt, 
Germany
Scientific Protein 
Laboratories, USA
Neelikon, India
Abbott Neustadt, 
Germany
Drug product 
Manufacturing sitea
Abbott Neustadt, 
Germany
AbbVie Cork,
Ireland
Abbott Neustadt, 
Germany
Abbott Neustadt, 
Germany
Almac Group LTD,
United Kingdom
Abbott Neustadt, 
Germany
Type of Blinding
Double-blindb
Double-blindb
Double-blind
Double-blind
Open-label
Open-label
Active ingredient
Pancrelipase a 
mixture of lipase 
(LP), protease and 
amylase of porcine 
origin
Pancrelipase a 
mixture of lipase 
(LP), protease and 
amylase of porcine 
origin
Pancrelipase a 
mixture of lipase 
(LP), protease and 
amylase of porcine 
origin
Pancrelipase a 
mixture of lipase 
(LP), protease and 
amylase of porcine 
origin
FD&C Blue No. 2
(E132)
Pancrelipase a 
mixture of lipase 
(LP), protease and 
amylase of porcine 
origin
Mode/route of 
administration
Oral
Oral
Oral
Oral
Oral
Oral
 


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Table 2.
Identity of Investigational Product (Continued)
Study Part(s)
Part 1
Part 1
Part 2
Part 2
Parts 1 and 2
Parts 1 and 2
Investigational Product 
Name
DB Creon®
(Pancrelipase 
orange/orange 
capsules)
DB Pancrelipase 
MP
DB Creon®
(pancrelipase 
clear/orange 
capsules)
DB Pancrelipase 
AAPIS
FD&C Blue No. 2 
(E132)
OL Creon®
(Pancrelipase)
Formulation
Commercially 
manufactured 
pancrelipase 
pellets filled into 
Swedish Orange 
opaque capsules 
for blinding
Pancrelipase 
pellets MP filled 
into Swedish 
Orange opaque 
capsules for 
blinding
Commercially 
manufactured 
pancrelipase 
pellets 
manufactured 
using commercial 
process filled into 
commercial 
transparent 
capsules with 
orange caps
Pancrelipase 
pellets 
manufactured 
using commercial 
process, with 
pancrelipase API 
sourced from 
alternate 
manufacturing site, 
filled into 
transparent 
capsules with 
orange caps
FD&C Blue No. 2 
(E132) powder, 
filled into hard 
capsules
Commercially 
manufactured 
pancrelipase 
pellets and 
capsules
Dosage Form
Delayed-release 
capsules
Delayed-release 
capsules MP
Delayed-release 
capsules
Delayed-release 
capsules
Hard gelatin 
capsules
Delayed-release 
capsules
Dose and units
24,000 USP units 
(Lipase) capsules
24,000 USP units 
(Lipase) capsules
24,000 USP units 
(Lipase) capsules
24,000 USP units 
(Lipase) capsules
250 mg
24,000 USP units 
(Lipase) capsules
 


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Table 2.
Identity of Investigational Product (Continued)
Study Part(s)
Part 1
Part 1
Part 2
Part 2
Parts 1 and 2
Parts 1 and 2
Investigational Product 
Name
DB Creon®
(Pancrelipase 
orange/orange 
capsules)
DB Pancrelipase 
MP
DB Creon®
(pancrelipase 
clear/orange 
capsules)
DB Pancrelipase 
AAPIS
FD&C Blue No. 2 
(E132)
OL Creon®
(Pancrelipase)
Excipients
Capsule Shell:
Gelatin, red iron 
oxide, titanium 
dioxide, and 
sodium lauryl 
sulfate
Capsule Shell: 
Hypromellose, red 
iron oxide, and 
titanium dioxide
Capsule Shell: 
Gelatin, red iron 
oxide, sodium 
lauryl sulfate, 
titanium dioxide, 
and yellow iron 
oxide
Capsule Shell: 
Gelatin, red iron 
oxide, sodium 
lauryl sulfate, 
titanium dioxide, 
and yellow iron 
oxide
Capsule Shell -
Gelatin, red iron 
oxide, sodium 
lauryl sulfate, and 
titanium dioxide
Capsule Shell:  
Gelatin, red iron
oxide, sodium 
lauryl sulfate, 
titanium dioxide,
and yellow iron 
oxide
Drug Product: 
cetyl alcohol, 
dimethicone, 
hypromellose 
phthalate, 
polyethylene 
glycol, and triethyl 
citrate
Drug Product: 
cetyl alcohol, 
dimethicone,
hypromellose 
phthalate, 
polyethylene 
glycol, and triethyl 
citrate
Drug Product: 
cetyl alcohol, 
dimethicone,
hypromellose 
phthalate, 
polyethylene 
glycol, and triethyl 
citrate
Drug Product: 
cetyl alcohol, 
dimethicone,
hypromellose 
phthalate, 
polyethylene 
glycol, and triethyl 
citrate
Drug Product: 
Each capsule 
contains 250 mg of 
FD&C Blue #2, 
with no additional 
excipients
Drug Product: 
cetyl alcohol, 
dimethicone,
hypromellose 
phthalate, 
polyethylene 
glycol, and triethyl 
citrate
FD&C = US Food, Drug & Cosmetics Act; MP = modernized process uniform coated pellets
a.
Capsule filling may occur at Catalent Germany Schorndorf, GmbH, Germany.
b.
Facilitated by the Unblinded Pharmacist.
 


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5.5.2.1
Packaging and Labeling
For the blinded treatment period of Part 1, AbbVie will supply to all sites open label study 
drug packaged in high density polyethylene (HDPE) bottles for Creon® (Pancrelipase) 
24,000 USP Units (Lipase) delayed release capsules and Pancrelipase 24,000 USP Units 
(Lipase) delayed release capsules (MP).  Each bottle will contain 100 capsules and will be 
labeled per local regulatory requirements. The blinding will be facilitated by a local 
Unblinded Pharmacist.
For the blinded treatment period of Part 2, AbbVie will supply to all sites double-blinded 
study drug packaged in high density polyethylene (HDPE) bottles for Creon®
(Pancrelipase) 24,000 USP Units (Lipase) delayed release capsules and Pancrelipase 
24,000 USP Units (Lipase) delayed release capsules (AAPIS).  Each bottle will contain 
100 capsules and will be labeled per local regulatory requirements.
For the screening period and for the interval between treatment Period 1 and treatment 
Period 2 (up to 28 days) for each study Part, open-label commercial Creon®
(Pancrelipase) 24,000 USP units (Lipase) delayed release capsules will be provided in 
250 ct bottles and labeled per local regulatory requirements. All labels must remain 
affixed to the bottle and the bottle should be kept closed except when dispensing study 
medication.
AbbVie will provide open label FD&C Blue No. 2 (E132) packaged in high density 
polyethylene (HDPE) bottles.  Each bottle will contain 50 capsules and will be labeled per 
local requirements.  Labels must remain affixed to the bottle and the bottle should be kept 
closed except when dispensing study medication.
5.5.2.2
Storage and Disposition of Study Drugs
All pancrelipase drugs must be stored at controlled room temperature (15° to 25°C or 59° 
to 77°F) and protected from moisture and freezing.  The minimum and maximum 
temperature must be recorded on business days to document proper storage conditions.  
Temperature excursions must be reported to AbbVie.  For the pancrelipase drug for the 
 


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screening period, for the interval between treatment periods, and for the interval between 
Parts (if applicable), subjects should be instructed to keep the bottle tightly closed 
between uses to protect from moisture.
The investigational products are for investigational use only and are to be used only 
within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under conditions specified on the label 
until dispensed for subject use or returned to AbbVie or representative.  Under necessary 
circumstances, sites will be allowed to ship open-label study drug to a subject's house 
using AbbVie's preferred courier, Marken.  Other courier services, selected by the site, 
may be used if Marken is not available.
The clinical site will maintain accurate records of the disposition of all clinical drug 
supplies received during the study.  These records shall include the amounts of drug 
supplied and the dates on which drug supplies were received from the Sponsor (or an 
authorized representative), dispensed to the subject, returned by the subject and returned 
to the Sponsor (or an authorized representative).  If errors or damages in the clinical drug 
supply shipments occur, the clinical site must contact the Sponsor (or an authorized 
representative) immediately. 
5.5.2.3
Preparation of Dosage Form
The preparation of blinded doses for the DB Treatment Periods for Part 1 only will need 
to be performed by an unblinded pharmacist or qualified designee.
5.5.3
Method of Assigning Subjects to Treatment Groups
For each study Part, all subjects enrolling into the DB Treatment Periods will be centrally 
randomized using an IRT system.  Before the study is initiated, contact information and 
user guidelines for the IRT system will be provided to each site.
 


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As subjects undergo the Screening Visit (Visit 1) of the first study Part, a unique subject 
number will be assigned to each subject by the IRT system.  This unique subject number 
will be used only for the assigned subject throughout the study.
At the start of each study Part, after confirming that the subject has met all eligibility 
criteria on Day 1 of DB Treatment Periods 1, each subject will be randomly assigned to 
one of the treatment sequence arms in a 1:1 ratio, as outlined in Section 8.4.
For enrollment of eligible subjects into the study, the site will utilize the IRT system in 
order to receive unique study drug kit numbers.  The study drug kit numbers will be 
assigned according to schedules that were computer-generated for each Part before the 
start of each Part of the study by the AbbVie Statistics Department, North Chicago, IL.
Randomization for study Part 1 and Part 2 are independent.
A copy of all of the randomization schedules will be kept by the Statistics Department at 
AbbVie and a copy will be forwarded to the IRT system provider.  Study drug may only 
be dispensed after contacting the IRT system and only to subjects enrolled in the study 
according to kit numbers provided by the IRT system.
5.5.4
Selection and Timing of Dose for Each Subject
During each DB treatment period, subjects will receive 96,000 LU with each of the 
3 planned meals and 48,000 LU with each of the 2 planned snacks, with a total of 
384,000 LU per day.  Study drug will be administered to subjects by study site staff at 
each meal/snack time during the 2 treatment periods for each Study Part.
5.5.5
Blinding
All AbbVie personnel with direct oversight of the conduct and management of the trial 
(with the exception of AbbVie Drug Supply Management and AbbVie unblinded Site 
Monitor), the investigator, study site personnel (with the exception of the site unblinded 
pharmacist for study Part 1) and the subject, will remain blinded to each subject's 
 


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treatment and until completion of the study for all subjects.  The IRT system will provide 
access to blinded subject treatment information in the case of a medical emergency.
The study blind may be broken if, in the opinion of the Investigator, it is in the subject's 
best interest.  AbbVie must be notified before breaking the blind unless identification of 
the study drug is required for emergency therapeutic measures. If an emergency 
therapeutic measure is necessary which warrants breaking of the blind, AbbVie must be 
notified within 24 hours of the blind being broken.
The date and reason for blind break must be recorded in source documentation and on the 
appropriate eCRF.
If one study Part (Part 1 or Part 2) is completed earlier than the other study Part, the 
database lock and formal unblinded analysis for the completed study Part will be 
performed.  Analysis of one Part will not unblind the other.  The AbbVie study team will 
review the efficacy and safety results from the unblinded analysis of the completed Part 
and an interim study report for the corresponding study Part may be prepared for 
regulatory submission.
5.5.5.1
Blinding of Data for Independent Data Monitoring 
Committee (IDMC)
The external independent DMC will review unblinded safety data during the study.  The 
frequency and the scope of data reviews and suggest relevant data for review and full 
details of DMC responsibilities and members and credentials will be included in the DMC 
Charter for Study M16-111.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will dispense study 
drug only to subjects enrolled in the study in accordance with the protocol.  The study 
drug must not be used for reasons other than that described in the protocol.
 


