Conditions: Exocrine Pancreatic Insufficiency (EPI) Cystic Fibrosis (CF)
Keywords: Exocrine pancreatic insufficiency EPI Cystic Fibrosis CF Pancreatic enzyme replacement therapy (PERT) Lipase
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 41
Healthy volunteers: no

Brief summary:
The primary objectives of this study are to assess the safety and efficacy of MS1819-SD vs porcine pancreatic enzyme replacement therapy (PERT) in patients with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF).

Detailed description:
This is a Phase 2, open-label, multi-center, 2x2 crossover study assessing the safety and efficacy of MS1819-SD (spray dried) vs porcine PERT given at the same dose that was being administered during the pre-study period.

MS1819-SD will be assessed in a 2x2 crossover including at least 30 patients completing both periods.

Arms:
arm 1: Patients in arm will further be randomized to receive either the sequence consisting of MS1819 2240 mg/day for 3 weeks followed by PERT for another 3 weeks. During the PERT treatment period the patients will take their stable pre-study PERT dose. arm 2: Patients in arm will be randomized to receive PERT for 3 weeks followed by MS1819 2240 mg/day for another 3 weeks. During the PERT treatment period the patients will take their stable pre-study PERT dose.

Interventions: intervention 1: MS1819 intervention 2: Porcine PERT
Intervention descriptions: intervention 1: MS1819, an oral, non-systemic, that is non-enterically-coated. It is a yeast-derived (non-porcine) lipase pancreatic enzyme replacement. intervention 2: Porcine PERT is being used as a comparator to MS1819 as a second drug/intervention

Protocol document:
Prot_000.pdf: 
Official Title: 
Clinical Study Protocol 
OPTION: A Phase 2, Open-Label, Multicenter, 
2x2 Crossover Trial to assess the Safety and 
Efficacy of MS1819-SD in Patients with 
Exocrine Pancreatic with Insufficiency due to 
Cystic Fibrosis 
NCT03746483 
Date of Document 
October 30, 2018 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 1 of 65 
 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess the Safety 
and Efficacy of MS1819-SD in Patients with Exocrine Pancreatic Insufficiency 
due to Cystic Fibrosis  
 
Study Name: 
OPTION: A Phase 2, Open-Label, Multicenter, 2x2 
Crossover Trial to assess the Safety and Efficacy of 
MS1819-SD in Patients with Exocrine Pancreatic with 
Insufficiency due to Cystic Fibrosis 
Protocol Number: 
AZ-CF2001 
Investigational Product: 
MS1819-SD 
Phase: 
Phase 2a 
Sponsor: 
AzurRx BioPharma, Inc. 
760 Parkside Avenue 
Suite 304 
Brooklyn, NY 11226 
USA 
Protocol Date: 
October 30, 2018 
Protocol Version: 
Version 2.0  
CONFIDENTIAL 
This protocol may not be reproduced or communicated to a third party without 
the written permission of AzurRx. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 2 of 65 
 
1. PROTOCOL APPROVAL SIGNATURES 
 
Protocol Title: 
Study Name:  
A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess 
the Safety and Efficacy of MS1819-SD in Patients with Exocrine 
Pancreatic Insufficiency due to Cystic Fibrosis 
OPTION: A Phase 2, Open-Label, Multicenter, 2x2 Crossover 
Trial to assess the Safety and Efficacy of MS1819-SD in Patients 
with Exocrine Pancreatic with Insufficiency due to Cystic Fibrosis 
Protocol Number: 
AZ-CF2001 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current Good 
Clinical Practice (GCP), and applicable regulatory requirements. 
Sponsor Signatory 
James Pennington, MD  
Chief Medical Officer 
AzurRx BioPharma, Inc. 
760 Parkside Avenue 
Suite 304 
Brooklyn, NY 11226 
USA 
Signature 
Date  
 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 3 of 65 
 
2. SYNOPSIS 
Name of Sponsor/Company: AzurRx BioPharma, Inc. 
Name of Investigational Product: MS1819-SD 
Protocol Number: AZ-CF2001 
Protocol Title: A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess the Safety and Efficacy 
of MS1819-SD in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis 
Study Name: OPTION: A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess the Safety and 
Efficacy of MS1819-SD in Patients with Exocrine Pancreatic with Insufficiency due to Cystic Fibrosis 
Study Site(s): This study will be conducted at approximately 15 sites in North America and European Union. 
Number of Patients: Approximately 30 
Phase of Development: 2a 
Objectives 
The primary objectives of this study are to assess the safety and efficacy of MS1819-SD vs porcine 
pancreatic enzyme replacement therapy (PERT) in patients with exocrine pancreatic insufficiency (EPI) due 
to cystic fibrosis (CF).   
Study Design 
This is a Phase 2, open-label, multicenter, 2x2 crossover study assessing the safety and efficacy of MS1819-
SD (2240 mg/day) vs porcine PERT given at the same dose that was being administered during the prestudy 
period. 
MS1819-SD will be assessed in a 2x2 crossover including at least 30 patients completing both periods (ie, 
15 for each sequence of treatments).  Patients will be randomized to receive either the sequence consisting 
of MS1819-SD for 3 weeks followed by PERT for another 3 weeks or the opposite sequence of treatments 
(PERT for 3 weeks followed by MS1819-SD for another 3 weeks).  
Randomized patients will be males and females 18 years or older. The primary efficacy endpoint is the 
coefficient of fat absorption (CFA) that will be assessed at the end of the 3-week period of treatment for 
each 2x2 crossover. 
Inclusion Criteria 
To be eligible for study entry, patients must satisfy all of the following inclusion criteria: 
1. Signed and dated informed consent form by patient as required by AzurRx or designee and appropriate 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
2. Age ³18 years at the time of screening 
3. Male or female 
4. Cystic fibrosis, based on 2 clinical features consistent with CF, plus initial diagnostic sweat chloride 
³60 mmol/L by quantitative pilocarpine iontophoresis or genotype 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 4 of 65 
 
5. Under stable dose of porcine PERT ≥1 month; stable dose is defined as dose of medication not changed 
during this time period, and the medication must be commercially available and be administered in the 
recommended dose range. 
6. A fair or better nutritional status as defined by: 
· 
BMI ≥16.0 kg/m2 for female patients ≥18 years of age, or 
· 
BMI ≥16.5 kg/m2 for male patients ≥18 years of age 
7. Fecal elastase <100 µg/g of stool at screening 
8. Clinically stable with no documented evidence of significant respiratory symptoms that would require 
administration of intravenous antibiotics, oxygen supplementation, or hospitalization within 30 days of 
screening or during the screening period.  
9. Male and Female patients, if of childbearing potential, must use a reliable method of contraception 
during the study. A reliable method of birth control is defined as one of the following: oral or injectable 
contraceptives, intrauterine device, contraceptive implants, tubal ligation, hysterectomy, or a double-
barrier method (diaphragm with spermicidal foam or jelly, or a condom), abstinence or vasectomy. 
Periodic abstinence (calendar, symptothermal, or post-ovulation methods) is not an acceptable method 
of contraception.  The preferred and usual lifestyle of the patient must also be evaluated in determining 
if sexual abstinence is a reliable method of birth control 
10. Be considered reliable and capable of adhering to the protocol, according to the judgment of the 
Investigator 
Exclusion Criteria 
Patients will be excluded from the study if one or more of the following criteria are applicable: 
1. History or diagnosis of fibrosing colonopathy 
2. Total or partial gastrectomy 
3. A history of solid organ transplant or significant surgical resection of the bowel; significant resection of 
the bowel is defined as any resection of the terminal ileum or ileocecal valve. Patients who have had 
qualitative, long-term changes in nutritional status after any other bowel resection (eg, increased or new 
need for pancreatic enzyme supplementation compared with preoperative status to maintain the same 
nutritional status) should also be excluded. 
4. Any chronic diarrheal illness unrelated to pancreatic insufficiency (eg, infectious gastroenteritis, sprue, 
inflammatory bowel disease) 
5. Known hypersensitivity or other severe reaction to any ingredient of the investigational medicinal 
product (IMP) 
6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥5 ×upper limit of normal 
(ULN), or total bilirubin level ≥1.5 ×ULN at the Screening visit, unless due to Gilbert’s 
syndrome. Cases of suspected or confirmed Gilbert’s syndrome should be discussed with the Medical 
Monitor 
7. Signs and/or symptoms of liver cirrhosis or portal hypertension (eg, splenomegaly, ascites, esophageal 
varices), or documented liver disease unrelated to CF 
8. Patients with a known allergy to the stool marker (FD&C Blue #2) 
9. Feeding via an enteral tube during 6 months before screening 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 5 of 65 
 
10. Routine use of anti-diarrheals, anti-spasmodics, or cathartic laxatives, or a change in chronic osmotic 
laxatives (eg, polyethylene glycol) regimen in the previous 3 months 
11. History of severe constipation with <1 evacuation/week under appropriate laxative therapy within the 
last 12 months before screening 
12. Documentation of distal intestinal pseudo-obstruction syndrome within the last 12 months before 
screening 
13. Forced expiratory volume ≤30% at the Screening visit 
14. Lactation or known pregnancy or positive pregnancy test at screening for women of childbearing 
potential 
15. Participation in another clinical study involving an IMP within 30 days before inclusion or 
concomitantly with this study 
16. Patient’s with poorly controlled diabetes according to the Investigator’s judgment 
Concomitant and Prohibited Medication 
Standard–of–care medications are allowed (eg, antibiotics, mucolytic agents, aerosols, CFTR modulators). 
Patients taking CFTR modulators should be on stable doses for at least 3 months. Patients should not start 
taking CFTR modulators during the duration of the study.   
Gastric acid suppressants are allowed but must be on stable dosage for 30 days before screening and must 
not be altered in dose or stopped during the study. 
Prohibited medications during the entire clinical study will be as follows: 
• 
Orlistat lipase inhibitor (eg, Alli®, Xenical®) 
• 
Laxatives consisting of mineral oil and castor oil (chronic use of osmotic laxatives is permitted) 
• 
Symptomatic treatments of diarrhea: loperamide (eg, loperamide generic, Imodium®, Imodium A-D®, 
Diamode®, Imotil®, Kao-Paverin®); atropine/diphenoxylate (Lonox®); and atropine/diphenoxylate 
(Lomocot®). 
Investigational Product, Dosage, Duration and Mode of Administration   
MS1819-SD is supplied as 140-mg capsule to be administered orally and taken with food. Daily doses will 
be fractionated according to the eating pattern of the patient. 
Duration of Study   
The estimated study duration will be determined by when all patients complete the study. Each patient will 
have approximately 21 days for screening, followed by approximately 6 weeks on study.  A 2-week End of 
Study/Early termination period will occur when each patient completes his/her treatment period of study or 
withdraws from the study.  Approximately a 3-week period for data collection and analysis will occur at the 
end of the study.  
 
 
 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 6 of 65 
 
 
 
Criteria for Evaluation   
Safety endpoints:  
AEs, SAEs, drop outs, and laboratory values. 
 
Efficacy Endpoints:  
Primary Endpoints:  
The primary efficacy endpoint is the CFA that will be assessed at the end of each 3-week treatment period.  
Secondary Endpoints:   
• 
Stool weights  
• 
Signs and symptoms of malabsorption 
• 
CNA 
• 
Body Weight 
• 
Body mass index 
• 
Serum liposoluble vitamins A, D, E, and K 
Statistical Methods 
Statistical methods will be further detailed in the Statistical Analysis plan (SAP).  
Sample size: The primary objectives of the trial are to assess the safety and investigate the relative efficacy 
of MS1819 as noninferior to porcine PERT. At least 30 patients completing both periods are judged enough 
to adequately assess their safety. Any event not occurring in the study would have a 95% CI on the rate 
extending from 0% to 10%; thus events not occurring may be assumed to be uncommon in the population 
(<10%).  Assuming a standard deviation of 20% for the paired differences in CFA measurements, within 
each patient, a noninferiority margin of 15%, a more favorable than expected difference of -4.0% in CFA 
means between MS1819 vs porcine PERT that favors PERT, a sample size of 30 patients completing both 
periods will provide a power of around 80% to show noninferiority to porcine PERT at the 2-sided nominal 
0.05 level of significance (that is, a one-sided alpha of 0.025). Accounting for a 20% dropout rate, 38 patients 
will be sufficient to achieve a power of at least 80%.   
Analysis Sets: 
Safety Set: Patients receiving at least one dose of treatment. 
Efficacy Sets 
• 
Intent-to-Treat Set: Patients as randomized and receiving at least one dose of treatment. 
The primary analysis will be performed in the ITT set. 
• 
Per Protocol Set: ITT patients completing both periods and without any major protocol 
deviation. A sensitivity analysis will be performed in the Per Protocol Set. 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 7 of 65 
 
Handling Missing Data:  
Missing data will not be replaced.   
 
Safety Analysis:   
Safety (AEs, SAEs, dropouts, and safety laboratory values) will be assessed by descriptive methods. 
Efficacy Analysis:   
• 
Primary Efficacy Endpoint 
o 
Primary Model of Analysis: The primary endpoint (ie, the CFA assessed at the 
end of each 3-week treatment period [Visit 6 or Visit 9]), will be analyzed in a 
mixed model including terms for sequence (MS1819-PERT vs PERT- MS1819); 
random patient nested in sequence; period (1 vs 2); and treatment (MS1819 vs 
porcine PERT). The treatment effect, along with the 95% confidence interval 
(difference in adjusted CFA means, MS1819 minus porcine PERT), will be 
estimated in this model. Noninferiority will be claimed if the lower bound of the 
95% confidence interval is greater than -15%, where 15% is the noninferiority 
margin. If noninferiority can be claimed, then superiority will be tested. 
Subgroup Analyses: Analyses of CFA considering the same approach used for the 
primary set will be performed in the following subgroups: 
§ 
by CFA level while receiving porcine PERT (<80% vs ³80%). Of note, it 
is expected that about 75% of enrolled patients will have CFAs while 
receiving porcine PERTs of 80% or greater.  An analysis will be done in 
the subgroup of patients with CFA below 80% while receiving porcine 
PERT, as well as in the subgroup of patients with CFA of 80% or greater 
while receiving porcine PERT.  
§ 
By those receiving or not receiving gastric acid suppression 
• 
Key Secondary Efficacy Endpoints 
o 
Stool weights, and signs and symptoms of malabsorption will be analyzed with the 
same approach used for the primary endpoint, switching non-parametric and semi-
parametric methods employed in the case that model assumptions are violated. 
 
 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 8 of 65 
 
3. TABLE OF CONTENTS 
1. 
Protocol Approval Signatures ............................................................................... 2 
2. 
Synopsis ................................................................................................................... 3 
3. 
Table of Contents ................................................................................................... 8 
4. 
List of Abbreviations ........................................................................................... 12 
5. 
Introduction .......................................................................................................... 13 
5.1 
Exocrine Pancreatic Insufficiency ...................................................................... 13 
5.2 
Exocrine Pancreatic Insufficiency due to Cystic Fibrosis ................................ 13 
5.3 
Standard of Care for the Compensation of Exocrine Pancreatic 
Insufficiency .......................................................................................................... 14 
5.4 
Investigational Product (MS1819-SD) ............................................................... 15 
5.5 
Preclinical Studies with MS1819 ........................................................................ 16 
5.5.1 
In Vitro Studies ..................................................................................... 16 
5.5.2 
In Vivo Studies ...................................................................................... 16 
5.6 
Clinical Studies with MS1819 ............................................................................. 17 
5.6.1 
FLIP110 First-in-Man Study with MS1819-FD ................................... 17 
5.6.2 
MS1819/16/01 Phase 2a Study with MS1819-SD ................................ 18 
5.7 
Rationale ............................................................................................................... 18 
5.8 
Dose Justification ................................................................................................. 18 
6. 
Study Objectives ................................................................................................... 20 
6.1 
Primary Objectives .............................................................................................. 20 
7. 
Investigational Plan .............................................................................................. 21 
7.1 
Overall Study Design and Plan: Description ..................................................... 21 
7.1.1 
Schedule of Assessments ...................................................................... 23 
7.2 
Study Endpoints ................................................................................................... 28 
7.2.1 
Primary Efficacy Endpoints .................................................................. 28 
7.2.2 
Secondary Efficacy Endpoints .............................................................. 28 
7.2.3 
Safety Endpoints ................................................................................... 28 
7.3 
Discussion of Study Design .................................................................................. 29 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 9 of 65 
 
7.3.1 
Number of Planned Patients .................................................................. 29 
7.3.2 
Inclusion Criteria ................................................................................... 29 
7.3.3 
Exclusion Criteria ................................................................................. 30 
7.3.4 
Removal of Patients from the Study ..................................................... 31 
7.4 
Investigational Products Administered .............................................................. 32 
7.4.1 
MS1819-SD Administration ................................................................. 32 
7.4.2 
Porcine PERT ........................................................................................ 33 
7.4.3 
Method of Assigning Patients to Treatment Groups ............................. 33 
7.5 
Previous and Concomitant Therapy .................................................................. 33 
7.6 
Study Drug Materials and Management ........................................................... 34 
7.6.1 
MS1819-SD .......................................................................................... 34 
7.6.1.1 
MS1819-SD Shipment, Receipt, and Storage ....................................... 34 
7.6.1.2 
MS1819-SD Misuse/Overdose ............................................................. 34 
7.6.1.3 
MS1819-SD and porcine PERT Compliance ........................................ 35 
7.6.1.4 
MS1819-SD Supply, Resupply, and Accountability ............................ 35 
7.6.1.5 
MS1819-SD Return, Destruction, and Recall ....................................... 35 
7.6.2 
Nonabsorbable Dye Marker .................................................................. 36 
7.6.2.1 
Shipment, Receipt, and Storage and Dispensing .................................. 36 
8. 
Timing of study procedures ................................................................................ 37 
8.1 
Screening Period .................................................................................................. 37 
8.1.1 
Visit 1, D-21 to D1: Screening Visit ..................................................... 37 
8.1.2 
Visit 2 Telephone (T) ............................................................................ 38 
8.2 
First Treatment Period (Visits 3, 4 (T), 5 (T), and 6) ........................................ 38 
8.2.1 
Visit 3 (Day 1): Randomization Visit - Must Occur Within 21 
Days of Visit 1 ...................................................................................... 38 
8.2.2 
V4 (T) (Day 8 ± 2) and V5 (T) (Day 15 ± 2) ........................................ 39 
8.2.3 
Visit 6: Stool Collection in Controlled Supervised Facility 
(Day 17 ± 7) .......................................................................................... 39 
8.3 
Second Treatment Period (Visits 7 [T], 8 [T] and 9) ......................................... 41 
8.3.1 
V7 (T) (Day 29 ± 2) and V8 (T) (Day 36 ± 2) ...................................... 41 
8.3.2 
Visit 9: Stool Collection in Controlled Supervised Facility 
(Day 38 ± 7) .......................................................................................... 41 
8.3.3 
Visit 10: End-of-Study /Early Withdrawal Visit (Day 56 ± 2) ............. 42 
8.3.3.1 
Instructions for Supervised Confinement for V6 and V9 ..................... 43 
9. 
Safety Assessments ............................................................................................... 44 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 10 of 65 
 
9.1 
Definitions ............................................................................................................. 44 
9.1.1 
Adverse Event ....................................................................................... 44 
9.1.2 
Serious Adverse Event .......................................................................... 45 
9.1.3 
“Serious” vs “Severe” Adverse Event .................................................. 46 
9.1.4 
SAE Definition Clarifications ............................................................... 46 
9.2 
Reporting Procedures for All Adverse Events .................................................. 47 
9.3 
Grading of Adverse Events, ................................................................................ 47 
9.4 
Relationship to Study Drug ................................................................................. 48 
9.5 
Serious Adverse Event Reporting Procedures .................................................. 48 
9.6 
Pregnancy Reporting Procedures ....................................................................... 49 
9.7 
Hepatic Monitoring .............................................................................................. 49 
9.8 
Data Safety Monitoring Board ............................................................................ 50 
9.9 
Appropriateness of Measurements ..................................................................... 50 
10. 
Statistical Methods ............................................................................................... 51 
10.1 General Considerations ....................................................................................... 51 
10.2 Sample Size Determination ................................................................................. 51 
10.3 Analysis Sets ......................................................................................................... 52 
10.4 Handling Missing Data ........................................................................................ 53 
10.5 Demographic, Other Baseline Characteristics and Medication ...................... 53 
10.5.1 
Patient Disposition and Withdrawals .................................................... 53 
10.5.2 
Demographic and Other Baseline Characteristics ................................ 54 
10.6 Safety Analysis ...................................................................................................... 54 
10.7 Efficacy Analysis .................................................................................................. 54 
10.7.1 
Primary Efficacy Endpoint .................................................................... 54 
10.7.2 
Secondary Efficacy Endpoints .............................................................. 55 
11. 
Quality Assurance and Quality Control ............................................................ 56 
11.1 Audit and Inspection ............................................................................................ 56 
11.2 Monitoring ............................................................................................................ 56 
11.2.1 
Responsibilities of the Monitor ............................................................. 56 
11.3 Data Management and Coding ........................................................................... 57 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 11 of 65 
 