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During each of the treatment periods, the subjects will be actively monitored by site 
personnel for compliance with the study drug intake requirements.
Subjects will be considered compliant if at least 90% of scheduled blinded study drug 
doses are taken during each of the blinded treatment periods.  The Study Coordinator or 
other site personnel will keep an inventory of the study drug and document compliance 
for each individual study medication intake.
5.5.7
Drug Accountability
The investigator or representative will verify that study drug supplies are received intact 
and in the correct amounts.  This will be documented by signing and dating the Proof of 
Receipt or similar document or via direct recording in the IRT system.  An accurate 
(running) inventory of study drug will be kept by the site, and will include the lot number, 
Proof of Receipt number(s), the number of capsules dispensed, subject number, initials of 
person who dispensed/administered the drug, and the date study drug was 
dispensed/administered for each subject.  An overall accountability of the study drug will 
be performed and verified by the AbbVie monitor throughout the study and at the site 
close-out visit.  All study drug unit doses must be inventoried, accounted for, and returned 
to AbbVie or destroyed per instructions from AbbVie and according to local regulations.  
A copy of the Drug Accountability Form, in accordance with instructions provided by the 
AbbVie monitor, will also be included in the shipment.
The investigator and/or named sub-investigators agree not to supply study medication to 
any persons not enrolled in the study.  They also agree not to supply study medication to 
subjects who have completed their participation in the study (after Visit 6).
Intake of blue dye capsules and study drug compliance check will be recorded in the 
eCRF.
 


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5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The study Part 1 utilizes a cross-over as the optimal design to demonstrate non-inferiority 
for pancrelipase formulated as pancrelipase DR capsules MP 24,000 USP Units (lipase) as 
compared to Creon® (pancrelipase) Delayed Release capsules 24,000 USP Units (lipase).  
Each subject is able to serve as his/her own control, thus minimizing the number of 
subjects exposed to meet the primary objective.  
The study Part 2 utilizes a cross-over as the optimal design to demonstrate non-inferiority 
for pancrelipase formulated as Pancrelipase DR capsules manufactured with AAPIS, 
24,000 USP Units (Lipase) as compared to Creon® (pancrelipase) DR capsules 
24,000 USP Units (lipase).  Each subject is able to serve as his/her own control, thus 
minimizing the number of subjects exposed to meet the primary objective.
For both study Parts, due to the nature of the effects of pancrelipase on fat absorption, and 
the lack of absorption of pancrelipase, there is no concern related to any carry over effect 
with immediate rollover between DB Treatment Period 1 and DB Treatment Period 2.  
This interval is not intended as a washout period and any imbalance in this period length 
would not lead to any difference on study endpoints.  The flexibility in the duration of the 
interval between the DB treatment period is intended to allow subjects to deal with 
logistical aspects (such as school and work schedules) related to the need for 
hospitalization/confinement during DB treatment, and to allow sites to more effectively 
manage their staffing and occupancy.  The same applies to the interval between Parts, for 
subjects who elect to participate on both Parts.
The active control used in this study is commercially available Creon® (pancrelipase) 
Delayed Release capsules 24,000 USP Units (lipase) with previously demonstrated safety 
and efficacy.
 


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DB treatment is chosen for this study to enhance scientific rigor in the study, and to 
eliminate any possibility of subjects biasing the results by altering diet consumption or 
stool collection during the study.
5.6.2
Appropriateness of Measurements
The measurements included in this study are standard measurements used in studies 
assessing the pharmacodynamics and safety of pancreatic enzyme replacement therapies.
In studies investigating the efficacy of pancreatic enzyme supplementation, the commonly 
employed and scientifically accepted primary endpoint to determine efficacy is the CFA.  
The CFA reflects fat absorption and is a gauge for the lipase activity in pancreatic enzyme 
supplements on the digestion of dietary fat.  The CFA endpoint is also appropriate for 
studies that assess pharmacodynamics endpoints but are not designed to determine 
efficacy of a compound versus placebo.  The effects on the CFA can be observed even 
after a short treatment period of 3 – 7 days.  Thus, 5 days of study drug treatment is
generally accepted and sufficient in trials using the CFA as the endpoint.
The CNA reflects protein absorption and is a gauge for the protease activity in pancreatic 
enzyme supplements on the digestion of dietary protein.
5.6.3
Suitability of Subject Population
Patients aged 12 years or older with CF were selected for this study because they 
represent a commonly diagnosed and investigated population in terms of maldigestion and 
secondary malabsorption due to EPI.  The clinical symptoms, the need for enzyme 
supplementation and the therapeutic objectives for treating maldigestion are well defined 
in these patients.
Patients with pancreatic insufficiency often have a variable dosing regimen highly 
dependent on food intake and pattern.  Even though patients may be well controlled by 
their PERT prior to study participation, there is a risk that participation in the study with a 
diet that contains different amounts of fat and protein than their usual pre-study diet may 
 


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result in some gastrointestinal symptoms.  However, considering the short duration of the 
study periods with study drug intake, and the fact that subjects will be carefully observed 
during confinement/hospitalization, and return immediately to their usual diet, and the fact 
that the PERT dose during confinement will be adjusted to the new fat content of the diet, 
the risk of destabilizing their underlying condition is considered minimal.
It has been previously shown that an inverse linear correlation exists between the level of 
the remaining endogenous lipase activity and the improvement in CFA induced by 
PERTs.7  The enrollment of subjects with low endogenous lipase activity (more severe 
disease) may improve the interpretability and clinical relevance of on-treatment CFA 
values in PERT trials.
Therefore, in order to select a more severe patient population, the most conservative 
cutoff for fecal elastase-1 of < 15 µg/g was chosen to select subjects with EPI.  Removing 
the requirement for a screening off-PERT CFA < 70% is particularly relevant, given the 
challenges elicited by the ongoing COVID-19 pandemic.
5.6.4
Selection of Doses in the Study
The maximum labeled dose of Creon® (4,000 LU/g fat intake/day) has been selected for 
this study, and is also applied to the pancrelipase DR MP drug product and the 
pancrelipase DR AAPIS drug product, as the effect of the MP drug product and AAPIS 
drug product is believed to be non-inferior to that of Creon®.  The maximum labeled dose 
is chosen to provide sufficient lipase to adequately digest the dietary fat required in the 
study without exceeding the maximum recommended dose of pancrelipase contained in 
the Cystic Fibrosis Foundation guidelines.
5.6.5
Assessments for COVID-19 Infection
In the setting of the COVID-19 pandemic, assessments for COVID-19 infection in this 
study are being conducted to:
 


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●
Protect subjects from potentially worse outcomes associated with COVID-19 
infection due to study related procedures in the setting of the confinement 
periods.
General screening for COVID-19 infection (e.g., temperature checks, symptoms, 
exposures to COVID-19 infected person[s]) prior to a study visit will be conducted per 
local standard of care.
Study-required assessments will include COVID-19 testing (done locally or via central 
laboratory) prior to each Double-Blind Treatment Period confinement.  COVID-19 test 
results must be available and reviewed prior to the subject entering each confinement 
period.  
Additional COVID-19 testing outside of study-required testing may be done per the 
discretion of the investigator.
6.0
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 after it is released for 
distribution.
Complaints associated with any component of the investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Section 6.1
through Section 6.1.6.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
 


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considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide another cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject, 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event 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 accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
 


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6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes 
with the activities of daily living of a study subject.  Disability 
is not intended to include experiences of relatively minor 
medical significance such as headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained 
ankle).
 


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or stillbirth 
is considered an important medical event.  Examples of such 
events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each adverse 
event:
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.
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
 


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Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, another cause of event must be provided by the investigator for the serious adverse 
event.
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration (starting at the 
time the subject is dispensed OL drug at the screening period of the first study part) until 
30 days following discontinuation of DB study drug administration of the last study part 
have elapsed will be collected, whether solicited or spontaneously reported by the subject.
Adverse event information will be collected in each Part as shown in Figure 2.
 


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Figure 2.
Adverse Event Collection for each Study Part
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system, or if RAVE® is not operable, should be documented 
on the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event.
Email:  PPDINDPharmacovigilance@abbvie.com
FAX to:  +1 (847) 938-0660
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 




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Reference Safety Information (RSI).  The RSI in effect at the start of the IND Annual 
reporting period serves as the RSI during the reporting period.  For follow-up reports, the 
RSI in place at the time of occurrence of the 'suspected' Serious Adverse Reaction will be 
used to assess expectedness.
6.1.6
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 5.3.1.1).  If a pregnancy occurs in a study 
subject or in the partner of a study subject, information regarding the pregnancy and the 
outcome will be collected.  In the event of pregnancy occurring in a subject's partner 
during the study, written informed consent from the partner must be obtained before 
collection of any such information.  A separate consent will be provided by AbbVie for 
this purpose.  Pregnancies in study subject's partners will be collected from the date of the 
first dose through 30 days following the last dose of study drug.
While pregnancy in a study subject is not considered an adverse event, the medical 
outcome for either mother or infant, meeting any serious criteria including an elective or 
spontaneous abortion, is considered a serious adverse event and must be reported to 
AbbVie within 24 hours of the site becoming aware of the event.
6.1.7
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).
 


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All cases of suspected or confirmed COVID-19 infection must be discussed with the TA 
MD 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.).
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
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 (example:  printing illegible), 
missing components/product, or packaging issues.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form available in the electronic data capture (EDC) system used to collect 
information during the study.  Product Complaints occurring during the study will be 
followed-up to a satisfactory conclusion.  All follow-up information is to be reported to 
the Sponsor (or an authorized representative) and documented in source as required by the 
Sponsor.  Product Complaints associated with adverse events will be reported in the study 
summary.  All other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
 




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8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
Complete and specific details of the statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP).  These will include analysis 
populations, hypotheses to be tested, methods for summarizing the data, statistical tests to 
be performed, missing data handling, analysis conventions, and primary estimand 
attributes.  The analysis will be performed using SAS (SAS Institute Inc., Cary, NC, 
USA).  
The number of observations, mean, standard deviation, median, minimum and maximum 
will be summarized for continuous variables.  Discrete variables will be summarized by 
counts and percentages.  Medical History will be presented by count and percentage of 
subjects broken down by Body System and Diagnosis.
All the analyses will be performed separately for Part 1 and Part 2.
8.1.1
Definition for Analysis Populations
The analysis populations will be defined separately for Part 1 and Part 2.
The Intent-to-Treat (ITT) Population includes all randomized subjects.  Subjects will be 
included in the analysis according to the treatment sequence that they are randomized to.  
ITT population will be used for summaries of subjects' disposition and baseline 
characteristics.
The Evaluable Set consists of all randomized subjects who complete both treatment 
periods and have 100% stool samples collected for both treatment periods.  Subjects will 
be included in the analysis according to the study drug that they actually received.  The 
Evaluable Set will be used for the efficacy analysis for the primary and secondary 
endpoints.
 


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The Safety Analysis Set consists of all randomized subjects who received at least 1 dose 
of double-blind study drug.  Subjects will be included in the analysis according to the 
study drug that they actually received.
8.1.2
Primary and Secondary Endpoint Analyses
Non-inferiority assessments will be performed based on subjects who complete both 
treatment periods.  The primary pharmacodynamic variable will be the CFA.  The CFA 
values, measured at the end of the two cross-over periods, will be analyzed using a mixed 
effects model including sequence, period and treatment group as fixed effects and subjects 
within sequence as a random effect.  From this model, the mean CFA difference between 
two treatment groups will be estimated, along with its two-sided 99% confidence interval 
(CI) that will be compared with a non-inferiority margin of 12%.  If the upper bound of 
the 99% CI of CFA difference (Creon® - Pancrelipase DR MP in Part 1, or Creon® -
Pancrelipase DR AAPIS in Part 2) rules out the margin, the non-inferiority of the 
Pancrelipase product investigated in that Part to Creon® will be declared.
The two-sided 95% CI for the estimate of the mean CFA difference will also be provided.  
The primary estimand and specified estimand attributes for each study Part will be 
described in the SAP.  Supplementary analyses for the primary endpoint will be described 
in the SAP.
The secondary pharmacodynamic variables will be the CNA, stool fat, and stool weight.  
These variables will also be analyzed separately using a mixed effects model including 
sequence, period and treatment group as fixed effects and subjects within sequence as a 
random effect.  From this model, an estimate of the treatment difference along with its 
two-sided 95% CI will be derived.  All comparisons for all secondary pharmacodynamic 
variables between the treatment groups will be descriptive.
Additional exploratory pharmacodynamic variables include stool frequency, stool 
consistency, diarrhea, abdominal pain, bloating, and flatulence.  These variables will be 
summarized by treatment group using descriptive statistics.
 


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8.1.3
Safety Analysis
Safety analyses will be carried out using the Safety Analysis Set.  Treatment-emergent 
AEs and SAEs, will be summarized and reported.  Treatment-emergent AEs for DB 
Treatment Period 1 are defined as reported AEs that have a start date either on or after the 
first dose of the study drug during DB Treatment Period 1 and up to the end of DB 
Treatment Period 1.  For DB Treatment Period 2, treatment emergent AEs are defined as 
reported AEs that have a start date either on or after the first dose of study drug during DB 
Treatment Period 2 and up to the end of DB Treatment Period 2.  Adverse Events that 
occur during the administration of OL Creon® will be summarized separately for events 
that happen during the screening period and after randomization.  The number and percent 
of subjects experiencing AEs will be tabulated by system organ class (SOC) and Medical 
Dictionary for Drug Regulatory Activities (MedDRA®) preferred term.  In addition, 
summary of AEs by severity and relationship to study drug will be presented.  Serious 
AEs, or AEs that lead to premature study discontinuation will be listed and described in 
detail.  All these summaries will be done by treatment group.  Mean change in vital signs 
and laboratory variables at each visit will be summarized.  The last evaluation prior to the 
first dose of DB study drug in the corresponding treatment period will be used as baseline 
for the analysis in that treatment period.  A frequency table will be presented for 
Potentially Clinically Important (PCI) vital sign findings.  Shift tables for laboratory 
variables will be presented according to the reference ranges (low, normal or high).
Due to the small number of subjects per treatment group, only summary statistics will be 
applied to all the safety parameters.
8.2
Determination of Sample Size
8.2.1
Non-inferiority Margin Justification
The selection of a non-inferiority margin of 12% for the CFA is based on historical 
placebo-controlled Creon® Study S245.3.126, which had a similar study design 
(two-period, two-sequence cross-over) as Study M16-111, and enrolled 31 CF subjects 
with confirmed EPI based on the eligibility criteria of a historical CFA < 70%, or current 
 


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or historical fecal elastase-1 < 50 µg/g.  The effect of Creon® compared to placebo in 
CFA was estimated as 39.02% (95% CI:  32.3% – 45.8%).  However, it is expected that 
the current study will enroll subjects with more severe EPI than the subjects in 
Study S245.3.126, as the enrollment criteria for EPI in the current study is more stringent: 
subjects need to have a baseline fecal elastase less than 15 µg/g to be enrolled.  Therefore, 
the non-inferiority margin for comparing Pancrelipase DR MP to Creon® (Part 1) or 
comparing Pancrelipase DR AAPIS to Creon® (Part 2) should be derived based on 
Creon's effect in a more comparable subject population in the historical study.  At the time 
of the writing of this amendment, all subjects enrolled in Study M16-111 had a screening 
FE-1 of less than 15 µg/g and a screening CFA below 50%.
A subgroup analyses in Study S245.3.126 has been performed to estimate the Creon effect 
in subjects with a more severe EPI, defined as having a CFA of 50% or less during the 
placebo treatment period (since the screening FE-1 value was not collected in 
Study S245.3.126).  The Creon effect compared to placebo in CFA was estimated as 
52.25% (95% CI:  47.0% – 57.5%) in this subject population.  Based on the lower bound 
of the 95% CI for the estimate of Creon effect, a non-inferiority margin of 12% would 
preserve over 70% of that effect ((47-12)/47=74%).
8.2.2
Sample Size Determination
For each study Part, it is assumed that the expected difference in means of CFA between 
Creon® and Pancrelipase DR MP (Part 1) or between Creon® and Pancrelipase DR AAPIS
(Part 2) is 0.  For Part 1, with 22 subjects completing the 2 crossover treatment periods 
and having valid CFA in both periods, the power to claim non-inferiority is approximately 
96% based on one-sided type I error of 0.005 (i.e., based on two-sided 99% CI for non-
inferiority assessment), assuming a standard deviation (SD) of 12% for the within-subject 
treatment difference. 
For Part 2, with 18 subjects completing the 2 crossover treatment periods and having valid 
CFA in both periods, the power to claim non-inferiority is approximately 98% based on 
one-sided type I error of 0.005 (i.e., based on two-sided 99% CI for non-inferiority 
 


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assessment), assuming a standard deviation (SD) of 10% for the within-subject treatment 
difference (see Section 8.2.3). 
Table 3.
Study Power for Non-Inferiority in Primary Endpoint of CFA
SD of Treatment Difference
Power (N=22)
Power (N=18)
8%
99%
99%
10%
99%
98%
12%
96%
89%
14%
87%
75%
Note:
Power for non-inferiority in primary endpoint by evaluable sample size, if true CFA difference is 0.
It is expected that a screening failure rate of about 30% will be observed and that 
approximately 10-15% of the subjects will drop out during the crossover treatment 
periods.  Based on these assumptions, approximately 36 subjects will be screened and 
approximately 26 subjects will be randomized in Part 1 to expect 22 subjects to complete 
the crossover treatment periods, and approximately 30 subjects will be screened and 
approximately 20 subjects will be randomized in Part 2 to expect 18 subjects to complete 
the crossover treatment periods.
8.2.3
Blinded Sample Size Re-Estimation (BSSR)
For Part 1, with a sample size of 22 evaluable subjects, the study Part is sufficiently 
powered if the SD of the within-subject treatment difference in CFA is 12%.  For Part 2, 
with a sample size of 18 evaluable subjects, the study Part is sufficiently powered if the 
SD of the within-subject treatment difference in CFA is 10%.  However, if the actual SD 
for a respective study Part is larger than the assumed SD (12% or 10% for Part 1 or Part 2, 
respectively), the power for that study Part may be insufficient.  In order to ensure the 
assumption of SD holds for the study, a blinded review and estimate of the SD will be 
conducted for each study Part when the CFA data from the two treatment periods for 
approximately half of the planned subjects are available.  If the estimate of the SD is 
much different from the assumed SD, the sample size of the study may be adjusted based 
 


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on the estimated SD from the blinded data.  The detailed BSSR plan is documented in the 
SAP.
As of the date of the approval of protocol amendment 7, Part 1 BSSR has been completed.  
The blinded estimate of the SD for the within-subject treatment difference in CFA from 
Part 1 was approximately 7%.  Per the BSSR plan specified in the SAP, the Part 1 sample 
size remains the same as 22 evaluable subjects.  However, the assumption of the SD used 
in the Part 2 sample size determination has been adjusted to 10%.
8.3
Study Data Reporting
If one study Part (Part 1 or Part 2) is completed earlier than the other study Part, the 
database lock and formal unblinded analysis for the completed study Part will be 
performed.  Analysis of one Part will not unblind the other.  The AbbVie study team will 
review the efficacy and safety results from the unblinded analysis of the completed Part 
and an interim study report for the corresponding study Part may be prepared for 
regulatory submission.
8.4
Randomization Methods
For Part 1 at Visit 2 (DB Treatment Period 1 Day 1), eligible subjects will be randomized 
in a 1:1 ratio, to one of the 2 treatment sequence arms as shown below:
Sequence Arm
Treatment Period 1
Treatment Period 2
A
Pancrelipase DR capsules MP
Creon® (Pancrelipase) DR capsules 
B
Creon® (Pancrelipase) DR capsules 
Pancrelipase DR capsules MP
MP = modernized process uniform coated pellets, large scale
Subjects randomized to Sequence Arm A will take pancrelipase DR 24,000 MP drug 
product during DB Treatment Period 1 and then take Creon® during DB Treatment 
Period 2.  Subjects randomized to Sequence Arm B will take Creon® during DB 
Treatment Period 1 and then take pancrelipase DR MP-drug product during DB Treatment 
Period 2.
 


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For Part 2 at Visit 2 (DB Treatment Period 1 Day 1), eligible subjects will be randomized 
in a 1:1 ratio, to one of the 2 treatment sequence arms as shown below:
Sequence Arm
Treatment Period 1
Treatment Period 2
C
Pancrelipase DR capsules AAPIS
Creon® (Pancrelipase) DR capsules 
D
Creon® (Pancrelipase) DR capsules 
Pancrelipase DR AAPIS
AAPIS = Delayed-release capsules of pancrelipase manufactured at an Alternate Active Pharmaceutical Ingredient Site; 
DR = Delayed release
Subjects randomized to Sequence Arm C will take Pancrelipase DR capsules AAPIS drug 
product during DB Treatment Period 1 and then take Creon® during DB Treatment 
Period 2.  Subjects randomized to Sequence Arm B will take Creon® during DB 
Treatment Period 1 and then take Pancrelipase DR capsules AAPIS drug product during 
DB Treatment Period 2.
The randomization is central without any stratification.  Randomization schedules for Part 
1 and Part 2 are independent from each other.  The randomization schedule will be 
prepared by the Randomization Personnel of AbbVie.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, USPI, the informed consent and all other forms 
of subject information related to the study (e.g., advertisements used to recruit subjects) 
and any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will 
review the ethical, scientific and medical appropriateness of the study before it is 
conducted.  IEC/IRB approval of the protocol, informed consent and subject information 
and/or advertising, as relevant, will be obtained prior to the authorization of drug 
shipment to a study site.
 


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Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any SAEs that meet the reporting criteria, as dictated by local regulations, will be 
reported to both responsible Ethics Committees and Regulatory Agencies, as required by 
local regulations.  During the conduct of the study, the investigator should promptly 
provide written reports (e.g., ICH Expedited Reports, and any additional reports required 
by local regulations) to the IEC/IRB of any changes that affect the conduct of the study 
and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonisation (ICH) GCP guidelines, applicable regulations and guidelines governing 
clinical study conduct and ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject 
and answer all questions regarding this study.  Prior to any study-related screening 
procedures being performed on the subject, the informed consent statement will be 
reviewed and signed and dated by the subject, the person who administered the informed 
consent, and any other signatories according to local requirements.  When deemed 
necessary by the IRB/IEC, the documented assent of subjects who are minor children 
must be obtained.  If a subject reaches 18 years of age prior to completion of study 
participation, the investigator will obtain a new Informed Consent from the subject before 
further study participation. 
A copy of the informed consent and the subject assent will be given to the 
subject/subject's representative (in case of a minor child) and the original will be placed in 
 


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the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent and assent, if applicable, were obtained prior 
to any study-related procedures and that the subject/subject's representative received a 
signed copy of each document.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the ICF.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.  The printed report from ABVDiet will serve as source 
document for the fat and protein consumption and will be maintained by the clinical site.
The investigator/institution will permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
 


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through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The EPI Symptom Diary must be completed for each subject enrolled in this study using a 
paper questionnaire.  The questionnaire will serve as source data for the study. 
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
 