12. 
Ethics ..................................................................................................................... 58 
12.1 Ethics and Regulatory Considerations ............................................................... 58 
12.2 Ethical Conduct of the Study .............................................................................. 58 
12.3 Informed Consent ................................................................................................ 58 
12.4 Patient Confidentiality ......................................................................................... 59 
13. 
Reporting and Publication, Including Archiving .............................................. 60 
14. 
References ............................................................................................................. 61 
15. 
Appendices ............................................................................................................ 64 
15.1 Investigator Signature Page ................................................................................ 64 
15.2 Clinical Laboratory Tests .................................................................................... 65 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ...................................................................... 23 
Table 2:  
MS1819-SD Typical Dosing schedule – Groups .................................. 33 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 12 of 65 
 
4. LIST OF ABBREVIATIONS  
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CF 
cystic fibrosis 
CFA 
coefficient of fat absorption 
CFFT 
Cystic Fibrosis Foundation Therapeutics, Inc. 
CFTR 
cystic fibrosis transmembrane conductance regulator 
cGCP 
current Good Clinical Practice 
cGMP 
current Good Manufacturing practice 
CI 
confidence interval 
CRF 
case report form 
CRO 
contract research organization 
DSMB 
Data and Safety Monitoring Board 
EPI 
Exocrine pancreatic insufficiency 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FD 
freeze-dried 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDL 
high density lipoprotein 
ICF 
informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
Institutional review board 
ITT 
intent-to-treat 
LDL 
low density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
PERT 
Pancreatic Enzyme Replacement Therapy 
PP 
per protocol 
PPI 
proton pump inhibitor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
spray dried 
SOP 
standard operating procedures 
ULN 
upper limit of normal 
VLDL 
very low density lipoprotein 
WHO 
World Health Organization 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 13 of 65 
 
5. INTRODUCTION 
5.1 
Exocrine Pancreatic Insufficiency  
The pancreas is both an endocrine and exocrine organ. As an exocrine gland, it secretes 
pancreatic juice containing digestive enzymes and a bicarbonate-rich fluid that neutralizes 
acidic gastric secretions, providing the correct pH for duodenal digestion by the pancreatic 
enzymes that assist in the absorption of nutrients in the small intestine. Exocrine pancreatic 
insufficiency (EPI) is defined by a deficiency of exocrine pancreatic enzymes which results 
in the inability to maintain normal digestion. The symptomatology of EPI is mainly due to 
pancreatic lipase deficiency, an enzyme that hydrolyzes triglycerides into monoglycerides 
and free fatty acids. 
Lipid maldigestion due to lipase deficiency can lead to weight loss; steatorrhea (characterized 
by greasy diarrhea); fat-soluble vitamin deficiencies (eg, vitamins A, D, E, and K); and can 
eventually lead to vitamin B12 deficiency and a potential decrease in quality of life (King et 
al, 1979). In EPI due to cystic fibrosis (CF) or chronic pancreatitis, there is a decrease in 
bicarbonate output, causing a lower intestinal pH, which leads to precipitation of bile salt 
acids and impairment of micelle formation of fats. Fat maldigestion is further exacerbated by 
lower levels of pancreatic lipase and colipase leading to decreased hydrolysis of intraluminal 
fat (Struyvenberg et al, 2017).  
5.2 
Exocrine Pancreatic Insufficiency due to Cystic Fibrosis 
Cystic fibrosis is an autosomal recessive chronic progressive disorder with high morbidity 
and a shortened life expectancy. It affects approximately 70,000 people worldwide (Cystic 
Fibrosis Foundation). In most Caucasian populations, CF prevalence is 7-8 cases per 100,000 
inhabitants but is less frequent in other populations (Farrell, 2008; Banks et al, 2010; Cystic 
Fibrosis Foundation Patient Registry 2010). In the United States, there are approximately 
30,000 affected individuals (Cystic Fibrosis Foundation Patient Registry, 2016). The disease 
occurs as a consequence of a mutation in the gene encoding for the CF transmembrane 
conductance regulator (CFTR) protein, a plasma membrane ion channel that mediates 
transport of chloride, bicarbonate, and other anions. Dysfunction of the CFTR gene leads to 
a decrease in luminal fluid volume and decreased pH, resulting in protein precipitation within 
the ductal lumen and loss of normal acinar cell function. Mutation of both alleles of CFTR 
results in the production of thick mucus, which causes a multisystem disease of the upper 
and lower respiratory tract, the digestive system, and the reproductive tract. 
Cystic fibrosis is frequently associated with EPI and is usually observed at birth because of 
in utero exocrine pancreatic damage. A neonatal screening study found that 63% of infants 
with CF were exocrine insufficient, and approximately 30% of the exocrine sufficient group 
would become insufficient over the next 36 months (Waters et al, 1990). Individuals with 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 14 of 65 
 
less severe CFTR mutations (Class IV, V, or VI) were more likely to develop EPI later in life 
(Ledder et al, 2014; Bodewes et al, 2015). 
5.3 
Standard of Care for the Compensation of Exocrine Pancreatic Insufficiency 
Porcine pancreatic enzyme replacement therapy (PERT) is the standard of care to prevent 
maldigestion, malnutrition, and excessive weight loss (Greenberger and Toskes 2008, 
Dhanasekaran and Toskes 2010, Greenberger and Toskes 2013). This therapy uses animal 
pancreatic extracts, which have been marketed since 1938. Porcine pancreatic extracts 
(porcine PERT) consist of an enzymatic mixture from pig pancreas, namely amylase, 
protease, and lipase, which digest starch, protein, and lipids, respectively. Therapy with 
porcine PERTs has demonstrated efficacy on the maldigestion symptoms due to EPI. 
Despite their long-term use, major concerns have been raised by the CF Foundation, the CF 
community, and the Food and Drug Administration (FDA) because of the animal ingredients 
used for porcine PERTs and the risk of transmission of conventional and nonconventional 
infectious agents. Furthermore, therapy with porcine PERTs has clear limitations: 
• The protease enzymatic constituents of porcine PERTs are suspected to cause 
fibrosing colonopathy (Kimura et al, 1998; Kimura et al. 1999), a severe adverse 
event (AE) observed at high doses in young patients with CF.  
• To prevent this risk of fibrosing colonopathy, the CF Foundation recommended that 
dosages should be limited to 500-2500 lipase units/kg/meal, ≤10,000 lipase 
units/kg/day, or ≤4000 lipase units/g of dietary fat/day (Stallings et al, 2008). 
Noticeably, porcine PERTs have only mild or null effects on creatorrhea (Van 
Hoozen et al, 1997, Airinei et al, 2011). 
• Incomplete correction of the lipid malabsorption, which can only be reached by 
high doses of enteric coated enzyme therapy in approximately 50% of patients with 
EPI caused by chronic pancreatitis and/or pancreatectomy [Dominguez-Munoz et al, 
2006; Safdi et al, 2006]. An internal survey based on all publicly available 
individual data show that only 25% of patients affected by CF with EPI had fully 
normalized coefficient of fat absorption (CFA) (ie, CFA higher than 93%) on 
porcine PERT substitution therapy. The incomplete enzymatic activity of porcine 
PERTs in the physiochemical environment of the upper digestive tract explains their 
reduced efficacy. A number of factors are involved, including the gastric acid pH in 
the range of 1 to 4; the intestinal pH ranging from 4 to 6 (porcine PERTs are active 
at pH > 6.5 in presence of biliary salts); and the protease content of the upper 
digestive tract (i.e., gastric pepsin). 
• The hazard of zoonotic pathogen transmission to humans remains possible with 
porcine PERTs because of their animal origins. For example, the porcine parvovirus 
may be present in these extracts, with (minimal) risk that it can cross species and 
transmit diseases to humans (Cherney, 2008).  


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 15 of 65 
 
• Most pancreatic enzyme products are unstable. To compensate for enzyme 
degradation over time, most manufacturers currently include overfill in the finished 
product. Therefore, their composition is poorly standardized and results in large 
‘lot-to-lot’ variation of efficacy and composition. As product instability requires the 
product to be stored at cool temperatures, efficacy can decrease once the bottle is 
open (eg, 6 months for Creon®). 
• Some additional concerns identified with porcine PERTs include irritation of oral 
mucosa if chewed/retained and hyperuricemia because of the presence of purines in 
porcine pancreatic extracts [Package insert Creon, Pancreaze, Zenpep, Pertzye]. In 
addition, patients with an allergy to proteins of porcine origin may have severe 
allergic reactions. 
• Because all of the currently marketed PERTs are porcine derived, there is a supply 
risk (both quality and quantity) that is dependent on the availability of pig herds.  
 
Because of the risks and limitations of porcine PERT, new drugs are demanded by 
pharmaceutical regulatory agencies and patient associations.  
A fundamental question is the value and usefulness of a lipase-only enzyme replacement 
therapy, such as MS1819-SD for patients with EPI.  For decades, the only available enzyme 
supplements to treat EPI have been porcine-derived pancreatic enzymes containing a mixture 
of lipase, protease, and amylase.  While the importance of the individual components in 
treating maldigestion has not been prospectively assessed, it is widely agreed that the earliest 
and sometimes only sign of malabsorption is steatorrhea (DiMagno et al, 1993; Ferrone et al, 
2007).  Extrapancreatic sources of protease and amylase exist (Dominguez-Munoz, 2007; 
Hammer et al, 2010), whereas little lipase is available other than that secreted by the 
pancreas.  Furthermore, some have suggested that protease deficiency can be treated in part 
with essential amino-acid mixtures (Engelen et al, 2014 ).  Most agree that amylase is the 
least important of the 3 supplemental pancreatic enzymes (Ladas et al, 1993) perhaps because 
of high amylase content in salivary gland secretions.  In summary, the future value of a lipase-
only supplement, either as a lipase-only replacement therapy in patients with mild to 
moderate EPI, or as an augmenting lipase for hyporesponsive patients reaching maximal 
doses of porcine enzyme treatment, remains to be seen.  Furthermore, whether other 
nonporcine enzymes might be added to MS1819-SD should be considered. This Phase 2 
study is the first step in development of MS1819-SD for use in CF patients with EPI.  If a 
safe and efficacious dose for treatment of steatorrhea can be established, then appropriate 
Phase 3 studies can be considered. 
5.4 
Investigational Product (MS1819-SD)  
MS1819-SD is a preparation of a recombinant yeast lipase, designated LIP2, which is a 
secreted enzyme, isolated from the strictly aerobic Yarrowia lipolytica that is found in 
various foods such as cheese and olive oil. This nonpathogen micro-organism is widely used 
as a biocatalyst (eg, erythritol production, a polyol used as a food additive) and is generally 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 16 of 65 
 
recognized as safe by the FDA for several industrial processes. The genetically engineered 
strain of Yarrowia lipolytica contains 5 additional copies of the LIP2 gene integrated into its 
genome (total of 6 including the endogenous native LIP2 gene). The genetic stability of the 
strain has been assessed for 100 generations, providing a safety margin as the full 
fermentation process corresponds to approximately 30 generations. Both current Good 
Manufacturing Practice (cGMP)-compliant Master Cell Bank and Working Cell Bank have 
been manufactured. 
The LIP2 gene product is a 334 amino-acid precursor that is released extracellularly as a 301 
amino-acid protein after cleavage of its peptide signal. The protein is naturally glycosylated 
which provides efficient protection against the proteolysis by the gastric pepsin (Pignede et 
al, 2000). At least 4 secreted glycosylated isoforms of LIP2 have been characterized (Aloulou 
et al, 2007). 
Until 2009, the active ingredient for MS1819 (recombinant yeast lipase, designated LIP2) 
was freeze-dried (FD) to obtain a final drug substance, MS1819-FD. From 2010 onwards, 
the process was changed for large scale production and the active ingredient for MS1819 was 
mixed with maltodextrin at a 1:2 ratio (dry weight/weight) and then spray dried (SD) to obtain 
a final drug substance, MS1819-SD.  
In this clinical study AZ-CF2001, MS1819-SD is supplied in capsules of 
hydroxyl-propylmethyl cellulose containing 140 mg of MS1819-SD. 
5.5 
Preclinical Studies with MS1819 
5.5.1 
In Vitro Studies 
The enzymatic activity of LIP2 has been extensively investigated in vitro and has an 
appropriate profile to compensate the EPI in patients with severe chronic pancreatic diseases. 
For example, the optimal activity of LIP2 occurs at pH 4–6, which is usually found in the 
duodenum of CF patients with decreased pancreas derived bicarbonate. In addition, LIP2 
enzymatic activity is not inactivated by bile salts, which are normally present in the 
duodenum below the Vaters ampulla. Furthermore, LIP2 is active on triglycerides with a 
wide range of fatty-acid lengths, including long-chain triglycerides, which are the 
predominant forms of triglycerides in the human diet. Compared with the porcine pancreatic 
lipase, LIP2 is more active than the porcine pancreatic lipase with all triglycerides tested at 
pH ranging from 4 to 6. 
5.5.2 
In Vivo Studies  
The efficacy of MS1819-FD has been investigated in minipigs; in which experimental 
pancreatitis and EPI were induced by pancreatic duct ligation. Daily doses of MS1819-FD 
10.5 mg or greater were administered once a day nearly completely corrected the CFA of 
approximately 20 kg minipigs (Aloulou 2015). 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 17 of 65 
 
The safety of MS1819-FD has been investigated in 2 nonclinical regulatory trials whereby 
MS1819-FD was well tolerated at dosages up to 1000 mg/kg in rats and 250 mg/kg in 
minipigs for up to 13 weeks. 
In summary, MS1819-FD was effective in minipigs and was nontoxic in both rodents and 
nonrodent species up to a maximum feasible dose of over 3 month’s administration. 
5.6 
Clinical Studies with MS1819 
5.6.1 
FLIP110 First-in-Man Study with MS1819-FD 
The efficacy and safety of MS1819-FD have been investigated in a first-in-man study, 
FLIP110. This exploratory clinical trial without predefined statistical analysis objectives, was 
a randomized, double blind, placebo controlled, parallel study. 
Patients affected with chronic pancreatitis or pancreatectomy and severe EPI, were randomly 
assigned to 2 phases with an allocation ratio of 2:1 to receive MS1819-FD 20 mg 3 times a 
day or a ‘dummy’ placebo treatment identical in aspect and taste. Each treatment was given 
for a phase of 1 week after a 1-week washout phase.  
Twelve patients were randomly included: 8 in MS1819-FD phase and 4 in the placebo phase. 
Three patients in the MS1819-FD phase were excluded from the per protocol (PP) analysis 
because of severe protocol deviations (ie, steatorrhea < 7 g/day in the baseline phase 
demonstrating the lack of significant EPI in these patients). 
The primary endpoint of the study was defined as the relative change in steatorrhea compared 
with baseline. A nonstatistically significant difference of the primary endpoint was found 
between the 2 phases both in intent-to-treat (ITT: -14.6 % ± 26.6 in the MS1819-FD phase 
vs +16.9 % ± 40 in the placebo phase; not significant) and PP analysis (-15.8 % ± 20.6 in the 
MS1819-FD phase vs +16.9 % ± 40 in the placebo phase; not significant), respectively. 
Secondary efficacy endpoints also support the efficacy of MS1819-FD compared with 
placebo in both ITT and PP populations, including the absolute change in CFA (ITT: +6.1 ± 
13.4 vs -6.7% ± 11.0), number of daily evacuations over 7 days (ITT: -19.2% ± 22.8 vs +4.1% 
± 11.7; p =.09), the weight of stools (ITT: -10.6% ± 27.4 vs +25.5% ± 48.2; not significant), 
and Bristol scale, which is a classification of the form of human feces to evaluate the 
effectiveness of treatments for diseases of the bowel (ITT: -5.13% ± 15.5 vs +2.46% ± 16.6; 
p<.0001). 
MS1819-FD was well tolerated with no serious adverse events (SAEs). Only 2 AEs were 
observed: constipation (2 patients in the MS1819 group) and hypoglycemia (2 patients in the 
MS1819 group and 1 patient in the placebo group). 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 18 of 65 
 
In summary, the FLIP110 study supports the continued clinical investigations of the efficacy 
of higher doses of MS1819-FD using established surrogate biomarkers for EPI correction. 
5.6.2 
MS1819/16/01 Phase 2a Study with MS1819-SD 
An open-label, dose escalation Phase 2a study (MS1819/16/01) was conducted to investigate 
the safety of escalating doses of MS1819-SD in 11 patients with EPI caused by chronic 
pancreatitis or pancreatectomy 
The primary objective of this study was to investigate the safety of escalating doses of 
MS1819-SD (280 mg/day, 560 mg/day, 1120 mg/day, and 2240 mg/day). Safety assessments 
included immunoallergic side effects, digestive symptoms, and clinical laboratory tests. The 
secondary objective of this study was to investigate the efficacy of MS1819-SD by 
assessment of CFA.  
Data from the first 8 treated patients are available and demonstrates clinical activity, where 
the greatest MS1819-SD response showed 14.5% improvement in CFA. The maximal 
absolute CFA response to treatment was 64.2%, with a trend to an inverse relationship to 
baseline CFA. Positive trends were observed on endpoints such as fecal nitrogen, Bristol 
stool scale, number of daily evacuations, and weight of stool, consistent with the CFA results. 
No SAEs or notable mild to moderate events have been reported to date (Interim Analysis).  
5.7 
Rationale 
Because of the limitations of porcine PERT therapy (outlined in Section 5.3), new drugs are 
required for the treatment of EPI due to CF or chronic pancreatitis. MS1819-SD has none of 
the highlighted drawbacks and the results from the FLIP110 study and preliminary results 
from the MS1819/16/01 study support the safety and efficacy of MS1819. Therefore, it is 
considered as an appropriate drug candidate for the treatment of EPI caused by CF. 
This study, OPTION, is designed to assess the efficacy and safety of 2240 mg/day of 
MS1819-SD in patients with CF.  This dose, recently studied in patients with chronic 
pancreatitis, is the highest dose studied to date, and was well tolerated.  If this dose is well 
tolerated in patients with CF and shows evidence of improved digestion, higher doses may 
be considered for study. 
5.8 
Dose Justification 
While this is the first study of MS1819-SD in patients with CF, previous studies in patients 
with chronic pancreatitis have included doses of MS1819-SD up to 2240 mg/day (see Section 
5.6.2). A total of 11 patients have now received up to 3 weeks daily treatment; the tolerability 
has been acceptable. To bridge from these studies into patients with CF, we have set the 
dosage for this study at 2240 mg/day.  