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11.0
Data Quality Assurance
Site Training
Prior to the first site activation, an investigators' meeting will be held to ensure the study 
is conducted according to GCP and regulatory guidelines and that all participating sites 
are trained on the study in accordance to the protocol.  This will support consistency and 
compliance to the protocol procedures that are critical to the success and validity of the 
clinical trial data.  In addition to protocol training, Investigators and site staff will be 
trained on diet planning and compliance, stool collection procedures, dispensation and 
handling of the study drug and expectations regarding ABVDiet completion.  Details 
regarding potential side effects and permissible/prohibited concomitant treatments will be 
discussed.  Procedures for defining, monitoring and reporting AEs and SAEs will be 
outlined.  Clearly defined roles and responsibility of the clinical investigators as well as 
study team contacts will be presented during the investigators' meeting.  Breakout 
sessions involving the site dietitian and central dietitian will occur to allow for training on 
the ABVDiet tool and diet requirements.
Prior to enrolling any subject in the study, a Site Initiation Visit will be held at each 
clinical site with AbbVie personnel (and/or their representatives), the investigators, and 
the appropriate site personnel.  The visit's agenda will include a detailed discussion and 
review of the protocol and essential documents, performance of study procedures, eCRF 
completion, AE monitoring and reporting and specimen collection methods.  The 
personnel at the study site will be trained on the study procedures, when applicable, by an 
AbbVie monitor or designee.
Manuals pertaining to the use of all relevant systems (EDC, central lab, ABVDiet, etc.) 
will be made available to sites at the time of the site initiation visit.
Monitoring
The AbbVie monitor will monitor the study site throughout the study.  A source document 
review will be performed against entries on the eCRFs and a quality assurance check will 
 


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be performed to ensure that the investigator is complying with the protocol and 
regulations.  
Monitoring visits will be scheduled at mutually agreeable times periodically throughout 
the study and at a frequency deemed appropriate for the study.  Monitoring visits will be 
conducted to evaluate the progress of the study, ensure the rights and wellbeing of 
subjects are protected, check that the reported clinical study data are accurate, complete 
and verifiable from available source documents and the conduct of the study is in 
compliance with the approved protocol and applicable amendments, GCPs and applicable 
national regulatory requirements.  A monitoring visit will include a review of the essential 
clinical study documents (regulatory documents, CRFs, source documents.  Drug 
disposition records, subject ICFs, etc.) as well as discussion on the conduct of the study 
with the Investigator and site study staff.  The investigator and site study staff should be 
available during these to facilitate the review of the clinical study record and 
resolve/document any discrepancies found during the monitoring visit.
In addition, ongoing Medical Safety monitoring of the data will be conducted by a 
physician or representative at AbbVie.
Data Quality Assurance
Data entered into eCRFs will be electronically transferred to AbbVie and imported into 
the database using validated software throughout the study.  Computer logic and manual 
checks will be created to identify items such as inconsistent study dates.  Any necessary 
corrections will be made to the eCRF.
Routine hematology, serum chemistry, stools weight and content, pregnancy testing will 
be analyzed using a central laboratory.  The data from these analyses will be electronically 
transferred from the central laboratory to the study database using validated software.  A 
review of all laboratory results will be conducted by the Investigator, the AbbVie monitor, 
a physician, and other appropriate personnel at AbbVie.
 


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The consumed amounts of fat, protein and calories will be calculated by ABVDiet.  The 
applicable endpoint data will be electronically transferred from ABVDiet to the EDC 
system and will be reviewed by the central dietitian, the AbbVie monitor and other 
appropriate personnel at AbbVie.  ABVDiet will be accessible to the AbbVie monitor and 
AbbVie study team to allow review of diet compliance throughout the course of the study.
12.0
Use of Information
All information concerning pancrelipase and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of 
pancrelipase.  This information may be disclosed as deemed necessary by AbbVie to other 
clinical investigators, other pharmaceutical companies, and to governmental agencies.  To 
allow for the use of the information derived from this clinical study and to ensure 
complete and thorough analysis, the investigator is obligated to provide AbbVie with 
complete test results and all data developed in this study and to provide direct access to 
source data/documents for trial-related monitoring, audits, IEC/IRB review and regulatory 
inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study (by name and subject number).  This list will be maintained at the 
site and will not be retrieved by AbbVie.
 


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13.0
Completion of the Study
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end of study is defined as the date of the last subject's last visit.
 


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for pancrelipase.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Phase 4 Study to Compare US Marketed Creon® Drug Product 
with Drug Product Manufactured with a Modernized Process at an 
Alternate Manufacturing Site and with Drug Product manufactured 
with the approved manufacturing process at an alternate Active 
Pharmaceutical Ingredient Site, in Subjects with EPI due to Cystic 
Fibrosis
Protocol Date:
15 September 2021
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


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15.0
Reference List
1.
Borowitz D, Baker RD, Stallings V, et al.  Consensus report on nutrition for 
pediatric patients with cystic fibrosis.  J Pediat Gastroenterol Nutr.  
2002;35(3):246-59.
2.
Ramsey BW, Farrell PM, Pencharz P, et al.  Nutritional assessment and 
management in cystic fibrosis:  a consensus report.  The consensus committee.  Am 
J Clin Nutr.  1992;55(1):108-16.
3.
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): S4-14.
4.
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.
5.
Van de Kamer JH, Ten Bokkel-Huinink H, Weyers HA.  Rapid method for the 
determination of fat in feces.  J Biol Chem.  1949;177(1):347-55. 
6.
Kjeldahl J.  A new method for the determination of nitrogen in organic matter.  
Anal Chem.  1883;22(1):366-82.
7.
Gao WY, Mulberg AE. Dependence of PERT endpoint on endogenous lipase 
activity. Pancreas. 2014;43(8):1232-8.
 


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
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., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
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 investigation and all amendments.
 


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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.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.
 


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Therapeutic Area MD
Development
Therapeutic Area Associate VP
Development
Program Lead
Development Operations
Study Project Manager
Development Operations 
Director
Statistics
Senior Director
Statistics
 


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Appendix C.
Study Activities
a. Overall Study Activities for Study Part 1 and Study Part 2
Activity
Screening
Double-Blind Treatment Period
Follow-Up Period
DB Treatment Period 1
Interval
DB Treatment Period 2
Visit 6
Visit 1o
Visit 2
Visit 3
Up to 28 
Daysc
Visit 4
Visit 5a
30 Days Post Hospital 
Discharge
Day 1
Day 6, 7 or 8b
Day 1
Day 6, 7 or 8b
Informed Consentp
X
Medical History
X
Xd
Xf
Previous dose of PERT
X
Xf
Concomitant Medication Review
X
X
X
X
X
X
Physical Examination
Xr
X
X
Xf
X
Height
X
Body weight
X
Xe
Xe
Xe
Xe
Vital Signs
Xr
X
X
X
X
Clinical Laboratory Tests
Xr
X
X
Xf
X
Stool Collection for Fecal Elastase 
Testing
Xs
Pregnancy Testingg
X
X
X
Diet Plan Design
Xh
Start hospitalization/confinement
X
X
IRT system contact
Xi
Xj
Xl
Xk
Xq
 


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Activity
Screening
Double-Blind Treatment Period
Follow-Up Period
DB Treatment Period 1
Interval
DB Treatment Period 2
Visit 6
Visit 1o
Visit 2
Visit 3
Up to 28 
Daysc
Visit 4
Visit 5a
30 Days Post Hospital 
Discharge
Day 1
Day 6, 7 or 8b
Day 1
Day 6, 7 or 8b
Adverse Events Review
See Table b. "Treatment Periods 
Activities"
See Table b. "Treatment Periods 
Activities"
X
Study Drug Administration
X
Treatment Compliance Check
Diet Administration
Dietary Records
Stool Collection
EPI Symptom Diary
Hospital/Confinement site 
discharge
Xf
X
COVID-19 Testing
Xm
Xm,n
COVID-19 signs and symptoms 
screening
X
X
a.
Or early termination visit (except hospitalization and stool collection/dietary record).
b.
Days 6, 7 or 8 depending on the first appearance of the 2nd dyed stool after the 2nd stool dye marker is administered.
c.
In exceptional circumstances, this period may be extended upon consultation with the sponsor.
d.
To be updated only if there is new historical information available since Visit 1.
e.
Done in the morning prior to any food intake and prior to any blood sampling.
f.
If subject elects to enter directly into DB Treatment Period 2 from DB Treatment Period 1, this is not required.
g.
For females with child-bearing potential:  serum pregnancy test at the Screening Visit (Visit 1) and urine pregnancy test for other visits specified above.
h.
Diet plans both the treatment periods for each study Part should be done prior to V2.
i.
Unique subject number assignment.  Subjects who are participating in both study Parts will only be assigned a subject number at the start of the first study Part they 
participate in and will use this number throughout the study.
 


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j.
Randomization and study drug kit number allocation for DB Treatment Period 1.
k.
Study drug kit number allocation for DB Treatment Period 2.
l.
At discharge to assign drug for interval between Treatment Period 1 and Treatment Period 2.
m.
Subjects must have a negative viral COVID-19 test result, from a COVID-19 test done within 7 days prior to entering the DB treatment Period confinements (Visit 2 and 
Visit 4).
n.
Subjects who choose to go directly from DB Treatment Period 1 confinement to DB Treatment Period 2 confinement do not need to perform a COVID-19 test unless 
otherwise directed by the investigator.
o.
Subjects participating in both Parts and ≤ 30 days have occurred since Visit 5 of the previous Part, will not need screening repeated, but eligibility needs to be confirmed at 
Visit 2 of the second study Part.
p.
Subjects who have already completed one study part prior to this amendment approval, and want to participate in the second part must sign the amended consent.  Also, 
subjects who have agreed to participate in both study parts and it has been greater than 30 days between parts must resign the consent.
q.
For the follow up period, the subject will be dispensed a 30 day supply of open label Creon®, at the dose they received during the screening period, to be taken during the 
follow up period.
r.
This does not need to be repeated if subject is participating in both parts and < 30 days between Visit 5 and Visit 1 of the next study part.
s.
A pre-screening consent may also be obtained from the subject prior to the screening visit so a stool sample can be collected and brought to the study site at the Screening 
Visit.
 


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b. Treatment Periods (Hospitalization/Confinement) Activities for Study Part 1 and Study Part 2
Activity
Treatment Periods (DB 1 and DB 2)
Visits 2 and 4
Visits 3 and 5
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6, 7 or 8a
Hospitalization/Confinement
X
X
X
X
X
Xa
Study Drug Administration
X
X
X
X
X
Xb,e,f
Treatment Compliance Check
X
X
X
X
X
X
Stool marker (blue dye) to be taken after last food intake (bedtime) 
X
X
Diet
X
X
X
X
X
X
Dietary Records
Xc
X
Xc
Stool Collection
Xd
Xd
Xd
Xa
EPI Symptom Diaryg
X
X
X
X
X
Xh
Concomitant Medication Review
X
X
X
X
X
Xa
Adverse Events Review
X
X
X
X
X
Xa
a.
Days 6, 7 or 8 depending on the appearance of the 1st blue dyed stool after the intake of the 2nd stool dye marker on Treatment Period Day 5 evening.
b.
Until 2nd stool marker is passed on Day 6, 7 or 8.
c.
Dietary record starts with Day 3 breakfast (1st meal following 1st stool dye marker intake on Day 2), and ends with Day 5 dinner or 2nd snack (last meal prior to 2nd stool dye 
marker intake on Day 5).
d.
Stool collection starts after the subject passes the first stool dye marker (excluding the first blue dyed stool), and ends with the first blue dyed stool (including the blue dyed 
stool) after the second stool dye marker administration.
e.
Study drug for the interval between Treatment Period 1 and Treatment Period 2 will be dispensed at discharge from confinement/hospitalization at Visit 3.
f.
For the follow up period, the subject will be dispensed a supply of open label Creon®, at the dose they received during the screening period, to be taken during the follow up
period.
 


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g.
Completed prior to the administration of study drug, prior to breakfast on each day of study confinement.
h.
Completed by the subject each day until subject is discharged.
 

SAP_001.pdf: 
Pancrelipase
M16-111 – Statistical Analysis Plan
Version 5.0 – 21 March 2022
1
Statistical Analysis Plan for Study M16-111
A Phase 4 Study to Compare US Marketed Creon®
Drug Product with Drug Product Manufactured with 
a Modernized Process at an Alternate Manufacturing 
Site and with Drug Product Manufactured with the 
Approved Manufacturing Process at an Alternate 
Active Pharmaceutical Ingredient Site, in Subjects 
with EPI due to Cystic Fibrosis
Date:  21 March 2022
Version 5.0
 
NCT03924947


Pancrelipase
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Version 5.0 – 21 March 2022
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Table of Contents
1.0
Introduction...........................................................................4
2.0
Study Design and Objectives ................................................4
2.1
Objectives and Hypotheses..................................................................... 4
2.2
Study Design Overview.......................................................................... 5
2.3
Treatment Assignment and Blinding....................................................... 7
2.4
Sample Size Determination .................................................................... 7
2.4.1
Blinded Sample Size Re-Estimation (BSSR) .......................................... 9
3.0
Endpoints.............................................................................11
3.1
Primary Endpoint(s) ............................................................................. 11
3.2
Secondary Endpoint(s) ......................................................................... 12
3.3
Additional Exploratory Endpoint(s)...................................................... 13
3.4
Safety Endpoint(s)................................................................................ 13
4.0
Analysis Populations ...........................................................14
5.0
Subject Disposition..............................................................15
6.0
Study Drug Duration and Compliance ..............................16
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ...................17
7.1
Demographics and Baseline Characteristics.......................................... 18
7.2
Medical History.................................................................................... 18
7.3
Prior and Concomitant Medications...................................................... 18
8.0
Efficacy Analyses.................................................................19
8.1
General Considerations......................................................................... 19
8.2
Handling of Missing Data..................................................................... 19
8.3
Primary Efficacy Endpoint(s) and Analyses.......................................... 20
8.3.1
Primary Efficacy Analysis.................................................................... 20
8.3.2
Main Analysis of Primary Efficacy Endpoint........................................ 20
8.3.3
Supplementary Analyses of the Primary Efficacy Endpoint .................. 22
8.4
Secondary Efficacy Endpoint(s) and Analyses...................................... 23
8.4.1
Secondary Efficacy Analyses ............................................................... 23
8.5
Additional Exploratory Efficacy Endpoint(s) and Analyses .................. 23
8.5.1
Additional Exploratory Efficacy Analyses............................................ 23


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9.0
Safety Analyses....................................................................24
9.1
General Considerations......................................................................... 24
9.2
Adverse Events..................................................................................... 24
9.2.1
AEs During the Screening Confinement Period .................................... 24
9.2.2
AEs During the Open Label Period(s)................................................... 25
9.2.3
AEs During the Double-Blind Treatment Period................................... 26
9.2.3.1
Treatment-Emergent Adverse Events.................................................... 26
9.2.3.2
Adverse Event Overview...................................................................... 26
9.2.3.3
Treatment-Emergent Adverse Events by SOC and/or PT...................... 27
9.2.3.4
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation ........................................................................... 27
9.3
Analysis of Laboratory Data................................................................. 27
9.4
Analysis of Vital Signs......................................................................... 28
10.0
Interim Analyses..................................................................28
10.1
Data Monitoring Committee................................................................. 29
11.0
Overall Type-I Error Control.............................................29
12.0
Version History ...................................................................30
13.0
References............................................................................32
List of Tables
Table 1.
Study Power for Non-Inferiority in Primary Endpoint of CFA................ 9
Table 2.
Study M16-111 Estimand Attributes..................................................... 22
Table 3.
SAP Version History Summary ............................................................ 30
List of Figures
Figure 1.
Study Schematic..................................................................................... 6
List of Appendices
Appendix A.
Protocol Deviations .............................................................................. 33
Appendix B.
Potentially Clinically Important Criteria for Safety Endpoints .............. 34


Pancrelipase
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1.0
Introduction
This Statistical Analysis Plan (SAP) describes the statistical analyses for pancrelipase 
Study M16-111 "A Phase 4 Study to Compare US Marketed Creon® Drug Product with 
Drug Product Manufactured with a Modernized Process at an Alternate Manufacturing 
Site and with Drug Product Manufactured with the Approved Manufacturing Process at an 
Alternate Active Pharmaceutical Ingredient Site (Protocol Amendment 6), in Subjects 
with EPI due to Cystic Fibrosis."
Study M16-111 examines the efficacy and safety of pancrelipase manufactured with a 
modernized process (MP) in subjects with Exocrine Pancreatic Insufficiency (EPI) due to 
Cystic Fibrosis (CF).  This examination is being conducted in Part 1 of this study.
Study M16-111 also examines the efficacy and safety of pancrelipase manufactured with 
the approved process at an Alternate Active Pharmaceutical Ingredient Site (AAPIS) in 
subjects with EPI due to CF.  This examination is being conducted in Part 2 of this study.
Unless otherwise specified, summaries and analyses will be performed within each study 
Part (Part 1 or Part 2), without integration of data between study Parts.
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 and Hypotheses
The objective of Part 1 is to demonstrate non-inferiority of pancrelipase Delayed-Release 
(DR) capsules MP 24,000 USP Units (lipase) drug product compared to an active control 
[pancrelipase DR capsules 24,000 USP Units (lipase) currently marketed in the US as 


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Creon®] in subjects with EPI due to CF, as measured by the coefficient of absorption 
(CFA).
The objective of Part 2 is to demonstrate non-inferiority of DR capsules of pancrelipase 
AAPIS 24,000 USP Units (lipase) compared to an active control [pancrelipase DR 
capsules 24,000 USP Units (lipase) currently marketed in the US as Creon®] in subjects 
with EPI due to CF, as measured by CFA.
Safety will also be evaluated for each study Part.
2.2
Study Design Overview
Part 1 is a Phase 4, double-blind, randomized, active-controlled, two-period, two-
sequence crossover design that will test pancrelipase DR capsules MP for non-inferiority 
compared to the currently US marketed Creon® in subjects of 12 years or older with EPI 
due to CF, as measured by CFA.  Part 2 is a Phase 4, double-blind, randomized, active-
controlled, two-period, two-sequence crossover design that will test pancrelipase DR 
capsules AAPIS for non-inferiority compared to the currently US marketed Creon® in 
subjects of 12 years or older with EPI due to CF, as measured by CFA.
For study Part 1, the target number of evaluable subjects is 22, with a screening of 
approximately 36 subjects and enrollment/randomization of approximately 26 subjects to 
meet scientific and regulatory objectives without enrolling an undue number of subjects in 
alignment with ethical considerations.  Therefore, if the target number of subjects in Part 
1 (22) has completed the study, there is a possibility that additional subjects in screening 
will not be enrolled in this Part.  
For study Part 2, the target number of evaluable subjects is 18, with a screening of 
approximately 30 subjects and enrollment/randomization of approximately 20 subjects to 
meet scientific and regulatory objectives without enrolling an undue number of subjects, 
in alignment with ethical considerations.  Therefore, if the target number of evaluable 
subjects in Part 2 (18) has completed the study, there is a possibility that additional 


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6
subjects in screening will not be enrolled in this Part.  See Section 2.4 Sample size 
determination for details.
The study will be conducted in the US.  See Figure 1.
Figure 1.
Study Schematic
OL = Open Label; DB = Double-Blind; R = Randomization; Pancrelipase DR MP = Pancrelipase Delayed Release 
Modernized Process capsules 24,000 USP Units (lipase); Pancrelipase AAPIS = delayed-release capsules of 
pancrelipase manufactured at an Alternate Active Pharmaceutical Ingredient Site; Creon® (pancrelipase) = US approved 
and marketed Creon® (pancrelipase) Delayed Release capsules 24,000 USP Units (lipase)
*
Subjects who participate in both Part 1 and Part 2 may not need to repeat screening.
**
For subjects who participate in both Part 1 and Part 2, the follow up period of the first Part will end at Visit 6 of the 
current Part or the day before Visit 1 of the next study Part, whichever comes first.
Note:
First blue dye marker administered bedtime of study confinement Day 2 and stools collection starts once 
subject passes first blue dye marker.  Second blue dye marker administered on study confinement Day 5 and 
stool collection continues until the appearance of the next blue dyed stool and stool collection will then stop.


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2.3
Treatment Assignment and Blinding
Within each Part, subjects will be randomized in a 1:1 ratio to one of the 2 treatment 
sequence arms as shown below. The randomization is central without any stratification.
Part 1:
Sequence Arm
Treatment Period 1
Treatment Period 2
A
Pancrelipase DR capsules MP
Creon® (Pancrelipase) DR capsules
B
Creon® (Pancrelipase) DR capsules
Pancrelipase DR capsules MP
DR = Delayed release; MP = Modernized Process uniform coated pellets, large scale
Part 2:
Sequence Arm
Treatment Period 1
Treatment Period 2
C
Pancrelipase DR capsules AAPIS
Creon® (Pancrelipase) DR capsules
D
Creon® (Pancrelipase) DR capsules
Pancrelipase DR capsules AAPIS
AAPIS = Delayed-release capsules of pancrelipase manufactured at an Alternate Active Pharmaceutical Ingredient Site; 
DR = Delayed release
2.4
Sample Size Determination
The sample size determination consists of a power calculation for the total number of 
evaluable subjects needed and assumptions for percentage of drop-outs for the total 
number of subjects enrolled.  A non-inferiority margin of 12% is chosen for the study.  
This non-inferiority margin for comparing Pancrelipase DR MP to Creon® (Part 1) or 
comparing Pancrelipase DR AAPIS to Creon® (Part 2) was derived based on Creon's 
effect in a more comparable subject population in the historical study with a similar study 
design as follows:  
Based on historical data from 4 placebo-controlled studies (Studies S223.3.1011, 
S223.3.1022, S245.3.1263, S245.3.1274), the effect in CFA is 36.8% (95% confidence 
interval:  32.6% – 41.0%) comparing Pancrelipase DR Capsules 24,000 with placebo.


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Specifically, in the historical placebo-controlled Creon® Study S245.3.1263, which had a 
similar study design as Study M16-111 (as a two-period, two-sequence cross-over study 
conducted in an adult population at the same dose strength as M16-111), the effect of 
Creon® compared to placebo in CFA was estimated as 39.02% (95% CI:  32.3% – 45.8%) 
based on 31 enrolled CF subjects with confirmed EPI based on the eligibility criteria of a 
historical CFA < 70%, or current or historical Fecal Elastase-1 (FE-1) < 50 µg/g.  
However, it is expected that the current Study M16-111 will enroll subjects with more 
severe EPI than the subjects in Study S245.3.126, as the enrollment criteria for EPI in the 
current study is more stringent: subjects need to have a baseline FE-1 less than 15 µg/g to 
be enrolled.  At the time of the protocol amendment 6, all subjects enrolled (N=10) in 
Study M16-111 had a screening FE-1 of less than 15 µg/g and a screening CFA below 
50%.
A subgroup analysis in Study S245.3.126 was performed to estimate the Creon effect in 
subjects with a more severe EPI, defined as having a CFA of 50% or less during the 
placebo treatment period (since the screening FE-1 value was not collected in 
Study S245.3.126).  The Creon effect compared to placebo in CFA was estimated as 
52.25% (95% CI:  47.0% – 57.5%) in this subject population.  Based on the lower bound 
of the 95% CI for the estimate of Creon effect, a non-inferiority margin of 12% would 
preserve over 70% of that effect ((47-12)/47=74%).
For each study Part, it is assumed that the expected difference in means of CFA between 
Creon® and Pancrelipase DR MP (Part 1) or between Creon® and Pancrelipase DR AAPIS
(Part 2) is 0.  For Part 1, with 22 subjects who complete the two crossover treatment 
periods and have valid CFA as the primary endpoint, the power of the study to claim non-
inferiority by comparing the 99% confidence interval (CI; i.e., based on one-sided type I 
error of 0.005) with a margin of 12% is approximately 96%, assuming a standard 
deviation (SD) of 12% for the within-subject treatment difference.
For Part 2, with 18 subjects completing the 2 crossover treatment periods and having valid 
CFA in both periods, the power to claim non-inferiority is approximately 98% based on 
one-sided type I error of 0.005 (i.e., based on two-sided 99% CI for non-inferiority 