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 19 of 65 
 
The use of mass (mg) for dose expression, rather than USP lipase units is the result of the 
biochemical difference between porcine pancreatic-derived lipase and the microbial-derived 
lipase from the yeast Yarrowia lipolytica (Aloulou et al, 2015).  Porcine lipase is active at 
pH >7, while peak yeast-derived lipase activity occurs at pH 6.  The USP assay for porcine 
lipase units is conducted using an olive oil substrate at pH 9, while the enzymatic activity for 
MS1819-SD is assayed using tributyrin as substrate at pH 6.  No validated conversion factor 
is available for conversion of USP lipase units to tributyrin units.  It has been suggested by 
the FDA for microbial-derived lipase products that mass rather than units be used for dose 
expression (Heubi et al, 2016). 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 20 of 65 
 
6. STUDY OBJECTIVES  
6.1 
Primary Objectives 
The primary objectives of this study are to assess the safety and efficacy of MS1819-SD vs 
porcine PERT in patients with EPI due to CF.   
The primary safety objective of the study is to assess the safety and tolerability of a dose of 
2240 mg/day of MS1819-SD in patients with EPI caused by CF. Efficacy will be evaluated 
by comparing treatment with MS1819-SD to treatment with porcine PERT. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 21 of 65 
 
7. 
INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan: Description 
The OPTION study is a Phase 2, open-label, multicenter, 2x2 crossover trial to assess the 
safety and efficacy of MS1819-SD in patients with EPI due to CF in male and female patients 
aged 18 years or older. Efficacy will be evaluated by comparing treatment with MS1819-SD 
to treatment with porcine PERT. Refer to Figure 1 for a flow chart of the study design. 
During the treatment period, patients will be randomized to either MS1819-SD 
(2240 mg/day) or to their prestudy porcine PERT.  
A Data and Safety Monitoring Board (DSMB), consisting of members external to AzurRx 
BioPharma, Inc., and including members of the Cystic Fibrosis Foundation Therapeutics, 
Inc. (CFFT) DSMB, will monitor safety throughout the trial. After the study is complete, the 
DSMB will review the efficacy/safety data.  
Dosages will typically be fractionated as follows: 1/4 of the daily dose at each 3 main meals, 
and 1/8 at each of the 2 snacks (ie, 2240 mg/day will be fractionated as follows: 4 capsules 
of 140 mg with the morning, noontime, and evening meals, plus 2 capsules of 140 mg with 
the morning and evening snacks). Individual variations may occur as long as total daily dose 
is achieved. 
The dose of prestudy porcine PERT will be the same dose that was being administered during 
the prestudy period.  
The study will not employ a washout period between the first treatment period and the second 
treatment period. Recent experience with crossover lipase enzyme treatment from 
commercial PERTs to investigational lipase has demonstrated that symptoms of 
malabsorption may become evident within a matter of days, indicating little residual 
carryover effect of the original lipase (clintrials.gov NCT 02279498; clintrials.gov 
NCT0305140).  Furthermore, the 3-week duration of treatment with either study agent is well 
established as sufficient to show the degree of lipase effectiveness (FDA Package Insert, 
CREON; FDA Package insert, PANCREAZE). 
This study is divided into 4 main periods.  
• Screening Period (up to 21 days) 
• First Treatment Period (approximately 3 weeks) of the crossover design 
• Second Treatment Period (approximately 3 weeks) of the crossover design 
• End-of-Study/Early Withdrawal (approximately 2 weeks) 
Refer to Section 7.1.1 (Table 1) for the Schedule of Assessments. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 22 of 65 
 
Figure 1: 
OPTION Study Design Flow Chart 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 23 of 65 
 
7.1.1 
Schedule of Assessments 
Table 1: 
Schedule of Assessments 
 
SCREENING 
INITIAL TREATMENT PERIOD 
SECOND TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 (T)b 
3 
4 (T)c 
5 (T)c 
6d 
7 (T)c 
8 (T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit Window (days) 
V1 to V2 interval ≤21 
days 
±2 
±1 
±7 
±2 
±2 
±7 
±2 
Pre-Visit Instructions 
 
X 
 
 
 
 
 
 
 
 
Supervised 
confinement 
 
 
 
 
 
X 
 
 
X 
 
Clinical Assessments 
Obtain 
informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Complete history and 
physical 
X 
 
 
 
 
 
 
 
 
 
Focused 
physical 
exame 
 
 
X 
 
 
X 
 
 
X 
X 
Confirm 
CF 
diagnosis 
X 
 
 
 
 
 
 
 
 
 
Height/weight, vital 
signs (sitting) 
X 
 
X 
 
 
X 
 
 
X 
 
Inclusion/exclusion 
criteria review 
X 
 
X 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 24 of 65 
 
 
SCREENING 
INITIAL TREATMENT PERIOD 
SECOND TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 (T)b 
3 
4 (T)c 
5 (T)c 
6d 
7 (T)c 
8 (T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit Window (days) 
V1 to V2 interval ≤21 
days 
±2 
±1 
±7 
±2 
±2 
±7 
±2 
Confirm scheduled 
date for next 
supervised 
confinement visit 
 
 
 
X 
X 
 
X 
X 
 
 
Study Treatment 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Instruct regarding 
prestudy 
PERT/Dispense 
study drug MS1819-
SD 
 
 
X 
 
 
X 
 
 
X 
 
Verify study drug 
count at the end of 
confinement 
 
 
 
 
 
X 
 
 
X 
 
Return MS1819-SD 
(only for those on 
MS1819-SD) at the 
end of confinement  
 
 
 
 
 
X 
 
 
X 
 
Record fat and 
protein intake and 
study drug taken at 
all meals and snacks 
 
 
 
 
 
X 
 
 
X 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 25 of 65 
 
 
SCREENING 
INITIAL TREATMENT PERIOD 
SECOND TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 (T)b 
3 
4 (T)c 
5 (T)c 
6d 
7 (T)c 
8 (T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit Window (days) 
V1 to V2 interval ≤21 
days 
±2 
±1 
±7 
±2 
±2 
±7 
±2 
Cross over to 
alternative treatmentf 
 
 
 
 
 
X 
 
 
 
 
Efficacy Measures 
Malabsorption signs 
& symptoms 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
72-hour controlled 
diet record 
 
 
 
 
 
X 
 
 
X 
 
Marker-to-marker 
stool collection and 
stool weightg 
 
 
 
 
 
X 
 
 
X 
 
Laboratory Tests 
Urinalysis 
X 
 
X 
 
 
X 
 
 
X 
 
Pregnancy test 
(serum for V1 
screening and urine 
dipstick for other 
visits)h 
X 
 
X 
 
 
X 
 
 
X 
X 
Hematology, clinical 
chemistry, PT/INR, 
and aPTTi 
X 
 
 
 
 
X 
 
 
X 
 
Fasting lipids 
(patient to come in 
X 
 
 
 
 
X 
 
 
X 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 26 of 65 
 
 
SCREENING 
INITIAL TREATMENT PERIOD 
SECOND TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 (T)b 
3 
4 (T)c 
5 (T)c 
6d 
7 (T)c 
8 (T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit Window (days) 
V1 to V2 interval ≤21 
days 
±2 
±1 
±7 
±2 
±2 
±7 
±2 
fasting status) and 
pre-albumin 
Vitamin A, D, E, and 
K 
X 
 
X 
 
 
X 
 
 
X 
X 
Serum samples for 
anti-LIP2 lipase 
antibodies and 
MS1819-SD 
concentrations 
 
 
X 
 
 
X 
 
 
X 
X 
Fecal pancreatic 
elastasej 
X 
 
 
 
 
 
 
 
 
 
Diagnostic Test 
Spirometry 
X 
 
 
 
 
 
 
 
 
 
Resume Prescribed PERT 
Switch back to 
prescribed porcine 
PERTk 
 
 
 
 
 
 
 
 
X 
 
A  Screening procedures can occur up to 21 days before V1 through the first day of dosing (V3). 
B  This first study telephone call will occur once eligibility for the patient is determined. Instructions on the randomization visit will also be 
communicated and patients will be told to bring in their prestudy porcine with them for V3. 
C 
Visits 4, 5, 7, and 8 are telephone visits to assess any changes to AEs and concomitant medications in addition to confirming the visit date for 
the next scheduled supervised confinement. 
D Visit 6 and Visit 9 are the first and second scheduled confinement visits and can take up to 7 days. A 7 day window is permitted around the 
scheduled confinement for both V6 and V9 to accommodate for scheduling. Patient should bring their prestudy porcine PERT to V3. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 27 of 65 
 
E  
 The Focused Physical Exam will evaluate gastrointestinal tract, heart, and lungs. 
F  At the end of V6 (after the last stool sample has been collected), Patients that were randomized to MS1819-SD will begin treatment with their 
prestudy porcine PERT. Patients that were randomized to their prestudy porcine PERT will begin treatment with MS1819-SD. 
G  The stool samples and weight will be sent and analysed at the central laboratory. 
H  A serum pregnancy test must be conducted in females of reproductive potential at screening.  Pregnancy status will be re-evaluated via urine 
pregnancy test in these Patients at Visit 3,6,9 and at the End-of-Study or Early Termination visit. 
I  On the basis of laboratory safety values, unscheduled hepatic monitoring testing may be performed in Patients with new, clinically-meaningful 
increases in liver function tests occurring during the study, in consultation with study designated Medical Monitor. These tests are to be done 
through the central labs. 
J 
Fecal pancreatic elastase will be sent and analysed by the central laboratory. 
K At the end of V9, Patients should resume their prescribed porcine PERT.  For Patients that were on their prescribed porcine PERT during V9 no 
change will be needed. 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 28 of 65 
 
 
CONFIDENTIAL 
7.2 
Study Endpoints 
7.2.1 
Primary Efficacy Endpoints 
Safety and efficacy will be primary endpoints. Safety will be evaluated by descriptive 
methods. Efficacy will be assessed by noninferiority of CFA, between the MS1819-SD 
treatment vs the porcine PERT treatment. 
7.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of the study include: 
• A comparison of 72-hour stool weights, MS1819-SD vs porcine PERT 
• Signs and symptoms of malabsorption 
o Stool frequency (number of bowel movements per day) 
o Stool consistency (graded as 0=hard, 1=formed/normal, 2=soft, 
3=watery, or 4=overt diarrhea) 
o Bloating (graded as 0=none, 1=mild, 2=moderate, 3=severe) 
o Abdominal pain (graded as 0=none, 1=mild, 2=moderate, or 3=severe) 
o Flatulence (graded as 0=none, 1=mild, 2=moderate, or 3=severe) 
o Incidence of visible oil/grease in stool (Yes/No) 
o Increased stool quantity (graded as 0=none, 1=mild, 2=moderate, or 
3=severe) 
o Worsening of overall bowel habit (graded as 0=none, 1=mild, 
2=moderate, or 3=severe) 
• CNA  
• Body weight 
• Body mass index 
• Serum liposoluble vitamins A, D, E and K 
 
 
7.2.3 
Safety Endpoints 
AEs, SAEs and drop outs. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 29 of 65 
 
 
CONFIDENTIAL 
In addition, laboratory test results will be summarized (Section 15.2): 
• Hematology  
• Biochemistry  
• Fasting lipid profile  
• Urinalysis 
• Serum MS1819 concentrations 
• Antibodies against LIP2 lipase 
7.3 
Discussion of Study Design 
7.3.1 
Number of Planned Patients  
Approximately 30 patients are planned to complete the study pending a safety assessment 
after each group completes their clinical treatments and evaluations. To account for a possible 
20% dropout rate, approximately 38 patients are planned to be enrolled. 
The statistical considerations on which the planned number of patients is based are described 
in Section 10. 
7.3.2 
Inclusion Criteria 
To be eligible for study entry, patients must satisfy all of the following inclusion criteria: 
1. Signed and dated informed consent form by patient as required by AzurRx or 
designee and appropriate Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) 
2. Age ³18 years at the time of screening 
3. Male or female 
4. Cystic fibrosis, based on 2 clinical features consistent with CF, plus initial diagnostic 
sweat chloride ³60 mmol/L by quantitative pilocarpine iontophoresis or genotype 
5. Under stable dose of porcine PERT ≥1 month; stable dose is defined as dose of 
medication not changed during this time period, and the medication must be 
commercially available and be administered in the recommended dose range. 
6. A fair or better nutritional status as defined by: 
• BMI ≥16.0 kg/m2 for female patients ≥18 years of age, or 
• BMI ≥16.5 kg/m2 for male patients ≥18 years of age 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 30 of 65 
 
 
CONFIDENTIAL 
7. Fecal elastase <100 µg/g of stool at screening 
8. Clinically stable with no documented evidence of significant respiratory symptoms 
that 
would 
require 
administration 
of 
intravenous 
antibiotics, 
oxygen 
supplementation, or hospitalization within 30 days of screening or during the 
screening period.  
9. Male and Female patients, if of childbearing potential, must use a reliable method of 
contraception during the study. A reliable method of birth control is defined as one 
of the following: oral or injectable contraceptives, intrauterine device, contraceptive 
implants, tubal ligation, hysterectomy, or a double-barrier method (diaphragm with 
spermicidal foam or jelly, or a condom), abstinence or vasectomy. Periodic 
abstinence (calendar, symptothermal, or post-ovulation methods) is not an acceptable 
method of contraception.  The preferred and usual lifestyle of the patient must also 
be evaluated in determining if sexual abstinence is a reliable method of birth control 
10. Be considered reliable and capable of adhering to the protocol, according to the 
judgment of the Investigator 
7.3.3 
Exclusion Criteria 
Patients will be excluded from the study if one or more of the following criteria are 
applicable: 
1. Established or suspected fibrosing colonopathy 
2. Total or partial gastrectomy 
3. A history of solid organ transplant, or significant surgical resection of the 
bowel; significant resection of the bowel is defined as any resection of the terminal 
ileum or ileocecal valve. Patients who have had qualitative, long-term changes in 
nutritional status after any other bowel resection (eg, increased or new need for 
pancreatic enzyme supplementation compared with preoperative status to maintain 
the same nutritional status) should also be excluded. 
4. Any chronic diarrheal illness unrelated to pancreatic insufficiency (eg, infectious 
gastroenteritis, sprue, inflammatory bowel disease) 
5. Known hypersensitivity or other severe reaction to any ingredient of the 
investigational medicinal product (IMP) 
6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥5 
×upper limit of normal (ULN) or total bilirubin level ≥1.5 ×ULN at the Screening 
visit, unless due to Gilbert’s syndrome. Cases of suspected or confirmed Gilbert’s 
syndrome should be discussed with the Medical Monitor. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 31 of 65 
 
 
CONFIDENTIAL 
7. Signs and/or symptoms of liver cirrhosis or portal hypertension (eg, splenomegaly, 
ascites, esophageal varices), or documented liver disease unrelated to CF 
8. Patients with a known allergy to the stool marker (FD&C Blue #2) 
9. Feeding via an enteral tube during 6 months before screening 
10. Routine use of anti-diarrheals, anti-spasmodics, or cathartic laxatives, or a change in 
chronic osmotic laxatives (eg, polyethylene glycol) regimen in the previous 3 months 
11. History of severe constipation with <1 evacuation/week under appropriate laxative 
therapy within the last 12 months before screening 
12. Documentation of distal intestinal pseudo-obstruction syndrome within the last 12 
months before screening 
13. Forced expiratory volume ≤30% at the Screening visit 
14. Lactation or known pregnancy or positive pregnancy test at screening for women of 
childbearing potential 
15. Participation in another clinical study involving an IMP within 30 days before 
inclusion or concomitantly with this study 
16. Patient’s with poorly controlled diabetes according to the Investigator’s judgment  
7.3.4 
Removal of Patients from the Study   
A patient may be withdrawn from the study at any time for any of the following reasons: 
• Loss to follow-up 
• Withdrawal of consent, for any reason, at any time 
• Major protocol deviations that could compromise the interpretation of the 
results 
• Occurrence of an immunoallergic reaction 
• Occurrence of an adverse reaction (ie, an SAE related to IMP) that justifies the 
discontinuation of the IMP 
• Pregnancy 
The date of withdrawal and the reason for withdrawal must be fully documented in the case 
report form (CRF) and a short narrative description should be added in the patient’s medical 
records. 
If at the time of withdrawal, the patient has received the investigational study product 
(partially or totally), study staff should encourage the patient to attend the Early Withdrawal 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 32 of 65 
 
 
CONFIDENTIAL 
Visit for follow-up safety investigations. These patients will be included in the ITT efficacy 
analysis and safety analysis. 
If the reason for discontinuation is an AE, then the Investigator will seek to obtain follow-up 
information and to document the event until its resolution or stabilization. In any case, the 
Investigator will take all necessary measures to ensure the patient's safety and ensure the 
patient is treated in accordance with local standard of care. 
If a patient is lost to follow-up, then the Investigator should make every effort to obtain 
maximum information on the reasons for the nonattendance to the visit and on the patient’s 
state of health. All attempts will be documented in the patient’s medical records. 
Pregnancy 
Patients will be instructed that known or suspected pregnancy occurring during the study, in 
patients or female partners of male patients, should be confirmed and reported to the 
Investigator. Any patient who becomes pregnant during the study must be promptly 
withdrawn from the study. Upon discontinuation from the study, only those procedures that 
would not expose the patient to undue risk will be performed. The Investigator should also 
be notified of pregnancy occurring during the study but confirmed after completion of the 
study. In the event that a patient is subsequently found to be pregnant after inclusion in the 
study, any pregnancy will be followed to term, and the status of mother and child will be 
reported to the Sponsor after delivery. 
Full details will be recorded in the CRF, or an SAE report will be completed if the patient 
has completed the study. 
7.4 
Investigational Products Administered 
7.4.1 
MS1819-SD Administration 
At the time of prescribing, the Investigator or delegated site staff will fill in a source 
document with the appropriate dosing instructions. 
MS1819-SD doses will typically be fractionated as follows: 1/4 of the daily dosage at each 3 
main meals, and 1/8 at each of the 2 snacks (eg, for 2240 mg/day will be fractionated as 
follows: 4 capsules of 140 mg with the morning, noontime, and evening meals; plus 2 
capsules of 140 mg with the morning and evening snacks).   
Please refer to Table 2 for dosing guidance. 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 33 of 65 
 
 
CONFIDENTIAL 
Table 2:  
MS1819-SD Typical Dosing Schedule  
 
Dose: 2240 mg/day 
Breakfast 
4 x 140 mg capsules 
Snack 1 
2 x 140 mg capsules 
Lunch 
4 x 140 mg capsules 
Snack 2 
2 x 140 mg capsules 
Dinner 
4 x 140 mg capsules 
Total 
16 (140 mg) capsules/day 
Note: Individual variations may occur as long as correct total daily dose is achieved. 
7.4.2 
Porcine PERT 
Patients will take their porcine PERT at the same dose that was being administered during 
the prestudy period, during the appropriate treatment period.  
7.4.3 
Method of Assigning Patients to Treatment Groups 
Patients will be randomized 1:1.  
7.5 
Previous and Concomitant Therapy 
Standard-of-care medications are allowed (eg, antibiotics, mucolytic agents, aerosols, CFTR 
modulators). Patients taking CFTR modulators should be on stable doses for at least 3 
months. Patients should not start taking CFTR modulators during the duration of the study.   
Gastric acid suppressants are allowed but must be on stable dosage for 30 days before 
screening and must not be altered in dose or stopped during the study. 
Prohibited medications during the entire clinical study will be as follows: 
• Orlistat lipase inhibitor (eg, Alli®, Xenical®) 
• Laxatives consisting of mineral oil and castor oil; chronic use of osmotic 
laxatives is permitted 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 34 of 65 
 
 
CONFIDENTIAL 
• Symptomatic treatments of diarrhea: loperamide (eg, loperamide generic, 
Imodium®, Imodium A-D®, Diamode®, Imotil®, Kao-Paverin®); 
atropine/diphenoxylate (Lonox®); and atropine/diphenoxylate (Lomocot®). 
7.6 
Study Drug Materials and Management  
7.6.1 
MS1819-SD 
Study drug MS1819 will be supplied by the Sponsor for use in the protocol and is limited to 
investigational use only. Please refer to current Investigator’s Brochure for additional 
information.  
MS1819-SD is 70% pure preparation of LIP2 protein. The concentrated ultra-filtration 
product obtained from fermentation is mixed with maltodextrin (1:2 ratio, based on the lipase 
dry weight) and subjected to spray drying (i.e., the drug substance). The drug product is 
formulated with inactive excipients and formulated in nonanimal origin capsules of 
hydroxypropylmethyl cellulose (also named HPMC or hypromellose). MS1819-SD capsules 
will be used in the study with 140 mg active pharmaceutical ingredient in each capsule. 
MS1819-SD will be supplied as per following dosage form and will be provided in blister 
packs (wallets) in boxes: 
• A white hard HPMC capsule filled with an off-white to light grey powder containing 
approximately140 mg of MS1819-SD. 
7.6.1.1 MS1819-SD Shipment, Receipt, and Storage 
MS1819-SD will be supplied in blister packs to the sites by the Sponsor, in accordance with 
local requirements. The IMP will be shipped at room temperature. The site is responsible for 
the appropriate storage of the IMP. The IMP must be stored in a secured limited-access area 
and maintained at room temperature ≤ 25°C. 
7.6.1.2 MS1819-SD Misuse/Overdose 
Any IMP misuse or overdose associated or not associated with any AE should be reported to 
the Sponsor or designee as an SAE. Overdose is considered as dose taken above the 
prescribed daily dose for the current dosing phase. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 35 of 65 
 
 
CONFIDENTIAL 
7.6.1.3 MS1819-SD and porcine PERT Compliance 
The Investigator is responsible for ensuring compliance. Compliance with MS1819-SD and 
porcine PERT will be cross-checked with IMP accountability (number of capsules and 
blisters) 
7.6.1.4 MS1819-SD Supply, Resupply, and Accountability 
On receipt, the pharmacist or delegated site staff will record the date, details of the bottle, 
and quantity of capsules.  
The investigational sites will be re-supplied with IMPs according to their respective 
recruitment rates. 
The pharmacist or delegated site staff will be provided with specific forms for accountability 
of the IMP (including the returned blisters). Records will be kept up-to-date throughout the 
study and must be complete and accurate. 
Used and unused IMPs must be made available to the Monitor or Sponsor designee who will 
verify the IMP accountability and cross-check pharmacy and Investigator records for 
compliance to the protocol requirements. Any discrepancy must be accounted for and 
documented. 
7.6.1.5 MS1819-SD Return, Destruction, and Recall 
Return of IMP: 
• Unused, partially used, or empty blisters will be returned by the patient to the 
site at the end of each cycle.  
• At the end of the study, the Sponsor will conduct a final reconciliation between 
delivered, dispensed, and used/unused IMPs. 
Destruction of IMP: 
• Unused, partially used, or empty blisters must not be destroyed at the 
Investigative Sites without written authorization from the Sponsor.  
• Unused, partially used, or empty blisters returned to the pharmacy will be 
destroyed at the Hospital Pharmacy or Sponsor’s Drug Distributor only after 
IMP accountability forms have been fully and accurately completed and 
verified by the Monitor. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 36 of 65 
 