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assessment with a margin of 12%), assuming a standard deviation (SD) of 10% for the 
within-subject treatment difference (see Section 2.4.1 for justification of 10% SD based 
on BSSR). 
Table 1.
Study Power for Non-Inferiority in Primary Endpoint of CFA
SD of Treatment Difference
Power (N=22)
Power (N=18)
8%
99%
99%
10%
99%
98%
12%
96%
89%
14%
87%
75%
Note:
Power for non-inferiority in primary endpoint by evaluable sample size, if true CFA difference is 0.
It is expected that a screening failure rate of about 30% will be observed and that 
approximately 10-15% of the subjects will drop out during the treatment periods.  Based 
on these assumptions, approximately 36 subjects will be screened and approximately 
26 subjects will be randomized in Part 1 to expect 22 subjects to complete the crossover 
treatment periods with evaluable CFA in both treatment periods, and approximately 30 
subjects will be screened and approximately 20 subjects will be randomized in Part 2 to 
expect 18 subjects to complete the crossover treatment periods with evaluable CFA in 
both treatment periods.
2.4.1
Blinded Sample Size Re-Estimation (BSSR)
As of the date of the approval of SAP version 4.0, Part 1 BSSR has been completed.  The 
blinded estimate of the SD for the within-subject treatment difference in CFA from Part 1 
was approximately 7%.  Per the BSSR plan specified in the SAP, the Part 1 sample size 
remains the same as 22 evaluable subjects.  However, the assumption of the SD used in 
the Part 2 sample size determination has been adjusted to 10%.
For Part 1, with a sample size of 22 evaluable subjects, the study Part is sufficiently 
powered if the SD of the within-subject treatment difference in CFA is 12%.  For Part 2, 
with a sample size of 18 evaluable subjects, the study Part is sufficiently powered if the 
SD of the within-subject treatment difference in CFA is 10%.  However, if the actual SD 


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for a respective study Part is larger than the assumed SD (12% or 10% for Part 1 or Part 2, 
respectively), the power for the study may be insufficient.  In order to ensure the 
assumption of SD holds for the study, a blinded review and estimate of the SD will be 
conducted for each study Part when the CFA data from the two treatment periods are 
available for approximately half of the planned subjects (i.e., 13 or 10 subjects for Part 1 
or Part 2, respectively).  It will be performed by the AbbVie study statistician.  Since the 
study database will not be un-blinded to conduct the BSSR, AbbVie does not plan to put 
additional firewalls in place.
Detailed methodology of the BSSR
The initial sample size   is determined by
  = 2
[ 	
 (1 −) +  	
 (1 −)]



where  is the one-sided type I error, 1 − is the power,  is the non-inferiority margin, 
and 
 is the within-subject variance estimate.  When  = 0.005, 1 −  = 0.96,  =
−12, SD of treatment difference = 12 (then  
 =
 !
 = 72), then    = 22.  When  =
0.005, 1 −  = 0.98,  = −12, SD of treatment difference = 10 (then  
 =
 !
 = 50), 
then    = 18.
Interim BSSR will be conducted when CFA data for the first $  (e.g., $ = 13 or 10 for 
Part 1 or Part 2, respectively) subjects are available.  Within-subject variance 
 will be 
estimated using the blinded estimate of the total variance ()
 based on $   subjects.5  The 
total interim variance ()
 will be estimated with the formula below.
()
 = 
1
2($   −1) * * (+,- −+̅)
/0 /
-2 

,2 


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where +,- is period difference (Period 2 – Period 1) for subject j in sequence i, +̅ is the 
overall mean for all +,-, which can be calculated without knowledge of the treatment 
allocation.  ()
  is an unbiased estimate of 
 if there is no treatment difference. I.e.,
3(()
 ) = 
 + 
$ 
2($ −1) (45 −46)
where 45 −46 denotes the treatment difference.  
Then the estimated sample size will be calculated as
  
7 = 2
[ 	
  
7(1 −) +  	
  
7(1 −)]

()

with  = 0.005, 1 −  = 0.90,  = −12.
In order to incorporate a cap on the sample size of 50 subjects (e.g., 89: = 50), the final 
recalculated sample size will be
;<89= = min(max (  , ;), 89: )
Based on the formula above, the final recalculated sample size will be always greater than 
or equal to the initial sample size of evaluable subjects (22 or 18 for Part 1 or Part 2, 
respectively) and less than or equal to the limit of 50 evaluable subjects.
3.0
Endpoints
3.1
Primary Endpoint(s)
The primary efficacy endpoint is the CFA measured at the end of each treatment period.
The CFA is calculated as 100•[fat intake – fat excretion]/fat intake.


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Fat intake will be determined from fat content of food consumed on Day 3, 4, 5 of each 
treatment period.  Fat excretion will be determined from the fat content in the stool(s) 
collected after the first blue dyed stool (exclusive) and until the second blue dyed stool 
(inclusive) during each treatment period.
3.2
Secondary Endpoint(s)
The secondary efficacy endpoints include:
●
CNA measured at the end of each treatment period.
The CNA is calculated as 100•[nitrogen intake – nitrogen excretion]/nitrogen 
intake.
Nitrogen intake will be determined from protein content of food consumed on 
Day 3, 4, 5 of each treatment period.  Based on the assumption that all proteins 
are polypeptide chains with a mass containing 16% nitrogen on average, 
calculated protein intake is to be converted into nitrogen intake by multiplying 
the grams of protein ingested by 0.16.  Nitrogen excretion will be determined 
from the nitrogen content in the stool(s) collected after the first blue dyed stool 
(exclusive) and until the second blue dyed stool (inclusive) during each 
treatment period.
●
Stool fat.
Stool fat will be determined from the stool fat in the stool(s) collected after the 
first blue dyed stool (exclusive) and until the second blue dyed stool (inclusive)
during each treatment period.
●
Stool weight.
Stool weight will be determined from the net weight of the stool samples 
collected after the first blue dyed stool (exclusive) and until the second blue 
dyed stool (inclusive) during each treatment period.


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3.3
Additional Exploratory Endpoint(s)
To assess additional exploratory endpoints, subjects will complete an EPI Symptom Diary 
on a daily basis during each confinement treatment period.  Additional exploratory 
efficacy endpoints include:
●
Stool frequency
Stool frequency will be determined by self-report on the EPI Symptom Diary 
(number of bowel movements over the last 24 hours).
●
Stool consistency
Stool consistency will be determined by self-report on the EPI Symptom Diary 
(No bowel movements over the last 24 hours, Hard/difficult to pass, 
Formed/normal, Loose/watery).
●
Diarrhea
Diarrhea will be determined by self-report on the EPI Symptom Diary (None, 
Mild, Moderate, Severe).
●
Abdominal pain
Abdominal pain will be determined by self-report on the EPI Symptom Diary 
(None, Mild, Moderate, Severe).
●
Bloating
Bloating will be determined by self-report on the EPI Symptom Diary (None, 
Mild, Moderate, Severe).
●
Flatulence
Flatulence will be determined by self-report on the EPI Symptom Diary (None, 
Mild, Moderate, Severe).
3.4
Safety Endpoint(s)
The safety variables include:
●
Percentage of subjects reporting treatment-emergent adverse events (TEAEs).
●
Analysis of laboratory data and vital signs.


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4.0
Analysis Populations
The following population sets will be defined and used for the analyses for each study 
Part.
The Screening Confinement Set consists of all subjects who started screening 
confinement.  The screening confinement period was removed from the study design in 
protocol amendment 6.  Therefore, the Screening Confinement Set (denoted SC-P1) is 
only defined for Part 1 and includes subjects screened under protocol Amendment 5 or 
earlier.
The Intent-to-Treat (ITT) Population includes all randomized subjects in each study Part 
(denoted as ITT-P1 and ITT-P2 for Part 1 and Part 2, respectively). Subjects will be 
included in the analysis according to the treatment sequence to which they are 
randomized.
The Evaluable Set (ES) consists of all randomized subjects in each study Part who 
complete both double-blind (DB) treatment periods and have 100% of stool samples
collected and analyzed by the laboratory and valid total fat intake value for both DB 
treatment periods.  The ES for Part 1 and Part 2 will be denoted as ES-P1 and ES-P2, 
respectively.  Subjects will be included in the analysis according to the study drug that 
they actually received.
The Safety Analysis Set consists of all randomized subjects who received at least 1 dose 
of study drug in the DB treatment periods in each study Part (denoted as SA-P1 and 
SA-P2 for Part 1 and Part 2, respectively).  Subjects will be included in the analysis 
according to the regimen that they actually received.
The Open Label Safety Analysis Set in each study Part consists of all subjects who 
received at least 1 dose of open label Creon during any study period (denoted as 
OLSA-P1 and OLSA-P2 for Part 1 and Part 2, respectively).  For Part 1, subjects who 
received open label Creon during the maintenance period (only applicable for subjects 
enrolled prior to protocol amendment 6) will also be included in OLSA-P1.


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For Part 1, the population sets include: the Screening Confinement Set (SC-P1), Intent-to-
Treat Population (ITT-P1), Evaluable Set (ES-P1), Safety Analysis Set (SA-P1) and Open 
Label Safety Analysis Set (OLSA-P1).  For Part 2, the population sets include:  the Intent-
to-Treat Population (ITT-P2), Evaluable Set (ES-P2), Safety Analysis Set (SA-P2) and 
Open Label Safety Analysis Set (OLSA-P2).
5.0
Subject Disposition
The total number of subjects who started and completed screening confinement and the 
duration of screening confinement (days) will be summarized for the Screening 
Confinement Set for study Part 1 using SC-1.  Reasons for exclusion, including screen 
failure, will be summarized.
The number and percentage of subjects who prematurely discontinued open-label Creon
for study Part 1 and Part 2 will be summarized for all reasons and primary reason using 
OLSA-P1 and OLSA-P2, respectively.
A summary of subject accountability will be provided for the ITT Population for study 
Part 1 and Part 2 using ITT-P1 and ITT-P2, respectively.  The number of subjects in each 
of the following categories will be summarized for each treatment sequence:
●
Subjects randomized in the study
●
Subjects who took at least one dose of study drug in DB Treatment Period 1
●
Subjects who completed DB Treatment Period 1
●
Subjects who took at least one dose of study drug in DB Treatment Period 2
●
Subjects who completed DB Treatment Period 2
●
Subjects who prematurely discontinued study drug in DB Treatment Period 1 
(all reasons and primary reason)
●
Subjects who prematurely discontinued study drug in DB Treatment Period 2 
(all reasons and primary reason)
●
Subjects who prematurely discontinued the study Part (all reasons and primary 
reason)


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6.0
Study Drug Duration and Compliance
For the Safety Analysis Set, duration of double-blind treatment will be summarized per 
treatment period for each regimen using SA-P1 and SA-P2 for study Part 1 and Part 2, 
respectively.  Duration of treatment is defined for each subject as last dose date of the 
corresponding DB treatment minus first dose date of the corresponding DB treatment + 1.  
Duration of treatment will be summarized using the number of subjects treated, mean, 
standard deviation, median, minimum and maximum.
Descriptive statistics will also be provided for average lipase units/fat (g) intake in 
Days 3 - 5 and average lipase units/weight (kg) in Days 3 - 5 per regimen during the DB 
treatment periods for the Safety Analysis Set.  In addition, the number and percentage of 
subjects will be summarized by categorized average lipase units/fat intake (g) in 
Days 3 - 5 for the following categories:
●
< 2500
●
2500 - 3500
●
3500 - 4500
●
4500 – 5500
●
> 5500
Treatment compliance in each DB treatment period will be summarized by regimen and 
overall for the Safety Analysis Set. Treatment compliance in each DB treatment period is 
defined as the number of capsules taken divided by the number of capsules that should 
have been taken in Days 3 - 5 of that treatment period. 
The number and percentage of subjects who are at least 90% treatment compliant with 
study drug administration will be summarized for each DB treatment period. In addition, 
compliance rate will be summarized using the number of observations, mean, standard 
deviation, median, minimum and maximum for each DB treatment period.


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In addition, duration of exposure to open-label (OL) Creon during the period prior to 
randomization (for subjects who are never randomized, this will be the screening period 
or maintenance period when OL Creon is administered), will be summarized for the Open 
Label Safety Analysis Set for study Part 1 and Part 2 using OLSA-1 and OLSA-2, 
respectively. For OLSA-1, this includes the Maintenance Period (for subjects screened 
before protocol amendment 6) and the Screening Period (for subjects screened after 
protocol amendment 6). Duration of treatment is defined for each subject as last dose date
of OL Creon prior to Visit 2 minus first dose date of OL Creon + 1.  Duration of treatment 
will be summarized using the number of subjects treated, mean, standard deviation, 
median, minimum and maximum.
Duration of exposure to OL Creon between DB Treatment Period 1 (TP1) and DB
Treatment Period 2 (TP2) and after TP2 will be summarized for the Safety Analysis Set
for study Part 1 and Part 2 using SA-P1 or SA-P2, respectively. Duration of treatment is 
defined for each subject as last dose date of OL Creon prior to Visit 4 minus first dose 
date of OL Creon after Visit 3 + 1 plus last dose date of OL Creon after Visit 5 minus first 
dose date of OL Creon after Visit 5 + 1.  In other words, the total duration for the interval 
between TP1 and TP2, and the period after TP2 will be summed to calculate the duration 
of open-label treatment following randomization.  Duration of treatment will be 
summarized using the number of subjects treated, mean, standard deviation, median, 
minimum and maximum. 
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 ITT Population for study Part 1 and 
Part 2 using ITT-P1 and ITT-P2, respectively.  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).


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7.1
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized overall and by treatment 
sequence for the ITT Population by study Part.
Continuous demographic and baseline characteristics variables include age, weight, 
height, body mass index (BMI), systolic blood pressure, diastolic blood pressure, pulse 
rate, and FE-1, and for ITT-P1 only, CFA in Screening Confinement Period.  Categorical 
demographic and baseline characteristics variables include sex, ethnicity, race, and age 
(12 - 18, > 18 years).
Safety related baseline characteristics including height, weight, body mass index, systolic 
blood pressure, diastolic blood pressure, and pulse rate will be summarized by treatment 
sequence for each DB treatment period for the ITT Population.
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment sequence for the ITT Population by study Part.  The 
system organ class (SOC) will be presented in alphabetical order, and the preferred terms 
(PTs) will be presented in alphabetical order within each SOC.  Subjects reporting more 
than one condition/diagnosis will be counted only once in each row (SOC or PT).
7.3
Prior and Concomitant Medications
A prior medication is defined as any medication taken prior to the date of the first dose of 
study drug in the DB treatment period. A concomitant medication for each DB treatment 
period is defined as any medication that started prior to the date of the first dose of study 
drug and continued to be taken after the first dose of study drug for that period or any 
medication that started on or after the date of the first dose of study drug but not after the 
date of the last dose of study drug for that period.


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Medications will be summarized for the ITT Population for study Part 1 and Part 2 using 
ITT-P1 and ITT-P2, respectively. The number and percent of subjects who received a 
prior medication will be summarized overall and by treatment sequence by the generic 
name assigned by the most current version of the World Health Organization (WHO) 
Drug Dictionary in alphabetical order for prior medications. Also, the number and 
percentage of subjects who received a concomitant medication will be summarized by
regimen per treatment sequence and overall by the generic name assigned by the most 
current version of the WHO Drug Dictionary in alphabetical order for concomitant 
medications.
8.0
Efficacy Analyses
8.1
General Considerations
All efficacy analyses will be conducted for the Evaluable Set for study Part 1 and Part 2 
using ES-P1 and ES-P2, respectively, unless otherwise specified.  Efficacy analyses based 
on the EPI Symptom Diary will be conducted for the ITT Population for study Part 1 and 
Part 2 using ITT-P1 and ITT-P2, respectively.  
The number of observations, mean, standard deviation, median, minimum and maximum 
will be summarized.  
8.2
Handling of Missing Data
For the primary efficacy endpoint, the Evaluable Set in each study Part is used which 
requires all subjects to have completed both DB treatment periods and have 100% of stool 
samples collected and analyzed by the laboratory and valid total fat intake value.  Thus, 
there should be no missing data for the CFA calculation.  Fat intake in the calculation will 
use the fat content data of recorded food consumed in Days 3 - 5 of the corresponding 
treatment period.  No fat content will be imputed for missing records of food consumed.  
Similarly, for the secondary endpoint of CNA, there should be no missing data for the 
CNA calculation due to the definition of Evaluable Set.  Nitrogen intake will be calculated 
from the protein content of recorded food consumed in Days 3 - 5 of the corresponding 


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treatment period.  No protein content will be imputed for missing records of food 
consumed.  There should also be no missing data for the secondary endpoints of stool fat 
or stool weight due to the definition of the Evaluable Set, so there will be no imputation of 
stool fat or stool weight for missing records.  For the additional exploratory efficacy 
endpoints, non-missing data will be summarized and reported, with no imputation of 
missing records.
8.3
Primary Efficacy Endpoint(s) and Analyses
8.3.1
Primary Efficacy Analysis
The CFA will be analyzed using a mixed effects model including sequence, period and 
regimen as fixed effects and subjects within sequence as a random effect.  From this 
model, an estimate of the treatment difference along with a 99% CI will be derived and 
used to compare with a non-inferiority margin of 12%. The 95% CI for the estimate of 
the treatment difference will also be provided.
8.3.2
Main Analysis of Primary Efficacy Endpoint
In each study Part, the primary efficacy endpoint of CFA (defined in Section 3.1) will be 
analyzed based on the Evaluable Set (ES-P1 and ES-P2 for study Part 1 and Part 2, 
respectively).  The following methods will be used to address potential intercurrent 
events:
●
Subjects with premature discontinuation of study drug in Part 1 or Part 2 or 
who did not receive any dose of study drug in both treatment periods for Part 1 
or Part 2 will be excluded from ES-P1 or ES-P2, respectively
●
Subjects without 100% of stool samples collected and analyzed by the 
laboratory in both treatment periods in Part 1 or Part 2 will be excluded from 
ES-P1 or ES-P2, respectively
The estimand corresponding to the primary efficacy endpoint for Part 1 is the mean CFA 
difference between Pancrelipase DR capsules MP and Creon® (pancrelipase) DR 
capsules among participants who complete both treatment periods and have 100% of stool


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samples collected and analyzed by the laboratory in both treatment periods.  The estimand 
corresponding to the primary efficacy endpoint for Part 2 is the mean CFA difference 
between Pancrelipase DR capsules AAPIS and Creon® (pancrelipase) DR capsules 
among participants who complete both treatment periods and have 100% of stool samples 
collected and analyzed by the laboratory in both treatment periods.  The attributes of the 
estimands corresponding to the primary efficacy endpoint for each study Part are 
summarized in Table 2.


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Table 2.
Study M16-111 Estimand Attributes
Estimand
Attributes of the Estimand
Population
Endpoint
Treatment
Handling of 
Intercurrent Events 
(IEs)
Population-
Level 
Summary
Part 1 
Primary
Evaluable set in 
Part 1 (CF 
subjects who are 
randomized and 
complete both 
treatment periods 
and have 100% of 
stool samples 
collected and 
analyzed by the 
laboratory in 
Part 1)
CFA at 
treatment 
Periods 1 
and 2
Pancrelipase 
DR capsules 
MP or
Creon®
(pancrelipase) 
DR capsules
IE1: Premature 
discontinuation from 
either of the 
treatment periods in 
Part 1
IE2: Subjects without 
100% stool sample 
collected in Part 1
Subjects with IE1 or 
IE2 will be excluded 
from the analysis 
population. 
Mean CFA 
difference 
between two 
treatment 
groups
Part 2 
Primary
Evaluable set in 
Part 2 (CF 
subjects who were 
randomized and 
completed both 
treatment periods 
and have 100% of 
stool samples 
collected and 
analyzed by the 
laboratory in 
Part 2)
CFA at 
treatment 
Periods 1 
and 2
Pancrelipase 
DR capsules 
AAPIS or
Creon®
(pancrelipase) 
DR capsules
IE1: Premature 
discontinuation from 
either of the 
treatment periods in 
Part 2 
IE2: Subjects without 
100% stool sample 
collected in Part 2 
Subjects with IE1 or 
IE2 will be excluded 
from the analysis 
population.
Mean CFA 
difference 
between two 
treatment 
groups
AAPIS = alternate active pharmaceutical ingredient site; CF = cystic fibrosis; CFA = coefficient of fat absorption; 
DB = double-blind; DR = delayed-release; IE = intercurrent event; MP = modernized process
8.3.3
Supplementary Analyses of the Primary Efficacy Endpoint
The following supplementary analysis of the primary efficacy endpoint will be conducted.  
In each study Part, the primary analysis will be repeated using all randomized subjects 


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(ITT-P1 and ITT-P2 for Part 1 and Part 2, respectively).  In this analysis, subjects will be 
included using their observed CFA measurements from each available treatment period.
8.4
Secondary Efficacy Endpoint(s) and Analyses
8.4.1
Secondary Efficacy Analyses
The secondary efficacy endpoints will be the CNA, stool fat, and stool weight.  These 
variables will also be analyzed separately using a mixed effects model including 
sequence, period and regimen as fixed effects and subjects within sequence as a random 
effect.  From this model, an estimate of the treatment difference along with a 95% CI will 
be derived.  All comparisons for all secondary variables between the regimen will be 
descriptive.
8.5
Additional Exploratory Efficacy Endpoint(s) and Analyses
8.5.1
Additional Exploratory Efficacy Analyses
The additional exploratory efficacy endpoints will be stool frequency, stool consistency, 
diarrhea, abdominal pain, bloating, and flatulence.  Stool frequency will be summarized 
for the ITT Population by regimen for each diary day for Days 1-6 and by regimen for 
average stool frequency, which is calculated as the mean stool frequency for each subject 
of all non-missing diary days for Days 1-6.  Stool consistency, diarrhea, abdominal pain, 
bloating and flatulence will be summarized (number and percentage for each ordinal 
category) for each diary day by regimen.  Diary Days 1-6 will be included in the summary 
table.  All comparisons for all additional exploratory variables between the regimen will 
be descriptive.
The EPI Symptom Diary, which collects assessments for the additional exploratory 
variables, was added as a case report form (CRF) as part of protocol amendment 6 (after 
many Part 1 subjects were already enrolled).  Summary tables for the additional 
exploratory efficacy endpoints will only be provided for Part 1 if 6 or more subjects in the 
ITT Population complete at least one diary day in each treatment period of Part 1.


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9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized separately by study Part for the Screening Confinement 
Set, Safety Analysis Set, and the Open Label Safety Analysis Set.  For the Safety Analysis 
Set, safety summaries will be presented by regimen and overall.  Subjects are assigned to 
a regimen based on the treatment actually received on the first day of dosing of the 
corresponding treatment period, regardless of the treatment randomized.  For Part 1, 
safety analyses will be conducted using SC-P1, SA-P1 and OLSA-P1.  For Part 2, safety 
analyses will be conducted using SA-P2 and OLSA-P2.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA SOCs 
and PTs 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.
9.2.1
AEs During the Screening Confinement Period
AEs and SAEs that have a start date either on or after the first day of the Screening 
Confinement Period, and up to the end day of the Screening Confinement Period will be 
summarized by SOC and PT for the Screening Confinement Set for Part 1 using SC-P1.
Listing of SAEs during the Screening Confinement Period will also be provided for the 
Screening Confinement Set.