 
CONFIDENTIAL 
• If an on-site destruction is required, then the site must obtain written 
authorization for destruction from the Sponsor, which will be filed along with 
the certificate of destruction in the IMP section of the pharmacy site file. 
Recall: 
• If an IMP batch is suspected to be defective, then the Sponsor will immediately 
inform the Investigator and the hospital pharmacist. 
• The Monitor will coordinate with the investigative site staff for the return of the 
concerned batches as per the return procedure. Depending on the study status, 
new batches may be sent to the investigational site. 
7.6.2 
Nonabsorbable Dye Marker 
The dye marker FD&C Blue #2, also named Indigo carmine or Indigotin, will be supplied in 
accordance with current Good Manufacturing Practices (cGMP).  
7.6.2.1 Shipment, Receipt, and Storage and Dispensing  
The dye marker will be supplied. The dye makers should remain between 15–25°C (room 
temperature) and will not require temperature monitoring during shipment and storage. The 
bottle must be placed in secure location at site. 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 37 of 65 
 
 
CONFIDENTIAL 
8.  TIMING OF STUDY PROCEDURES 
Patients will provide written informed consent before any study-related procedures are 
performed. 
The study Schedule of Assessments is included in Section 7.1.1 (Table 1). 
8.1 
Screening Period 
Throughout the screening period, Patients are to remain on their prestudy porcine PERT. 
8.1.1 
Visit 1, D-21 to D1: Screening Visit  
The following procedures will be performed at the Screening Visit (which may take place 
over more than one day): 
• Obtain signed informed consent from the patient before any study-related 
assessments are made 
• Collect relevant medical history, including concomitant illnesses/diseases, 
previous/concomitant medications, and record AEs 
• Complete physical 
• Specific CF assessment including a pulmonary function test by spirometry to 
determine FEV1 >30% of predicted normal for age, sex, and height at screening 
and a sweat chloride test 
• Record body height and weight 
• Record vital signs while sitting (blood pressure, pulse rate, breathing rate, and 
temperature) 
• Assess for eligibility (against the inclusion and exclusion criteria) 
• Record demographic data such as ethnic origin, date of birth, and sex 
• Collect urine sample for urinalysis 
• Perform a serum pregnancy test, if applicable 
• Collect samples for hematology, clinical chemistry, PT/INR, activated partial 
thromboplastin time (aPTT) 
• Collect blood samples for vitamin determination (A, D, E, and K) 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 38 of 65 
 
 
CONFIDENTIAL 
• Patients will be required to fast before the collection of screening laboratory 
tests. 
• Collect samples for fasting lipids and prealbumin 
• Obtain a stool sample for fecal pancreatic elastase concentration in the selected 
central laboratory 
 
8.1.2 
Visit 2 Telephone (T) 
Once patient eligibility is confirmed, patients will be contacted by telephone and instructed 
to:   
• Refrain from alcohol consumption for 24 hours before the visit 
• Bring their prestudy porcine PERT with them to the clinic in the event they are 
randomized to their prestudy PERT 
 
8.2 
First Treatment Period (Visits 3, 4 (T), 5 (T), and 6)  
8.2.1 
Visit 3 (Day 1): Randomization Visit - Must Occur Within 21 Days of Visit 1 
During the first treatment period, patients will be randomized to either a fixed dose of 
MS1819-SD or to their prestudy porcine PERT. Visit 3 will take place if the patient is eligible 
to continue on the basis of data obtained at the Screening visit. The following procedures will 
be performed: 
• Review Inclusion /Exclusion Criteria 
• Focused physical exam to evaluate gastrointestinal tract, heart, and lungs 
• Record body height and weight 
• Record vital signs while sitting (blood pressure, pulse rate, breathing rate, and 
temperature) 
• Record any changes in AEs and concomitant medication  
• Randomization to either a fixed dose of MS1819-SD or to continue their 
prestudy porcine PERT  
• Instruct patients on use and dosing   
• Instruct/dispense study drug to patient (if randomized to MS1819-SD), 
otherwise patients are to continue on their prestudy porcine PERT 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 39 of 65 
 
 
CONFIDENTIAL 
• Assess and record malabsorption signs and symptoms 
• Collect urine sample for urinalysis 
• Perform a urine pregnancy test (urine dip stick), if applicable 
• Collect blood samples for vitamin determination (A, D, E, and K) 
• Collect a serum sample for circulating anti-LIP2 lipase antibodies and MS1819-
SD concentrations  
 
8.2.2 
V4 (T) (Day 8 ± 2) and V5 (T) (Day 15 ± 2) 
The following procedures will be performed: 
• Record any changes in AEs and concomitant medication review.  
• Assess and record malabsorption signs and symptoms 
• Confirm patient scheduled date for V6 (first stool collection in supervised 
controlled setting) and remind patients to come in fasted status. 
8.2.3 
Visit 6: Stool Collection in Controlled Supervised Facility (Day 17 ± 7) 
Patients will be admitted for a maximum of 7 days to a facility providing supervised 
confinement for collection of stool for determination of CFA, CNA, and stool weight. The 
timing of the previous visits (Visit 1 and Visit 2) should be made with the aim of 
accommodating the patients’ schedules for the supervised confinement. To accommodate 
patients’ schedules for the supervised confinement, a ±7 day visit window is permitted.  
• During the third week (Visit 3) (±1 week), patients will undergo admission to 
a controlled supervised facility for stool collection to support the CFA and CNA 
assessment and weight. A ±7 day visit window is allowed to accommodate 
investigative site staff and patients schedules for the supervised confinement.  
• After appearance of fecal stool dye markers has been measured, patients CFA 
and CNA will be measured under their dose of MS1819-SD or prestudy dose 
of porcine PERT using standardized high-fat meals during the 3-day 
standardized diet. 
• The CFA calculation will be based on the measured fecal fat content in relation 
to ingested fat quantities during the 3-day stool collection period. 
After completion of the initial treatment period during the completion of V3, patients will be 
instructed to switch their study medication to either a fixed dose of MS1819-SD or their 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 40 of 65 
 
 
CONFIDENTIAL 
prestudy porcine PERT. The stool collection and dietary procedures will be conducted as 
described in Section 8.3.3.1. (Instructions for Supervised Confinement) 
The following procedures will be performed at Visit 6: 
• Focused physical exam to evaluate gastrointestinal tract, heart, and lungs 
• Record body height and weight 
• Record vital signs while sitting (blood pressure, pulse rate, breathing rate, and 
temperature) 
• Record any changes in AEs and concomitant medication  
• Instruct/dispense study drug 
• Verify study drug count on the last day of confinement 
• Return MS1819-SD (only for patients randomized to MS-1819SD) on the last 
day of confinement 
• Assess and record malabsorption signs and symptoms 
• Begin 72-hour controlled diet  
• Marker-to-marker stool collection and stool weight (central laboratory will 
weigh the stool that is collected) 
• Collect urine sample for urinalysis 
• Perform a urine pregnancy test (urine dip stick), if applicable 
• Collect samples for hematology, clinical chemistry, PT/INR, and aPTT  
• Collect samples for fasting lipids and prealbumin 
• Collect blood samples for vitamin determination (A, D, E, and K) 
• Collect a serum sample for circulating anti-LIP2 lipase antibodies and MS1819-
SD concentrations  
• Record all fat, protein, and dose of study drug taken with every meal and snack 
during the confinement period 
At the end of the supervised confinement (once the second blue dye marker sample has been 
collected), patients will crossover to their new treatment). Patients randomized to MS1819-
SD will begin treatment on their prestudy porcine PERT. Patients randomized to their 
prestudy porcine PERT will begin treatment on MS1819-SD.  


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 41 of 65 
 
 
CONFIDENTIAL 
8.3 
Second Treatment Period (Visits 7 [T], 8 [T] and 9) 
The second treatment period will begin once patients have passed their second blue dye 
marker at the end of V6, and the stool sample collection is complete. As soon as this has 
occurred, patients will crossover to their new treatment (either MS1819-SD or patient’s 
prestudy porcine PERT). 
8.3.1 
V7 (T) (Day 29 ± 2) and V8 (T) (Day 36 ± 2) 
The following procedures will be performed: 
• Record any changes in AEs and concomitant medication review.  
• Assess and record malabsorption signs and symptoms 
• Confirm patient scheduled date for V9 (second stool collection in supervised 
controlled setting) and remind patients to come in fasted status. 
8.3.2 
Visit 9: Stool Collection in Controlled Supervised Facility (Day 38 ± 7) 
Patients will be admitted for a maximum of 7 days to a facility providing supervised 
confinement for collection of stools for determination of CFA, CNA and stool weight. The 
stool collection and dietary procedures will be conducted as described in Section 8.3.3.1 
(Instructions for Supervised Confinement). The following procedures will be performed at 
Visit 9: 
• Focused physical exam to evaluate gastrointestinal tract, heart, and lungs 
• Record body height and weight 
• Record vital signs while sitting (blood pressure, pulse rate, breathing rate, and 
temperature) 
• Record any changes in AEs and concomitant medication  
• Instruct/dispense study drug 
• Verify study drug count on the last day of confinement 
• Return MS1819-SD (only for patients that crossed over to MS-1819SD) on the 
last day of confinement 
• Assess and record malabsorption signs and symptoms 
• Begin 72-hour controlled diet  


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 42 of 65 
 
 
CONFIDENTIAL 
• Marker-to-marker stool collection and stool weight (central laboratory will 
weigh the stool that is collected) 
• Collect urine sample for urinalysis 
• Perform a urine pregnancy test (urine dip stick), if applicable 
• Collect samples for hematology, clinical chemistry, PT/INR, and aPTT  
• Collect samples for fasting lipids and prealbumin 
• Collect blood samples for vitamin determination (A, D, E, and K) 
• Collect a serum sample for circulating anti-LIP2 lipase antibodies and MS1819-
SD concentrations  
• At the end of the supervised confinement (once the second blue dye marker 
sample has been collected): 
o All patients are to resume therapy on their prestudy porcine PERT. 
Patients who crossed over to MS1819-SD will resume treatment on their 
prestudy porcine PERT; Patients who crossed over to their prestudy 
PERT will continue with their prescribed therapy.   
o Patients on MS1819-SD will return all study drug. 
• Remind patients of their scheduled Visit 10 date 
8.3.3 
Visit 10: End-of-Study /Early Withdrawal Visit (Day 56 ± 2) 
Patients will return to the clinic for their End of Study visit approximately 2 weeks after their 
last dose of study drug (either MS1819-SD or the patient’s prestudy porcine PERT).  In the 
event that patients do not complete V9, an Early Withdrawal visit will be held approximately 
2 weeks after the last dose of study drug (either MS1819-SD or the patient’s prestudy porcine 
PERT). The procedures scheduled for the End-of-Study visit are the same as those that should 
be conducted for the Early Withdrawal visit.  The following procedures will be performed at 
the End-of-Study/Early Withdrawal Visit: 
• Focused physical exam to evaluate gastrointestinal tract, heart, and lungs 
• Record any changes in AEs and concomitant medication   
• Assess and record malabsorption signs and symptoms 
• Collect a serum sample for circulating anti-LIP2 lipase antibodies and MS1819-
SD concentrations  
• Collect blood samples for vitamin determination (A, D, E, and K) 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 43 of 65 
 
 
CONFIDENTIAL 
• Perform a urine pregnancy test (urine dip stick), if applicable 
 
8.3.3.1 Instructions for Supervised Confinement for V6 and V9 
Beginning at breakfast (the first meal) on Day 1 of the supervised confinement, patients will 
be placed on a 72-hour controlled diet, with 100 g fat/day (3 meals and 2 snacks per day) and 
a minimum of 1.5 to 2 g of protein per kg of body weight. Although it is preferred to have 
the patient consume exactly 100 g of fat per day, the fat excretion assay remains valid with a 
fat intake range within 15% of the goal (ie, 85 to 115 g of fat per day). The nutritional 
planning and calculation of dietary fat and nitrogen (protein) intake will be conducted by a 
qualified dietician at each site. The actual fat and nitrogen (protein) intake will be calculated 
from the recorded type and amount of food consumed. A central laboratory will calculate 
CFA, CNA, and stool weight values on the basis of dietary intake and the fat and nitrogen 
excreted in stool. 
An indicator marker (500 mg of Food, Drug, and Cosmetics [FD&C] Blue #2) will be 
provided as two 250-mg capsules. The first marker (consisting of two 250-mg capsules) will 
be given at the beginning of breakfast or first meal on Day 1 of the supervised confinement 
to mark the start of the controlled diet. The second marker (two 250-mg capsules) will be 
given at the beginning of breakfast or first meal on Day 4 to mark the end of the controlled 
diet. Stool collection for fecal fat and nitrogen assessments must begin after the first marker 
has passed (the first stool containing the first marker is discarded) and is completed when the 
second marker has passed (the first stool containing the second marker is collected). Patients 
must continue the supervised confinement until the second stool marker is passed. The 
controlled diet will be maintained until the patient takes the second marker. Although it is 
not part of the controlled diet, the breakfast or first meal consumed on Day 4 of the supervised 
confinement should mimic (as closely as possible) the breakfast or first meal consumed on 
Day 1 of the supervised confinement. 
If the patient has not passed the first blue dye marker within 4 days after ingesting the first 
dye marker capsules, or within 2 days after ingesting the second dye marker capsules, then 
5-10 mg of oral bisacodyl may be given. Bisacodyl is the only laxative that may be given 
during the marker-to-marker stool collection period. Note: Patients on a stable chronic 
osmotic laxative may continue this therapy during the marker-to-marker stool collection. 
The supervised confinement may take place within an inpatient facility or within an 
alternative confinement setting. This will be discussed and approved on an individual case 
basis by the sponsor.  The alternative confinement setting will require the supervision of 
trained study site staff to oversee the study procedures. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 44 of 65 
 
 
CONFIDENTIAL 
9. SAFETY ASSESSMENTS 
The planned Schedule of Assessments is included in Section 7.1.1 (Table 1). 
9.1 
Definitions 
9.1.1 
Adverse Event 
An AE is any untoward medical occurrence experienced by a patient in a clinical 
investigation; it does not necessarily have a causal relationship with this study drug. An AE 
can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Active or worsening of EPI is not considered an AE for the purposes of this study.  Worsening 
of EPI disease should not be recorded as an AE, but should be recorded in the appropriate 
EPI CRF.   
Adverse events may also include postdose complications that occur as a result of 
protocol-mandated procedures (eg, invasive procedures such as venipuncture, biopsy, etc.).  
Preexisting events that increase in severity or change in nature during, or as a consequence 
of, use of a medicinal product in a human clinical study will also be considered AEs.  Any 
preexisting medical condition or diagnosis associated with a clinically significant laboratory 
abnormality should be documented on the CRF or eCRF.  The Investigator should attempt to 
establish a diagnosis of the event based on signs, symptoms, and other clinical information. 
In such cases, the unifying diagnosis should be documented as the AE, rather than the 
individual signs and symptoms (eg, runny nose, scratch throat, cough, and low grade fever 
should be recorded as a upper respiratory infection and not each of the individual symptoms). 
An AE does NOT include the following: 
• Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, 
transfusion); the condition that necessitates the procedure is an AE 
• Any preexisting disease or condition or laboratory abnormality present or 
detected before the start of administration of study medication that does not 
worsen 
• Laboratory abnormalities without clinical manifestations, which do not require 
medical intervention, or that do not result in termination or delay of study 
medication 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 45 of 65 
 
 
CONFIDENTIAL 
• Situations where an untoward medical occurrence has not occurred (eg, 
hospitalization for elective surgery, social, or convenience admissions) 
• Overdose of any study drug or concomitant medication without any signs or 
symptoms, unless the patient is hospitalized for observation 
• Worsening and/or flares of EPI disease activity. This should be recorded in the 
appropriate EPI CRF. However, if disease worsening meets any of the criteria 
for an SAE, it must be recorded on the SAE form and reported to the Sponsor 
or designee within 24 hours of becoming aware of the event. 
9.1.2 
Serious Adverse Event 
An SAE is defined as any adverse experience occurring at any dose of study medication that 
occurs between the time the patient signs the informed consent form through the end-of-study 
that results in any of the following outcomes: 
• Death 
• Life-threatening situation (patient is at immediate risk of death) 
• In-patient hospitalization or prolongation of existing hospitalization for a 
clinically relevant reason (note that this excludes “social” hospitalization for 
nonmedical causes such as lack of transportation to home) 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a patient who received study 
drug 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or patient may 
require medical or surgical intervention to prevent one of the outcomes listed 
in this definition.  Examples may include, but are not limited to: 
o Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
o Blood dyscrasias that do not result in hospitalization 
o Seizures that do not result in hospitalization 
A hospitalization meeting the regulatory definition for “serious” is any in-patient hospital 
admission that includes a minimum of an overnight stay in a health care facility.   


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 46 of 65 
 
 
CONFIDENTIAL 
Worsening and/or flares of EPI disease activity should be recorded in the appropriate EPI 
CRF.  However, if disease worsening meets any of the criteria for an SAE, then it must be 
recorded on the SAE form and reported to the Sponsor or designee within 24 hours of 
becoming aware of the event. 
9.1.3 
“Serious” vs “Severe” Adverse Event 
To avoid confusion or misunderstanding over the difference between the terms “serious” and 
“severe,” which are not synonymous, the following note of clarification is provided 
(excerpted from International Council for Harmonisation [ICH] E2A):  
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache).  This is not the same as 
“serious,” which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient’s life or functioning.  Seriousness (not severity) serves 
as a guide for defining regulatory reporting obligations. 
9.1.4 
SAE Definition Clarifications 
• Death is an outcome of an AE, and not an AE in itself.  
• All deaths during study through the end-of-study, regardless of cause or 
relationship, must be reported. 
• “Occurring at any dose” does not imply that the patient is actively receiving 
study drug at the time of the event. 
• “Life-threatening” means that the patient was at immediate risk of death from 
the event as it occurred. This does not include an event that might have led to 
death, had it occurred with greater severity. 
• Complications that occur during hospitalizations are AEs.  If an AE prolongs 
hospitalization, it is an SAE. 
• “In-patient hospitalization” means the patient has been formally admitted to a 
hospital for medical reasons, for any length of time, excepting situations where 
an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social, or convenience admissions). Hospitalization may or 
may not be overnight.  It does not include presentation and care within an 
emergency department (although an emergency department visit may define a 
medically important event, which is also considered an SAE).   


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 47 of 65 
 
 
CONFIDENTIAL 
• If any AE worsens during the study and eventually meets the criteria for an 
SAE the AE should be recorded as a new SAE. 
9.2 
Reporting Procedures for All Adverse Events 
AEs will be recorded in the CRF for all patients from the time the patient signs the informed 
consent form through the end of the study or patient withdrawal. 
The Investigator is responsible for ensuring that all AEs (as defined in Section 9.1 and as 
further specified below) observed by the Investigator or reported by patients are collected 
and recorded in the patients’ medical records, in the CRF, and as an SAE in the electronic 
data capture system.  These AEs will include the following: 
1. All SAEs (as defined in Section 9.1.2) that occur. 
2. All nonserious AEs (as defined in Section 9.1.1) that occur. 
The following AE attributes must be assigned by the Investigator:   
• AE diagnosis or syndrome(s) (if known, signs or symptoms if not known);  
• event description (with detail appropriate to the event);  
• dates of onset and resolution; severity; assessment of relatedness to study drug; 
and 
• action taken with study medication.   
The Investigator may be asked to provide follow-up information, discharge summaries, and 
extracts from medical records or CRFs. 
It will be left to the Investigator’s clinical judgment to determine whether the relatedness of 
an AE, and of sufficient severity to require the patient’s removal from treatment or from the 
study. A patient may also voluntarily withdraw from treatment because of what he or she 
perceives as an intolerable AE. If either of these situations arises, the patient should be 
strongly encouraged to complete the End-of-Therapy assessments and be under medical 
supervision until symptoms cease or the condition becomes stable. 
9.3 
Grading of Adverse Events,  
The Investigator will be asked to provide an assessment of the severity of the AE using the 
categories noted below.  This assessment is subjective, and the Investigator should use 
medical judgment to compare the reported AE to similar events observed in clinical practice.  
It is important to recognize that severity is not equivalent to event seriousness. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 48 of 65 
 
 
CONFIDENTIAL 
Grade 1 (Mild):  usually transient; requires no special treatment and does not generally 
interfere with the patient’s daily activities. 
Grade 2 (Moderate):  produces a mild to moderate level of inconvenience to the patient 
and may interfere with daily activities.  These events are usually ameliorated by simple 
therapeutic measures. 
Grade 3 (Severe):  significantly interrupts daily activity and requires systemic drug 
therapy or other medical treatment. 
9.4 
Relationship to Study Drug 
For each reported AE, the Investigator must make an assessment of the relationship of the 
event to the study drug using the following scale: 
Unrelated:  The event is definitely not or unlikely associated with study drug 
administration and is judged because of causes other than the study drug. 
Related:  Events considered to be related are those that follow a reasonable temporal 
sequence from administration of the study drug, that are not easily explained by another 
cause such as known characteristics of the patient’s clinical state or other treatment or 
confirmed by improvement on stopping or slowing administration of the study agent (de-
challenge), if applicable.  
9.5 
Serious Adverse Event Reporting Procedures 
Serious adverse events will be recorded from the time the patient signs the informed consent 
form through the end of study.  AEs will be followed until the event resolves or stabilizes, or 
until the end of study for that patient. 
If the AE is an SAE and is assessed as “related to study drug”, it must be followed until either 
the event is considered stable or resolved. 
Any SAE assessed as “unrelated to study drug” will be followed as clinically indicated until 
its resolution or, if not resolving, until considered stable or until the final study visit for that 
patient whichever comes first. 
All SAEs that occur must be reported within 24 hours of discovery or notification of the 
event.  Initial SAE information and all amendments or additions must be recorded as an SAE 
in the electronic data capture system and sent to the Sponsor or designee.   


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 49 of 65 
 
 
CONFIDENTIAL 
If a patient is permanently withdrawn from the study because of an SAE, then this 
information must be captured as an SAE in the initial or follow-up electronic data capture 
record as well as the End-of-Therapy CRF. 
The Investigator should notify the appropriate IEC/IRB of SAEs occurring at the site and 
other SAE reports received from AzurRx, in accordance with local procedures and statutes. 
AzurRx will ensure that applicable regulatory authorities receive all relevant information on 
an SAE, in accordance with regulatory requirements.  Results of AzurRx’s investigation of 
other safety information shall be submitted, as required. 
9.6 
Pregnancy Reporting Procedures 
Patients must be instructed to inform the Investigator immediately if they or their partners 
become pregnant after the patient has received their first dose of investigational product 
during the study.  The following actions should be taken in the event of a confirmed 
pregnancy: 
1. For female patients, study drug should be discontinued immediately. 
2. The pregnancy should be reported to the Safety Group within 24 hours of 
notification using the applicable Pregnancy Report Form. 
3. The Investigator should counsel the patient regarding the possible effects of 
previous study drug exposure on the fetus and the need to inform the study site of 
the outcome of the pregnancy. 
4. The patient or the patient’s pregnant partner must be monitored until the 
immediate postnatal period or until termination of the pregnancy.  The outcome 
should be reported to the Medical Monitor using the Pregnancy Outcome Form. 
Pregnancy is not an AE in and of itself. However, any pregnancy complications or elective 
terminations of a pregnancy for medical reasons will be recorded as an AE or SAE.  A 
spontaneous abortion is always considered an SAE and will be reported as described in the 
AE and SAE sections (Section 9.2 and Section 9.5).  Furthermore, any SAE occurring as an 
adverse pregnancy outcome poststudy must be reported to the Medical Monitor. 
9.7 
Hepatic Monitoring 
The following guidelines are provided for the management of serum transaminase elevations 
in patients with new, clinically-meaningful increases in liver function tests occurring during 
the study. All cases of new (ie, since screening) elevations in ALT or AST ³ 3 times ULN or 
any questions concerning the management of a patient with elevated serum transaminases 
should be discussed with the study Medical Monitor.  


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 50 of 65 
 
 
CONFIDENTIAL 
Patients who experience a new (ie, since screening) elevation in ALT or AST level to ≥3 × 
ULN OR total bilirubin ≥1.5 × ULN will have hepatic monitoring until one of the following 
occurs:  
• Withdrawal from study if elevation in ALT or AST level to ≥3 × ULN is 
associated with a rise in total serum bilirubin to ≥2 × ULN (without laboratory 
findings of cholestasis [elevated serum alkaline phosphatase ≥2 × ULN]) 
• Withdrawal from study if elevation in ALT or AST level to ≥5 × ULN is 
associated with new or exacerbated gastrointestinal (GI) symptoms (ie, nausea, 
vomiting, right upper quadrant pain, and/or jaundice) and other causes are not 
evident 
• Withdrawal from the study if elevation in ALT or AST is ≥10 × ULN regardless 
of serum bilirubin level 
Causes of acute elevation of transaminases should be considered and ruled out (e.g., viral 
hepatitis, concomitant medications).  
Patients discontinued from study drug administration should resume porcine PERT therapy 
according to physician prescription.   
9.8 
Data Safety Monitoring Board 
An external, independent data monitoring committee (DMC) will monitor and protect the 
safety and risk/benefit of the study patients throughout the study duration and evaluate the 
risk/benefit of study drug.  The DMC will consist of suitably qualified individuals, including 
CF experts.   
9.9 
Appropriateness of Measurements 
The efficacy and safety assessments planned for this study are widely used and generally 
recognized as reliable, accurate, and relevant to the assessment of biological products 
administered to patients with CF. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 51 of 65 
 
 
CONFIDENTIAL 
10. 
STATISTICAL METHODS  
10.1 General Considerations 
The statistical methods will be further detailed in the Statistical Analysis Plan (SAP). 
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the description for making the change, will be 
described in the SAP and in the clinical study report. Additional exploratory analyses of the 
data will be conducted as deemed appropriate.  
Statistical methodology and analyses will be in accordance with the principles outlined by 
the International Council for Harmonisation (ICH) E9 guidelines.   
Tables, listings, and figures will be produced in accordance with the principles outlined by 
the ICH E3 guidelines.   
Summaries will consist of descriptive statistics including the nonmissing counts, mean, 
standard deviation, median, Interquartiles (IQ), minimum and maximum values for 
continuous variables, and number and percentage of patients in each defined category for 
categorical variables.  
Statistical tests will be performed at a one-sided 2.5% alpha. However, for the purposes of 
simplicity and clarity, displays will utilize the equivalent two-sided 5% nominal significance 
level along with 95% two-sided confidence intervals (CI).  The primary goal of the study is 
to establish the safety of the chosen dose level; with the sample size, it is not anticipated that 
inferential statistics will achieve significance. 
There will be no adjustment for multiplicity arising from secondary efficacy analyses of the 
primary endpoint and/or secondary endpoint testing. The primary efficacy analysis of the 
primary endpoint aims to compare the efficacy of MS1819 vs porcine PERT.  
As a general rule, missing data will not be replaced.  
 
10.2 Sample Size Determination 
The primary objectives of the trial are to assess the safety of MS1819 and whether the 
efficacy of MS1819 is noninferior to porcine PERT.  


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 52 of 65 
 
 
CONFIDENTIAL 
With regard to safety assessment, at least 30 patients completing both periods are judged 
enough to adequately assess their safety. Any event not occurring in the study would have a 
95% CI on the rate extending from 0% to 10%; thus events not occurring may be assumed to 
be uncommon in the population (<10%).   
With regard to efficacy, the primary objective is to show that the efficacy of MS1819, 
measured on the primary endpoint (ie, the CFA), is noninferior to porcine PERT.  
• The noninferiority is chosen equal to 15% and the rationale for this choice is as 
follows: the difference in mean change from baseline in CFA between the 
reference and placebo was found to be approximately 32.6% in Trapnell (2011). 
According to the guidance on Noninferiority Clinical Trials to establish 
effectiveness (2016), the noninferiority (NI) margin should preserve a specified 
fraction of the difference between the reference and placebo. A NI margin of 
15% preserves 54% of the estimated difference between the reference and 
placebo.   
• In a recent unpublished trial, the standard deviation of the change in CFA was 
found to be around 16% among patients with a baseline CFA at or above 80%. 
As some patients enrolled in this trial might have a CFA under porcine PERT 
lower than 80%, a higher standard deviation of around 20% is expected.   
• Because the patients enrolled in the trial are already stabilized on porcine 
PERT, it is expected that the difference in CFA means between MS1819 and 
porcine PERT slightly favors PERT, which is expected to be around -8%.  
Out of an abundance of caution, the planned sample size is limited to roughly 30 subjects 
completing. However, assuming a standard deviation of 20% for the paired differences in 
CFA measurements within each patient, a noninferiority margin of 15%, a more favorable 
than expected difference of -4.0% in CFA means between MS1819 vs porcine PERT that 
favors PERT, a sample size of 30 patients completing both periods will provide a power of 
around 80% to show noninferiority of MS1819 to porcine PERT at the 0.05 2-sided nominal 
0.05 level of significance (that is, a one-sided alpha of 0.025). Accounting for a 20% dropout 
rate, 38 patients will be sufficient to achieve a power of at least 80%.   
10.3 Analysis Sets 
• Randomized set: patients as randomized.  Unless specified otherwise, this set 
will be used for all patient listings and summaries of patient disposition.  
• Safety Set: patients receiving at least one dose of treatment. Patients will be 
analyzed according to the treatment actually received. The Safety Set will be 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 53 of 65 
 
 
CONFIDENTIAL 
used for all analyses of safety endpoints unless specified otherwise and for the 
presentation of patients in listings related to dosing of study drug. 
• Efficacy sets: 
o ITT Set: Patients as randomized and receiving at least one dose of 
treatment. The ITT set is considered as the primary set for the efficacy 
analysis. The ITT set will be used for all analyses of efficacy endpoints. 
o Per Protocol Set: Subset of the ITT set comprising all patients who do 
not violate the terms of the protocol in a way that would affect the study 
outcome significantly, as determined by the study clinician. Protocol 
deviations will be captured throughout the study and classified as minor 
or major and reviewed at a data review meeting before database lock. 
Attendees will include appropriate individuals from the Sponsor and 
contract research organization. Each major deviation will be categorized 
as either important or not important with respect to the effect on the 
primary endpoint analysis. A sensitivity analysis will be performed in 
the Per Protocol Set. 
10.4 Handling Missing Data  
Missing data will not be replaced.   
10.5 Demographic, Other Baseline Characteristics and Medication 
Demographics, other baseline characteristics, and medications will be summarized for the 
Safety Set unless specified otherwise. 
10.5.1 Patient Disposition and Withdrawals 
The following will be summarized: 
• Number of screen failures  
• Number of patients included in the Randomized Set, ITT, and PP sets 
• Number of patients who completed the study (both treatment periods) 
• 
Number of patients who discontinued the study early with reasons  
The patient disposition, inclusion and exclusion criteria not met, eligibility for each analysis 
set, and protocol deviations will be listed.  


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 54 of 65 
 
 
CONFIDENTIAL 
10.5.2 Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the Safety Set: 
• for each sequence of each crossover  
• for each crossover 
• for all patients  
10.6 Safety Analysis   
Safety (AEs, SAEs, drop outs, and safety laboratory values) will be assessed by descriptive 
methods. A DSMB will be in charge to assess the safety of MS1819.  The DSMB Chairperson 
will receive SAE reports in real time during the study.  In addition, the DSMB will do a full 
data review at the end of the study to assess overall safety. 
10.7  Efficacy Analysis   
10.7.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the CFA assessed at the end of each 3-week 
treatment period (Visit 6 or Visit 9). CFA will be calculated as follows: 
CFA (%) = 100 ((fat intake (g) − fat excretion (g))/ fat intake (g)) 
 
Primary Analysis:   
The primary analysis of the primary endpoint, i.e. the CFA assessed at the end of each 
treatment period (Visit 6 or Visit 9), will be performed in the ITT set. 
The primary endpoint will be analyzed in a mixed model including terms for sequence 
(MS1819-PERT vs PERT- MS1819); random patient nested in sequence; period (1 vs 2); and 
treatment (MS1819 vs porcine PERT). The treatment effect, along with the 95% confidence 
interval (difference in adjusted CFA means, MS1819 minus porcine PERT), will be estimated 
in this model. Noninferiority will be claimed if the lower bound of the 95% confidence 
interval is greater than -15%, where 15% is the noninferiority margin. If noninferiority can 
be claimed, then superiority will be tested. 
The possible carryover effect, which is entirely confounded with the sequence effect in a 2x2 
crossover design, will be estimated. If there is a notable carryover, the analysis will be 
reported for each period separately.       


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 55 of 65 
 
 
CONFIDENTIAL 
Residuals of the model will be checked, and plotted vs predicted values. 
Secondary Analysis: 
The same analysis as described above will be performed in the PP set.  
Subgroup analyses: Analyses of CFA considering the same approach used for the primary 
set will be performed in the following subgroups: 
• by CFA level while receiving porcine PERT (<80% vs ³80%). Of note, it is 
expected that about 75% of enrolled Patients will have CFAs while receiving 
porcine PERTs of 80% or greater. An analysis will be done in the subgroup of 
Patients with CFA below 80% while receiving porcine PERT, as well as in the 
subgroup of patients with CFA of 80% or greater while receiving porcine 
PERT.  
• By those receiving versus not receiving gastric acid suppression. 
10.7.2 Secondary Efficacy Endpoints 
Coefficient of nitrogen absorption will be calculated and analyzed in the same manner as 
CFA. 
Stool weights, and signs and symptoms for malabsorption will first be analyzed with the 
same approach used for the primary endpoint. Models for analyzing the secondary endpoints 
will be further detailed in the SAP. If these analyses reveal gross departures from model 
assumptions, a nonparametric or a (Hodges-Lehmann) semiparametric approach will be 
proposed to analyze non-normally distributed endpoints. 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 56 of 65 
 
 
CONFIDENTIAL 
11. 
QUALITY ASSURANCE AND QUALITY CONTROL 
11.1 Audit and Inspection 
An audit/inspection may be carried out by qualified Sponsor staff, by subcontracted auditors 
or by representatives of national or foreign Health Authorities to ensure that the study is 
conducted as per protocol and in accordance with regulatory requirements, and to ensure the 
validity of the data. Participation in this study implies acceptance to cooperate in any 
potential audit/inspection. 
The audit/inspection may consist of an inspection of the premises and equipment together 
with verification of the study documents and data. The investigational team must be available 
for inspection or audit. When the Sponsor or the Investigator is informed that an inspection 
is to be performed, the other party must be informed immediately. 
Audits/inspection may take place after the end of the study. 
11.2 Monitoring 
Data for each patient will be recorded on a CRF. Data collection must be completed for each 
patient who signs an informed consent form (ICF). 
In accordance with cGCP and ICH guidelines, the study monitor will carry out source 
document verification at regular intervals to ensure that the data collected in the CRF are 
accurate and reliable.  
The Investigator must permit the monitor, the IEC/IRB, the Sponsor’s internal auditors, and 
representatives from regulatory authorities, direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the CRFs.   
11.2.1 Responsibilities of the Monitor 
Instructions for monitoring will be documented in a monitoring plan. 
The responsibilities of the study monitor are defined in ICH-E6, Chapter 5. The Monitor, 
who is mandated by the Sponsor, must ensure that the study is conducted in accordance with 
GCP guidelines and all applicable local laws, and that the rights, the security and the well-
being of the patients are respected. 
During the conduct of the study, the monitor reports any deviations or persistent poor 
compliance with the study requirements and the Sponsor makes decisions about appropriate 
corrective actions. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 57 of 65 
 
 
CONFIDENTIAL 
Compliance: 
• The monitor has the responsibility of assessing the progress of the study, of checking 
that the informed consent forms have been signed by the patient ensuring adhesion 
to and compliance with the study protocol and other study-related documents, and 
of ensuring the accuracy and completeness of the CRFs. Inconsistencies in the study 
records are to be resolved. 
Source Data Verification: 
• The monitor will perform source document verification and validation and request 
clarification to ensure the accuracy, completeness, and reliability of data. 
Investigational Medicinal Product: 
• The monitor must ensure that IMP handling is properly carried out and documented. 
He/she must ensure that the Investigator site file is up-to-date with regard to essential 
documents. 
11.3 Data Management and Coding 
The assigned contract research organization will be responsible for activities associated with 
the data management of this study. This will include setting up a relevant database and data 
transfer mechanisms, along with appropriate validation of data and resolution of queries.  
Study centers will enter data directly into an electronic data capture system by completing 
the CRF. Data entered into the eCRF must be verifiable against source documents at the study 
center. Data to be recorded directly on the eCRF will be identified and the eCRF will be 
considered the source document. Any changes to the data entered into the electronic data 
capture system will be recorded in the audit trail and will be FDA CFR 21 Part 11 compliant.  


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 58 of 65 
 
 
CONFIDENTIAL 
12. ETHICS 
12.1 Ethics and Regulatory Considerations 
The current study is to be conducted in accordance with globally accepted standards of GCP 
(ICH-E6), the Clinical Trial Directive 2001/20/EC, the GCP Directive 2005/28/EC, the 
revised version of the Declaration of Helsinki set out in the European Directive, and with 
applicable local requirements. 
The protocol will be submitted to the Health Authorities and a properly constituted IEC or 
IRB for formal approval of the study conduct in accordance with local regulations. 
The study may not begin until the protocol has received appropriate approval from the Health 
Authorities in accordance with local requirements. 
In accordance with specific local requirements, the Investigator may be responsible for 
submitting the protocol and any amendments to the local IEC/IRB. A copy of the decision 
letter, a list and versions of documents submitted, and a list of IEC/IRB members and their 
affiliation should be provided by the Investigator to the Sponsor. 
During the study, the Sponsor should promptly notify the Investigators and Health 
Authorities of any relevant information that could affect the safety of patients or effect on 
the conduct of the study. The regulatory authorities will be notified that the study has ended 
on completion of the study. 
12.2 Ethical Conduct of the Study 
The Investigator(s) and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, GCP, ICH 
guidelines, and applicable national laws, local laws, and regulatory requirements. 
12.3 Informed Consent 
Before a patient’s participation in this clinical study, the Investigator is responsible for 
obtaining written informed consent from the patient or legally acceptable representative after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study and before any protocol-specific screening procedures or any investigational products 
are administered.  A legally acceptable representative is an individual or other body 
authorized under applicable law to consent, on behalf of a prospective patient, to the patient’s 
participation in the clinical study.  The Investigator is also responsible for asking the patient 
if the patient agrees to have his/her primary care physician informed of the patient’s 
participation in the clinical study.  If the patient agrees to such notification, the Investigator 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 59 of 65 
 
 
CONFIDENTIAL 
shall inform the patient’s primary care physician of the patient’s participation in the clinical 
study. 
The acquisition of informed consent and the patient’s agreement or refusal of his/her 
notification of the primary care physician should be documented in the patient’s medical 
records, and the informed consent form should be signed and personally dated by the patient 
or a legally acceptable representative and by the person who conducted the informed consent 
discussion (not necessarily an Investigator).  The original signed informed consent form 
should be retained in accordance with institutional policy, and a copy of the signed consent 
form should be provided to the patient or legally acceptable representative. 
If a potential patient is illiterate or visually impaired and does not have a legally acceptable 
representative, then the Investigator must provide an impartial witness to read the informed 
consent form to the patient and must allow for questions.  Thereafter, both the patient and the 
witness must sign the informed consent form to attest that informed consent was freely given 
and understood.   
12.4 Patient Confidentiality 
Patient data will be kept strictly confidential. Patient anonymity will be protected by using 
number codes and /or initials. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 60 of 65 
 
 
CONFIDENTIAL 
13. REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
The Investigator shall not divulge unpublished data or information related to the study 
provided by the Sponsor, including but not limited to the study product characteristics, the 
Investigator’s Brochure, the study protocol, case report forms, assay methods, or scientific 
data, to any third party without written approval from the Sponsor. In addition, any new 
information that may become available during the course of the study shall be considered as 
confidential and shall not be used for any purpose other than the performance of the clinical 
study. 
The study data are the property of the Sponsor. The Investigator and any of the research staff 
shall obtain written approval from the Sponsor before the publication/communication of the 
results of any work carried out during or in relation to the study. Publication and/or 
communication of the results of the clinical study will be of a cooperative nature involving 
authors representing the Sponsor, the Investigators, and the scientific committee, if any. 
The Sponsor reserves the right to request modification of the content and/or timing of any 
publication or presentation if a patent application, an existing patent, or other proprietary 
rights may be jeopardized. 
Authorship of any publication related to the study and the order of presentation of the authors’ 
names shall be approved by the Sponsor. The Sponsor shall not use an Investigator’s name 
in any publication without his/her written permission and vice versa. 
The Sponsor should retain all essential study-related documents, i.e., documents which 
permit evaluation of the conduct of a study and the quality of the data produced, in 
accordance with the applicable regulatory requirements of his/her country. These essential 
documents include, but are not limited to, signed protocol, Investigator’s Brochure, printed 
CRFs, medical records, laboratory reports, informed consent forms, drug disposition records, 
safety reports, information regarding participants who discontinued, and other relevant 
documents and data. 
Study-related documents should be kept together in the Investigator site file provided to the 
Investigator by the Sponsor. Sufficient information about the identity of all study patients 
(eg, name, medical records number, patient number, and study number) should be retained 
by the Investigator so that any Sponsor representatives, auditors, or inspectors may access 
this information when required. The Investigator must retain all records for 15 years or longer 
if required by specific local requirements. The Investigator will contact the Sponsor for 
authorization before the destruction of any study records or in the event of accidental loss or 
destruction of any of them. All records should be kept in a secure area; however, in the cases 
of audit or inspection, they should be rapidly made available. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 61 of 65 
 
 
CONFIDENTIAL 
14. REFERENCES 
Airinei GC, Gaudichon C, Bos C, Bon N, Kapel B, Bejou JJ, et al. Postprandial protein 
metabolism but not a faecal test reveals protein malabsorption in patients with pancreatic 
exocrine insufficiency. Clin Nutr. 2011; 30: 831–7. 
Aloulou A, Rodriguez D, Puccinelli N, Mouz J, Leclaire Y, Leblond Y, et al. Purification 
and biochemical characterization of the LIP2 lipase from Yarrowia lipolytica. Biochim 
Biophys Acta. 2007;1771: 228–37. 
Aloulou A, Schue M, Puccinelli D, Milano S, Delchambre C, Leblond Y, et al. Yarrowia 
lipolytica lipase 2 is stable and highly active in test meals and increases fat absorption in an 
animal model of pancreatic exocrine insufficiency. Gastroenterology. 2015; 149: 1910-1919. 
 