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9.2.2
AEs During the Open Label Period(s)
AEs and SAEs that have a start date during an Open Label Period will be summarized by 
SOC and PT for the Open Label Safety Analysis Set for study Part 1 and Part 2 using 
OLSA-P1 and OLSA-P2, respectively.  These AEs and SAEs include the following: 
●
For Part 2 and for Part 1 subjects enrolled under protocol amendment 6 or later: 
AEs and SAEs that have a start date either on or after the first dose date of OL 
Creon in Screening Period, and before the first dose of the study drug in DB 
Treatment Period 1 (if the subject entered the DB treatment period), or on or 
after the first dose date of OL Creon in the Screening Period (if the subjects 
never entered the DB treatment period)
●
For Part 1 subjects enrolled under protocol amendment 5 or earlier: AEs and 
SAEs that have a start date either on or after the first dose date of the 
Maintenance Period, and before the first dose of the study drug in DB 
Treatment Period 1 (if the subject entered the DB treatment period), or on or 
after the first dose date of the Maintenance Period (if the subject never entered 
the DB treatment period)
●
For Part 1 and Part 2: AEs and SAEs that have a start date either on or after the 
first dose date of the Open Label Period after DB Treatment Period 1, and 
before the first dose of the study drug in DB Treatment Period 2 (if the subject 
entered DB Treatment Period 2), or on or after first dose date of the Open Label 
Period after DB Treatment Period 1 (if the subject never entered the DB 
treatment period)
●
For Part 2 and for Part 1 subjects enrolled after protocol amendment 6: AEs and 
SAEs that have a start date either on or after the first dose date of OL Creon in 
the Follow Up Period after DB Treatment Period 2
Listing of SAEs during the Open Label Period(s) will also be provided for the Open Label 
Safety Analysis Set.


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9.2.3
AEs During the Double-Blind Treatment Period
9.2.3.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs for the regimen administered in DB Treatment Period 1 are 
defined as reported AEs that have a start date either on or after the first dose of the study 
drug during DB Treatment Period 1, and up to the end of DB Treatment Period 1, defined 
as the earliest of: the first dose date of OL Creon after Visit 3, the start of the first dose of 
DB Treatment Period 2, or 30 days after the last dose of study drug during DB Treatment 
Period 1.  For the regimen administered in DB Treatment Period 2, treatment emergent 
AEs are defined as reported AEs that have a start date either on or after the first dose of 
study drug during DB Treatment Period 2, and up to the end of DB Treatment Period 2, 
defined as the earlier of the first dose date of OL Creon after Visit 5 or 30 days after the 
last dose of study drug during DB Treatment Period 2.
9.2.3.2
Adverse Event Overview
An overview of AEs will be presented for the Safety Analysis Set for study Part 1 and 
Part 2 using SA-P1 and SA-P2, respectively.  The overview will consist of the number 
and percentage of subjects experiencing at least one event for each of the following AE 
categories:
●
Any treatment-emergent AE
●
Any treatment-emergent AE related to study drug according to the investigator
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
All deaths


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9.2.3.3
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT for the Safety 
Analysis Set for study Part 1 and Part 2 using SA-P1 and SA-P2, respectively; by 
maximum relationship to study drug as 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.
In addition, treatment-emergent adverse events will be summarized by PT and sorted by 
decreasing frequency overall.
9.2.3.4
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 the Safety Analysis Set for study 
Part 1 and Part 2 using SA-P1 and SA-P2, respectively.
9.3
Analysis of Laboratory Data
The clinical laboratory tests defined in the protocol (e.g., hematology and clinical 
chemistry) will be summarized by regimen for the Safety Analysis Set for study Part 1 
and Part 2 using SA-P1 and SA-P2, respectively.
Each laboratory variable will be summarized by visit with the number of non-missing 
observations, mean and standard deviation, median, minimum and maximum.  Mean 
change from start to end of DB treatment period will be summarized for each laboratory
variable by regimen, with the number of observations, mean at start of DB treatment 
period, and mean at end of DB treatment period.  An ANOVA model with treatment as a 
factor will be used to compare change from start to end of DB treatment period between 
regimens.  The LS mean, standard error, and 95% CI will be presented for the change 


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from start to end of DB treatment period within each regimen and between regimen 
difference.
Changes in laboratory parameters during treatment with each regimen will be tabulated 
using shift tables as low, normal, or high based on the normal ranges of the laboratory 
used for each sample. A shift table from baseline to any post-baseline value during 
treatment with each regimen according to the normal range will be provided for each 
hematology and clinical chemistry parameter.
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, weight, and 
body temperature will be summarized by regimen for the Safety Analysis Set for study 
Part 1 and Part 2 using SA-P1 and SA-P2, respectively.
Each vital sign variable will be summarized by visit with the number of non-missing 
observations, mean and standard deviation, median, minimum and maximum.  Mean 
change from start to end of DB treatment period will be summarized for each vital sign 
variable by regimen, with the number of observations, mean at start of DB treatment 
period, and mean at end of DB treatment period.  An ANOVA model with treatment as a 
factor will be used to compare change from start to end of DB treatment period between 
regimens.  The LS mean, standard error, and 95% CI will be presented for the change 
from start to end of DB treatment period within each regimen and between regimen 
difference.
Vital sign variables will be evaluated based on potentially clinically important (PCI) 
criteria (Appendix B).  For each vital sign PCI criterion, the number and percentage of 
subjects who have a vital sign value meeting the criteria will be summarized by regimen.
10.0
Interim Analyses
No formal interim analysis is planned.


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As described in Section 2.4.1, a blinded sample size re-estimation will be conducted for 
each study Part when approximately half of the planned subjects in each Part (i.e., 
13 subjects) have completed the two DB treatment periods and have the corresponding 
CFA data available for both periods.
10.1
Data Monitoring Committee
An external data monitoring committee (DMC) composed of persons independent of 
AbbVie and with relevant expertise in their field will review unblinded 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.
Since there are no efficacy analyses for early stopping, no alpha adjustment is needed.
11.0
Overall Type-I Error Control
This study has one primary efficacy endpoint for which non-inferiority is tested at type I 
error of 0.01 by constructing two-sided 99% CI of the treatment difference for non-
inferiority assessment. A unique non-inferiority assessment will be conducted separately 
for each study Part.  Because each study Part will assess the non-inferiority of a different 
investigational product with separate randomization for populations in each study Part, 
adjustment for multiplicity is not planned.
For all the secondary endpoints, two-sided 95% CI will be calculated for the treatment 
difference estimate. Since all comparisons for all secondary variables will be descriptive,
adjustment for multiplicity is not planned.
For BSSR (refer to Section 2.4.1), analytically and through simulations, it has been shown 
that the procedures do not meaningfully affect Type I error rate6. As such, no multiplicity 
adjustment is planned for the BSSR.


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Since there are no efficacy analyses for early stopping planned for the DMC review, no 
alpha spending is needed due to the DMC review.
12.0
Version History
Table 3.
SAP Version History Summary
Version
Date
Summary
1.0
26 Feb 2019
Original version
2.0
16 Jan 2020

Added the Screening Confinement Set and the Maintenance Set, 
and updated the definition of the other analysis populations in 
Section 4.0;

Added the description of subject disposition, study drug duration 
and compliance, demographics, baseline characteristics, medical 
history, and prior/concomitant medications in Section 5.0, 
Section 6.0, and Section 7.0 due to SAP template change;

Added safety analyses of adverse events for the Screening 
Confinement Set and the Maintenance Set in Section 9.2;

Added description of data monitoring committee in Section 10.1.


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Table 3.
SAP Version History Summary (Continued)
3.0
05 Apr 2021

Updated study title and Figure 1 to match protocol Amendment 6;

Added study Part 2 to Section 1.0, Section 2.0, Section 4.0, 
Section 5.0, Section 6.0, Section 7.0, Section 8.0, Section 9.0, 
Section 10.0, and Section 11.0;

Updated sample sizes and non-inferiority margin in Section 2.2 and
Section 2.4;

Added Additional Exploratory Endpoints in Section 3.3, 
Section 8.2, and Section 8.5;

Added Open Label Safety Analysis Set to Section 4.0, Section 5.0, 
Section 6.0, Section 9.1 and Section 9.2.2;

Removed Maintenance Set from Section 4.0, Section 5.0, 
Section 6.0, Section 9.1 and Section 9.2.2;

Added clarification that Analysis Populations are defined by study 
Part in Section 4.0, Section 5.0, Section 6.0, Section 7.0, 
Section 8.0, Section 9.0, Section 10.0, and Section 11.0;

Added clarification that exposure to open label Creon will be 
reported separately for exposure before randomization and for 
exposure after randomization in Section 6.0;

Removed the AE summaries for maintenance period, added the AE 
summaries for open label Creon;

Updated the TEAE definition for double-blind treatment period in 
Section 9.2.3;

Added clarification that Safety Analysis Set will be population used 
in Section 9.3 and Section 9.4.
4.0
24 Sep 2021

Updated sample sizes for study Part 2 in Section 2.2 and 
Section 2.4.

Added description of primary endpoint estimand and its attributes 
to Section 8.3.

Added supplementary analyses of the primary efficacy endpoint in 
Section 8.3.3.
5.0
21 Mar 2022

Added clarification that Evaluable Set is defined based on 100% 
stool sample collection that is analyzable, ie, 100% of stool samples 
collected and analyzed by the laboratory.

Updated analysis population for EPI Symptom Diary efficacy 
endpoints to be the ITT population.


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13.0
References
1.
AbbVie.  CR200.0126.  A comparison of the efficacy and safety of Creon®20 and 
placebo in the treatment of steatorrhea in pediatric and adolescent cystic fibrosis 
patients with clinical exocrine pancreatic insufficiency.  1996.
2.
AbbVie.  CR200.0143.  A comparison of the efficacy and safety of Creon®20 and 
placebo in the treatment of steatorrhea in adult cystic fibrosis patients with clinical 
exocrine pancreatic insufficiency.  1997.
3.
Trapnell BC, Maguiness K, Graff GR, et al.  Efficacy and safety of Creon® 24,000 
in subjects with exocrine pancreatic insufficiency due to cystic fibrosis.  J Cyst 
Fibros.  2009;8(6):370-7.
4.
Graff GR, Maguiness K, McNarmara J, et al.  Efficacy and tolerability of a new 
formulation of pancrelipase delayed-release capsules in children aged 7 to 11 years 
with exocrine pancreatic insufficiency and cystic fibrosis:  a multicenter, 
randomized, double-blind, placebo-controlled, two-period crossover, superiority 
study.  Clin Ther.  2010;32(1):89-103.
5.
Golkowski D, Friede T, Kieser M.  Blinded sample size re-estimation in crossover 
bioequivalence trials.  Pharm Stat.  2014;13(3):157-62.
6.
Kieser M, Friede T.  Simple procedures for blinded sample size adjustment that do 
not affect the type I error rate.  Stat Med.  2003;22(23):3571-81.


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


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Appendix B.
Potentially Clinically Important Criteria for Safety Endpoints
The criteria for Potentially Clinically Important (PCI) vital sign findings are described in 
Table B.
Table B.
Criteria for Potentially Clinically Important Vital Sign Values
Vital Signs Variables
Criterion
Definition of Potentially Clinically Important
Systolic Blood Pressure 
(mmHg)
Low
Value ≤ 90 and ≥ 20 decrease from Baseline
High
Value ≥ 180 and ≥ 20 increase from Baseline
Diastolic Blood Pressure 
(mmHg)
Low
Value ≤ 50 and ≥ 15 decrease from Baseline
High
Value ≥ 105 and ≥ 15 increase from Baseline
Pulse (bpm)
Low
Value ≤ 50 and ≥ 15 decrease from Baseline
High
Value ≥ 120 and ≥ 15 increase from Baseline
Weight (kg)
Low
≥ 7% decrease from Baseline
High
≥ 7% increase from Baseline
Temperature (°C)
High
Value ≥ 38.3 and ≥1.1 increase from Baseline