Banks PA, Conwell DL, Toskes PP. The management of acute and chronic pancreatitis. 
Gastroenterol Hepatol (N Y). 2010;6(2 Suppl 3):1–16. 
Bodewes FAJA, Verkade HJ, Taminiau JAJM, Borowitz D, Wilschanski M. Cystic fibrosis 
and the role of gastrointestinal outcome measures in the new era of therapeutic CFTR 
modulation. J Cyst Fibros. 2015;14:169–77. 
Cherney, B. 2008. Viral Safety Issues for the Pancreatic Enzyme Product CREON. F. 
report, FDA. https://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4402s1-02-FDA-
Cherney%20.pdf. (Accessed 25 October 2017.) 
Cystic Fibrosis Foundation Patient Registry. Annual Data Report 2016. 
Cystic Fibrosis Foundation. What is cystic fibrosis? http://www.cff.org/AboutCF/. Accessed 
20 October 2017. 
Dhanasekaran R, Toskes PP. Pancrelipase for pancreatic disorders: An update. Drugs Today 
(Barc). 2010;46: 855–66. 
DiMagno EP, Clain JE, Layer P. 1993.Chronic Pancreatitis: In GO VI ed. The Pancreas: 
biology, pathophysiology and disease. 2nd ed. New York, Raven Press; 665-706. 
Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. 
Current Gastroenterol Rep.2007; 9: 116-122. 
Dominguez-Munoz JE, Iglesias-Garcia J, Iglesias-Rey M, Vilarino-Insua M. Optimising the 
therapy of exocrine pancreatic insufficiency by the association of a proton pump inhibitor to 
enteric coated pancreatic extracts. Gut. 2006;55: 1056–7. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 62 of 65 
 
 
CONFIDENTIAL 
Engelen MPKJ,Com G, Deutz NEP. Protein is an important but undervalued macronutrient 
in the nutritional care of patients with cystic fibrosis. Current Opinion Clin Nutr Metab Care. 
2014; 17: 515-520. 
 
Farrell, PM. The prevalence of cystic fibrosis in the European Union. J Cyst Fibros. 2008;7: 
450–3. 
Ferrone M, Raimondo M, Scolapio JS. Pancreatic enzyme pharmacotherapy. 
Pharmacotherapy. 2007; 27: 910-920. 
 
Greenberger N, Toskes P. 2008. Acute and Chronic Pancreatitis. Harrison's Principles of 
Internal Medicine. A. Fauci, E. Braunwald, D. Kasper et al. Columbus, OH, McGraw-Hill. 
Greenberger N, Toskes P. 2013. Acute and Chronic Pancreatitis. Harrison's Gastroenterology 
and Hepatology. D. Longo and A. Fauci. Columbus, OH, McGraw-Hill Medical. 
Hammer HF. Pancreatic exocrine insufficiency: diagnostic evaluation and replacement 
therapy with pancreatic enzymes. Dig Dis. 2010; 28: 339-343. 
 
Heubi JE, Schaeffer D, Ahrens RC, Sollo N, Strausbaugh S, Graff G, et al. Safety and 
efficacy of a novel microbial lipase in patients with exocrine pancreatic insufficiency due to 
cystic fibrosis: a randomized controlled clinical trial.  The Journal of Pediatrics. 2016; 176: 
156-161. 
 
 Kimura, R.E., et al. Indomethacin and pancreatic enzymes synergistically damage intestine 
of rats. Dig Dis Sci, 1998. 43: 2322-32.  
Kimura, R.E., et al. The effects of high-dose ibuprofen and pancreatic enzymes on the 
intestine of the rat, J Pediatr Gastroenterol Nutr, 1999; 29:178-83. 
King CE, Leibach L, Toskes PP. Clinically significant vitamin B12 deficiency secondary to 
malabsorption of protein-bound vitamin B12. Dig Dis Sci. 1979;24: 397–402. 
Ladas SD, Giorgiotis K, Raptis SA.  Complex carbohydrate malabsorption in exocrine 
pancreatic insufficiency. Gut. 1993; 34: 984-987. 
 
Ledder O, Haller W, Couper RT, Lewindon P, Oliver M. Cystic fibrosis: an update for 
clinicians. Part 2: hepatobiliary and pancreatic manifestations. J Gastroenterol Hepatol. 2014; 
29: 1954–62.Pignede G, Wang H, Fudalej F, Gaillardin C, Seman M, Nicaud JM. 
Characterization of an extracellular lipase encoded by LIP2 in Yarrowia lipolytica. J 
Bacteriol. 2000;182: 2802–10. 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 63 of 65 
 
 
CONFIDENTIAL 
Safdi M, Bekal PK, Martin S, Saeed ZA, Burton F, Toskes PP. The effects of oral pancreatic 
enzymes (Creon 10 capsule) on steatorrhea: a multicenter, placebo-controlled, parallel group 
trial in subjects with chronic pancreatitis. Pancreas. 2006;33:156–62. 
Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H. Clinical Practice 
Guidelines on, S. Nutrition and G. Ad Hoc Working. Evidence-based practice 
recommendations for nutrition-related management of children and adults with cystic fibrosis 
and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108: 
832–9. 
Struyvenberg MR, Martin CR, Freedman SD. Practical guide to exocrine pancreatic 
insufficiency - Breaking the myths. BMC Med. 2017;15:29. 
Van Hoozen CM, Peeke PG, Taubeneck M, Frey CF, Halsted CH.  Efficacy of enzyme 
supplementation after surgery for chronic pancreatitis. Pancreas. 1997;14: 174–80. 
Waters DL, Dorney SF, Gaskin KJ, Gruca MA, O’Halloran M, Wilcken B. Pancreatic 
function in infants identified as having cystic fibrosis in a neonatal screening program. N 
Engl J Med. 1990;322:303–8. 
 
 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 64 of 65 
 
 
CONFIDENTIAL 
15. APPENDICES 
15.1 Investigator Signature Page 
Protocol Title:  
Study Name:  
A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess 
the Safety and Efficacy of MS1819-SD in Patients with Exocrine 
Pancreatic Insufficiency due to Cystic Fibrosis 
OPTION: A Phase 2, Open-Label, Multicenter, 2x2 Crossover 
Trial to assess the Safety and Efficacy of MS1819-SD in Patients 
with Exocrine Pancreatic with Insufficiency due to Cystic Fibrosis 
Protocol Number: 
AZ-CF2001 
Confidentiality and cGCP Compliance Statement 
I have read and understand the protocol (Study No. AZ-CF2001) and the Investigator’s 
Brochure and I agree that it contains all the ethical, legal, and scientific information necessary 
to conduct this study.  I will conduct this protocol as outlined herein and will make every 
effort to complete the study within the time designated. 
I will provide copies of the protocol and access to all information furnished by AzurRx 
BioPharma, Inc. to study personnel under my supervision.  I will discuss this material with 
them to ensure that they are fully informed about the drug and the study. 
I understand that the study may be terminated or enrollment suspended at any time by AzurRx 
BioPharma, Inc., with or without cause, or by me if it becomes necessary to protect the best 
interest of the study patients. 
 
________________________________________________________________ 
Investigator Name (print) 
 
 
________________________________________________________________ 
Signature  
 
 
 
 
 
 
 
Date 


AzurRx 
OPTION 
October 30, 2018 
AZ-CF2001  
Version 2.0  
Page 65 of 65 
 
15.2 
Clinical Laboratory Tests 
 
 
Clinical Chemistry: 
Hematology: 
Serum Concentrations of: 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Chloride 
Leukocytes (WBC) 
Bicarbonate 
Absolute counts of: 
Blood urea nitrogen (BUN) 
Neutrophils, segmented 
Total Calcium 
Neutrophils, juvenile (bands) 
Phosphorus 
Lymphocytes 
Magnesium 
Monocytes 
Glucose 
Eosinophils 
Creatinine 
Basophils 
Albumin 
Platelets 
Prealbumin 
Total protein 
Other: 
Alkaline phosphatase 
Serum pregnancy testa 
Alanine aminotransferase (ALT) 
Urine pregnancy testa 
Aspartate aminotransferase (AST) 
Activated partial thromboplastin time (aPTT) 
Lactate dehydrogenase (LDH) 
Prothrombin 
time/International 
normalized 
ratio 
(PT/INR) 
Total bilirubin 
Vitamin A (retinol) 
Direct bilirubin 
Vitamin D (25-OH-D) 
Uric Acid 
Vitamin E (α-tocopherol) 
Vitamin K (K1) 
Fasting Lipid Profile: 
Stool: 
Total cholesterol 
Marker-to-marker stool collection 
Triglycerides 
Fecal Elastase 
Low Density Lipoprotein (LDL) 
 
High Density Lipoprotein (HDL) 
 
Very Low Density Lipoprotein (VLDL) 
 
Note:  All labs will be assayed by AzurRx designated central laboratory unless otherwise noted. 
a. 
Only for females of child bearing potential 
 
 
 

SAP_001.pdf: 
 
Official Title: 
Statistical Analysis Plan 
A Phase 2, Open Label, Multicenter, 2 x 2  
Crossover Trial to assess the 
Safety and Efficacy of MS 1819 SD in Patients 
with Exocrine Pancreatic 
Insufficiency due to Cystic Fibrosis 
 
NCT03746483 
 
 
Date of Document 
September 4, 2019 


 
STATISTICAL ANALYSIS PLAN 
04 September FINAL 2.0 
 
 
 
 
 
A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess the 
Safety and Efficacy of MS1819-SD in Patients with Exocrine Pancreatic 
Insufficiency due to Cystic Fibrosis 
 
 
 
OPTION Study 
PROTOCOL NUMBER AZ-CF2001 
 
 
 
 
SPONSORED BY 
 
AzurRx BioPharma, Inc. 
760 Parkside Avenue 
Suite 304 
Brooklyn, NY 11226 
 
 
 
 
PREPARED BY 
 
Rho, Inc. 
2635 E NC Hwy 54 
Durham, NC  27713 
Telephone:  (919) 408-8000 
Fax:  (919) 408-0999 
 
 
 
This document is confidential and proprietary to AzurRx BioPharma, Inc..  Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disclosed without the prior written approval of AzurRx BioPharma, 
Inc., except that this document may be disclosed to appropriate Institutional Review Boards under the 
condition that they keep the information confidential. 
Version:  AZ-CF2001_SAP_v2.0 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
 
 
 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
0.1 
07 March 2019 
Draft 1 Creation 
0.2 
17 April 2019 
Draft 2 Creation 
1.0 
07 May 2019 
Finalization of Version 1.0 
1.2 
18 July 2019 
Update for mITT population and 
analysis relative to first dose  
2.0 
04 September 2019 
Finalization of Version 2.0  
 
 
 
 
 
 
 
 
 
 
 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 2 of 37 
 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
APPROVALS 
Approved: 
 
 
 
 
Date: 
 
 
 
James Pennington, MD 
Chief Medical Officer 
AzurRx BioPharma, Inc. 
 
 
 
 
 
 
 
 
 
Date: 
 
 
 
Patricia Stephenson 
Principal Statistical Scientist 
Rho, Inc. 
 
 
 
 
 
 
 
Date: 
 
 
 
Maria Keesee 
Biostatistician 
Rho, Inc. 
 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 3 of 37 
04-Sep-2019 | 8:54:33 AM ED
04-Sep-2019 | 9:16:16 AM E
05-Sep-2019 | 9:56:42 AM PD


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .............................................................................................. 6 
1. 
PURPOSE OF THE ANALYSES ............................................................................... 7 
2. 
PROTOCOL SUMMARY ........................................................................................... 8 
2.1 
Study Objectives ............................................................................................ 8 
2.1.1 
Primary Objective .................................................................................. 8 
2.1.2 
Secondary Objectives ........................................................................... 8 
2.2 
Overall Study Design and Plan ...................................................................... 8 
2.3 
Study Population ............................................................................................ 9 
2.4 
Treatment Regimens ...................................................................................... 9 
2.5 
Treatment Group Assignments or Randomization ......................................... 9 
2.6 
Sample Size Determination ............................................................................ 9 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .................................. 11 
4. 
ANALYSIS POPULATIONS .................................................................................... 12 
4.1 
Modified Intent-to-Treat Population .............................................................. 12 
4.2 
Per-Protocol Population ............................................................................... 12 
4.3 
Safety Population ......................................................................................... 12 
5. 
STUDY SUBJECTS ................................................................................................. 13 
5.1 
Disposition of Subjects ................................................................................. 13 
5.2 
Protocol Deviations ...................................................................................... 14 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 15 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................ 16 
8. 
SAFETY EVALUATION ........................................................................................... 17 
8.1 
Overview of Safety Analysis Methods .......................................................... 17 
8.2 
Extent of Exposure ....................................................................................... 18 
8.3 
Adverse Events ............................................................................................ 18 
8.4 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .... 20 
8.5 
Clinical Laboratory Evaluation ...................................................................... 20 
8.6 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 20 
8.6.1 
Vital Signs ........................................................................................... 20 
8.6.2 
Physical Examinations ........................................................................ 21 
8.6.3 
Other Safety Measures ....................................................................... 21 
8.6.3.1 
Prior and Concomitant Medications ....................................... 21 
9. 
EFFICACY EVALUATION ....................................................................................... 23 
9.1 
Overview of Efficacy Analysis Issues ........................................................... 23 
9.1.1 
Handling of Dropouts or Missing Data ................................................ 23 
9.1.2 
Assessment Time Windows ................................................................ 23 
9.2 
Analysis Methods ......................................................................................... 24 
9.2.1 
Primary Efficacy Analyses .................................................................. 24 
9.2.1.1 
Supportive Analyses of the Primary Efficacy Analysis ........... 25 
9.2.1.2 
Subgroup Analyses ................................................................ 25 
9.2.2 
Secondary Efficacy Analyses .............................................................. 25 
9.2.2.1 
Coefficient of Nitrogen Absorption ......................................... 25 
9.2.2.2 
Stool Weight ........................................................................... 26 
9.2.2.3 
Malabsorption Signs and Symptoms ..................................... 27 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 4 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
9.2.2.4 
Weight and BMI ..................................................................... 27 
9.2.2.5 
Serum Liposoluble Vitamin (A, D, E, and K) Levels ............... 28 
10. DATA MONITORING ............................................................................................... 29 
10.1 
Data Monitoring ............................................................................................ 29 
11. DIFFERENCES BETWEEN THE SAP AND PROTOCOL AND CHANGES TO 
THE ANALYSES PLANNED IN THE PROTOCOL ................................................. 30 
11.1 
Differences between the SAP and Protocol and Changes to the Analyses 
Planned in Protocol Version 2 ...................................................................... 30 
12. REFERENCES ......................................................................................................... 31 
13. APPENDICES .......................................................................................................... 32 
13.1 
Study Flow Chart .......................................................................................... 32 
13.2 
Schedule of Events ...................................................................................... 33 
13.3 
Protocol Deviation Types ............................................................................. 36 
14. ATTACHMENTS ...................................................................................................... 37 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 5 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CDC 
Centers for Disease Control 
CF 
cystic fibrosis 
CFA 
coefficient of fat absorption 
CFF 
Cystic Fibrosis Foundation 
CFFT 
Cystic Fibrosis Foundation Therapeutics 
CFTR 
cystic fibrosis transmembrane conductance regulator 
CI 
confidence interval(s) 
CNA 
coefficient of nitrogen absorption 
CRF 
case report form 
CSR 
clinical study report 
DSMB 
data safety monitoring board 
EPI 
exocrine pancreatic insufficiency 
ICH 
International Conference on Harmonisation 
mITT 
Modified Intent-to-treat 
IP 
investigational product 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
PERT 
pancreatic enzyme replacement therapy 
PP 
per-protocol 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
TEAE 
treatment-emergent adverse event 
U 
units 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 6 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
1. PURPOSE OF THE ANALYSES 
The statistical analysis plan (SAP) is being developed after review of the AzurRx 
Biopharma, Inc. (AzurRx), protocol number AZ-CF2001, but before any analyses of the 
data.  The SAP contains detailed information to aid in the implementation of the 
statistical analyses and reporting of the study data for use in the clinical study report 
(CSR).  This SAP is being written with due consideration of the recommendations 
outlined in the most recent International Conference on Harmonisation (ICH) E9 
Guideline entitled Guidance for Industry:  Statistical Principles for Clinical Trials and the 
most recent ICH E3 Guideline, entitled Guidance for Industry:  Structure and Content of 
Clinical Study Reports. 
This SAP describes the analysis sets that will be analyzed, the subject characteristics 
parameters, the efficacy parameters, and the safety parameters that will be evaluated.  
The details of the specific statistical methods that will be used will be provided in this 
SAP.  If differences occur between analyses described in the SAP and the current 
protocol, those found in this SAP will assume primacy.  If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be 
completed and will be identified in the CSR.  Table and listing specifications are 
provided in a separate document.   
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 7 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
2. PROTOCOL SUMMARY 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objectives of this study are to assess the safety and efficacy of MS1819-SD 
vs porcine pancreatic enzyme replacement therapy (PERT) in patients with exocrine 
pancreatic insufficiency (EPI) due to cystic fibrosis (CF).   
The primary safety objective of the study is to assess the safety and tolerability of a dose 
of 2240 mg/day of MS1819-SD in patients with EPI caused by CF.  The primary efficacy 
objective of the study is to demonstrate the non-inferiority of MS1819-SD to porcine 
PERT for the coefficient of fat absorption (CFA) at the end of each treatment period in 
subjects with EPI due to CF. 
2.1.2 Secondary Objectives 
To evaluate and compare effects of MS1819-SD and porcine PERT on other measures of 
digestion including the coefficient of nitrogen absorption (CNA), stool weight, body 
weight, body mass index (BMI), signs and symptoms of malabsorption, and serum 
liposoluble vitamins A, D, E, and K. 
2.2 Overall Study Design and Plan 
This is a Phase 2, open-label, multicenter, 2x2 crossover study assessing the safety and 
efficacy of MS1819-SD (2240 mg/day) in patients with EPI due to CF for male and 
female patients aged 18 years or older.  Efficacy will be evaluated by comparing 
treatment with MS1819-SD to treatment with porcine PERT at the same dose that was 
being administered during the prestudy period.   
MS1819-SD will be assessed in a 2x2 crossover including at least 30 patients completing 
both periods such that at least 15 patients will complete each sequence of treatments.  
Patients will be randomized to receive either the sequence consisting of MS1819-SD for 
3 weeks followed by PERT for another 3 weeks or the opposite sequence of treatments 
(PERT for 3 weeks followed by MS1819-SD for another 3 weeks).  
The study will not employ a washout period between the first treatment period and the 
second treatment period.  Recent experience with crossover lipase enzyme treatment from 
commercial PERTs to investigational lipase has demonstrated that symptoms of 
malabsorption may become evident within a matter of days, indicating little residual 
carryover effect of the original lipase.  Furthermore, the 3-week duration of treatment 
with either study agent is well established as sufficient to show the degree of lipase 
effectiveness. 
Dosages will typically be fractionated as follows: 1/4 of the daily dose at each 3 main 
meals, and 1/8 at each of the 2 snacks (ie, 2240 mg/day will be fractionated as follows: 4 
capsules of 140 mg with the morning, noontime, and evening meals, plus 2 capsules of 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 8 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
140 mg with the morning and evening snacks).  Individual variations may occur as long 
as total daily dose is achieved. 
The dose of prestudy porcine PERT will be the same dose that was being administered 
during the prestudy period.  
Randomized patients will be males and females 18 years or older.  The primary efficacy 
endpoint is the coefficient of fat absorption (CFA) that will be assessed at the end of the 
3-week period of treatment for each 2x2 crossover. 
A study flow chart is presented in Appendix 13.1, and a schedule of events is presented in 
Appendix 13.2. 
2.3 Study Population 
Subjects that are ≥18 years of age with EPI due to CF will be enrolled.  The inclusion and 
exclusion criteria for the study are enumerated in Sections 7.3.2 and 7.3.3 of the protocol, 
respectively. 
2.4 Treatment Regimens 
At randomization, subjects will be assigned in a 1:1 ratio to receive either the sequence 
consisting of MS1819-SD for 3 weeks followed by PERT for another 3 weeks or the 
opposite sequence of treatments (PERT for 3 weeks followed by MS1819-SD for another 
3 weeks). 
Subjects will receive 2240 mg/day of MS1819-SD while in the MS1819-SD period of 
their treatment sequence.  Subjects will receive the same dose of PERT that was being 
administered during the prestudy period while in the porcine PERT period of their 
treatment sequence.  
2.5 Treatment Group Assignments or Randomization 
Subjects who meet all of the enrollment criteria will be randomized to receive MS1819-
SD followed by PERT or PERT followed by MS1819-SD using a 1:1 allocation ratio.     
2.6 Sample Size Determination 
The primary objectives of the trial are to assess the safety of MS1819 and whether the 
efficacy of MS1819 is noninferior to porcine PERT.  The sample size was primarily 
selected to be sufficient to address the safety objectives of this trial.  Given the sample 
size, efficacy will be assessed with the understanding that adequate power for assessing 
efficacy would only be achieved for differences that are more favorable than expected. 
With regard to safety assessment, at least 30 patients completing both periods are judged 
enough to adequately assess safety.  Any event not occurring in the study would have a 
95% CI on the rate extending from 0% to 10%; thus events not occurring may be 
assumed to be uncommon in the population (<10%).   
Version:  AZ-CF2001_SAP_v2.0 
 
Page 9 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
With regard to efficacy, the primary objective is to show that the efficacy of MS1819, 
measured on the primary endpoint (ie, the CFA), is noninferior to porcine PERT.  
• The noninferiority is chosen equal to 15% and the rationale for this choice is 
as follows: the difference in mean change from baseline in CFA between 
the reference and placebo was found to be approximately 32.6% in Trapnell 
(2011). According to the guidance on Noninferiority Clinical Trials to 
establish effectiveness (2016), the noninferiority (NI) margin should 
preserve a specified fraction of the difference between the reference and 
placebo. A NI margin of 15% preserves 54% of the estimated difference 
between the reference and placebo.   
• In a recent unpublished trial, the standard deviation of the change in CFA 
was found to be around 16% among patients with a baseline CFA at or 
above 80%.  As some patients enrolled in this trial might have a CFA under 
porcine PERT lower than 80%, a higher standard deviation of around 20% 
is expected.   
• Because the patients enrolled in the trial are already stabilized on porcine 
PERT, it is expected that the difference in CFA means between MS1819 
and porcine PERT slightly favors PERT, which is expected to be around -
8%.  
Out of an abundance of caution, the planned sample size is limited to roughly 30 subjects 
completing.  With regard to safety assessment, 30 patients completing both periods are 
judged enough to adequately assess safety.  However, assuming a standard deviation of 
20% for the paired differences in CFA measurements within each patient, a noninferiority 
margin of 15%, a more favorable than expected difference of -4.0% in CFA means 
between MS1819 vs porcine PERT that favors PERT, a sample size of 30 patients 
completing both periods will provide a power of around 80% to show noninferiority of 
MS1819 to porcine PERT at the 0.05 2-sided nominal 0.05 level of significance (that is, a 
one-sided alpha of 0.025).  Accounting for a 20% dropout rate, 38 patients will be 
sufficient to achieve a power of at least 80%. 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 10 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following is a list of general analysis and reporting conventions to be applied for this 
study. 
Categorical variables will be summarized using counts (n) and percentages (%) and will 
be presented in the form “n (xx.x).”  If a count is 0, 0% will be shown for the percentage.  
To ensure completeness, summaries for categorical and discrete variables will include all 
categories, even if no subjects had a response in a particular category. 
Continuous variables will be summarized using mean, SD, minimum, maximum, median 
and number of subjects.  The 25th and 75th percentiles will be provided for distributions 
that are known to be skewed.  The mean, median, 25th percentile, 75th percentile, and 
confidence intervals (CI) will be reported to 1 more level of precision than the original 
observations, and the SD will be reported to 2 more levels of precision than the original 
observations.  The minimum and maximum will be the same precision as the original 
data. 
When p-values are provided, they will be rounded to 3 decimal places; p-values that 
round to “0.000” will be presented as “<0.001.”  Unless otherwise stated, all statistical 
tests of treatment effects will be conducted at a 2-sided alpha level of 0.05. 
All analysis will be performed using SAS® System version 9.3 or later. 
Dates in listings will be displayed as yyyy-mm-dd (e.g., 2015-01-24). 
In general, age will be calculated in years using the date of birth and the date of 
randomization as [(date of randomization – date of birth)]/365.25, rounded down to the 
next largest integer using the floor function.  For any listing that includes screen failures, 
age will be labeled as age at screening and will be calculated in years using the date of 
birth and the date of Visit 1 as [(date of Visit 1 – date of birth)]/365.25, rounded down to 
the next largest integer using the floor function.   
In order to present summaries by treatment group regardless of sequence, the following 
parameters will be summarized as described below:  safety laboratory, vital signs, signs 
and symptoms of malabsorption, weight, BMI, and serum liposoluble vitamins A, D, E, 
and K. These endpoints will be summarized relative to the time of first dose on a given 
study treatment.  All post-randomization measurements will be relative to the time of the 
first dose.  For example, in the MS1819 treatment column, the measurement at first dose 
will be Visit 3 if a subject is randomized to the MS1819-PERT sequence, and Visit 6 if a 
subject is randomized to the PERT-MS1819 sequence.   
Version:  AZ-CF2001_SAP_v2.0 
 
Page 11 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
4. ANALYSIS POPULATIONS 
The following 3 analysis populations will be identified for this study: 
4.1 Modified Intent-to-Treat Population 
The modified intent-to-treat (mITT) population includes all randomized subjects who 
receive at least 1 dose of treatment and have at least 1 sufficient stool sample.  A stool 
sample will be considered sufficient if the date and time associated with the second blue 
dye marker is recorded, indicating that the stool sample collection is complete.  The 
mITT will be used for efficacy analyses.  Subjects will be analyzed according to the 
treatment group to which they were randomized regardless of the actual treatment 
received, unless stated otherwise. 
 
4.2 Per-Protocol Population 
The per-protocol (PP) population is a subset of the mITT population and includes all 
mITT subjects without major protocol deviations that could impact the efficacy analyses.  
Subjects who are found to be <80% compliant with MS1819 will be excluded from the 
PP population.  The PP population will be used as supportive to the mITT population.   
Prior to database lock, the protocol deviations will be reviewed and the PP Population 
will be determined.  Subjects will be included in the treatment sequence to which they 
were randomized regardless of the actual treatment sequence received. 
 
4.3 Safety Population 
The safety population, which will be used for all safety analyses unless stated otherwise, 
will include all randomized subjects who receive at least 1 dose of treatment.  Subjects in 
the safety population will be analyzed according to the actual treatment received 
regardless of their randomized assignment.   
 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 12 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
5. STUDY SUBJECTS 
5.1 Disposition of Subjects 
The disposition of subjects will be summarized for all subjects screened in the study.  The 
following disposition information will be summarized overall: 
• The number of subjects screened. 
• The number of subjects who failed screening and the reason for screen failure. 
All percentages will use the number of screened subjects as the denominator. 
The following disposition information will be summarized by treatment sequence for all 
subjects randomized in the study: 
• The number of subjects randomized. 
• The number and percentage of subjects in the mITT population, PP population, 
and safety population. 
• The number and percentage of subjects who completed the first treatment period 
(through Visit 6) 
• The number and percentage of subjects who withdrew from the first treatment 
period and the reason for withdrawal 
• The number and percentage of subjects who completed the second treatment 
period (through Visit 9) 
• The number and percentage of subjects who withdrew from the second treatment 
period and the reason for withdrawal 
• The number and percentage of subjects who completed the study (through visit 
10) 
• The number and percentage of subjects who withdrew from the study and the 
reason for withdrawal  
All percentages will use the number of randomized subjects as the denominator. 
A data listing of subject disposition for all randomized subjects and a data listing of 
screen failures will also be provided.   
 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 13 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
5.2 Protocol Deviations 
Protocol deviations will be identified on an ongoing basis by the study team and recorded 
on the protocol deviation case report form (CRF) page. 
The number and percentage of subjects with:  
• at least 1 protocol deviation;  
• at least 1 major protocol deviation;  
• at least 1 protocol deviation for each protocol deviation type  
will be summarized for the mITT population by treatment sequence.   
Protocol deviation type is selected on the CRF from the list noted in Appendix 13.3. 
Line listings will be provided to the study team for the manual classification of major vs. 
minor protocol deviations and the AzurRx study team will confirm classification of major 
vs. minor at a data review meeting prior to database lock.  Each major deviation will be 
categorized as either important or not important with respect to the effect on the primary 
endpoint analysis.     
All subjects in the mITT population having a protocol deviation and the details for the 
protocol deviation will be identified in a subject-level data listing.  The listings will 
include the date of the deviation, protocol deviation type, if it was IRB reportable, date 
reported to IRB, any noted comments, and the deviation corrective and preventative 
action (CAPA). 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 14 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Subject demographics and other baseline characteristics will be summarized by treatment 
sequence and overall descriptively for the mITT population.  The demographic and 
baseline characteristic summaries will be used to describe the study population as well as 
to check for balance among the treatment groups. 
Demographic data will include age, sex, race, and ethnicity.  Age (years) will be 
calculated using the date of birth and the date of randomization, as described in Section 3.   
Baseline characteristic data will include gastric acid suppression use at randomization, 
CFTR (cystic fibrosis transmembrane conductance regulator) modulator use at 
randomization (yes, no), name of pre-randomization PERT, pre-randomization PERT 
dose (lipase units/kg/day), weight, height, body mass index (BMI), and years since 
diagnosis of EPI.  Pre-randomization PERT dose (lipase units/kg/day) will also be 
summarized by region. 
Descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum 
values) will be presented for continuous variables for each treatment sequence.  For 
qualitative or categorical variables, the number and percentage of subjects within each 
category will be presented by treatment sequence.   
Individual data for demographics, baseline characteristics, and medical history will be 
presented in the data listings for subjects in the mITT population.  A data listing of any 
inclusion/exclusion criteria not met will also be presented for all screened subjects. 
Partial missing dates will be imputed for the purposes of determining time since 
diagnosis of EPI as follows:   
• For a partially missing diagnosis date where the day is missing, but the month and 
year are present, the day will be set to the first day of the month.  
• For a partially missing diagnosis date where the day and the month are missing, 
but the year is present, the month and day will be set to January 1st.  
Years since diagnosis of EPI will be calculated in years using the imputed diagnosis date 
and the date of randomization as [(date of randomization – diagnosis date)]/365.25, 
rounded to one decimal place. 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 15 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
7. MEASUREMENTS OF TREATMENT COMPLIANCE 
Treatment compliance will be summarized for MS1819-SD in terms of mg/day using a 
compliance rate.  Given that subjects were to take the dose associated with their pre-study 
PERT during treatment with PERT, detailed pill information was not collected and thus 
compliance rate for PERT will not be summarized. 
The compliance rate for MS1819-SD will be calculated as: 
[Actual Dose mg/day / Expected Dose mg/day]*100   
The actual dose (mg/day) a subject received will be calculated as: 
[(number pills dispensed – number of pills returned)*140 mg]/number of actual  
study days on MS1819-SD,  
where the number of actual study days on MS1819-SD is calculated as:  
((date/time of last MS1819-SD dose – date/time of first MS1819-SD dose) / 
86400) + 1.   
The expected dose for MS1819-SD is 2240 mg/day. 
Treatment compliance will be summarized by each study period and overall for MS1819-
SD using descriptive statistics.    
As described in Section 4.2, subjects found to be <80% compliant with MS1819-SD will 
be excluded from the PP population. 
Individual data for study drug (number of pills) dispensed and returned and treatment 
compliance will be listed for all subjects in the mITT population.  
 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 16 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
8. SAFETY EVALUATION 
8.1 Overview of Safety Analysis Methods 
All safety analyses will be performed using the safety population and summarized by 
actual treatment (MS1819-SD regardless of period vs. PERT regardless of period) 
allowing direct intrasubject comparison of the tolerability of MS1819-SD vs. PERT.  
Safety measures summarized will include AEs, laboratory data, vital signs, and 
concomitant medications.  Additionally, exposure to study treatment during the study will 
be displayed. 
Safety data will not be imputed, except for partial and missing dates, which will be 
imputed only for defining treatment-emergent AEs (TEAEs) and concomitant 
medications.  Imputed dates will not be presented in data listings. 
TEAEs will be defined as any AEs that occur or are reported to worsen in severity on or 
after the date of first dose of study treatment in period 1.  Partial dates will be imputed for 
the purposes of defining TEAEs as follows:   
• For a missing start day where the month and year are present, the start day will be 
set to the first day of the month, unless 1) the first day of the month is before the 
date of first dose of study treatment and the month and year are the same as the 
month and year of the date of first dose of study treatment, and 2) the end date is 
on or after the date of first dose of study treatment or the end date is completely 
missing, in which case the start day will be set to the first day of first dose of 
study treatment.  
• For a missing start day and month where the year is present, the start day and 
month will be set to January 1st, unless 1) January 1st is before the date of first 
dose of study treatment and the year is the same as the year of the date of first 
dose of study treatment, and 2) the end date is on or after the date of first dose of 
study treatment or the end date is completely missing, in which case the start day 
and month will be set to that of the date of first dose of study treatment. 
• For a missing end day where the month and year are present, the end day will be 
set to the last day of the month, unless the month and year are the same as the 
month and year of the last contact date for the subject, in which case the end day 
will be set to that of the subject’s last contact date. 
• For a missing end day and month where the year is present, the end day and 
month will be set to the subject’s last contact date, unless the year of the subject’s 
last contact date is greater than the end year, in which case the end day and month 
will be set to December 31st. 
To categorize events with partial dates into their associated treatment periods, the 
imputation rules above will be defined relative to the first dose of the treatment period of 
interest separately.  Thus, in the aforementioned rules, ‘study treatment’ refers to the 
treatment in the specified treatment period.  Per the imputation rules, events with partial 
dates may require two imputed start dates to account for each treatment period.  For 
example, an event with missing start day where the start month is the same as the 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 17 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
treatment start month for both study treatments will have the start date imputed to both 
the treatment start date of the first study period and the treatment start date of the second 
study period.  
Partial and completely missing dates will be imputed for the purposes of classifying 
concomitant medications as follows:   
• Partial dates will be imputed following the same algorithm as above for TEAEs. 
• For a missing start date (i.e., day, month, and year are missing), the start date will 
be set to the date of first dose of study treatment for each period unless the stop 
date is prior the date of first dose of study treatment for a given period, in which 
case the start date will be set to the stop date. 
• For a missing stop date (i.e., day, month, and year are missing), the medication 
will be treated as ongoing. 
8.2 Extent of Exposure 
Time on treatment (weeks) will be calculated as (date of last dose of study drug – date 
first dose of study drug + 1)/7.  Time on treatment will be summarized by treatment 
group for each period using descriptive statistics for all subjects in the safety population.   
The date and time of the first and last dose of each study period will be presented in a 
data listing for all subjects in the safety population. 
8.3 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 21.1 to identify the system organ class and preferred term.   
Adverse events that occur or are reported to worsen in severity on or after date of first 
dose of study treatment in period 1 will be considered to be TEAEs.   
TEAEs will be categorized as occurring in either study period 1 or study period 2 
according to the following rules: 
•  Adverse events that occur or are reported to worsen in severity on or after date 
and time of start of period 1 study treatment and on or before date and time of end 
of period 1 study treatment will be attributed to study period 1.  Adverse events 
that occur or are reported to worsen in severity on the start date of period 1 study 
treatment that do not have a time associated with the event will be attributed to 
study period 1.    
• Adverse events that occur or are reported to worsen in severity after the end date 
of period 1 study treatment and on or before the date of end of period 2 study 
treatment will be attributed to study period 2.  Adverse events that occur or are 
reported to worsen in severity on the date of end of period 2 study treatment that 
do not have a time associated with the event will be attributed to study period 2.       
Version:  AZ-CF2001_SAP_v2.0 
 
Page 18 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
• Adverse events that occur on the crossover date between study period 1 and study 
period 2 that do not have a time associated with the event will be attributed to 
study period 1. 
• Adverse events that occur in both study period 1 and study period 2 will be 
attributed to both study periods.   
TEAEs that occurred after the subject’s last study period will be classified as follow-up 
TEAEs.  If a subject entered both the first and second study periods, any event occurring 
after the end date of the second study period will be considered a follow-up TEAE.  If a 
subject discontinued prior to the start of the second study period, any event occurring 
after the end date of the first study period will be considered a follow-up TEAE. 
TEAEs will be summarized for all subjects in the safety population.  TEAEs will be 
summarized by treatment group.  The total number of TEAEs occurring will be shown.  
The number and percentage of subjects experiencing any TEAE will also be provided.  In 
addition, summary tables will reflect a count and percentage of subjects experiencing at 
least 1 TEAE in each system organ class and preferred term.  All percentages will use the 
number of subjects in the safety population as the denominator.  Therefore, if a subject 
has more than 1 AE within a system organ class, the subject will be counted only once in 
that system organ class.  If a subject has more than 1 AE that codes to the same preferred 
term, the subject will be counted only once for that preferred term.  Tabular summaries 
will be sorted by descending frequency by system organ class and by preferred term in 
the MS1819 treatment group.  
Treatment-emergent AEs will be presented by treatment group and overall with 
percentages that use the number of subjects in the safety population as the denominator.   
Treatment-emergent AEs will also be summarized by maximum relationship to study 
drug and maximum severity.  Relationship to each study treatment (MS1819-SD and 
prestudy PERT) will be scored as Related or Unrelated.  Severity will be rated as Mild, 
Moderate, or Severe.  All percentages will use the number of safety subjects as the 
denominator.  Summary tables will reflect a count and percentage of subjects 
experiencing at least 1 TEAE in each system organ class, preferred term and grouping, 
relationship, or severity.  If a subject experiences more than 1 AE within a system organ 
class or preferred term, that subject will be counted only once for that event under the 
maximum severity or most related category for the study drug.  Similarly, in the event 
that relationship or severity data are missing, the study analysis will follow the 
assumption of maximum relationship or severity in the summary tables.  These 
summaries will be presented by treatment group and overall with percentages that use the 
number of subjects in the safety population as the denominator.  The tabular summaries 
will be sorted by descending frequency by system organ class and by preferred term in 
the MS1819 treatment group. 
All AEs will be presented in data listings for subjects in the safety population.   
Version:  AZ-CF2001_SAP_v2.0 
 
Page 19 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
8.4 Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
Treatment-emergent SAEs, TEAEs leading to study discontinuation, TEAEs resulting in 
death, treatment-emergent SAEs by relatedness, treatment-emergent SAEs leading to 
discontinuation, and treatment-emergent SAEs resulting in death will be summarized for 
all subjects in the safety population.  Summary tables will reflect a count and percentage 
of subjects experiencing at least 1 TEAE in each system organ class and preferred term 
within each AE subset (serious, leading to discontinuation, death).  These summaries will 
be presented by treatment group and overall with percentages that use the number of 
subjects in the safety population as the denominator.  These tabular summaries will be 
sorted by descending frequency by system organ class and by preferred term in the 
MS1819 treatment group.  
Adverse events leading to study discontinuation, AEs resulting in death, and SAEs will 
be presented in data listings for subjects in the safety population. 
8.5 Clinical Laboratory Evaluation 
Values at Screening and at 3 weeks post first dose, as described in Section 3, for 
laboratory parameters for hematology and clinical chemistry will be summarized by 
treatment group for the safety population using descriptive statistics.  Values at 
Screening, Visit 3 (At Randomization), At First Dose, and at 3 Weeks Post First Dose, as 
described in Section 3, for laboratory parameters for urinalysis will be summarized by 
treatment group for the safety population using descriptive statistics.  
Shift tables based on classification of values with respect to the reference range will be 
summarized for the safety population for critical clinical chemistry and hematology 
laboratory tests by treatment group.  Critical clinical chemistry and hematology 
laboratory tests are listed in the appendix for Table Display Specifications.   
Post-baseline elevations in alanine aminotransferase (≥3 times the upper limit of normal 
[ULN]), aspartate aminotransferase (≥3 times ULN), total bilirubin (≥1.5 times ULN) 
will be summarized by treatment group at Screening and at 3 Weeks Post First Dose. 
Hematology, clinical chemistry, hepatic monitoring, urinalysis, and pregnancy results 
will be presented in data listings for subjects in the safety population.  
8.6 Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
8.6.1 Vital Signs 
Values at Visit 3 (At Randomization), At First Dose, and at 3 Weeks Post First Dose, as 
described in Section 3,  in systolic blood pressure, diastolic blood pressure, heart rate, 
respiratory rate, and temperature will be summarized by treatment group for the safety 
population using descriptive statistics.   
Version:  AZ-CF2001_SAP_v2.0 
 
Page 20 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
Vital sign values will be presented in a data listing for all subjects in the safety 
population. 
8.6.2 Physical Examinations 
A physical examination will be performed at study visits 3, 6, 9, and 10.  An indication of 
whether the examination was performed, date of the examination, and an indication of 
whether abnormal findings that were clinically significant were found will be collected.  
Because details of clinically significant abnormal findings will be entered on the medical 
history or AE form as appropriate, this data will be summarized with medical history and 
AEs, respectively. 
8.6.3 Other Safety Measures 
 Prior and Concomitant Medications 
8.6.3.1
The prior and concomitant medications will be coded using the latest version of World 
Health Organization Drug Dictionary (WHO Drug) Global Version (September 2018) to 
identify the drug class and preferred drug name.   
Concomitant medications will include all medications that started on or after day of first 
dose of the study treatment in the first period or that stopped on or after day of first dose 
of study treatment in the first period.  Prior medications will include all medications that 
started and stopped prior to the day of first dose of the study treatment in the first study 
period. 
Concomitant medications will be categorized as occurring in study period 1 or study 
period 2.  Concomitant medications that started or stopped on or after day of first dose of 
study treatment in period 1 and before the start of period 2 are attributed to period 1.  
Concomitant medications that started prior to the first dose of study treatment in period 1 
and stopped on or after day of first dose of study treatment in period 1, or are ongoing, 
are attributed to period 1.  Concomitant medications that started or stopped on or after 
day of first dose of study treatment in period 2 are attributed to period 2.  Concomitant 
medications that started prior to the study and are stopped on or after day of first dose of 
study treatment in period 2, or are ongoing, are attributed to period 2.  
The number and percentage of subjects using prior and concomitant medications will be 
tabulated for each study period by Anatomical Therapeutic Chemical (ATC) level 1 term, 
ATC level 2 term, and preferred drug name for all subjects in the safety population.  If a 
subject has more than 1 medication within an ATC level 1 term, the subject will be 
counted only once in that ATC level 1 term.  Similarly, if a subject has more than 1 
medication within an ATC level 2 term, the subject will be counted only once in that 
ATC level 2 term.  If a subject has more than 1 medication that codes to the same 
preferred drug name, the subject will be counted only once for that preferred drug name.  
All percentages will use the number of subjects in the safety population as the 
denominator.  The tabular summary will be sorted by descending frequency by ATC level 
1 term, ATC level 2 term, and preferred drug name.  
Version:  AZ-CF2001_SAP_v2.0 
 
Page 21 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
Prior medications will be summarized overall by planned treatment sequence.  
Concomitant medications will be presented by actual treatment group and overall with 
percentages that use the number of subjects in the safety population as the denominator.   
Prior and concomitant medication data will also be presented in a data listing for subjects 
in the safety population. 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 22 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
9. EFFICACY EVALUATION 
9.1 Overview of Efficacy Analysis Issues 
9.1.1 Handling of Dropouts or Missing Data 
Missing data will not be replaced.  
9.1.2 Assessment Time Windows 
Rules for assessment time windows are addressed in Section 9.2 for each efficacy 
endpoint. 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 23 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
 
 
9.2 Analysis Methods 
9.2.1 Primary Efficacy Analyses 
The primary efficacy endpoint is the CFA assessed at the end of each 3-week treatment 
period (Visit 6 or Visit 9).  CFA is evaluated by the 72-hour marker-to-marker stool 
sample collection (1 measure at Visit 6 and 1 at Visit 9) and standardized high-fat diet 
during each supervised confinement.  Coefficient of fat absorption represents the 
percentage of fat absorbed from the diet by the subject and is calculated from the results 
of the quantitative fecal fat measurement in conjunction with the dietary fat intake.  
CFA will be calculated by using 2 data points: 
• Fat consumption in grams as provided by the qualified dietician at each site. 
• Fat excretion in grams/24h as provided by the central laboratory. 
CFA will be calculated as follows: 
(Grams/24h of fat consumed – Grams/24h of fat excreted) x 100 
Grams/24h of fat consumed 
The primary efficacy endpoint analysis will use the mITT population and be analyzed as 
randomized.  For the analysis of CFA, if a subject switches study treatments (i.e. MS1819 
to PERT or PERT to MS1819) during the confinement period, prior to the end of the 
stool collection, then the CFA value during that confinement period will be excluded 
from the analysis.  The primary method for the analysis of the primary efficacy endpoint 
will be based on a mixed model.  Missing CFA values will not be imputed.  
The mixed model will include terms for sequence (MS1819-PERT, PERT-MS1819), 
random patient nested in sequence, period (1, 2), treatment (MS1819, PERT), and gastric 
acid suppression use (Y, N).  The mixed model will be implemented using SAS® Proc 
MIXED, as shown in the model code below.  The DDFM=KR option denotes the 
Kenward-Roger method for the denominator degrees of freedom.  The variable GASTFL 
in the code below is the gastric acid suppression use flag (Y, N).   
PROC MIXED; 
 
 
CLASS SUBJECT SEQUENCE PERIOD TREATMENT GASTFL; 
MODEL CFA = SEQUENCE TREATMENT PERIOD GASTFL / 
DDFM=KR; 
 
 
RANDOM SUBJECT(SEQUENCE); 
 
 
LSMEANS TREATMENT / CL DIFF;  
RUN; 
The 95% CI of the difference in CFA for MS1819-SD minus CFA for porcine PERT will 
be used to assess the primary objective.  Non-inferiority of MS1819-SD to porcine PERT 
is achieved if the lower bound of the 95% CI of the difference is greater than -15%, 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 24 of 37 
 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
where 15% is the non-inferiority margin.  If non-inferiority is achieved, then superiority 
will be tested. 
The carryover effect will be estimated and tested.  If there is a notable carryover, the 
primary endpoint analysis will be reported for each period separately.  
The least squares (LS) means, 95% CIs of the LS means, and the SEs by treatment group 
will also be presented.  In addition, CFA at the end of the first period (Visit 6) and CFA 
at the end of the second period (Visit 9) will also be summarized by treatment group 
using descriptive statistics. 
Fat consumed (g/24h), fat excreted (g/24h), and CFA (%) will be listed by visit for all 
subjects in the mITT population. 
Details of each supervised confinement, including controlled diet and marker-to-marker 
stool collection, will be listed for all subjects in the mITT population.  
 Supportive Analyses of the Primary Efficacy Analysis 
9.2.1.1
A secondary (supportive) analysis to the primary method for the analysis of the primary 
efficacy measure will be conducted using the per-protocol population, according to 
randomized treatment group.  For this analysis, LS means, 95% CIs of the LS means, SEs 
of the LS means, LS mean estimate of the treatment difference (MS1819-SD minus 
porcine PERT), SE of the difference, and 95% CI of the difference will be displayed.   
 Subgroup Analyses  
9.2.1.2
Subgroup analyses comparing MS1819-SD to porcine PERT using CFA at the end of 
each treatment period as the dependent variable will be performed for: 
• CFA level while receiving porcine PERT (<80%, ≥80%) 
• Gastric acid suppression use (yes, no) 
The primary efficacy endpoint analysis will be repeated for each subgroup using the 
mITT population, according to randomized treatment group.  For the gastric acid 
suppression use subgroup, gastric acid suppression use will be removed as a covariate 
from the model.  For each analysis, LS means, 95% CIs of the LS means, SEs of the LS 
means, LS mean estimate of the treatment difference (MS1819-SD minus porcine PERT), 
SE of the difference, and 95% CI of the difference will be displayed for each subgroup. 
In addition, CFA for each subgroup will be summarized by treatment group using 
descriptive statistics. 
9.2.2 Secondary Efficacy Analyses 
 Coefficient of Nitrogen Absorption 
9.2.2.1
CNA at the end of each treatment period (Visit 6, Visit 9) will be analyzed.  CNA will be 
expressed as the percentage of nitrogen (protein) absorbed from the subject’s diet. 
CNA will be calculated using 2 data points: 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 25 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
• Nitrogen consumption in grams as provided by the qualified dietician at each site 
• Nitrogen excretion in grams/24h as provided by the central laboratory 
CNA will be calculated as follows: 
(Grams/24h of nitrogen consumed – Grams/24h of nitrogen excreted) x 100 
Grams/24h of nitrogen consumed 
The method for the analysis of CNA will be analogous to the method used for the 
primary efficacy analysis, as described in Section 9.2.1.  For the analysis of CNA, if a 
subject switches study treatments (i.e. MS1819 to PERT or PERT to MS1819) during the 
confinement period, prior to the end of the stool collection, then the CNA value during 
that confinement period will be excluded from the analysis.  Missing CNA values will 
not be imputed.  
The 15% non-inferiority margin used for the primary efficacy analysis of CFA will also 
be applied to test the non-inferiority of MS1819-SD to porcine PERT in CNA at the end 
of each treatment period.   
A secondary (supportive) analysis to the method for the analysis of CNA will be 
conducted using the per-protocol population, according to randomized treatment group. 
In addition, CNA at the end of each treatment period (Visit 6, Visit 9) will be 
summarized by treatment group using descriptive statistics. 
Nitrogen consumed (g/24h), nitrogen excreted (g/24h), and CNA (%) will be listed by 
visit for all subjects in the mITT population. 
 Stool Weight 
9.2.2.2
Stool weight during the 72-hour marker-to-marker stool collections will be evaluated at 
the end of each treatment period (Visit 6, Visit 9).  All collected stool will be shipped to 
the central lab for determination of the stool weight as described under the primary 
efficacy measure.   
Stool weight at the end of each treatment period will be analyzed from stool samples 
collected during the 2 confinement periods (Visit 6 and Visit 9).   
Stool weight at the end of each treatment period (Visit 6, Visit 9) will be summarized by 
treatment group using descriptive statistics.  If a subject switches study treatments (i.e. 
MS1819 to PERT or PERT to MS1819) during the confinement period, prior to the end 
of the stool collection, then the stool weight value during that confinement period will be 
excluded from the summary.   
If a subject has more than one stool weight record for a given visit (Visit 6 or Visit 9), 
only the heaviest value will be included in the summary. 
Stool weight will be listed by visit for all subjects in the mITT population. 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 26 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
 Malabsorption Signs and Symptoms 
9.2.2.3
Signs and symptoms of malabsorption will be evaluated at Visits 3, 4, 5, 6, 7, 8, 9, and 
10.  
The EPI malabsorption symptoms will be evaluated according to the following measures:   
• Stool frequency (number of bowel movements per day);  
• Stool consistency (graded as 0 = hard, 1 = formed/normal, 2 = soft, 3 = 
watery, or 4 = overt diarrhea);  
• Bloating (graded as 0 = none, 1 = mild, 2 = moderate, or 3 = severe); 
• Abdominal pain (graded as 0 = none, 1 = mild, 2 = moderate, or 3 = 
severe); 
• Flatulence (graded as 0 = none, 1 = mild, 2 = moderate, or 3 = severe);  
• Incidences of visible oil/grease in stool (Yes/No).  
• Increased stool quantity (graded as 0 = none, 1 = mild, 2 = moderate, or 3 
= severe); and 
• Worsening of overall bowel habit (graded as 0 = none, 1 = mild, 2 = 
moderate, or 3 = severe). 
Stool frequency will be summarized by treatment group for the mITT population using 
descriptive statistics.  Stool frequency will be summarized at Visit 3 (At Randomization), 
At First Dose, 1 Week Post First Dose, 2 Weeks Post First Dose, and 3 Weeks Post First 
Dose, as described in Section 3. 
The number and percentage of subjects within each category for stool consistency, 
bloating, abdominal pain, flatulence, incidence of visible oil/grease in stool, increased 
stool quantity, and worsening of overall bowel habit at each study visit and by treatment 
group will also be provided Visit 3 (At Randomization), At First Dose, 1 Week Post First 
Dose, 2 Weeks Post First Dose, and 3 Weeks Post First Dose, as described in Section 3.  
Shifts from Visit 3 will be presented for stool consistency, bloating, abdominal pain, 
flatulence, increased stool quantity, and worsening of overall bowel habit for the mITT 
population by treatment group. 
Signs and symptoms of malabsorption will be listed for all subjects in the mITT 
population. 
 Weight and BMI 
9.2.2.4
Weight and BMI will be evaluated at Visits 1, 3, 6 and 9.   
Weight and BMI at Visit 3 (At Randomization), At First Dose, and at 3 Weeks Post First 
Dose, as described in Section 3, will be summarized for the mITT population using 
descriptive statistics by treatment group.   
 Weight and BMI will be listed for all subjects in the mITT population.  
Version:  AZ-CF2001_SAP_v2.0 
 
Page 27 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
 Serum Liposoluble Vitamin (A, D, E, and K) Levels 
9.2.2.5
Analyses of certain lab values will be undertaken to evaluate markers of nutritional 
status.  Specifically, the laboratory parameters to be summarized will include blood levels 
of vitamin A, D, E, and K.  Vitamin A, D, E, and K levels will be evaluated at Visits 1, 3, 
6, 9, and 10.   
Vitamin A, D, E, and K levels will be summarized by treatment group for Visit 3 (At 
Randomization), At First Dose, and at 3 Weeks Post First Dose, as described in 
Section 3, using descriptive statistics.  
Vitamin A, D, E, and K levels will be listed for all subjects in the mITT population.  
 
  
Version:  AZ-CF2001_SAP_v2.0 
 
Page 28 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
10. DATA MONITORING 
10.1 Data Monitoring  
An external, independent Data and Safety Monitoring Board (DSMB) consisting of  
members of the Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) DSMB, will 
monitor safety throughout the trial.  After the study is complete, the DSMB will review 
the efficacy/safety data.  Additional safety reviews may be conducted, at the request of 
the Data Safety Monitoring Board (DSMB) or DSMB Chair.   
Since the planned DSMB review will occur after the completion of the study, the DSMB 
will review a subset of the analyses specified in the SAP and a separate DSMB analysis 
plan is not required.  
 Details are described in the DSMB charter. 
 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 29 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
11. DIFFERENCES BETWEEN THE SAP AND PROTOCOL AND CHANGES 
TO THE ANALYSES PLANNED IN THE PROTOCOL 
No subjects were enrolled under the original protocol, so only differences between the 
SAP and protocol and changes to the analyses planned in Version 2.0 of the protocol are 
described below. 
11.1 Differences between the SAP and Protocol and Changes to the 
Analyses Planned in Protocol Version 2 
In section 10.7.2, the protocol states that stool weight and signs and symptoms of 
malabsorption will be analyzed with the same approach used for the primary endpoint.  
Instead, stool weight will be summarized using descriptive statistics.  Since the signs and 
symptoms of malabsorption are categorical variables, this SAP specifies that these 
variables will be summarized by frequency tables in order to preserve the most 
information and given that it may not be reasonable to treat the differences between 
categories as uniformly quantifiable.   
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 30 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
12. REFERENCES 
US Federal Register. (1998) International Conference on Harmonization; Guidance for 
Industry: Statistical Principles for Clinical Trials. Department of Health and Human 
Services: Food and Drug Administration.  Federal Register, Vol. 63, No. 179, September 
16, 1998, page 49583. 
US Federal Register. (1996) International Conference on Harmonization; Guidance for 
Industry: Structure and Content of Clinical Study Reports. Department of Health and 
Human Services: Food and Drug Administration.  Federal Register Vol. 61, July 17, 
1996, page 37320.  
Kenward, M. G., and Roger, J. H. (1997). Small Sample Inference for Fixed Effects from 
Restricted Maximum Likelihood. Biometrics, 53, 983–997. 
 
Senn, S. & Barnett, V. (2002). Cross-over Trials in Clinical Research (2nd ed.). New 
York, NY: John Wiley & Sons, Ltd. 
 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 31 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
13. APPENDICES 
13.1 Study Flow Chart 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 32 of 37 
 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
13.2 Schedule of Events 
Schedule of Assessments 
 
SCREENING 
INITIAL TREATMENT PERIOD 
SECOND TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 
(T)b 
3 
4 
(T)c 
5 
(T)c 
6d 
7 
(T)c 
8 
(T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit 
Window 
(days) 
V1 to V2 interval 
≤21 days 
±2 
±1 
±7 
±2 
±2 
±7 
±2 
Pre-Visit 
Instructions 
 
X 
 
 
 
 
 
 
 
 
Supervised 
confinement 
 
 
 
 
 
X 
 
 
X 
 
Clinical Assessments 
Obtain 
informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Complete 
history 
and physical 
X 
 
 
 
 
 
 
 
 
 
Focused 
physical 
exame 
 
 
X 
 
 
X 
 
 
X 
X 
Confirm 
CF 
diagnosis 
X 
 
 
 
 
 
 
 
 
 
Height/weight, 
vital signs (sitting) 
X 
 
X 
 
 
X 
 
 
X 
 
Inclusion/exclusion 
criteria review 
X 
 
X 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm scheduled 
date for next 
supervised 
confinement visit 
 
 
 
X 
X 
 
X 
X 
 
 
Study Treatment 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Instruct regarding 
prestudy 
PERT/Dispense 
study drug 
MS1819-SD 
 
 
X 
 
 
X 
 
 
X 
 
Verify study drug 
 
 
 
 
 
X 
 
 
X 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 33 of 37 
 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
 
SCREENING 
INITIAL TREATMENT PERIOD 
SECOND TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 
(T)b 
3 
4 
(T)c 
5 
(T)c 
6d 
7 
(T)c 
8 
(T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit 
Window 
(days) 
V1 to V2 interval 
≤21 days 
±2 
±1 
±7 
±2 
±2 
±7 
±2 
count at the end of 
confinement 
Return MS1819-
SD (only for those 
on MS1819-SD) at 
the end of 
confinement  
 
 
 
 
 
X 
 
 
X 
 
Record fat and 
protein intake and 
study drug taken at 
all meals and 
snacks 
 
 
 
 
 
X 
 
 
X 
 
Cross over to 
alternative 
treatmentf 
 
 
 
 
 
X 
 
 
 
 
Efficacy Measures 
Malabsorption 
signs & symptoms 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
72-hour controlled 
diet record 
 
 
 
 
 
X 
 
 
X 
 
Marker-to-marker 
stool collection and 
stool weightg 
 
 
 
 
 
X 
 
 
X 
 
Laboratory Tests 
Urinalysis 
X 
 
X 
 
 
X 
 
 
X 
 
Pregnancy test 
(serum for V1 
screening and urine 
dipstick for other 
visits)h 
X 
 
X 
 
 
X 
 
 
X 
X 
Hematology, 
clinical chemistry, 
PT/INR, and aPTTi 
X 
 
 
 
 
X 
 
 
X 
 
Fasting lipids 
(patient to come in 
fasting status) and 
pre-albumin 
X 
 
 
 
 
X 
 
 
X 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 34 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
 
SCREENING 
INITIAL TREATMENT PERIOD 
SECOND TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 
(T)b 
3 
4 
(T)c 
5 
(T)c 
6d 
7 
(T)c 
8 
(T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit 
Window 
(days) 
V1 to V2 interval 
≤21 days 
±2 
±1 
±7 
±2 
±2 
±7 
±2 
Vitamin A, D, E, 
and K 
X 
 
X 
 
 
X 
 
 
X 
X 
Serum samples for 
anti-LIP2 lipase 
antibodies and 
MS1819-SD 
concentrations 
 
 
X 
 
 
X 
 
 
X 
X 
Fecal pancreatic 
elastasej 
X 
 
 
 
 
 
 
 
 
 
Diagnostic Test 
Spirometry 
X 
 
 
 
 
 
 
 
 
 
Resume Prescribed PERT 
Switch back to 
prescribed porcine 
PERTk 
 
 
 
 
 
 
 
 
X 
 
A  Screening procedures can occur up to 21 days before V1 through the first day of dosing (V3). 
B  This first study telephone call will occur once eligibility for the patient is determined. Instructions on the randomization 
visit will also be communicated and patients will be told to bring in their prestudy porcine with them for V3. 
C Visits 4, 5, 7, and 8 are telephone visits to assess any changes to AEs and concomitant medications in addition to 
confirming the visit date for the next scheduled supervised confinement. 
D Visit 6 and Visit 9 are the first and second scheduled confinement visits and can take up to 7 days. A 7 day window is 
permitted around the scheduled confinement for both V6 and V9 to accommodate for scheduling. Patient should bring 
their prestudy porcine PERT to V3. 
E  
 The Focused Physical Exam will evaluate gastrointestinal tract, heart, and lungs. 
F  At the end of V6 (after the last stool sample has been collected), Patients that were randomized to MS1819-SD will 
begin treatment with their prestudy porcine PERT. Patients that were randomized to their prestudy porcine PERT will 
begin treatment with MS1819-SD. 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 35 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
13.3 Protocol Deviation Types 
The CRF includes the following protocol deviation types: 
• Consent not obtained  
• Re-consent not obtained  
• Study assessment(s) administered prior to obtaining consent  
• Missing signed consent form  
• Incomplete consent form  
• Missing documentation of consent process  
• Consent form signature error  
• Violation of inclusion criteria  
• Violation of exclusion criteria  
• Accidental unblindingAdministered incorrect study treatment to subject 
• Non-compliance with study treatment 
• Treatment with prohibited concomitant medications  
• Visit missed  
• Visit out of window  
• Study procedure/assessment missed  
• Study procedure/assessment out of window  
• Study procedure/assessment performed incorrectly 
•  Unnecessary study procedure/assessment performed  
• Missing source documents for study procedure/assessment  
• Incomplete source documents for study procedure/assessment  
• Pregnancy reporting out of window  
• SAE reporting out of window 
• Other 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 36 of 37 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2001 
 
04 September 2019 
14. 
ATTACHMENTS 
• Table Display Specifications 
• Listing Display Specifications 
 
Version:  AZ-CF2001_SAP_v2.0 
 
Page 37 of 37